Drug Intercation

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.

Dulera 200 mcg/5 mcg per ACTUAT Metered Dose Inhaler, 120 ACTUAT

Generic Name: MOMETASONE FUROATE AND FORMOTEROL FUMARATE DIHYDRATE

Brand Name: Dulera

Substance Name(s):
FORMOTEROL FUMARATE
MOMETASONE FUROATE

DRUG INTERACTIONS

7 In clinical trials, concurrent administration of DULERA and other drugs, such as short-acting beta2-agonist and intranasal corticosteroids have not resulted in an increased frequency of adverse drug reactions. No formal drug interaction studies have been performed with DULERA. The drug interactions of the combination are expected to reflect those of the individual components. Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution. May cause increased systemic corticosteroid effects. (7.1) Adrenergic agents: Use with caution. Additional adrenergic drugs may potentiate sympathetic effects. (7.2) Xanthine derivatives and diuretics: Use with caution. May potentiate ECG changes and/or hypokalemia. (7.3, 7.4) MAO inhibitors, tricyclic antidepressants, macrolides, and drugs that prolong QTc interval: Use with extreme caution. May potentiate effect on the cardiovascular system. (7.5) Beta-blockers: Use with caution and only when medically necessary. May decrease effectiveness and produce severe bronchospasm. (7.6) Halogenated hydrocarbons: There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons. (7.7) 7.1 Inhibitors of Cytochrome P450 3A4 The main route of metabolism of corticosteroids, including mometasone furoate, a component of DULERA, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4). After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased. Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the systemic exposure to, mometasone furoate. Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3)]. 7.2 Adrenergic Agents If additional adrenergic drugs are to be administered by any route, they should be used with caution because the pharmacologically predictable sympathetic effects of formoterol, a component of DULERA, may be potentiated. 7.3 Xanthine Derivatives Concomitant treatment with xanthine derivatives may potentiate any hypokalemic effect of formoterol, a component of DULERA. 7.4 Diuretics Concomitant treatment with diuretics may potentiate the possible hypokalemic effect of adrenergic agonists. The ECG changes and/or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of DULERA with non-potassium-sparing diuretics. 7.5 Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and Drugs Known to Prolong the QTc Interval DULERA should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, macrolides, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the action of formoterol, a component of DULERA, on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias. 7.6 Beta-Adrenergic Receptor Antagonists Beta-adrenergic receptor antagonists (beta-blockers) and formoterol may inhibit the effect of each other when administered concurrently. Beta-blockers not only block the therapeutic effects of beta2-agonists, such as formoterol, a component of DULERA, but may produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, e.g., as prophylaxis after myocardial infarction, there may be no acceptable alternatives to the use of beta-blockers in patients with asthma. In this setting, cardioselective beta-blockers could be considered, although they should be administered with caution. 7.7 Halogenated Hydrocarbons There is an elevated risk of arrhythmias in patients receiving concomitant anesthesia with halogenated hydrocarbons.

OVERDOSAGE

10 10.1 Signs and Symptoms DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the risks associated with overdosage for the individual components described below apply to DULERA. Mometasone Furoate: Chronic overdosage may result in signs/symptoms of hypercorticism [see Warnings and Precautions (5.7)]. Single oral doses up to 8000 mcg of mometasone furoate have been studied on human volunteers with no adverse reactions reported. Formoterol Fumarate: The expected signs and symptoms with overdosage of formoterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the following signs and symptoms: angina, hypertension or hypotension, tachycardia, with rates up to 200 beats/min., arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, hypokalemia, hyperglycemia, and insomnia. Metabolic acidosis may also occur. Cardiac arrest and even death may be associated with an overdose of formoterol. The minimum acute lethal inhalation dose of formoterol fumarate in rats is 156 mg/kg (approximately 63,000 times the MRHD on a mcg/m2 basis). The median lethal oral doses in Chinese hamsters, rats, and mice provide even higher multiples of the MRHD. 10.2 Treatment DULERA: Treatment of overdosage consists of discontinuation of DULERA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medication can produce bronchospasm. There is insufficient evidence to determine if dialysis is beneficial for overdosage of DULERA. Cardiac monitoring is recommended in cases of overdosage.

DESCRIPTION

11 DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg are combinations of mometasone furoate and formoterol fumarate dihydrate for oral inhalation only. One active component of DULERA is mometasone furoate, a corticosteroid having the chemical name 9,21-dichloro-11(Beta),17-dihydroxy-16 (alpha)-methylpregna-1,4-diene-3,20-dione 17-(2-furoate) with the following chemical structure: Mometasone furoate is a white powder with an empirical formula of C27H30Cl2O6, and molecular weight 521.44. It is practically insoluble in water; slightly soluble in methanol, ethanol, and isopropanol; soluble in acetone. One active component of DULERA is formoterol fumarate dihydrate, a racemate. Formoterol fumarate dihydrate is a selective beta2-adrenergic bronchodilator having the chemical name of (±)-2-hydroxy-5-[(1RS)-1-hydroxy-2-[[(1RS)-2-(4-methoxyphenyl)-1-methylethyl]-amino]ethyl]formanilide fumarate dihydrate with the following chemical structure: Formoterol fumarate dihydrate has a molecular weight of 840.9, and its empirical formula is (C19H24N2O4)2•C4H4O4•2H2O. Formoterol fumarate dihydrate is a white to yellowish powder, which is freely soluble in glacial acetic acid, soluble in methanol, sparingly soluble in ethanol and isopropanol, slightly soluble in water, and practically insoluble in acetone, ethyl acetate, and diethyl ether. Each DULERA 100 mcg/5 mcg and 200 mcg/5 mcg is a hydrofluoroalkane (HFA-227) propelled pressurized metered dose inhaler containing sufficient amount of drug for 60 or 120 inhalations [see How Supplied/Storage and Handling (16)]. After priming, each actuation of the inhaler delivers 115 or 225 mcg of mometasone furoate and 5.5 mcg of formoterol fumarate dihydrate in 69.6 mg of suspension from the valve and delivers 100 or 200 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate from the actuator. The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between actuation of the device and inspiration through the delivery system. DULERA also contains anhydrous alcohol as a cosolvent and oleic acid as a surfactant. DULERA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray. Image of Mometasone Furoate Chemical Structure Image of Formoterol Fumarate Dihydrate Chemical Structure

CLINICAL STUDIES

14 14.1 Asthma The safety and efficacy of DULERA were demonstrated in two randomized, double-blind, parallel group, multicenter clinical trials of 12 to 26 weeks in duration involving 1509 patients 12 years of age and older with persistent asthma uncontrolled on medium or high dose inhaled corticosteroids (baseline FEV1 means of 66% to 73% of predicted normal). These studies included a 2 to 3-week run-in period with mometasone furoate to establish a certain level of asthma control. One clinical trial compared DULERA to placebo and the individual components, mometasone furoate and formoterol (Trial 1) and one clinical trial compared two different strengths of DULERA to mometasone furoate alone (Trial 2). Trial 1: Clinical Trial with DULERA 100 mcg/5 mcg This 26-week, placebo-controlled trial evaluated 781 patients 12 years of age and older comparing DULERA 100 mcg/5 mcg (n=191 patients), mometasone furoate 100 mcg (n=192 patients), formoterol fumarate 5 mcg (n=202 patients) and placebo (n=196 patients); each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This study included a 2 to 3-week run-in period with mometasone furoate 100 mcg, 2 inhalations twice daily. This trial included patients ranging from 12 to 76 years of age, 41% male and 59% female, and 72% Caucasian and 28% non-Caucasian. Patients had persistent asthma and were not well controlled on medium dose of inhaled corticosteroids prior to randomization. All treatment groups were balanced with regard to baseline characteristics. Mean FEV1 and mean percent predicted FEV1 were similar among all treatment groups (2.33 L, 73%). Eight (4%) patients receiving DULERA 100 mcg/5 mcg, 13 (7%) patients receiving mometasone furoate 100 mcg, 47 (23%) patients receiving formoterol fumarate 5 mcg and 46 (23%) patients receiving placebo discontinued the study early due to treatment failure. FEV1 AUC(0-12 hr) was assessed as a co-primary efficacy endpoint to evaluate the contribution of the formoterol component to DULERA. Patients receiving DULERA 100 mcg/5 mcg had significantly higher increases from baseline at Week 12 in mean FEV1 AUC(0-12 hr) compared to mometasone furoate 100 mcg (the primary treatment comparison) and vs. placebo (both p<0.001) (Figure 1). These differences were maintained through Week 26. Figure 1 shows the change from baseline post-dose serial FEV1 evaluations in Trial 1. Figure 1 Trial 1 – DULERA 100 mcg/5 mcg – FEV1 Serial Evaluations for Observed Cases at Week 12 Change from Baseline by Treatment Clinically judged deteriorations in asthma or reductions in lung function were assessed as another primary endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg (primary treatment comparison DULERA vs. formoterol). Deteriorations in asthma were defined as any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Fewer patients who received DULERA 100 mcg/5 mcg reported an event compared to patients who received formoterol 5 mcg (p<0.001). Table 3: Trial 1 – Clinically Judged Deterioration in Asthma or Reduction in Lung FunctionIncludes only the first event day for each patient. Patients could have experienced more than one event criterion. DULERA 100 mcg/ 5 mcgTwo inhalations, twice daily. (n=191) Mometasone Furoate 100 mcg (n=192) Formoterol 5 mcg (n=202) Placebo (n=196) Clinically judged deterioration in asthma or reduction in lung function 58 (30%) 65 (34%) 109 (54%) 109 (56%) Decrease in FEV1 Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication). 18 (9%) 19 (10%) 31 (15%) 41 (21%) Decrease in PEFDecrease in AM or PM peak expiratory flow (PEF) on 2 or more consecutive days below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period). 37 (19%) 41 (21%) 62 (31%) 61 (31%) Emergency treatment 0 1 (<1%) 4 (2%) 1 (<1%) Hospitalization 1 (<1%) 0 0 0 Treatment with excluded asthma medicationThirty patients received glucocorticosteroids; 1 patient received formoterol via dry powder inhaler in the Formoterol 5 mcg group. 2 (1%) 4 (2%) 17 (8%) 8 (4%) The change in mean trough FEV1 from baseline to Week 12 was assessed as another endpoint to evaluate the contribution of mometasone furoate 100 mcg to DULERA 100 mcg/5 mcg. A significantly greater increase in mean trough FEV1 was observed for DULERA 100 mcg/5 mcg compared to formoterol 5 mcg (the primary treatment comparison) as well as to placebo (Table 4). Table 4: Trial 1 – Change in Trough FEV1 from Baseline to Week 12 Treatment Arm N Baseline (L) Change From Baseline at Week 12 (L) Treatment Difference from Placebo (L) P-Value vs. Placebo P-Value vs. Formoterol LS means and p-values are from Week 12 estimates of a longitudinal analysis model. DULERA 100 mcg/5 mcg 167 2.33 0.13 0.18 <0.001 <0.001 Mometasone furoate 100 mcg 175 2.36 0.07 0.12 <0.001 0.058 Formoterol fumarate 5 mcg 141 2.29 0.00 0.05 0.170 Placebo 145 2.30 -0.05 The effect of DULERA 100 mcg/5 mcg, two inhalations twice daily on selected secondary efficacy endpoints, including proportion of nights with nocturnal awakenings (-60% vs. -15%), change in total rescue medication use (-0.6 vs. +1.1 puffs/day), change in morning peak flow (+18.1 vs. -28.4 L/min) and evening peak flow (+10.8 vs. -32.1 L/min) further supports the efficacy of DULERA 100 mcg/5 mcg compared to placebo. The subjective impact of asthma on patients' health-related quality of life was evaluated by the Asthma Quality of Life Questionnaire (AQLQ(S)) (based on a 7-point scale where 1 = maximum impairment and 7 = no impairment). A change from baseline ≥0.5 points is considered a clinically meaningful improvement. The mean difference in AQLQ between patients receiving DULERA 100 mcg/5 mcg and placebo was 0.5 [95% CI 0.32, 0.68]. Image of Figure 1 Trial 2: Clinical Trial With DULERA 200 mcg/5 mcg This 12-week double-blind trial evaluated 728 patients 12 years of age and older comparing DULERA 200 mcg/5 mcg (n=255 patients) with DULERA 100 mcg/5 mcg (n=233 patients) and mometasone furoate 200 mcg (n=240 patients), each administered as 2 inhalations twice daily by metered dose inhalation aerosols. All other maintenance therapies were discontinued. This trial included a 2 to 3-week run-in period with mometasone furoate 200 mcg, 2 inhalations twice daily. Patients had persistent asthma and were uncontrolled on high dose inhaled corticosteroids prior to study entry. All treatment groups were balanced with regard to baseline characteristics. This trial included patients ranging from 12 to 84 years of age, 44% male and 56% female, and 89% Caucasian and 11% non-Caucasian. Mean FEV1 and mean percent predicted FEV1 values were similar among all treatment groups (2.05 L, 66%). Eleven (5%) patients receiving DULERA 100 mcg/5 mcg, 8 (3%) patients receiving DULERA 200 mcg/5 mcg and 13 (5%) patients receiving mometasone furoate 200 mcg discontinued the trial early due to treatment failure. The primary efficacy endpoint was the mean change in FEV1 AUC(0-12 hr) from baseline to Week 12. Patients receiving DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg had significantly greater increases from baseline at Day 1 in mean FEV1 AUC(0-12 hr) compared to mometasone furoate 200 mcg. The difference was maintained over 12 weeks of therapy. Mean change in trough FEV1 from baseline to Week 12 was also assessed to evaluate the relative contribution of mometasone furoate to DULERA 100 mcg/5 mcg and DULERA 200 mcg/5 mcg (Table 5). A greater numerical increase in the mean trough FEV1 was observed for DULERA 200 mcg/5 mcg compared to DULERA 100 mcg/5 mcg and mometasone furoate 200 mcg. Table 5: Trial 2 – Change in Trough FEV1 from Baseline to Week 12 Treatment Arm N Baseline (L) Change from Baseline at Week 12 (L) DULERA 100 mcg/5 mcg 232 2.10 0.14 DULERA 200 mcg/5 mcg 255 2.05 0.19 Mometasone furoate 200 mcg 239 2.07 0.10 Clinically judged deterioration in asthma or reduction in lung function was assessed as an additional endpoint. Fewer patients who received DULERA 200 mcg/5 mcg or DULERA 100/5 mcg compared to mometasone furoate 200 mcg alone reported an event, defined as in Trial 1 by any of the following: a 20% decrease in FEV1; a 30% decrease in PEF on two or more consecutive days; emergency treatment, hospitalization, or treatment with systemic corticosteroids or other asthma medications not allowed per protocol. Table 6: Trial 2 – Clinically Judged Deterioration in Asthma or Reduction in Lung FunctionIncludes only the first event day for each patient. Patients could have experienced more than one event criterion. DULERA 100 mcg/ 5 mcgTwo inhalations, twice daily. (n=233) DULERA 200 mcg/ 5 mcg (n=255) Mometasone Furoate 200 mcg (n=240) Clinically judged deterioration in asthma or reduction in lung function 29 (12%) 31 (12%) 44 (18%) Decrease in FEV1 Decrease in absolute FEV1 below the treatment period stability limit (defined as 80% of the average of the two predose FEV1 measurements taken 30 minutes and immediately prior to the first dose of randomized trial medication). 23 (10%) 17 (7%) 33 (14%) Decrease in PEF on two consecutive daysDecrease in AM or PM peak expiratory flow (PEF) below the treatment period stability limit (defined as 70% of the AM or PM PEF obtained over the last 7 days of the run-in period). 2 (1%) 4 (2%) 3 (1%) Emergency treatment 2 (1%) 1 (<1%) 1 (<1%) Hospitalization 0 1 (<1%) 0 Treatment with excluded asthma medicationTwenty four patients received glucocorticosteroids; 1 patient received albuterol in the DULERA 200 mcg / 5 mcg group. 5 (2%) 8 (3%) 12 (5%) Other Studies In addition to Trial 1 and Trial 2, the safety and efficacy of the individual components, mometasone furoate MDI 100 mcg and 200 mcg, in comparison to placebo were demonstrated in three other, 12-week, placebo controlled trials which evaluated the mean change in FEV1 from baseline as a primary endpoint. The safety and efficacy of formoterol MDI 5 mcg alone in comparison to placebo was replicated in another 26-week trial that evaluated a lower dose of mometasone furoate MDI in combination with formoterol.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied DULERA is available in two strengths and supplied in the following package sizes (Table 7): Table 7 Package NDC DULERA 100 mcg/5 mcg 120 inhalations 0085-7206-01 DULERA 100 mcg/5 mcg 60 inhalations (institutional pack) 0085-7206-07 DULERA 200 mcg/5 mcg 120 inhalations 0085-4610-01 DULERA 200 mcg/5 mcg 60 inhalations (institutional pack) 0085-4610-05 Each strength is supplied as a pressurized aluminum canister that has a blue plastic actuator integrated with a dose counter and a green dust cap. Each 120-inhalation canister has a net fill weight of 13 grams and each 60-inhalation canister has a net fill weight of 8.8 grams. Each canister is placed into a carton. Each carton contains 1 canister and a Medication Guide. Initially the dose counter will display “64” or “124” actuations. After the initial priming with 4 actuations, the dose counter will read “60” or “120” and the inhaler is now ready for use. 16.2 Storage and Handling The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister. The canister should not be removed from the actuator because the correct amount of medication may not be discharged; the dose counter may not function properly; reinsertion may cause the dose counter to count down by 1 and discharge a puff. The correct amount of medication in each inhalation cannot be ensured after the labeled number of actuations from the canister has been used, even though the inhaler may not feel completely empty and may continue to operate. The inhaler should be discarded when the labeled number of actuations has been used (the dose counter will read “0”). Store at controlled room temperature 20–25°C (68–77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. The 120-inhalation inhaler does not require specific storage orientation. For the 60-inhalation inhaler, after priming, store the inhaler with the mouthpiece down or in a horizontal position. For best results, the canister should be at room temperature before use. Shake well and remove the cap from the mouthpiece of the actuator before using. Keep out of reach of children. Avoid spraying in eyes. Contents Under Pressure: Do not puncture. Do not use or store near heat or open flame. Exposure to temperatures above 120°F may cause bursting. Never throw container into fire or incinerator.

GERIATRIC USE

8.5 Geriatric Use A total of 77 patients 65 years of age and older (11 of whom were 75 years and older) have been treated with DULERA in 3 clinical trials up to 52 weeks in duration. Similar efficacy and safety results were observed in an additional 28 patients 65 years of age and older who were treated with DULERA in another clinical trial. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. As with other products containing beta2-agonists, special caution should be observed when using DULERA in geriatric patients who have concomitant cardiovascular disease that could be adversely affected by beta2-agonists. Based on available data for DULERA or its active components, no adjustment of dosage of DULERA in geriatric patients is warranted.

DOSAGE FORMS AND STRENGTHS

3 DULERA is a pressurized metered dose inhaler that is available in 2 strengths. DULERA 100 mcg/5 mcg delivers 100 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation. DULERA 200 mcg/5 mcg delivers 200 mcg of mometasone furoate and 5 mcg of formoterol fumarate dihydrate per actuation. Inhalation aerosol containing a combination of mometasone furoate (100 or 200 mcg) and formoterol fumarate dihydrate (5 mcg) per actuation. (3)

MECHANISM OF ACTION

12.1 Mechanism of Action DULERA: DULERA contains both mometasone furoate and formoterol fumarate; therefore, the mechanisms of actions described below for the individual components apply to DULERA. These drugs represent two different classes of medications (a synthetic corticosteroid and a selective long-acting beta2-adrenergic receptor agonist) that have different effects on clinical, physiological, and inflammatory indices of asthma. Mometasone furoate: Mometasone furoate is a corticosteroid demonstrating potent anti-inflammatory activity. The precise mechanism of corticosteroid action on asthma is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation and in the asthmatic response. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma. Mometasone furoate has been shown in vitro to exhibit a binding affinity for the human glucocorticoid receptor, which is approximately 12 times that of dexamethasone, 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone. The clinical significance of these findings is unknown. Formoterol fumarate: Formoterol fumarate is a long-acting selective beta2-adrenergic receptor agonist (beta2-agonist). Inhaled formoterol fumarate acts locally in the lung as a bronchodilator. In vitro studies have shown that formoterol has more than 200-fold greater agonist activity at beta2-receptors than at beta1-receptors. Although beta2-receptors are the predominant adrenergic receptors in bronchial smooth muscle and beta1-receptors are the predominant receptors in the heart, there are also beta2-receptors in the human heart comprising 10% to 50% of the total beta-adrenergic receptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta2-agonists may have cardiac effects. The pharmacologic effects of beta2-adrenoceptor agonist drugs, including formoterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3′, 5′-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that formoterol is an inhibitor of the release of mast cell mediators, such as histamine and leukotrienes, from the human lung. Formoterol also inhibits histamine-induced plasma albumin extravasation in anesthetized guinea pigs and inhibits allergen-induced eosinophil influx in dogs with airway hyper-responsiveness. The relevance of these in vitro and animal findings to humans is unknown.

INDICATIONS AND USAGE

1 DULERA is a combination product containing a corticosteroid and a long-acting beta2-adrenergic agonist indicated for: Treatment of asthma in patients 12 years of age and older. (1.1) Important limitations: Not indicated for the relief of acute bronchospasm. (1.1) 1.1 Treatment of Asthma DULERA is indicated for the treatment of asthma in patients 12 years of age and older. Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients [see Warnings and Precautions (5.1)]. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. Important Limitation of Use DULERA is NOT indicated for the relief of acute bronchospasm.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of DULERA have been established in patients 12 years of age and older in 3 clinical trials up to 52 weeks in duration. In the 3 clinical trials, 101 patients 12 to 17 years of age were treated with DULERA. Patients in this age-group demonstrated efficacy results similar to those observed in patients 18 years of age and older. There were no obvious differences in the type or frequency of adverse drug reactions reported in this age group compared to patients 18 years of age and older. Similar efficacy and safety results were observed in an additional 22 patients 12 to 17 years of age who were treated with DULERA in another clinical trial. The safety and efficacy of DULERA have not been established in children less than 12 years of age. Controlled clinical studies have shown that inhaled corticosteroids may cause a reduction in growth velocity in pediatric patients. In these studies, the mean reduction in growth velocity was approximately 1 cm per year (range 0.3 to 1.8 per year) and appears to depend upon dose and duration of exposure. This effect was observed in the absence of laboratory evidence of hypothalamic-pituitary-adrenal (HPA) axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with orally inhaled corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up” growth following discontinuation of treatment with orally inhaled corticosteroids has not been adequately studied. The growth of children and adolescents receiving orally inhaled corticosteroids, including DULERA, should be monitored routinely (e.g., via stadiometry). If a child or adolescent on any corticosteroid appears to have growth suppression, the possibility that he/she is particularly sensitive to this effect should be considered. The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risks associated with alternative therapies. To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, each patient should be titrated to his/her lowest effective dose [see Dosage and Administration (2.2)].

PREGNANCY

8.1 Pregnancy Risk Summary There are no randomized clinical studies of DULERA, mometasone furoate, or formoterol fumarate in pregnant women. There are clinical considerations with the use of DULERA in pregnant women [see Clinical Considerations]. Animal reproduction studies with DULERA are not available; however, studies are available with its individual components, mometasone furoate and formoterol fumarate. In animal reproduction studies, subcutaneous administration of mometasone furoate to pregnant mice, rats, or rabbits caused increased fetal malformations and decreased fetal survival and growth following administration of doses that produced exposures approximately 1/3 to 8 times the maximum recommended human dose (MRHD) on a mcg/m2 or AUC basis [see Data]. However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. In animal reproduction studies, oral administration of formoterol fumarate to pregnant rats and rabbits caused increased fetal malformations (rats and rabbits), decreased fetal weight (rats), and increased neonatal mortality (rats) following administration of doses that produced exposures approximately 1200 to 49,000 times the MRHD on a mg/m2 or AUC basis [see Data]. These adverse effects generally occurred at large multiples of the MRHD when formoterol fumarate was administered by the oral route to achieve high systemic exposures. No effects were observed in a study with rats that received formoterol fumarate by the inhalation route at an exposure approximately 500 times the MRHD. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk In women with poorly or moderately controlled asthma, there is an increased risk of several perinatal adverse outcomes such as preeclampsia in the mother and prematurity, low birth weight, and small for gestational age in the neonate. Pregnant women with asthma should be closely monitored and medication adjusted as necessary to maintain optimal asthma control. Labor or delivery There are no adequate and well-controlled human studies that have studied the effects of DULERA during labor and delivery. Because of the potential for beta-agonist interference with uterine contractility, use of DULERA during labor should be restricted to those patients in whom the benefits clearly outweigh the risk. Data Animal Data Mometasone Furoate In an embryofetal development study with pregnant mice dosed throughout the period of organogenesis, mometasone furoate produced cleft palate at an exposure approximately one-third of the MRHD (on a mcg/m2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at an exposure approximately equivalent to the MRHD (on a mcg/m2 basis with a maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with a dose that produced an exposure approximately one-tenth of the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 20 mcg/kg and above). In an embryofetal development study with pregnant rats dosed throughout the period of organogenesis, mometasone furoate produced fetal umbilical hernia at exposures approximately 6 times the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at exposures approximately 3 times the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 300 mcg/kg and above). In another reproductive toxicity study, pregnant rats were dosed with mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at an exposure that was approximately 8 times the MRHD (on an area under the curve (AUC) basis with a maternal subcutaneous dose of 15 mcg/kg). There were no findings with an exposure approximately 4 times the MRHD (on an AUC basis with a maternal subcutaneous dose of 7.5 mcg/kg). Embryofetal development studies were conducted with pregnant rabbits dosed with mometasone furoate by either the topical dermal route or oral route throughout the period of organogenesis. In the study using the topical dermal route, mometasone furoate caused multiple malformations in fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at an exposure approximately 3 times the MRHD (on a mcg/m2 basis with maternal topical dermal doses of 150 mcg/kg and above). In the study using the oral route, mometasone furoate caused increased fetal resorptions and cleft palate and/or head malformations (hydrocephaly and domed head) at an exposure approximately 1/2 of the MRHD (on AUC basis with a maternal oral dose of 700 mcg/kg). At an exposure approximately 2 times the MRHD (on an AUC basis with a maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No effects were observed at an exposure approximately 1/10 of the MRHD (on an AUC basis with a maternal oral dose of 140 mcg/kg). Formoterol Fumarate In embryofetal development studies with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate did not cause malformations in either species. However, for pregnant rats dosed throughout organogenesis, formoterol fumarate caused delayed fetal ossification at an exposure approximately 80 times the MRHD (on a mcg/m2 basis with maternal oral doses of 200 mcg/kg and higher) and decreased fetal weight at an exposure approximately 2400 times the MRHD (on a mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). In a pre- and post-natal development study with rats dosed during the late stage of pregnancy, formoterol fumarate caused stillbirth and neonatal mortality at an exposure approximately 2400 times the MRHD (on a mcg/m2 basis with maternal oral doses of 6000 mcg/kg and above). However, no effects were observed in this study at an exposure approximately 80 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 200 mcg/kg). In embryofetal development studies, conducted by another testing laboratory, with pregnant rats and rabbits dosed throughout the period of organogenesis, formoterol fumarate was teratogenic in both species. Umbilical hernia, a malformation, was observed in rat fetuses at exposures approximately 1200 times the MRHD (on a mcg/m2 basis with maternal oral doses of 3000 mcg/kg/day and above). Brachygnathia, a skeletal malformation, was observed in rat fetuses at an exposure approximately 6100 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 15,000 mcg/kg/day). In another study with rats, no teratogenic effects were observed with exposures up to approximately 500 times the MRHD (on a mcg/m2 basis with a maternal inhalation dose of 1200 mcg/kg/day). Subcapsular cysts on the liver were observed in rabbit fetuses at an exposure approximately 49,000 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 60,000 mcg/kg/day). No teratogenic effects were observed with exposures up to approximately 3000 times the MRHD (on a mcg/m2 basis with a maternal oral dose of 3500 mcg/kg).

BOXED WARNING

WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another long-acting beta2-adrenergic agonist (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, DULERA should only be used for patients not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. [See Warnings and Precautions (5.1).] WARNING: ASTHMA-RELATED DEATH See full prescribing information for complete boxed warning. Long-acting beta2-adrenergic agonists (LABA), such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Data from a large placebo-controlled U.S. study that compared the safety of another LABA (salmeterol) or placebo added to usual asthma therapy showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of the LABA, including formoterol. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. When treating patients with asthma, prescribe DULERA only for patients with asthma not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. (1.1, 5.1)

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Asthma-related death: Long-acting beta2-adrenergic agonists increase the risk. Prescribe only for recommended patient populations. (5.1) Deterioration of disease and acute episodes: Do not initiate in acutely deteriorating asthma or to treat acute symptoms. (5.2) Use with additional long-acting beta2-agonist: Do not use in combination because of risk of overdose. (5.3) Localized infections: Candida albicans infection of the mouth and throat may occur. Monitor patients periodically for signs of adverse effects on the oral cavity. Advise patients to rinse the mouth following inhalation. (5.4) Immunosuppression: Potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex infections. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Use with caution in patients with these infections because of the potential for worsening of these infections. (5.5) Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids. Taper patients slowly from systemic corticosteroids if transferring to DULERA. (5.6) Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals. If such changes occur, discontinue DULERA slowly. (5.7) Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Risk of increased systemic corticosteroid effects. Exercise caution when used with DULERA. (5.8) Paradoxical bronchospasm: Discontinue DULERA and institute alternative therapy if paradoxical bronchospasm occurs. (5.9) Patients with cardiovascular disorders: Use with caution because of beta-adrenergic stimulation. (5.11) Decreases in bone mineral density: Monitor patients with major risk factors for decreased bone mineral content. (5.12) Effects on growth: Monitor growth of pediatric patients. (5.13) Glaucoma and cataracts: Monitor patients with change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts closely. (5.14) Coexisting conditions: Use with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, thyrotoxicosis, diabetes mellitus, and ketoacidosis. (5.15) Hypokalemia and hyperglycemia: Be alert to hypokalemia and hyperglycemia. (5.16) 5.1 Asthma-Related Death Long-acting beta2-adrenergic agonists, such as formoterol, one of the active ingredients in DULERA, increase the risk of asthma-related death. Currently available data are inadequate to determine whether concurrent use of inhaled corticosteroids or other long-term asthma control drugs mitigates the increased risk of asthma-related death from LABA. Available data from controlled clinical trials suggest that LABA increase the risk of asthma-related hospitalization in pediatric and adolescent patients. Therefore, when treating patients with asthma, physicians should only prescribe DULERA for patients with asthma not adequately controlled on a long-term asthma control medication, such as an inhaled corticosteroid or whose disease severity clearly warrants initiation of treatment with both an inhaled corticosteroid and LABA. Once asthma control is achieved and maintained, assess the patient at regular intervals and step down therapy (e.g., discontinue DULERA) if possible without loss of asthma control, and maintain the patient on a long-term asthma control medication, such as an inhaled corticosteroid. Do not use DULERA for patients whose asthma is adequately controlled on low or medium dose inhaled corticosteroids. A 28-week, placebo-controlled US study comparing the safety of salmeterol with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol (13/13,176 in patients treated with salmeterol vs. 3/13,179 in patients treated with placebo; RR 4.37, 95% CI 1.25, 15.34). This finding with salmeterol is considered a class effect of the LABAs, including formoterol, one of the active ingredients in DULERA. No study adequate to determine whether the rate of asthma-related death is increased with DULERA has been conducted. Clinical studies with formoterol suggested a higher incidence of serious asthma exacerbations in patients who received formoterol fumarate than in those who received placebo. The sizes of these studies were not adequate to precisely quantify the differences in serious asthma exacerbation rates between treatment groups. 5.2 Deterioration of Disease and Acute Episodes DULERA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of asthma. DULERA has not been studied in patients with acutely deteriorating asthma. The initiation of DULERA in this setting is not appropriate. Increasing use of inhaled, short-acting beta2-agonists is a marker of deteriorating asthma. In this situation, the patient requires immediate re-evaluation with reassessment of the treatment regimen, giving special consideration to the possible need for replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating systemic corticosteroids. Patients should not use more than 2 inhalations twice daily (morning and evening) of DULERA. DULERA is not indicated for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. An inhaled, short-acting beta2-agonist, not DULERA, should be used to relieve acute symptoms such as shortness of breath. When prescribing DULERA, the physician must also provide the patient with an inhaled, short-acting beta2-agonist (e.g., albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of DULERA. When beginning treatment with DULERA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs. 5.3 Excessive Use of DULERA and Use with Other Long-Acting Beta2-Agonists As with other inhaled drugs containing beta2-adrenergic agents, DULERA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing long-acting beta2-agonists, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using DULERA should not use an additional long-acting beta2-agonist (e.g., salmeterol, formoterol fumarate, arformoterol tartrate) for any reason, including prevention of exercise-induced bronchospasm (EIB) or the treatment of asthma. 5.4 Local Effects In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans have occurred in patients treated with DULERA. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while remaining on treatment with DULERA therapy, but at times therapy with DULERA may need to be interrupted. Advise patients to rinse the mouth after inhalation of DULERA. 5.5 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or who are not properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. DULERA should be used with caution, if at all, in patients with active or quiescent tuberculosis infection of the respiratory tract, untreated systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. 5.6 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to DULERA because deaths due to adrenal insufficiency have occurred in asthmatic patients during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more per day of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although DULERA may improve control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of corticosteroid systemically and does NOT provide the mineralocorticoid activity necessary for coping with these emergencies. During periods of stress or severe asthma attack, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a medical identification card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe asthma attack. Patients requiring systemic corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to DULERA. Lung function (FEV1 or PEF), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of systemic corticosteroids. In addition to monitoring asthma signs and symptoms, patients should be observed for signs and symptoms of adrenal insufficiency such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to DULERA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, e.g., rhinitis, conjunctivitis, eczema, arthritis, and eosinophilic conditions. During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal, e.g., joint and/or muscular pain, lassitude, and depression, despite maintenance or even improvement of respiratory function. 5.7 Hypercorticism and Adrenal Suppression Mometasone furoate, a component of DULERA, will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone. Since mometasone furoate is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of DULERA in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose. Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with DULERA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients, particularly when mometasone furoate is administered at higher than recommended doses over prolonged periods of time. If such effects occur, the dosage of DULERA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms. 5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of DULERA with ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. 5.9 Paradoxical Bronchospasm and Upper Airway Symptoms DULERA may produce inhalation induced bronchospasm with an immediate increase in wheezing after dosing that may be life-threatening. If inhalation induced bronchospasm occurs, it should be treated immediately with an inhaled, short-acting bronchodilator. DULERA should be discontinued immediately and alternative therapy instituted. 5.10 Immediate Hypersensitivity Reactions Immediate hypersensitivity reactions may occur after administration of DULERA, as demonstrated by cases of urticaria, flushing, allergic dermatitis, and bronchospasm. 5.11 Cardiovascular and Central Nervous System Effects Excessive beta-adrenergic stimulation has been associated with seizures, angina, hypertension or hypotension, tachycardia with rates up to 200 beats/min, arrhythmias, nervousness, headache, tremor, palpitation, nausea, dizziness, fatigue, malaise, and insomnia. Therefore, DULERA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Formoterol fumarate, a component of DULERA, can produce a clinically significant cardiovascular effect in some patients as measured by pulse rate, blood pressure, and/or symptoms. Although such effects are uncommon after administration of DULERA at recommended doses, if they occur, the drug may need to be discontinued. In addition, beta-agonists have been reported to produce ECG changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression. The clinical significance of these findings is unknown. Fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. 5.12 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids, including mometasone furoate, one of the components of DULERA. The clinical significance of small changes in BMD with regard to long-term outcomes, such as fracture, is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants and corticosteroids) should be monitored and treated with established standards of care. In a 2-year double-blind study in 103 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 85%–88% predicted), treatment with mometasone furoate dry powder inhaler 200 mcg twice daily resulted in significant reductions in lumbar spine (LS) BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.015 (-1.43%) for the mometasone furoate group compared to 0.002 (0.25%) for the placebo group. In another 2-year double-blind study in 87 male and female asthma patients 18 to 50 years of age previously maintained on bronchodilator therapy (Baseline FEV1 82%–83% predicted), treatment with mometasone furoate 400 mcg twice daily demonstrated no statistically significant changes in lumbar spine BMD at the end of the treatment period compared to placebo. The mean change from Baseline to Endpoint in the lumbar spine BMD was -0.018 (-1.57%) for the mometasone furoate group compared to -0.006 (-0.43%) for the placebo group. 5.13 Effect on Growth Orally inhaled corticosteroids, including DULERA, may cause a reduction in growth velocity when administered to pediatric patients. Monitor the growth of pediatric patients receiving DULERA routinely (e.g., via stadiometry). To minimize the systemic effects of orally inhaled corticosteroids, including DULERA, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Use in Specific Populations (8.4)]. 5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long-term administration of inhaled corticosteroids, including mometasone furoate, a component of DULERA. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts [see Adverse Reactions (6)]. 5.15 Coexisting Conditions DULERA, like other medications containing sympathomimetic amines, should be used with caution in patients with aneurysm, pheochromocytoma, convulsive disorders, or thyrotoxicosis; and in patients who are unusually responsive to sympathomimetic amines. Doses of the related beta2-agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis. 5.16 Hypokalemia and Hyperglycemia Beta2-agonist medications may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation. Clinically significant changes in blood glucose and/or serum potassium were seen infrequently during clinical studies with DULERA at recommended doses.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-Approved patient labeling (Medication Guide and Instructions for Use). Asthma-Related Death Patients should be informed that formoterol, one of the active ingredients in DULERA, increases the risk of asthma-related death. In pediatric and adolescent patients, formoterol may increase the risk of asthma-related hospitalization. They should also be informed that data are not adequate to determine whether the concurrent use of inhaled corticosteroids, the other component of DULERA, or other long-term asthma-control therapy mitigates or eliminates this risk [see Warnings and Precautions (5.1)]. Not for Acute Symptoms DULERA is not indicated to relieve acute asthma symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting, beta2-agonist (the health care provider should prescribe the patient with such medication and instruct the patient in how it should be used). Patients should be instructed to seek medical attention immediately if they experience any of the following: If their symptoms worsen Significant decrease in lung function as outlined by the physician If they need more inhalations of a short-acting beta2-agonist than usual Patients should be advised not to increase the dose or frequency of DULERA. The daily dosage of DULERA should not exceed two inhalations twice daily. If they miss a dose, they should be instructed to take their next dose at the same time they normally do. DULERA provides bronchodilation for up to 12 hours. Patients should not stop or reduce DULERA therapy without physician/provider guidance since symptoms may recur after discontinuation [see Warnings and Precautions (5.2)]. Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed DULERA, other long-acting beta2-agonists should not be used [see Warnings and Precautions (5.3)]. Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing with DULERA therapy, but at times therapy with DULERA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth after inhalation is advised [see Warnings and Precautions (5.4)]. Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex [see Warnings and Precautions (5.5)]. Hypercorticism and Adrenal Suppression: Patients should be advised that DULERA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids. Patients should taper slowly from systemic corticosteroids if transferring to DULERA [see Warnings and Precautions (5.7)]. Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk and should be monitored and, where appropriate, be treated for this condition [see Warnings and Precautions (5.12)]. Reduced Growth Velocity: Patients should be informed that orally inhaled corticosteroids, a component of DULERA, may cause a reduction in growth velocity when administered to pediatric patients. Physicians should closely follow the growth of pediatric patients taking corticosteroids by any route [see Warnings and Precautions (5.13)]. Glaucoma and Cataracts: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (glaucoma or cataracts); regular eye examinations should be considered [see Warnings and Precautions (5.14)]. Risks Associated With Beta-Agonist Therapy Patients should be informed that treatment with beta2-agonists may lead to adverse events which include palpitations, chest pain, rapid heart rate, tremor or nervousness [see Warnings and Precautions (5.11)]. Instructions for Use Patients should be instructed regarding the following: Read the Medication Guide before use and follow the Instructions for Use carefully. Patients should be reminded to: Remove the cap from the mouthpiece of the actuator before use. Not remove the canister from the actuator. Not wash inhaler in water. The mouthpiece should be cleaned using a dry wipe after every 7 days of use.

DOSAGE AND ADMINISTRATION

2 For oral inhalation only. (2) Treatment of asthma in patients ≥12 years: 2 inhalations twice daily of DULERA 100 mcg/5 mcg or 200 mcg/5 mcg. Starting dosage is based on prior asthma therapy. (2.2) 2.1 General DULERA should be administered only by the orally inhaled route (see Patient Instructions for Use in the Medication Guide). After each dose, the patient should be advised to rinse his/her mouth with water without swallowing. The cap from the mouthpiece of the actuator should be removed before using DULERA. DULERA should be primed before using for the first time by releasing 4 test sprays into the air, away from the face, shaking well before each spray. In cases where the inhaler has not been used for more than 5 days, prime the inhaler again by releasing 4 test sprays into the air, away from the face, shaking well before each spray. The DULERA canister should only be used with the DULERA actuator. The DULERA actuator should not be used with any other inhalation drug product. Actuators from other products should not be used with the DULERA canister. 2.2 Dosing DULERA should be administered as two inhalations twice daily every day (morning and evening) by the orally inhaled route. Shake well prior to each inhalation. The recommended starting dosages for DULERA treatment are based on prior asthma therapy. Table 1: Recommended Dosages for DULERA Previous Therapy Recommended Dose Maximum Recommended Daily Dose Inhaled medium dose corticosteroids DULERA 100 mcg/5 mcg, 2 inhalations twice daily 400 mcg/20 mcg Inhaled high dose corticosteroids DULERA 200 mcg/5 mcg, 2 inhalations twice daily 800 mcg/20 mcg The maximum daily recommended dose is two inhalations of DULERA 200 mcg/5 mcg twice daily. Do not use more than two inhalations twice daily of the prescribed strength of DULERA as some patients are more likely to experience adverse effects with higher doses of formoterol. If symptoms arise between doses, an inhaled short-acting beta2-agonist should be taken for immediate relief. If a previously effective dosage regimen of DULERA fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options, e.g., replacing the current strength of DULERA with a higher strength, adding additional inhaled corticosteroid, or initiating oral corticosteroids, should be considered. The maximum benefit may not be achieved for 1 week or longer after beginning treatment. Individual patients may experience a variable time to onset and degree of symptom relief. For patients ≥12 years of age who do not respond adequately after 2 weeks of therapy, higher strength may provide additional asthma control.

Diphenhydramine Hydrochloride 50 MG Oral Capsule

Generic Name: DIPHENHYDRAMINE HCL

Brand Name: Sleep Aid Maximum Strength

Substance Name(s):
DIPHENHYDRAMINE HYDROCHLORIDE

WARNINGS

Warnings Do not use for children under 12 years of age with any other product containing diphenhydramine, even one used on skin Ask a doctor before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma trouble urinating due to an enlarged prostate gland Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers. When using this product avoid alcoholic drinks. Stop use and ask a doctor if sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness. If pregnant or breast-feeding, ask a health professional before use. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away.

INDICATIONS AND USAGE

Use for relief of occasional sleeplessness.

INACTIVE INGREDIENTS

Inactive ingredients edible white ink, FD&C blue #1, gelatin, glycerin, light mineral oil*, polyethylene glycol, purified water, sorbitol-sorbitan *may contain this ingredient

PURPOSE

Purpose Nighttime sleep-aid

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.

ASK DOCTOR

Ask a doctor before use if you have a breathing problem such as emphysema or chronic bronchitis glaucoma trouble urinating due to an enlarged prostate gland

DOSAGE AND ADMINISTRATION

Directions adults and children 12 years of age and over: 1 softgel (50 mg) at bedtime if needed, or as directed by a doctor

PREGNANCY AND BREAST FEEDING

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

DO NOT USE

Do not use for children under 12 years of age with any other product containing diphenhydramine, even one used on skin

STOP USE

Stop use and ask a doctor if sleeplessness persists continuously for more than 2 weeks. Insomnia may be a symptom of a serious underlying medical illness.

ACTIVE INGREDIENTS

Active ingredient (in each softgel) Diphenhydramine HCl 50 mg Purpose Nighttime sleep-aid

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking sedatives or tranquilizers.

Ondansetron 4 MG Oral Tablet

Generic Name: ONDANSETRON HYDROCHLORIDE

Brand Name: ondansetron

Substance Name(s):
ONDANSETRON HYDROCHLORIDE

WARNINGS

Hypersensitivity reactions have been reported in patients who have exhibited hypersensitivity to other selective 5-HT3 receptor antagonists. ECG changes including QT interval prolongation has been seen in patients receiving ondansetron. In addition, post-marketing cases of Torsade de Pointes have been reported in patients using ondansetron. Avoid ondansetron hydrochloride in patients with congenital long QT syndrome. ECG monitoring is recommended in patients with electrolyte abnormalities (e.g., hypokalemia or hypomagnesemia), congestive heart failure, bradyarrhythmias or patients taking other medicinal products that lead to QT prolongation.

DRUG INTERACTIONS

Drug Interactions Ondansetron does not itself appear to induce or inhibit the cytochrome P-450 drug-metabolizing enzyme system of the liver (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Because ondansetron is metabolized by hepatic cytochrome P-450 drug-metabolizing enzymes (CYP3A4, CYP2D6, CYP1A2), inducers or inhibitors of these enzymes may change the clearance and, hence, the half-life of ondansetron. On the basis of available data, no dosage adjustment is recommended for patients on these drugs. Apomorphine Based on reports of profound hypotension and loss of consciousness when apomorphine was administered with ondansetron, concomitant use of apomorphine with ondansetron is contraindicated (see CONTRAINDICATIONS). Phenytoin, Carbamazepine, and Rifampicin In patients treated with potent inducers of CYP3A4 (i.e., phenytoin, carbamazepine, and rifampicin), the clearance of ondansetron was significantly increased and ondansetron blood concentrations were decreased. However, on the basis of available data, no dosage adjustment for ondansetron is recommended for patients on these drugs.1, 3 Tramadol Although no pharmacokinetic drug interaction between ondansetron and tramadol has been observed, data from 2 small studies indicate that ondansetron may be associated with an increase in patient controlled administration of tramadol.4, 5 Chemotherapy Tumor response to chemotherapy in the P-388 mouse leukemia model is not affected by ondansetron. In humans, carmustine, etoposide, and cisplatin do not affect the pharmacokinetics of ondansetron. In a crossover study in 76 pediatric patients, I.V. ondansetron did not increase blood levels of high-dose methotrexate.

OVERDOSAGE

There is no specific antidote for ondansetron overdose. Patients should be managed with appropriate supportive therapy. Individual intravenous doses as large as 150 mg and total daily intravenous doses as large as 252 mg have been inadvertently administered without significant adverse events. These doses are more than 10 times the recommended daily dose. In addition to the adverse events listed above, the following events have been described in the setting of ondansetron overdose: “Sudden blindness” (amaurosis) of 2 to 3 minutes’ duration plus severe constipation occurred in 1 patient that was administered 72 mg of ondansetron intravenously as a single dose. Hypotension (and faintness) occurred in a patient that took 48 mg of ondansetron tablets. Following infusion of 32 mg over only a 4-minute period, a vasovagal episode with transient second-degree heart block was observed. In all instances, the events resolved completely.

DESCRIPTION

The active ingredient in ondansetron tablets is ondansetron hydrochloride (HCl) as the dihydrate, the racemic form of ondansetron and a selective blocking agent of the serotonin 5-HT3 receptor type. Chemically it is (±) 1, 2, 3, 9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one, monohydrochloride, dihydrate. It has the following structural formula: The molecular formula is C18H19N3O•HCl•2H2O, representing a molecular weight of 365.9. Ondansetron HCl dihydrate is a white to off-white powder that is soluble in water and normal saline. Each 4 mg ondansetron tablet, USP for oral administration contains ondansetron hydrochloride dihydrate equivalent to 4 mg of ondansetron. Each 8 mg ondansetron tablet, USP for oral administration contains ondansetron hydrochloride dihydrate equivalent to 8 mg of ondansetron. Each tablet also contains the inactive ingredients croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, titanium dioxide, triacetin, and iron oxide yellow (8 mg tablet only). This product meets USP Dissolution Test 3. chemical structure

HOW SUPPLIED

Product: 50090-1600 NDC: 50090-1600-0 10 TABLET, FILM COATED in a BOTTLE NDC: 50090-1600-1 6 TABLET, FILM COATED in a BOTTLE NDC: 50090-1600-2 20 TABLET, FILM COATED in a BOTTLE NDC: 50090-1600-3 8 TABLET, FILM COATED in a BOTTLE NDC: 50090-1600-4 3 TABLET, FILM COATED in a BOTTLE NDC: 50090-1600-5 12 TABLET, FILM COATED in a BOTTLE Product: 50090-1015 NDC: 50090-1015-0 4 TABLET, FILM COATED in a BOTTLE NDC: 50090-1015-1 10 TABLET, FILM COATED in a BOTTLE NDC: 50090-1015-2 3 TABLET, FILM COATED in a BOTTLE NDC: 50090-1015-3 30 TABLET, FILM COATED in a BOTTLE NDC: 50090-1015-4 6 TABLET, FILM COATED in a BOTTLE

GERIATRIC USE

Geriatric Use Of the total number of subjects enrolled in cancer chemotherapy-induced and postoperative nausea and vomiting in US- and foreign-controlled clinical trials, for which there were subgroup analyses, 938 were 65 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. Dosage adjustment is not needed in patients over the age of 65 (see CLINICAL PHARMACOLOGY).

INDICATIONS AND USAGE

INDICATIONS & USAGE Prevention of nausea and vomiting associated with highly emetogenic cancer chemotherapy, including cisplatin ≥ 50 mg/m2. Prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy. Prevention of nausea and vomiting associated with radiotherapy in patients receiving either total body irradiation, single high-dose fraction to the abdomen, or daily fractions to the abdomen. Prevention of postoperative nausea and/or vomiting. As with other antiemetics, routine prophylaxis is not recommended for patients in whom there is little expectation that nausea and/or vomiting will occur postoperatively. In patients where nausea and/or vomiting must be avoided postoperatively, ondansetron tablets are recommended even where the incidence of postoperative nausea and/or vomiting is low.

PEDIATRIC USE

Pediatric Use Little information is available about dosage in pediatric patients 4 years of age or younger (see CLINICAL PHARMACOLOGYand DOSAGE AND ADMINISTRATIONsections for use in pediatric patients 4 to 18 years of age).

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category B. Reproduction studies have been performed in pregnant rats and rabbits at daily oral doses up to 15 and 30 mg/kg/day, respectively, and have revealed no evidence of impaired fertility or harm to the fetus due to ondansetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed

NUSRING MOTHERS

Nursing Mothers Ondansetron is excreted in the breast milk of rats. It is not known whether ondansetron is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ondansetron is administered to a nursing woman.

DOSAGE AND ADMINISTRATION

Prevention of Nausea and Vomiting Associated With Highly Emetogenic Cancer Chemotherapy The recommended adult oral dosage of ondansetron tablets is 24 mg given as three 8 mg tablets administered 30 minutes before the start of single-day highly emetogenic chemotherapy, including cisplatin ≥ 50 mg/m2. Multiday, single-dose administration of a 24 mg dosage has not been studied. Pediatric Use There is no experience with the use of a 24 mg dosage in pediatric patients. Geriatric Use The dosage recommendation is the same as for the general population Prevention of Nausea and Vomiting Associated With Moderately Emetogenic Cancer Chemotherapy The recommended adult oral dosage is one 8 mg ondansetron tablet given twice a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with a subsequent dose 8 hours after the first dose. One 8 mg ondansetron tablet should be administered twice a day (every 12 hours) for 1 to 2 days after completion of chemotherapy. Pediatric Use For pediatric patients 12 years of age and older, the dosage is the same as for adults. For pediatric patients 4 through 11 years of age, the dosage is one 4 mg ondansetron tablet or one 4 mg given 3 times a day. The first dose should be administered 30 minutes before the start of emetogenic chemotherapy, with subsequent doses 4 and 8 hours after the first dose. One 4 mg ondansetron tablet should be administered 3 times a day (every 8 hours) for 1 to 2 days after completion of chemotherapy. Geriatric Use The dosage is the same as for the general population. Prevention of Nausea and Vomiting Associated With Radiotherapy, Either Total Body Irradiation, or Single High-Dose Fraction or Daily Fractions to the Abdomen The recommended oral dosage is one 8 mg ondansetron tablet given 3 times a day. For total body irradiation, one 8 mg ondansetron tablet should be administered 1 to 2 hours before each fraction of radiotherapy administered each day. For single high-dose fraction radiotherapy to the abdomen, one 8 mg ondansetron tablet should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for 1 to 2 days after completion of radiotherapy. For daily fractionated radiotherapy to the abdomen, one 8 mg ondansetron tablet should be administered 1 to 2 hours before radiotherapy, with subsequent doses every 8 hours after the first dose for each day radiotherapy is given. Pediatric Use There is no experience with the use of ondansetron tablet in the prevention of radiation-induced nausea and vomiting in pediatric patients. Geriatric Use The dosage recommendation is the same as for the general population. Postoperative Nausea and Vomiting The recommended dosage is 16 mg given as two 8 mg ondansetron tablets 1 hour before induction of anesthesia. Pediatric Use There is no experience with the use of ondansetron tablets in the prevention of postoperative nausea and vomiting in pediatric patients. Geriatric Use The dosage is the same as for the general population. Dosage Adjustment for Patients With Impaired Renal Function The dosage recommendation is the same as for the general population. There is no experience beyond first-day administration of ondansetron. Dosage Adjustment for Patients With Impaired Hepatic Function In patients with severe hepatic impairment (Child-Pugh2 score of 10 or greater), clearance is reduced and apparent volume of distribution is increased with a resultant increase in plasma half-life. In such patients, a total daily dose of 8 mg should not be exceeded.

Plaquenil 200 MG Oral Tablet

Generic Name: HYDROXYCHLOROQUINE SULFATE

Brand Name: Plaquenil

Substance Name(s):
HYDROXYCHLOROQUINE SULFATE

WARNINGS

, General PLAQUENIL is not effective against chloroquine-resistant strains of P. falciparum. Before starting a long-term treatment, both eyes should be carefully examined for visual acuity, central visual field and color vision. Examination should also include fundoscopy. These examinations should be repeated at least annually. Retinal toxicity is largely dose-related. The risk of retinal damage is small with daily doses of up to 6.5 mg/kg body weight. Exceeding the recommended daily dose sharply increases the risk of retinal toxicity. This examination should be more frequent and adapted to the patient in the following situations: -daily dosage exceeding 6.5 mg/kg ideal body weight. Absolute body weight used as a guide to dosage, could result in an overdosage in the obese; -renal insufficiency; -cumulative dose more than 200 g; -elderly; -impaired visual acuity. If any visual disturbance occurs (visual acuity, color vision), the drug should be immediately discontinued and the patient closely observed for possible progression of the abnormality. Retinal changes (and visual disturbances) may progress even after cessation of the therapy. (See ADVERSE REACTIONS section) Suicidal behavior has been reported in very rare cases in patients treated with hydroxychloroquine. Children are especially sensitive to the 4-aminoquinoline compounds. A number of fatalities have been reported following the accidental ingestion of chloroquine, sometimes in relatively small doses (0.75 g or 1 g in one 3-year-old child). Patients should be strongly warned to keep these drugs out of the reach of children. Use of PLAQUENIL in patients with psoriasis may precipitate a severe attack of psoriasis. When used in patients with porphyria the condition may be exacerbated. The preparation should not be used in these conditions unless in the judgment of the physician the benefit to the patient outweighs the possible hazard. Usage in Pregnancy Usage of this drug during pregnancy should be avoided except in the suppression or treatment of malaria when in the judgment of the physician the benefit outweighs the possible hazard. It should be noted that radioactively-tagged chloroquine administered intravenously to pregnant, pigmented CBA mice passed rapidly across the placenta. It accumulated selectively in the melanin structures of the fetal eyes and was retained in the ocular tissues for five months after the drug had been eliminated from the rest of the body.

OVERDOSAGE

The 4-aminoquinoline compounds are very rapidly and completely absorbed after ingestion, and in accidental overdosage, or rarely with lower doses in hypersensitive patients, toxic symptoms may occur within 30 minutes. The symptoms of overdosage may include headache, drowsiness, visual disturbances, cardiovascular collapse, convulsions, hypokalemia, rhythm and conduction disorders including QT prolongation, torsade de pointe, ventricular tachycardia and ventricular fibrillation, followed by sudden potentially fatal respiratory and cardiac arrest. Immediate medical attention is required, as these effects may appear shortly after the overdose. Treatment is symptomatic and must be prompt with immediate evacuation of the stomach by emesis (at home, before transportation to the hospital) or gastric lavage until the stomach is completely emptied. If finely powdered, activated charcoal is introduced by the stomach tube, after lavage, and within 30 minutes after ingestion of the tablets, it may inhibit further intestinal absorption of the drug. To be effective, the dose of activated charcoal should be at least five times the estimated dose of hydroxychloroquine ingested. Convulsions, if present, should be controlled before attempting gastric lavage. If due to cerebral stimulation, cautious administration of an ultrashort-acting barbiturate may be tried but, if due to anoxia, it should be corrected by oxygen administration, artificial respiration or, in shock with hypotension, by vasopressor therapy. Because of the importance of supporting respiration, tracheal intubation or tracheostomy, followed by gastric lavage, may also be necessary. Exchange transfusions have been used to reduce the level of 4-aminoquinoline drug in the blood. A patient who survives the acute phase and is asymptomatic should be closely observed for at least six hours. Fluids may be forced, and sufficient ammonium chloride (8 g daily in divided doses for adults) may be administered for a few days to acidify the urine to help promote urinary excretion in cases of both overdosage and sensitivity.

DESCRIPTION

Hydroxychloroquine sulfate is a colorless crystalline solid, soluble in water to at least 20 percent; chemically the drug is 2-[[4-[(7-Chloro-4-quinolyl)amino]pentyl]ethylamino] ethanol sulfate (1:1). PLAQUENIL (hydroxychloroquine sulfate) tablets contain 200 mg hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral administration. Inactive Ingredients: Dibasic Calcium Phosphate, Hydroxypropyl Methylcellulose, Magnesium Stearate, Polyethylene glycol 400, Polysorbate 80, Corn Starch, Titanium Dioxide.

HOW SUPPLIED

PLAQUENIL tablets are white, to off-white, film coated tablets imprinted “PLAQUENIL” on one face in black ink. Each tablet contains 200 mg hydroxychloroquine sulfate (equivalent to 155 mg base). Bottles of 100 tablets (NDC 0024-1562-10). Dispense in a tight, light-resistant container as defined in the USP/NF. Store at room temperature up to 30° C (86° F).

INDICATIONS AND USAGE

INDICATIONS PLAQUENIL is indicated for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also indicated for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis.

BOXED WARNING

WARNING PHYSICIANS SHOULD COMPLETELY FAMILIARIZE THEMSELVES WITH THE COMPLETE CONTENTS OF THIS LEAFLET BEFORE PRESCRIBING HYDROXYCHLOROQUINE.