Drug Intercation

montelukast 10 MG (as montelukast sodium 10.4 MG) Oral Tablet

Generic Name: MONTELUKAST SODIUM

Brand Name: Montelukast Sodium

Substance Name(s):
MONTELUKAST SODIUM

DRUG INTERACTIONS

7 No dose adjustment is needed when montelukast sodium is co-administered with theophylline, prednisone, prednisolone, oral contraceptives, terfenadine, digoxin, warfarin, gemfibrozil, itraconazole, thyroid hormones, sedative hypnotics, non-steroidal anti-inflammatory agents, benzodiazepines, decongestants, and Cytochrome P450 (CYP) enzyme inducers [see Clinical Pharmacology (12.3)].

OVERDOSAGE

10 No specific information is available on the treatment of overdosage with montelukast sodium. In chronic asthma studies, montelukast has been administered at doses up to 200 mg/day to adult patients for 22 weeks and, in short-term studies, up to 900 mg/day to patients for approximately a week without clinically important adverse experiences. In the event of overdose, it is reasonable to employ the usual supportive measures; e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive therapy, if required. There have been reports of acute overdosage in post-marketing experience and clinical studies with montelukast sodium. These include reports in adults and children with a dose as high as 1000 mg. The clinical and laboratory findings observed were consistent with the safety profile in adults and pediatric patients. There were no adverse experiences in the majority of overdosage reports. The most frequently occurring adverse experiences were consistent with the safety profile of montelukast sodium and included abdominal pain, somnolence, thirst, headache, vomiting and psychomotor hyperactivity. It is not known whether montelukast is removed by peritoneal dialysis or hemodialysis.

DESCRIPTION

11 Montelukast sodium, the active ingredient in montelukast sodium tablets and montelukast sodium chewable tablets, is a selective and orally active leukotriene receptor antagonist that inhibits the cysteinyl leukotriene CysLT1 receptor. Montelukast sodium is described chemically as [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl) ethenyl]phenyl]-3-[2-(1-hydroxy-1-‑methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. The molecular formula is C35H35CINNaO3S, and its molecular weight is 608.18. The structural formula is: Montelukast sodium is a hygroscopic, optically active, white to off-white powder. Montelukast sodium is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile. Each 10 mg film-coated montelukast sodium tablet contains 10.4 mg montelukast sodium, which is equivalent to 10 mg of montelukast, and the following inactive ingredients:anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, and yellow ferric oxide. Each 4 mg and 5 mg chewable montelukast sodium tablet contains 4.2 and 5.2 mg montelukast sodium, respectively, which are equivalent to 4 and 5 mg of montelukast, respectively. Both chewable tablets contain the following inactive ingredients: mannitol, microcrystalline cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. image-2

CLINICAL STUDIES

14 14.1 Asthma Adults and Adolescents 15 Years of Age and Older with Asthma Clinical trials in adults and adolescents 15 years of age and older demonstrated there is no additional clinical benefit to montelukast doses above 10 mg once daily. The efficacy of montelukast sodium for the chronic treatment of asthma in adults and adolescents 15 years of age and older was demonstrated in two (U.S. and Multinational) similarly designed, randomized, 12-week, double-blind, placebo-controlled trials in 1576 patients (795 treated with montelukast sodium, 530 treated with placebo, and 251 treated with active control). The median age was 33 years (range 15 to 85); 56.8% were females and 43.2% were males. The ethnic/racial distribution in these studies was 71.6% Caucasian, 17.7% Hispanic, 7.2% other origins and 3.5% Black. Patients had mild or moderate asthma and were non-smokers who required approximately 5 puffs of inhaled β-agonist per day on an “as-needed” basis. The patients had a mean baseline percent of predicted forced expiratory volume in 1 second (FEV1) of 66% (approximate range, 40 to 90%). The co-primary endpoints in these trials were FEV1 and daytime asthma symptoms. In both studies after 12 weeks, a random subset of patients receiving montelukast sodium was switched to placebo for an additional 3 weeks of double-blind treatment to evaluate for possible rebound effects. The results of the U.S. trial on the primary endpoint, morning FEV1, expressed as mean percent change from baseline averaged over the 12-week treatment period, are shown in FIGURE 2. Compared with placebo, treatment with one montelukast sodium 10 mg tablet daily in the evening resulted in a statistically significant increase in FEV1 percent change from baseline (13.0%-change in the group treated with montelukast sodium vs. 4.2%-change in the placebo group, p<0.001); the change from baseline in FEV1 for montelukast sodium was 0.32 liters compared with 0.10 liters for placebo, corresponding to a between-group difference of 0.22 liters (p<0.001, 95% CI 0.17 liters, 0.27 liters). The results of the Multinational trial on FEV1 were similar. FIGURE 2: FEV1 Mean Percent Change from Baseline (U.S. Trial: Montelukast sodium N=406; Placebo N=270) (ANOVA Model) The effect of montelukast sodium on other primary and secondary endpoints, represented by the Multinational study is shown in TABLE 2. Results on these endpoints were similar in the US study. TABLE 2 Effect of Montelukast Sodium on Primary and Secondary Endpoints in a Multinational Placebo-controlled Trial (ANOVA Model) Montelukast Sodium Placebo Endpoint N Baseline Mean Change from Baseline N Baseline Mean Change from Baseline Daytime Asthma Symptoms (0 to 6 scale) 372 2.35 -0.49p<0.001, compared with placebo 245 2.40 -0.26 β-agonist (puffs per day) 371 5.35 -1.65 241 5.78 -0.42 AM PEFR (L/min) 372 339.57 25.03 244 335.24 1.83 PM PEFR (L/min) 372 355.23 20.13 244 354.02 -0.49 Nocturnal Awakenings (#/week) 285 5.46 -2.03 195 5.57 -0.78 Both studies evaluated the effect of montelukast sodium on secondary outcomes, including asthma attack (utilization of health-care resources such as an unscheduled visit to a doctor's office, emergency room, or hospital; or treatment with oral, intravenous, or intramuscular corticosteroid), and use of oral corticosteroids for asthma rescue. In the Multinational study, significantly fewer patients (15.6% of patients) on montelukast sodium experienced asthma attacks compared with patients on placebo (27.3%, p < 0.001). In the US study, 7.8% of patients on montelukast sodium and 10.3% of patients on placebo experienced asthma attacks, but the difference between the two treatment groups was not significant (p = 0.334). In the Multinational study, significantly fewer patients (14.8% of patients) on montelukast sodium were prescribed oral corticosteroids for asthma rescue compared with patients on placebo (25.7%, p < 0.001). In the US study, 6.9% of patients on montelukast sodium and 9.9% of patients on placebo were prescribed oral corticosteroids for asthma rescue, but the difference between the two treatment groups was not significant (p = 0.196). image3 Onset of Action and Maintenance of Effects In each placebo-controlled trial in adults, the treatment effect of montelukast sodium, measured by daily diary card parameters, including symptom scores, “as-needed” β-agonist use, and PEFR measurements, was achieved after the first dose and was maintained throughout the dosing interval (24 hours). No significant change in treatment effect was observed during continuous once-daily evening administration in non-placebo-controlled extension trials for up to one year. Withdrawal of montelukast sodium in asthmatic patients after 12 weeks of continuous use did not cause rebound worsening of asthma. Pediatric Patients 6 to 14 Years of Age with Asthma The efficacy of montelukast sodium in pediatric patients 6 to 14 years of age was demonstrated in one 8-week, double-blind, placebo-controlled trial in 336 patients (201 treated with montelukast sodium and 135 treated with placebo) using an inhaled β-agonist on an “as-needed” basis. The patients had a mean baseline percent predicted FEV1 of 72% (approximate range, 45 to 90%) and a mean daily inhaled β-agonist requirement of 3.4 puffs of albuterol. Approximately 36% of the patients were on inhaled corticosteroids. The median age was 11 years (range 6 to 15); 35.4% were females and 64.6% were males. The ethnic/racial distribution in this study was 80.1% Caucasian, 12.8% Black, 4.5% Hispanic, and 2.7% other origins. Compared with placebo, treatment with one 5 mg montelukast sodium chewable tablet daily resulted in a significant improvement in mean morning FEV1 percent change from baseline (8.7% in the group treated with montelukast sodium vs. 4.2% change from baseline in the placebo group, p<0.001). There was a significant decrease in the mean percentage change in daily “as-needed” inhaled β-agonist use (11.7% decrease from baseline in the group treated with montelukast sodium vs. 8.2% increase from baseline in the placebo group, p<0.05). This effect represents a mean decrease from baseline of 0.56 and 0.23 puffs per day for the montelukast and placebo groups, respectively. Subgroup analyses indicated that younger pediatric patients aged 6 to 11 had efficacy results comparable to those of the older pediatric patients aged 12 to 14. Similar to the adult studies, no significant change in the treatment effect was observed during continuous once-daily administration in one open-label extension trial without a concurrent placebo group for up to 6 months. Pediatric Patients 2 to 5 Years of Age with Asthma The efficacy of montelukast sodium for the chronic treatment of asthma in pediatric patients 2 to 5 years of age was explored in a 12-week, placebo-controlled safety and tolerability study in 689 patients, 461 of whom were treated with montelukast sodium. The median age was 4 years (range 2 to 6); 41.5% were females and 58.5% were males. The ethnic/racial distribution in this study was 56.5% Caucasian, 20.9% Hispanic, 14.4% other origins, and 8.3% Black. While the primary objective was to determine the safety and tolerability of montelukast sodium in this age group, the study included exploratory efficacy evaluations, including daytime and overnight asthma symptom scores, β-agonist use, oral corticosteroid rescue, and the physician’s global evaluation. The findings of these exploratory efficacy evaluations, along with pharmacokinetics and extrapolation of efficacy data from older patients, support the overall conclusion that montelukast sodium is efficacious in the maintenance treatment of asthma in patients 2 to 5 years of age. Effects in Patients on Concomitant Inhaled Corticosteroids Separate trials in adults evaluated the ability of montelukast sodium to add to the clinical effect of inhaled corticosteroids and to allow inhaled corticosteroid tapering when used concomitantly. One randomized, placebo-controlled, parallel-group trial (n=226) enrolled adults with stable asthma with a mean FEV1 of approximately 84% of predicted who were previously maintained on various inhaled corticosteroids (delivered by metered-dose aerosol or dry powder inhalers). The median age was 41.5 years (range 16 to 70); 52.2% were females and 47.8% were males. The ethnic/racial distribution in this study was 92.0% Caucasian, 3.5% Black, 2.2% Hispanic, and 2.2% Asian. The types of inhaled corticosteroids and their mean baseline requirements included beclomethasone dipropionate (mean dose, 1203 mcg/day), triamcinolone acetonide (mean dose, 2004 mcg/day), flunisolide (mean dose, 1971 mcg/day), fluticasone propionate (mean dose, 1083 mcg/day), or budesonide (mean dose, 1192 mcg/day). Some of these inhaled corticosteroids were non-U.S.-approved formulations, and doses expressed may not be ex-actuator. The pre-study inhaled corticosteroid requirements were reduced by approximately 37% during a 5- to 7-week placebo run-in period designed to titrate patients toward their lowest effective inhaled corticosteroid dose. Treatment with montelukast sodium resulted in a further 47% reduction in mean inhaled corticosteroid dose compared with a mean reduction of 30% in the placebo group over the 12-week active treatment period (p≤0.05). It is not known whether the results of this study can be generalized to patients with asthma who require higher doses of inhaled corticosteroids or systemic corticosteroids. In another randomized, placebo-controlled, parallel-group trial (n=642) in a similar population of adult patients previously maintained, but not adequately controlled, on inhaled corticosteroids (beclomethasone 336 mcg/day), the addition of montelukast sodium to beclomethasone resulted in statistically significant improvements in FEV1 compared with those patients who were continued on beclomethasone alone or those patients who were withdrawn from beclomethasone and treated with montelukast or placebo alone over the last 10 weeks of the 16-week, blinded treatment period. Patients who were randomized to treatment arms containing beclomethasone had statistically significantly better asthma control than those patients randomized to montelukast sodium alone or placebo alone as indicated by FEV1, daytime asthma symptoms, PEFR, nocturnal awakenings due to asthma, and “as-needed” β-agonist requirements. In adult patients with asthma with documented aspirin sensitivity, nearly all of whom were receiving concomitant inhaled and/or oral corticosteroids, a 4-week, randomized, parallel-group trial (n=80) demonstrated that montelukast sodium, compared with placebo, resulted in significant improvement in parameters of asthma control. The magnitude of effect of montelukast sodium in aspirin-sensitive patients was similar to the effect observed in the general population of asthma patients studied. The effect of montelukast sodium on the bronchoconstrictor response to aspirin or other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients has not been evaluated [see Warnings and Precautions (5.3)]. 14.2 Exercise-Induced Bronchoconstriction (EIB) Exercise-Induced Bronchoconstriction (Adults and Adolescents 15 years of age and older) The efficacy of montelukast, 10 mg, when given as a single dose 2 hours before exercise for the prevention of EIB was investigated in three (U.S. and Multinational), randomized, double-blind, placebo-controlled crossover studies that included a total of 160 adult and adolescent patients 15 years of age and older with EIB. Exercise challenge testing was conducted at 2 hours, 8.5 or 12 hours, and 24 hours following administration of a single dose of study drug (montelukast 10 mg or placebo). The primary endpoint was the mean maximum percent fall in FEV1 following the 2 hours post-dose exercise challenge in all three studies (Study A, Study B, and Study C). In Study A, a single dose of montelukast sodium 10 mg demonstrated a statistically significant protective benefit against EIB when taken 2 hours prior to exercise. Some patients were protected from EIB at 8.5 and 24 hours after administration; however, some patients were not. The results for the mean maximum percent fall at each timepoint in Study A are shown in TABLE 3 and are representative of the results from the other two studies. TABLE 3: Mean Maximum Percent Fall in FEV1 Following Exercise Challenge in Study A (N=47) ANOVA Model Time of exercise challenge following medication administration Mean Maximum percent fall in FEV1 Least-squares mean Treatment difference % for Montelukast Sodium versus Placebo (95%CI) Montelukast Sodium Placebo 2 hours 13 22 -9 (-12, -5) 8.5 hours 12 17 -5 (-9, -2) 24 hours 10 14 -4 (-7, -1) Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. The efficacy of montelukast sodium for prevention of EIB in patients below 6 years of age has not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. In a 12-week, randomized, double-blind, parallel group study of 110 adult and adolescent asthmatics 15 years of age and older, with a mean baseline FEV1 percent of predicted of 83% and with documented exercise-induced exacerbation of asthma, treatment with montelukast sodium, 10 mg, once daily in the evening, resulted in a statistically significant reduction in mean maximal percent fall in FEV1 and mean time to recovery to within 5% of the pre-exercise FEV1. Exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). This effect was maintained throughout the 12-week treatment period indicating that tolerance did not occur. Montelukast sodium did not, however, prevent clinically significant deterioration in maximal percent fall in FEV1 after exercise (i.e., ≥20% decrease from pre-exercise baseline) in 52% of patients studied. In a separate crossover study in adults, a similar effect was observed after two once-daily 10 mg doses of montelukast sodium. In pediatric patients 6 to 14 years of age, using the 5 mg chewable tablet, a 2-day crossover study demonstrated effects similar to those observed in adults when exercise challenge was conducted at the end of the dosing interval (i.e., 20 to 24 hours after the preceding dose). 14.3 Allergic Rhinitis (Seasonal and Perennial) Seasonal Allergic Rhinitis The efficacy of montelukast sodium tablets for the treatment of seasonal allergic rhinitis was investigated in 5 similarly designed, randomized, double-blind, parallel-group, placebo-and active-controlled (loratadine) trials conducted in North America. The 5 trials enrolled a total of 5029 patients, of whom 1799 were treated with montelukast sodium tablets. Patients were 15 to 82 years of age with a history of seasonal allergic rhinitis, a positive skin test to at least one relevant seasonal allergen, and active symptoms of seasonal allergic rhinitis at study entry. The period of randomized treatment was 2 weeks in 4 trials and 4 weeks in one trial. The primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing) as assessed by patients on a 0-3 categorical scale. Four of the five trials showed a significant reduction in daytime nasal symptoms scores with montelukast sodium 10 mg tablets compared with placebo. The results of one trial are shown below. The median age in this trial was 35.0 years (range 15 to 81); 65.4% were females and 34.6% were males. The ethnic/racial distribution in this study was 83.1% Caucasian, 6.4% other origins, 5.8% Black, and 4.8% Hispanic. The mean changes from baseline in daytime nasal symptoms score in the treatment groups that received montelukast sodium tablets, loratadine, and placebo are shown in TABLE 4. The remaining three trials that demonstrated efficacy showed similar results. TABLE 4: Effects of Montelukast Sodium on Daytime Nasal Symptoms ScoreAverage of individual scores of nasal congestion, rhinorrhea, nasal itching, sneezing as assessed by patients on a 0 to 3 categorical scale. in a Placebo- and Active-controlled Trial in Patients with Seasonal Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean Montelukast 10 mg (344) 2.09 -0.39 -0.13Statistically different from placebo (p≤0.001). (-0.21, -0.06) Placebo (351) 2.10 -0.26 N.A. Active ControlThe study was not designed for statistical comparison between montelukast sodium and the active control (loratadine). (Loratadine 10 mg) (599) 2.06 -0.46 -0.24 (-0.31, -0.17) Perennial Allergic Rhinitis The efficacy of montelukast sodium tablets for the treatment of perennial allergic rhinitis was investigated in 2 randomized, double-blind, placebo-controlled studies conducted in North America and Europe. The two studies enrolled a total of 3357 patients, of whom 1632 received montelukast sodium 10 mg tablets. Patients 15 to 82 years of age with perennial allergic rhinitis as confirmed by history and a positive skin test to at least one relevant perennial allergen (dust mites, animal dander, and/or mold spores), who had active symptoms at the time of study entry, were enrolled. In the study in which efficacy was demonstrated, the median age was 35 years (range 15 to 81); 64.1% were females and 35.9% were males. The ethnic/racial distribution in this study was 83.2% Caucasian, 8.1% Black, 5.4% Hispanic, 2.3% Asian, and 1.0% other origins. Montelukast sodium 10 mg tablets once daily was shown to significantly reduce symptoms of perennial allergic rhinitis over a 6-week treatment period (TABLE 5); in this study the primary outcome variable was mean change from baseline in daytime nasal symptoms score (the average of individual scores of nasal congestion, rhinorrhea, and sneezing). TABLE 5: Effects of Montelukast Sodium on Daytime Nasal Symptoms Score Average of individual scores of nasal congestion, rhinorrhea, sneezing as assessed by patients on a 0 to 3 categorical scale. in a Placebo-controlled Trial in Patients with Perennial Allergic Rhinitis (ANCOVA Model) Treatment Group (N) Baseline Mean Score Mean Change from Baseline Difference Between Treatment and Placebo (95% CI) Least-Squares Mean Montelukast 10 mg (1000) 2.09 -0.42 -0.08Statistically different from placebo (p≤0.001). (-0.12, -0.04) Placebo (980) 2.10 -0.35 N.A. The other 6-week study evaluated montelukast 10 mg (n=626), placebo (n=609), and an active-control (cetirizine 10 mg; n=120). The primary analysis compared the mean change from baseline in daytime nasal symptoms score for montelukast sodium vs. placebo over the first 4 weeks of treatment; the study was not designed for statistical comparison between montelukast sodium and the active-control. The primary outcome variable included nasal itching in addition to nasal congestion, rhinorrhea, and sneezing. The estimated difference between montelukast sodium and placebo was -0.04 with a 95% CI of (-0.09, 0.01). The estimated difference between the active-control and placebo was -0.10 with a 95% CI of (-0.19, -0.01).

HOW SUPPLIED

16 /STORAGE AND HANDLING Montelukast Sodium Chewable Tablets, 4 mg, are pink, oval, biconvex-shaped chewable tablets, engraved with “APO” on one side and “M4” on the other side. They are supplied as follows: Unit dose packages of 30 (3 x 10) NDC 68084-638-21 Montelukast Sodium Chewable Tablets, 5 mg, are pink, round, biconvex-shaped chewable tablets, engraved with “APO” on one side and “M5” on the other side. They are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-619-01 Montelukast Sodium Film-Coated Tablets, 10 mg, are beige, rounded square-shaped, biconvex film-coated tablets, engraved with “APO” on one side and “M10” on the other side. They are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-620-01 Storage Store montelukast 4 mg chewable tablets, 5 mg chewable tablets and 10 mg film-coated tablets at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture and light.

RECENT MAJOR CHANGES

Warnings and Precautions Neuropsychiatric Events (5.4) 11/2012

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects in clinical studies of montelukast, 3.5% were 65 years of age and over, and 0.4% were 75 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The pharmacokinetic profile and the oral bioavailability of a single 10 mg oral dose of montelukast are similar in elderly and younger adults. The plasma half-life of montelukast is slightly longer in the elderly. No dosage adjustment in the elderly is required.

DOSAGE FORMS AND STRENGTHS

3 •Montelukast Sodium Film-Coated Tablets, 10 mg, are beige, rounded square-shaped, biconvex film-coated tablets, engraved with “APO” on one side and “M10” on the other side. •Montelukast Sodium Chewable Tablets, 5 mg, are pink, round, biconvex-shaped tablets, engraved with “APO” on one side and “M5” on the other side. •Montelukast Sodium Chewable Tablets, 4 mg, are pink, oval, biconvex-shaped tablets, engraved with “APO” on one side and “M4” on the other side. 1.Montelukast Sodium Film-Coated Tablets, 10 mg 2.Montelukast Sodium Chewable Tablets, 5 mg and 4 mg

MECHANISM OF ACTION

12.1 Mechanism of Action The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene (CysLT) receptors. The CysLT type-1 (CysLT1) receptor is found in the human airway (including airway smooth muscle cells and airway macrophages) and on other pro-inflammatory cells (including eosinophils and certain myeloid stem cells). CysLTs have been correlated with the pathophysiology of asthma and allergic rhinitis. In asthma, leukotriene-mediated effects include airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process. In allergic rhinitis, CysLTs are released from the nasal mucosa after allergen exposure during both early- and late-phase reactions and are associated with symptoms of allergic rhinitis. Montelukast is an orally active compound that binds with high affinity and selectivity to the CysLT1 receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or β-adrenergic receptor). Montelukast inhibits physiologic actions of LTD4 at the CysLT1 receptor without any agonist activity.

INDICATIONS AND USAGE

1 Montelukast sodium tablets are a leukotriene receptor antagonist indicated for: 1.Prophylaxis and chronic treatment of asthma in patients 2 years of age and older (1.1). 2.Acute prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older (1.2). 3.Relief of symptoms of allergic rhinitis (AR): seasonal allergic rhinitis (SAR) in patients 2 years of age and older, and perennial allergic rhinitis (PAR) in patients 2 years of age and older (1.3). 1.1 Asthma Montelukast sodium is indicated for the prophylaxis and chronic treatment of asthma in adults and pediatric patients 2 years of age and older. 1.2 Exercise-Induced Bronchoconstriction (EIB) Montelukast sodium is indicated for prevention of exercise-induced bronchoconstriction (EIB) in patients 15 years of age and older. Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.3 Allergic Rhinitis Montelukast sodium is indicated for the relief of symptoms of seasonal allergic rhinitis in patients 2 years of age and older and perennial allergic rhinitis in patients 2 years of age and older.

PEDIATRIC USE

8.4 Pediatric Use Safety and efficacy of montelukast sodium have been established in adequate and well-controlled studies in pediatric patients with asthma 6 to 14 years of age. Safety and efficacy profiles in this age group are similar to those seen in adults [see Adverse Reactions (6.1), Clinical Pharmacology, Special Populations (12.3), and Clinical Studies (14.1, 14.2)]. The efficacy of montelukast sodium for the treatment of seasonal allergic rhinitis in pediatric patients 2 to 14 years of age and for the treatment of perennial allergic rhinitis in pediatric patients 2 years to 14 years of age is supported by extrapolation from the demonstrated efficacy in patients 15 years of age and older with allergic rhinitis as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. The safety of montelukast sodium 4 mg chewable tablets in pediatric patients 2 to 5 years of age with asthma has been demonstrated by adequate and well-controlled data [see Adverse Reactions (6.1)]. Efficacy of montelukast sodium in this age group is extrapolated from the demonstrated efficacy in patients 6 years of age and older with asthma and is based on similar pharmacokinetic data, as well as the assumption that the disease course, pathophysiology and the drug’s effect are substantially similar among these populations. Efficacy in this age group is supported by exploratory efficacy assessments from a large, well-controlled safety study conducted in patients 2 to 5 years of age. The safety of montelukast sodium 4 mg and 5 mg chewable tablets in pediatric patients aged 2 to 14 years with allergic rhinitis is supported by data from studies conducted in pediatric patients aged 2 to 14 years with asthma. A safety study in pediatric patients 2 to 14 years of age with seasonal allergic rhinitis demonstrated a similar safety profile [see Adverse Reactions (6.1)]. The safety and effectiveness in pediatric patients below the age of 12 months with asthma and 6 months with perennial allergic rhinitis have not been established. The safety and effectiveness in pediatric patients below the age of 6 years with exercise-induced bronchoconstriction have not been established. Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. Growth Rate in Pediatric Patients A 56-week, multi-center, double-blind, randomized, active- and placebo-controlled parallel group study was conducted to assess the effect of montelukast sodium on growth rate in 360 patients with mild asthma, aged 6 to 8 years. Treatment groups included montelukast 5 mg once daily, placebo, and beclomethasone dipropionate administered as 168 mcg twice daily with a spacer device. For each subject, a growth rate was defined as the slope of a linear regression line fit to the height measurements over 56 weeks. The primary comparison was the difference in growth rates between montelukast sodium and placebo groups. Growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for the montelukast sodium, placebo, and beclomethasone treatment groups were 5.67 (5.46, 5.88), 5.64 (5.42, 5.86), and 4.86 (4.64, 5.08), respectively. The differences in growth rates, expressed as least-squares (LS) mean (95% CI) in cm/year, for montelukast sodium minus placebo, beclomethasone minus placebo, and montelukast sodium minus beclomethasone treatment groups were 0.03 (-0.26, 0.31), -0.78 (-1.06, -0.49); and 0.81 (0.53, 1.09), respectively. Growth rate (expressed as mean change in height over time) for each treatment group is shown in FIGURE 1. FIGURE 1: Change in Height (cm) from Randomization Visit by Scheduled Week (Treatment Group Mean ± Standard Error†of the Mean) image-1

PREGNANCY

8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, montelukast sodium should be used during pregnancy only if clearly needed. Teratogenic Effect No teratogenicity was observed in rats and rabbits at doses approximately 100 and 110 times, respectively, the maximum recommended daily oral dose in adults based on AUCs [see Nonclinical Toxicology (13.2)]. During worldwide marketing experience, congenital limb defects have been rarely reported in the offspring of women being treated with montelukast sodium during pregnancy. Most of these women were also taking other asthma medications during their pregnancy. A causal relationship between these events and montelukast sodium has not been established.

NUSRING MOTHERS

8.3 Nursing Mothers Studies in rats have shown that montelukast is excreted in milk. It is not known if montelukast is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when montelukast sodium is given to a nursing mother.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS 1.Do not prescribe montelukast sodium to treat an acute asthma attack (5.1). 2.Advise patients to have appropriate rescue medication available (5.1). 3.Inhaled corticosteroid may be reduced gradually. Do not abruptly substitute montelukast sodium for inhaled or oral corticosteroids (5.2). 4.Patients with known aspirin sensitivity should continue to avoid aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium (5.3). 5.Neuropsychiatric events have been reported with montelukast sodium. Instruct patients to be alert for neuropsychiatric events. Evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur (5.4 and 6.2). 6.Systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, has been reported. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy (5.5 and 6.2). 7.Inform patients with phenylketonuria that the 4 mg and 5 mg chewable tablets contain phenylalanine (5.6). 5.1 Acute Asthma Montelukast sodium is not indicated for use in the reversal of bronchospasm in acute asthma attacks, including status asthmaticus. Patients should be advised to have appropriate rescue medication available. Therapy with montelukast sodium can be continued during acute exacerbations of asthma. Patients who have exacerbations of asthma after exercise should have available for rescue a short-acting inhaled β-agonist. 5.2 Concomitant Corticosteroid Use While the dose of inhaled corticosteroid may be reduced gradually under medical supervision, montelukast sodium should not be abruptly substituted for inhaled or oral corticosteroids. 5.3 Aspirin Sensitivity Patients with known aspirin sensitivity should continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium. Although montelukast sodium is effective in improving airway function in asthmatics with documented aspirin sensitivity, it has not been shown to truncate bronchoconstrictor response to aspirin and other non-steroidal anti-inflammatory drugs in aspirin-sensitive asthmatic patients [see Clinical Studies (14.1)]. 5.4 Neuropsychiatric Events Neuropsychiatric events have been reported in adult, adolescent, and pediatric patients taking montelukast sodium. Post-marketing reports with montelukast sodium use include agitation, aggressive behavior or hostility, anxiousness, depression, disorientation, disturbance in attention, dream abnormalities, hallucinations, insomnia, irritability, memory impairment, restlessness, somnambulism, suicidal thinking and behavior (including suicide), and tremor. The clinical details of some post-marketing reports involving montelukast sodium appear consistent with a drug-induced effect. Patients and prescribers should be alert for neuropsychiatric events. Patients should be instructed to notify their prescriber if these changes occur. Prescribers should carefully evaluate the risks and benefits of continuing treatment with montelukast sodium if such events occur [see Adverse Reactions (6.2)]. 5.5 Eosinophilic Conditions Patients with asthma on therapy with montelukast sodium may present with systemic eosinophilia, sometimes presenting with clinical features of vasculitis consistent with Churg-Strauss syndrome, a condition which is often treated with systemic corticosteroid therapy. These events usually, but not always, have been associated with the reduction of oral corticosteroid therapy. Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients. A causal association between montelukast sodium and these underlying conditions has not been established [see Adverse Reactions (6.2)]. 5.6 Phenylketonuria Phenylketonuric patients should be informed that the 4 mg and 5 mg chewable tablets contain phenylalanine (a component of aspartame), 1.344 and 1.68 mg per 4 mg and 5 mg chewable tablet, respectively.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information) 17.1 Information for Patients 1.Patients should be advised to take montelukast sodium daily as prescribed, even when they are asymptomatic, as well as during periods of worsening asthma, and to contact their physicians if their asthma is not well controlled. 2.Patients should be advised that oral montelukast sodium is not for the treatment of acute asthma attacks. They should have appropriate short-acting inhaled β-agonist medication available to treat asthma exacerbations. Patients who have exacerbations of asthma after exercise should be instructed to have available for rescue a short-acting inhaled β-agonist. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. 3.Patients should be advised that, while using montelukast sodium medical attention should be sought if short-acting inhaled bronchodilators are needed more often than usual, or if more than the maximum number of inhalations of short-acting bronchodilator treatment prescribed for a 24-hour period are needed. 4.Patients receiving montelukast sodium should be instructed not to decrease the dose or stop taking any other anti-asthma medications unless instructed by a physician. 5.Patients should be instructed to notify their physician if neuropsychiatric events occur while using montelukast sodium. 6.Patients with known aspirin sensitivity should be advised to continue avoidance of aspirin or non-steroidal anti-inflammatory agents while taking montelukast sodium. 7.Phenylketonuric patients should be informed that the 4-mg and 5-mg chewable tablets contain phenylalanine (a component of aspartame). MONTELUKAST SODIUM TABLETS 10 mg MONTELUKAST SODIUM CHEWABLE TABLETS 4 mg and 5 mg PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Apotex Corp. as follows: (4 mg / 30 UD) NDC 68084-638-21 packaged from NDC 60505-3573 (5 mg / 100 UD) NDC 68084-619-01 packaged from NDC 60505-3574 (10 mg / 100 UD) NDC 68084-620-01 packaged from NDC 60505-3562 Packaged and Distributed by: American Health Packaging Columbus, OH 43217 8261901/1213 17.2 FDA-Approved Patient Labeling 8261901/1213 Patient Information Montelukast Sodium Tablets Montelukast Chewable Tablets Read the Patient Information Leaflet that comes with montelukast sodium tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or your treatment. What is montelukast sodium? •Montelukast sodium is a prescription medicine that blocks substances in the body called leukotrienes. This may help to improve symptoms of asthma and allergic rhinitis. Montelukast sodium tablet does not contain a steroid. Montelukast sodium tablet is used to: 1.Prevent asthma attacks and for the long-term treatment of asthma in adults and children ages 2 years and older. Do not take montelukast sodium tablet if you need relief right away for a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks. 2.Prevent exercise-induced asthma in people 15 years of age and older. 3.Help control the symptoms of allergic rhinitis (sneezing, stuffy nose, runny nose, itching of the nose). Montelukast sodium tablet is used to treat: •outdoor allergies that happen part of the year (seasonal allergic rhinitis) in adults and children ages 2 years and older, and •indoor allergies that happen all year (perennial allergic rhinitis) in adults and children ages 2 years and older. Who should not take montelukast sodium tablet? Do not take montelukast sodium tablet if you are allergic to any of its ingredients. See the end of this leaflet for a complete list of the ingredients in montelukast sodium tablet. What should I tell my healthcare provider before taking montelukast sodium tablet? Before taking montelukast sodium tablet, tell your healthcare provider if you: •are allergic to aspirin •have phenylketonuria. Montelukast sodium chewable tablets contain aspartame, a source of phenylalanine •have any other medical conditions •are pregnant or plan to become pregnant. Talk to your doctor if you are pregnant or plan to become pregnant, as montelukast sodium tablet may not be right for you. •are breast-feeding or plan to breast-feed. It is not known if montelukast sodium passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking montelukast sodium tablet. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Some medicines may affect how montelukast sodium tablet works, or montelukast sodium tablet may affect how your other medicines work. How should I take montelukast sodium tablets? For anyone who takes montelukast sodium tablets: •Take montelukast sodium tablet exactly as prescribed by your healthcare provider. Your healthcare provider will tell you how much montelukast sodium tablet to take, and when to take it. •Do not stop taking montelukast sodium tablet or change when you take it without talking with your healthcare provider. •You can take montelukast sodium tablet with food or without food. • If you or your child misses a dose of montelukast sodium tablet, just take the next dose at your regular time. Do not take 2 doses at the same time. •If you take too much montelukast sodium tablets, call your healthcare provider or a Poison Control Center right away. For adults and children 2 years of age and older with asthma: •Take montelukast sodium tablet 1 time each day, in the evening. Continue to take montelukast sodium tablet every day for as long as your healthcare provider prescribes it, even if you have no asthma symptoms. •Tell your healthcare provider right away if your asthma symptoms get worse, or if you need to use your rescue inhaler medicine more often for asthma attacks. • Do not take montelukast sodium tablet if you need relief right away from a sudden asthma attack. If you get an asthma attack, you should follow the instructions your healthcare provider gave you for treating asthma attacks. •Always have your rescue inhaler medicine with you for asthma attacks. •Do not stop taking or lower the dose of your other asthma medicines unless your healthcare provider tells you to. For patients 15 years of age and older for the prevention of exercise-induced asthma: •Take montelukast sodium tablet at least 2 hours before exercise. •Always have your rescue inhaler medicine with you for asthma attacks. •If you take montelukast sodium tablet every day for chronic asthma or allergic rhinitis, do not take another dose to prevent exercise-induced asthma. Talk to your healthcare provider about your treatment for exercise-induced asthma. • Do not take 2 doses of montelukast sodium tablet within 24 hours (1 day). For adults and children 2 years of age and older with seasonal allergic rhinitis, or for adults and children 2 years of age and older with perennial allergic rhinitis: •Take montelukast sodium tablet 1 time each day, at about the same time each day. What is the dose of montelukast sodium tablet? The dose of montelukast sodium tablet prescribed for your or your child’s condition is based on age: •2 to 5 years: one 4 mg chewable tablet •6 to 14 years: one 5 mg chewable tablet. •15 years and older: one 10 mg tablet. What should I avoid while taking montelukast sodium tablet? If you have asthma and aspirin makes your asthma symptoms worse, continue to avoid taking aspirin or other medicines called non‑-steroidal anti-inflammatory drugs (NSAIDs) while taking montelukast sodium tablet. What are the possible side effects of montelukast sodium tablet? Montelukast sodium tablet may cause serious side effects. • Behavior and mood-related changes. Tell your healthcare provider right away if you or your child have any of these symptoms while taking montelukast sodium tablet: •agitation including aggressive behavior or hostility •attention problems •bad or vivid dreams •depression •disorientation (confusion) •feeling anxious •hallucinations (seeing or hearing things that are not really there) •irritability •memory problems •restlessness •sleep walking •suicidal thoughts and actions (including suicide) •tremor •trouble sleeping Tell your healthcare provider right away if you get one or more of these symptoms: •a feeling of pins and needles or numbness of arms or legs •a flu-like illness •rash •severe inflammation (pain and swelling) of the sinuses (sinusitis) The most common side effects with montelukast sodium tablet include: •upper respiratory infection •fever •headache •sore throat •cough •stomach pain •diarrhea •earache or ear infection •flu •runny nose •sinus infection Other side effects with montelukast sodium tablet include: •increased bleeding tendency, low blood platelet count •allergic reactions [including swelling of the face, lips, tongue, and/or throat (which may cause trouble breathing or swallowing), hives and itching] •dizziness, drowsiness, pins and needles/numbness, seizures (convulsions or fits) •palpitations •nose bleed, stuffy nose •heartburn, indigestion, inflammation of the pancreas, nausea, stomach or intestinal upset, vomiting •hepatitis •bruising, rash, severe skin reactions (erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis) that may occur without warning •joint pain, muscle aches and muscle cramps •tiredness, swelling Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of montelukast sodium tablet. For more information ask your healthcare provider or pharmacist. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store montelukast sodium tablets? •Store montelukast sodium tablets at 59°F to 86°F (15° to 30°C). •Keep montelukast sodium tablets in a dry place and away from light. General Information about the safe and effective use of montelukast sodium tablets Medicines are sometimes prescribed for purposes other than those mentioned in Patient Information Leaflets. Do not use montelukast sodium tablet for a condition for which it was not prescribed. Do not give montelukast sodium tablet to other people even if they have the same symptoms you have. It may harm them. Keep montelukast sodium tablets and all medicines out of the reach of children. This leaflet summarizes information about montelukast sodium tablets. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about montelukast sodium tablets that is written for health professionals. What are the ingredients in montelukast sodium tablets? Active ingredient: montelukast sodium Inactive ingredients: • 4 mg and 5 mg chewable tablets: mannitol, microcrystalline cellulose, red ferric oxide, croscarmellose sodium, cherry flavor, aspartame, and magnesium stearate. •People with Phenylketonuria: montelukast sodium 4 mg chewable tablets contain 1.344 mg of phenylalanine, and montelukast sodium 5 mg chewable tablets contain 1.68 mg of phenylalanine. • 10 mg tablet: anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate. The film coating consists of: hydroxypropyl methylcellulose, hydroxypropyl cellulose, titanium dioxide, red ferric oxide, and yellow ferric oxide. Pediatric use information for patients ages 6 to 14 years of age for prevention of exercise-induced asthma is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. MONTELUKAST SODIUM TABLETS 10 mg MONTELUKAST SODIUM CHEWABLE TABLETS 4 mg and 5 mg Packaged and Distributed by: American Health Packaging Columbus, OH 43217 8261901/1213

DOSAGE AND ADMINISTRATION

2 Administration (by indications): 1.Asthma (2.1): Once daily in the evening for patients 2 years and older. 2.Acute prevention of EIB (2.2): 10 mg tablet at least 2 hours before exercise for patients 15 years of age and older. 3.Seasonal allergic rhinitis (2.3): Once daily for patients 2 years and older. 4.Perennial allergic rhinitis (2.3): Once daily for patients 2 years and older. Dosage (by age) (2): 1.15 years and older: one 10 mg tablet. 2.6 to 14 years: one 5 mg chewable tablet. 3.2 to 5 years: one 4 mg chewable tablet. Patients with both asthma and allergic rhinitis should take only one dose daily in the evening (2.4). 2.1 Asthma Montelukast sodium should be taken once daily in the evening. The following doses are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet. For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet. Safety and effectiveness in pediatric patients less than 12 months of age with asthma have not been established. There have been no clinical trials in patients with asthma to evaluate the relative efficacy of morning versus evening dosing. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening. Efficacy has been demonstrated for asthma when montelukast was administered in the evening without regard to time of food ingestion. 2.2 Exercise-Induced Bronchoconstriction (EIB) in Patients 15 Years of Age and Older For prevention of EIB, a single 10 mg dose of montelukast should be taken at least 2 hours before exercise. An additional dose of montelukast should not be taken within 24 hours of a previous dose. Patients already taking montelukast sodium daily for another indication (including chronic asthma) should not take an additional dose to prevent EIB. All patients should have available for rescue a short-acting β-agonist. Safety and efficacy in patients younger than 15 years of age have not been established. Daily administration of montelukast sodium for the chronic treatment of asthma has not been established to prevent acute episodes of EIB. Pediatric use information for patients ages 6 to 14 years of age for acute prevention of exercise-induced bronchoconstriction (EIB) is approved for Merck Sharp & Dohme Corp’s montelukast tablet products. However, due to Merck Sharp & Dohme Corp’s marketing exclusivity rights; this drug product is not labeled with that pediatric information. 2.3 Allergic Rhinitis For allergic rhinitis, montelukast sodium should be taken once daily. Efficacy was demonstrated for seasonal allergic rhinitis when montelukast was administered in the morning or the evening without regard to time of food ingestion. The time of administration may be individualized to suit patient needs. The following doses for the treatment of symptoms of seasonal allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet. For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet. Safety and effectiveness in pediatric patients younger than 2 years of age with seasonal allergic rhinitis have not been established. The following doses for the treatment of symptoms of perennial allergic rhinitis are recommended: For adults and adolescents 15 years of age and older: one 10 mg tablet. For pediatric patients 6 to 14 years of age: one 5 mg chewable tablet. For pediatric patients 2 to 5 years of age: one 4 mg chewable tablet Safety and effectiveness in pediatric patients younger than 6 months of age with perennial allergic rhinitis have not been established. 2.4 Asthma and Allergic Rhinitis Patients with both asthma and allergic rhinitis should take only one montelukast sodium dose daily in the evening.

Codeine Phosphate 2 MG/ML / Promethazine Hydrochloride 1.25 MG/ML Oral Solution

Generic Name: PROMETHAZINE HYDROCHLORIDE AND CODEINE PHOSPHATE

Brand Name: promethazine hydrochloride and codeine phosphate

Substance Name(s):
CODEINE PHOSPHATE
PROMETHAZINE HYDROCHLORIDE

WARNINGS

Respiratory Depression in Children The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients. Respiratory depression leading to arrest, coma, and death has occurred with the use of codeine antitussives in young children, particularly in the under-one-year infants whose ability to deactivate the drug is not fully developed. Codeine: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultrarapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultra-rapid metabolizers of codeine. (See PRECAUTIONS -Nursing Mothers). Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing). (See OVERDOSAGE). Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy. (See CONTRAINDICATIONS). When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose. Dosage of codeine SHOULD NOT BE INCREASED if cough fails to respond; an unresponsive cough should be reevaluated in 5 days or sooner for possible underlying pathology, such as foreign body or lower respiratory tract disease. Codeine may cause or aggravate constipation. Administration of codeine may be accompanied by histamine release and should be used with caution in atopic children. Head Injury and Increased Intracranial Pressure: The respiratory-depressant effects of narcotic analgesics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure. Narcotics may produce adverse reactions which may obscure the clinical course of patients with head injuries. Asthma and Other Respiratory Conditions: Narcotic analgesics or cough suppressants, including codeine, should not be used in asthmatic patients (see CONTRAINDICATIONS ). Nor should they be used in acute febrile illness associated with productive cough or in chronic respiratory disease where interference with ability to clear the tracheobronchial tree of secretions would have a deleterious effect on the patient’s respiratory function. Hypotensive Effect: Codeine may produce orthostatic hypotension in ambulatory patients. Promethazine: CNS Depression — Promethazine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine HCl (see PRECAUTIONS-Information for Patients and Drug Interactions ). Respiratory Depression —Promethazine may lead to potentially fatal respiratory depression. Use of Promethazine in patients with compromised respiratory function (e.g., COPD, sleep apnea) should be avoided. Lower Seizure Threshold —Promethazine may lower seizure threshold. It should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold. Bone-Marrow Depression —Promethazine should be used with caution in patients with bone-marrow depression. Leukopenia and agranulocytosis have been reported, usually when promethazine HCl has been used in association with other known marrow-toxic agents. Neuroleptic Malignant Syndrome —A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine HCl alone or in combination with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias). The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g. pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology. The management of NMS should include 1) immediate discontinuation of promethazine HCl, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine HCl should be carefully considered. Use in Pediatric Patients The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. The association does not directly relate to individualized weight-based dosing, which might otherwise permit safe administration. Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in these patients (see – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine and CONTRAINDICATIONS). Excessively large dosages of antihistamines, including promethazine hydrochloride, in pediatric patients may cause sudden death (see OVERDOSAGE ). Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride in pediatric patients. In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine HCl. Other Considerations Administration of promethazine has been associated with reported cholestatic jaundice.

DRUG INTERACTIONS

Drug Interactions: Codeine: In patients receiving MAO inhibitors, an initial small test dose is advisable to allow observation of any excessive narcotic effects or MAOI interaction. Promethazine CNS Depressants —Promethazine may increase, prolong, or intensify the sedative action of other central-nervous system depressants, such as alcohol, sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricylic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine HCl. When given concomitantly with promethazine, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half. Dosage must be individualized. Excessive amounts of promethazine HCl relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain. Epinephrine —Because of the potential for promethazine to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine overdose. Anticholinergics —Concomitant use of other agents with anticholinergic properties should be undertaken with caution. Monoamine Oxidase Inhibitors (MAOI) —Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAOI and phenothiazines are used concomitantly.

OVERDOSAGE

Codeine: Serious overdose with codeine is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The triad of coma, pinpoint pupils, and respiratory depression is strongly suggestive of opiate poisoning. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest, and death may occur. Promethazine is additive to the depressant effects of codeine. It is difficult to determine what constitutes a standard toxic or lethal dose. However, the lethal oral dose of codeine in an adult is reported to be in the range of 0.5 to 1.0 gram. Infants and children are believed to be relatively more sensitive to opiates on a body-weight basis. Elderly patients are also comparatively intolerant to opiates. Promethazine: Signs and symptoms of overdosage with promethazine HCl range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness, and sudden death. Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex). Stimulation may be evident, especially in children and geriatric patients. Convulsions may rarely occur. A paradoxical-type reaction has been reported in children receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares. Atropine-like signs and symptoms – dry mouth, fixed dilated pupils, flushing, as well as gastrointestinal symptoms may occur. Treatment: The treatment of overdosage with promethazine and codeine is essentially symptomatic and supportive. Only in cases of extreme overdosage or individual sensitivity do vital signs including respiration, pulse, blood pressure, temperature, and EKG need to be monitored. Activated charcoal orally or by lavage may be given, or sodium or magnesium sulfate orally as a cathartic. Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. The narcotic antagonist, naloxone hydrochloride, may be administered when significant respiratory depression occurs with promethazine and codeine; any depressant effects of promethazine are not reversed with naloxone. Diazepam may be used to control convulsions. Avoid analeptics, which may cause convulsions. Acidosis and electrolyte losses should be corrected. A rise in temperature or pulmonary complications may signal the need for institution of antibiotic therapy. Severe hypotension usually responds to the administration of norepinephrine or phenylephrine. EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure. Limited experience with dialysis indicates that it is not helpful.

DESCRIPTION

Each 5 mL (one teaspoonful), for oral administration contains: Promethazine hydrochloride 6.25 mg; codeine phosphate 10 mg. Alcohol 7%. Inactive Ingredients: ascorbic acid, citric acid, D & C yellow #10, edetate disodium, ethyl alcohol, FD&C Blue #1, FD&C Red #40, glycerin, methylparaben, pineapple flavor, purified water, sodium benzoate, sodium citrate, sucralose, and sucrose. Codeine is one of the naturally occurring phenanthrene alkaloids of opium derived from the opium poppy; it is classified pharmacologically as a narcotic analgesic. Codeine phosphate may be chemically designated as 7,8- Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan- 6α-ol phosphate (1:1) (salt) hemihydrate. The phosphate salt of codeine occurs as white, needle-shaped crystals or white crystalline powder. Codeine phosphate is freely soluble in water and slightly soluble in alcohol. It has a molecular weight of 406.37, a molecular formula of C18H21NO3 • H3PO4 • 1/2H2O, and the following structural formula: Promethazine hydrochloride, a phenothiazine derivative, is chemically designated as (±) -10-[2-(Dimethylamino) propyl] phenothiazine monohydrochloride. Promethazine hydrochloride occurs as a white to faint yellow, practically odorless, crystalline powder which slowly oxidizes and turns blue on prolonged exposure to air. It is soluble in water and freely soluble in alcohol. It has a molecular weight of 320.88, a molecular formula of C17H20N2S • HCl, and the following structural formula: structure.jpg Strut2.jpg

HOW SUPPLIED

Promethazine Hydrochloride and Codeine Phosphate Syrup contains promethazine hydrochloride, USP 6.25 mg/5 mL, codeine phosphate, USP 10 mg/5 mL and alcohol 7 percent. It is supplied in a clear green, pineapple flavored syrup and is available as follows: NDC 63187-595-04 4 fl. oz. (118 mL) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries, Inc. Bryan, OH 43506 Relabeled By: Proficient Rx LP Thousand Oaks, CA 91320 5981T05 Iss: 03/15

GERIATRIC USE

Geriatric Use: Clinical studies of promethazine hydrochloride and codeine phosphate syrup did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of promethazine hydrochloride and codeine phosphate syrup and observed closely.

INDICATIONS AND USAGE

Promethazine hydrochloride and codeine phosphate syrup is indicated for the temporary relief of coughs and upper respiratory symptoms associated with allergy or the common cold.

PEDIATRIC USE

Pediatric Use: The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population (see WARNINGS – Boxed Warning and Use in Pediatric Patients). Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in these patients (see WARNINGS – Death Related to Ultra-Rapid Metabolism of Codeine to Morphine and CONTRAINDICATIONS). The combination of promethazine hydrochloride and codeine phosphate should be used with caution in pediatric patient 6 years and older (see WARNINGS – Use in Pediatric Patients).

PREGNANCY

Pregnancy: Teratogenic Effects-Pregnancy Category C. Codeine: A study in rats and rabbits reported no teratogenic effect of codeine administered during the period of organogenesis in doses ranging from 5 to 120 mg/kg. In the rat, doses at the 120-mg/kg level, in the toxic range for the adult animal, were associated with an increase in embryo resorption at the time of implantation. In another study a single 100-mg/kg dose of codeine administered to pregnant mice reportedly resulted in delayed ossification in the offspring. There are no studies in humans, and the significance of these findings to humans, if any, is not known. Promethazine: Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg of promethazine HCl. These doses are from approximately 2.1 to 4.2 times the maximum recommended total daily dose of promethazine for a 50-kg subject, depending upon the indication for which the drug is prescribed. Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats. Specific studies to test the action of the drug on parturition, lactation, and development of the animal neonate were not done, but a general preliminary study in rats indicated no effect on these parameters. Although antihistamines have been found to produce fetal mortality in rodents, the pharmacological effects of histamine in the rodent do not parallel those in man. There are no adequate and well-controlled studies of promethazine in pregnant women. Promethazine and codeine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Dependence has been reported in newborns whose mothers took opiates regularly during pregnancy. Withdrawal signs include irritability, excessive crying, tremors, hyperreflexia, fever, vomiting, and diarrhea. Signs usually appear during the first few days of life. Promethazine administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

NUSRING MOTHERS

Nursing Mothers: It is not known whether promethazine is excreted in human milk. Codeine is secreted into human milk. In women with normal codeine metabolism (normal CYP2D6 activity), the amount of codeine secreted into human milk is low and dose-dependent. Despite the common use of codeine products to manage postpartum pain, reports of adverse events in infants are rare. However, some women are ultra-rapid metabolizers of codeine. These women achieve higher-than-expected serum levels of codeine’s active metabolite, morphine, leading to higher-than-expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants. Therefore, maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. The risk of infant exposure to codeine and morphine through breast milk should be weighed against the benefits of breastfeeding for both the mother and baby. Caution should be exercised when codeine is administered to a nursing woman. If a codeine containing product is selected, the lowest dose should be prescribed for the shortest period of time to achieve the desired clinical effect. Mothers using codeine should be informed about when to seek immediate medical care and how to identify the signs and symptoms of neonatal toxicity, such as drowsiness or sedation, difficulty breastfeeding, breathing difficulties, and decreased tone, in their baby. Nursing mothers who are ultrarapid metabolizers may also experience overdose symptoms such as extreme sleepiness, confusion or shallow breathing. Prescribers should closely monitor mother-infant pairs and notify treating pediatricians about the use of codeine during breastfeeding. (See Warnings- Death Related to Ultra-Rapid Metabolism of Codeine to Morphine.) Caution should be exercised when promethazine hydrochloride and codeine phosphate syrup is administered to a nursing woman.

BOXED WARNING

WARNING: Respiratory Depression in Children and Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory Depression in Children The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age. Concomitant administration of promethazine products with other respiratory depressants has an association with respiratory depression, and sometimes death, in pediatric patients. Postmarketing cases of respiratory depression, including fatalities, have been reported with use of promethazine hydrochloride in pediatric patients less than 2 years of age. A wide range of weight-based doses of promethazine hydrochloride have resulted in respiratory depression in these patients. Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism.

INFORMATION FOR PATIENTS

Information for Patients: Patients should be advised to measure Promethazine Hydrochloride and Codeine Phosphate Syrup with an accurate measuring device. A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when a half a teaspoon is measured. A pharmacist can recommend an appropriate measuring device and can provide instructions for measuring the correct dose. Promethazine and codeine may cause marked drowsiness or may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery. Ambulatory patients should be told to avoid engaging in such activities until it is known that they do not become drowsy or dizzy from promethazine and codeine therapy. Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities. The concomitant use of alcohol or other central-nervous-system depressants, such as sedatives/hypnotics (including barbiturates), narcotics, narcotic analgesics, general anesthetics, tricyclic antidepressants, and tranquilizers may enhance impairment and should be avoided or their dosage reduced (see WARNINGS-CNS Depression and PRECAUTIONS-Drug Interactions ). Patients should be advised to report any involuntary muscle movements. Avoid prolonged exposure to the sun. Codeine, like other narcotic analgesics, may produce orthostatic hypotension in some ambulatory patients. Patients should be cautioned accordingly. Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. As a result, codeine is contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine for other reasons to monitor for signs of respiratory depression. Nursing mothers taking codeine can also have higher morphine levels in their breast milk if they are ultra-rapid metabolizers. These higher levels of morphine in breast milk may lead to life-threatening or fatal side effects in nursing babies. Instruct nursing mothers to watch for signs of morphine toxicity in their infants including increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness. Instruct nursing mother to talk to the baby’s doctor immediately if they notice these signs and, if they cannot reach the doctor right away, to take the baby to an emergency room or call 911 (or local emergency services).

DOSAGE AND ADMINISTRATION

The combination of promethazine hydrochloride and codeine phosphate is contraindicated in pediatric patients less than 6 years of age, because the combination may cause fatal respiratory depression in this age population. It is important that promethazine hydrochloride and codeine phosphate syrup is measured with an accurate measuring device (see PRECAUTIONS-Information for Patients ). A household teaspoon is not an accurate measuring device and could lead to overdosage, especially when half a teaspoon is to be measured. It is strongly recommended that an accurate measuring device be use. A pharmacist can provide an appropriate device and can provide instruction for measuring the correct dose. The average effective dose for adults and children 12 years of age and over is: 1 teaspoonful (5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours. The average effective dose for children 6 years and under 12 years of age is ½ to 1 teaspoonful (2.5 mL to 5 mL) every 4 to 6 hours, not to exceed 30 mL in 24 hours.

Cefuroxime 250 MG Oral Tablet

Generic Name: CEFUROXIME AXETIL

Brand Name: cefuroxime axetil

Substance Name(s):
CEFUROXIME AXETIL

DRUG INTERACTIONS

7 •Oral Contraceptives: Effects on gut flora may lower estrogen reabsorption and reduce efficacy of oral contraceptives. (7.1) •Drugs that reduce gastric acidity may lower the bioavailability of cefuroxime axetil tablets. (7.2) •Co-administration with probenecid increases systemic exposure to cefuroxime axetil tablets and is therefore not recommended. (7.3) 7.1 Oral Contraceptives Cefuroxime axetil may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. Counsel patients to consider alternate supplementary (non-hormonal) contraceptive measures during treatment. 7.2 Drugs that Reduce Gastric Acidity Drugs that reduce gastric acidity may result in a lower bioavailability of cefuroxime axetil compared with administration in the fasting state. Administration of drugs that reduce gastric acidity may negate the food effect of increased absorption of cefuroxime axetil when administered in the postprandial state. Administer cefuroxime axetil at least 1 hour before or 2 hours after administration of short-acting antacids. Histamine-2 (H2) antagonists and proton pump inhibitors should be avoided. 7.3 Probenecid Concomitant administration of probenecid with cefuroxime axetil tablets increases serum concentrations of cefuroxime [see CLINICAL PHARMACOLOGY (12.3)]. Co-administration of probenecid with cefuroxime axetil is not recommended. 7.4 Drug/Laboratory Test Interactions A false-positive reaction for glucose in the urine may occur with copper reduction tests (e.g., Benedict’s or Fehling’s solution), but not with enzyme-based tests for glycosuria. As a false-negative result may occur in the ferricyanide test, it is recommended that either the glucose oxidase or hexokinase method be used to determine blood/plasma glucose levels in patients receiving cefuroxime axetil. The presence of cefuroxime does not interfere with the assay of serum and urine creatinine by the alkaline picrate method.

OVERDOSAGE

10 Overdosage of cephalosporins can cause cerebral irritation leading to convulsions or encephalopathy. Serum levels of cefuroxime can be reduced by hemodialysis and peritoneal dialysis.

DESCRIPTION

11 Cefuroxime axetil tablets USP contain cefuroxime as cefuroxime axetil. Cefuroxime axetil is a semisynthetic, cephalosporin antibacterial drug for oral administration. The chemical name of cefuroxime axetil (1-(acetyloxy) ethyl ester of cefuroxime) is (RS)-1-hydroxyethyl (6R,7R)-7-[2-(2-furyl)glyoxylamido]-3-(hydroxymethyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]-oct-2-ene-2-carboxylate, 72-(Z)-(O-methyl-oxime), 1-acetate 3-carbamate. Its molecular formula is C20H22N4O10S, and it has a molecular weight of 510.48. Cefuroxime axetil is in the amorphous form and has the following structural formula: Cefuroxime axetil tablets USP are film-coated and contain the equivalent of 250 or 500 mg of cefuroxime as cefuroxime axetil. Cefuroxime axetil tablets USP contain the inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hydrogenated vegetable oil, hypromellose, microcrystalline cellulose, propylene glycol, polyethylene glycol, sodium lauryl sulfate, talc and titanium dioxide. Steucture

CLINICAL STUDIES

14 14.1 Acute Bacterial Maxillary Sinusitis One adequate and well-controlled trial was performed in subjects with acute bacterial maxillary sinusitis. In this trial, each subject had a maxillary sinus aspirate collected by sinus puncture before treatment was initiated for presumptive acute bacterial sinusitis. All subjects had radiographic and clinical evidence of acute maxillary sinusitis. In the trial, the clinical effectiveness of cefuroxime axetil in treating acute maxillary sinusitis was comparable to an oral antimicrobial agent containing a specific β-lactamase inhibitor. However, microbiology data demonstrated cefuroxime axetil to be effective in treating acute bacterial maxillary sinusitis due only to Streptococcus pneumoniae or non-β-lactamase–producing Haemophilus influenzae. Insufficient numbers of β-lactamase–producing Haemophilus influenzae and Moraxella catarrhalis isolates were obtained in this trial to adequately evaluate the effectiveness of cefuroxime axetil in treating acute bacterial maxillary sinusitis due to these 2 organisms. This trial randomized 317 adult subjects, 132 subjects in the United States and 185 subjects in South America. Table 12 shows the results of the intent-to-treat analysis. Table 12. Clinical Effectiveness of Cefuroxime Axetil Tablets in the Treatment of Acute Bacterial Maxillary Sinusitis US Subjects 95% confidence interval around the success difference [-0.08, +0.32]. South American Subjects 95% confidence interval around the success difference [-0.10, +0.16]. Cefuroxime Axetil Tablets 250 mg Twice Daily (n = 49) Controlc (n = 43) Cefuroxime Axetil Tablets 250 mg Twice Daily (n = 49) Controlc (n = 43) Clinical success (cure + improvement) 65% 53% 77% 74% Clinical cure 53% 44% 72% 64% Clinical improvement 12% 9% 5% 10% In this trial and in a supporting maxillary puncture trial, 15 evaluable subjects had non β-lactamase–producing Haemophilus influenzae as the identified pathogen. Of these, 67% (10/15) had this pathogen eradicated. Eighteen (18) evaluable subjects had Streptococcus pneumoniae as the identified pathogen. Of these, 83% (15/18) had this pathogen eradicated. 14.2 Early Lyme Disease Two adequate and well-controlled trials were performed in subjects with early Lyme disease. All subjects presented with physician-documented erythema migrans, with or without systemic manifestations of infection. Subjects were assessed at 1 month posttreatment for success in treating early Lyme disease (Part I) and at 1 year posttreatment for success in preventing the progression to the sequelae of late Lyme disease (Part II). A total of 355 adult subjects (181 treated with cefuroxime axetil and 174 treated with doxycycline) were randomized in the 2 trials, with diagnosis of early Lyme disease confirmed in 79% (281/355). The clinical diagnosis of early Lyme disease in these subjects was validated by 1) blinded expert reading of photographs, when available, of the pretreatment erythema migrans skin lesion, and 2) serologic confirmation (using enzyme-linked immunosorbent assay [ELISA] and immunoblot assay [“Western” blot]) of the presence of antibodies specific to Borrelia burgdorferi, the etiologic agent of Lyme disease. The efficacy data in Table 14 are specific to this “validated” patient subset, while the safety data below reflect the entire patient population for the 2 trials. Clinical data for evaluable subjects in the “validated” patient subset are shown in Table 13. Table 13. Clinical Effectiveness of Cefuroxime Axetil Tablets Compared with Doxycycline in the Treatment of Early Lyme Disease Part I (1 Month after 20 Days of Treatment) 95% confidence interval around the satisfactory difference for Part I (-0.08, +0.05). Part II (1 Year after 20 Days of Treatment) 95% confidence interval around the satisfactory difference for Part II (-0.13, +0.07). Cefuroxime Axetil Tablets 500 mg Twice Daily (n = 125) Doxycycline 100 mg 3 Times Daily (n = 108) Cefuroxime Axetil Tablets 500 mg Twice Daily (n = 105 n’s include subjects assessed as unsatisfactory clinical outcomes (failure + recurrence) in Part I (Cefuroxime Axetil Tablets – 11 [5 failure, 6 recurrence]; doxycycline – 8 [6 failure, 2 recurrence]). ) Doxycycline 100 mg 3Times Daily (n = 83 ) Satisfactory clinical outcomeSatisfactory clinical outcome includes cure + improvement (Part I) and success + improvement (Part II). 91% 93% 84% 87% Clinical cure/success 72% 73% 73% 73% Clinical improvement 19% 19% 10% 13% Cefuroxime axetil and doxycycline were effective in prevention of the development of sequelae of late Lyme disease. While the incidence of drug-related gastrointestinal adverse reactions was similar in the 2 treatment groups (cefuroxime axetil – 13%; doxycycline – 11%), the incidence of drug-related diarrhea was higher in the cefuroxime axetil arm versus the doxycycline arm (11% versus 3%, respectively). 14.3 Secondary Bacterial Infections of Acute Bronchitis Four randomized, controlled clinical trials were performed comparing 5 days versus 10 days of cefuroxime axetil for the treatment of subjects with secondary bacterial infections of acute bronchitis. These trials enrolled a total of 1,253 subjects (Study 1 n = 360; Study 2 n = 177; Study 3 n = 362; Study 4 n = 354). The protocols for Study 1 and Study 2 were identical and compared cefuroxime axetil 250 mg twice daily for 5 days, cefuroxime axetil 250 mg twice daily for 10 days, and AUGMENTIN® (amoxicillin/clavulanate potassium) 500 mg 3 times daily for 10 days. These 2 trials were conducted simultaneously. Study 3 and Study 4 compared cefuroxime axetil 250 mg twice daily for 5 days, cefuroxime axetil 250 mg twice daily for 10 days, and CECLOR® (cefaclor) 250 mg 3 times daily for 10 days. They were otherwise identical to Study 1 and Study 2 and were conducted over the following 2 years. Subjects were required to have polymorphonuclear cells present on the Gram stain of their screening sputum specimen, but isolation of a bacterial pathogen from the sputum culture was not required for inclusion. Table 14 demonstrates the results of the clinical outcome analysis of the pooled trials Study 1/Study 2 and Study 3/Study 4, respectively. Table 14. Clinical Effectiveness of Cefuroxime Axetil Tablets 250 mg Twice Daily in Secondary Bacterial Infections of Acute Bronchitis: Comparison of 5 versus 10 Days’ Treatment Duration Study 1 and Study 2 95% confidence interval around the success difference [-0.164, +0.029]. Study 3 and Study 4 95% confidence interval around the success difference [-0.061, +0.103]. 5 Day (n = 127) 10 Day (n = 139) 5 Day (n = 173) 10 Day (n = 192) Clinical success (cure + improvement) 80% 87% 84% 82% Clinical cure 61% 70% 73% 72% Clinical improvement 19% 17% 11% 10% The response rates for subjects who were both clinically and bacteriologically evaluable were consistent with those reported for the clinically evaluable subjects.

HOW SUPPLIED

16 /STORAGE AND HANDLING Cefuroxime axetil tablets USP, 250 mg of cefuroxime (as cefuroxime axetil), are white to off-white capsule-shaped, film-coated tablets with “LUPIN” debossed on one side and “302” on the other side, supplied in bottles of 20 and 60. Bottle of 20 – 68788-9700-2 Bottle of 30 – 68788-9700-3 Bottle of 60 – 68788-9700-6 Cefuroxime axetil tablets USP, 500 mg of cefuroxime (as cefuroxime axetil), are white to off-white capsule-shaped, film-coated tablets with “LUPIN” debossed on one side and “303” on the other side, supplied in bottles of 20 and 60. Bottle of 20 – 68788-9701-2 Bottle of 30 – 68788-9701-3 Bottle of 60 – 68788-9701-6 Store the tablets at 20 to 25°C (68 to 77°F) [See USP Controlled Room Temperature].

GERIATRIC USE

8.5 Geriatric Use Of the total number of subjects who received cefuroxime axetil in 20 clinical trials, 375 were aged 65 and older while 151 were aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. Reported clinical experience has not identified differences in responses between the elderly and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out. Cefuroxime is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

DOSAGE FORMS AND STRENGTHS

3 •Tablets: 250 mg and 500 mg (3) Cefuroxime axetil tablets are off-white, capsule-shaped, film-coated tablets available in the following strengths: •250 mg of cefuroxime (as cefuroxime axetil) are white to off-white capsule-shaped, film-coated tablets with “LUPIN” debossed on one side and “302” on the other side. •500 mg of cefuroxime (as cefuroxime axetil) are white to off-white capsule-shaped, film-coated tablets with “LUPIN” debossed on one side and “303” on the other side.

MECHANISM OF ACTION

12.1 Mechanism of Action Cefuroxime axetil is an antibacterial drug [see CLINICAL PHARMACOLOGY (12.4)].

INDICATIONS AND USAGE

1 Cefuroxime axetil tablets USP are a cephalosporin antibacterial drug indicated for the treatment of the following infections due to susceptible bacteria: (1) •Pharyngitis/tonsillitis (adults and pediatric patients) (1.1) •Acute bacterial otitis media (pediatric patients) (1.2) •Acute bacterial maxillary sinusitis (adults and pediatric patients) (1.3) •Acute bacterial exacerbations of chronic bronchitis and secondary bacterial infections of acute bronchitis (adults and pediatric patients 13 years and older) (1.4) •Uncomplicated skin and skin-structure infections (adults and pediatric patients 13 years and older) (1.5) •Uncomplicated urinary tract infections (adults and pediatric patients 13 years and older) (1.6) •Uncomplicated gonorrhea (adults and pediatric patients 13 years and older) (1.7) •Early Lyme disease (adults and pediatric patients 13 years and older) (1.8) To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefuroxime axetil tablets USP and other antibacterial drugs, cefuroxime axetil tablets USP should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. 1.1 Pharyngitis/Tonsillitis Cefuroxime axetil tablets USP are indicated for the treatment of adult patients and pediatric patients (13 years and older) with mild-to-moderate pharyngitis/tonsillitis caused by susceptible strains of Streptococcus pyogenes. Limitations of Use •The efficacy of cefuroxime axetil in the prevention of rheumatic fever was not established in clinical trials. •The efficacy of cefuroxime axetil in the treatment of penicillin-resistant strains of Streptococcus pyogenes has not been demonstrated in clinical trials. 1.2 Acute Bacterial Otitis Media Cefuroxime axetil tablets USP are indicated for the treatment of pediatric patients (who can swallow tablets whole) with acute bacterial otitis media caused by susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae (including β-lactamase–producing strains), Moraxella catarrhalis (including β-lactamase–producing strains), or Streptococcus pyogenes. 1.3 Acute Bacterial Maxillary Sinusitis Cefuroxime axetil tablets USP are indicated for the treatment of adult and pediatric patients (13 years and older) with mild-to-moderate acute bacterial maxillary sinusitis caused by susceptible strains of Streptococcus pneumoniae or Haemophilus influenzae (non-β-lactamase–producing strains only). Limitations of Use The effectiveness of cefuroxime axetil for sinus infections caused by β-lactamase–producing Haemophilus influenzae or Moraxella catarrhalis in patients with acute bacterial maxillary sinusitis was not established due to insufficient numbers of these isolates in the clinical trials [see CLINICAL STUDIES (14.1)]. 1.4 Acute Bacterial Exacerbations of Chronic Bronchitis and Secondary Bacterial Infections of Acute Bronchitis Cefuroxime axetil tablets USP are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with mild-to-moderate acute bacterial exacerbations of chronic bronchitis and secondary bacterial infections of acute bronchitis caused by susceptible strains of Streptococcus pneumoniae, Haemophilus influenzae (β-lactamase–negative strains), or Haemophilus parainfluenzae (β-lactamase–negative strains). 1.5 Uncomplicated Skin and Skin-structure Infections Cefuroxime axetil tablets USP are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated skin and skin-structure infections caused by susceptible strains of Staphylococcus aureus (including β-lactamase–producing strains) or Streptococcus pyogenes. 1.6 Uncomplicated Urinary Tract Infections Cefuroxime axetil tablets USP are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated urinary tract infections caused by susceptible strains of Escherichia coli or Klebsiella pneumoniae. 1.7 Uncomplicated Gonorrhea Cefuroxime axetil tablets USP are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with uncomplicated gonorrhea, urethral and endocervical, caused by penicillinase producing and non-penicillinase–producing susceptible strains of Neisseria gonorrhoeae and uncomplicated gonorrhea, rectal, in females, caused by non-penicillinase–producing susceptible strains of Neisseria gonorrhoeae. 1.8 Early Lyme Disease (erythema migrans) Cefuroxime axetil tablets USP are indicated for the treatment of adult patients and pediatric patients (aged 13 and older) with early Lyme disease (erythema migrans) caused by susceptible strains of Borrelia burgdorferi. 1.10 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefuroxime axetil and other antibacterial drugs, cefuroxime axetil should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of cefuroxime axetil have been established for pediatric patients aged 3 months to 12 years for acute bacterial maxillary sinusitis based upon its approval in adults. Use of cefuroxime axetil in pediatric patients is supported by pharmacokinetic and safety data in adults and pediatric patients, and by clinical and microbiological data from adequate and well-controlled trials of the treatment of acute bacterial maxillary sinusitis in adults and of acute otitis media with effusion in pediatric patients. It is also supported by postmarketing adverse events surveillance. [See INDICATIONS AND USAGE (1), DOSAGE AND ADMINISTRATION (2), ADVERSE REACTIONS (6), CLINICAL PHARMACOLOGY (12.3).]

PREGNANCY

8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, cefuroxime axetil should be used during pregnancy only if clearly needed. Reproduction studies have been performed in mice at doses up to 3,200 mg/kg/day (14 times the recommended maximum human dose based on body surface area) and in rats at doses up to 1,000 mg/kg/day (9 times the recommended maximum human dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to cefuroxime axetil.

NUSRING MOTHERS

8.3 Nursing Mothers Because cefuroxime is excreted in human milk, caution should be exercised when cefuroxime axetil is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Serious hypersensitivity (anaphylactic) reactions: In the event of a serious reaction, discontinue cefuroxime axetil tablets and institute appropriate therapy. (5.1) • Clostridium difficile -associated diarrhea (CDAD): If diarrhea occurs, evaluate patients for CDAD. (5.2) 5.1 Anaphylactic Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on β-lactam antibacterials. These reactions are more likely to occur in individuals with a history of β-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Cefuroxime axetil is contraindicated in patients with a known hypersensitivity to cefuroxime axetil or other β-lactam antibacterial drugs [see CONTRAINDICATIONS (4)]. Before initiating therapy with cefuroxime axetil, inquire about previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, discontinue cefuroxime axetil and institute appropriate therapy. 5.2 Clostridium difficile-associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including cefuroxime axetil, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Potential for Microbial Overgrowth The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. 5.4 Development of Drug-resistant Bacteria Prescribing cefuroxime axetil either in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. 5.6 Interference with Glucose Tests A false-positive result for glucose in the urine may occur with copper reduction tests, and a false-negative result for blood/plasma glucose may occur with ferricyanide tests in subjects receiving cefuroxime axetil [see DRUG INTERACTIONS (7.4)].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Allergic Reactions Inform patients that cefuroxime axetil is a cephalosporin that can cause allergic reactions in some individuals [see WARNINGS AND PRECAUTIONS (5.1)]. Clostridium difficile-associated Diarrhea Inform patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If this occurs, advise patients to contact their physician as soon as possible. Crushing Tablets Instruct patients to swallow the tablet whole, without crushing the tablet. Patients who cannot swallow the tablet whole should receive the oral suspension. Drug Resistance Inform patients that antibacterial drugs, including cefuroxime axetil, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefuroxime axetil is prescribed to treat a bacterial infection, inform patients that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefuroxime axetil or other antibacterial drugs in the future. AUGMENTIN is registered trademarks of the GSK group of companies. Manufactured for: Lupin Pharmaceuticals, Inc. Baltimore, Maryalnd 21202 United States. Manufactured by: Lupin Limited Mandideep 462 046 INDIA. Revised: November 2015 ID#: 243305 Repackaged by Preferred Pharmaceuticals, Inc.

DOSAGE AND ADMINISTRATION

2 •Tablets and oral suspension are not bioequivalent and are therefore not substitutable on a milligram-per-milligram basis. (2.1) •Administer tablets with or without food. (2.2) •Administer cefuroxime axetil tablets USP as described in the dosage guidelines. (2.2) •Dosage adjustment is required for patients with impaired renal function. (2.5) Adult Patients and Pediatric Patients Dosage Guidelines for Cefuroxime Axetil Tablets USP Infection Dosage Duration (Days) Adults and Adolescents (13 years and older) Pharyngitis/tonsillitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial exacerbations of chronic bronchitis (mild to moderate) 250 or 500 mg every 12 hours 10 Secondary bacterial infections of acute bronchitis 250 or 500 mg every 12 hours 5 to 10 Uncomplicated skin and skin-structure infections 250 or 500 mg every 12 hours 10 Uncomplicated urinary tract infections 250 mg every 12 hours 7 to 10 Uncomplicated gonorrhea 1,000 mg single dose Early Lyme disease 500 mg every 12 hours 20 Pediatric Patients younger than 13 years (who can swallow tablets whole) Acute bacterial otitis media 250 mg every 12 hours Acute bacterial maxillary sinusitis 250 mg every 12 hours 2.1 Important Administration Instructions •Cefuroxime axetil tablets USP and cefuroxime axetil for oral suspension are not bioequivalent and are therefore not substitutable on a milligram-per-milligram basis [see CLINICAL PHARMACOLOGY (12.3)] . •Administer cefuroxime axetil tablets USP tablets as described in the appropriate dosage guidelines [see (2.2)]. •Administer cefuroxime axetil tablets USP with or without food. •Pediatric patients (aged 13 years and older) who cannot swallow the cefuroxime axetil tablets USP whole should receive cefuroxime axetil for oral suspension because the tablet has a strong, persistent bitter taste when crushed [see (2.2)]. 2.2 Dosage for cefuroxime axetil tablets USP Administer cefuroxime axetil tablets USP as described in the dosage guidelines table below with or without food. Table 1. Adult Patients and Pediatric Patients Dosage Guidelines for Cefuroxime Axetil Tablets USP Infection Dosage Duration (Days) Adults and Adolescents (13 years and older) Pharyngitis/tonsillitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis (mild to moderate) 250 mg every 12 hours 10 Acute bacterial exacerbations of chronic bronchitis (mild to moderate) 250 or 500 mg every 12 hours 10a Secondary bacterial infections of acute bronchitis 250 or 500 mg every 12 hours 5 to 10 Uncomplicated skin and skin-structure infections 250 or 500 mg every 12 hours 10 Uncomplicated urinary tract infections 250 mg every 12 hours 7 to 10 Uncomplicated gonorrhea 1,000 mg single dose Early Lyme disease 500 mg every 12 hours 20 Pediatric Patients younger than 13 years (who can swallow tablets whole)b Acute bacterial otitis media 250 mg every 12 hours 10 Acute bacterial maxillary sinusitis 250 mg every 12 hours 10 2.5 Dosage in Patients with Impaired Renal Function A dosage interval adjustment is required for patients whose creatinine clearance is <30 mL/min, as listed in Table 4 below, because cefuroxime is eliminated primarily by the kidney [see CLINICAL PHARMACOLOGY (12.3)]. Table 4. Dosing in Adults with Renal Impairment Creatinine Clearance (mL/min) Recommended Dosage ≥30 No dosage adjustment 10 to ˂30 Standard individual dose given every 24 hours ˂10 (without hemodialysis) Standard individual dose given every 48 hours Hemodialysis A single additional standard dose should be given at the end of each dialysis

Guaifenesin 20 MG/ML Oral Solution

Generic Name: GUAIFENESIN

Brand Name: Broncomar SF

Substance Name(s):
GUAIFENESIN

WARNINGS

Warnings Do not exceed recommended dosage

INDICATIONS AND USAGE

Uses Help loosen phlegm (mucus) and thin bronchial secretions to drain bronchial tubes and make cough more productive.

INACTIVE INGREDIENTS

Inactive ingredients Blue cohosh, citric acid, echinacea, eucalyptus oil, ginkgo biloba, glycerin, gold seal root, honey flavor, horehound herb, licorice root, menthol, mullein, myrrh, potassium sorbate, slippery elm bark, sodium benzoate, propylene glycol, water, sodium chloride, sucralose, wild cherry bark and zinc sulfate.

PURPOSE

Purpose Expectorant

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

DOSAGE AND ADMINISTRATION

Directions Do not take more than 6 doses in any 24-hour period Shake well before use Age Dose Adults and children 12 years and over 10 mL (2 tsps) every 4 hours Children 6 to under 12 years of age. 5 mL (1 tsps) every 4 hours Children under 6 years of age Do not use

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use if you have a chronic pulmonary disease or shortness of breath unless directed by a doctor Ask the doctor before use if you have cough that occurs with too much phlegm (mucus) cough that lasts or is chronic such as occurs with smoking, asthma, chronic bronchitis or emphysema

STOP USE

Stop use and ask the doctor if Nervoisness, dizziness or sleeplessness occurs. Cough persists for more than 1 week, tends to recur, or accompanied by fever, rash or persistent headache. A persistent cough may be sign of a serious condition

ACTIVE INGREDIENTS

Acvtive ingredients: (in each 5ml) Purpose Guaifenesin 100 mg …………………………….. Expectorant

SPIRIVA 18 MCG Inhalant Powder Capsule

Generic Name: TIOTROPIUM BROMIDE MONOHYDRATE

Brand Name: Spiriva

Substance Name(s):
TIOTROPIUM BROMIDE MONOHYDRATE

DRUG INTERACTIONS

7 Not recommended for use with other anticholinergics since this has not been studied (7.2) 7.1 Sympathomimetics, Methylxanthines, Steroids SPIRIVA HandiHaler has been used concomitantly with short-acting and long-acting sympathomimetic (beta-agonists) bronchodilators, methylxanthines, and oral and inhaled steroids without increases in adverse drug reactions. 7.2 Anticholinergics The co-administration of SPIRIVA HandiHaler with other anticholinergic-containing drugs (e.g., ipratropium) has not been studied and is therefore not recommended. 7.3 Cimetidine, Ranitidine No clinically significant interaction occurred between tiotropium and cimetidine or ranitidine [ see Clinical Pharmacology (12.3) ].

OVERDOSAGE

10 High doses of tiotropium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a single inhaled dose of up to 282 mcg tiotropium in 6 healthy volunteers. In a study of 12 healthy volunteers, bilateral conjunctivitis and dry mouth were seen following repeated once-daily inhalation of 141 mcg of tiotropium. Accidental Ingestion Acute intoxication by inadvertent oral ingestion of SPIRIVA capsules is unlikely since it is not well-absorbed systemically. A case of overdose has been reported from postmarketing experience. A female patient was reported to have inhaled 30 capsules over a 2.5 day period, and developed altered mental status, tremors, abdominal pain, and severe constipation. The patient was hospitalized, SPIRIVA HandiHaler was discontinued, and the constipation was treated with an enema. The patient recovered and was discharged on the same day. No mortality was observed at inhalation tiotropium doses up to 32.4 mg/kg in mice, 267.7 mg/kg in rats, and 0.6 mg/kg in dogs. These doses correspond to 7300, 120,000, and 850 times the recommended human daily inhalation dose on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.

DESCRIPTION

11 SPIRIVA HandiHaler consists of a capsule dosage form containing a dry powder formulation of tiotropium intended for oral inhalation only with the HandiHaler device. Each light green, hard gelatin SPIRIVA capsule contains 18 mcg tiotropium (equivalent to 22.5 mcg tiotropium bromide monohydrate) blended with lactose monohydrate (which may contain milk proteins) as the carrier. The dry powder formulation within the SPIRIVA capsule is intended for oral inhalation only. The active component of SPIRIVA HandiHaler is tiotropium. The drug substance, tiotropium bromide monohydrate, is an anticholinergic with specificity for muscarinic receptors. It is chemically described as (1α, 2ß, 4ß, 5α, 7ß)-7-[(Hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate. It is a synthetic, non-chiral, quaternary ammonium compound. Tiotropium bromide is a white or yellowish white powder. It is sparingly soluble in water and soluble in methanol. The structural formula is: Tiotropium bromide (monohydrate) has a molecular mass of 490.4 and a molecular formula of C19H22NO4S2Br • H2O. The HandiHaler device is an inhalation device used to inhale the dry powder contained in the SPIRIVA capsule. The dry powder is delivered from the HandiHaler device at flow rates as low as 20 L/min. Under standardized in vitro testing, the HandiHaler device delivers a mean of 10.4 mcg tiotropium when tested at a flow rate of 39 L/min for 3.1 seconds (2 L total). In a study of 26 adult patients with COPD and severely compromised lung function [mean FEV1 1.02 L (range 0.45 to 2.24 L); 37.6% of predicted (range 16% to 65%)], the median peak inspiratory flow (PIF) through the HandiHaler device was 30.0 L/min (range 20.4 to 45.6 L/min). The amount of drug delivered to the lungs will vary depending on patient factors such as inspiratory flow and peak inspiratory flow through the HandiHaler device, which may vary from patient to patient, and may vary with the exposure time of the SPIRIVA capsule outside the blister pack. SPIRIVA Structure

CLINICAL STUDIES

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6-Month to 1-Year Trials The data described below reflect exposure to SPIRIVA HandiHaler in 2663 patients. SPIRIVA HandiHaler was studied in two 1-year placebo-controlled trials, two 1-year active-controlled trials, and two 6-month placebo-controlled trials in patients with COPD. In these trials, 1308 patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a day. The population had an age ranging from 39 to 87 years with 65% to 85% males, 95% Caucasian, and had COPD with a mean pre-bronchodilator forced expiratory volume in one second (FEV1) percent predicted of 39% to 43%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. An additional 6-month trial conducted in a Veteran’s Affairs setting is not included in this safety database because only serious adverse events were collected. The most commonly reported adverse drug reaction was dry mouth. Dry mouth was usually mild and often resolved during continued treatment. Other reactions reported in individual patients and consistent with possible anticholinergic effects included constipation, tachycardia, blurred vision, glaucoma (new onset or worsening), dysuria, and urinary retention. Four multicenter, 1-year, placebo-controlled and active-controlled trials evaluated SPIRIVA HandiHaler in patients with COPD. Table 1 shows all adverse reactions that occurred with a frequency of ≥3% in the SPIRIVA HandiHaler group in the 1-year placebo-controlled trials where the rates in the SPIRIVA HandiHaler group exceeded placebo by ≥1%. The frequency of corresponding reactions in the ipratropium-controlled trials is included for comparison. Table 1 Adverse Reactions (% Patients) in One-Year COPD Clinical Trials Body System (Event) Placebo-Controlled Trials Ipratropium-Controlled Trials SPIRIVA (n = 550) Placebo (n = 371) SPIRIVA (n = 356) Ipratropium (n = 179) Body as a Whole Chest Pain (non-specific) 7 5 5 2 Edema, Dependent 5 4 3 5 Gastrointestinal System Disorders Dry Mouth 16 3 12 6 Dyspepsia 6 5 1 1 Abdominal Pain 5 3 6 6 Constipation 4 2 1 1 Vomiting 4 2 1 2 Musculoskeletal System Myalgia 4 3 4 3 Resistance Mechanism Disorders Infection 4 3 1 3 Moniliasis 4 2 3 2 Respiratory System (Upper) Upper Respiratory Tract Infection 41 37 43 35 Sinusitis 11 9 3 2 Pharyngitis 9 7 7 3 Rhinitis 6 5 3 2 Epistaxis 4 2 1 1 Skin and Appendage Disorders Rash 4 2 2 2 Urinary System Urinary Tract Infection 7 5 4 2 Arthritis, coughing, and influenza-like symptoms occurred at a rate of ≥3% in the SPIRIVA HandiHaler treatment group, but were <1% in excess of the placebo group. Other reactions that occurred in the SPIRIVA HandiHaler group at a frequency of 1% to 3% in the placebo-controlled trials where the rates exceeded that in the placebo group include: Body as a Whole: allergic reaction, leg pain; Central and Peripheral Nervous System: dysphonia, paresthesia; Gastrointestinal System Disorders: gastrointestinal disorder not otherwise specified (NOS), gastroesophageal reflux, stomatitis (including ulcerative stomatitis); Metabolic and Nutritional Disorders: hypercholesterolemia, hyperglycemia; Musculoskeletal System Disorders: skeletal pain; Cardiac Events: angina pectoris (including aggravated angina pectoris); Psychiatric Disorder: depression; Infections: herpes zoster; Respiratory System Disorder (Upper): laryngitis; Vision Disorder: cataract. In addition, among the adverse reactions observed in the clinical trials with an incidence of <1% were atrial fibrillation, supraventricular tachycardia, angioedema, and urinary retention. In the 1-year trials, the incidence of dry mouth, constipation, and urinary tract infection increased with age [ see Use in Specific Populations (8.5) ]. Two multicenter, 6-month, controlled studies evaluated SPIRIVA HandiHaler in patients with COPD. The adverse reactions and the incidence rates were similar to those seen in the 1-year controlled trials. 4-Year Trial The data described below reflect exposure to SPIRIVA HandiHaler in 5992 COPD patients in a 4-year placebo-controlled trial. In this trial, 2986 patients were treated with SPIRIVA HandiHaler at the recommended dose of 18 mcg once a day. The population had an age range from 40 to 88 years, was 75% male, 90% Caucasian, and had COPD with a mean pre-bronchodilator FEV1 percent predicted of 40%. Patients with narrow-angle glaucoma, or symptomatic prostatic hypertrophy or bladder outlet obstruction were excluded from these trials. When the adverse reactions were analyzed with a frequency of ≥3% in the SPIRIVA HandiHaler group where the rates in the SPIRIVA HandiHaler group exceeded placebo by ≥1%, adverse reactions included (SPIRIVA HandiHaler, placebo): pharyngitis (12.5%, 10.8%), sinusitis (6.5%, 5.3%), headache (5.7%, 4.5%), constipation (5.1%, 3.7%), dry mouth (5.1%, 2.7%), depression (4.4%, 3.3%), insomnia (4.4%, 3.0%), and arthralgia (4.2%, 3.1%). Additional Adverse Reactions Other adverse reactions not previously listed that were reported more frequently in COPD patients treated with SPIRIVA HandiHaler than placebo include: dehydration, skin ulcer, stomatitis, gingivitis, oropharyngeal candidiasis, dry skin, skin infection, and joint swelling.

HOW SUPPLIED

16 /STORAGE AND HANDLING SPIRIVA HandiHaler consists of SPIRIVA capsules and the HandiHaler device. SPIRIVA capsules contain 18 mcg of tiotropium and are light green, with the Boehringer Ingelheim company logo on the SPIRIVA capsule cap and TI 01 on the SPIRIVA capsule body, or vice versa. The HandiHaler device is gray colored with a green piercing button. It is imprinted with SPIRIVA HandiHaler (tiotropium bromide inhalation powder), the Boehringer Ingelheim company logo, and the Pfizer company logo. It is also imprinted to indicate that SPIRIVA capsules should not be stored in the HandiHaler device and that the HandiHaler device is only to be used with SPIRIVA capsules. SPIRIVA capsules are packaged in an aluminum/aluminum blister card and joined along a perforated-cut line. SPIRIVA capsules should always be stored in the blister and only removed immediately before use. The drug should be used immediately after the packaging over an individual SPIRIVA capsule is opened. The following packages are available: carton containing 6 SPIRIVA capsules (5 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 54868-5109-0) carton containing 90 SPIRIVA capsules (9 unit-dose blister cards) and 1 HandiHaler inhalation device (NDC 54868-5109-1) Storage Store at 25°C (77°F); excursions permitted to 15°–30°C (59°–86°F) [see USP Controlled Room Temperature]. The SPIRIVA capsules should not be exposed to extreme temperature or moisture. Do not store SPIRIVA capsules in the HandiHaler device.

RECENT MAJOR CHANGES

Indications and Usage (1) 12/2009 Dosage and Administration (2) 12/2009 Contraindications (4) 12/2009 Warnings and Precautions, Immediate Hypersensitivity Reactions (5.2) 12/2009 Worsening of Narrow-Angle Glaucoma (5.4) 12/2009 Worsening of Urinary Retention (5.5) 12/2009 Renal Impairment (5.6) 12/2009

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients who received SPIRIVA HandiHaler in the 1-year clinical trials, 426 were <65 years, 375 were 65 to 74 years, and 105 were ≥75 years of age. Within each age subgroup, there were no differences between the proportion of patients with adverse events in the SPIRIVA HandiHaler and the comparator groups for most events. Dry mouth increased with age in the SPIRIVA HandiHaler group (differences from placebo were 9.0%, 17.1%, and 16.2% in the aforementioned age subgroups). A higher frequency of constipation and urinary tract infections with increasing age was observed in the SPIRIVA HandiHaler group in the placebo-controlled studies. The differences from placebo for constipation were 0%, 1.8%, and 7.8% for each of the age groups. The differences from placebo for urinary tract infections were –0.6%, 4.6%, and 4.5%. No overall differences in effectiveness were observed among these groups. Based on available data, no adjustment of SPIRIVA HandiHaler dosage in geriatric patients is warranted [ see Clinical Pharmacology (12.3) ].

DOSAGE FORMS AND STRENGTHS

3 SPIRIVA HandiHaler consists of SPIRIVA capsules and a HandiHaler device. SPIRIVA capsules contain 18 mcg dry powder formulation of tiotropium in a light green, hard gelatin capsule with TI 01 printed on one side and Boehringer Ingelheim company logo on the other side. Supplied with a HandiHaler device. SPIRIVA capsules for oral inhalation: 18 mcg tiotropium powder, for use with HandiHaler device (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Tiotropium is a long-acting, antimuscarinic agent, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors, M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3-receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine-induced bronchoconstriction effects was dose-dependent and lasted longer than 24 hours. The bronchodilation following inhalation of tiotropium is predominantly a site-specific effect.

INDICATIONS AND USAGE

1 SPIRIVA HandiHaler (tiotropium bromide inhalation powder) is indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. SPIRIVA HandiHaler is indicated to reduce exacerbations in COPD patients. SPIRIVA HandiHaler is an anticholinergic indicated for the long-term, once-daily, maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), and for reducing COPD exacerbations (1)

PEDIATRIC USE

8.4 Pediatric Use SPIRIVA HandiHaler is approved for use in the maintenance treatment of bronchospasm associated with COPD and for the reduction of COPD exacerbations. COPD does not normally occur in children. The safety and effectiveness of SPIRIVA HandiHaler in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Teratogenic Effects, Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. SPIRIVA HandiHaler should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No evidence of structural alterations was observed in rats and rabbits at inhalation tiotropium doses of up to approximately 660 and 6 times the recommended human daily inhalation dose (RHDID) on a mg/m2 basis, respectively. However, in rats, tiotropium caused fetal resorption, litter loss, decreases in the number of live pups at birth and the mean pup weights, and a delay in pup sexual maturation at inhalation tiotropium doses of approximately 35 times the RHDID on a mg/m2 basis. In rabbits, tiotropium caused an increase in post-implantation loss at an inhalation dose of approximately 360 times the RHDID on a mg/m2 basis. Such effects were not observed at inhalation doses of approximately 4 and 80 times the RHDID on a mg/m2 basis, respectively. These dose multiples may be over-estimated due to difficulties in measuring deposited doses in animal inhalation studies.

NUSRING MOTHERS

8.3 Nursing Mothers Clinical data from nursing women exposed to tiotropium are not available. Based on lactating rodent studies, tiotropium is excreted into breast milk. It is not known whether tiotropium is excreted in human milk, but because many drugs are excreted in human milk and given these findings in rats, caution should be exercised if SPIRIVA HandiHaler is administered to a nursing woman.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Not for acute use: Not for use as a rescue medication (5.1) Immediate hypersensitivity reactions: Discontinue SPIRIVA HandiHaler at once and consider alternatives if immediate hypersensitivity reactions, including angioedema, occur. Use with caution in patients with severe hypersensitivity to milk proteins. (5.2) Paradoxical bronchospasm: Discontinue SPIRIVA HandiHaler and consider other treatments if paradoxical bronchospasm occurs (5.3) Worsening of narrow-angle glaucoma may occur. Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if this occurs. (5.4) Worsening of urinary retention may occur. Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if this occurs. (5.5) 5.1 Not for Acute Use SPIRIVA HandiHaler is intended as a once-daily maintenance treatment for COPD and is not indicated for the initial treatment of acute episodes of bronchospasm (i.e., rescue therapy). 5.2 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions, including angioedema (including swelling of the lips, tongue, or throat), itching, or rash may occur after administration of SPIRIVA HandiHaler. If such a reaction occurs, therapy with SPIRIVA HandiHaler should be stopped at once and alternative treatments should be considered. Given the similar structural formula of atropine to tiotropium, patients with a history of hypersensitivity reactions to atropine should be closely monitored for similar hypersensitivity reactions to SPIRIVA HandiHaler. In addition, SPIRIVA HandiHaler should be used with caution in patients with severe hypersensitivity to milk proteins. 5.3 Paradoxical Bronchospasm Inhaled medicines, including SPIRIVA HandiHaler, may cause paradoxical bronchospasm. If this occurs, treatment with SPIRIVA HandiHaler should be stopped and other treatments considered. 5.4 Worsening of Narrow-Angle Glaucoma SPIRIVA HandiHaler should be used with caution in patients with narrow-angle glaucoma. Prescribers and patients should be alert for signs and symptoms of acute narrow-angle glaucoma (e.g., eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.5 Worsening of Urinary Retention SPIRIVA HandiHaler should be used with caution in patients with urinary retention. Prescribers and patients should be alert for signs and symptoms of prostatic hyperplasia or bladder-neck obstruction (e.g., difficulty passing urine, painful urination). Instruct patients to consult a physician immediately should any of these signs or symptoms develop. 5.6 Renal Impairment As a predominantly renally excreted drug, patients with moderate to severe renal impairment (creatinine clearance of ≤50 mL/min) treated with SPIRIVA HandiHaler should be monitored closely for anticholinergic side effects [ see Clinical Pharmacology (12.3) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved Patient Labeling (17.6) 17.1 Instructions for Administering SPIRIVA HandiHaler It is important for patients to understand how to correctly administer SPIRIVA capsules using the HandiHaler device [ see Patient Counseling Information (17.6) ]. Patients should be instructed that SPIRIVA capsules should only be administered via the HandiHaler device and the HandiHaler device should not be used for administering other medications. The contents of SPIRIVA capsules are for oral inhalation only and must not be swallowed . SPIRIVA capsules should always be stored in sealed blisters. Only one SPIRIVA capsule should be removed immediately before use or its effectiveness may be reduced. Additional SPIRIVA capsules that are exposed to air (i.e., not intended for immediate use) should be discarded. 17.2 Paradoxical Bronchospasm Patients should be informed that SPIRIVA HandiHaler can produce paradoxical bronchospasm. If paradoxical bronchospasm occurs, patients should discontinue SPIRIVA HandiHaler. 17.3 Urinary Retention Difficulty passing urine and dysuria may be symptoms of new or worsening prostatic hyperplasia or bladder outlet obstruction. Patients should be instructed to consult a physician immediately should any of these signs or symptoms develop. 17.4 Visual Effects Eye pain or discomfort, blurred vision, visual halos or colored images in association with red eyes from conjunctival congestion and corneal edema may be signs of acute narrow-angle glaucoma. Patients should be told to consult a physician immediately should any of these signs and symptoms develop. Miotic eye drops alone are not considered to be effective treatment. Patients should be told that care must be taken not to allow the powder to enter into the eyes as this may cause blurring of vision and pupil dilation. 17.5 Acute Exacerbation Patients should understand that SPIRIVA HandiHaler is a once-daily maintenance bronchodilator and should not be used for immediate relief of breathing problems (i.e., as a rescue medication). 17.6 FDA-approved Patient Labeling Patient Information and Patient’s Instructions for Use are supplied as tear-off leaflets following the full prescribing information and should be dispensed with each new prescription and refill. Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA Marketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Pfizer Inc New York, NY 10017 USA Licensed from: Boehringer Ingelheim International GmbH Address medical inquiries to: (800) 542-6257 or (800) 459-9906 TTY. SPIRIVA® and HandiHaler® are registered trademarks and are used under license from Boehringer Ingelheim International GmbH. ©Copyright 2009 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVED SPIRIVA® (tiotropium bromide inhalation powder) is covered by U.S. Patent Nos. RE38,912, RE39,820, 5,478,578, 6,777,423, 6,908,928, 7,070,800, and 7,309,707 with other patents pending. The HandiHaler® inhalation device is covered by U.S. Design Patent No. D355,029 with other patents pending. Rev: December 2009 IT1600WL1609 10004551/07 65626-08 Relabeling of “Additional Barcode” by: Physicians Total Care, Inc. Tulsa, OK 74146

DOSAGE AND ADMINISTRATION

2 DO NOT SWALLOW SPIRIVA CAPSULES FOR USE WITH HANDIHALER DEVICE ONLY FOR ORAL INHALATION ONLY SPIRIVA capsules must not be swallowed as the intended effects on the lungs will not be obtained. The contents of the SPIRIVA capsules are only for oral inhalation and should only be used with the HandiHaler device [ see Overdosage (10) ]. The recommended dose of SPIRIVA HandiHaler is two inhalations of the powder contents of one SPIRIVA capsule, once-daily, with the HandiHaler device [ see Patient Counseling Information (17.6) ]. For administration of SPIRIVA HandiHaler, a SPIRIVA capsule is placed into the center chamber of the HandiHaler device. The SPIRIVA capsule is pierced by pressing and releasing the green piercing button on the side of the HandiHaler device. The tiotropium formulation is dispersed into the air stream when the patient inhales through the mouthpiece [ see Patient Counseling Information (17.6) ]. No dosage adjustment is required for geriatric, hepatically-impaired, or renally-impaired patients. However, patients with moderate to severe renal impairment given SPIRIVA HandiHaler should be monitored closely for anticholinergic effects [ see Warnings and Precautions (5.6), Use in Specific Populations (8.5, 8.6, 8.7), and Clinical Pharmacology (12.3) ]. DO NOT swallow SPIRIVA capsules (2) For Use with the HandiHaler Device ONLY (2) For Oral Inhalation ONLY (2) Two inhalations of the powder contents of a single SPIRIVA capsule (18 mcg) once daily (2)

Warfarin Sodium 5 MG Oral Tablet

Generic Name: WARFARIN SODIUM

Brand Name: Warfarin Sodium

Substance Name(s):
WARFARIN SODIUM

DRUG INTERACTIONS

7 Drugs may interact with warfarin sodium through pharmacodynamic or pharmacokinetic mechanisms. Pharmacodynamic mechanisms for drug interactions with warfarin sodium are synergism (impaired hemostasis, reduced clotting factor synthesis), competitive antagonism (vitamin K), and alteration of the physiologic control loop for vitamin K metabolism (hereditary resistance). Pharmacokinetic mechanisms for drug interactions with warfarin sodium are mainly enzyme induction, enzyme inhibition, and reduced plasma protein binding. It is important to note that some drugs may interact by more than one mechanism. More frequent INR monitoring should be performed when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs, including drugs intended for short-term use (e.g., antibiotics, antifungals, corticosteroids) [see Boxed Warning ]. Consult the labeling of all concurrently used drugs to obtain further information about interactions with warfarin sodium or adverse reactions pertaining to bleeding. Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding. (7) Inhibitors and inducers of CYP2C9, 1A2, or 3A4: May alter warfarin exposure. Monitor INR closely when any such drug is used with warfarin sodium. (7.1) Drugs that increase bleeding risk: Closely monitor patients receiving any such drug (e.g., other anticoagulants, antiplatelet agents, nonsteroidal anti-inflammatory drugs, serotonin reuptake inhibitors). (7.2) Antibiotics and antifungals: Closely monitor INR when initiating or stopping an antibiotic or antifungal course of therapy. (7.3) Botanical (herbal) products: Some may influence patient response to warfarin sodium necessitating close INR monitoring. (7.4) 7.1 CYP450 Interactions CYP450 isozymes involved in the metabolism of warfarin include CYP2C9, 2C19, 2C8, 2C18, 1A2, and 3A4. The more potent warfarin S-enantiomer is metabolized by CYP2C9 while the R-enantiomer is metabolized by CYP1A2 and 3A4. Inhibitors of CYP2C9, 1A2, and/or 3A4 have the potential to increase the effect (increase INR) of warfarin by increasing the exposure of warfarin. Inducers of CYP2C9, 1A2, and/or 3A4 have the potential to decrease the effect (decrease INR) of warfarin by decreasing the exposure of warfarin. Examples of inhibitors and inducers of CYP2C9, 1A2, and 3A4 are below in Table 2; however, this list should not be considered all-inclusive. Consult the labeling of all concurrently used drugs to obtain further information about CYP450 interaction potential. The CYP450 inhibition and induction potential should be considered when starting, stopping, or changing dose of concomitant mediations. Closely monitor INR if a concomitant drug is a CYP2C9, 1A2, and/or 3A4 inhibitor or inducer. Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.2 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3. Because bleeding risk is increased when these drugs are used concomitantly with warfarin, closely monitor patients receiving any such drug with warfarin. Table 3: Drugs that Can Increase the Risk of Bleeding Drug Class Specific Drugs Anticoagulants argatroban, dabigatran, bivalirudin, desirudin, heparin, lepirudin Antiplatelet Agents aspirin, cilostazol, clopidogrel, dipyridamole, prasugrel, ticlopidine Nonsteroidal Anti-Inflammatory Agents celecoxib, diclofenac, diflunisal, fenoprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, oxaprozin, piroxicam, sulindac Serotonin Reuptake Inhibitors citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, paroxetine, sertraline, venlafaxine, vilazodone 7.3 Antibiotics and Antifungals There have been reports of changes in INR in patients taking warfarin and antibiotics or antifungals, but clinical pharmacokinetic studies have not shown consistent effects of these agents on plasma concentrations of warfarin. Closely monitor INR when starting or stopping any antibiotic or antifungal in patients taking warfarin. 7.4 Botanical (Herbal) Products and Foods Exercise caution when botanical (herbal) products are taken concomitantly with warfarin sodium. Few adequate, well-controlled studies evaluating the potential for metabolic and/or pharmacologic interactions between botanicals and warfarin sodium exist. Due to a lack of manufacturing standardization with botanical medicinal preparations, the amount of active ingredients may vary. This could further confound the ability to assess potential interactions and effects on anticoagulation. Some botanicals may cause bleeding events when taken alone (e.g., garlic and Ginkgo biloba) and may have anticoagulant, antiplatelet, and/or fibrinolytic properties. These effects would be expected to be additive to the anticoagulant effects of warfarin sodium. Conversely, some botanicals may decrease the effects of warfarin sodium (e.g., co-enzyme Q10, St. John’s wort ginseng). Some botanicals and foods can interact with warfarin sodium through CYP450 interactions (e.g., echinacea, grapefruit juice, ginkgo, goldenseal, St. John’s wort). Monitor the patient’s response with additional INR determinations when initiating or discontinuing any botanicals.

OVERDOSAGE

10 10.1 Signs and Symptoms Bleeding (e.g., appearance of blood in stools or urine, hematuria, excessive menstrual bleeding, melena, petechiae, excessive bruising or persistent oozing from superficial injuries, unexplained fall in hemoglobin) is a manifestation of excessive anticoagulation. 10.2 Treatment The treatment of excessive anticoagulation is based on the level of the INR, the presence or absence of bleeding, and clinical circumstances. Reversal of warfarin sodium anticoagulation may be obtained by discontinuing warfarin sodium therapy and, if necessary, by administration of oral or parenteral vitamin K1. The use of vitamin K1 reduces response to subsequent warfarin sodium therapy and patients may return to a pretreatment thrombotic status following the rapid reversal of a prolonged INR. Resumption of warfarin sodium administration reverses the effect of vitamin K, and a therapeutic INR can again be obtained by careful dosage adjustment. If rapid re-anticoagulation is indicated, heparin may be preferable for initial therapy. Prothrombin complex concentrate (PCC), fresh frozen plasma, or activated Factor VII treatment may be considered if the requirement to reverse the effects of warfarin sodium is urgent. A risk of hepatitis and other viral diseases is associated with the use of blood products; PCC and activated Factor VII are also associated with an increased risk of thrombosis. Therefore, these preparations should be used only in exceptional or life-threatening bleeding episodes secondary to warfarin sodium overdosage.

DESCRIPTION

11 Warfarin sodium is an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors. Chemically, it is 3-(α-acetonylbenzyl)-4-hydroxycoumarin and is a racemic mixture of the R- and S-enantiomers. Crystalline warfarin sodium is an isopropanol clathrate. Its empirical formula is C19H15NaO4, and its structural formula is represented by the following: Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and ether. Warfarin Sodium Tablets, USP for oral use also contain: All strengths: Anhydrous lactose, corn starch, and magnesium stearate 1 mg: D&C Red No. 6 Barium Lake. 2 mg: FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake. 2.5 mg: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake. 3 mg: D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake. 4 mg: FD&C Blue No. 1 Aluminum Lake. 5 mg: D&C Red No. 6 Barium Lake, D&C Yellow No. 10 Aluminum Lake. 6 mg: D&C Yellow No.10 Aluminum Lake, FD&C Blue No.2 Aluminum Lake. 7.5 mg: D&C Yellow No. 10 Aluminum Lake. 10 mg: Dye Free Chemical Structure

CLINICAL STUDIES

14 14.1 Atrial Fibrillation In five prospective, randomized, controlled clinical trials involving 3711 patients with nonrheumatic AF, warfarin significantly reduced the risk of systemic thromboembolism including stroke (see Table 4). The risk reduction ranged from 60% to 86% in all except one trial (CAFA: 45%), which was stopped early due to published positive results from two of these trials. The incidence of major bleeding in these trials ranged from 0.6% to 2.7% (see Table 4). Table 4: Clinical Studies of Warfarin in Non-Rheumatic AF PatientsAll study results of warfarin vs. control are based on intention-to-treat analysis and include ischemic stroke and systemic thromboembolism, excluding hemorrhagic stroke and transient ischemic attacks. N Thromboembolism % Major Bleeding Study Warfarin-Treated Patients Control Patients PT Ratio INR % Risk Reduction p-value Warfarin-Treated Patients Control Patients AFASAK 335 336 1.5-2.0 2.8-4.2 60 0.027 0.6 0.0 SPAF 210 211 1.3-1.8 2.0-4.5 67 0.01 1.9 1.9 BAATAF 212 208 1.2-1.5 1.5-2.7 86 <0.05 0.9 0.5 CAFA 187 191 1.3-1.6 2.0-3.0 45 0.25 2.7 0.5 SPINAF 260 265 1.2-1.5 1.4-2.8 79 0.001 2.3 1.5 Trials in patients with both AF and mitral stenosis suggest a benefit from anticoagulation with warfarin sodium [see Dosage and Administration (2.2) ]. 14.2 Mechanical and Bioprosthetic Heart Valves In a prospective, randomized, open-label, positive-controlled study in 254 patients with mechanical prosthetic heart valves, the thromboembolic-free interval was found to be significantly greater in patients treated with warfarin alone compared with dipyridamole/aspirin-treated patients (p<0.005) and pentoxifylline/aspirin-treated patients (p<0.05). The results of this study are presented in Table 5. Table 5: Prospective, Randomized, Open-Label, Positive-Controlled Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Patients Treated With Event Warfarin Dipyridamole/ Aspirin Pentoxifylline/ Aspirin py= patient years Thromboembolism 2.2/100 py 8.6/100 py 7.9/100 py Major Bleeding 2.5/100 py 0.0/100 py 0.9/100 py In a prospective, open-label, clinical study comparing moderate (INR 2.65) vs. high intensity (INR 9.0) warfarin therapies in 258 patients with mechanical prosthetic heart valves, thromboembolism occurred with similar frequency in the two groups (4.0 and 3.7 events per 100 patient years, respectively). Major bleeding was more common in the high intensity group. The results of this study are presented in Table 6. Table 6: Prospective, Open-Label Clinical Study of Warfarin in Patients with Mechanical Prosthetic Heart Valves Event Moderate Warfarin Therapy INR 2.65 High Intensity Warfarin Therapy INR 9.0 py= patient years Thromboembolism 4.0/100 py 3.7/100 py Major Bleeding 0.95/100 py 2.1/100 py In a randomized trial in 210 patients comparing two intensities of warfarin therapy (INR 2.0-2.25 vs. INR 2.5-4.0) for a three-month period following tissue heart valve replacement, thromboembolism occurred with similar frequency in the two groups (major embolic events 2.0% vs. 1.9%, respectively, and minor embolic events 10.8% vs. 10.2%, respectively). Major hemorrhages occurred in 4.6% of patients in the higher intensity INR group compared to zero in the lower intensity INR group. 14.3 Myocardial Infarction WARIS (The Warfarin Re-Infarction Study) was a double-blind, randomized study of 1214 patients 2 to 4 weeks post-infarction treated with warfarin to a target INR of 2.8 to 4.8. The primary endpoint was a composite of total mortality and recurrent infarction. A secondary endpoint of cerebrovascular events was assessed. Mean follow-up of the patients was 37 months. The results for each endpoint separately, including an analysis of vascular death, are provided in Table 7: Table 7: WARIS – Endpoint Analysis of Separate Events Event Warfarin (N=607) Placebo (N=607) RR (95% CI) % Risk Reduction (p-value) RR=Relative risk; Risk reduction=(1-RR); CI=Confidence interval; MI=Myocardial infarction; py=patient years Total Patient Years of Follow-up 2018 1944 Total Mortality 94 (4.7/100 py) 123 (6.3/100 py) 0.76 (0.60, 0.97) 24 (p=0.030) Vascular Death 82 (4.1/100 py) 105 (5.4/100 py) 0.78 (0.60, 1.02) 22 (p=0.068) Recurrent MI 82 (4.1/100 py) 124 (6.4/100 py) 0.66 (0.51, 0.85) 34 (p=0.001) Cerebrovascular Event 20 (1.0/100 py) 44 (2.3/100 py) 0.46 (0.28, 0.75) 54 (p=0.002) WARIS II (The Warfarin, Aspirin, Re-Infarction Study) was an open-label, randomized study of 3630 patients hospitalized for acute myocardial infarction treated with warfarin to a target INR 2.8 to 4.2, aspirin 160 mg per day, or warfarin to a target INR 2.0 to 2.5 plus aspirin 75 mg per day prior to hospital discharge. The primary endpoint was a composite of death, nonfatal reinfarction, or thromboembolic stroke. The mean duration of observation was approximately 4 years. The results for WARIS II are provided in the Table 8. Table 8: WARIS II – Distribution of Events According to Treatment Group Event Aspirin (N=1206) Warfarin (N=1216) Aspirin plus Warfarin (N=1208) Rate Ratio (95% CI) p-value CI=confidence interval ND=not determined No. of Events Major BleedingMajor bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion. 8 33 28 3.35The rate ratio is for aspirin plus warfarin as compared with aspirin. (ND) 4.00The rate ratio is for warfarin as compared with aspirin. (ND) ND ND Minor BleedingMinor bleeding episodes were defined as non-cerebral hemorrhage not necessitating surgical intervention or blood transfusion. 39 103 133 3.21 (ND) 2.55 (ND) ND ND Composite EndpointsIncludes death, nonfatal reinfarction, and thromboembolic cerebral stroke. 241 203 181 0.81 (0.69-0.95) 0.71 (0.60-0.83) 0.03 0.001 Reinfarction 117 90 69 0.56 (0.41-0.78) 0.74 (0.55-0.98) <0.001 0.03 Thromboembolic Stroke 32 17 17 0.52 (0.28-0.98) 0.52 (0.28-0.97) 0.03 0.03 Death 92 96 95 0.82 There were approximately four times as many major bleeding episodes in the two groups receiving warfarin than in the group receiving aspirin alone. Major bleeding episodes were not more frequent among patients receiving aspirin plus warfarin than among those receiving warfarin alone, but the incidence of minor bleeding episodes was higher in the combined therapy group.

HOW SUPPLIED

16 /STORAGE AND HANDLING Tablets Warfarin Sodium Tablets, USP are single scored, flat beveled capsule shaped tablets, engraved numerically with 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 on one side and engraved with “WARFARIN” on top of “TARO” on the other side. They are packaged with potencies and colors as follows: Bottles of 100 Bottles of 1000 Bottles of 5000 Cartons of 100 10×10 blister packs 1 mg Pink NDC 51672-4027-1 NDC 51672-4027-3 NDC 51672-4027-7 NDC 51672-4027-0 2 mg Lavender NDC-51672-4028-1 NDC-51672-4028-3 NDC-51672-4028-7 NDC-51672-4028-0 2.5 mg Green NDC 51672-4029-1 NDC 51672-4029-3 NDC 51672-4029-7 NDC 51672-4029-0 3 mg Tan NDC 51672-4030-1 NDC 51672-4030-3 NDC 51672-4030-7 NDC 51672-4030-0 4 mg Blue NDC 51672-4031-1 NDC 51672-4031-3 NDC 51672-4031-7 NDC 51672-4031-0 5 mg Peach NDC 51672-4032-1 NDC 51672-4032-3 NDC 51672-4032-7 NDC 51672-4032-0 6 mg Teal NDC 51672-4033-1 NDC 51672-4033-3 NDC 51672-4033-7 NDC 51672-4033-0 7.5 mg Yellow NDC 51672-4034-1 NDC 51672-4034-3 NDC 51672-4034-0 10 mg White (dye free) NDC 51672-4035-1 NDC 51672-4035-3 NDC 51672-4035-0 Protect from light and moisture. Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP. Store the unit-dose blister packages in the carton until contents have been used.

RECENT MAJOR CHANGES

Contraindications (4) 10/2011 Warnings and Precautions, Use in Pregnant Women with Mechanical Heart Valves (5.5) 10/2011

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients receiving warfarin sodium in controlled clinical trials for which data were available for analysis, 1885 patients (24.4%) were 65 years and older, while 185 patients (2.4%) were 75 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Patients 60 years or older appear to exhibit greater than expected INR response to the anticoagulant effects of warfarin [see Clinical Pharmacology (12.3) ]. Warfarin sodium is contraindicated in any unsupervised patient with senility. Observe caution with administration of warfarin sodium to elderly patients in any situation or with any physical condition where added risk of hemorrhage is present. Consider lower initiation and maintenance doses of warfarin sodium in elderly patients [see Dosage and Administration (2.2, 2.3) ].

DOSAGE FORMS AND STRENGTHS

3 Warfarin Sodium Tablets, USP are single scored, engraved numerically with 1, 2, 2½, 3, 4, 5, 6, 7½, or 10 on one side, and engraved with “WARFARIN” on top of “TARO” on the other side. Warfarin Sodium Tablets, USP are supplied in the following strengths: Warfarin Sodium Tablets, USP Strength Color 1 mg pink 2 mg lavender 2.5 mg green 3 mg tan 4 mg blue 5 mg peach 6 mg teal 7.5 mg yellow 10 mg white (dye-free) Scored tablets: 1, 2, 2-1/2, 3, 4, 5, 6, 7-1/2, or 10 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Warfarin acts by inhibiting the synthesis of vitamin K-dependent clotting factors, which include Factors II, VII, IX, and X, and the anticoagulant proteins C and S. Vitamin K is an essential cofactor for the post ribosomal synthesis of the vitamin K-dependent clotting factors. Vitamin K promotes the biosynthesis of γ-carboxyglutamic acid residues in the proteins that are essential for biological activity. Warfarin is thought to interfere with clotting factor synthesis by inhibition of the C1 subunit of vitamin K epoxide reductase (VKORC1) enzyme complex, thereby reducing the regeneration of vitamin K1 epoxide [see Clinical Pharmacology (12.5) ].

INDICATIONS AND USAGE

1 Warfarin sodium tablets, USP are indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (PE). Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation (AF) and/or cardiac valve replacement. Reduction in the risk of death, recurrent myocardial infarction (MI), and thromboembolic events such as stroke or systemic embolization after myocardial infarction. Warfarin sodium is a vitamin K antagonist indicated for: Prophylaxis and treatment of venous thrombosis and its extension, pulmonary embolism (1) Prophylaxis and treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement (1) Reduction in the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction (1) Limitation of Use Warfarin sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. (1) Limitations of Use Warfarin sodium has no direct effect on an established thrombus, nor does it reverse ischemic tissue damage. Once a thrombus has occurred, however, the goals of anticoagulant treatment are to prevent further extension of the formed clot and to prevent secondary thromboembolic complications that may result in serious and possibly fatal sequelae.

PEDIATRIC USE

8.4 Pediatric Use Adequate and well-controlled studies with warfarin sodium have not been conducted in any pediatric population, and the optimum dosing, safety, and efficacy in pediatric patients is unknown. Pediatric use of warfarin sodium is based on adult data and recommendations, and available limited pediatric data from observational studies and patient registries. Pediatric patients administered warfarin sodium should avoid any activity or sport that may result in traumatic injury. The developing hemostatic system in infants and children results in a changing physiology of thrombosis and response to anticoagulants. Dosing of warfarin in the pediatric population varies by patient age, with infants generally having the highest, and adolescents having the lowest milligram per kilogram dose requirements to maintain target INRs. Because of changing warfarin requirements due to age, concomitant medications, diet, and existing medical condition, target INR ranges may be difficult to achieve and maintain in pediatric patients, and more frequent INR determinations are recommended. Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries. Infants and children receiving vitamin K-supplemented nutrition, including infant formulas, may be resistant to warfarin therapy, while human milk-fed infants may be sensitive to warfarin therapy.

PREGNANCY

8.1 Pregnancy Pregnancy Category D for women with mechanical heart valves [see Warnings and Precautions (5.5) ] and Pregnancy Category X for other pregnant populations [see Contraindications (4) ]. Warfarin Sodium Tablets, USP are contraindicated in women who are pregnant except in pregnant women with mechanical heart valves, who are at high risk of thromboembolism, and for whom the benefits of warfarin sodium may outweigh the risks. Warfarin sodium can cause fetal harm when administered to a pregnant woman. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy), fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. The reproductive and developmental effects of warfarin sodium have not been evaluated in animals. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. In humans, warfarin crosses the placenta, and concentrations in fetal plasma approach the maternal values. Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring. Warfarin embryopathy is characterized by nasal hypoplasia with or without stippled epiphyses (chondrodysplasia punctata) and growth retardation (including low birth weight). Central nervous system and eye abnormalities have also been reported, including dorsal midline dysplasia characterized by agenesis of the corpus callosum, Dandy-Walker malformation, midline cerebellar atrophy, and ventral midline dysplasia characterized by optic atrophy. Mental retardation, blindness, schizencephaly, microcephaly, hydrocephalus, and other adverse pregnancy outcomes have been reported following warfarin exposure during the second and third trimesters of pregnancy [see Contraindications (4) and Warnings and Precautions (5.6) ].

NUSRING MOTHERS

8.3 Nursing Mothers Based on published data in 15 nursing mothers, warfarin was not detected in human milk. Among the 15 full-term newborns, 6 nursing infants had documented prothrombin times within the expected range. Prothrombin times were not obtained for the other 9 nursing infants. Monitor breast-feeding infants for bruising or bleeding. Effects in premature infants have not been evaluated. Caution should be exercised when warfarin sodium is administered to a nursing woman.

BOXED WARNING

WARNING: BLEEDING RISK Warfarin sodium can cause major or fatal bleeding [see Warnings and Precautions (5.1) ]. Perform regular monitoring of INR in all treated patients [see Dosage and Administration (2.1) ]. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy [see Drug Interactions (7) ]. Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ]. WARNING: BLEEDING RISK See full prescribing information for complete boxed warning. Warfarin sodium can cause major or fatal bleeding. (5.1) Perform regular monitoring of INR in all treated patients. (2.1) Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. (7) Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding. (17)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Tissue necrosis: Necrosis or gangrene of skin or other tissues can occur, with severe cases requiring debridement or amputation. Discontinue warfarin sodium and consider alternative anticoagulants if necessary. (5.2) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death. Discontinue warfarin sodium if such emboli occur. (5.3) Heparin-induced thrombocytopenia (HIT): Initial therapy with warfarin sodium in HIT has resulted in cases of amputation and death. Warfarin sodium may be considered after platelet count has normalized. (5.4) Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks. (5.5) 5.1 Hemorrhage Warfarin sodium can cause major or fatal bleeding. Bleeding is more likely to occur within the first month. Risk factors for bleeding include high intensity of anticoagulation (INR >4.0), age greater than or equal to 65, history of highly variable INRs, history of gastrointestinal bleeding, hypertension, cerebrovascular disease, anemia, malignancy, trauma, renal impairment, certain genetic factors [see Clinical Pharmacology (12.5) ], certain concomitant drugs [see Drug Interactions (7) ], and long duration of warfarin therapy. Perform regular monitoring of INR in all treated patients. Those at high risk of bleeding may benefit from more frequent INR monitoring, careful dose adjustment to desired INR, and a shortest duration of therapy appropriate for the clinical condition. However, maintenance of INR in the therapeutic range does not eliminate the risk of bleeding. Drugs, dietary changes, and other factors affect INR levels achieved with warfarin sodium therapy. Perform more frequent INR monitoring when starting or stopping other drugs, including botanicals, or when changing dosages of other drugs [see Drug Interactions (7) ]. Instruct patients about prevention measures to minimize risk of bleeding and to report signs and symptoms of bleeding [see Patient Counseling Information (17) ]. 5.2 Tissue Necrosis Necrosis and/or gangrene of skin and other tissues is an uncommon but serious risk (<0.1%). Necrosis may be associated with local thrombosis and usually appears within a few days of the start of warfarin sodium therapy. In severe cases of necrosis, treatment through debridement or amputation of the affected tissue, limb, breast, or penis has been reported. Careful clinical evaluation is required to determine whether necrosis is caused by an underlying disease. Although various treatments have been attempted, no treatment for necrosis has been considered uniformly effective. Discontinue warfarin sodium therapy if necrosis occurs. Consider alternative drugs if continued anticoagulation therapy is necessary. 5.3 Systemic Atheroemboli and Cholesterol Microemboli Anticoagulation therapy with warfarin sodium may enhance the release of atheromatous plaque emboli. Systemic atheroemboli and cholesterol microemboli can present with a variety of signs and symptoms depending on the site of embolization. The most commonly involved visceral organs are the kidneys followed by the pancreas, spleen, and liver. Some cases have progressed to necrosis or death. A distinct syndrome resulting from microemboli to the feet is known as "purple toes syndrome." Discontinue warfarin sodium therapy if such phenomena are observed. Consider alternative drugs if continued anticoagulation therapy is necessary. 5.4 Heparin-Induced Thrombocytopenia Do not use warfarin sodium as initial therapy in patients with heparin-induced thrombocytopenia (HIT) and with heparin-induced thrombocytopenia with thrombosis syndrome (HITTS). Cases of limb ischemia, necrosis, and gangrene have occurred in patients with HIT and HITTS when heparin treatment was discontinued and warfarin therapy was started or continued. In some patients, sequelae have included amputation of the involved area and/or death. Treatment with warfarin sodium may be considered after the platelet count has normalized. 5.5 Use in Pregnant Women with Mechanical Heart Valves Warfarin sodium can cause fetal harm when administered to a pregnant woman. While warfarin sodium is contraindicated during pregnancy, the potential benefits of using warfarin sodium may outweigh the risks for pregnant women with mechanical heart valves at high risk of thromboembolism. In those individual situations, the decision to initiate or continue warfarin sodium should be reviewed with the patient, taking into consideration the specific risks and benefits pertaining to the individual patient's medical situation, as well as the most current medical guidelines. Warfarin sodium exposure during pregnancy causes a recognized pattern of major congenital malformations (warfarin embryopathy and fetotoxicity), fatal fetal hemorrhage, and an increased risk of spontaneous abortion and fetal mortality. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1) ]. 5.6 Females of Reproductive Potential Warfarin sodium exposure during pregnancy can cause pregnancy loss, birth defects, or fetal death. Discuss pregnancy planning with females of reproductive potential who are on warfarin sodium therapy [see Contraindications (4) and Use in Specific Populations (8.8) ]. 5.7 Other Clinical Settings with Increased Risks In the following clinical settings, the risks of warfarin sodium therapy may be increased: Moderate to severe hepatic impairment Infectious diseases or disturbances of intestinal flora (e.g., sprue, antibiotic therapy) Use of an indwelling catheter Severe to moderate hypertension Deficiency in protein C-mediated anticoagulant response: warfarin sodium reduces the synthesis of the naturally occurring anticoagulants, protein C and protein S. Hereditary or acquired deficiencies of protein C or its cofactor, protein S, have been associated with tissue necrosis following warfarin administration. Concomitant anticoagulation therapy with heparin for 5 to 7 days during initiation of therapy with warfarin sodium may minimize the incidence of tissue necrosis in these patients. Eye surgery: In cataract surgery, warfarin sodium use was associated with a significant increase in minor complications of sharp needle and local anesthesia block but not associated with potentially sight-threatening operative hemorrhagic complications. As warfarin sodium cessation or reduction may lead to serious thromboembolic complications, the decision to discontinue warfarin sodium before a relatively less invasive and complex eye surgery, such as lens surgery, should be based upon the risks of anticoagulant therapy weighed against the benefits. Polycythemia vera Vasculitis Diabetes mellitus 5.8 Endogenous Factors Affecting INR The following factors may be responsible for increased INR response: diarrhea, hepatic disorders, poor nutritional state, steatorrhea, or vitamin K deficiency. The following factors may be responsible for decreased INR response: increased vitamin K intake or hereditary warfarin resistance.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Advise patients to: Tell their physician if they fall often as this may increase their risk for complications. Strictly adhere to the prescribed dosage schedule. Do not take or discontinue any other drug, including salicylates (e.g., aspirin and topical analgesics), other over-the-counter drugs, and botanical (herbal) products except on advice of your physician. Notify their physician immediately if any unusual bleeding or symptoms occur. Signs and symptoms of bleeding include: pain, swelling or discomfort, prolonged bleeding from cuts, increased menstrual flow or vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or dark brown urine, red or tar black stools, headache, dizziness, or weakness. Contact their doctor –immediately if they think they are pregnant –to discuss pregnancy planning –if they are considering breast-feeding Avoid any activity or sport that may result in traumatic injury. Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy. Carry identification stating that they are taking warfarin sodium. If the prescribed dose of warfarin sodium is missed, take the dose as soon as possible on the same day but do not take a double dose of warfarin sodium the next day to make up for missed doses. Eat a normal, balanced diet to maintain a consistent intake of vitamin K. Avoid drastic changes in dietary habits, such as eating large amounts of leafy, green vegetables. Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever. Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days.

DOSAGE AND ADMINISTRATION

2 Individualize dosing regimen for each patient, and adjust based on INR response. (2.1, 2.2) Knowledge of genotype can inform initial dose selection. (2.3) Monitoring: Obtain daily INR determinations upon initiation until stable in the therapeutic range. Obtain subsequent INR determinations every 1 to 4 weeks. (2.4) Review conversion instructions from other anticoagulants. (2.8) 2.1 Individualized Dosing The dosage and administration of warfarin sodium must be individualized for each patient according to the patient’s INR response to the drug. Adjust the dose based on the patient’s INR and the condition being treated. Consult the latest evidence-based clinical practice guidelines from the American College of Chest Physicians (ACCP) to assist in the determination of the duration and intensity of anticoagulation with warfarin sodium [see References (15) ]. 2.2 Recommended Target INR Ranges and Durations for Individual Indications An INR of greater than 4.0 appears to provide no additional therapeutic benefit in most patients and is associated with a higher risk of bleeding. Venous Thromboembolism (including deep venous thrombosis [DVT] and PE) Adjust the warfarin dose to maintain a target INR of 2.5 (INR range, 2.0-3.0) for all treatment durations. The duration of treatment is based on the indication as follows: For patients with a DVT or PE secondary to a transient (reversible) risk factor, treatment with warfarin for 3 months is recommended. For patients with an unprovoked DVT or PE, treatment with warfarin is recommended for at least 3 months. After 3 months of therapy, evaluate the risk-benefit ratio of long-term treatment for the individual patient. For patients with two episodes of unprovoked DVT or PE, long-term treatment with warfarin is recommended. For a patient receiving long-term anticoagulant treatment, periodically reassess the risk-benefit ratio of continuing such treatment in the individual patient. Atrial Fibrillation In patients with non-valvular AF, anticoagulate with warfarin to target INR of 2.5 (range, 2.0-3.0). In patients with non-valvular AF that is persistent or paroxysmal and at high risk of stroke (i.e., having any of the following features: prior ischemic stroke, transient ischemic attack, or systemic embolism, or 2 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. In patients with non-valvular AF that is persistent or paroxysmal and at an intermediate risk of ischemic stroke (i.e., having 1 of the following risk factors: age greater than 75 years, moderately or severely impaired left ventricular systolic function and/or heart failure, history of hypertension, or diabetes mellitus), long-term anticoagulation with warfarin is recommended. For patients with AF and mitral stenosis, long-term anticoagulation with warfarin is recommended. For patients with AF and prosthetic heart valves, long-term anticoagulation with warfarin is recommended; the target INR may be increased and aspirin added depending on valve type and position, and on patient factors. Mechanical and Bioprosthetic Heart Valves For patients with a bileaflet mechanical valve or a Medtronic Hall (Minneapolis, MN) tilting disk valve in the aortic position who are in sinus rhythm and without left atrial enlargement, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) is recommended. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with caged ball or caged disk valves, therapy with warfarin to a target INR of 3.0 (range, 2.5-3.5) is recommended. For patients with a bioprosthetic valve in the mitral position, therapy with warfarin to a target INR of 2.5 (range, 2.0-3.0) for the first 3 months after valve insertion is recommended. If additional risk factors for thromboembolism are present (AF, previous thromboembolism, left ventricular dysfunction), a target INR of 2.5 (range, 2.0-3.0) is recommended. Post-Myocardial Infarction For high-risk patients with MI (e.g., those with a large anterior MI, those with significant heart failure, those with intracardiac thrombus visible on transthoracic echocardiography, those with AF, and those with a history of a thromboembolic event), therapy with combined moderate-intensity (INR, 2.0-3.0) warfarin plus low-dose aspirin (≤100 mg/day) for at least 3 months after the MI is recommended. Recurrent Systemic Embolism and Other Indications Oral anticoagulation therapy with warfarin has not been fully evaluated by clinical trials in patients with valvular disease associated with AF, patients with mitral stenosis, and patients with recurrent systemic embolism of unknown etiology. However, a moderate dose regimen (INR 2.0-3.0) may be used for these patients. 2.3 Initial and Maintenance Dosing The appropriate initial dosing of warfarin sodium varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Clinical factors including age, race, body weight, sex, concomitant medications, and comorbidities Genetic factors (CYP2C9 and VKORC1 genotypes) [see Clinical Pharmacology (12.5) ] Select the initial dose based on the expected maintenance dose, taking into account the above factors. Modify this dose based on consideration of patient-specific clinical factors. Consider lower initial and maintenance doses for elderly and/or debilitated patients and in Asian patients [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]. Routine use of loading doses is not recommended as this practice may increase hemorrhagic and other complications and does not offer more rapid protection against clot formation. Individualize the duration of therapy for each patient. In general, anticoagulant therapy should be continued until the danger of thrombosis and embolism has passed [see Dosage and Administration (2.2) ]. Dosing Recommendations without Consideration of Genotype If the patient’s CYP2C9 and VKORC1 genotypes are not known, the initial dose of warfarin sodium is usually 2 to 5 mg once daily. Determine each patient’s dosing needs by close monitoring of the INR response and consideration of the indication being treated. Typical maintenance doses are 2 to 10 mg once daily. Dosing Recommendations with Consideration of Genotype Table 1 displays three ranges of expected maintenance warfarin sodium doses observed in subgroups of patients having different combinations of CYP2C9 and VKORC1 gene variants [see Clinical Pharmacology (12.5) ]. If the patient’s CYP2C9 and/or VKORC1 genotype are known, consider these ranges in choosing the initial dose. Patients with CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3 may require more prolonged time (>2 to 4 weeks) to achieve maximum INR effect for a given dosage regimen than patients without these CYP variants. Table 1: Three Ranges of Expected Maintenance Warfarin Sodium Daily Doses Based on CYP2C9 and VKORC1 GenotypesRanges are derived from multiple published clinical studies. VKORC1 –1639G>A (rs9923231) variant is used in this table. Other co-inherited VKORC1 variants may also be important determinants of warfarin dose. VKORC1 CYP2C9 *1/*1 *1/*2 *1/*3 *2/*2 *2/*3 *3/*3 GG 5-7 mg 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg AG 5-7 mg 3-4 mg 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg AA 3-4 mg 3-4 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 0.5-2 mg 2.4 Monitoring to Achieve Optimal Anticoagulation Warfarin sodium is a narrow therapeutic range (index) drug, and its action may be affected by factors such as other drugs and dietary vitamin K. Therefore, anticoagulation must be carefully monitored during warfarin sodium therapy. Determine the INR daily after the administration of the initial dose until INR results stabilize in the therapeutic range. After stabilization, maintain dosing within the therapeutic range by performing periodic INRs. The frequency of performing INR should be based on the clinical situation but generally acceptable intervals for INR determinations are 1 to 4 weeks. Perform additional INR tests when other warfarin products are interchanged with warfarin sodium, as well as whenever other medications are initiated, discontinued, or taken irregularly. Heparin, a common concomitant drug, increases the INR [see Dosage and Administration (2.8) and Drug Interactions (7) ]. Determinations of whole blood clotting and bleeding times are not effective measures for monitoring of warfarin sodium therapy. 2.5 Missed Dose The anticoagulant effect of warfarin sodium persists beyond 24 hours. If a patient misses a dose of warfarin sodium at the intended time of day, the patient should take the dose as soon as possible on the same day. The patient should not double the dose the next day to make up for a missed dose. 2.7 Treatment During Dentistry and Surgery Some dental or surgical procedures may necessitate the interruption or change in the dose of warfarin sodium therapy. Consider the benefits and risks when discontinuing warfarin sodium even for a short period of time. Determine the INR immediately prior to any dental or surgical procedure. In patients undergoing minimally invasive procedures who must be anticoagulated prior to, during, or immediately following these procedures, adjusting the dosage of warfarin sodium to maintain the INR at the low end of the therapeutic range may safely allow for continued anticoagulation. 2.8 Conversion From Other Anticoagulants Heparin Since the full anticoagulant effect of warfarin sodium is not achieved for several days, heparin is preferred for initial rapid anticoagulation. During initial therapy with warfarin sodium, the interference with heparin anticoagulation is of minimal clinical significance. Conversion to warfarin sodium may begin concomitantly with heparin therapy or may be delayed 3 to 6 days. To ensure therapeutic anticoagulation, continue full dose heparin therapy and overlap warfarin sodium therapy with heparin for 4 to 5 days and until warfarin sodium has produced the desired therapeutic response as determined by INR, at which point heparin may be discontinued. As heparin may affect the INR, patients receiving both heparin and warfarin sodium should have INR monitoring at least: 5 hours after the last intravenous bolus dose of heparin, or 4 hours after cessation of a continuous intravenous infusion of heparin, or 24 hours after the last subcutaneous heparin injection. Warfarin sodium may increase the activated partial thromboplastin time (aPTT) test, even in the absence of heparin. A severe elevation (>50 seconds) in aPTT with an INR in the desired range has been identified as an indication of increased risk of postoperative hemorrhage. Other Anticoagulants Consult the labeling of other anticoagulants for instructions on conversion to warfarin sodium.

enoxaparin sodium 40 MG in 0.4 ML Prefilled Syringe

Generic Name: ENOXAPARIN SODIUM

Brand Name: Enoxaparin sodium

Substance Name(s):
ENOXAPARIN SODIUM

DRUG INTERACTIONS

7 Whenever possible, agents which may enhance the risk of hemorrhage should be discontinued prior to initiation of enoxaparin sodium therapy. These agents include medications such as: anticoagulants, platelet inhibitors including acetylsalicylic acid, salicylates, NSAIDs (including ketorolac tromethamine), dipyridamole, or sulfinpyrazone. If co-administration is essential, conduct close clinical and laboratory monitoring [see Warnings and Precautions (5.9) ]. Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium or conduct close clinical and laboratory monitoring (5.9, 7)

OVERDOSAGE

10 Accidental overdosage following administration of enoxaparin sodium may lead to hemorrhagic complications. Injected enoxaparin sodium may be largely neutralized by the slow IV injection of protamine sulfate (1% solution). The dose of protamine sulfate should be equal to the dose of enoxaparin sodium injected: 1 mg protamine sulfate should be administered to neutralize 1 mg enoxaparin sodium, if enoxaparin sodium was administered in the previous 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin sodium may be administered if enoxaparin sodium was administered greater than 8 hours previous to the protamine administration, or if it has been determined that a second dose of protamine is required. The second infusion of 0.5 mg protamine sulfate per 1 mg of enoxaparin sodium may be administered if the aPTT measured 2 to 4 hours after the first infusion remains prolonged. If at least 12 hours have elapsed since the last enoxaparin sodium injection, protamine administration may not be required; however, even with higher doses of protamine, the aPTT may remain more prolonged than following administration of heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information consult the labeling of protamine sulfate injection products.

DESCRIPTION

11 Enoxaparin sodium injection is a sterile aqueous solution containing enoxaparin sodium, a low molecular weight heparin. The pH of the injection is 5.5 to 7.5. Enoxaparin sodium is obtained by alkaline depolymerization of heparin benzyl ester derived from porcine intestinal mucosa. Its structure is characterized by a 2-O-sulfo-4-enepyranosuronic acid group at the non-reducing end and a 2-N,6-O-disulfo-D-glucosamine at the reducing end of the chain. About 20% (ranging between 15% and 25%) of the enoxaparin structure contains an 1,6 anhydro derivative on the reducing end of the polysaccharide chain. The drug substance is the sodium salt. The average molecular weight is about 4500 daltons. The molecular weight distribution is: 8000 daltons ≤18% STRUCTURAL FORMULA R XX = Percent of polysaccharide chain containing 1,6 anhydro derivative on the reducing end.= 15 to 25% n= 0 to 20 100 – X H n =1 to 21 Enoxaparin sodium injection 100 mg/mL Concentration contains 10 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1000 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection. Enoxaparin sodium injection 150 mg/mL Concentration contains 15 mg enoxaparin sodium (approximate anti-Factor Xa activity of 1500 IU [with reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard]) per 0.1 mL Water for Injection. The enoxaparin sodium prefilled syringes and graduated prefilled syringes are preservative-free and intended for use only as a single-dose injection. The multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative [see Dosage and Administration (2) and How Supplied (16) ]. Chemical Structure Chemical Structure

CLINICAL STUDIES

14 14.1 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes or who have additional risk factors such as malignancy or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE). In a double-blind, parallel group study of patients undergoing elective cancer surgery of the gastrointestinal, urological, or gynecological tract, a total of 1116 patients were enrolled in the study, and 1115 patients were treated. Patients ranged in age from 32 to 97 years (mean age 67 years) with 52.7% men and 47.3% women. Patients were 98% Caucasian, 1.1% Black, 0.4% Asian and 0.4% others. Enoxaparin sodium 40 mg SC, administered once a day, beginning 2 hours prior to surgery and continuing for a maximum of 12 days after surgery, was comparable to heparin 5000 U every 8 hours SC in reducing the risk of DVT. The efficacy data are provided below [see Table 14]. Table 14 Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery Indication Dosing Regimen Enoxaparin Sodium 40 mg q.d. SC n (%) Heparin 5000 U q8h SC n (%) All Treated Abdominal Surgery Patients 555 (100) 560 (100) Treatment Failures Total VTEVTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin (%) 56 (10.1) (95% CICI = Confidence Interval: 8 to 13) 63 (11.3) (95% CI: 9 to 14) DVT Only (%) 54 (9.7) (95% CI: 7 to 12) 61 (10.9) (95% CI: 8 to 13) In a second double-blind, parallel group study, enoxaparin sodium 40 mg SC once a day was compared to heparin 5000 U every 8 hours SC in patients undergoing colorectal surgery (one-third with cancer). A total of 1347 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 50.1 years) with 54.2% men and 45.8% women. Treatment was initiated approximately 2 hours prior to surgery and continued for approximately 7 to 10 days after surgery. The efficacy data are provided below [see Table 15]. Table 15 Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Colorectal Surgery Indication Dosing Regimen Enoxaparin Sodium 40 mg q.d. SC n (%) Heparin 5000 U q8h SC n (%) All Treated Colorectal Surgery Patients 673 (100) 674 (100) Treatment Failures Total VTEVTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin (%) 48 (7.1) (95% CICI = Confidence Interval: 5 to 9) 45 (6.7) (95% CI: 5 to 9) DVT Only (%) 47 (7.0) (95% CI: 5 to 9) 44 (6.5) (95% CI: 5 to 8) 14.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery Enoxaparin sodium has been shown to reduce the risk of post-operative deep vein thrombosis (DVT) following hip or knee replacement surgery. In a double-blind study, enoxaparin sodium 30 mg every 12 hours SC was compared to placebo in patients with hip replacement. A total of 100 patients were randomized in the study and all patients were treated. Patients ranged in age from 41 to 84 years (mean age 67.1 years) with 45% men and 55% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued for 10 to 14 days after surgery. The efficacy data are provided below [see Table 16]. Table 16 Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Indication Dosing Regimen Enoxaparin Sodium 30 mg q12h SC n (%) Placebo q12h SC n (%) All Treated Hip Replacement Patients 50 (100) 50 (100) Treatment Failures Total DVT (%) 5 (10)p value versus placebo = 0.0002 23 (46) Proximal DVT (%) 1 (2)p value versus placebo = 0.0134 11 (22) A double-blind, multicenter study compared three dosing regimens of enoxaparin sodium in patients with hip replacement. A total of 572 patients were randomized in the study and 568 patients were treated. Patients ranged in age from 31 to 88 years (mean age 64.7 years) with 63% men and 37% women. Patients were 93% Caucasian, 6% Black, <1% Asian, and 1% others. Treatment was initiated within two days after surgery and was continued for 7 to 11 days after surgery. The efficacy data are provided below [see Table 17]. Table 17 Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Indication Dosing Regimen 10 mg q.d. SC n (%) 30 mg q12h SC n (%) 40 mg q.d. SC n (%) All Treated Hip Replacement Patients 161 (100) 208 (100) 199 (100) Treatment Failures Total DVT (%) 40 (25) 22 (11)p value versus enoxaparin sodium 10 mg once a day = 0.0008 27 (14) Proximal DVT (%) 17 (11) 8 (4)p value versus enoxaparin sodium 10 mg once a day = 0.0168 9 (5) There was no significant difference between the 30 mg every 12 hours and 40 mg once a day regimens. In a double-blind study, enoxaparin sodium 30 mg every 12 hours SC was compared to placebo in patients undergoing knee replacement surgery. A total of 132 patients were randomized in the study and 131 patients were treated, of which 99 had total knee replacement and 32 had either unicompartmental knee replacement or tibial osteotomy. The 99 patients with total knee replacement ranged in age from 42 to 85 years (mean age 70.2 years) with 36.4% men and 63.6% women. After hemostasis was established, treatment was initiated 12 to 24 hours after surgery and was continued up to 15 days after surgery. The incidence of proximal and total DVT after surgery was significantly lower for enoxaparin sodium compared to placebo. The efficacy data are provided below [see Table 18]. Table 18 Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis Following Total Knee Replacement Surgery Indication Dosing Regimen Enoxaparin Sodium 30 mg q12h SC n (%) Placebo q12h SC n (%) All Treated Total Knee Replacement Patients 47 (100) 52 (100) Treatment Failures Total DVT (%) 5 (11)p value versus placebo = 0.0001 (95% CICI = Confidence Interval: 1 to 21) 32 (62) (95% CI: 47 to 76) Proximal DVT (%) 0 (0)p value versus placebo = 0.013 (95% Upper CLCL = Confidence Limit: 5) 7 (13) (95% CI: 3 to 24) Additionally, in an open-label, parallel group, randomized clinical study, enoxaparin sodium 30 mg every 12 hours SC in patients undergoing elective knee replacement surgery was compared to heparin 5000 U every 8 hours SC. A total of 453 patients were randomized in the study and all were treated. Patients ranged in age from 38 to 90 years (mean age 68.5 years) with 43.7% men and 56.3% women. Patients were 92.5% Caucasian, 5.3% Black, and 0.6% others. Treatment was initiated after surgery and continued up to 14 days. The incidence of deep vein thrombosis was significantly lower for enoxaparin sodium compared to heparin. Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery: In a study of extended prophylaxis for patients undergoing hip replacement surgery, patients were treated, while hospitalized, with enoxaparin sodium 40 mg SC, initiated up to 12 hours prior to surgery for the prophylaxis of post-operative DVT. At the end of the peri-operative period, all patients underwent bilateral venography. In a double-blind design, those patients with no venous thromboembolic disease were randomized to a post-discharge regimen of either enoxaparin sodium 40 mg (n = 90) once a day SC or to placebo (n = 89) for 3 weeks. A total of 179 patients were randomized in the double-blind phase of the study and all patients were treated. Patients ranged in age from 47 to 87 years (mean age 69.4 years) with 57% men and 43% women. In this population of patients, the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo. The efficacy data are provided below [see Table 19]. Table 19 Efficacy of Enoxaparin Sodium in the Extended Prophylaxis of Deep Vein Thrombosis Following Hip Replacement Surgery Indication (Post-Discharge) Post-Discharge Dosing Regimen Enoxaparin Sodium 40 mg q.d. SC n (%) Placebo q.d. SC n (%) All Treated Extended Prophylaxis Patients 90 (100) 89 (100) Treatment Failures Total DVT (%) 6 (7)p value versus placebo = 0.008 (95% CICI= Confidence Interval: 3 to 14) 18 (20) (95% CI: 12 to 30) Proximal DVT (%) 5 (6)p value versus placebo = 0.537 (95% CI: 2 to 13) 7 (8) (95% CI: 3 to 16) In a second study, patients undergoing hip replacement surgery were treated, while hospitalized, with enoxaparin sodium 40 mg SC, initiated up to 12 hours prior to surgery. All patients were examined for clinical signs and symptoms of venous thromboembolic (VTE) disease. In a double-blind design, patients without clinical signs and symptoms of VTE disease were randomized to a post-discharge regimen of either enoxaparin sodium 40 mg (n = 131) once a day SC or to placebo (n = 131) for 3 weeks. A total of 262 patients were randomized in the study double-blind phase and all patients were treated. Patients ranged in age from 44 to 87 years (mean age 68.5 years) with 43.1% men and 56.9% women. Similar to the first study the incidence of DVT during extended prophylaxis was significantly lower for enoxaparin sodium compared to placebo, with a statistically significant difference in both total DVT (enoxaparin sodium 21 [16%] versus placebo 45 [34%]; p = 0.001) and proximal DVT (enoxaparin sodium 8 [6%] versus placebo 28 [21%]; p = <0.001). 14.3 Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness In a double blind multicenter, parallel group study, enoxaparin sodium 20 mg or 40 mg once a day SC was compared to placebo in the prophylaxis of deep vein thrombosis (DVT) in medical patients with severely restricted mobility during acute illness (defined as walking distance of <10 meters for ≤3 days). This study included patients with heart failure (NYHA Class III or IV); acute respiratory failure or complicated chronic respiratory insufficiency (not requiring ventilatory support): acute infection (excluding septic shock); or acute rheumatic disorder [acute lumbar or sciatic pain, vertebral compression (due to osteoporosis or tumor), acute arthritic episodes of the lower extremities]. A total of 1102 patients were enrolled in the study, and 1073 patients were treated. Patients ranged in age from 40 to 97 years (mean age 73 years) with equal proportions of men and women. Treatment continued for a maximum of 14 days (median duration 7 days). When given at a dose of 40 mg once a day SC, enoxaparin sodium significantly reduced the incidence of DVT as compared to placebo. The efficacy data are provided below [see Table 20]. Table 20 Efficacy of Enoxaparin Sodium in the Prophylaxis of Deep Vein Thrombosis in Medical Patients with Severely Restricted Mobility During Acute Illness Indication Dosing Regimen Enoxaparin Sodium 20 mg q.d. SC n (%) Enoxaparin Sodium 40 mg q.d. SC n (%) Placebo n (%) All Treated Medical Patients During Acute Illness 351 (100) 360 (100) 362 (100) Treatment FailureTreatment failures during therapy, between Days 1 and 14 Total VTEVTE = Venous thromboembolic events which included DVT, PE, and death considered to be thromboembolic in origin (%) 43 (12.3) 16 (4.4) 43 (11.9) Total DVT (%) 43 (12.3) (95% CICI = Confidence Interval 8.8 to 15.7) 16 (4.4) (95% CI 2.3 to 6.6) 41 (11.3) (95% CI 8.1 to 14.6) Proximal DVT (%) 13 (3.7) 5 (1.4) 14 (3.9) At approximately 3 months following enrollment, the incidence of venous thromboembolism remained significantly lower in the enoxaparin 40 mg treatment group versus the placebo treatment group. 14.4 Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism In a multicenter, parallel group study, 900 patients with acute lower extremity deep vein thrombosis (DVT) with or without pulmonary embolism (PE) were randomized to an inpatient (hospital) treatment of either (i) enoxaparin sodium 1.5 mg/kg once a day SC, (ii) enoxaparin sodium 1 mg/kg every 12 hours SC, or (iii) heparin IV bolus (5000 IU) followed by a continuous infusion (administered to achieve an aPTT of 55 to 85 seconds). A total of 900 patients were randomized in the study and all patients were treated. Patients ranged in age from 18 to 92 years (mean age 60.7 years) with 54.7% men and 45.3% women. All patients also received warfarin sodium (dose adjusted according to PT to achieve an International Normalization Ratio [INR] of 2.0 to 3.0), commencing within 72 hours of initiation of enoxaparin sodium or standard heparin therapy, and continuing for 90 days. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days and until the targeted warfarin sodium INR was achieved. Both enoxaparin sodium regimens were equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism (DVT and/or PE). The efficacy data are provided below [see Table 21]. Table 21 Efficacy of Enoxaparin Sodium in Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism Indication Dosing RegimenAll patients were also treated with warfarin sodium commencing within 72 hours of enoxaparin sodium or standard heparin therapy. Enoxaparin Sodium 1.5 mg/kg q.d. SC n (%) Enoxaparin Sodium 1 mg/kg q12h SC n (%) Heparin aPTT Adjusted IV Therapy n (%) All Treated DVT Patients with or without PE 298 (100) 312 (100) 290 (100) Patient Outcome Total VTEVTE = venous thromboembolic event (DVT and/or PE) (%) 13 (4.4)The 95% Confidence Intervals for the treatment differences for total VTE were: Enoxaparin sodium once a day versus heparin (-3.0 to 3.5) Enoxaparin sodium every 12 hours versus heparin (-4.2 to 1.7). 9 (2.9) 12 (4.1) DVT Only (%) 11 (3.7) 7 (2.2) 8 (2.8) Proximal DVT (%) 9 (3.0) 6 (1.9) 7 (2.4) PE (%) 2 (0.7) 2 (0.6) 4 (1.4) Similarly, in a multicenter, open-label, parallel group study, patients with acute proximal DVT were randomized to enoxaparin sodium or heparin. Patients who could not receive outpatient therapy were excluded from entering the study. Outpatient exclusion criteria included the following: inability to receive outpatient heparin therapy because of associated co-morbid conditions or potential for non-compliance and inability to attend follow-up visits as an outpatient because of geographic inaccessibility. Eligible patients could be treated in the hospital, but ONLY enoxaparin patients were permitted to go home on therapy (72%). A total of 501 patients were randomized in the study and all patients were treated. Patients ranged in age from 19 to 96 years (mean age 57.8 years) with 60.5% men and 39.5% women. Patients were randomized to either enoxaparin sodium 1 mg/kg every 12 hours SC or heparin IV bolus (5000 IU) followed by a continuous infusion administered to achieve an aPTT of 60 to 85 seconds (in-patient treatment). All patients also received warfarin sodium as described in the previous study. Enoxaparin sodium or standard heparin therapy was administered for a minimum of 5 days. Enoxaparin sodium was equivalent to standard heparin therapy in reducing the risk of recurrent venous thromboembolism. The efficacy data are provided below [see Table 22]. Table 22 Efficacy of Enoxaparin Sodium in Treatment of Deep Vein Thrombosis Indication Dosing RegimenAll patients were also treated with warfarin sodium commencing on the evening of the second day of enoxaparin sodium or standard heparin therapy. Enoxaparin Sodium 1 mg/kg q12h SC Heparin aPTT Adjusted IV Therapy n (%) n (%) All Treated DVT Patients 247 (100) 254 (100) Patient Outcome Total VTEVTE = venous thromboembolic event (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]). (%) 13 (5.3) The 95% Confidence Intervals for the treatment difference for total VTE was: enoxaparin sodium versus heparin (- 5.6 to 2.7). 17 (6.7) DVT Only (%) 11 (4.5) 14 (5.5) Proximal DVT (%) 10 (4.0) 12 (4.7) PE (%) 2 (0.8) 3 (1.2) 14.5 Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction In a multicenter, double-blind, parallel group study, patients who recently experienced unstable angina or non-Q-wave myocardial infarction were randomized to either enoxaparin sodium 1 mg/kg every 12 hours SC or heparin IV bolus (5000 U) followed by a continuous infusion (adjusted to achieve an aPTT of 55 to 85 seconds). A total of 3171 patients were enrolled in the study, and 3107 patients were treated. Patients ranged in age from 25–94 years (median age 64 years), with 33.4% of patients female and 66.6% male. Race was distributed as follows: 89.8% Caucasian, 4.8% Black, 2.0% Asian, and 3.5% other. All patients were also treated with aspirin 100 to 325 mg per day. Treatment was initiated within 24 hours of the event and continued until clinical stabilization, revascularization procedures, or hospital discharge, with a maximal duration of 8 days of therapy. The combined incidence of the triple endpoint of death, myocardial infarction, or recurrent angina was lower for enoxaparin sodium compared with heparin therapy at 14 days after initiation of treatment. The lower incidence of the triple endpoint was sustained up to 30 days after initiation of treatment. These results were observed in an analysis of both all-randomized and all-treated patients. The efficacy data are provided below [see Table 23]. Table 23 Efficacy of Enoxaparin Sodium in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction (Combined Endpoint of Death, Myocardial Infarction, or Recurrent Angina) Indication Dosing RegimenAll patients were also treated with aspirin 100 to 325 mg per day. Reduction (%) p Value Enoxaparin Sodium 1mg/kg q12h SC Heparin aPTT Adjusted IV Therapy n (%) n (%) All Treated Unstable Angina and Non-Q-Wave MI Patients 1578 (100) 1529 (100) TimepointEvaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days). 48 Hours 96 (6.1) 112 (7.3) 1.2 0.120 14 Days 261 (16.5) 303 (19.8) 3.3 0.017 30 Days 313 (19.8) 358 (23.4) 3.6 0.014 The combined incidence of death or myocardial infarction at all time points was lower for enoxaparin sodium compared to standard heparin therapy, but did not achieve statistical significance. The efficacy data are provided below [see Table 24]. Table 24 Efficacy of Enoxaparin Sodium in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction (Combined Endpoint of Death or Myocardial Infarction) Indication Dosing RegimenAll patients were also treated with aspirin 100 to 325 mg per day. Reduction (%) p Value Enoxaparin Sodium 1 mg/kg q12h SC n (%) Heparin aPTT Adjusted IV Therapy n (%) All Treated Unstable Angina and Non-Q-Wave MI Patients 1578 (100) 1529 (100) TimepointEvaluation timepoints are after initiation of treatment. Therapy continued for up to 8 days (median duration of 2.6 days). 48 Hours 16 (1.0) 20 (1.3) 0.3 0.126 14 Days 76 (4.8) 93 (6.1) 1.3 0.115 30 Days 96 (6.1) 118 (7.7) 1.6 0.069 In a survey one year following treatment, with information available for 92% of enrolled patients, the combined incidence of death, myocardial infarction, or recurrent angina remained lower for enoxaparin sodium versus heparin (32.0% vs 35.7%). Urgent revascularization procedures were performed less frequently in the enoxaparin group as compared to the heparin group, 6.3% compared to 8.2% at 30 days (p = 0.047). 14.6 Treatment of Acute ST-Segment Elevation Myocardial Infarction In a multicenter, double-blind, double-dummy, parallel group study, patients with acute ST-segment elevation myocardial infarction (STEMI) who were to be hospitalized within 6 hours of onset and were eligible to receive fibrinolytic therapy were randomized in a 1:1 ratio to receive either enoxaparin sodium or unfractionated heparin. Study medication was initiated between 15 minutes before and 30 minutes after the initiation of fibrinolytic therapy. Unfractionated heparin was administered beginning with an IV bolus of 60 U/kg (maximum 4000 U) and followed with an infusion of 12 U/kg per hour (initial maximum 1000 U per hour) that was adjusted to maintain an aPTT of 1.5 to 2 times the control value. The IV infusion was to be given for at least 48 hours. The enoxaparin dosing strategy was adjusted according to the patient's age and renal function. For patients younger than 75 years of age, enoxaparin sodium was given as a single 30 mg intravenous bolus plus a 1 mg/kg SC dose followed by an SC injection of 1 mg/kg every 12 hours. For patients at least 75 years of age, the IV bolus was not given and the SC dose was reduced to 0.75 mg/kg every 12 hours. For patients with severe renal insufficiency (estimated creatinine clearance of less than 30 mL per minute), the dose was to be modified to 1 mg/kg every 24 hours. The SC injections of enoxaparin sodium were given until hospital discharge or for a maximum of eight days (whichever came first). The mean treatment duration for enoxaparin sodium was 6.6 days. The mean treatment duration of unfractionated heparin was 54 hours. When percutaneous coronary intervention was performed during study medication period, patients received antithrombotic support with blinded study drug. For patients on enoxaparin sodium, the PCI was to be performed on enoxaparin (no switch) using the regimen established in previous studies, i.e. no additional dosing, if the last SC administration was less than 8 hours before balloon inflation, IV bolus of 0.3 mg/kg enoxaparin sodium if the last SC administration was more than 8 hours before balloon inflation. All patients were treated with aspirin for a minimum of 30 days. Eighty percent of patients received a fibrin-specific agent (19% tenecteplase, 5% reteplase and 55% alteplase) and 20% received streptokinase. Among 20,479 patients in the ITT population, the mean age was 60 years, and 76% were male. Racial distribution was: 87% Caucasian, 9.8% Asian, 0.2% Black, and 2.8% other. Medical history included previous MI (13%), hypertension (44%), diabetes (15%) and angiographic evidence of CAD (5%). Concomitant medication included aspirin (95%), beta-blockers (86%), ACE inhibitors (78%), statins (70%) and clopidogrel (27%). The MI at entry was anterior in 43%, non-anterior in 56%, and both in 1%. The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days after randomization. Total follow-up was one year. The rate of the primary efficacy end point (death or myocardial re-infarction) was 9.9% in the enoxaparin group, and 12.0% in the unfractionated heparin group, a 17% reduction in the relative risk, (P=0.000003) [see Table 25]. Table 25 Efficacy of Enoxaparin Sodium in the Treatment of Acute ST-Segment Elevation Myocardial Infarction Enoxaparin Sodium (N=10,256) UFH (N=10,223) Relative Risk (95% CI) P Value Note: Urgent revascularization denotes episodes of recurrent myocardial ischemia (without infarction) leading to the clinical decision to perform coronary revascularization during the same hospitalization. CI denotes confidence intervals. Outcome at 48 hours n (%) n (%) Death or Myocardial Re-infarction 478 (4.7) 531 (5.2) 0.90 (0.80 to 1.01) 0.08 Death 383 (3.7) 390 (3.8) 0.98 (0.85 to 1.12) 0.76 Myocardial Re-infarction 102 (1.0) 156 (1.5) 0.65 (0.51 to 0.84) <0.001 Urgent Revascularization 74 (0.7) 96 (0.9) 0.77 (0.57 to 1.04) 0.09 Death or Myocardial Re-infarction or Urgent Revascularization 548 (5.3) 622 (6.1) 0.88 (0.79 to 0.98) 0.02 Outcome at 8 Days Death or Myocardial Re-infarction 740 (7.2) 954 (9.3) 0.77 (0.71 to 0.85) <0.001 Death 559 (5.5) 605 (5.9) 0.92 (0.82 to 1.03) 0.15 Myocardial Re-infarction 204 (2.0) 379 (3.7) 0.54 (0.45 to 0.63) <0.001 Urgent Revascularization 145 (1.4) 247 (2.4) 0.59 (0.48 to 0.72) <0.001 Death or Myocardial Re-infarction or Urgent Revascularization 874 (8.5) 1181 (11.6) 0.74 (0.68 to 0.80) <0.001 Outcome at 30 Days Primary efficacy endpoint (Death or Myocardial Re-infarction) 1017 (9.9) 1223 (12.0) 0.83 (0.77 to 0.90) 0.000003 Death 708 (6.9) 765 (7.5) 0.92 (0.84 to 1.02) 0.11 Myocardial Re-infarction 352 (3.4) 508 (5.0) 0.69 (0.60 to 0.79) <0.001 Urgent Revascularization 213 (2.1) 286 (2.8) 0.74 (0.62 to 0.88) <0.001 Death or Myocardial Re-infarction or Urgent Revascularization 1199 (11.7) 1479 (14.5) 0.81 (0.75 to 0.87) <0.001 The beneficial effect of enoxaparin sodium on the primary end point was consistent across key subgroups including age, gender, infarct location, history of diabetes, history of prior myocardial infarction, fibrinolytic agent administered, and time to treatment with study drug (see Figure 1); however, it is necessary to interpret such subgroup analyses with caution. Figure 1. Relative Risks of and Absolute Event Rates for the Primary End Point at 30 Days in Various Subgroups The primary efficacy end point was the composite of death from any cause or myocardial re-infarction in the first 30 days. The overall treatment effect of enoxaparin sodium as compared to the unfractionated heparin is shown at the bottom of the figure. For each subgroup, the circle is proportional to the number and represents the point estimate of the treatment effect and the horizontal lines represent the 95 percent confidence intervals. Fibrin-specific fibrinolytic agents included alteplase, tenecteplase and reteplase. Time to treatment indicates the time from the onset of symptoms to the administration of study drug (median, 3.2 hours). The beneficial effect of enoxaparin sodium on the primary end point observed during the first 30 days was maintained over a 12 month follow-up period (see Figure 2). Figure 2 – Kaplan-Meier plot – death or myocardial re-infarction at 30 days – ITT population There is a trend in favor of enoxaparin sodium during the first 48 hours, but most of the treatment difference is attributed to a step increase in the event rate in the UFH group at 48 hours (seen in Figure 2), an effect that is more striking when comparing the event rates just prior to and just subsequent to actual times of discontinuation. These results provide evidence that UFH was effective and that it would be better if used longer than 48 hours. There is a similar increase in endpoint event rate when enoxaparin was discontinued, suggesting that it too was discontinued too soon in this study. The rates of major hemorrhages (defined as requiring 5 or more units of blood for transfusion, or 15% drop in hematocrit or clinically overt bleeding, including intracranial hemorrhage) at 30 days were 2.1% in the enoxaparin group and 1.4% in the unfractionated heparin group. The rates of intracranial hemorrhage at 30 days were 0.8% in the enoxaparin group 0.7% in the unfractionated heparin group. The 30-day rate of the composite endpoint of death, myocardial re-infarction or ICH (a measure of net clinical benefit) was significantly lower in the enoxaparin group (10.1%) as compared to the heparin group (12.2%). Figure 1 Figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING Enoxaparin sodium injection is available in two concentrations [see Tables 26 and 27]: Table 26 100 mg/mL Concentration Dosage Unit / StrengthStrength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin sodium 30 and 40 mg prefilled syringes, and 60, 80, and 100 mg graduated prefilled syringes each contain 10 mg enoxaparin sodium per 0.1 mL Water for Injection. Anti-Xa ActivityApproximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. Package Size (per carton) Label Color NDC # 0955- Prefilled SyringesEach enoxaparin sodium prefilled syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle. 30 mg/0.3 mL 3000 IU 10 syringes Medium Blue 1003-10 40 mg/0.4 mL 4000 IU 10 syringes Yellow 1004-10 Graduated Prefilled Syringes 60 mg/0.6 mL 6000 IU 10 syringes Orange 1006-10 80 mg/0.8 mL 8000 IU 10 syringes Brown 1008-10 100 mg/1 mL 10,000 IU 10 syringes Black 1010-10 Multiple-Dose VialEach enoxaparin sodium multiple-dose vial contains 15 mg benzyl alcohol per 1 mL as a preservative. 300 mg/3 mL 30,000 IU 1 vial Red 1016-01 Table 27 150 mg/mL Concentration Dosage Unit / StrengthStrength represents the number of milligrams of enoxaparin sodium in Water for Injection. Enoxaparin sodium 120 and 150 mg graduated prefilled syringes contain 15 mg enoxaparin sodium per 0.1 mL Water for Injection. Anti-Xa ActivityApproximate anti-Factor Xa activity based on reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard. Package Size (per carton) Syringe Label Color NDC # 0955- Graduated Prefilled SyringesEach enoxaparin sodium graduated prefilled syringe is for single, one-time use only and is affixed with a 27 gauge × 1/2 inch needle. 120 mg / 0.8 mL 12,000 IU 10 syringes Purple 1012-10 150 mg / 1 mL 15,000 IU 10 syringes Navy Blue 1015-10 Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Do not store the multiple-dose vials for more than 28 days after the first use. Keep out of the reach of children.

RECENT MAJOR CHANGES

Boxed Warning 10/13 Warnings and Precautions ( 5.1 ) 10/13

GERIATRIC USE

8.5 Geriatric Use Prevention of Deep Vein Thrombosis in Hip, Knee and Abdominal Surgery; Treatment of Deep Vein Thrombosis, Prevention of Ischemic Complications of Unstable Angina and Non-Q-wave Myocardial Infarction Over 2800 patients, 65 years and older, have received enoxaparin sodium in pivotal clinical trials. The efficacy of enoxaparin sodium in the geriatric (≥65 years) was similar to that seen in younger patients (<65 years). The incidence of bleeding complications was similar between geriatric and younger patients when 30 mg every 12 hours or 40 mg once a day doses of enoxaparin sodium were employed. The incidence of bleeding complications was higher in geriatric patients as compared to younger patients when enoxaparin sodium was administered at doses of 1.5 mg/kg once a day or 1 mg/kg every 12 hours. The risk of enoxaparin-associated bleeding increased with age. Serious adverse events increased with age for patients receiving enoxaparin sodium. Other clinical experience (including postmarketing surveillance and literature reports) has not revealed additional differences in the safety of enoxaparin sodium between geriatric and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised. Enoxaparin sodium should be used with care in geriatric patients who may show delayed elimination of enoxaparin. Monitoring of geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function should be considered [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) ]. Treatment of Acute ST-Segment Elevation Myocardial Infarction In the clinical study for treatment of acute ST-segment elevation myocardial infarction, there was no evidence of difference in efficacy between patients ≥75 years of age (n = 1241) and patients less than 75 years of age (n=9015). Patients ≥75 years of age did not receive a 30 mg IV bolus prior to the normal dosage regimen and had their SC dose adjusted to 0.75 mg/kg every 12 hours [see Dosage and Administration (2.3 )]. The incidence of bleeding complications was higher in patients ≥65 years of age as compared to younger patients (<65 years).

DOSAGE FORMS AND STRENGTHS

3 Enoxaparin sodium injection is available in two concentrations: 100 mg/mL concentration (3.1): Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL,100 mg/1 mL Multiple-dose vial: 300 mg/3 mL 150 mg/mL concentration (3.2): Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/1 mL 3.1 100 mg/mL Concentration -Prefilled Syringes 30 mg/0.3 mL, 40 mg/0.4 mL -Graduated Prefilled Syringes 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL -Multiple-Dose Vials 300 mg/3 mL 3.2 150 mg/mL Concentration -Graduated Prefilled Syringes 120 mg/0.8 mL, 150 mg/1 mL

MECHANISM OF ACTION

12.1 Mechanism of Action Enoxaparin is a low molecular weight heparin which has antithrombotic properties.

INDICATIONS AND USAGE

1 Enoxaparin sodium is a low molecular weight heparin [LMWH] indicated for: Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness (1.1) Inpatient treatment of acute DVT with or without pulmonary embolism (1.2) Outpatient treatment of acute DVT without pulmonary embolism. (1.2) Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI] (1.3) Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI] (1.4) 1.1 Prophylaxis of Deep Vein Thrombosis Enoxaparin sodium is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): in patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.1) ]. in patients undergoing hip replacement surgery, during and following hospitalization. in patients undergoing knee replacement surgery. in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness. 1.2 Treatment of Acute Deep Vein Thrombosis Enoxaparin sodium is indicated for: the inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium. the outpatient treatment of acute deep vein thrombosis without pulmonary embolism when administered in conjunction with warfarin sodium. 1.3 Prophylaxis of Ischemic Complications of Unstable Angina and Non-Q-Wave Myocardial Infarction Enoxaparin sodium is indicated for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin. 1.4 Treatment of Acute ST-Segment Elevation Myocardial Infarction Enoxaparin sodium, when administered concurrently with aspirin, has been shown to reduce the rate of the combined endpoint of recurrent myocardial infarction or death in patients with acute ST-segment elevation myocardial infarction (STEMI) receiving thrombolysis and being managed medically or with percutaneous coronary intervention (PCI).

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness of enoxaparin sodium in pediatric patients have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category B All pregnancies have a background risk of birth defect, loss, or other adverse outcome regardless of drug exposure. The fetal risk summary below describes the potential of enoxaparin sodium to increase the risk of developmental abnormalities above the background risk. Fetal Risk Summary Enoxaparin does not cross the placenta, and is not expected to result in fetal exposure to the drug. Human data from a retrospective cohort study, which included 693 live births, suggest that enoxaparin sodium does not increase the risk of major developmental abnormalities. Based on animal data, enoxaparin is not predicted to increase the risk of major developmental abnormalities (see Data ). Clinical Considerations Pregnancy alone confers an increased risk for thromboembolism that is even higher for women with thromboembolic disease and certain high risk pregnancy conditions. While not adequately studied, pregnant women with mechanical prosthetic heart valves may be at even higher risk for thrombosis [see Warnings and Precautions (5.7) and Use in Specific Populations (8.6) ]. Pregnant women with thromboembolic disease, including those with mechanical prosthetic heart valves and those with inherited or acquired thrombophilias, have an increased risk of other maternal complications and fetal loss regardless of the type of anticoagulant used. All patients receiving anticoagulants, including pregnant women, are at risk for bleeding. Pregnant women receiving enoxaparin should be carefully monitored for evidence of bleeding or excessive anticoagulation. Consideration for use of a shorter acting anticoagulant should be specifically addressed as delivery approaches [see Boxed Warning ]. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women should be apprised of the potential hazard to the fetus and the mother if enoxaparin is administered during pregnancy. It is not known if monitoring of anti-Factor Xa activity and dose adjustment (by weight or anti-Factor Xa activity) of enoxaparin sodium affect the safety and the efficacy of the drug during pregnancy. Cases of “gasping syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–405 mg/kg/day). The multiple-dose vial of enoxaparin sodium contains 15 mg benzyl alcohol per 1 mL as a preservative [see Warnings and Precautions (5.8) ]. Data Human Data – There are no adequate and well-controlled studies in pregnant women. A retrospective study reviewed the records of 604 women who used enoxaparin during pregnancy. A total of 624 pregnancies resulted in 693 live births. There were 72 hemorrhagic events (11 serious) in 63 women. There were 14 cases of neonatal hemorrhage. Major congenital anomalies in live births occurred at rates (2.5%) similar to background rates. There have been postmarketing reports of fetal death when pregnant women received enoxaparin sodium. Causality for these cases has not been determined. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. A clinical study using enoxaparin in pregnant women with mechanical prosthetic heart valves has been conducted [see Warnings and Precautions (5.7) ]. Animal Data – Teratology studies have been conducted in pregnant rats and rabbits at SC doses of enoxaparin up to 15 times the recommended human dose (by comparison with 2 mg/kg as the maximum recommended daily dose). There was no evidence of teratogenic effects or fetotoxicity due to enoxaparin. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether enoxaparin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from enoxaparin, a decision should be made whether to discontinue nursing or discontinue enoxaparin sodium, taking into account the importance of enoxaparin sodium to the mother and the known benefits of nursing.

BOXED WARNING

WARNING: SPINAL/EPIDURAL HEMATOMAS Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants. A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of enoxaparin sodium and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7) ]. WARNING: SPINAL/EPIDURAL HEMATOMA See full prescribing information for complete boxed warning. Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: Use of indwelling epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants A history of traumatic or repeated epidural or spinal punctures A history of spinal deformity or spinal surgery Optimal timing between the administration of enoxaparin sodium and neuraxial procedures is not known. Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary[see Warnings and Precautions (5.1) and Drug Interactions (7) ].

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Increased risk of hemorrhage: Use with caution in patients at risk (5.1) Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal (5.2) Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage (5.3) History of heparin-induced thrombocytopenia: Use with caution (5.4) Thrombocytopenia: Monitor thrombocytopenia closely (5.5) Interchangeability with other heparins: Do not exchange with heparin or other LMWHs (5.6) Pregnant women with mechanical prosthetic heart valves and their fetuses, may be at increased risk and may need more frequent monitoring and dosage adjustment (5.7) 5.1 Increased Risk of Hemorrhage Cases of epidural or spinal hemorrhage and subsequent hematomas have been reported with the use of enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture procedures, resulting in long-term or permanent paralysis. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity [see Boxed Warning, Adverse Reactions (6.2) and Drug Interactions (7) ]. To reduce the potential risk of bleeding associated with the concurrent use of enoxaparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of enoxaparin [see Clinical Pharmacology (12.3) ]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. Placement or removal of a catheter should be delayed for at least 12 hours after administration of lower doses (30 mg once or twice daily or 40 mg once daily) of enoxaparin sodium and at least 24 hours after the administration of higher doses (0.75 mg/kg twice daily, 1 mg/kg twice daily, or 1.5 mg/kg once daily) of enoxaparin sodium. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided. Patients receiving the 0.75 mg/kg twice daily dose or the1mg/kg twice daily dose should not receive the second enoxaparin sodium dose in the twice daily regimen to allow a longer delay before catheter placement or removal. Likewise, although a specific recommendation for timing of a subsequent enoxaparin sodium dose after catheter removal cannot be made, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors. For patients with creatinine clearance <30mL/minute, additional considerations are necessary because elimination of enoxaparin is more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of enoxaparin sodium (30 mg once daily) and at least 48 hours for the higher dose (1 mg/kg/day) [see Clinical Pharmacology (12.3) ]. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae. Enoxaparin sodium should be used with extreme caution in conditions with increased risk of hemorrhage, such as bacterial endocarditis, congenital or acquired bleeding disorders, active ulcerative and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal, or ophthalmological surgery, or in patients treated concomitantly with platelet inhibitors. Major hemorrhages including retroperitoneal and intracranial bleeding have been reported. Some of these cases have been fatal. Bleeding can occur at any site during therapy with enoxaparin sodium. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. 5.2 Percutaneous Coronary Revascularization Procedures To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, non-Q-wave myocardial infarction and acute ST-segment elevation myocardial infarction, adhere precisely to the intervals recommended between enoxaparin sodium doses. It is important to achieve hemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation [see Dosage and Administration (2.1) ]. 5.3 Use of Enoxaparin sodium with Concomitant Medical Conditions Enoxaparin sodium should be used with care in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage. 5.4 History of Heparin-Induced Thrombocytopenia Enoxaparin sodium should be used with extreme caution in patients with a history of heparin-induced thrombocytopenia. 5.5 Thrombocytopenia Thrombocytopenia can occur with the administration of enoxaparin sodium. Moderate thrombocytopenia (platelet counts between 100,000/mm3 and 50,000/mm3) occurred at a rate of 1.3% in patients given enoxaparin sodium, 1.2% in patients given heparin, and 0.7% in patients given placebo in clinical trials. Platelet counts less than 50,000/mm3 occurred at a rate of 0.1% in patients given enoxaparin sodium, in 0.2% of patients given heparin, and 0.4% of patients given placebo in the same trials. Thrombocytopenia of any degree should be monitored closely. If the platelet count falls below 100,000/mm3, enoxaparin sodium should be discontinued. Cases of heparin-induced thrombocytopenia with thrombosis have also been observed in clinical practice. Some of these cases were complicated by organ infarction, limb ischemia, or death [see Warnings and Precautions (5.4) ]. 5.6 Interchangeability with Other Heparins Enoxaparin sodium cannot be used interchangeably (unit for unit) with heparin or other low molecular weight heparins as they differ in manufacturing process, molecular weight distribution, anti-Xa and anti-IIa activities, units, and dosage. Each of these medicines has its own instructions for use. 5.7 Pregnant Women with Mechanical Prosthetic Heart Valves The use of enoxaparin sodium for thromboprophylaxis in pregnant women with mechanical prosthetic heart valves has not been adequately studied. In a clinical study of pregnant women with mechanical prosthetic heart valves given enoxaparin (1 mg/kg twice daily) to reduce the risk of thromboembolism, 2 of 8 women developed clots resulting in blockage of the valve and leading to maternal and fetal death. Although a causal relationship has not been established these deaths may have been due to therapeutic failure or inadequate anticoagulation. No patients in the heparin/warfarin group (0 of 4 women) died. There also have been isolated postmarketing reports of valve thrombosis in pregnant women with mechanical prosthetic heart valves while receiving enoxaparin for thromboprophylaxis. Women with mechanical prosthetic heart valves may be at higher risk for thromboembolism during pregnancy, and, when pregnant, have a higher rate of fetal loss from stillbirth, spontaneous abortion and premature delivery. Therefore, frequent monitoring of peak and trough anti-Factor Xa levels, and adjusting of dosage may be needed [see Use in Specific Populations (8.6) ]. 5.8 Benzyl Alcohol Enoxaparin sodium multiple-dose vials contain benzyl alcohol as a preservative. The administration of medications containing benzyl alcohol as a preservative to premature neonates has been associated with a fatal "gasping syndrome". Because benzyl alcohol may cross the placenta, enoxaparin sodium multiple-dose vials, preserved with benzyl alcohol, should be used with caution in pregnant women and only if clearly needed [see Use in Specific Populations (8.1) ]. 5.9 Laboratory Tests Periodic complete blood counts, including platelet count, and stool occult blood tests are recommended during the course of treatment with enoxaparin sodium. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) are relatively insensitive measures of enoxaparin activity and, therefore, unsuitable for monitoring. Anti-Factor Xa may be used to monitor the anticoagulant effect of enoxaparin sodium in patients with significant renal impairment. If during enoxaparin sodium therapy abnormal coagulation parameters or bleeding should occur, anti-Factor Xa levels may be used to monitor the anticoagulant effects of enoxaparin sodium [see Clinical Pharmacology (12.3) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION If patients have had neuraxial anesthesia or spinal puncture, and particularly, if they are taking concomitant NSAIDs, platelet inhibitors, or other anticoagulants, they should be informed to watch for signs and symptoms of spinal or epidural hematoma, such as tingling, numbness (especially in the lower limbs) and muscular weakness. If any of these symptoms occur the patient should contact his or her physician immediately. Additionally, the use of aspirin and other NSAIDs may enhance the risk of hemorrhage. Their use should be discontinued prior to enoxaparin therapy whenever possible; if co-administration is essential, the patient’s clinical and laboratory status should be closely monitored [see Drug Interactions (7) ]. Patients should also be informed: of the instructions for injecting enoxaparin sodium if their therapy is to continue after discharge from the hospitals. it may take them longer than usual to stop bleeding. they may bruise and/or bleed more easily when they are treated with enoxaparin sodium. they should report any unusual bleeding, bruising, or signs of thrombocytopenia (such as a rash of dark red spots under the skin) to their physician [see Warnings and Precautions (5.1, 5.5) ]. to tell their physicians and dentists they are taking enoxaparin sodium and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken [see Warnings and Precautions (5.3) ]. to tell their physicians and dentists of all medications they are taking, including those obtained without a prescription, such as aspirin or other NSAIDs [see Drug Interactions (7) ].

DOSAGE AND ADMINISTRATION

2 All patients should be evaluated for a bleeding disorder before administration of enoxaparin sodium, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring enoxaparin activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9) ]. For subcutaneous use, enoxaparin sodium should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), enoxaparin sodium can be mixed with normal saline solution (0.9%) or 5% dextrose in water. Enoxaparin sodium is not intended for intramuscular administration. Indication Dose DVT prophylaxis in abdominal surgery 40 mg SC once daily DVT prophylaxis in knee replacement surgery 30 mg SC every 12 hours DVT prophylaxis in hip replacement surgery 30 mg SC every 12 hours or 40 mg SC once daily DVT prophylaxis in medical patients 40 mg SC once daily Inpatient treatment of acute DVT with or without pulmonary embolism 1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily* Outpatient treatment of acute DVT without pulmonary embolism 1 mg/kg SC every 12 hours* Unstable angina and non-Q-wave MI 1 mg/kg SC every 12 hours (with aspirin) Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration (2.1)] 30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin) Acute STEMI in patients ≥75 years of age 0.75 mg/kg SC every 12 hours (no bolus) (with aspirin) See recommended durations for enoxaparin therapy (2.1) *See recommendations regarding transitioning to warfarin therapy (2.1) Adjust the dose for patients with severe renal impairment (2.2, 8.7) 2.1 Adult Dosage Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of enoxaparin sodium is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials. Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of enoxaparin sodium is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with enoxaparin sodium 40 mg once a day be administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials. Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of enoxaparin sodium is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of enoxaparin sodium has been administered in the controlled clinical trial. Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of enoxaparin sodium). Enoxaparin sodium should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of enoxaparin sodium administration has been administered in controlled clinical trials. Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of enoxaparin sodium is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with enoxaparin sodium should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of enoxaparin sodium has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies (14.5) ]. Treatment of Acute ST-Segment Elevation Myocardial Infarction: In patients with acute ST-segment elevation myocardial infarction, the recommended dose of enoxaparin sodium is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and Administration (2.3) ]. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. In the pivotal clinical study, the enoxaparin sodium treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days. For patients managed with percutaneous coronary intervention (PCI): If the last enoxaparin sodium SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last enoxaparin sodium SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin sodium should be administered [see Warnings and Precautions (5.2) ]. 2.2 Renal Impairment Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding. The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. Table 1 Dosage Regimens for Patients with Severe Renal Impairment (creatinine clearance <30mL/minute) Indication Dosage Regimen Prophylaxis in abdominal surgery 30 mg administered SC once daily Prophylaxis in hip or knee replacement surgery 30 mg administered SC once daily Prophylaxis in medical patients during acute illness 30 mg administered SC once daily Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered SC once daily Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered SC once daily Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin 1 mg/kg administered SC once daily Treatment of acute ST-segment elevation myocardial infarction in patients <75 years of age, when administered in conjunction with aspirin 30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily. Treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, when administered in conjunction with aspirin 1 mg/kg administered SC once daily (no initial bolus) 2.3 Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3) ]. No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2) ]. 2.4 Administration Enoxaparin sodium injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration. The use of a tuberculin syringe or equivalent is recommended when using enoxaparin sodium multiple-dose vials to assure withdrawal of the appropriate volume of drug. Enoxaparin sodium must not be administered by intramuscular injection. Enoxaparin sodium is intended for use under the guidance of a physician. For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided. Subcutaneous Injection Technique: Patients should be lying down and enoxaparin sodium administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection. Enoxaparin sodium prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection. Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister. Do not remove by pulling on the plunger as this may damage the syringe. Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient. Figure A Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B). Figure B Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C). Figure C Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (see Figure D). Figure D Immediately dispose of the syringe in the nearest sharps container (see Figure E). Figure E NOTE: The safety system can only be activated once the syringe has been emptied. Activation of the safety system must be done only after removing the needle from the patient's skin. Do not replace the needle shield after injection. The safety system should not be sterilized. Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others. Figure A Figure B Figure C Figure D Figure E Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should be used. Enoxaparin sodium should be administered through an intravenous line. Enoxaparin sodium should not be mixed or co-administered with other medications. To avoid the possible mixture of enoxaparin sodium with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of enoxaparin sodium to clear the port of drug. Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.

lamoTRIgine 300 MG 24HR Extended Release Oral Tablet

Generic Name: LAMOTRIGINE

Brand Name: Lamotrigine

Substance Name(s):
LAMOTRIGINE

DRUG INTERACTIONS

7. Valproate increases lamotrigine concentrations more than 2-fold. (7, 12.3) Carbamazepine, phenytoin, phenobarbital, and primidone decrease lamotrigine concentrations by approximately 40%. (7, 12.3) Estrogen-containing oral contraceptives and rifampin also decrease lamotrigine concentrations by approximately 50%. (7, 12.3) Significant drug interactions with lamotrigine are summarized in Table 4. Additional details of these drug interaction studies, which were conducted using immediate-release lamotrigine, are provided in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)]. Table 4. Established and Other Potentially Significant Drug Interactions ↓ = Decreased (induces lamotrigine glucuronidation). ↑ = Increased (inhibits lamotrigine glucuronidation). ? = Conflicting data. Concomitant Drug Effect on Concentration of Lamotrigine or Concomitant Drug Clinical Comment Estrogen-containing oral contraceptive preparations containing 30 mcg ethinylestradiol and 150 mcg levonorgestrel ↓ lamotrigine ↓ levonorgestrel Decreased lamotrigine levels approximately 50%. Decrease in levonorgestrel component by 19%. Carbamazepine and carbamazepine epoxide ↓ lamotrigine ? carbamazepine epoxide Addition of carbamazepine decreases lamotrigine concentration approximately 40%. May increase carbamazepine epoxide levels. Phenobarbital/Primidone ↓ lamotrigine Decreased lamotrigine concentration approximately 40%. Phenytoin ↓ lamotrigine Decreased lamotrigine concentration approximately 40%. Rifampin ↓ lamotrigine Decreased lamotrigine AUC approximately 40%. Valproate ↑ lamotrigine ? valproate Increased lamotrigine concentrations slightly more than 2-fold. Decreased valproate concentrations an average of 25% over a 3-week period then stabilized in healthy volunteers; no change in controlled clinical trials in epilepsy patients.

OVERDOSAGE

10. 10.1 Human Overdose Experience Overdoses involving quantities up to 15 g have been reported for immediate-release lamotrigine, some of which have been fatal. Overdose has resulted in ataxia, nystagmus, increased seizures, decreased level of consciousness, coma, and intraventricular conduction delay. 10.2 Management of Overdose There are no specific antidotes for lamotrigine. Following a suspected overdose, hospitalization of the patient is advised. General supportive care is indicated, including frequent monitoring of vital signs and close observation of the patient. If indicated, emesis should be induced; usual precautions should be taken to protect the airway. It is uncertain whether hemodialysis is an effective means of removing lamotrigine from the blood. In 6 renal failure patients, about 20% of the amount of lamotrigine in the body was removed by hemodialysis during a 4-hour session. A Poison Control Center should be contacted for information on the management of overdosage of lamotrigine extended-release tablets.

DESCRIPTION

11. Lamotrigine, an AED of the phenyltriazine class, is chemically unrelated to existing AEDs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-as-triazine, its molecular formula is C9H7N5Cl2, and its molecular weight is 256.09. Lamotrigine is a white or almost white powder and has a pKa of 5.7. Lamotrigine is very slightly soluble in water and in 0.1M hydrochloric acid. The structural formula is: Lamotrigine Extended-Release Tablets are supplied for oral administration as 25 mg (yellow, enteric-coated, circular shaped tablet), 50 mg (pink, enteric-coated, circular shaped tablet), 100 mg (light brown, enteric-coated, circular shaped tablet), 200 mg (pink, enteric-coated, circular shaped tablet) and 300 mg (pink, enteric-coated, circular shaped tablet). Each tablet contains the labeled amount of lamotrigine and the following inactive ingredients: diethyl phthalate, hypromellose, lactose monohydrate, magnesium stearate, methacrylic acid copolymer, polyethylene glycol, talc, titanium dioxide, iron oxide yellow for (25 mg and 100 mg) and iron oxide red for (50 mg, 100 mg, 200 mg and 300 mg). Lamotrigine extended-release tablets contain a modified-release eroding formulation as the core. The tablets are coated with enteric coat to enable a controlled release of drug in the acidic environment of the stomach. The combination of this and the modified-release core are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels. Structure

CLINICAL STUDIES

14. 14.1 14.1 14.2 Adjunctive Therapy for Partial Onset Seizures The effectiveness of immediate-release lamotrigine as adjunctive therapy was initially established in 3 pivotal multicenter, placebo-controlled, double-blind clinical trials in 355 adults with refractory partial onset seizures. The effectiveness of lamotrigine extended-release tablets as adjunctive therapy in partial onset seizures, with or without secondary generalization, was established in a 19-week, multicenter, double-blind, placebo-controlled trial in 236 patients, 13 years of age and older (approximately 93% of patients were aged 16 to 65 years). Approximately 36% were from the U.S. and approximately 64% were from other countries including Argentina, Brazil, Chile, Germany, India, Korea, Russian Federation, and Ukraine. Patients with at least 8 partial onset seizures during an 8-week prospective baseline phase (or 4-week prospective baseline coupled with a 4-week historical baseline documented with seizure diary data) were randomized to treatment with lamotrigine extended-release tablets (n = 116) or placebo (n = 120) added to their current regimen of 1 or 2 AEDs. Approximately half of the patients were taking 2 concomitant AEDs at baseline. Target doses ranged from 200 to 500 mg/day of lamotrigine extended-release tablets based on concomitant AED (target dose = 200 mg for valproate, 300 mg for AEDs not altering plasma lamotrigine, and 500 mg for enzyme-inducing AEDs). The median partial seizure frequency per week at baseline was 2.3 for lamotrigine extended-release tablets and 2.1 for placebo. The primary endpoint was the median percent change from baseline in partial onset seizure frequency during the entire double-blind treatment phase. The median percent reductions in weekly partial onset seizures were 47% in patients treated with lamotrigine extended-release tablets and 25% on placebo, a difference that was statistically significant, defined as a 2-sided P value <0.05. Figure 1 presents the percentage of patients (X-axis) with a percent reduction in partial seizure frequency (responder rate) from baseline through the entire treatment period at least as great as that represented on the Y-axis. The proportion of patients achieving any particular level of reduction in partial seizure frequency was consistently higher for the group treated with lamotrigine extended-release tablets compared with the placebo group. For example, 44% of patients randomized to lamotrigine extended-release tablets experienced a 50% or greater reduction in partial seizure frequency, compared with 21% of patients randomized to placebo. Figure 1. Proportion of Patients by Responder Rate for Lamotrigine Extended-Release Tablets and Placebo Group (Partial Onset Seizure Study) Figure 1

HOW SUPPLIED

16. /STORAGE AND HANDLING Lamotrigine extended-release tablets 25 mg are available as yellow, enteric-coated, circular shaped tablets, debossed with “W” on one side and “271” on the other side. NDC 64679-271-01, bottle of 30 tablets NDC 64679-271-02, bottle of 500 tablets NDC 64679-271-04, unit dose of 100 tablets 50 mg are available as pink, enteric-coated, circular shaped tablets, debossed with “W” on one side and “274” on the other side. NDC 64679-274-01, bottle of 30 tablets NDC 64679-274-02, bottle of 500 tablets NDC 64679-274-03, unit dose of 100 tablets 100 mg are available as light brown, enteric-coated, circular shaped tablets, debossed with “W” on one side and “273” on the other side. NDC 64679-273-01, bottle of 30 tablets NDC 64679-273-02, bottle of 500 tablets NDC 64679-273-04, unit dose of 100 tablets 200 mg are available as pink, enteric-coated, circular shaped tablets, debossed with “W” on one side and “272” on the other side. NDC 64679-272-01, bottle of 30 tablets NDC 64679-272-02, bottle of 500 tablets NDC 64679-272-04, unit dose of 100 tablets 300 mg are available as pink, enteric-coated, circular shaped tablets, debossed with “W” on one side and “275” on the other side. NDC 64679-275-01, bottle of 30 tablets NDC 64679-275-02, bottle of 500 tablets NDC 64679-275-04, unit dose of 100 tablets Storage: Store at 20°-25°C (68°-77°F); [see USP Controlled Room Temperature].

RECENT MAJOR CHANGES

Warnings and Precautions, Multiorgan Hypersensitivity and Organ Failure (5.2) August 2011

GERIATRIC USE

8.5 Geriatric Use Clinical studies of lamotrigine extended-release tablets for epilepsy did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects or exhibit a different safety profile than that of younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3. Extended-Release Tablets: 25 mg, 50 mg, 100 mg, 200 mg and 300 mg. (3.1, 16) 3.1 Extended-Release Tablets 25 mg, yellow, enteric-coated, circular shaped tablet, debossed with “W” on one side and “271” on the other side. 50 mg, pink, enteric-coated, circular shaped tablet, debossed with “W” on one side and “274” on the other side. 100 mg, light brown, enteric-coated, circular shaped tablet, debossed with “W” on one side and “273” on the other side. 200 mg, pink, enteric-coated, circular shaped tablet, debossed with “W” on one side and “272” on the other side. 300 mg, pink, enteric-coated, circular shaped tablet, debossed with “W” on one side and “275” on the other side. 3.2 Potential Medication Errors Patients should be strongly advised to visually inspect their tablets to verify that they are receiving lamotrigine extended-release tablets, as opposed to other medications, and that they are receiving the correct formulation of lamotrigine each time they fill their prescription. Depictions of the lamotrigine extended-release tablets can be found in the Medication Guide.

MECHANISM OF ACTION

12.1 Mechanism of Action The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock and pentylenetetrazol tests, and prevented seizures in the visually and electrically evoked after-discharge tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known. One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate). Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The IC50 for lamotrigine effects on NMDA-induced currents (in the presence of 3 μM of glycine) in cultured hippocampal neurons exceeded 100 μM.

INDICATIONS AND USAGE

1. Lamotrigine extended-release tablet is an antiepileptic drug (AED) indicated for: adjunctive therapy for partial onset seizures with or without secondary generalization in patients ≥13 years of age. (1.1) Limitation of use: Safety and effectiveness in patients less than 13 years of age have not been established. (1.3) 1.1 Adjunctive Therapy Lamotrigine extended-release tablets are indicated as adjunctive therapy for partial onset seizures with or without secondary generalization in patients ≥13 years of age. 1.2 1.2 1.3 Limitation of Use Safety and effectiveness of lamotrigine extended-release tablets for use in patients less than 13 years of age have not been established.

PREGNANCY

8.1 Pregnancy As with other AEDs, physiological changes during pregnancy may affect lamotrigine concentrations and/or therapeutic effect. There have been reports of decreased lamotrigine concentrations during pregnancy and restoration of pre-partum concentrations after delivery. Dosage adjustments may be necessary to maintain clinical response. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal studies, lamotrigine was developmentally toxic at doses lower than those administered clinically. Lamotrigine extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. When lamotrigine was administered to pregnant mice, rats, or rabbits during the period of organogenesis (oral doses of up to 125, 25, and 30 mg/kg, respectively), reduced fetal body weight and increased incidences of fetal skeletal variations were seen in mice and rats at doses that were also maternally toxic. The no-effect doses for embryo-fetal developmental toxicity in mice, rats, and rabbits (75, 6.25, and 30 mg/kg, respectively) are similar to (mice and rabbits) or less than the human dose of 400 mg/day on a body surface area (mg/m2) basis. In a study in which pregnant rats were administered lamotrigine (oral doses of 5 or 25 mg/kg) during the period of organogenesis and offspring were evaluated postnatally, behavioral abnormalities were observed in exposed offspring at both doses. The lowest effect dose for developmental neurotoxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the higher dose tested. When pregnant rats were administered lamotrigine (oral doses of 5, 10, or 20 mg/kg) during the latter part of gestation, increased offspring mortality (including stillbirths) was seen at all doses. The lowest effect dose for peri/postnatal developmental toxicity in rats is less than the human dose of 400 mg/day on a mg/m2 basis. Maternal toxicity was observed at the two highest doses tested. Lamotrigine decreases fetal folate concentrations in rat, an effect known to be associated with adverse pregnancy outcomes in animals and humans. Pregnancy Registry: To provide information regarding the effects of in utero exposure to lamotrigine extended-release tablets, physicians are advised to recommend that pregnant patients taking lamotrigine extended-release tablets enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll-free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org.

NUSRING MOTHERS

8.3 Nursing Mothers Lamotrigine is present in milk from lactating women taking lamotrigine extended-release tablets. Data from multiple small studies indicate that lamotrigine plasma levels in human milk-fed infants have been reported to be as high as 50% of the maternal serum levels. Neonates and young infants are at risk for high serum levels because maternal serum and milk levels can rise to high levels postpartum if lamotrigine dosage has been increased during pregnancy but not later reduced to the pre-pregnancy dosage. Lamotrigine exposure is further increased due to the immaturity of the infant glucuronidation capacity needed for drug clearance. Events including apnea, drowsiness, and poor sucking have been reported in infants who have been human milk-fed by mothers using lamotrigine; whether or not these events were caused by lamotrigine is unknown. Human milk fed infants should be closely monitored for adverse events resulting from lamotrigine. Measurement of infant serum levels should be performed to rule out toxicity if concerns arise. Human milk-feeding should be discontinued in infants with lamotrigine toxicity. Caution should be exercised when lamotrigine extended-release tablet is administered to a nursing woman.

BOXED WARNING

WARNING: SERIOUS SKIN RASHES WARNING: SERIOUS SKIN RASHES See full prescribing information for complete boxed warning. Cases of life-threatening serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, and/or rash-related death have been caused by lamotrigine. The rate of serious rash is greater in pediatric patients than in adults. Additional factors that may increase the risk of rash include (5.1): coadministration with valproate exceeding recommended initial dose of lamotrigine extended-release tablets exceeding recommended dose escalation of lamotrigine extended-release tablets. Benign rashes are also caused by lamotrigine; however, it is not possible to predict which rashes will prove to be serious or life threatening. Lamotrigine extended-release tablets should be discontinued at the first sign of rash, unless the rash is clearly not drug related. (5.1) Lamotrigine extended-release tablets can cause serious rashes requiring hospitalization and discontinuation of treatment. The incidence of these rashes, which have included Stevens Johnson syndrome, is approximately 0.8% (8 per 1,000) in pediatric patients (aged 2 to 16 years) receiving immediate-release lamotrigine as adjunctive therapy for epilepsy and 0.3% (3 per 1,000) in adults on adjunctive therapy for epilepsy. In a prospectively followed cohort of 1,983 pediatric patients (aged 2 to 16 years) with epilepsy taking adjunctive immediate-release lamotrigine, there was 1 rash-related death. Lamotrigine extended-release tablet is not approved for patients less than 13 years of age. In worldwide postmarketing experience, rare cases of toxic epidermal necrolysis and/or rash-related death have been reported in adult and pediatric patients, but their numbers are too few to permit a precise estimate of the rate. The risk of serious rash caused by treatment with lamotrigine extended-release tablet is not expected to differ from that with the immediate-release lamotrigine. However, the relatively limited treatment experience with lamotrigine extended-release tablets makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release tablets. Other than age, there are as yet no factors identified that are known to predict the risk of occurrence or the severity of rash caused by lamotrigine extended-release tablets. There are suggestions, yet to be proven, that the risk of rash may also be increased by (1) coadministration of lamotrigine extended-release tablets with valproate (includes valproic acid and divalproex sodium), (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets. However, cases have occurred in the absence of these factors. Nearly all cases of life-threatening rashes caused by the immediate-release lamotrigine have occurred within 2 to 8 weeks of treatment initiation. However, isolated cases have occurred after prolonged treatment (e.g., 6 months). Accordingly, duration of therapy cannot be relied upon as means to predict the potential risk heralded by the first appearance of a rash. Although benign rashes are also caused by lamotrigine extended-release tablets, it is not possible to predict reliably which rashes will prove to be serious or life-threatening. Accordingly, lamotrigine extended-release tablets should ordinarily be discontinued at the first sign of rash, unless the rash is clearly not drug-related. Discontinuation of treatment may not prevent a rash from becoming life threatening or permanently disabling or disfiguring [see Warnings and Precautions (5.1)].

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Life-threatening serious rash and/or rash-related death: Discontinue at the first sign of rash, unless the rash is clearly not drug related. (Boxed Warning, 5.1) Fatal or life-threatening hypersensitivity reaction: Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), may be fatal or life threatening. Early signs may include rash, fever, and lymphadenopathy. These reactions may be associated with other organ involvement, such as hepatitis, hepatic failure, blood dyscrasias, or acute multiorgan failure. Lamotrigine extended-release tablets should be discontinued if alternate etiology for this reaction is not found. (5.2) Blood dyscrasias (e.g., neutropenia, thrombocytopenia, pancytopenia): May occur, either with or without an associated hypersensitivity syndrome. Monitor for signs of anemia, unexpected infection, or bleeding. (5.3) Suicidal behavior and ideation: Monitor for suicidal thoughts or behaviors. (5.4) Aseptic meningitis: Monitor for signs of meningitis. (5.5) Medication errors due to product name confusion: Strongly advise patients to visually inspect tablets to verify the received drug is correct. (3.2, 5.6, 16, 17.10) 5.1 Serious Skin Rashes The risk of serious rash caused by treatment with lamotrigine extended-release tablet is not expected to differ from that with immediate-release lamotrigine [see Boxed Warning]. However, the relatively limited treatment experience with lamotrigine extended-release tablets makes it difficult to characterize the frequency and risk of serious rashes caused by treatment with lamotrigine extended-release tablets. Pediatric Population: The incidence of serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine in a prospectively followed cohort of pediatric patients (aged 2 to 16 years) with epilepsy receiving adjunctive therapy with immediate-release lamotrigine was approximately 0.8% (16 of 1,983). When 14 of these cases were reviewed by 3 expert dermatologists, there was considerable disagreement as to their proper classification. To illustrate, one dermatologist considered none of the cases to be Stevens-Johnson syndrome; another assigned 7 of the 14 to this diagnosis. There was 1 rash-related death in this 1,983-patient cohort. Additionally, there have been rare cases of toxic epidermal necrolysis with and without permanent sequelae and/or death in US and foreign postmarketing experience. There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in pediatric patients. In pediatric patients who used valproate concomitantly, 1.2% (6 of 482) experienced a serious rash compared with 0.6% (6 of 952) patients not taking valproate. Lamotrigine extended-release tablet is not approved in patients less than 13 years of age. Adult Population: Serious rash associated with hospitalization and discontinuation of immediate-release lamotrigine occurred in 0.3% (11 of 3,348) of adult patients who received immediate-release lamotrigine tablets in premarketing clinical trials of epilepsy. In worldwide postmarketing experience, rare cases of rash-related death have been reported, but their numbers are too few to permit a precise estimate of the rate. Among the rashes leading to hospitalization were Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, and those associated with multiorgan hypersensitivity [see Warnings and Precautions (5.2)]. There is evidence that the inclusion of valproate in a multidrug regimen increases the risk of serious, potentially life-threatening rash in adults. Specifically, of 584 patients administered immediate-release lamotrigine with valproate in epilepsy clinical trials, 6 (1%) were hospitalized in association with rash; in contrast, 4 (0.16%) of 2,398 clinical trial patients and volunteers administered immediate-release lamotrigine in the absence of valproate were hospitalized. Patients With History of Allergy or Rash to Other Antiepileptic Drugs: The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation of lamotrigine extended-release tablets are exceeded and in patients with a history of allergy or rash to other AEDs. 5.2 Multiorgan Hypersensitivity Reactions and Organ Failure Multiorgan hypersensitivity reactions, also known as Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have occurred with lamotrigine. Some have been fatal or life threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. This disorder is variable in its expression and other organ systems not noted here may be involved. Fatalities associated with acute multiorgan failure and various degrees of hepatic failure have been reported in 2 of 3,796 adult patients and 4 of 2,435 pediatric patients who received lamotrigine in epilepsy clinical trials. Rare fatalities from multiorgan failure have also been reported in postmarketing use. Isolated liver failure without rash or involvement of other organs has also been reported with lamotrigine. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though a rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Lamotrigine extended-release tablets should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Prior to initiation of treatment with lamotrigine extended-release tablets, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. 5.3 Blood Dyscrasias There have been reports of blood dyscrasias with immediate-release lamotrigine that may or may not be associated with multiorgan hypersensitivity (also known as DRESS) [see Warnings and Precautions (5.2)]. These have included neutropenia, leukopenia, anemia, thrombocytopenia, pancytopenia, and, rarely, aplastic anemia and pure red cell aplasia. 5.4 Suicidal Behavior and Ideation AEDs, including lamotrigine extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (monotherapy and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately 1 case of suicidal thinking or behavior for every 530 patients treated. There were 4 suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanism of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients With Events Per 1,000 Patients Drug Patients With Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients With Events Per 1,000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing lamotrigine extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression; any unusual changes in mood or behavior; or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.5 Aseptic Meningitis Therapy with lamotrigine increases the risk of developing aseptic meningitis. Because of the potential for serious outcomes of untreated meningitis due to other causes, patients should also be evaluated for other causes of meningitis and treated as appropriate. Postmarketing cases of aseptic meningitis have been reported in pediatric and adult patients taking lamotrigine for various indications. Symptoms upon presentation have included headache, fever, nausea, vomiting, and nuchal rigidity. Rash, photophobia, myalgia, chills, altered consciousness, and somnolence were also noted in some cases. Symptoms have been reported to occur within 1 day to one and a half months following the initiation of treatment. In most cases, symptoms were reported to resolve after discontinuation of lamotrigine. Re-exposure resulted in a rapid return of symptoms (from within 30 minutes to 1 day following re-initiation of treatment) that were frequently more severe. Some of the patients treated with lamotrigine who developed aseptic meningitis had underlying diagnoses of systemic lupus erythematosus or other autoimmune diseases. Cerebrospinal fluid (CSF) analyzed at the time of clinical presentation in reported cases was characterized by a mild to moderate pleocytosis, normal glucose levels, and mild to moderate increase in protein. CSF white blood cell count differentials showed a predominance of neutrophils in a majority of the cases, although a predominance of lymphocytes was reported in approximately one third of the cases. Some patients also had new onset of signs and symptoms of involvement of other organs (predominantly hepatic and renal involvement), which may suggest that in these cases the aseptic meningitis observed was part of a hypersensitivity reaction [see Warnings and Precautions (5.2)]. 5.6 Potential Medication Errors Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine extended-release tablets clearly. Depictions of the lamotrigine extended-release tablets can be found in the Medication Guide. Each lamotrigine extended-release tablet has a distinct debossing and is debossed with “W” on one side and “271” on the other side for 25 mg, “W” on one side and “274” on the other side for 50 mg, “W” on one side and “273” on the other side for 100 mg, “W” on one side and “272” on the other side for 200 mg and “W” on one side and “275” on the other side for 300 mg. These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. Lamotrigine extended-release tablets are supplied in circular, unit-of-use bottles containing 30 tablets and 100 unit dose blister pack. Additionally, Lamotrigine extended-release tablets are also supplied as 500 count bottle pack. The label on the bottle includes a depiction of the tablets which further communicates to patients and pharmacists that the medication is lamotrigine extended-release tablets and the specific tablet strength included in the bottle. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine extended-release tablets each time they fill their prescription. 5.7 Concomitant Use With Oral Contraceptives Some estrogen-containing oral contraceptives have been shown to decrease serum concentrations of lamotrigine [see Clinical Pharmacology (12.3)]. Dosage adjustments will be necessary in most patients who start or stop estrogen-containing oral contraceptives while taking lamotrigine extended-release tablets [see Dosage and Administration (2.1)]. During the week of inactive hormone preparation (pill-free week) of oral contraceptive therapy, plasma lamotrigine levels are expected to rise, as much as doubling at the end of the week. Adverse reactions consistent with elevated levels of lamotrigine, such as dizziness, ataxia, and diplopia, could occur. 5.8 Withdrawal Seizures As with other AEDs, lamotrigine extended-release tablets should not be abruptly discontinued. In patients with epilepsy there is a possibility of increasing seizure frequency. Unless safety concerns require a more rapid withdrawal, the dose of lamotrigine extended-release tablets should be tapered over a period of at least 2 weeks (approximately 50% reduction per week) [see Dosage and Administration (2.1)]. 5.9 Status Epilepticus Valid estimates of the incidence of treatment-emergent status epilepticus among patients treated with immediate-release lamotrigine are difficult to obtain because reporters participating in clinical trials did not all employ identical rules for identifying cases. At a minimum, 7 of 2,343 adult patients had episodes that could unequivocally be described as status epilepticus. In addition, a number of reports of variably defined episodes of seizure exacerbation (e.g., seizure clusters, seizure flurries) were made. 5.10 Sudden Unexplained Death in Epilepsy During the premarketing development of the immediate-release formulation of lamotrigine, 20 sudden and unexplained deaths were recorded among a cohort of 4,700 patients with epilepsy (5,747 patient-years of exposure). Some of these could represent seizure-related deaths in which the seizure was not observed, e.g., at night. This represents an incidence of 0.0035 deaths per patient-year. Although this rate exceeds that expected in a healthy population matched for age and sex, it is within the range of estimates for the incidence of sudden unexplained deaths in patients with epilepsy not receiving lamotrigine (ranging from 0.0005 for the general population of patients with epilepsy, to 0.004 for a recently studied clinical trial population similar to that in the clinical development program for immediate-release lamotrigine, to 0.005 for patients with refractory epilepsy). Consequently, whether these figures are reassuring or suggest concern depends on the comparability of the populations reported upon to the cohort receiving immediate-release lamotrigine and the accuracy of the estimates provided. Probably most reassuring is the similarity of estimated sudden unexplained death in epilepsy (SUDEP) rates in patients receiving immediate-release lamotrigine and those receiving other AEDs, chemically unrelated to each other, that underwent clinical testing in similar populations. Importantly, that drug is chemically unrelated to lamotrigine. This evidence suggests, although it certainly does not prove, that the high SUDEP rates reflect population rates, not a drug effect. 5.11 Addition of Lamotrigine Extended-Release Tablets to a Multidrug Regimen That Includes Valproate Because valproate reduces the clearance of lamotrigine, the dosage of lamotrigine in the presence of valproate is less than half of that required in its absence [see Dosage and Administration (2.1, 2.2), Drug Interactions (7)]. 5.12 Binding in the Eye and Other Melanin-Containing Tissues Because lamotrigine binds to melanin, it could accumulate in melanin-rich tissues over time. This raises the possibility that lamotrigine may cause toxicity in these tissues after extended use. Although ophthalmological testing was performed in one controlled clinical trial, the testing was inadequate to exclude subtle effects or injury occurring after long-term exposure. Moreover, the capacity of available tests to detect potentially adverse consequences, if any, of lamotrigine binding to melanin is unknown [see Clinical Pharmacology (12.2)]. Accordingly, although there are no specific recommendations for periodic ophthalmological monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects. 5.13 Laboratory Tests Plasma Concentrations of Lamotrigine: The value of monitoring plasma concentrations of lamotrigine in patients treated with lamotrigine extended-release tablets has not been established. Because of the possible pharmacokinetic interactions between lamotrigine and other drugs, including AEDs (see Table 5), monitoring of the plasma levels of lamotrigine and concomitant drugs may be indicated, particularly during dosage adjustments. In general, clinical judgment should be exercised regarding monitoring of plasma levels of lamotrigine and other drugs and whether or not dosage adjustments are necessary. Effect on Leukocytes: Treatment with lamotrigine extended-release tablets caused an increased incidence of subnormal (below the reference range) values in some hematology analytes (e.g., total white blood cells, monocytes). The treatment effect (Lamotrigine extended-release tablets % – Placebo %) incidence of subnormal counts was 3% for total white blood cells and 4% for monocytes.

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). 17.1 Rash Prior to initiation of treatment with lamotrigine extended-release tablets, the patient should be instructed that a rash or other signs or symptoms of hypersensitivity (e.g., fever, lymphadenopathy) may herald a serious medical event and that the patient should report any such occurrence to a physician immediately. 17.2 Multiorgan Hypersensitivity Reactions, Blood Dyscrasias and Organ Failure Patients should be instructed that multiorgan hypersensitivity reactions and acute multiorgan failure may occur with lamotrigine. Isolated organ failure or isolated blood dyscrasias without evidence of multiorgan hypersensitivity may also occur. Patients should contact their physician immediately if they experience any signs or symptoms of these conditions [see Warnings and Precautions (5.2, 5.3)]. 17.3 Suicidal Thinking and Behavior Patients, their caregivers, and families should be counseled that AEDs, including lamotrigine extended-release tablets, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression; any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior; or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 17.4 Worsening of Seizures Patients should be advised to notify their physician if worsening of seizure control occurs. 17.5 Central Nervous System Adverse Effects Patients should be advised that lamotrigine extended-release tablets may cause dizziness, somnolence, and other symptoms and signs of central nervous system depression. Accordingly, they should be advised neither to drive a car nor to operate other complex machinery until they have gained sufficient experience on lamotrigine extended-release tablets to gauge whether or not it adversely affects their mental and/or motor performance. 17.6 Pregnancy and Nursing Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. Patients should also be encouraged to enroll in the NAAED Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll-free number 1-888-233-2334 [see Use in Specific Populations (8.1)]. Patients who intend to breastfeed should be informed that lamotrigine extended-release tablet is present in breast milk and that they should monitor their child for potential adverse effects of this drug. Benefits and risks of continuing breastfeeding should be discussed with the patient. 17.7 Oral Contraceptive Use Women should be advised to notify their physician if they plan to start or stop use of oral contraceptives or other female hormonal preparations. Starting estrogen-containing oral contraceptives may significantly decrease lamotrigine plasma levels and stopping estrogen-containing oral contraceptives (including the pill-free week) may significantly increase lamotrigine plasma levels [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)]. Women should also be advised to promptly notify their physician if they experience adverse reactions or changes in menstrual pattern (e.g., break-through bleeding) while receiving lamotrigine extended-release tablets in combination with these medications. 17.8 Discontinuing lamotrigine extended-release tablets Patients should be advised to notify their physician if they stop taking lamotrigine extended-release tablets for any reason and not to resume lamotrigine extended-release tablets without consulting their physician. 17.9 Aseptic Meningitis Patients should be advised that lamotrigine extended-release tablets may cause aseptic meningitis. Patients should be advised to notify their physician immediately if they develop signs and symptoms of meningitis such as headache, fever, nausea, vomiting, stiff neck, rash, abnormal sensitivity to light, myalgia, chills, confusion, or drowsiness while taking lamotrigine extended-release tablets. 17.10 Potential Medication Errors Medication errors involving lamotrigine have occurred. In particular, the name lamotrigine can be confused with the names of other commonly used medications. Medication errors may also occur between the different formulations of lamotrigine. To reduce the potential of medication errors, write and say lamotrigine extended-release tablets clearly. Depictions of the lamotrigine extended-release tablets can be found in the Medication Guide. Each lamotrigine extended-release tablet has a distinct debossing and is debossed with “W” on one side and “271” on the other side for 25 mg; “W” on one side and “274” on the other side for 50 mg; “W” on one side and “273” on the other side for 100 mg; “W” on one side and “272” on the other side for 200 mg and “W” on one side and “275” on the other side for 300 mg. These distinctive features serve to identify the different presentations of the drug and thus may help reduce the risk of medication errors. Lamotrigine extended-release tablets are supplied in circular, unit-of-use bottles containing 30 tablets and 100 unit dose blister pack. Additionally, lamotrigine extended-release tablets are also supplied as 500 count bottle pack. The label on the bottle includes a depiction of the tablets which further communicates to patients and pharmacists that the medication is lamotrigine extended-release tablets and the specific tablet strength included in the bottle. To avoid the medication error of using the wrong drug or formulation, patients should be strongly advised to visually inspect their tablets to verify that they are lamotrigine extended-release tablets each time they fill their prescription and to immediately talk to their doctor/pharmacist if they receive a lamotrigine extended-release tablets without debossed on the tablet as they may have received the wrong medication [see Dosage Forms and Strengths (3), How Supplied/Storage and Handling (16)]. Manufactured by: Wockhardt Limited, Mumbai, India. Distributed by: Wockhardt USA LLC. 20 Waterview Blvd. Parsippany, NJ 07054 USA. Iss.240812

DOSAGE AND ADMINISTRATION

2. Do not exceed the recommended initial dosage and subsequent dose escalation. (2.1) Initiation of adjunctive therapy requires slow titration dependent on concomitant AEDs; the prescriber must refer to the appropriate algorithm in Dosage and Administration (2.2) ● Adjunct therapy target therapeutic dose range is 200 to 600 mg daily and is dependent on concomitant AEDs. (2.2) Conversion from immediate-release lamotrigine to lamotrigine extended-release tablet: The initial dose of lamotrigine extended-release tablets should match the total daily dose of the immediate-release lamotrigine. Patients should be closely monitored for seizure control after conversion. (2.4) Do not restart lamotrigine extended-release tablets in patients who discontinued due to rash unless the potential benefits clearly outweigh the risks. (2.1, 5.1) Adjustments to maintenance doses are likely in patients starting or stopping estrogen-containing oral contraceptives. (2.1, 5.7) Discontinuation: Taper over a period of at least 2 weeks (approximately 50% dose reduction per week). (2.1, 5.8) Lamotrigine extended-release tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided. 2.1 General Dosing Considerations Rash: There are suggestions, yet to be proven, that the risk of severe, potentially life-threatening rash may be increased by (1) coadministration of lamotrigine extended-release tablets with valproate, (2) exceeding the recommended initial dose of lamotrigine extended-release tablets, or (3) exceeding the recommended dose escalation for lamotrigine extended-release tablets. However, cases have occurred in the absence of these factors [see Boxed Warning]. Therefore, it is important that the dosing recommendations be followed closely. The risk of nonserious rash may be increased when the recommended initial dose and/or the rate of dose escalation for lamotrigine extended-release tablet is exceeded and in patients with a history of allergy or rash to other AEDs. It is recommended that lamotrigine extended-release tablets not be restarted in patients who discontinued due to rash associated with prior treatment with lamotrigine, unless the potential benefits clearly outweigh the risks. If the decision is made to restart a patient who has discontinued lamotrigine extended-release tablets, the need to restart with the initial dosing recommendations should be assessed. The greater the interval of time since the previous dose, the greater consideration should be given to restarting with the initial dosing recommendations. If a patient has discontinued lamotrigine for a period of more than 5 half-lives, it is recommended that initial dosing recommendations and guidelines be followed. The half-life of lamotrigine is affected by other concomitant medications [see Clinical Pharmacology (12.3)]. Lamotrigine Extended-Release Tablets Added to Drugs Known to Induce or Inhibit Glucuronidation: Drugs other than those listed in the Clinical Pharmacology section [see Clinical Pharmacology (12.3)] have not been systematically evaluated in combination with lamotrigine. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine extended-release tablets may require adjustment based on clinical response. Target Plasma Levels: A therapeutic plasma concentration range has not been established for lamotrigine. Dosing of lamotrigine extended-release tablets should be based on therapeutic response [see Clinical Pharmacology (12.3)]. Women Taking Estrogen-Containing Oral Contraceptives: Starting Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: Although estrogen-containing oral contraceptives have been shown to increase the clearance of lamotrigine [see Clinical Pharmacology (12.3)], no adjustments to the recommended dose-escalation guidelines for lamotrigine extended-release tablets should be necessary solely based on the use of estrogen-containing oral contraceptives. Therefore, dose escalation should follow the recommended guidelines for initiating adjunctive therapy with lamotrigine extended-release tablets based on the concomitant AED or other concomitant medications (see Table 1). See below for adjustments to maintenance doses of lamotrigine extended-release tablets in women taking estrogen-containing oral contraceptives. Adjustments to the Maintenance Dose of Lamotrigine Extended-Release Tablets in Women Taking Estrogen-Containing Oral Contraceptives: (1) Taking Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions, (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be increased by as much as 2-fold over the recommended target maintenance dose in order to maintain a consistent lamotrigine plasma level [see Clinical Pharmacology (12.3)]. (2) Starting Estrogen-Containing Oral Contraceptives: In women taking a stable dose of lamotrigine extended-release tablets and not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose will in most cases need to be increased by as much as 2-fold in order to maintain a consistent lamotrigine plasma level. The dose increases should begin at the same time that the oral contraceptive is introduced and continue, based on clinical response, no more rapidly than 50 to 100 mg/day every week. Dose increases should not exceed the recommended rate (see Table 1) unless lamotrigine plasma levels or clinical response support larger increases. Gradual transient increases in lamotrigine plasma levels may occur during the week of inactive hormonal preparation (pill-free week), and these increases will be greater if dose increases are made in the days before or during the week of inactive hormonal preparation. Increased lamotrigine plasma levels could result in additional adverse reactions, such as dizziness, ataxia, and diplopia. If adverse reactions attributable to lamotrigine extended-release tablets consistently occur during the pill-free week, dose adjustments to the overall maintenance dose may be necessary. Dose adjustments limited to the pill-free week are not recommended. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary. (3) Stopping Estrogen-Containing Oral Contraceptives: For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], the maintenance dose of lamotrigine extended-release tablets will in most cases need to be decreased by as much as 50% in order to maintain a consistent lamotrigine plasma level. The decrease in dose of lamotrigine extended-release tablets should not exceed 25% of the total daily dose per week over a 2-week period, unless clinical response or lamotrigine plasma levels indicate otherwise [see Clinical Pharmacology (12.3)]. For women taking lamotrigine extended-release tablets in addition to carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation [see Drug Interactions (7), Clinical Pharmacology (12.3)], no adjustment to the dose of lamotrigine extended-release tablets should be necessary. Women and Other Hormonal Contraceptive Preparations or Hormone Replacement Therapy: The effect of other hormonal contraceptive preparations or hormone replacement therapy on the pharmacokinetics of lamotrigine has not been systematically evaluated. It has been reported that ethinylestradiol, not progestogens, increased the clearance of lamotrigine up to 2-fold, and the progestin-only pills had no effect on lamotrigine plasma levels. Therefore, adjustments to the dosage of lamotrigine extended-release tablets in the presence of progestogens alone will likely not be needed. Patients With Hepatic Impairment: Experience in patients with hepatic impairment is limited. Based on a clinical pharmacology study in 24 patients with mild, moderate, and severe liver impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)], the following general recommendations can be made. No dosage adjustment is needed in patients with mild liver impairment. Initial, escalation, and maintenance doses should generally be reduced by approximately 25% in patients with moderate and severe liver impairment without ascites and 50% in patients with severe liver impairment with ascites. Escalation and maintenance doses may be adjusted according to clinical response. Patients With Renal Impairment: Initial doses of lamotrigine extended-release tablets should be based on patients’ concomitant medications (see Table 1); reduced maintenance doses may be effective for patients with significant renal impairment [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Few patients with severe renal impairment have been evaluated during chronic treatment with immediate-release lamotrigine. Because there is inadequate experience in this population, lamotrigine extended-release tablets should be used with caution in these patients. Discontinuation Strategy: For patients receiving lamotrigine extended-release tablets in combination with other AEDs, a re-evaluation of all AEDs in the regimen should be considered if a change in seizure control or an appearance or worsening of adverse reactions is observed. If a decision is made to discontinue therapy with lamotrigine extended-release tablets, a step-wise reduction of dose over at least 2 weeks (approximately 50% per week) is recommended unless safety concerns require a more rapid withdrawal [see Warnings and Precautions (5.8)]. Discontinuing carbamazepine, phenytoin, phenobarbital, primidone, or other drugs such as rifampin that induce lamotrigine glucuronidation should prolong the half-life of lamotrigine; discontinuing valproate should shorten the half-life of lamotrigine. 2.2 Adjunctive Therapy for Partial Onset Seizures This section provides specific dosing recommendations for patients ≥13 years of age. Specific dosing recommendations are provided depending upon concomitant AED or other concomitant medications. Table 1. Escalation Regimen for Lamotrigine Extended-Release Tablets in Patients ≥13 Years of Age a Valproate has been shown to inhibit glucuronidation and decrease the apparent clearance of lamotrigine [see Drug Interactions (7), Clinical Pharmacology (12.3)]. b These drugs induce glucuronidation and increase clearance [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Other drugs which have similar effects include estrogen- containing oral contraceptives [see Drug Interactions (7), Clinical Pharmacology (12.3)]. Dosing recommendations for oral contraceptives can be found in General Dosing Considerations [see Dosage and Administration (2.1)]. Patients on rifampin, or other drugs that induce lamotrigine glucuronidation and increase clearance, should follow the same dosing titration/maintenance regimen as that used with anticonvulsants that have this effect. c Dose increases at week 8 or later should not exceed 100 mg daily at weekly intervals. For Patients TAKING Valproatea For Patients NOT TAKING Carbamazepine, Phenytoin, Phenobarbital, Primidoneb, or Valproatea For Patients TAKING Carbamazepine, Phenytoin, Phenobarbital, or Primidoneb and NOT TAKING Valproatea Weeks 1 and 2 25 mg every other day 25 mg every day 50 mg every day Weeks 3 and 4 25 mg every day 50 mg every day 100 mg every day Week 5 50 mg every day 100 mg every day 200 mg every day Week 6 100 mg every day 150 mg every day 300 mg every day Week 7 150 mg every day 200 mg every day 400 mg every day Maintenance range (week 8 and onward) 200 to 250 mg every dayc 300 to 400 mg every dayc 400 to 600 mg every dayc 2.3 2.3 2.4 Conversion From Immediate-Release Lamotrigine Tablets to Lamotrigine Extended-Release Tablets Patients may be converted directly from immediate-release lamotrigine to lamotrigine extended-release tablets. The initial dose of lamotrigine extended-release tablets should match the total daily dose of immediate-release lamotrigine. However, some subjects on concomitant enzyme-inducing agents may have lower plasma levels of lamotrigine on conversion and should be monitored [see Clinical Pharmacology (12.3)]. Following conversion to lamotrigine extended-release tablets, all patients (but especially those on drugs that induce lamotrigine glucuronidation) should be closely monitored for seizure control [see Drug Interactions (7)]. Depending on the therapeutic response after conversion, the total daily dose may need to be adjusted within the recommended dosing instructions (Table 1).

doxycycline hyclate 100 MG Oral Tablet

Generic Name: DOXYCYCLINE HYCLATE

Brand Name: Doxycycline Hyclate

Substance Name(s):
DOXYCYCLINE HYCLATE

WARNINGS

THE USE OF DRUGS OF THE TETRACYCLINE CLASS DURING TOOTH DEVELOPMENT (LAST HALF OF PREGNANCY, INFANCY AND CHILDHOOD TO THE AGE OF 8 YEARS) MAY CAUSE PERMANENT DISCOLORATION OF THE TEETH (YELLOW-GRAY-BROWN). This adverse reaction is more common during long-term use of the drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. TETRACYCLINE DRUGS, THEREFORE, SHOULD NOT BE USED IN THIS AGE GROUP, EXCEPT FOR ANTHRAX, INCLUDING INHALATIONAL ANTHRAX (POST-EXPOSURE) UNLESS OTHER DRUGS ARE NOT LIKELY TO BE EFFECTIVE OR ARE CONTRAINDICATED. Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including doxycycline, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in prematures given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has also been noted in animals treated early in pregnancy. If any tetracycline is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. The antianabolic action of the tetracyclines may cause an increase in BUN. Studies to date indicate that this does not occur with the use of doxycycline in patients with impaired renal function. Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. Patients apt to be exposed to direct sunlight or ultraviolet light should be advised that this reaction can occur with tetracycline drugs, and treatment should be discontinued at the first evidence of skin erythema.

DRUG INTERACTIONS

Drug Interactions Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. Since bacteriostatic drugs may interfere with the bactericidal action of penicillin, it is advisable to avoid giving tetracyclines in conjunction with penicillin. Absorption of tetracyclines is impaired by antacids containing aluminum, calcium, or magnesium, and iron-containing preparations. Absorption of tetracyclines is impaired by bismuth subsalicylate. Barbiturates, carbamazepine, and phenytoin decrease the half-life of doxycycline. The concurrent use of tetracycline and methoxyflurane has been reported to result in fatal renal toxicity. Concurrent use of tetracycline may render oral contraceptives less effective.

OVERDOSAGE

In case of overdosage, discontinue medication, treat symptomatically and institute supportive measures. Dialysis does not alter serum half-life and thus would not be of benefit in treating cases of overdosage.

DESCRIPTION

Doxycycline is a broad-spectrum antibiotic synthetically derived from oxytetracycline. The chemical designation of this light-yellow crystalline powder is 4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride, compound with ethyl alcohol (2:1), monohydrate. Doxycycline hyclate is soluble in water, while doxycycline monohydrate is very slightly soluble in water. Doxycycline has a high degree of lipoid solubility and a low affinity for calcium binding. It is highly stable in normal human serum. Doxycycline will not degrade into an epianhydro form. Each tablet, for oral administration, contains doxycycline hyclate equivalent to 100 mg doxycycline. Each capsule for oral administration contains doxycycline hyclate equivalent to 50 mg or 100 mg doxycycline. In addition, each tablet and capsule contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, methylcellulose, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, stearic acid, and titanium dioxide. In addition, the 100 mg tablet contains FD&C Yellow No. 6, FD&C Red No. 40, and hypromellose; the 50 mg capsule contains FD&C Blue No. 1, and D&C Yellow No. 10; the 100 mg capsule contains FD&C Blue No. 1. The structural formula is as follows: (C22H24N2O8 • HCl)2 • C2H6O • H2O M.W. 1025.89 Chemical Structure

HOW SUPPLIED

Available as a blue and white capsule with yellow powder, imprinted with company logo and 2984, containing doxycycline hyclate, equivalent to 50 mg doxycycline, packaged in bottles of 50 capsules; as a light blue capsule with yellow powder, imprinted with company logo and 2985, containing doxycycline hyclate, equivalent to 100 mg doxycycline, packaged in bottles of 50 and 500 capsules and unit dose boxes of 100 capsules; and as an orange film-coated tablet, debossed with company logo and 3626, containing doxycycline hyclate, equivalent to 100 mg doxycycline, packaged in bottles of 20, 50, 100, 200 and 500 tablets, and unit dose boxes of 100 tablets. PHARMACIST: Dispense in a tight, light-resistant container as defined in the USP. Use child-resistant closure (as required). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].

INDICATIONS AND USAGE

To reduce the development of drug-resistant bacteria and maintain effectiveness of doxycycline hyclate and other antibacterial drugs, doxycycline hyclate should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Treatment Doxycycline is indicated for the treatment of the following infections: Rocky Mountain spotted fever, typhus fever and the typhus group, Q fever, rickettsialpox, and tick fevers caused by Rickettsiae. Respiratory tract infections caused by Mycoplasma pneumoniae. Lymphogranuloma venereum caused by Chlamydia trachomatis. Psittacosis (ornithosis) caused by Chlamydia psittaci. Trachoma caused by Chlamydia trachomatis, although the infectious agent is not always eliminated as judged by immunofluorescence. Inclusion conjunctivitis caused by Chlamydia trachomatis. Uncomplicated urethral, endocervical or rectal infections in adults caused by Chlamydia trachomatis. Nongonococcal urethritis caused by Ureaplasma urealyticum. Relapsing fever due to Borrelia recurrentis. Doxycycline is also indicated for the treatment of infections caused by the following gram-negative microorganisms: Chancroid caused by Haemophilus ducreyi. Plague due to Yersinia pestis (formerly Pasteurella pestis). Tularemia due to Francisella tularensis (formerly Pasteurella tularensis). Cholera caused by Vibrio cholerae (formerly Vibrio comma). Campylobacter fetus infections caused by Campylobacter fetus (formerly Vibrio fetus). Brucellosis due to Brucella species (in conjunction with streptomycin). Bartonellosis due to Bartonella bacilliformis. Granuloma inguinale caused by Calymmatobacterium granulomatis. Because many strains of the following groups of microorganisms have been shown to be resistant to doxycycline, culture and susceptibility testing are recommended. Doxycycline is indicated for treatment of infections caused by the following gram-negative microorganisms, when bacteriologic testing indicates appropriate susceptibility to the drug: Escherichia coli. Enterobacter aerogenes (formerly Aerobacter aerogenes). Shigella species. Acinetobacter species (formerly Mima species and Herellea species). Respiratory tract infections caused by Haemophilus influenzae. Respiratory tract and urinary tract infections caused by Klebsiella species. Doxycycline is indicated for treatment of infections caused by the following gram-positive microorganisms when bacteriologic testing indicates appropriate susceptibility to the drug: Upper respiratory infections caused by Streptococcus pneumoniae (formerly Diplococcus pneumoniae). Anthrax due to Bacillus anthracis, including inhalational anthrax (post-exposure): to reduce the incidence or progression of disease following exposure to aerosolized Bacillus anthracis. When penicillin is contraindicated, doxycycline is an alternative drug in the treatment of the following infections: Uncomplicated gonorrhea caused by Neisseria gonorrhoeae. Syphilis caused by Treponema pallidum. Yaws caused by Treponema pertenue. Listeriosis due to Listeria monocytogenes. Vincent’s infection caused by Fusobacterium fusiforme. Actinomycosis caused by Actinomyces israelii. Infections caused by Clostridium species. In acute intestinal amebiasis, doxycycline may be a useful adjunct to amebicides. In severe acne, doxycycline may be useful adjunctive therapy. Prophylaxis Doxycycline is indicated for the prophylaxis of malaria due to Plasmodium falciparum in short-term travelers (< 4 months) to areas with chloroquine and/or pyrimethamine-sulfadoxine resistant strains. See DOSAGE AND ADMINISTRATION section and Information for Patients subsection of the PRECAUTIONS section.

PEDIATRIC USE

Pediatric Use See WARNINGS and DOSAGE AND ADMINISTRATION

PREGNANCY

Pregnancy Teratogenic effects Pregnancy Category D There are no adequate and well-controlled studies on the use of doxycycline in pregnant women. The vast majority of reported experience with doxycycline during human pregnancy is short-term, first trimester exposure. There are no human data available to assess the effects of long-term therapy of doxycycline in pregnant women such as that proposed for treatment of anthrax exposure. An expert review of published data on experiences with doxycycline use during pregnancy by TERIS – the Teratogen Information System – concluded that therapeutic doses during pregnancy are unlikely to pose a substantial teratogenic risk (the quantity and quality of data were assessed as limited to fair), but the data are insufficient to state that there is no riska. A case-control study (18,515 mothers of infants with congenital anomalies and 32,804 mothers of infants with no congenital anomalies) shows a weak but marginally statistically significant association with total malformations and use of doxycycline anytime during pregnancy. Sixty-three (0.19%) of the controls and 56 (0.30%) of the cases were treated with doxycycline. This association was not seen when the analysis was confined to maternal treatment during the period of organogenesis (i.e., in the second and third months of gestation) with the exception of a marginal relationship with neural tube defect based on only two exposed casesb. A small prospective study of 81 pregnancies describes 43 pregnant women treated for 10 days with doxycycline during early first trimester. All mothers reported their exposed infants were normal at 1 year of agec. Nonteratogenic effects See WARNINGS

NUSRING MOTHERS

Nursing Mothers Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including doxycycline, by the breastfed infant is not known. Short-term use by lactating women is not necessarily contraindicated; however, the effects of prolonged exposure to doxycycline in breast milk are unknownd. Because of the potential for serious adverse reactions in nursing infants from doxycycline, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother (see WARNINGS ).

INFORMATION FOR PATIENTS

Information for Patients Patients taking doxycycline for malaria prophylaxis should be advised: – that no present-day antimalarial agent, including doxycycline, guarantees protection against malaria. – to avoid being bitten by mosquitoes by using personal protective measures that help avoid contact with mosquitoes, especially from dusk to dawn (e.g., staying in well-screened areas, using mosquito nets, covering the body with clothing, and using an effective insect repellent). – that doxycycline prophylaxis: – should begin 1 to 2 days before travel to the malarious area. – should be continued daily while in the malarious area and after leaving the malarious area. – should be continued for 4 further weeks to avoid development of malaria after returning from an endemic area. – should not exceed 4 months. All patients taking doxycycline should be advised: – to avoid excessive sunlight or artificial ultraviolet light while receiving doxycycline and to discontinue therapy if phototoxicity (e.g., skin eruption, etc.) occurs. Sunscreen or sunblock should be considered (see WARNINGS ). – to drink fluids liberally along with doxycycline to reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS ). – that the absorption of tetracyclines is reduced when taken with foods, especially those which contain calcium. However, the absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk (see DRUG INTERACTIONS ). – that the absorption of tetracyclines is reduced when taking bismuth subsalicylate (see DRUG INTERACTIONS ). – that the use of doxycycline might increase the incidence of vaginal candidiasis. Patients should be counseled that antibacterial drugs including doxycycline should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When doxycycline is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by doxycycline or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

DOSAGE AND ADMINISTRATION

THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE DIFFERS FROM THAT OF THE OTHER TETRACYCLINES. EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS. Adults The usual dose of oral doxycycline is 200 mg on the first day of treatment (administered 100 mg every 12 hours) followed by a maintenance dose of 100 mg/day. The maintenance dose may be administered as a single dose or as 50 mg every 12 hours. In the management of more severe infections (particularly chronic infections of the urinary tract), 100 mg every 12 hours is recommended. For children above eight years of age The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight divided into two doses on the first day of treatment, followed by 1 mg/lb of body weight given as a single daily dose or divided into two doses, on subsequent days. For more severe infections up to 2 mg/lb of body weight may be used. For children over 100 pounds the usual adult dose should be used. The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage. When used in streptococcal infections, therapy should be continued for 10 days. Administration of adequate amounts of fluid along with capsule and tablet forms of drugs in the tetracycline class is recommended to wash down the drugs and reduce the risk of esophageal irritation and ulceration (see ADVERSE REACTIONS ). If gastric irritation occurs, it is recommended that doxycycline be given with food or milk. The absorption of doxycycline is not markedly influenced by simultaneous ingestion of food or milk. Studies to date have indicated that administration of doxycycline at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment. Uncomplicated gonococcal infections in adults (except anorectal infections in men): 100 mg, by mouth, twice a day for 7 days. As an alternate single visit dose, administer 300 mg stat followed in one hour by a second 300 mg dose. The dose may be administered with food, including milk or carbonated beverage, as required. Uncomplicated urethral, endocervical, or rectal infection in adults caused by Chlamydia trachomatis: 100 mg, by mouth, twice a day for 7 days. Nongonococcal urethritis (NGU) caused by C. trachomatis and U. urealyticum: 100 mg, by mouth, twice a day for 7 days. Syphilis – early Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 2 weeks. Syphilis of more than one year’s duration Patients who are allergic to penicillin should be treated with doxycycline 100 mg, by mouth, twice a day for 4 weeks. Acute epididymo-orchitis caused by N. gonorrhoeae: 100 mg, by mouth, twice a day for at least 10 days. Acute epididymo-orchitis caused by C. trachomatis: 100 mg, by mouth, twice a day for at least 10 days. For the prophylaxis of malaria For adults, the recommended dose is 100 mg daily. For children over 8 years of age, the recommended dose is 2 mg/kg given once daily up to the adult dose. Prophylaxis should begin 1 to 2 days before travel to the malarious area. Prophylaxis should be continued daily during travel in the malarious area and for 4 weeks after the traveler leaves the malarious area. Inhalational anthrax (post-exposure) ADULTS: 100 mg of doxycycline, by mouth, twice a day for 60 days. CHILDREN: weighing less than 100 pounds (45 kg); 1 mg/lb (2.2 mg/kg) of body weight, by mouth, twice a day for 60 days. Children weighing 100 pounds or more should receive the adult dose.

Lisinopril 5 MG Oral Tablet

WARNINGS

OVERDOSAGE

Following a single oral dose of 20 g/kg, no lethality occurred in rats, and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril can be removed by hemodialysis (see WARNINGS, AnaphylactoidReactions During Membrane Exposure).

DESCRIPTION

Lisinopril USP is an oral long-acting angiotensin converting enzyme inhibitor. Lisinopril USP, a synthetic peptide derivative, is chemically described as (S)-1-[N 2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L- proline dihydrate. It has the following structural formula: C21H31N3O5M.W. 441.53 Lisinopril USP is a white to off-white, crystalline powder. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol. Lisinopril tablets USP are supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets for oral administration. In addition to the active ingredient lisinopril USP, each tablet contains the following inactive ingredients: dibasic calcium phosphate anhydrous, magnesium stearate, mannitol, pregelatinized starch, and talc. MM1

HOW SUPPLIED

Lisinopril Tablets USP, 2.5 mg are available as white, round, flat-faced, beveled-edged, unscored tablets, debossed on one side and “3757” on the other side containing 2.5 mg lisinopril USP, packaged in bottles of 100 and 500 tablets. Lisinopril Tablets USP, 5 mg are available as white, square-shaped tablets, debossed with a bisect on one side and “3758” on the other side containing 5 mg lisinopril USP, packaged in bottles of 100, 500, and 1000 tablets. Lisinopril Tablets USP, 10 mg are available as white, arc triangle shaped, unscored tablets, debossed on one side and “3759” on the other side containing 10 mg lisinopril USP, packaged in bottles of 100, 500, and 1000 tablets. Lisinopril Tablets USP, 20 mg are available as white, pentagonal-shaped, unscored tablets, debossed on one side and “3760” on the other side containing 20 mg lisinopril USP, packaged in bottles of 100, 500, and 1000 tablets. Lisinopril Tablets USP, 30 mg are available as white, oval-shaped, unscored tablets, debossed on one side and “3762” on the other side containing 30 mg lisinopril USP, packaged in bottles of 100 and 500 tablets. Lisinopril Tablets USP, 40 mg are available as white, round, flat-faced, beveled-edged, unscored tablets, debossed on one side and “3761” on the other side containing 40 mg lisinopril USP, packaged in bottles of 100 and 500 tablets. Dispense in a tight container as defined in the USP, with a child-resistant closure (as required). Store at 20to 25(68to 77[See USP Controlled Room Temperature]. PROTECT FROM MOISTURE, FREEZING AND EXCESSIVE HEAT KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN. MM2 MM3 MM4 MM5 MM6 MM7

INDICATIONS AND USAGE

INDICATIONS & USAGE Hypertension Lisinopril tablets USP are indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including lisinopril. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education ProgramJoint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Lisinopril tablets USP may be administered alone or with other antihypertensive agents Heart Failure Lisinopril tablets USP are indicated as adjunctive therapy in the management of heart failure in patients who are not responding adequately to diuretics and digitalis. Acute Myocardial Infarction Lisinopril tablets USP are indicated for the treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers. In using lisinopril tablets USP, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that lisinopril tablets USP do not have a similar risk (see WARNINGS). In considering the use of lisinopril tablets USP, it should be noted that in controlled clinical trials, ACE inhibitors have an effect on blood pressure that is less in Black patients than in non-Blacks. In addition, ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients (see WARNINGS, Anaphylactoid and Possibly Related Reactions).

BOXED WARNING

WARNING FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue lisinopril tablets as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See WARNINGS, Fetal Toxicity.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION Hypertension Initial Therapy In patients with uncomplicated essential hypertension not on diuretic therapy, the recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 to 40 mg per day administered in a single daily dose. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. Doses up to 80 mg have been used but do not appear to give greater effect. If blood pressure is not controlled with lisinopril tablets USP alone, a low dose of a diuretic may be added. Hydrochlorothiazide, 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril tablets USP. Diuretic Treated Patients In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of lisinopril tablets USP. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with lisinopril tablets USP to reduce the likelihood of hypotension (see WARNINGS). The dosage of lisinopril tablets USP should be adjusted according to blood pressure response. If the patientblood pressure is not controlled with lisinopril tablets USP alone, diuretic therapy may be resumed as described above. If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see WARNINGSand PRECAUTIONS, Drug Interactions). Concomitant administration of lisinopril tablets USP with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS). Dosage Adjustment in Renal Impairment The usual dose of lisinopril tablets USP (10 mg) is recommended for patients with creatinine clearance > 30 mL/min (serum creatinine of up to approximately 3 mg/dL). For patients with creatinine clearance10 mL/min30 mL/min (serum creatinine3 mg/dL), the first dose is 5 mg once daily. For patients with creatinine clearance 3010Moderate to severe impairment10305Dialysis patients* * < 102.5 ** Heart Failure Lisinopril tablets USP are indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with lisinopril, USP in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension (see WARNINGSand PRECAUTIONS, Drug Interactions). The appearance of hypotension after the initial dose of lisinopril tablets USP does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. The usual effective dosage range is 5 to 40 mg per day administered as a single daily dose. The dose of lisinopril tablets USP can be increased by increments of no greater than 10 mg, at intervals of no less than 2 weeks to the highest tolerated dose, up to a maximum of 40 mg daily. Dose adjustment should be based on the clinical response of individual patients. Dosage Adjustment in Patients With Heart Failure and Renal Impairment or Hyponatremia In patients with heart failure who have hyponatremia (serum sodium 3 mg/dL), therapy with lisinopril tablets USP should be initiated at a dose of 2.5 mg once a day under close medical supervision (see WARNINGSand PRECAUTIONS, Drug Interactions). Acute Myocardial Infarction In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, the first dose of lisinopril tablets USP is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of lisinopril tablets USP once daily. Dosing should continue for six weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers. Patients with a low systolic blood pressure (120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of lisinopril tablets USP (see WARNINGS). If hypotension occurs (systolic blood pressure100 mmHg), a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour) lisinopril tablets USP should be withdrawn. For patients who develop symptoms of heart failure, see , Heart Failure. Dosage Adjustment in Patients With Myocardial Infarction With Renal Impairment In acute myocardial infarction, treatment with lisinopril tablets USP should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. No evaluation of dosing adjustments in myocardial infarction patients with severe renal impairment has been performed. Use in Elderly In general, the clinical response was similar in younger and older patients given similar doses of lisinopril tablets USP. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients, so that dosage adjustments should be made with particular caution. Pediatric Hypertensive Patients6 Years of Age The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see CLINICAL PHARMACOLOGY, PharmacokineticsandMetabolism and Pharmacodynamics and Clinical Effects). Lisinopril tablets USP are not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2 (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism and Pharmacodynamics and Clinical Effects and PRECAUTIONS). Preparation of Suspension (for 200 mL of a 1 mg/mL Suspension) Add 10 mL of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of lisinopril tablets USP and shake for at least one minute. Add 30 mL of Bicitradiluent and 160 mL of Ora-Sweet SFto the concentrate in the PET bottle and gently shake for several seconds to disperse the ingredients. The suspension should be stored at or below 25(77and can be stored for up to four weeks. Shake the suspension before each use.