vardenafil 10 MG (vardenafil hydrochloride 11.85 MG) Disintegrating Oral Tablet

DRUG INTERACTIONS

7 The drug interaction studies described below were conducted using vardenafil film-coated tablets.

• STAXYN can potentiate the hypotensive effects of nitrates, alpha-blockers, and antihypertensives.

( 7.1 ) • Do not use STAXYN with moderate or potent CYP3A4 inhibitors as co-administration will result in significant increases in plasma vardenafil concentrations.

( 7.2 ) 7.1 Potential for Pharmacodynamic Interactions with STAXYN Nitrates: Concomitant use of STAXYN and nitrates is contraindicated.

The blood pressure lowering effects of sublingual nitrates (0.4 mg) taken 1 and 4 hours after vardenafil and increases in heart rate when taken at 1, 4 and 8 hours after vardenafil were potentiated by a 20 mg dose of vardenafil in healthy middle-aged subjects.

These effects were not observed when vardenafil 20 mg was taken 24 hours before the nitroglycerin (NTG).

Potentiation of the hypotensive effects of nitrates for patients with ischemic heart disease has not been evaluated, and concomitant use of STAXYN and nitrates is contraindicated [see Contraindications ( 4.1 ) and Clinical Pharmacology ( 12.2 )] .

Alpha-Blockers: Patients taking alpha-blockers should not initiate vardenafil therapy with STAXYN.

Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be switched to STAXYN at the advice of their healthcare provider.

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.

PDE5 inhibitors, including STAXYN and alpha-adrenergic blocking agents are both vasodilators with blood-pressure-lowering effects.

When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.

Clinical pharmacology studies have been conducted with co-administration of vardenafil with alfuzosin, terazosin or tamsulosin.

[See Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.6 ), and Clinical Pharmacology ( 12.2 ).] Antihypertensives: STAXYN may add to the blood pressure lowering effect of antihypertensive agents.

In a clinical pharmacology study of patients with erectile dysfunction, single doses of 20 mg vardenafil caused a mean maximum decrease in supine blood pressure of 7 mmHg systolic and 8 mmHg diastolic (compared to placebo), accompanied by a mean maximum increase of heart rate of 4 beats per minute.

The maximum decrease in blood pressure occurred between 1 and 4 hours after dosing.

Following multiple dosing for 31 days, similar blood pressure responses were observed on Day 31 as on Day 1.

Alcohol: Vardenafil 20 mg did not potentiate the hypotensive effects of alcohol during the 4-hour observation period in healthy volunteers when administered with alcohol (0.5 g/kg body weight: approximately 40 mL of absolute alcohol in a 70 kg person).

Alcohol and vardenafil plasma levels were not altered when dosed simultaneously.

7.2 Effect of Other Drugs on Vardenafil In vitro studies Studies in human liver microsomes showed that vardenafil is metabolized primarily by cytochrome P450 (CYP) isoforms 3A4/5, and to a lesser degree by CYP2C9.

Therefore, inhibitors of these enzymes are expected to reduce vardenafil clearance [see Dosage and Administration (2.4) and Warnings and Precautions (5.2)] .

In vivo studies Do not use STAXYN with moderate and potent CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions ( 5 ) and Dosage and Administration ( 2.4 )] .

Potent CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil 5 mg in healthy volunteers.

[See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Indinavir (800 mg t.i.d.) co-administered with vardenafil 10 mg resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max and a 2-fold increase in vardenafil half-life.

[See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5 ).] Ritonavir (600 mg b.i.d.) co-administered with vardenafil 5 mg resulted in a 49-fold increase in vardenafil AUC and a 13-fold increase in vardenafil C max .

The interaction is a consequence of blocking hepatic metabolism of vardenafil by ritonavir, a HIV protease inhibitor and a highly potent CYP3A4 inhibitor, which also inhibits CYP2C9.

[See Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.2 ).] Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil C max when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5 )].

Other Drug Interactions No pharmacokinetic interactions were observed between vardenafil and the following drugs: glyburide, warfarin, digoxin, an antacid based on magnesium-aluminum hydroxide, and ranitidine.

In the warfarin study, vardenafil had no effect on the prothrombin time or other pharmacodynamic parameters.

Cimetidine (400 mg b.i.d.) had no effect on AUC and C max of vardenafil when co-administered with 20 mg vardenafil in healthy volunteers.

7.3 Effects of Vardenafil on Other Drugs In vitro studies Vardenafil and its metabolites had no effect on CYP1A2, 2A6, and 2E1 (Ki >100 micromolar).

Weak inhibitory effects toward other isoforms (CYP2C8, 2C9, 2C19, 2D6, 3A4) were found, but Ki values were in excess of plasma concentrations achieved following dosing.

The most potent inhibitory activity was observed for vardenafil metabolite M1, which had a Ki of 1.4 micromolar toward CYP3A4, which is about 20 times higher than the M1 C max values after an 80 mg vardenafil dose.

In vivo studies Nifedipine: Vardenafil 20 mg (film-coated tablets), when co-administered with slow-release nifedipine 30 mg or 60 mg once daily, did not affect the relative AUC or C max of nifedipine, a drug that is metabolized via CYP3A4.

Nifedipine did not alter the plasma levels of vardenafil when taken in combination.

STAXYN, when co-administered with slow-release nifedipine 30 mg or 60 mg once daily in patients whose hypertension was controlled with nifedipine, produced mean additional supine systolic/diastolic blood pressure reductions of 3/4 mmHg (age group 65 to 69 years) and 5/5 mmHg (age group 70 to 80 years) compared to placebo.

Ritonavir and Indinavir: Upon concomitant administration of 5 mg vardenafil with 600 mg b.i.d.

ritonavir, the C max and AUC of ritonavir were reduced by approximately 20%.

Upon administration of 10 mg of vardenafil (film-coated tablets) with 800 mg t.i.d.

indinavir, the C max and AUC of indinavir were reduced by 40% and 30%, respectively.

Aspirin: Vardenafil 10 mg and 20 mg did not potentiate the increase in bleeding time caused by aspirin (two 81 mg tablets).

Other Interactions: Vardenafil had no effect on the pharmacodynamics of glyburide (glucose and insulin concentrations) and warfarin (prothrombin time or other pharmacodynamic parameters).

OVERDOSAGE

10 The maximum dose of vardenafil for which human data are available is a single 120 mg dose of the film–coated tablets administered to healthy male volunteers.

The majority of these subjects experienced reversible back pain/myalgia and/or “abnormal vision.” Single doses up to 80 mg vardenafil and multiple doses up to 40 mg vardenafil administered once daily over 4 weeks were tolerated without producing serious adverse side effects.

When 40 mg of vardenafil was administered twice daily, cases of severe back pain were observed.

No muscle or neurological toxicity was identified.

In cases of overdose, standard supportive measures should be taken as required.

Renal dialysis is not expected to accelerate clearance because vardenafil is highly bound to plasma proteins and is not significantly eliminated in the urine.

DESCRIPTION

11 STAXYN (vardenafil hydrochloride) is an oral therapy for the treatment of erectile dysfunction.

This monohydrochloride salt of vardenafil is a selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific PDE5.

Vardenafil HCl is designated chemically as piperazine, 1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-, monohydrochloride and has the following structural formula: Vardenafil HCl is a nearly colorless, solid substance with a molecular weight of 579.1 g/mol and a solubility of 0.11 mg/mL in water.

STAXYN is formulated as white round orally disintegrating tablets with no debossing.

Each tablet contains 11.85 mg vardenafil hydrochloride, which corresponds to 10 mg vardenafil, and the following inactive ingredients: aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).

Structural Formula

CLINICAL STUDIES

14 The efficacy and safety of STAXYN were evaluated in two identical multi-national, randomized, double-blind, placebo-controlled trials (studies 1 and 2).

STAXYN was dosed without regard to meals on an as-needed basis in men with erectile dysfunction (ED), many of whom had multiple other medical conditions.

In both pivotal studies, randomization was stratified so that approximately 50% of patients were ≥65 years old.

Primary efficacy assessment was by means of the Erectile Function (EF) Domain score of the validated International Index of Erectile Function (IIEF) Questionnaire and two questions from the Sexual Encounter Profile (SEP) dealing with the ability to achieve vaginal penetration (SEP2), and the ability to maintain an erection long enough for successful intercourse (SEP3).

The primary endpoints were assessed at 3 months.

Study 1 evaluated 355 mainly European (Belgium, France, Germany, Spain, South Africa, and Netherlands) patients (mean age 61.9; 67% White, 4% Black, 3% Asian, 26% Unknown).

The mean baseline EF domain scores were 13 for both placebo and STAXYN groups.

Study 2 evaluated 331 mainly North American (USA, Canada, Mexico, and Australia) patients (mean age 61.7; 69% White, 5% Black, 4% Asian, 22% Hispanic).

The mean baseline EF domain scores were 12 for STAXYN and 13 for placebo.

In both studies STAXYN demonstrated clinically meaningful and statistically significant improvements over placebo in all 3 primary efficacy variables (see Table 7).

Table 7: Change from Baseline for the Primary Efficacy Variables in Studies 1 and 2 Study 1 Study 2 Placebo STAXYN p-value Placebo STAXYN p-value EF Domain Score (N=172) (N=181) (N=160) (N=167) Endpoint 14 21 14 21 Change from baseline 1.6 8.7 <.0001 1.5 8.5 <.0001 Insertion of Penis (SEP2) (N=169) (N=179) (N=161) (N=168) Endpoint 45% 74% 43% 69% Change from baseline 6.9% 35.9% <.0001 4.8% 30.8% <.0001 Maintenance of Erection (SEP3) (N=164) (N=178) (N=160) (N=168) Endpoint 26% 65% 27% 60% Change from baseline 11.6% 51.6% <.0001 12.4% 45.9% <.0001 14.1 Other Vardenafil Clinical Trials Using Film-Coated Tablets Patients with ED and Diabetes Mellitus Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose [10 and 20 mg vardenafil film-coated tablets], double-blind, placebo-controlled trial of patients with diabetes mellitus (n=439; mean age 57 years, range 33–81; 80% White, 9% Black, 8% Hispanic, and 3% Other).

Significant improvements in the EF Domain were shown in this study (EF Domain scores of 17 on 10 mg vardenafil and 19 on 20 mg vardenafil compared to 13 on placebo; p <0.0001).

Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (61% on 10 mg and 64% on 20 mg vardenafil compared to 36% on placebo; p <0.0001).

Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (49% on 10 mg, 54% on 20 mg vardenafil compared to 23% on placebo; p <0.0001).

Patients with ED after Radical Prostatectomy Vardenafil demonstrated clinically meaningful and statistically significant improvement in erectile function in a prospective, fixed-dose 10 and 20 mg vardenafil film-coated tablets, double-blind, placebo-controlled trial in post-prostatectomy patients (n=427, mean age 60, range 44–77 years; 93% White, 5% Black, 2% Other).

Significant improvements in the EF Domain were shown in this study (EF Domain scores of 15 on 10 mg vardenafil and 15 on 20 mg vardenafil compared to 9 on placebo; p <0.0001).

Vardenafil significantly improved the overall per-patient rate of achieving an erection sufficient for penetration (SEP2) (47% on 10 mg and 48% on 20 mg vardenafil compared to 22% on placebo; p <0.0001).

Vardenafil demonstrated a clinically meaningful and statistically significant increase in the overall per-patient rate of maintenance of erection to successful intercourse (SEP3) (37% on 10 mg, 34% on 20 mg vardenafil compared to 10% on placebo; p <0.0001).

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied STAXYN (vardenafil HCl) are white, round orally disintegrating tablets with no debossing.

STAXYN orally disintegrating tablets are packaged into foil blisterpacks and supplied as a 4 tablet unit.

Package Strength NDC Code 1 blister card containing 4 tablets 10 mg 0173-0822-04 In addition to the active ingredient, vardenafil, each tablet contains aspartame, peppermint flavor, magnesium stearate, and Pharmaburst™ B2 (crospovidone, mannitol, silica colloidal hydrated, and sorbitol).

16.2 Recommended Storage Store STAXYN at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

STAXYN is dispensed in blisterpacks.

The patient should be advised to examine the blisterpack before use and not use if blisters are torn, broken, or missing.

RECENT MAJOR CHANGES

Warnings and Precautions, Effects on the Eye ( 5.4 ) 8/2017

GERIATRIC USE

8.5 Geriatric Use Vardenafil AUC and C max in elderly males 65 years or older taking STAXYN were increased by 39% and 21%, respectively, in comparison to patients aged 45 years and below.

No overall differences in safety or effectiveness were observed between patients ≥65 years old and those < 65 years old in placebo-controlled clinical trials [see Clinical Pharmacology ( 12.3 )].

DOSAGE FORMS AND STRENGTHS

3 STAXYN is available in 10 mg white, round, orally disintegrating tablets (not scored), no debossing.

• STAXYN 10 mg: White, round, orally disintegrating tablets (not scored) ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Penile erection is a hemodynamic process initiated by the relaxation of smooth muscle in the corpus cavernosum and its associated arterioles.

During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells in the corpus cavernosum.

Nitric oxide activates the enzyme guanylate cyclase resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in the smooth muscle cells of the corpus cavernosum.

The cGMP in turn triggers smooth muscle relaxation, allowing increased blood flow into the penis, resulting in erection.

The tissue concentration of cGMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs).

The most abundant PDE in the human corpus cavernosum is the cGMP-specific PDE5; therefore, the inhibition of PDE5 enhances erectile function by increasing the amount of cGMP.

Because sexual stimulation is required to initiate the local release of nitric oxide, the inhibition of PDE5 has no effect in the absence of sexual stimulation.

In vitro studies have shown that vardenafil is a selective inhibitor of PDE5.

The inhibitory effect of vardenafil is more selective on PDE5 than for other known phosphodiesterases (>15-fold relative to PDE6, >130-fold relative to PDE1, >300-fold relative to PDE11, and >1,000-fold relative to PDE2, 3, 4, 7, 8, 9, and 10).

INDICATIONS AND USAGE

1 STAXYN ® is indicated for the treatment of erectile dysfunction.

• STAXYN is a phosphodiesterase 5 (PDE5) inhibitor indicated for the treatment of erectile dysfunction.

( 1 )

PEDIATRIC USE

8.4 Pediatric Use STAXYN is not indicated for use in pediatric patients.

Safety and efficacy in children has not been established.

PREGNANCY

8.1 Pregnancy Risk Summary STAXYN is not indicated for use in females.

There are no data with the use of STAXYN in pregnant women to inform any drug-associated risks.

In animal reproduction studies conducted in pregnant rats and rabbits, no adverse developmental outcomes were observed with oral administration of vardenafil during organogenesis at exposures for unbound vardenafil and its major metabolite at approximately 100 and 29 times, respectively, the maximum recommended human dose (MRHD) of 20 mg based on AUC (see Data) .

Data Animal Data No evidence of specific potential for teratogenicity, embryotoxicity or fetotoxicity was observed in rats and rabbits that received vardenafil at up to 18 mg/kg/day during organogenesis.

This dose is approximately 100 fold (rat) and 29 fold (rabbit) greater than the AUC values for unbound vardenafil and its major metabolite in humans given the MRHD of 20 mg.

In the rat pre-and postnatal development study, the NOAEL (no observed adverse effect level) for maternal toxicity was 8 mg/kg/day.

Retarded physical development of pups in the absence of maternal effects was observed following maternal exposure to 1 and 8 mg/kg possibly due to vasodilatation and/or secretion of the drug into milk.

The number of living pups born to rats exposed pre- and postnatally was reduced at 60 mg/kg/day.

Based on the results of the pre- and postnatal study, the developmental NOAEL is less than 1 mg/kg/day.

Based on plasma exposures in the rat developmental toxicity study, 1 mg/kg/day in the pregnant rat is estimated to produce total AUC values for unbound vardenafil and its major metabolite comparable to the human AUC at the MRHD of 20 mg.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS The evaluation of erectile dysfunction should include a medical assessment, a determination of potential underlying causes and the identification of appropriate treatment.

Before prescribing STAXYN, it is important to note the following: • Cardiovascular Effects: Patients should not use STAXYN if sex is inadvisable due to cardiovascular status.

( 5.1 ) • Potent and Moderate CYP3A4 Inhibitors: Do not use STAXYN in patients taking potent or moderate CYP3A4 inhibitors.

( 5.2 , 7.2 ) • Risk of Priapism: In the event that an erection lasts more than 4 hours, the patient should seek immediate medical assistance.

( 5.3 ) • Effects on the Eye: Patients should stop use of STAXYN, and seek medical attention in the event of sudden loss of vision in one or both eyes, which could be a sign of non arteritic anterior ischemic optic neuropathy (NAION).

STAXYN should be used with caution, and only when the anticipated benefits outweigh the risks, in patients with a history of NAION.

Patients with a “crowded” optic disc may also be at an increased risk of NAION.

( 5.5 , 6.2 ) • Alpha-Blockers: Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.

In some patients, concomitant use of these two drug classes can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting).

In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN.

( 2.4 , 5.6 ) • QT Prolongation: Patients with congenital QT syndrome or taking class IA or III antiarrhythmics should avoid using STAXYN.

( 5.7 , 12.2 ) • Phenylketonurics: Each STAXYN tablet contains 1.01 mg phenylalanine per tablet, which could be harmful for patients with phenylketonuria.

( 5.12 ) 5.1 Cardiovascular Effects General Physicians should consider the cardiovascular status of their patients, since there is a degree of cardiac risk associated with sexual activity.

Therefore, treatment for erectile dysfunction, including STAXYN, should not be used in men for whom sexual activity is not recommended because of their underlying cardiovascular status.

There are no controlled clinical data on the safety or efficacy of vardenafil in the following patients; and therefore its use is not recommended until further information is available: unstable angina; hypotension (resting systolic blood pressure of 170/110 mmHg); recent history of stroke, life-threatening arrhythmia, or myocardial infarction (within the last 6 months); severe cardiac failure.

Left Ventricular Outflow Obstruction Patients with left ventricular outflow obstruction (for example, aortic stenosis and idiopathic hypertrophic subaortic stenosis) can be sensitive to the action of vasodilators including PDE5 inhibitors.

Blood Pressure Effects Vardenafil has systemic vasodilatory properties that resulted in transient decreases in supine blood pressure in healthy volunteers (mean maximum decrease of 7 mmHg systolic and 8 mmHg diastolic) [see Clinical Pharmacology ( 12.2 )] .

While this normally would be expected to be of little consequence in most patients, prior to prescribing STAXYN, physicians should carefully consider whether their patients with underlying cardiovascular disease could be affected adversely by such vasodilatory effects.

5.2 Potential for Drug Interactions with Potent or Moderate CYP3A4 Inhibitors Concomitant administration with potent CYP3A4 inhibitors (such as ritonavir, indinavir, ketoconazole) or moderate CYP3A4 inhibitors (such as erythromycin) increases plasma concentrations of vardenafil.

Do not use STAXYN in patients taking potent or moderate CYP3A4 inhibitors.

[See Dosage and Administration ( 2.4 ), Drug Interactions ( 7.2 ) and Patient Counseling Information ( 17 ).] 5.3 Risk of Priapism There have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for this class of compounds, including vardenafil.

In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

STAXYN should be used with caution by patients with anatomical deformation of the penis (such as angulation, cavernosal fibrosis, or Peyronie’s disease) or by patients who have conditions that may predispose them to priapism (such as sickle cell anemia, multiple myeloma, or leukemia).

5.4 Effects on the Eye Physicians should advise patients to stop use of all phosphodiesterase type 5 (PDE5) inhibitors, including STAXYN, and seek medical attention in the event of sudden loss of vision in one or both eyes.

Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a rare condition and a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.

Based on published literature, the annual incidence of NAION is 2.5–11.8 cases per 100,000 in males aged ≥50.

An observational study evaluated whether recent use of PDE5 inhibitors, as a class, was associated with acute onset of NAION.

The results suggest an approximate 2 fold increase in the risk of NAION within 5 half-lives of PDE5 inhibitor use.

From this information, it is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.2 )] .

An observational case-crossover study evaluated the risk of NAION when PDE5 inhibitor use, as a class, occurred immediately before NAION onset (within 5 half-lives), compared to PDE5 inhibitor use in a prior time period.

The results suggest an approximate 2-fold increase in the risk of NAION, with a risk estimate of 2.15 (95% CI 1.06, 4.34).

A similar study reported a consistent result, with a risk estimate of 2.27 (95% CI 0.99, 5.20).

Other risk factors for NAION, such as the presence of “crowded” optic disc, may have contributed to the occurrence of NAION in these studies.

Neither the rare postmarketing reports, nor the association of PDE5 inhibitor use and NAION in the observational studies, substantiate a causal relationship between PDE5 inhibitor use and NAION [see Adverse Reactions ( 6.2 )].

Physicians should consider whether their patients with underlying NAION risk factors could be adversely affected by use of PDE5 inhibitors.

Individuals who have already experienced NAION are at increased risk of NAION recurrence.

Therefore, PDE5 inhibitors, including Staxyn, should be used with caution in these patients and only when the anticipated benefits outweigh the risks.

Individuals with “crowded” optic disc are also considered at greater risk for NAION compared to the general population, however, evidence is insufficient to support screening of prospective users of PDE5 inhibitors, including STAXYN, for this uncommon condition.

STAXYN has not been evaluated in patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, therefore its use is not recommended until further information is available in those patients.

5.5 Sudden Hearing Loss Physicians should advise patients to stop taking all PDE5 inhibitors, including STAXYN, and seek prompt medical attention in the event of sudden decrease or loss of hearing.

These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including vardenafil.

It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6.2 )].

5.6 Alpha-Blockers In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN.

Patients treated with alpha-blockers who have previously used vardenafil film-coated tablets may be changed to STAXYN at the advice of their healthcare provider.

Caution is advised when PDE5 inhibitors are co-administered with alpha-blockers.

PDE5 inhibitors, including STAXYN, and alpha-adrenergic blocking agents are both vasodilators with blood-pressure lowering effects.

When vasodilators are used in combination, an additive effect on blood pressure may be anticipated.

In some patients, concomitant use of these two drug classes can lower blood pressure significantly [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.2 )] leading to symptomatic hypotension (for example, fainting).

Consideration should be given to the following: • Patients should be stable on alpha-blocker therapy prior to initiating a PDE5 inhibitor.

Patients who demonstrate hemodynamic instability on alpha-blocker therapy alone are at increased risk of symptomatic hypotension with concomitant use of PDE5 inhibitors.

• In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose.

In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN.

Lower doses of vardenafil film-coated tablets should be used as initial therapy in these patients [see Dosage and Administration ( 2.4 )] .

• In those patients already taking an optimized dose of PDE5 inhibitor, alpha-blocker therapy should be initiated at the lowest dose.

Stepwise increases in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a PDE5 inhibitor.

• Safety of combined use of PDE5 inhibitors and alpha-blockers may be affected by other variables, including intravascular volume depletion and other anti-hypertensive drugs.

5.7 Congenital or Acquired QT Prolongation In a study of the effect of vardenafil on QT interval in 59 healthy males [see Clinical Pharmacology ( 12.2 )] , therapeutic (10 mg film-coated tablets) and supratherapeutic (80 mg) doses of vardenafil and the active control moxifloxacin (400 mg) produced similar increases in QTc interval.

A postmarketing study evaluating the effect of combining vardenafil with another drug of comparable QT effect showed an additive QT effect when compared with either drug alone [see Clinical Pharmacology ( 12.2 )] .

These observations should be considered in clinical decisions when prescribing vardenafil to patients with known history of QT prolongation or patients who are taking medications known to prolong the QT interval.

Patients taking Class 1A (for example, quinidine, procainamide) or Class III (for example, amiodarone, sotalol) antiarrhythmic medications or those with congenital QT prolongation, should avoid using STAXYN.

5.8 Hepatic Impairment Do not use STAXYN in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Dosage and Administration ( 2.3 ) Clinical Pharmacology ( 12.3 )] and Use in Specific Populations ( 8.6 )] .

5.9 Renal Impairment Do not use STAXYN in patients on renal dialysis, as vardenafil has not been evaluated in this population [see Dosage and Administration ( 2.3 ) and Use in Specific Populations ( 8.7 )].

5.10 Combination with Other Erectile Dysfunction Therapies The safety and efficacy of STAXYN used in combination with other treatments for erectile dysfunction have not been studied.

Therefore, the use of such combinations is not recommended.

5.11 Effects on Bleeding In humans, vardenafil film-coated tablet alone in doses up to 20 mg does not prolong the bleeding time.

There is no clinical evidence of any additive prolongation of the bleeding time when vardenafil is administered with aspirin.

STAXYN has not been administered to patients with bleeding disorders or significant active peptic ulceration.

Therefore STAXYN should be administered to these patients after careful benefit-risk assessment.

5.12 Phenylketonurics STAXYN contains aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.

Phenylketonurics: Each STAXYN tablet contains 1.01 mg phenylalanine per tablet.

5.13 Fructose Intolerance STAXYN contains sorbitol.

Patients with rare hereditary problems of fructose intolerance should not take STAXYN.

5.14 Sexually Transmitted Disease The use of STAXYN offers no protection against sexually transmitted diseases.

Counseling of patients about protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information) Use with Other Formulations of Vardenafil Inform patients that STAXYN is not interchangeable with vardenafil film-coated tablets (LEVITRA) as it provides higher systemic exposure.

They should also discuss that the maximum dosage is one STAXYN tablet per 24 hours.

Nitrates Discuss with patients that STAXYN is contraindicated with regular and/or intermittent use of organic nitrates.

Patients should be counseled that concomitant use of vardenafil with nitrates could cause blood pressure to suddenly drop to an unsafe level, resulting in dizziness, syncope, or even heart attack or stroke.

Guanylate Cyclase (GC) Stimulators Inform patients that Staxyn is contraindicated in patients who use guanylate cyclase stimulators, such as riociguat.

Cardiovascular Discuss with patients the potential cardiac risk of sexual activity for patients with preexisting cardiovascular risk factors.

Concomitant Use with Drugs which Lower Blood Pressure Inform patients that in some patients concomitant use of PDE5 inhibitors, including STAXYN, with alpha-blockers can lower blood pressure significantly leading to symptomatic hypotension (for example, fainting).

Patients who are taking alpha-blockers should only use STAXYN when previous treatment with vardenafil film-coated tablets has been well tolerated [see Dosage and Administration ( 2 ) and Drug Interactions ( 7 )].

Patients should be advised of the possible occurrence of symptoms related to postural hypotension and appropriate countermeasures.

Patients should be advised to contact the prescribing physician if other anti-hypertensive drugs or new medications that may interact with STAXYN are prescribed by another healthcare provider.

Recommended Administration Discuss with patients the appropriate use of STAXYN and its anticipated benefits.

It should be explained that sexual stimulation is required for an erection to occur after taking STAXYN.

STAXYN should be taken approximately 60 minutes before sexual activity.

Patients should be counseled regarding the dosing of STAXYN, especially regarding the maximum daily dose.

Patients should be advised to contact their healthcare provider if they are not satisfied with the quality of their sexual performance with STAXYN or in the case of an unwanted effect.

Priapism Inform patients that there have been rare reports of prolonged erections greater than 4 hours and priapism (painful erections greater than 6 hours in duration) for vardenafil and this class of compounds.

In the event that an erection persists longer than 4 hours, the patient should seek immediate medical assistance.

If priapism is not treated immediately, penile tissue damage and permanent loss of potency may result.

Drug Interactions Advise patients to contact the prescribing physician if new medications that may interact with STAXYN are prescribed by another healthcare provider.

Sudden Loss of Vision Inform patients to stop use of all PDE5 inhibitors, including STAXYN, and seek medical attention in the event of sudden loss of vision in one or both eyes.

Such an event may be a sign of non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision, including permanent loss of vision, that has been reported rarely postmarketing in temporal association with the use of all PDE5 inhibitors.

Physicians should also discuss with patients the increased risk of NAION in individuals who have already experienced NAION in one eye.

Physicians should also discuss with patients the increased risk of NAION among the general population in patients with a “crowded” optic disc, although evidence is insufficient to support screening of prospective users of PDE5 inhibitor, including Staxyn, for this uncommon condition [see Warnings and Precautions ( 5.4 ) and [see Adverse Reactions ( 6.1 )].

Sudden Hearing Loss Advise patients to stop taking PDE5 inhibitors, including STAXYN, and seek prompt medical attention in the event of sudden decrease or loss of hearing.

These events, which may be accompanied by tinnitus and dizziness, have been reported in temporal association to the intake of PDE5 inhibitors, including STAXYN.

It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors or to other factors [see Adverse Reactions ( 6 )].

Sexually Transmitted Disease Inform patients that STAXYN offers no protection against sexually transmitted diseases.

Counsel patients that protective measures necessary to guard against sexually transmitted diseases, including the Human Immunodeficiency Virus (HIV), should be considered.

Dose Adjustment STAXYN is available only in a single strength.

Patients who require a different dosage should be prescribed vardenafil film-coated tablets (LEVITRA).

DOSAGE AND ADMINISTRATION

2 • STAXYN is not interchangeable with vardenafil 10 mg film-coated tablets (LEVITRA).

STAXYN provides higher systemic exposure compared to vardenafil 10 mg film-coated tablets (LEVITRA).

( 2.1 ) • STAXYN is taken as needed, orally, approximately 60 minutes before sexual activity.

( 2.1 ) • The maximum recommended dosing frequency is one tablet per day.

( 2.1 ) • STAXYN should be placed on the tongue where it will disintegrate.

It should be taken without liquid.

( 2.1 ) • STAXYN may be taken with or without food.

( 2.2 ) 2.1 General STAXYN is available in 10 mg orally disintegrating tablets.

STAXYN is not interchangeable with vardenafil 10 mg film-coated tablets (LEVITRA).

STAXYN provides higher systemic exposure compared to vardenafil 10 mg film-coated tablets (LEVITRA).

[See Clinical Pharmacology ( 12.3 ).] STAXYN should be taken orally, as needed, approximately 60 minutes before sexual activity.

The maximum dosing frequency is one STAXYN tablet per day.

Sexual stimulation is required for a response to treatment.

STAXYN should be placed on the tongue where it will disintegrate.

The tablet should be taken without liquid.

It should be taken immediately upon removal from the blister.

Those patients who require a lower or higher dose of vardenafil need to be prescribed vardenafil film-coated tablets [see Patient Counseling Information ( 17 )] .

2.2 Use with Food STAXYN can be taken with or without food.

2.3 Use in Special Populations Hepatic Impairment: Do not use STAXYN in patients with moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions ( 5.8 ) and Clinical Pharmacology ( 12.3 )] .

Renal Impairment: Do not use STAXYN in patients on renal dialysis [see Warnings and Precautions ( 5.9 ) and Clinical Pharmacology ( 12.3 )] .

2.4 Concomitant Medications Nitrates : Concomitant use with nitrates in any form is contraindicated [see Contraindications ( 4.1 )] .

Guanylate Cyclase (GC) Stimulators, such as riociguat: Concomitant use is contraindicated [see Contraindications ( 4.2 )].

CYP3A4 Inhibitors: Do not use STAXYN with potent or moderate CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, atazanavir, clarithromycin and erythromycin [see Warnings and Precautions ( 5.2 ) and Drug Interactions ( 7.2 )] .

Alpha-Blockers: In those patients who are stable on alpha-blocker therapy, PDE5 inhibitors should be initiated at the lowest recommended starting dose.

Stepwise increase in alpha-blocker dose may be associated with further lowering of blood pressure in patients taking a phosphodiesterase (PDE5) inhibitor including vardenafil.

In patients taking alpha-blockers, do not initiate vardenafil therapy with STAXYN.

Lower doses of vardenafil film-coated tablets should be used as initial therapy in these patients.

[see Dosage and Administration ( 2.4 )] .

Patients taking alpha-blockers who have previously used vardenafil film-coated tablets may change to STAXYN at the advice of their healthcare provider.

[See Warnings and Precautions ( 5.6 ) and Drug Interactions ( 7.1 ).] A time interval between dosing should be considered when STAXYN is prescribed concomitantly with alpha-blocker therapy [see Clinical Pharmacology ( 12.2 )].

budesonide 0.09 MG/ACTUAT (0.08 MG/ACTUAT from the mouthpiece) Dry Powder Inhaler, 60 ACTUAT

DRUG INTERACTIONS

7 • Strong cytochrome P450 3A4 inhibitors (e.g., ritonavir): Use with caution.

May cause increased systemic corticosteroid effects.

(7.1) 7.1 Inhibitors of Cytochrome P4503A4 The main route of metabolism of corticosteroids, including budesonide, is via cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4).

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased.

Concomitant administration of CYP3A4 may inhibit the metabolism of, and increase the systemic exposure to, budesonide.

Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER 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 (5.7) ].

OVERDOSAGE

10 The potential for acute toxic effects following overdose of PULMICORT FLEXHALER is low.

If used at excessive doses for prolonged periods, systemic corticosteroid effects such as hypercorticism may occur [see Warnings and Precautions, Hypercorticism and Adrenal Suppression (5.6) ].

Another budesonide-containing dry powder inhaler at 3200 mcg daily administered for 6 weeks caused a significant reduction (27%) in the plasma cortisol response to a 6-hour infusion of ACTH compared with placebo (+1%).

The corresponding effect of 10 mg prednisone daily was a 35% reduction in the plasma cortisol response to ACTH.

The minimal inhalation lethal dose in mice was 100 mg/kg (approximately 280 times the maximum recommended daily inhalation dose in adults and approximately 330 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m 2 basis).

There were no deaths following the administration of an inhalation dose of 68 mg/kg in rats (approximately 380 times the maximum recommended daily inhalation dose in adults and approximately 450 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m 2 basis).

The minimal oral lethal dose was 200 mg/kg in mice (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age on a mcg/m 2 basis) and less than 100 mg/kg in rats (approximately 560 times the maximum recommended daily inhalation dose in adults and approximately 670 times the maximum recommended daily inhalation dose in children 6 to 17 years of age based on a mcg/m 2 basis).

Post-marketing experience showed that acute overdose of inhaled budesonide commonly remained asymptomatic.

The use of excessive doses (up to 6400 mcg daily) for prolonged periods showed systemic corticosteroid effects such as hypercorticism.

DESCRIPTION

11 Budesonide, the active component of PULMICORT FLEXHALER, is a corticosteroid designated chemically as (RS)-11β, 16α, 17,21-Tetrahydroxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with butyraldehyde.

Budesonide is provided as a mixture of two epimers (22R and 22S).

The empirical formula of budesonide is C 25 H 34 O 6 and its molecular weight is 430.5.

Its structural formula is: Budesonide is a white to off-white, tasteless, odorless powder that is practically insoluble in water and in heptane, sparingly soluble in ethanol, and freely soluble in chloroform.

Its partition coefficient between octanol and water at pH 7.4 is 1.6 x 10 3 .

PULMICORT FLEXHALER is an inhalation-driven multi-dose dry powder inhaler containing a formulation of 1 mg per actuation of micronized budesonide and micronized lactose monohydrate which contains trace levels of milk proteins [see Contraindications (4) and Post-marketing Experience (6.2) ].

Each actuation of PULMICORT FLEXHALER 180 mcg delivers 160 mcg budesonide from the mouthpiece and each actuation of PULMICORT FLEXHALER 90 mcg delivers 80 mcg budesonide from the mouthpiece (based on in vitro testing at 60 L/min for 2 sec).

Each PULMICORT FLEXHALER 180 mcg contains 120 actuations and each PULMICORT FLEXHALER 90 mcg contains 60 actuations.

In vitro testing has shown that the dose delivery for PULMICORT FLEXHALER is dependent on airflow through the device, as evidenced by a decrease in the fine particle dose at a flow rate of 30 L/min to a value that is approximately 40-50% of that produced at 60 L/min.

At a flow rate of 40 L/min, the fine particle dose is approximately 70% of that produced at 60 L/min.

Patient factors such as inspiratory flow rates will also affect the dose delivered to the lungs of patients in actual use [see Patient Information and Instructions for Use (17.11) ].

In asthmatic children age 6 to 17 (N=516, FEV 1 2.29 [0.97– 4.28]) peak inspiratory flow (PIF) through PULMICORT FLEXHALER was 72.5 [19.1 – 103.6] L/min).

Inspiratory flows were not measured in the adult pivotal study.

Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.

structural formula

CLINICAL STUDIES

14 14.1 Asthma The safety and efficacy of PULMICORT FLEXHALER were evaluated in two 12-week, double-blind, randomized, parallel-group, placebo-controlled clinical studies conducted at sites in the United States and Asia involving 1137 patients aged 6 to 80 years with mild to moderate asthma.

Study 1 evaluated PULMICORT FLEXHALER 180 mcg, PULMICORT TURBUHALER 200 mcg, and placebo, each administered as 1 inhalation once daily or 2 inhalations twice daily in patients 18 years of age and older with mild to moderate asthma previously treated with inhaled corticosteroids.

The delivered dose of PULMICORT FLEXHALER 180 mcg and PULMICORT TURBUHALER 200 mcg are the same; each delivers 160 mcg from the mouthpiece.

Study 2 evaluated PULMICORT FLEXHALER 90 mcg, 2 inhalations once daily or 4 inhalations twice daily, PULMICORT TURBUHALER 200 mcg, 1 inhalation once daily or 2 inhalations twice daily, and placebo in pediatric patients aged 6 to 17 years with mild to moderate asthma.

Both of the studies had a 2-week placebo treatment run-in period followed by a 12-week randomized treatment period.

The primary endpoint was the difference between baseline and the mean of the treatment-period FEV 1 (adults) or FEV 1 % predicted (children).

Patients ≥ 18 years of age and older (Study 1) This study enrolled 621 patients aged ≥18 to 80 years with mild-to-moderate asthma (mean baseline % predicted FEV 1 64.3%) whose symptoms were previously controlled on inhaled corticosteroids.

Mean change from baseline in FEV 1 in the PULMICORT FLEXHALER 180 mcg, 2 inhalations twice-daily group was 0.28 liters, as compared to 0.10 liters in the placebo group (p<0.001).

Secondary endpoints of morning and evening peak expiratory flow rate, daytime asthma symptom severity, nighttime asthma symptom severity, daily rescue medication use, and the percentage of patients who met predefined asthma related withdrawal criteria showed differences from baseline favoring PULMICORT FLEXHALER over placebo (p<0.001).

12-Week Trial in Adult Patients with Mild to Moderate Asthma (Study 1) Mean Change from Baseline in FEV 1 (L) Footnote: PULMICORT TURBUHALER; a different PULMICORT DPI.

Statistical model is analysis of covariance with treatment and region (US/Asia) as factors and the baseline value as the covariate.

Patients 6 to 17 years of age (Study 2) This study enrolled 516 patients aged 6 to 17 years with mild asthma (mean baseline % predicted FEV 1 84.9%).

The study population included patients previously treated with inhaled corticosteroids for no more than 30 days before the study began (4%) and patients who were naïve to inhaled corticosteroids (96%).

Mean change from baseline in % predicted FEV 1 during the 12-week treatment period in the PULMICORT FLEXHALER 90 mcg, 4 inhalations twice daily treatment group was 5.6 compared with 0.2 in the placebo group (p<0.001).

Secondary endpoints of morning and evening PEF showed differences from baseline favoring PULMICORT FLEXHALER over placebo (p<0.001).

12-Week Trial in Pediatric Patients With Mild Asthma (Study 2) Mean Change from Baseline in Percent Predicted FEV 1 Footnote: PULMICORT TURBUHALER; a different PULMICORT DPI.

Statistical model is analysis of covariance with treatment and region (US/Asia) as factors and the baseline value as the covariate.

figure 1 figure 2

HOW SUPPLIED

16 /STORAGE AND HANDLING PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following strength: 90 mcg.

Each dosage strength contains 60 actuations per device.

90 mcg/dose, 60 dose (NDC 21695-291-01) with a target fill weight of 165 mg (range 140-190).

PULMICORT FLEXHALER consists of a number of assembled plastic details, the main parts being the dosing mechanism, the storage unit for drug substance, and the mouthpiece.

The inhaler is protected by a white outer tubular cover screwed onto the inhaler.

The body of the inhaler is white and the turning grip is brown.

The PULMICORT FLEXHALER inhaler cannot be refilled and should be discarded when empty.

The number in the middle of the dose indicator window shows how many doses are left in the inhaler.

The inhaler is empty when the number zero (“0”) on the red background reaches the middle of the window.

If the unit is used beyond the point at which the zero reaches the middle of the window, the correct amount of medication may not be obtained and the unit should be discarded.

Store in a dry place at controlled room temperature 20-25°C (68-77°F) [see USP] with the cover tightly in place.

Keep out of the reach of children.

GERIATRIC USE

8.5 Geriatric Use Of the total number of patients in controlled clinical studies receiving inhaled budesonide, 153 (n=11 treated with PULMICORT FLEXHALER ) were 65 years of age or older and one was age 75 years or older.

No overall differences in safety were observed between these patients and younger patients.

Clinical studies did not include sufficient numbers of patients aged 65 years and over to determine differences in efficacy between elderly and younger patients.

Other reported clinical or medical surveillance experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 PULMICORT FLEXHALER is available as a dry powder for inhalation containing budesonide in the following 2 strengths: 90 mcg and 180 mcg.

Each inhaler contains 60 or 120 actuations.

FLEXHALER device containing budesonide (90 mcg or 180 mcg) as an inhalation powder.

(3)

MECHANISM OF ACTION

12.1 Mechanism of Action Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity.

In standard in vitro and animal models, budesonide has approximately a 200-fold higher affinity for the glucocorticoid receptor and a 1000-fold higher topical anti-inflammatory potency than cortisol (rat croton oil ear edema assay).

As a measure of systemic activity, budesonide is 40 times more potent than cortisol when administered subcutaneously and 25 times more potent when administered orally in the rat thymus involution assay.

The clinical significance of this is unknown.

The activity of PULMICORT FLEXHALER is due to the parent drug, budesonide.

In glucocorticoid receptor affinity studies, the 22R form was two times as active as the 22S epimer.

In vitro studies indicated that the two forms of budesonide do not interconvert.

The precise mechanism of corticosteroid actions on inflammation in asthma is not known.

Inflammation is an important component in the pathogenesis of asthma.

Corticosteroids have a wide range of inhibitory activities against multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation.

These anti-inflammatory actions of corticosteroids may contribute to their efficacy in asthma.

Studies in asthmatic patients have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects over a wide range of doses of inhaled budesonide.

This is explained by a combination of a relatively high local anti-inflammatory effect, extensive first pass hepatic degradation of orally absorbed drug (85-95%), and the low potency of formed metabolites (see below).

INDICATIONS AND USAGE

1 PULMICORT FLEXHALER is a corticosteroid indicated for: • Maintenance treatment of asthma as prophylactic therapy in adult and pediatric patients six years of age or older.

(1.1) Important Limitations: • Not indicated for the relief of acute bronchospasm.

(1.1) 1.1 Treatment of Asthma PULMICORT FLEXHALER is indicated for the maintenance treatment of asthma as prophylactic therapy in patients six years of age or older.

Important Limitations of Use: PULMICORT FLEXHALER is NOT indicated for the relief of acute bronchospasm.

PEDIATRIC USE

8.4 Pediatric Use In a 12-week pivotal study, 204 patients 6 to 17 years of age were treated with PULMICORT FLEXHALER twice daily [see Clinical Studies (14.1) ].

Efficacy results in this age group were similar to those observed in patients 18 years and older.

There were no obvious differences in the type or frequency of adverse events reported in this age group compared with patients 18 years of age and older.

The safety and effectiveness of PULMICORT FLEXHALER in asthma patients below 6 years of age have not been established.

Controlled clinical studies have shown that orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity in pediatric patients.

This effect has been 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.

In a study of asthmatic children 5-12 years of age, those treated with inhaled budesonide via a different PULMICORT dry powder inhaler 200 mcg twice daily (n=311) had a 1.1- centimeter reduction in growth compared with those receiving placebo (n=418) at the end of one year; the difference between these two treatment groups did not increase further over three years of additional treatment.

By the end of four years, children treated with a different PULMICORT dry powder inhaler and children treated with placebo had similar growth velocities.

Conclusions drawn from this study may be confounded by the unequal use of corticosteroids in the treatment groups and inclusion of data from patients attaining puberty during the course of the study.

The administration of inhaled budesonide via a different PULMICORT dry-powder inhaler in doses up to 800 mcg/day (mean daily dose 445 mcg/day) or via a pressurized metered-dose inhaler in doses up to 1200 mcg/day (mean daily dose 620 mcg/day) to 216 pediatric patients (age 3 to 11 years) for 2 to 6 years had no significant effect on statural growth compared with non-corticosteroid therapy in 62 matched control patients.

However, the long-term effect of inhaled budesonide on growth is not fully known.

The growth of pediatric patients receiving orally inhaled corticosteroids, including PULMICORT FLEXHALER, should be monitored (eg, 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.

To minimize the systemic effects of inhaled corticosteroids, including PULMICORT FLEXHALER, each patient should be titrated to the lowest dose that effectively controls his/her asthma [see Dosage and Administration (2) ].

PREGNANCY

8.1 Pregnancy Teratogenic Effects: Pregnancy Category B Studies of pregnant women, have not shown that inhaled budesonide increases the risk of abnormalities when administered during pregnancy.

The results from a large population-based prospective cohort epidemiological study reviewing data from three Swedish registries covering approximately 99% of the pregnancies from 1995-1997 (i.e., Swedish Medical Birth Registry; Registry of Congenital Malformations; Child Cardiology Registry) indicate no increased risk for congenital malformations from the use of inhaled budesonide during early pregnancy.

Congenital malformations were studied in 2014 infants born to mothers reporting the use of inhaled budesonide for asthma in early pregnancy (usually 10-12 weeks after the last menstrual period), the period when most major organ malformations occur.

The rate of recorded congenital malformations was similar compared to the general population rate (3.8% vs.

3.5%, respectively).

In addition, after exposure to inhaled budesonide, the number of infants born with orofacial clefts was similar to the expected number in the normal population (4 children vs.

3.3, respectively).

These same data were utilized in a second study bringing the total to 2534 infants whose mothers were exposed to inhaled budesonide.

In this study, the rate of congenital malformations among infants whose mothers were exposed to inhaled budesonide during early pregnancy was not different from the rate for all newborn babies during the same period (3.6%).

Despite the animal findings, it would appear that the possibility of fetal harm is remote if the drug is used during pregnancy.

Nevertheless, because the studies in humans cannot rule out the possibility of harm, PULMICORT FLEXHALER should be used during pregnancy only if clearly needed.

As with other glucocorticoids, budesonide produced fetal loss, decreased pup weight, and skeletal abnormalities at a subcutaneous dose in rabbits that was approximately 0.3 times the maximum recommended daily inhalation dose in adults on a mcg/m 2 basis and at a subcutaneous dose in rats that was approximately 3 times the maximum recommended daily inhalation dose in adults on a mcg/m 2 basis.

No teratogenic or embryocidal effects were observed in rats when budesonide was administered by inhalation at doses up to approximately equivalent to the maximum recommended daily inhalation dose in adults on a mcg/m 2 basis.

Experience with oral corticosteroids since their introduction in pharmacologic as opposed to physiologic doses suggests that rodents are more prone to teratogenic effects from corticosteroids than humans.

Nonteratogenic Effects Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy.

Such infants should be carefully observed.

NUSRING MOTHERS

8.3 Nursing Mothers Budesonide, like other corticosteroids, is secreted in human milk.

Data with budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother [see Clinical Pharmacology, Pharmacokinetics, Special Populations, Nursing Mothers (12.3) ].

No studies have been conducted in breastfeeding women specifically with PULMICORT FLEXHALER; however, the dose of budesonide available to the infant in breast milk, as a percentage of the maternal dose, would be expected to be similar.

PULMICORT FLEXHALER should be used in nursing women only if clinically appropriate.

Prescribers should weigh the known benefits of breastfeeding for the mother and the infant against the potential risks of minimal budesonide exposure in the infant.

Dosing considerations include prescription or titration to the lowest clinically effective dose and use of PULMICORT FLEXHALER immediately after breastfeeding to maximize the time interval between dosing and breastfeeding to minimize infant exposure.

However, in general, PULMICORT FLEXHALER use should not delay or interfere with infant feeding.

BOXED WARNING

Important Note: This medicine is to only be inhaled through the mouth (by oral inhalation only).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • 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.

(5.1) • Deterioration of asthma or acute episodes: PULMICORT FLEXHALER should not be used for relief of acute symptoms.

Patients require immediate re-evaluation during rapidly deteriorating asthma.

(5.2) • Hypersensitivity reactions: Anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.

Discontinue PULMICORT FLEXHALER if such reactions occur.

(5.3) • Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, bacterial, viral, or parasitic infection; or ocular herpes simplex).

Use with caution in patients with these infections.

More serious or even fatal course of chickenpox or measles can occur in susceptible patients.

(5.4) • Transferring patients from systemic corticosteroids: Risk of impaired adrenal function when transferring from oral steroids.

Taper patients slowly from systemic corticosteroids if transferring to PULMICORT FLEXHALER.

(5.5) • Hypercorticism and adrenal suppression: May occur with very high dosages or at the regular dosage in susceptible individuals.

If such changes occur, reduce PULMICORT FLEXHALER slowly.

(5.6) • Reduction in bone mineral density with long term administration.

Monitor patients with major risk factors for decreased bone mineral content.

(5.8) • Effects on growth: Monitor growth of pediatric patients.

(5.9) • Glaucoma and cataracts: Close monitoring is warranted.

(5.10) • Paradoxical bronchospasm: Discontinue PULMICORT FLEXHALER and institute alternative therapy if paradoxical bronchospasm occurs.

(5.11) • Eosinophilic conditions and Churg-Strauss: Be alert to eosinophilic conditions.

(5.12) 5.1 Local Effects In clinical studies, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in patients treated with PULMICORT FLEXHALER.

When such an infection develops, it should be treated with appropriate local or systemic (i.e.

oral antifungal) therapy while treatment with PULMICORT FLEXHALER continues, but at times, therapy with PULMICORT FLEXHALER may need to be interrupted.

Patients should rinse the mouth after inhalation of PULMICORT FLEXHALER.

5.2 Deterioration of Asthma or Acute Episodes PULMICORT FLEXHALER is not a bronchodilator and is not indicated for the rapid relief of bronchospasm or other acute episodes of asthma.

Patients should be instructed to contact their physician immediately if episodes of asthma not responsive to their usual doses of bronchodilators occur during the course of treatment with PULMICORT FLEXHALER.

During such episodes, patients may require therapy with oral corticosteroids.

An inhaled short acting beta 2 -agonist, not PULMICORT FLEXHALER, should be used to relieve acute symptoms such as shortness of breath.

When prescribing PULMICORT FLEXHALER, the physician must also provide the patient with an inhaled, short-acting beta 2 -agonist (e.g.

albuterol) for treatment of acute symptoms, despite regular twice-daily (morning and evening) use of PULMICORT FLEXHALER.

5.3 Hypersensitivity Reactions Including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.

Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4) and Adverse Reactions (6) ].

PULMICORT FLEXHALER contains small amounts of lactose, which contains trace levels of milk proteins.

It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy [see Contraindications (4) and Adverse Reactions, Post-marketing Experience (6.2) ].

5.4 Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals.

Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids.

In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure.

How the dose, route, and duration of corticosteroid administration affects 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 chicken pox, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, 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 chicken pox develops, treatment with antiviral agents may be considered.

The immune responsiveness to varicella vaccine was evaluated in pediatric patients with asthma ages 12 months to 8 years with budesonide inhalation suspension.

An open-label, nonrandomized clinical study examined the immune responsiveness to varicella vaccine in 243 asthma patients 12 months to 8 years of age who were treated with budesonide inhalation suspension 0.25 mg to 1 mg daily (n=151) or non-corticosteroid asthma therapy (n=92) (i.e., beta 2 -agonists, leukotriene receptor antagonists, cromones).

The percentage of patients developing a seroprotective antibody titer of ≥5.0 (gpELISA value) in response to the vaccination was similar in patients treated with budesonide inhalation suspension (85%), compared to patients treated with non-corticosteroid asthma therapy (90%).

No patient treated with budesonide inhalation suspension developed chicken pox as a result of vaccination.

Inhaled corticosteroids 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.

5.5 Transferring Patients from Systemic Corticosteroid Therapy Particular care is needed for patients who are transferred from systemically active corticosteroids to PULMICORT FLEXHALER 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 PULMICORT FLEXHALER may provide control of asthma symptoms during these episodes, in recommended doses it supplies less than normal physiological amounts of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies.

During periods of stress or a 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 a severe asthma attack.

Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to PULMICORT FLEXHALER.

Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with PULMICORT FLEXHALER.

Lung function (mean forced expiratory volume in 1 second [FEV 1 ] or morning peak expiratory flow [PEF]), beta-agonist use, and asthma symptoms should be carefully monitored during withdrawal of oral 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 PULMICORT FLEXHALER may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy, (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions).

Some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, depression) despite maintenance or even improvement of respiratory function.

5.6 Hypercorticism and Adrenal Suppression PULMICORT FLEXHALER will often help control asthma symptoms with less suppression of HPA function than therapeutically equivalent oral doses of prednisone.

Since budesonide is absorbed into the circulation and can be systemically active at higher doses, the beneficial effects of PULMICORT FLEXHALER in minimizing HPA dysfunction may be expected only when recommended dosages are not exceeded and individual patients are titrated to the lowest effective dose.

Since individual sensitivity to effects on cortisol production exists, physicians should consider this information when prescribing PULMICORT FLEXHALER.

Because of the possibility of systemic absorption of inhaled corticosteroids, patients treated with PULMICORT FLEXHALER 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 budesonide is administered at higher than recommended doses over prolonged periods of time.

If such effects occur, the dosage of PULMICORT FLEXHALER should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids and for management of asthma symptoms.

5.7 Interactions with Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER 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 budesonide may occur [ee Drug Interactions (7.1), Clinical Pharmacology (12.3) ].

5.8 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids.

The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown.

Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, post menopausal status, tobacco use, advance age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g, anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care.

5.9 Effect on Growth Orally inhaled corticosteroids, including budesonide, may cause a reduction in growth velocity when administered to pediatric patients.

Monitor the growth of pediatric patients receiving PULMICORT FLEXHALER routinely (e.g., via stadiometry).

To minimize the systemic effects of orally inhaled corticosteroids, including PULMICORT FLEXHALER, titrate each patient’s dose to the lowest dosage that effectively controls his/her symptoms [see Dosage and Administration (2.1), Use in Specific Populations (8.4) ].

5.10 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported following the long-term administration of inhaled corticosteroids, including budesonide.

Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

5.11 Paradoxical Bronchospasm and Upper Airway Symptoms As with other inhaled asthma medications, PULMICORT FLEXHALER can produce paradoxical bronchospasm, which may be life threatening.

If paradoxical bronchospasm occurs following dosing with PULMICORT FLEXHALER, it should be treated immediately with an inhaled, short-acting beta 2 – bronchodilator.

PULMICORT FLEXHALER should be discontinued immediately, and alternative therapy should be instituted.

5.12 Eosinophilic Conditions and Churg-Strauss Syndrome In rare cases, patients on inhaled corticosteroids may present with systemic eosinophilic conditions.

Some of these patients have clinical features of vasculitis consistent with Churg- Strauss syndrome, a condition that is often treated with systemic corticosteroid therapy.

These events usually, but not always, have been associated with the reduction and/or withdrawal of oral corticosteroid therapy following the introduction of inhaled corticosteroids.

Physicians should be alert to eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, and/or neuropathy presenting in their patients.

A causal relationship between budesonide and these underlying conditions has not been established.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Patients being treated with PULMICORT FLEXHALER should receive the following information and instructions.

This information is intended to aid the patient in the safe and effective use of the medication.

It is not a disclosure of all possible adverse or intended effects.

For proper use of PULMICORT FLEXHALER and to attain maximum improvement, the patient should read and follow the accompanying FDA Approved Patient Labeling.

17.1 Oral Candidiasis 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 therapy with PULMICORT FLEXHALER, but at times therapy with PULMICORT FLEXHALER may need to be temporarily interrupted under close medical supervision.

Rinsing the mouth after inhalation is advised.

[see Warnings and Precautions (5.1) ] 17.2 Not for Acute Symptoms PULMICORT FLEXHALER is not meant 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 beta 2 -agonist such as albuterol (The physician should provide that patient with such medication and instruct the patient in how it should be used.) Patients should be instructed to notify their physician immediately if they experience any of the following: Decreasing effectiveness of inhaled, short-acting beta 2 -agonists Need for more inhalations than usual of inhaled, short-acting beta 2 -agonists Significant decrease in lung function as outlined by the physician Patients should not stop therapy with PULMICORT FLEXHALER without physician/provider guidance since symptoms may recur after discontinuation.

[see Warnings and Precautions (5.1) ] 17.3 Hypersensitivity including Anaphylaxis Hypersensitivity reactions including anaphylaxis, rash, contact dermatitis, urticaria, angioedema, and bronchospasm have been reported with use of PULMICORT FLEXHALER.

Discontinue PULMICORT FLEXHALER if such reactions occur [see Contraindications (4), Warnings and Precautions (5.3), and Adverse Reactions (6) ].

PULMICORT FLEXHALER contains small amounts of lactose, which contains trace levels of milk proteins.

It is possible that cough, wheezing, or bronchospasm may occur in patients who have a severe milk protein allergy [see Contraindications (4) ].

17.4 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 (5.4) ].

17.5 Hypercorticism and Adrenal Suppression Patients should be advised that PULMICORT FLEXHALER 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 PULMICORT FLEXHALER [see Warnings and Precautions (5.5, 5.6) ].

17.6 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 [see Warnings and Precautions (5.8) ].

17.7 Reduced Growth Velocity Patients should be informed that orally inhaled corticosteroids, including budesonide inhalation powder, may cause a reduction in growth velocity when administered to pediatric patients.

Physicians should closely follow the growth of children and adolescents taking corticosteroids by any route [see Warnings and Precautions (5.9) ].

17.8 Ocular Effects Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered [see Warnings and Precautions (5.10) ].

17.9 Use Daily Patients should be advised to use PULMICORT FLEXHALER at regular intervals, since its effectiveness depends on regular use.

Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment.

If symptoms do not improve in that time frame or if the condition worsens, patients should be instructed to contact their physician.

17.10 How to Use Pulmicort Flexhaler Patients should be carefully instructed on the use of this drug product to assure optimal dose delivery.

The patient may not sense the presence of any medication entering their lungs when inhaling from PULMICORT FLEXHALER.

This lack of sensation does not mean that they did not get the medication.

They should not repeat their inhalation even if they did not feel the medication when inhaling [see Patient Information ].

17.11 FDA–Approved Patient Labeling

DOSAGE AND ADMINISTRATION

2 PULMICORT FLEXHALER should be administered twice daily by the orally inhaled route only.

After inhalation, the patient should rinse the mouth with water without swallowing [see Patient Counseling Information (17.1) ].

Patients should be instructed to prime PULMICORT FLEXHALER prior to its initial use, and instructed to inhale deeply and forcefully each time the device is used.

The safety and efficacy of PULMICORT FLEXHALER when administered in excess of recommended doses have not been established.

After asthma stability has been achieved, it is desirable to titrate to the lowest effective dosage to reduce the possibility of side effects.

For patients who do not respond adequately to the starting dose after 1-2 weeks of therapy with PULMICORT FLEXHALER, increasing the dose may provide additional asthma control.

For oral inhalation only.

Patients 18 Years of Age and Older: For patients 18 years of age and older, the recommended starting dosage is 360 mcg twice daily.

In some adult patients, a starting dose of 180 mcg twice daily may be adequate.

The maximum dosage should not exceed 720 mcg twice daily.

(2.1) Patients 6 to 17 Years of Age: The recommended starting dosage is 180 mcg twice daily.

In some pediatric patients, a starting dose of 360 mcg twice daily may be appropriate.

The maximum dosage should not exceed 360 mcg twice daily.

(2.1) 2.1 Asthma If asthma symptoms arise in the period between doses, an inhaled, short-acting beta 2 -agonist should be taken for immediate relief.

Patients 18 Years of Age and Older: For patients 18 years of age and older, the recommended starting dosage is 360 mcg twice daily.

In some adult patients, a starting dose of 180 mcg twice daily may be adequate.

The maximum dosage should not exceed 720 mcg twice daily.

Patients 6 to 17 Years of Age: The recommended starting dosage is 180 mcg twice daily.

In some pediatric patients, a starting dose of 360 mcg twice daily may be appropriate.

The maximum dosage should not exceed 360 mcg twice daily.

For all patients, it is desirable to titrate to the lowest effective dose after adequate asthma stability is achieved.

Improvement in asthma control following inhaled administration of budesonide can occur within 24 hours of initiation of treatment, although maximum benefit may not be achieved for 1 to 2 weeks, or longer.

Individual patients will experience a variable onset and degree of symptom relief.

If a previously effective dosage regimen of PULMICORT FLEXHALER fails to provide adequate control of asthma, the therapeutic regimen should be re-evaluated and additional therapeutic options (e.g.

replacing the lower strength of PULMICORT FLEXHALER with the higher strength or initiating oral corticosteroids) should be considered.

ipratropium bromide 0.017 MG/ACTUAT Metered Dose Inhaler, 200 ACTUAT

Generic Name: IPRATROPIUM BROMIDE
Brand Name: Atrovent HFA
  • Substance Name(s):
  • IPRATROPIUM BROMIDE

DRUG INTERACTIONS

7 ATROVENT HFA has been used concomitantly with other drugs, including sympathomimetic bronchodilators, methylxanthines, oral and inhaled steroids commonly used in the treatment of COPD.

With the exception of albuterol, there are no formal studies fully evaluating the interaction effects of ATROVENT HFA and these drugs with respect to safety and effectiveness.

Anticholinergics: May interact additively with concomitantly used anticholinergic medications.

Avoid administration of ATROVENT HFA with other anticholinergic-containing drugs ( 7.1 ) 7.1 Anticholinergic Agents There is potential for an additive interaction with concomitantly used anticholinergic medications.

Therefore, avoid coadministration of ATROVENT HFA with other anticholinergic-containing drugs as this may lead to an increase in anticholinergic adverse effects [ see Warnings and Precautions (5.4 , 5.5) ].

OVERDOSAGE

10 Acute overdose by inhalation is unlikely since ipratropium bromide is not well absorbed systemically after inhalation or oral administration.

DESCRIPTION

11 The active ingredient in ATROVENT HFA is ipratropium bromide (as the monohydrate).

It is an anticholinergic bronchodilator chemically described as 8-azoniabicyclo[3.2.1]octane, 3-(3-hydroxy-1-oxo-2-phenylpropoxy)-8-methyl-8-(1-methylethyl)-,bromide monohydrate, (3-endo, 8-syn)-: a synthetic quaternary ammonium compound, chemically related to atropine.

The structural formula for ipratropium bromide is: C 20 H 30 BrNO 3 ∙H 2 O ipratropium bromide Mol.

Wt.

430.4 Ipratropium bromide is a white to off-white crystalline substance, freely soluble in water and methanol, sparingly soluble in ethanol, and insoluble in lipophilic solvents such as ether, chloroform, and fluorocarbons.

ATROVENT HFA is a pressurized metered-dose aerosol unit for oral inhalation that contains a solution of ipratropium bromide.

The 200 inhalation unit has a net weight of 12.9 grams.

After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide from the valve in 56 mg of solution and delivers 17 mcg of ipratropium bromide from the mouthpiece.

The actual amount of drug delivered to the lung may depend on patient factors, such as the coordination between the actuation of the device and inspiration through the delivery system.

The excipients are HFA-134a (1,1,1,2-tetrafluoroethane) as propellant, sterile water, dehydrated alcohol, and anhydrous citric acid.

This product does not contain chlorofluorocarbons (CFCs) as propellants.

ATROVENT HFA should be primed before using for the first time by releasing 2 test sprays into the air away from the face.

In cases where the inhaler has not been used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face.

Chemical Structure

CLINICAL STUDIES

14 Conclusions regarding the efficacy of ATROVENT HFA were derived from two randomized, double-blind, controlled clinical studies.

These studies enrolled males and females ages 40 years and older, with a history of COPD, a smoking history of >10 pack-years, an FEV 1 <65% and an FEV 1 /FVC <70%.

One of the studies was a 12-week randomized, double-blind active, and placebo-controlled study in which 505 of the 507 randomized COPD patients were evaluated for the safety and efficacy of 42 mcg (n=124) and 84 mcg (n=126) ATROVENT HFA in comparison to 42 mcg (n=127) ATROVENT CFC and their respective placebos (HFA n=62, CFC n=66).

Data for both placebo HFA and placebo CFC were combined in the evaluation.

Serial FEV 1 (shown in Figure 1, below, as means adjusted for center and baseline effects on test day 1 and test day 85 (primary endpoint)) demonstrated that 1 dose (2 inhalations/21 mcg each) of ATROVENT HFA produced significantly greater improvement in pulmonary function than placebo.

During the six hours immediately post-dose on day 1, the average hourly improvement in adjusted mean FEV 1 was 0.148 liters for ATROVENT HFA (42 mcg) and 0.013 liters for placebo.

The mean peak improvement in FEV 1 , relative to baseline, was 0.295 liters, compared to 0.138 liters for placebo.

During the six hours immediately post-dose on day 85, the average hourly improvement in adjusted mean FEV 1 was 0.141 liters for ATROVENT HFA (42 mcg) and 0.014 liters for placebo.

The mean peak improvement in FEV 1 , relative to baseline, was 0.295 liters, compared to 0.140 liters for placebo.

ATROVENT HFA (42 mcg) was shown to be clinically comparable to ATROVENT CFC (42 mcg).

Figure 1 Day 1 and Day 85 (Primary Endpoint) Results In this study, both ATROVENT HFA and ATROVENT CFC formulations were equally effective in patients over 65 years of age and under 65 years of age.

The median time to improvement in pulmonary function (FEV 1 increase of 15% or more) was within approximately 15 minutes, reached a peak in 1 to 2 hours, and persisted for 2 to 4 hours in the majority of the patients.

Improvements in Forced Vital Capacity (FVC) were also demonstrated.

The other study was a 12-week, randomized, double-blind, active-controlled clinical study in 174 adults with COPD, in which ATROVENT HFA 42 mcg (n=118) was compared to ATROVENT CFC 42 mcg (n=56).

Safety and efficacy of HFA and CFC formulations were shown to be comparable.

The bronchodilatory efficacy and comparability of ATROVENT HFA vs ATROVENT CFC were also studied in a one-year open-label safety and efficacy study in 456 COPD patients.

The safety and efficacy of HFA and CFC formulations were shown to be comparable.

Figure 1

HOW SUPPLIED

16 /STORAGE AND HANDLING ATROVENT HFA is supplied in a pressurized stainless steel canister as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and a green protective cap (NDC 0597-0087-17).

The mouthpiece has an actuation indicator visible through a small window.

The indicator typically moves during every 5 to 7 actuations.

It displays the approximate number of actuations remaining in increments of 20, starting at “200” and decreasing until it reaches “0”.

The ATROVENT HFA canister is to be used only with the accompanying ATROVENT HFA mouthpiece.

This mouthpiece should not be used with other aerosol medications.

Similarly, the canister should not be used with other mouthpieces.

After priming, each actuation of ATROVENT HFA delivers 21 mcg of ipratropium bromide from the valve and 17 mcg from the mouthpiece.

Each canister has a net weight of 12.9 grams and provides sufficient medication for 200 actuations.

The inhaler should be discarded after the labeled number of actuations has been used when the indicator displays “0”.

The amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty.

Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

For optimal results, the canister should be at room temperature before use.

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 the inhaler into a fire or incinerator.

Keep out of reach of children.

Avoid spraying in eyes .

GERIATRIC USE

8.5 Geriatric Use In the pivotal 12-week study, both ATROVENT HFA and ATROVENT CFC formulations were equally effective in patients over 65 years of age and under 65 years of age.

Of the total number of subjects in clinical studies of ATROVENT HFA, 57% were ≥65 years of age.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

DOSAGE FORMS AND STRENGTHS

3 ATROVENT HFA is an inhalation aerosol supplied in a pressurized stainless steel canister as a metered-dose inhaler with a white mouthpiece that has a clear, colorless sleeve and a green protective cap.

Each pressurized metered-dose aerosol unit for oral inhalation contains a 12.9 g solution of ipratropium bromide that provides sufficient medication for 200 actuations.

After priming, each actuation of the inhaler delivers 21 mcg of ipratropium bromide (as the monohydrate) from the valve and delivers 17 mcg of ipratropium bromide from the mouthpiece.

Inhalation Aerosol: Each actuation of ATROVENT HFA Inhalation Aerosol delivers 17 mcg of ipratropium bromide from mouthpiece ( 3 ) Supplied in a 12.9 g canister containing 200 actuations ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally-mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released at the neuromuscular junctions in the lung.

Anticholinergics prevent the increases in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptors on bronchial smooth muscle.

INDICATIONS AND USAGE

1 ATROVENT HFA Inhalation Aerosol is indicated as a bronchodilator for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

ATROVENT HFA is an anticholinergic indicated for the maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema ( 1 )

PEDIATRIC USE

8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established.

PREGNANCY

8.1 Pregnancy Risk Summary Ipratropium is negligibly absorbed systemically following oral inhalation; therefore, maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3) ] .

There is limited experience with ipratropium bromide use in pregnant women.

Published literature, including cohort studies, case control studies and case series, over several decades have not identified a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

Based on animal reproduction studies, no evidence of structural alterations was observed when ipratropium bromide was administered to pregnant mice, rats and rabbits during organogenesis at doses up to approximately 200, 40,000, and 10,000 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (see Data ) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

All pregnancies have a background risk of birth defect, loss or other adverse outcomes.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal Data In animal reproduction studies, oral and inhalation administration of ipratropium bromide to pregnant mice, rats and rabbits during the period of organogenesis did not show evidence of fetal structural alterations.

The ipratropium bromide dose in oral studies in mice, rats, and rabbits was up to approximately 200, 40,000, and 10,000 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 10, 1000, and 125 mg/kg/day, respectively).

The ipratropium bromide dose in inhalation studies in rats and rabbits was up to approximately 60 and 140 times, respectively, the MRHDID in adults (on a mg/m 2 basis at maternal doses of 1.5 and 1.8 mg/kg/day, respectively).

Embryotoxicity was observed as increased resorption in rats at oral doses approximately 3600 times the MRHDID in adults (on a mg/m 2 basis at maternal doses of 90 mg/kg/day and above).

This effect is not considered relevant to human use due to the large doses at which it was observed and the difference in route of administration.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response ( 5.1 ) Hypersensitivity reactions including anaphylaxis: Discontinue ATROVENT HFA at once and consider alternative treatments ( 5.2 ) Paradoxical bronchospasm: Discontinue ATROVENT HFA and consider other treatments if paradoxical bronchospasm occurs ( 5.3 ) Ocular effects: Use with caution in patients with narrow-angle glaucoma and instruct patients to consult a physician immediately if signs or symptoms of narrow-angle glaucoma develop ( 5.4 ) Urinary retention: Use with caution in patients with prostatic hyperplasia or bladder-neck obstruction and instruct patients to consult a physician immediately if signs or symptoms of urinary retention develop ( 5.5 ) 5.1 Use for Maintenance Treatment Only ATROVENT HFA is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.

5.2 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema may occur after the administration of ATROVENT HFA.

In clinical trials and postmarketing experience with ipratropium-containing products, hypersensitivity reactions such as skin rash, pruritus, angioedema of tongue, lips and face, urticaria (including giant urticaria), laryngospasm and anaphylactic reactions have been reported [ see Adverse Reactions (6.1 , 6.2) ].

If such a reaction occurs, therapy with ATROVENT HFA should be stopped at once and alternative treatment should be considered [ see Contraindications (4) ] .

5.3 Paradoxical Bronchospasm ATROVENT HFA can produce paradoxical bronchospasm that can be life threatening.

If this occurs, treatment with ATROVENT HFA should be stopped and other treatments considered.

5.4 Ocular Effects ATROVENT HFA is an anticholinergic and its use may increase intraocular pressure.

This may result in precipitation or worsening of narrow-angle glaucoma.

Therefore, ATROVENT HFA should be used with caution in patients with narrow-angle glaucoma [ see Drug Interactions (7.1) ].

Patients should avoid spraying ATROVENT HFA into their eyes.

If a patient sprays ATROVENT HFA into their eyes, they may cause eye pain or discomfort, temporary blurring of vision, mydriasis, visual halos or colored images in association with red eyes from conjunctival and corneal congestion.

Advise patients to consult their physician immediately if any of these symptoms develop while using ATROVENT HFA Inhalation Aerosol.

5.5 Urinary Retention ATROVENT HFA is an anticholinergic and may cause urinary retention.

Therefore, caution is advised when administering ATROVENT HFA Inhalation Aerosol to patients with prostatic hyperplasia, or bladder-neck obstruction [ see Drug Interactions (7.1) ].

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Appropriate and safe use of ATROVENT HFA includes providing the patient with the information listed below and an understanding of the way it should be administered.

Advise patients that ATROVENT HFA is a bronchodilator for the maintenance treatment of bronchospasm associated with COPD and is not indicated for the initial treatment of acute episodes of bronchospasm where rescue therapy is required for rapid response.

Hypersensitivity Reactions Inform patients that hypersensitivity reactions, including urticaria, angioedema, rash, bronchospasm, anaphylaxis, and oropharyngeal edema, may occur after the administration of ATROVENT HFA.

Advise patients to immediately discontinue ATROVENT HFA and consult a physician [ see Warnings and Precautions (5.2) ].

Paradoxical Bronchospasm Inform patients that ATROVENT HFA can produce paradoxical bronchospasm that can be life-threatening.

If paradoxical bronchospasm occurs, patients should discontinue using ATROVENT HFA.

Ocular Effects Caution patients to avoid spraying the aerosol into their eyes and be advised that this may result in precipitation or worsening of narrow-angle glaucoma, mydriasis, increased intraocular pressure, acute eye pain or discomfort, temporary blurring of vision, visual halos or colored images in association with red eyes from conjunctival and corneal congestion.

Patients should also be advised that should any combination of these symptoms develop, they should consult their physician immediately.

Since dizziness, accommodation disorder, mydriasis, and blurred vision may occur with use of ATROVENT HFA, patients should be cautioned about engaging in activities requiring balance and visual acuity such as driving a car or operating appliances or machinery.

Urinary Retention Inform patients that ATROVENT HFA may cause urinary retention and should be advised to consult their physicians if they experience difficulty with urination.

Frequency of Use The action of ATROVENT HFA should last 2 to 4 hours.

Advise patients not to increase the dose or frequency of ATROVENT HFA without patients consulting their physician.

Advise patients to seek immediate medical attention if treatment with ATROVENT HFA becomes less effective for symptomatic relief, their symptoms become worse, and/or patients need to use the product more frequently than usual.

Concomitant Drug Use Advise patients on the use of ATROVENT HFA in relation to other inhaled drugs [ see Drug Interactions (7.1) ].

Use Only as Prescribed Remind patients that ATROVENT HFA should be used consistently as prescribed throughout the course of therapy.

Preparation for Use and Priming Instruct patients that priming ATROVENT HFA is essential to ensure appropriate content of the medication in each actuation.

Patients do not have to shake the ATROVENT HFA canister before use .

DOSAGE AND ADMINISTRATION

2 The usual starting dose of ATROVENT HFA is two inhalations four times a day.

Patients may take additional inhalations as required; however, the total number of inhalations should not exceed 12 in 24 hours.

ATROVENT HFA is a solution aerosol that does not require shaking.

However, as with any other metered-dose inhaler, some coordination is required between actuating the canister and inhaling the medication.

Patients should “prime” or actuate ATROVENT HFA before using for the first time by releasing 2 test sprays into the air away from the face.

In cases where the inhaler has not been used for more than 3 days, prime the inhaler again by releasing 2 test sprays into the air away from the face.

Patients should avoid spraying ATROVENT HFA into their eyes.

Each inhaler provides sufficient medication for 200 actuations.

The inhaler should be discarded after the labeled number of actuations has been used.

The amount of medication in each actuation cannot be assured after this point, even though the canister is not completely empty.

Patients should be instructed on the proper use of their inhaler [ see Patient Counseling Information (17) ].

For oral inhalation only Two inhalations four times a day, not to exceed 12 inhalations in 24 hours ( 2 )

Doxazosin 1 MG Oral Tablet

DRUG INTERACTIONS

7 • Strong cytochrome P450 (CYP) 3A inhibitors may increase exposure to doxazosin and increased risk of hypotension ( 7.1 ) • Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.

( 7.2 ) 7.1 CYP3A Inhibitors In vitro studies suggest that doxazosin is a substrate of CYP3A4.

Strong CYP3A inhibitors may increase exposure to doxazosin.

Monitor blood pressure and for symptoms of hypotension when doxazosin tablets are used concomitantly with strong CYP3A inhibitors [see Clinical Pharmacology (12.3) ] .

7.2 Phosphodiesterase-5 (PDE-5) Inhibitors Concomitant administration of doxazosin tablets with a phosphodiesterase-5 (PDE-5) inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.

Monitor blood pressure and for symptoms of hypotension [see Warnings and Precautions (5.1) ] .

OVERDOSAGE

10 Experience with doxazosin tablets overdosage is limited.

Two adolescents, who each intentionally ingested 40 mg doxazosin tablets with diclofenac or acetaminophen, were treated with gastric lavage with activated charcoal and made full recoveries.

A two-year-old child who accidently ingested 4 mg doxazosin tablets was treated with gastric lavage and remained normotensive during the five-hour emergency room observation period.

A six-month-old child accidentally received a crushed 1 mg tablet of doxazosin tablets and was reported to have been drowsy.

A 32-year-old female with chronic renal failure, epilepsy, and depression intentionally ingested 60 mg doxazosin tablets (blood level = 0.9 mcg/mL; normal values in hypertensives = 0.02 mcg/mL); death was attributed to a grand mal seizure resulting from hypotension.

A 39-year-old female who ingested 70 mg doxazosin tablets, alcohol, and Dalmane ® (flurazepam) developed hypotension which responded to fluid therapy.

The oral LD 50 of doxazosin is greater than 1000 mg/kg in mice and rats.

The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of fluid.

As doxazosin is highly protein bound, dialysis would not be indicated.

DESCRIPTION

11 Doxazosin tablets, USP are a quinazoline compound that is a selective inhibitor of the alpha 1 subtype of alpha-adrenergic receptors.

The chemical name of doxazosin mesylate is 1-(4-Amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzodioxan-2-ylcarbonyl) piperazine monomethanesulfonate.

The molecular formula for doxazosin mesylate is C 23 H 25 N 5 O 5 • CH 4 O 3 S and the molecular weight is 547.6.

It has the following structure: Doxazosin mesylate, USP is freely soluble in dimethylsulfoxide, soluble in dimethylformamide, slightly soluble in methanol, ethanol, and water (0.8% at 25°C), and very slightly soluble in acetone and methylene chloride.

Doxazosin tablets are available as colored tablets for oral use and contain 1 mg (white to off-white), 2 mg (pink), 4 mg (blue) and 8 mg (purple) of doxazosin as the free base.

The inactive ingredients for all tablets are: anhydrous lactose, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate (potato).

The 2 mg tablets also contain D&C Red No.

30 Aluminum Lake, the 4 mg tablets also contain FD&C Blue No.

2 Aluminum Lake, and the 8 mg tablets also contain D&C Red No.

30 Aluminum Lake and FD&C Blue No.

2 Aluminum Lake.

Doxazosin Structural Formula

CLINICAL STUDIES

14 14.1 Benign Prostatic Hyperplasia (BPH) The efficacy of doxazosin tablets was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials.

Doxazosin tablets treatment was superior to placebo in improving patient symptoms and urinary flow rate.

Significant relief with doxazosin tablets was seen as early as one week into the treatment regimen, with doxazosin tablets-treated patients (N = 173) showing a significant (p < 0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N = 41).

In long-term studies, improvement was maintained for up to 2 years of treatment.

In 66% to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate.

In three placebo-controlled studies of 14 to 16 weeks’ duration, obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires.

The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire.

Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire.

Uroflowmetric evaluations were performed at times of peak (2 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin tablets.

The results from the three placebo-controlled studies (N = 609) showing significant efficacy with 4 mg and 8 mg doxazosin are summarized in Table 3.

In all three studies, doxazosin tablets resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo.

Statistically significant improvements of 2.3 mL/sec to 3.3 mL/sec in maximum flow rate were seen with doxazosin tablets in Studies 1 and 2, compared to 0.1 mL/sec to 0.7 mL/sec with placebo.

In one fixed-dose study (Study 2), doxazosin tablets therapy (4 mg to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3 mL/sec to 3.3 mL/sec (Table 3) compared to placebo (0.1 mL/sec).

In this study, the only study in which weekly evaluations were made, significant improvement with doxazosin tablets versus placebo was seen after one week.

The proportion of patients who responded with a maximum flow rate improvement of ≥ 3 mL/sec was significantly larger with doxazosin tablets (34% to 42%) than placebo (13% to 17%).

A significantly greater improvement was also seen in average flow rate with doxazosin tablets (1.6 mL/sec) than with placebo (0.2 mL/sec).

The onset and time course of symptom relief and increased urinary flow from Study 1 are illustrated in Figure 1.

Table 3.

Summary of Effectiveness Data in Placebo-Controlled Trials Figure 1 – Study 1 14.2 Hypertension In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1 mg to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position.

Peak blood pressure effects (1 to 6 hours) were larger by about 50% to 75% (i.e., trough values were about 55% to 70% of peak effect), with the larger peak-trough differences seen in systolic pressures.

There was no apparent difference in the blood pressure response of Caucasians and blacks or of patients above and below age 65.

In the same patient population, patients receiving doxazosin tablets gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.

Table 4.

Mean Changes in Blood Pressure from Baseline to the Mean of the Final Efficacy Phase in Normotensives (Diastolic BP < 90 mmHg) in Two Double-blind, Placebo-controlled U.S.

Studies with Doxazosin Tablets 1 mg to 8 mg once daily PLACEBO (N = 85) DOXAZOSIN TABLETS (N = 183) Sitting BP (mmHg) Baseline Change Baseline Change Systolic 128.4 –1.4 128.8 –4.9 p ≤ 0.05 compared to placebo Diastolic 79.2 –1.2 79.6 –2.4 Standing BP (mmHg) Baseline Change Baseline Change Systolic 128.5 –0.6 128.5 –5.3 Diastolic 80.5 –0.7 80.4 –2.6

HOW SUPPLIED

16 /STORAGE AND HANDLING Doxazosin Tablets, USP are available as tablets for oral administration.

Each tablet contains doxazosin mesylate, USP equivalent to 1 mg, 2 mg or 4 mg of doxazosin.

The 2 mg are available as pink round tablets debossed with M over D10 on one side of the tablet and scored on the other side.

They are available as follows: Overbagged with 10 tablets per bag, NDC 55154-5659-0 Recommended Storage: Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] PHARMACIST: Dispense a Patient Information Leaflet with each prescription.

GERIATRIC USE

8.5 Geriatric Use Benign Prostatic Hyperplasia (BPH) The safety and effectiveness profile of doxazosin tablets was similar in the elderly (age ≥ 65 years) and younger (age < 65 years) patients.

Hypertension Clinical studies of doxazosin tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

DOSAGE FORMS AND STRENGTHS

3 Doxazosin Tablets, USP are available containing doxazosin mesylate, USP equivalent to 1 mg, 2 mg, 4 mg or 8 mg of doxazosin.

• The 1 mg tablets are white to off-white, round tablets debossed with M over D9 on one side of the tablet and scored on the other side.

• The 2 mg tablets are pink, round tablets debossed with M over D10 on one side of the tablet and scored on the other side.

• The 4 mg tablets are blue, round tablets debossed with M over D11 on one side of the tablet and scored on the other side.

• The 8 mg tablets are purple, round tablets debossed with M over D12 on one side of the tablet and scored on the other side.

• Tablets: 1 mg, 2 mg, 4 mg, 8 mg.

MECHANISM OF ACTION

12.1 Mechanism of Action Benign Prostatic Hyperplasia (BPH) The symptoms associated with benign prostatic hyperplasia (BPH), such as urinary frequency, nocturia, weak stream, hesitancy, and incomplete emptying are related to two components, anatomical (static) and functional (dynamic).

The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma.

However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate.

The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck.

The degree of tone in this area is mediated by the alpha 1 adrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule and bladder neck.

Blockade of the alpha 1 receptor decreases urethral resistance and may relieve the obstruction and BPH symptoms and improve urine flow.

Hypertension The mechanism of action of doxazosin tablets is selective blockade of the alpha 1 (postjunctional) subtype of adrenergic receptors.

Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha 1 agonist) and the systolic pressor effect of norepinephrine.

Doxazosin and prazosin have similar abilities to antagonize phenylephrine.

The antihypertensive effect of doxazosin tablets results from a decrease in systemic vascular resistance.

The parent compound doxazosin is primarily responsible for the antihypertensive activity.

The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6′- and 7′-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6′-hydroxy) to the antihypertensive effect of doxazosin in man is probably small.

The 6′- and 7′-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 µM, in vitro .

INDICATIONS AND USAGE

1 Doxazosin tablets are an alpha 1 adrenergic antagonist indicated for : • Signs and symptoms of Benign Prostatic Hyperplasia (BPH) • Treatment of Hypertension 1.1 Benign Prostatic Hyperplasia (BPH) Doxazosin tablets are indicated for the treatment of the signs and symptoms of BPH.

1.2 Hypertension Doxazosin tablets are indicated for the treatment of hypertension, to lower blood pressure.

Lowering blood pressure reduces the risk of fatal and nonfatal 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 this drug.

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 one 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 Program’s Joint 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.

Doxazosin tablets may be used alone or in combination with other antihypertensives.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of doxazosin tablets have not been established in children.

PREGNANCY

8.1 Pregnancy Risk Summary The limited available data with doxazosin tablets in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage.

However, untreated hypertension during pregnancy can result in increased maternal risks [see Clinical Considerations ] .

In animal reproduction studies, no adverse developmental effects were observed when doxazosin was orally administered to pregnant rabbits and rats during the period of organogenesis at doses of up to 41 mg/kg and 20 mg/kg, respectively (exposures in rabbits and rats were 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose).

A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival [see Data ] .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background 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 Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage).

Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.

Data Animal Data Radioactivity was found to cross the placenta following oral administration of labelled doxazosin to pregnant rats.

Studies in pregnant rabbits and rats at daily oral doses of up to 41 mg/kg and 20 mg/kg, respectively (plasma drug concentrations of 10 and 4 times, respectively, the human AUC exposures with a 12 mg/day therapeutic dose), have revealed no evidence of adverse developmental effects.

A dosage regimen of 82 mg/kg/day in the rabbit was associated with reduced fetal survival.

In peri- and postnatal studies in rats, postnatal development at maternal doses of 40 mg/kg/day or 50 mg/kg/day of doxazosin (about 8 times human AUC exposure with a 12 mg/day therapeutic dose) was delayed, as evidenced by slower body weight gain and slightly later appearance of anatomical features and reflexes.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Postural hypotension with or without syncope may occur.

( 5.1 ) • Risk of Intraoperative Floppy Iris Syndrome during cataract surgery.

( 5.2 ) • Screen for the presence of prostate cancer prior to treatment for BPH and at regular intervals afterwards.

( 5.3 ) 5.1 Postural Hypotension Postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of doxazosin tablets.

However, infrequently, symptomatic postural hypotension has also been reported later than a few hours after dosing.

As with other alpha-blockers, there is a potential for syncope, especially after the initial dose or after an increase in dosage strength.

Advise patient how to avoid symptoms resulting from postural hypotension and what measures to take should they develop.

Concomitant administration of doxazosin tablets with a PDE-5 inhibitor can result in additive blood pressure lowering effects and symptomatic hypotension.

5.2 Cataract Surgery Intraoperative Floppy Iris Syndrome (IFIS) has been observed during cataract surgery in some patients on or previously treated with alpha 1 blockers.

This variant of small pupil syndrome is characterized by the combination of a flaccid iris that billows in response to intraoperative irrigation currents, progressive intraoperative miosis despite preoperative dilation with standard mydriatic drugs, and potential prolapse of the iris toward the phacoemulsification incisions.

The patient’s surgeon should be prepared for possible modifications to their surgical technique, such as the utilization of iris hooks, iris dilator rings, or viscoelastic substances.

There does not appear to be a benefit of stopping alpha 1 blocker therapy prior to cataract surgery.

5.3 Prostate Cancer Carcinoma of the prostate causes many of the symptoms associated with BPH and the two disorders frequently co-exist.

Carcinoma of the prostate should therefore be ruled out prior to commencing therapy with doxazosin tablets for the treatment of BPH.

5.4 Priapism Alpha 1 antagonists, including doxazosin, have been associated with priapism (painful penile erection, sustained for hours and unrelieved by sexual intercourse or masturbation).

This condition can lead to permanent impotence if not promptly treated.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ).

Postural Hypotension: Advise patients of the possibility of syncopal and orthostatic symptoms, especially at the initiation of therapy, and urged to avoid driving or hazardous tasks for 24 hours after the first dose, after a dosage increase, and after interruption of therapy when treatment is resumed.

Advise patients to report symptoms to their healthcare provider.

Priapism: Advise patients of the possibility of priapism and to seek immediate medical attention if symptoms occur.

DOSAGE AND ADMINISTRATION

2 • For the treatment of BPH: Initiate therapy at 1 mg once daily.

Dose maybe titrated at 1 to 2 week intervals, up to 8 mg once daily.

( 2.2 ) • For the treatment of hypertension: Initiate therapy at 1 mg once daily.

Dose may be titrated as needed, up to 16 mg once daily.

( 2.3 ) 2.1 Dosing Information Following the initial dose and with each dose increase of doxazosin tablets, monitor blood pressure for at least 6 hours following administration.

If doxazosin tablets administration is discontinued for several days, therapy should be restarted using the initial dosing regimen.

2.2 Benign Prostatic Hyperplasia The recommended initial dosage of doxazosin tablets is 1 mg given once daily either in the morning or evening.

Depending on the individual patient’s urodynamics and BPH symptomatology, the dose may be titrated at 1 to 2 week intervals to 2 mg, and thereafter to 4 mg and 8 mg once daily.

The maximum recommended dose for BPH is 8 mg once daily.

Routinely monitor blood pressure in these patients.

2.3 Hypertension The initial dosage of doxazosin tablets is 1 mg given once daily.

Daily dosage may be doubled up 16 mg once daily, as needed, to achieve the desired reduction in blood pressure.

promethazine HCl 50 MG per 1 ML Injection

WARNINGS

Respiratory Depression Pediatrics Promethazine hydrochloride injection should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression.

Post-marketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients less than 2 years of age.

A wide range of weight-based doses of promethazine hydrochloride injection have resulted in respiratory depression in these patients.

Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age and older.

It is recommended that the lowest effective dose of promethazine hydrochloride injection be used in pediatric patients 2 years of age and older.

Avoid concomitant administration of other drugs with respiratory depressant effects because of an association with respiratory depression, and sometimes death, in pediatric patients.

Other Because of the risk of potentially fatal respiratory depression, use of promethazine hydrochloride injection in patients with compromised respiratory function or patients at risk for respiratory failure (e.g.

COPD, sleep apnea) should be avoided.

Severe Tissue Injury, Including Gangrene Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues, regardless of the route of administration.

Irritation and damage can also result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration.

Adverse event reports include burning, pain, erythema, swelling, sensory loss, palsies, paralysis, severe spasms of distal vessels, thrombophlebitis, venous thrombosis, phlebitis, abscesses, tissue necrosis, and gangrene.

In some cases surgical intervention, including fasciotomy, skin graft, and/or amputation have been required.

Because of the risks of intravenous injection, the preferred route of administration of promethazine hydrochloride injection is deep intramuscular injection (see DOSAGE AND ADMINISTATION ).

Subcutaneous injection is contraindicated.

Due to close proximity of arteries and veins in the areas most commonly used for intravenous injection, extreme care should be exercised to avoid perivascular extravasation or unintentional intra-arterial injection as pain, severe chemical irritation, severe spasm of distal vessels, and resultant gangrene requiring amputation are likely under such circumstances.

Aspiration of dark blood does not preclude intra-arterial needle placement because blood is discolored upon contact with promethazine hydrochloride injection.

Use of syringes with rigid plungers or small-bore needles might obscure typical arterial backflow if this is relied upon.

In the event that a patient complains of pain during intravenous injection of promethazine hydrochloride injection, the injection should be stopped immediately to evaluate for possible arterial injection or perivascular extravasation.

There is no proven successful management of unintentional intra-arterial injection or perivascular extravasation after it occurs.

Sympathetic block and hepar inization have been employed dur ing the acute management of unintentional intra-arterial injection, because of the results of animal experiments with other known arteriolar irritants.

CNS Depression Promethazine hydrochloride injection may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machinery.

The impairment may be amplified by concomitant use of other central-nervous-system depressants such as alcohol, sedative-hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore such agents should either be eliminated or given in reduced dosage in the presence of promethazine hydrochloride (see PRECAUTIONS – Information for Patients and Drug Interactions ).

Lower Seizure Threshold Promethazine hydrochloride injection may lower seizure threshold and should be used with caution in persons with seizure disorders or in persons who are using concomitant medications, such as narcotics or local anesthetics, which may also affect seizure threshold.

Bone-Marrow Depression Promethazine hydrochloride injection should be used with caution in patients with bone-marrow depression.

Leukopenia and agranulocytosis have been reported, usually when promethazine hydrochloride has been used in association with other known marrow-toxic agents.

Neuroleptic Malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with promethazine hydrochloride alone or in combination with antipsychotic drugs.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmias).

The diagnostic evaluation of patients with this syndrome is complicated.

In arriving at a diagnosis, it is important to identify cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).

Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever and primary central nervous system (CNS) pathology.

The management of NMS should include 1) immediate discontinuation of promethazine hydrochloride, antipsychotic drugs, if any, and other drugs not essential to concurrent therapy, 2) intensive symptomatic treatment and medical monitoring, and 3) treatment of any concomitant serious medical problems for which specific treatments are available.

There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.

Since recurrences of NMS have been reported with phenothiazines, the reintroduction of promethazine hydrochloride should be carefully considered.

Sulfite Sensitivity Promethazine hydrochloride injection contains sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthma episodes, in certain susceptible people.

The overall prevalence of sulfite sensitivity in the general population is unknown and probably low.

Sulfite sensitivity is seen more frequently in asthmatic that in nonasthmatic people.

Visual Inspection This product is light sensitive and should be inspected before use and discarded if either color or particulate is observed.

Cholestatic Jaundice Administration of promethazine has been associated with reported cholestatic jaundice.

DRUG INTERACTIONS

Drug Interactions CNS Depressants Promethazine hydrochloride injection may increase, prolong, or intensify the sedative action of central-nervous-system depressants, such as alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers; therefore, such agents should be avoided or administered in reduced dosage to patients receiving promethazine hydrochloride.

When given concomitantly with promethazine hydrochloride injection, the dose of barbiturates should be reduced by at least one-half, and the dose of narcotics should be reduced by one-quarter to one-half.

Dosage must be individualized.

Excessive amounts of promethazine hydrochloride injection relative to a narcotic may lead to restlessness and motor hyperactivity in the patient with pain; these symptoms usually disappear with adequate control of the pain.

Epinephrine Because of the potential for promethazine hydrochloride to reverse epinephrine’s vasopressor effect, epinephrine should NOT be used to treat hypotension associated with promethazine hydrochloride injection overdose.

Anticholinergics Concomitant use of other agents with anticholinergic properties should be undertaken with caution.

Monoamine Oxidase Inhibitors (MAO) Inhibitors Drug interactions, including an increased incidence of extrapyramidal effects, have been reported when some MAO Inhibitors and phenothiazines are used concomitantly.

This possibility should be considered with promethazine hydrochloride injection.

OVERDOSAGE

Signs and symptoms of overdosage range from mild depression of the central nervous system and cardiovascular system to profound hypotension, respiratory depression, unconsciousness and sudden death.

Other reported reactions include hyperreflexia, hypertonia, ataxia, athetosis, and extensor-plantar reflexes (Babinski reflex).

Stimulation may be evident, especially in pediatric patients and geriatric patients.

Convulsions may rarely occur.

A paradoxical-type reaction has been reported in pediatric patients receiving single doses of 75 mg to 125 mg orally, characterized by hyperexcitability and nightmares.

Atropine-like signs and symptoms–dry mouth; fixed, dilated pupils; flushing; etc., as well as gastrointestinal symptoms, may occur.

Treatment Treatment of overdosage is essentially symptomatic and supportive.

Only in cases of extreme overdosage or individual sensitivity do vital signs, including respiration, pulse, blood pressure, temperature, and EKG, need to be monitored.

Attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation.

Diazepam may be used to control convulsions.

Acidosis and electrolyte losses should be corrected.

Note that any depressant effects of promethazine hydrochloride injection are not reversed by naloxone.

Avoid analeptics, which may cause convulsions.

The treatment of choice for resulting hypotension is administration of intravenous fluids, accompanied by repositioning if indicated.

In the event that vasopressors are considered for the management of severe hypotension which does not respond to intravenous fluids and repositioning, the administration of norepinephrine or phenylephrine should be considered.

EPINEPHRINE SHOULD NOT BE USED, since its use in a patient with partial adrenergic blockade may further lower the blood pressure.

Extrapyramidal reactions may be treated with anticholinergic antiparkinson agents, diphenhydramine, or barbiturates.

Oxygen may also be administered.

Limited experience with dialysis indicates that it is not helpful.

DESCRIPTION

Promethazine hydrochloride injection, USP is a sterile, pyrogen-free solution for deep intramuscular or intravenous administration.

Promethazine hydrochloride (10 H -phenothiazine-10-ethanamine, N , N , α-trimethyl-, monohydrochloride, (±)-) is a racemic compound and has the following structural formula: Each mL contains promethazine hydrochloride, either 25 mg or 50 mg, edetate disodium 0.1 mg, calcium chloride 0.04 mg, sodium metabisulfite 0.25 mg and phenol 5 mg in Water for Injection.

pH 4.0 to 5.5; buffered with acetic acid-sodium acetate.

Promethazine hydrochloride injection is a clear, colorless solution.

The product is light sensitive.

It should be inspected before use and discarded if either color or particulate is observed.

Promethazine hydrochloride structural formula

HOW SUPPLIED

Promethazine Hydrochloride Injection, USP is available as follows: NDC Number Strength Package 54868-4021-0 25 mg/mL 1 mL fill in a 1 mL ampule 25 ampules per carton 54868-2088-0 50 mg/mL 1 mL fill in a 1 mL ampule 25 ampules per carton Store at 20 º – 25 ºC (68º – 77ºF).

[See USP Controlled Room Temperature ] .

Protect from light.

Keep covered in carton until time of use.

Do not use if solution has developed color or contains a precipitate.

Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A.

Estrada do Rio da Mó, nº 8, 8A e 8B – Fervença, 2705 – 906 Terrugem SNT PORTUGAL Distributed by: WEST-WARD PHARMACEUTICAL CORP.

465 Industrial Way West Eatontown, NJ 07724 USA Iss.: Oct 2009 Relabeling of “Additional Barcode Label” by: Physicians Total Care, Inc.

Tulsa, OK 74146

GERIATRIC USE

Geriatric Use ( patients approximately 60 years or older) Since therapeutic requirements for sedative drugs tend to be less in geriatric patients, the dosage should be reduced for these patients.

INDICATIONS AND USAGE

Promethazine hydrochloride injection is indicated for the following conditions: Amelioration of allergic reactions to blood or plasma.

In anaphylaxis as an adjunct to epinephrine and other standard measures after the acute symptoms have been controlled.

For other uncomplicated allergic conditions of the immediate type when oral therapy is impossible or contraindicated.

For sedation and relief of apprehension and to produce light sleep from which the patient can be easily aroused.

Active treatment of motion sickness.

Prevention and control of nausea and vomiting associated with certain types of anesthesia and surgery.

As an adjunct to analgesics for the control of postoperative pain.

Preoperative, postoperative, and obstetric (during labor) sedation.

Intravenously in special surgical situations, such as repeated bronchoscopy, ophthalmic surgery, and poor-risk patients, with reduced amounts of meperidine or other narcotic analgesic as an adjunct to anesthesia and analgesia.

PEDIATRIC USE

Pediatric Use Promethazine hydrochloride injection is contraindicated for use in pediatric patients less than 2 years of age, because of the potential for fatal respiratory depression.

Promethazine hydrochloride injection should be used with caution in pediatric patients 2 years of age and older (see WARNINGS – Respiratory Depression ).

Antiemetics are not recommended for treatment of uncomplicated vomiting in pediatric patients, and their use should be limited to prolonged vomiting of known etiology.

The extrapyramidal symptoms which can occur secondary to promethazine hydrochloride injection administration may be confused with the CNS signs of undiagnosed primary disease, e.g., encephalopathy or Reye´s syndrome or other hepatic diseases.

Excessively large dosages of antihistamines, including promethazine hydrochloride injection, in pediatric patients may cause sudden death (see OVERDOSAGE ).

Hallucinations and convulsions have occurred with therapeutic doses and overdoses of promethazine hydrochloride injection in pediatric patients.

In pediatric patients who are acutely ill associated with dehydration, there is an increased susceptibility to dystonias with the use of promethazine hydrochloride injection.

PREGNANCY

Pregnancy Teratogenic Effects –Pregnancy Category C Teratogenic effects have not been demonstrated in rat-feeding studies at doses of 6.25 and 12.5 mg/kg (approximately 2.1 and 4.2 times the maximum recommended human daily dose) of promethazine hydrochloride injection.

Daily doses of 25 mg/kg intraperitoneally have been found to produce fetal mortality in rats.

There are no adequate and well-controlled studies of promethazine hydrochloride injection in pregnant women.

Because animal reproduction studies are not always predictive of human response, promethazine hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Adequate studies to determine the action of the drug on parturition, lactation and development of the animal neonate have not been conducted.

Nonteratogenic Effects Promethazine hydrochloride injection administered to a pregnant woman within two weeks of delivery may inhibit platelet aggregation in the newborn.

NUSRING MOTHERS

Nursing Mothers It is not known whether promethazine hydrochloride injection 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 promethazine hydrochloride injection, 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.

BOXED WARNING

WARNINGS RESPIRATORY DEPRESSION – Pediatrics Promethazine hydrochloride injection should not be used in pediatric patients less than 2 years of age because of the potential for fatal respiratory depression.

Post-marketing cases of respiratory depression, including fatalities, have been reported with use of promethazine in pediatric patients less than 2 years of age.

Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age and older (see WARNINGS – Respiratory Depression ).

SEVERE TISSUE INJURY, INCLUDING GANGRENE Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues regardless of the route of administration.

Irritation and damage can result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration.

Adverse reactions include burning, pain, thrombophlebitis, tissue necrosis, and gan grene.

In some cases, surgical intervention, including fasciotomy, skin graft, and/or amputation have been required (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

Due to risks of intravenous injection, the preferred route of administration of promethazine hydrochloride injection is deep intramuscular injection.

Subcutaneous injection is contraindicated.

See DOSAGE AND ADMINISTRATION for important notes on administration.

INFORMATION FOR PATIENTS

Information for Patients Patients should be advised of the risk of respiratory depression, including potentially fatal respiratory depression in children less than 2 years of age (see WARNINGS – Respiratory Depression ).

Patients should be advised of the risk of severe tissue injury, including gangrene (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

Patients should be advised to immediately report persistent or worsening pain or burning at the injection site.

Promethazine hydrochloride injection may cause marked drowsiness or impair the mental or physical abilities required for the performance of potentially hazardous tasks, such as driving a vehicle or operating machiner y.

Pediatric patients should be supervised to avoid potential harm in bike riding or in other hazardous activities.

The concomitant use of alcohol, sedative/hypnotics (including barbiturates), general anesthetics, narcotics, narcotic analgesics, tricyclic antidepressants, and tranquilizers may enhance impairment (see WARNINGS – CNS Depression and PRECAUTIONS – Drug Interactions ).

Patients should be advised to report any involuntary muscle movements (see ADVERSE REACTIONS – Paradoxical Reactions ).

Patients should be advised to avoid prolonged exposure to the sun (see ADVERSE REACTIONS – Dermatologic ).

DOSAGE AND ADMINISTRATION

Important Notes on Administration Promethazine hydrochloride injection can cause severe chemical irritation and damage to tissues regardless of the route of administration.

Irritation and damage can result from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

The preferred parenteral route of administration for promethazine hydrochloride injection is by deep intramuscular injection.

Under no circumstances should promethazine hydrochloride injection be given by intra-arterial injection due to the likelihood of severe anteriospasm and the possibility of resultant gangrene (see WARNINGS – Severe Tissue Injury, Including Gangrene ).

Subcutaneous injection is contraindicated as it may result in tissue necrosis When administered intravenously, promethazine hydrochloride injection should be given in a concentration no greater than 25 mg per mL and at a rate not to exceed 25 mg per minute.

It is preferable to inject through the tubing of an intravenous infusion set that is known to be functioning satisfactorily.

In the event that a patient complains of pain during the intravenous injection fo promethazine hydrochloride injection, the injection should be stopped immediately to evaluate for a possible aterial injection or perivascular extravasation.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use promethazine hydrochloride injection if solution has developed color or contains precipitate.

To avoid the possibility of physical and/or chemical incompatibility, consult specialized literature before diluting with any injectable solution or combining with any other medication.

Do not use if there is a precipitate or any sign of incompatibility.

Allergic Conditions The average adult dose is 25 mg.

This dose may be repeated within two hours if necessary, but continued therapy, if indicated, should be via the oral route as soon as existing circumstances permit.

After initiation of treatment, dosage should be adjusted to the smallest amount adequate to relieve symptoms.

The average adult dose for amelioration of allergic reactions to blood or plasma is 25 mg.

Sedation In hospitalized adult patients, nighttime sedation may be achieved by a dose of 25 to 50 mg of promethazine hydrochloride injection.

Nausea and Vomiting For control of nausea and vomiting, the usual adult dose is 12.5 to 25 mg, not to be repeated more frequently than every four hours.

When used for control of postoperative nausea and vomiting, the dosage of analgesics and barbiturates should be reduced accordingly (see PRECAUTIONS – Drug Interactions ).

Antiemetics should not be used in vomiting of unknown etiology in children and adolescents (see PRECAUTIONS – Pediatric Use ).

Preoperative and Postoperative Use As an adjunct to preoperative or postoperative medication, 25 to 50 mg of promethazine hydrochloride injection in adults may be combined with appropriately reduced doses of analgesics and atropine-like drugs as desired.

Dosage of concomitant analgesic or hypnotic medication should be reduced accordingly (see PRECAUTIONS – Drug Interactions ).

Promethazine hydrochloride is contraindicated for use in pediatric patients less than two years of age.

Obstetrics Promethazine hydrochloride injection in doses of 50 mg will provide sedation and relieve apprehension in the early stages of labor.

When labor is definitely established, 25 to 75 mg (average dose, 50 mg) promethazine hydrochloride injection may be given with an appropriately reduced dose of any desired narcotic (see PRECAUTIONS – Drug Interactions ).

If necessary, promethazine hydrochloride injection with a reduced dose of analgesic may be repeated once or twice at four-hour intervals in the course of a normal labor.

A maximum total dose of 100 mg of promethazine hydrochloride injection may be administered during a 24-hour period to patients in labor.

Pediatric Patients Promethazine hydrochloride injection is c ontraindicated for use in pediatric patients less than 2 years of age (s ee WARNINGS – Respiratory Depression ).

Caution should be exercised when administering promethazine hydrochloride injection to pediatric patients 2 years of age or older.

It is recommended that the lowest effective dose of promethazine hydrochloride be used in pediatric patients 2 years of age and older and concomitant administration of other drugs with respiratory depressant effects be avoided (see WARNINGS – Respiratory Depression ).

In pediatric patients 2 years of age and older, the dosage should not exceed half that of the suggested adult dose.

As an adjunct to premedication, the suggested dose is 1.1 mg per kg of body weight in combination with an appropriately reduced dose of narcotic or barbiturate and the appropriate dose of an atropine-like drug (see PRECAUTIONS – Drug Interactions ).

Antiemetics should not be used in vomiting of unknown etiology in pediatric patients.

DRUG INTERACTIONS

7 Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4.

( 7 ) Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding.

( 7 ) 7.1 General Information 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.

7.2 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 medications.

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 7.3 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 7.4 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.

7.5 Botanical (Herbal) Products and Foods More frequent INR monitoring should be performed when starting or stopping botanicals.

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 Q 10 , 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).

The amount of vitamin K in food may affect therapy with warfarin sodium.

Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K.

Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

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 K 1 .

The use of vitamin K 1 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 tablets contain warfarin sodium, an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors.

The chemical name of warfarin sodium is 3-(α-acetonylbenzyl)-4-hydroxycoumarin sodium salt, which is a racemic mixture of the R – and S -enantiomers.

Crystalline warfarin sodium is an isopropanol clathrate.

Its empirical formula is C 19 H 15 NaO 4 , 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 non-rheumatic 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 Patients All 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) versus 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 to 2.25 vs.

INR 2.5 to 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 Vascular Death 94 (4.7/100 py) 82 (4.1/100 py) 123 (6.3/100 py) 105 (5.4/100 py) 0.76 (0.60, 0.97) 0.78 (0.60, 1.02) 24 (p=0.030) 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 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 No.

of Events CI=confidence interval ND=not determined Major Bleeding Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.

8 33 28 3.35 The rate ratio is for aspirin plus warfarin as compared with aspirin.

(ND) 4.00 The rate ratio is for warfarin as compared with aspirin.

(ND) ND ND Minor Bleeding Minor 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 Endpoints Includes 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 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° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

Store the hospital unit-dose blister packages in the carton until contents have been used.

Special Handling Procedures for proper handling and disposal of potentially hazardous drugs should be considered.

Guidelines on this subject have been published [see References (15) ].

Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Specific Populations (8.1) ].

RECENT MAJOR CHANGES

Dosage and Administration, Renal Impairment ( 2.5 ) 5/2017 Warnings and Precautions, Calciphylaxis ( 5.3 ) 9/2016 Warnings and Precautions, Acute kidney injury ( 5.4 ) 5/2017

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.

Conduct more frequent monitoring for bleeding 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 Single-Scored Tablets, USP Strength Color Engraved 1 mg pink 1 2 mg lavender 2 2.5 mg green 2½ 3 mg tan 3 4 mg blue 4 5 mg peach 5 6 mg teal 6 7.5 mg yellow 7½ 10 mg white (dye-free) 10 Scored tablets: 1, 2, 2½, 3, 4, 5, 6, 7½, 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 K 1 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 ) Limitations 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 Risk Summary 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 [see Warnings and Precautions (5.7) ].

Warfarin sodium can cause fetal harm.

Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring.

Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S.

general population and may not reflect the incidences observed in practice.

Consider the benefits and risks of warfarin sodium and possible risks to the fetus when prescribing warfarin sodium to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions 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) ].

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 ) Calciphylaxis: Fatal and serious cases have occurred.

Discontinue warfarin sodium and consider alternative anticoagulation therapy.

( 5.3 ) Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria.

( 5.4 ) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death.

Discontinue warfarin sodium if such emboli occur.

( 5.5 ) 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.

( 5.6 ) Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks.

( 5.7 ) 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 Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which 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 Calciphylaxis Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease.

When calciphylaxis is diagnosed in these patients, discontinue warfarin sodium and treat calciphylaxis as appropriate.

Consider alternative anticoagulation therapy.

5.4 Acute Kidney Injury In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with warfarin sodium, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations (8.6) ].

More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

5.5 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.

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS 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.

5.7 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) ].

5.8 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 5.9 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 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Instructions for Patients Advise patients to: Strictly adhere to the prescribed dosage schedule [see Dosage and Administration (2.1) ].

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 [see Dosage and Administration (2.6) ].

Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy [see Dosage and Administration (2.1) ].

Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days [see Clinical Pharmacology (12.2) ].

Avoid any activity or sport that may result in traumatic injury [see Use in Specific Populations (8.4) ].

And to tell their physician if they fall often as this may increase their risk for complications.

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 [see Drug Interactions (7.5) ].

Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see Warnings and Precautions (5) and Adverse Reactions (6) ].

Immediately contact their physician when experiencing pain and discoloration of the skin (a purple bruise like rash) mostly on areas of the body with a high fat content, such as breasts, thighs, buttocks, hips and abdomen [see Warnings and Precautions (5.2) ].

Immediately contact their physician when experiencing any unusual symptom or pain since warfarin sodium may cause small cholesterol or athero emboli.

On feet it may appear as a sudden cool, painful, purple discoloration of toe(s) or forefoot [see Warnings and Precautions (5.5) ].

Immediately contact their physician when taking warfarin sodium after any heparin formulation therapy and experiencing bloody or black stools or appearence of bruises, or bleeding [see Warnings and Precautions (5.6) ].

To tell all of their healthcare professionals and dentists that they are taking warfarin sodium.

This should be done before they have any surgery or dental procedure [see Dosage and Administration (2.7) ].

Carry identification stating that they are taking warfarin sodium.

Bleeding Risks Advise patients to: 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 [see Box Warning and Warnings and Precautions (5.1) ].

Concomitant Medications and Botanicals (Herbals) Advise patients to: 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 [see Drug Interactions (7) ].

Pregnancy and Nursing Advise patients to: Notify their physician if they are pregnant or planning to become pregnant or considering breast feeding [see Use in Specific Populations (8.1 , 8.2 , 8.3) ].

Avoid warfarin sodium during pregnancy except in pregnant women with mechanical heart valves, who are at risk of thromboembolism [see Contraindications (4) ].

Use effective measures to avoid pregnancy while taking warfarin sodium.

This is very important because their unborn baby could be seriously harmed if they take warfarin sodium while they are pregnant [see Use in Specific Populations (8.1 , 8.3) ].

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 International Normalized Ratio (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 regarding the duration and intensity of anticoagulation for the indicated conditions.

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 to 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 to 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 to 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 to 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 to 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 to 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 to 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 to 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 to 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 Genotypes Ranges are derived from multiple published clinical studies.

VKORC1 −1639G>A (rs9923231) variant is used in this table.

Other coinherited 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 has a narrow therapeutic range (index), 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 Renal Impairment No dosage adjustment is necessary for patients with renal failure.

Monitor INR more frequently in patients with compromised renal function to maintain INR within the therapeutic range [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6) ].

2.6 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.

DRUG INTERACTIONS

7 Concomitant use of drugs that increase bleeding risk, antibiotics, antifungals, botanical (herbal) products, and inhibitors and inducers of CYP2C9, 1A2, or 3A4.

( 7 ) Consult labeling of all concurrently used drugs for complete information about interactions with warfarin sodium or increased risks for bleeding.

( 7 ) 7.1 General Information 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.

7.2 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 medications.

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 7.3 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 7.4 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.

7.5 Botanical (Herbal) Products and Foods More frequent INR monitoring should be performed when starting or stopping botanicals.

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 Q 10 , 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).

The amount of vitamin K in food may affect therapy with warfarin sodium.

Advise patients taking warfarin sodium to eat a normal, balanced diet maintaining a consistent amount of vitamin K.

Patients taking warfarin sodium should avoid drastic changes in dietary habits, such as eating large amounts of green leafy vegetables.

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 K 1 .

The use of vitamin K 1 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 tablets contain warfarin sodium, an anticoagulant that acts by inhibiting vitamin K-dependent coagulation factors.

The chemical name of warfarin sodium is 3-(α-acetonylbenzyl)-4-hydroxycoumarin sodium salt, which is a racemic mixture of the R – and S -enantiomers.

Crystalline warfarin sodium is an isopropanol clathrate.

Its empirical formula is C 19 H 15 NaO 4 , 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 non-rheumatic 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 Patients All 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) versus 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 to 2.25 vs.

INR 2.5 to 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 Vascular Death 94 (4.7/100 py) 82 (4.1/100 py) 123 (6.3/100 py) 105 (5.4/100 py) 0.76 (0.60, 0.97) 0.78 (0.60, 1.02) 24 (p=0.030) 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 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 No.

of Events CI=confidence interval ND=not determined Major Bleeding Major bleeding episodes were defined as nonfatal cerebral hemorrhage or bleeding necessitating surgical intervention or blood transfusion.

8 33 28 3.35 The rate ratio is for aspirin plus warfarin as compared with aspirin.

(ND) 4.00 The rate ratio is for warfarin as compared with aspirin.

(ND) ND ND Minor Bleeding Minor 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 Endpoints Includes 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 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° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in a tight, light-resistant container as defined in the USP.

Store the hospital unit-dose blister packages in the carton until contents have been used.

Special Handling Procedures for proper handling and disposal of potentially hazardous drugs should be considered.

Guidelines on this subject have been published [see References (15) ].

Pharmacy and clinical personnel who are pregnant should avoid exposure to crushed or broken tablets [see Use in Specific Populations (8.1) ].

RECENT MAJOR CHANGES

Dosage and Administration, Renal Impairment ( 2.5 ) 5/2017 Warnings and Precautions, Calciphylaxis ( 5.3 ) 9/2016 Warnings and Precautions, Acute kidney injury ( 5.4 ) 5/2017

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.

Conduct more frequent monitoring for bleeding 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 Single-Scored Tablets, USP Strength Color Engraved 1 mg pink 1 2 mg lavender 2 2.5 mg green 2½ 3 mg tan 3 4 mg blue 4 5 mg peach 5 6 mg teal 6 7.5 mg yellow 7½ 10 mg white (dye-free) 10 Scored tablets: 1, 2, 2½, 3, 4, 5, 6, 7½, 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 K 1 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 ) Limitations 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 Risk Summary 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 [see Warnings and Precautions (5.7) ].

Warfarin sodium can cause fetal harm.

Exposure to warfarin during the first trimester of pregnancy caused a pattern of congenital malformations in about 5% of exposed offspring.

Because these data were not collected in adequate and well-controlled studies, this incidence of major birth defects is not an adequate basis for comparison to the estimated incidences in the control group or the U.S.

general population and may not reflect the incidences observed in practice.

Consider the benefits and risks of warfarin sodium and possible risks to the fetus when prescribing warfarin sodium to a pregnant woman.

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions 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) ].

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 ) Calciphylaxis: Fatal and serious cases have occurred.

Discontinue warfarin sodium and consider alternative anticoagulation therapy.

( 5.3 ) Acute kidney injury may occur during episodes of excessive anticoagulation and hematuria.

( 5.4 ) Systemic atheroemboli and cholesterol microemboli: Some cases have progressed to necrosis or death.

Discontinue warfarin sodium if such emboli occur.

( 5.5 ) 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.

( 5.6 ) Pregnant women with mechanical heart valves: Warfarin sodium may cause fetal harm; however, the benefits may outweigh the risks.

( 5.7 ) 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 Warfarin sodium can cause necrosis and/or gangrene of skin and other tissues, which 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 Calciphylaxis Warfarin sodium can cause fatal and serious calciphylaxis or calcium uremic arteriolopathy, which has been reported in patients with and without end-stage renal disease.

When calciphylaxis is diagnosed in these patients, discontinue warfarin sodium and treat calciphylaxis as appropriate.

Consider alternative anticoagulation therapy.

5.4 Acute Kidney Injury In patients with altered glomerular integrity or with a history of kidney disease, acute kidney injury may occur with warfarin sodium, possibly in relation to episodes of excessive anticoagulation and hematuria [see Use in Specific Populations (8.6) ].

More frequent monitoring of anticoagulation is advised in patients with compromised renal function.

5.5 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.

5.6 Limb Ischemia, Necrosis, and Gangrene in Patients with HIT and HITTS 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.

5.7 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) ].

5.8 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 5.9 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 Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Instructions for Patients Advise patients to: Strictly adhere to the prescribed dosage schedule [see Dosage and Administration (2.1) ].

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 [see Dosage and Administration (2.6) ].

Obtain prothrombin time tests and make regular visits to their physician or clinic to monitor therapy [see Dosage and Administration (2.1) ].

Be aware that if therapy with warfarin sodium is discontinued, the anticoagulant effects of warfarin sodium may persist for about 2 to 5 days [see Clinical Pharmacology (12.2) ].

Avoid any activity or sport that may result in traumatic injury [see Use in Specific Populations (8.4) ].

And to tell their physician if they fall often as this may increase their risk for complications.

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 [see Drug Interactions (7.5) ].

Contact their physician to report any serious illness, such as severe diarrhea, infection, or fever [see Warnings and Precautions (5) and Adverse Reactions (6) ].

Immediately contact their physician when experiencing pain and discoloration of the skin (a purple bruise like rash) mostly on areas of the body with a high fat content, such as breasts, thighs, buttocks, hips and abdomen [see Warnings and Precautions (5.2) ].

Immediately contact their physician when experiencing any unusual symptom or pain since warfarin sodium may cause small cholesterol or athero emboli.

On feet it may appear as a sudden cool, painful, purple discoloration of toe(s) or forefoot [see Warnings and Precautions (5.5) ].

Immediately contact their physician when taking warfarin sodium after any heparin formulation therapy and experiencing bloody or black stools or appearence of bruises, or bleeding [see Warnings and Precautions (5.6) ].

To tell all of their healthcare professionals and dentists that they are taking warfarin sodium.

This should be done before they have any surgery or dental procedure [see Dosage and Administration (2.7) ].

Carry identification stating that they are taking warfarin sodium.

Bleeding Risks Advise patients to: 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 [see Box Warning and Warnings and Precautions (5.1) ].

Concomitant Medications and Botanicals (Herbals) Advise patients to: 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 [see Drug Interactions (7) ].

Pregnancy and Nursing Advise patients to: Notify their physician if they are pregnant or planning to become pregnant or considering breast feeding [see Use in Specific Populations (8.1 , 8.2 , 8.3) ].

Avoid warfarin sodium during pregnancy except in pregnant women with mechanical heart valves, who are at risk of thromboembolism [see Contraindications (4) ].

Use effective measures to avoid pregnancy while taking warfarin sodium.

This is very important because their unborn baby could be seriously harmed if they take warfarin sodium while they are pregnant [see Use in Specific Populations (8.1 , 8.3) ].

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 International Normalized Ratio (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 regarding the duration and intensity of anticoagulation for the indicated conditions.

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 to 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 to 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 to 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 to 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 to 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 to 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 to 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 to 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 to 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 Genotypes Ranges are derived from multiple published clinical studies.

VKORC1 −1639G>A (rs9923231) variant is used in this table.

Other coinherited 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 has a narrow therapeutic range (index), 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 Renal Impairment No dosage adjustment is necessary for patients with renal failure.

Monitor INR more frequently in patients with compromised renal function to maintain INR within the therapeutic range [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6) ].

2.6 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.