Drug Intercation

Lotrel 5 MG / 20 MG Oral Capsule

Generic Name: AMLODIPINE BESYLATE AND BENAZEPRIL HYDROCHLORIDE

Brand Name: Lotrel

Substance Name(s):
AMLODIPINE BESYLATE
BENAZEPRIL HYDROCHLORIDE

DRUG INTERACTIONS

7 Potassium supplements/potassium-sparing diuretics: hyperkalemia ( 7.1) Lithium: Increased serum lithium levels; toxicity symptoms ( 7.1) Injectable gold: facial flushing, nausea, vomiting, hypotension ( 7.1) Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Risk of renal dysfunction, loss of antihypertensive effect ( 7.1) Do not exceed doses greater than 20 mg daily of simvastatin ( 7.1) mTOR inhibitors: increased risk of angioedema ( 7.1) Dual inhibition of the renin-angiotensin system (RAS): Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.1) 7.1 Drug/Drug Interactions Amlodipine Simvastatin: Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily. CYP3A4 Inhibitors: Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A4 inhibitors to determine the need for dose adjustment. CYP3A4 Inducers: No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be monitored when amlodipine is coadministered with CYP3A4 inducers. Benazepril Potassium Supplements and Potassium-Sparing Diuretics: Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient’s serum potassium should be monitored frequently. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When coadministering Lotrel and lithium, frequent monitoring of serum lithium levels is recommended. Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs. Antidiabetic Agents: In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions, and should be monitored accordingly. Mammalian Target of Rapamycin (mTOR) Inhibitors: The risk of angioedema may be increased in patients receiving coadministration of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus). Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Lotrel and other agents that block the RAS. Do not coadminister aliskiren with Lotrel in patients with diabetes. Avoid use of aliskiren with Lotrel in patients with renal impairment [glomerular filtration rate (GFR) < 60 mL/min].

OVERDOSAGE

10 Only a few cases of human overdose with amlodipine have been reported. One patient was asymptomatic after a 250 mg ingestion; another, who combined 70 mg of amlodipine with an unknown large quantity of a benzodiazepine, developed refractory shock and died. Human overdoses with any combination of amlodipine and benazepril have not been reported. In scattered reports of human overdoses with benazepril and other ACE inhibitors, there are no reports of death. Treatment: Patients should be admitted to hospital and, generally, should be managed in an intensive care setting, with continuous monitoring of cardiac function, blood gases, and blood biochemistry. Emergency supportive measures such as artificial ventilation or cardiac pacing should be instituted if appropriate. In the event of a potentially life-threatening oral overdose, use induction of vomiting or gastric lavage and/or activated charcoal to remove the drug from the gastrointestinal tract (only if presented within 1 hour after ingestion of Lotrel). Other clinical manifestations of overdose should be managed symptomatically based on modern methods of intensive care. To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison-Control Center. Telephone numbers of certified poison-control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient. The most likely effect of overdose with Lotrel is vasodilation, with consequent hypotension and tachycardia. Simple repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required. With abrupt return of peripheral vascular tone, overdoses of other dihydropyridine calcium channel blockers have sometimes progressed to pulmonary edema, and patients must be monitored for this complication. Analyses of bodily fluids for concentrations of amlodipine, benazepril, or their metabolites are not widely available. Such analyses are, in any event, not known to be of value in therapy or prognosis. No data are available to suggest physiologic maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of amlodipine, benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of amlodipine by hemodialysis or hemo-perfusion has not been reported, but amlodipine’s high protein binding makes it unlikely that these interventions will be of value. Angiotensin II could presumably serve as a specific antagonist-antidote to benazepril, but angiotensin II is essentially unavailable outside of scattered research laboratories.

DESCRIPTION

11 Lotrel is a combination of amlodipine besylate and benazepril hydrochloride. Benazepril hydrochloride is a white to off-white crystalline powder, soluble (greater than 100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is: Its empirical formula is C 24H 28N 2O 5•HCl, and its molecular weight is 460.96. Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group. Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is (R,S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate; its structural formula is: Its empirical formula is C 20H 25ClN 2O 5•C 6H 6O 3S, and its molecular weight is 567.1. Amlodipine besylate is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker. Lotrel capsules are formulated in 6 different strengths for oral administration with a combination of amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg, 20 mg or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, 5/40 mg, 10/20 mg and 10/40 mg. The inactive ingredients of the capsules are calcium phosphate, cellulose compounds, colloidal silicon dioxide, crospovidone, gelatin, hydrogenated castor oil (not present in 5/40 mg or 10/40 mg strengths), iron oxides, lactose monohydrate, magnesium stearate, polysorbate 80, silicon dioxide, sodium lauryl sulfate, sodium starch (potato) glycolate, starch (corn), talc, and titanium dioxide. Benazepril hydrochloride structural formula Amlodipine besylate structural formula

CLINICAL STUDIES

14 Over 950 patients received Lotrel once-daily in 6 double-blind, placebo-controlled studies. The antihypertensive effect of a single dose persisted for 24 hours, with peak reductions achieved 2 to 8 hours after dosing. Once-daily doses of benazepril/amlodipine using benazepril doses of 10 to 20 mg and amlodipine doses of 2.5 to 10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10–25/6–13 mmHg. In 2 studies in patients not adequately controlled on either benazepril 40 mg alone (n=329) or amlodipine 10 mg alone (n=812) once-daily doses of Lotrel 10/40 mg further decreased seated blood pressure compared to the respective monotherapy alone. Combination therapy was effective in blacks and nonblacks. Both components contributed to the antihypertensive efficacy in nonblacks, but virtually all of the antihypertensive effect in blacks could be attributed to the amlodipine component. Among nonblack patients in placebo-controlled trials comparing Lotrel to the individual components, the blood pressure lowering effects of the combination were shown to be additive and in some cases synergistic. During chronic therapy with Lotrel, the maximum reduction in blood pressure with any given dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of Lotrel have continued during therapy for at least 1 year. Abrupt withdrawal of Lotrel has not been associated with a rapid increase in blood pressure.

HOW SUPPLIED

16 /STORAGE AND HANDLING Lotrel is available as capsules containing amlodipine besylate equivalent to 5 mg of amlodipine, with 20 mg of benazepril hydrochloride providing for the following available combinations:5/20 mg. Capsules are imprinted with “Lotrel” and appropriate code. pink with 2 white bands /2265 Bottles of 30 Storage: Store at 25°C (77°F); excursions permitted to 15°C–30°C (59°F–86°F). [See USP controlled room temperature.] Protect from moisture. Dispense in tight container (USP).

RECENT MAJOR CHANGES

Warnings and Precautions ( 5.1) 04/2015

GERIATRIC USE

8.5 Geriatric Use In geriatric patients, exposure to amlodipine is increased, thus consider lower initial doses of Lotrel [see Clinical Pharmacology (12.3)]. Of the total number of patients who received Lotrel in U.S. clinical studies of Lotrel, over 19% were 65 years or older while about 2% were 75 years or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 Lotrel (amlodipine/benazepril) capsules are available as follows: 2.5/10 mg, 5/10 mg, 5/20 mg, 5/40 mg, 10/20 mg, and 10/40 mg. Capsules (amlodipine/benazepril mg): 2.5/10, 5/10, 5/20, 5/40, 10/20, 10/40 ( 3)

MECHANISM OF ACTION

12.1 Mechanism of Action Benazepril Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril and amlodipine for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L [see Warnings and Precautions (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotrel remains to be elucidated. While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension. Amlodipine Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

INDICATIONS AND USAGE

1 Lotrel is a combination capsule of amlodipine, a dihydropyridine calcium channel blocker (DHP CCB) and benazepril, an angiotensin-converting enzyme (ACE) inhibitor. Lotrel is indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent. ( 1) 1.1 Hypertension Lotrel is indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.

PEDIATRIC USE

8.4 Pediatric Use Neonates with a History of in utero Exposure to Lotrel If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited.

PREGNANCY

8.1 Pregnancy Pregnancy Category D Use of drugs that act on the RAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Lotrel as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the RAS from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the RAS for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Lotrel, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Lotrel for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

NUSRING MOTHERS

8.3 Nursing Mothers Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat. It is not known whether amlodipine is excreted in human milk. Nursing or drug should be discontinued.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Lotrel as soon as possible (5.5). Drugs that act directly on the renin-angiotensin system (RAS) can cause injury and death to the developing fetus (5.5) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning When pregnancy is detected, discontinue Lotrel as soon as possible (5.5). Drugs that act directly on the renin-angiotensin system (RAS) can cause injury and death to the developing fetus ( 5.5).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Anaphylactoid reactions, including angioedema ( 5.1) Myocardial infarction or increased angina in patients with obstructive coronary artery disease. ( 5.2) Assess for hypotension and hyperkalemia. ( 5.4, 5.8) Titrate slowly in patients with impaired hepatic or severely impaired renal function. ( 5.6, 5.7) 5.1 Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lotrel) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lotrel) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks. Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema [see Drug Interactions (7)]. Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Lotrel and treat immediately. [see ]. Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Lotrel and treat immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., administer subcutaneous epinephrine injection 1:1000 (0.3 to 0.5 mL), promptly [see Adverse Reactions (6)]. Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Two patients undergoing desensitizing treatment with hymenoptera (wasp sting) venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera (wasp sting) venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.2 Increased Angina and/or Myocardial Infarction Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease. 5.3 Patients with Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy As with all other vasodilators, special caution is required when using amlodipine in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy. 5.4 Hypotension Lotrel can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume or salt depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before starting therapy with benazepril. If hypotension occurs, the patient should be placed in the supine position and if necessary given physiological saline intravenously. Treatment with benazepril can be continued once blood pressure and volume have returned to normal. In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death. In such patients, start Lotrel therapy under close medical supervision; follow closely for the first 2 weeks of treatment and whenever the dose of the benazepril component is increased or a diuretic is added or its dose increased. Symptomatic hypotension is also possible in patients with severe aortic stenosis. 5.5 Fetal Toxicity Pregnancy Category D Use of drugs that act on the RAS during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Lotrel as soon as possible [see Use in Specific Populations (8.1)]. 5.6 Hepatitis and Hepatic Failure There have been rare reports of predominantly cholestatic hepatitis and isolated cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The mechanism is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevation of hepatic enzymes should discontinue the ACE inhibitor and be kept under medical surveillance. 5.7 Impaired Renal Function Monitor renal function periodically in patients treated with Lotrel. Changes in renal function, including acute renal failure, can be caused by drugs that affect the RAS. Patients whose renal function may depend in part on the activity of the RAS (e.g., patients with renal artery stenosis, severe heart failure, post-myocardial infarction or volume depletion) or who are on NSAIDS or ARBs may be at particular risk of developing acute renal failure on Lotrel. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Lotrel. 5.8 Hyperkalemia Monitor serum potassium periodically in patients receiving Lotrel. Drugs that affect the RAS can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. In U.S. placebo-controlled trials of Lotrel, hyperkalemia [serum potassium at least 0.5 mEq/L greater than the upper limit of normal (ULN)] not present at baseline occurred in approximately 1.5% of hypertensive patients receiving Lotrel. Increases in serum potassium were generally reversible. 5.9 Cough Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough. 5.10 Surgery/Anesthesia In patients undergoing surgery or during anesthesia with agents that produce hypotension, benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Female patients of childbearing age should be told about the consequences of exposure to Lotrel during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible [see Warnings and Precautions (5.5)]. T2015-87 May 2015

DOSAGE AND ADMINISTRATION

2 Usual starting dose is 2.5/10 mg. (2.1) May be used as add-on therapy for patients not adequately controlled with either a dihydropyridine calcium channel blocker or an ACE inhibitor ( 2.2) Patients who experience edema with amlodipine may be switched to Lotrel containing a lower dose of amlodipine. ( 2.1) 2.1 General Considerations The recommended initial dose of Lotrel is 1 capsule of amlodipine 2.5 mg/benazepril 10 mg orally once-daily. It is usually appropriate to begin therapy with Lotrel only after a patient has either (a) failed to achieve the desired antihypertensive effect with amlodipine or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema. The antihypertensive effect of Lotrel is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to amlodipine 10 mg/benazepril 40 mg once-daily. The dosing should be individualized and adjusted according to the patient’s clinical response. Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5 to 10 mg while benazepril is effective in doses of 10 to 80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups. 2.2 Dosage Adjustment in Renal Impairment Renal Impairment: Lotrel is not recommended in patients with creatinine clearance (CrCl) less than or equal to 30 mL/min. No dose adjustment of Lotrel is required in patients with CrCl greater than 30 mL/min/1.73m2 (serum creatinine roughly less than or equal to 3 mg/dL or 265 micromol/L) [see Warnings and Precautions (5.7), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)]. 2.3 Replacement Therapy Lotrel may be substituted for the titrated components.

Pravastatin Sodium 80 MG Oral Tablet

Generic Name: PRAVASTATIN SODIUM

Brand Name: pravastatin sodium

Substance Name(s):
PRAVASTATIN SODIUM

DRUG INTERACTIONS

7. For the concurrent therapy of either cyclosporine, fibrates, niacin (nicotinic acid), or erythromycin, the risk of myopathy increases [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ]. Concomitant lipid-lowering therapies: use with fibrates or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with pravastatin sodium. ( 7) Cyclosporine: combination increases exposure. Limit pravastatin to 20 mg once daily. ( 2.5, 7.1) Clarithromycin: combination increases exposure. Limit pravastatin to 40 mg once daily. ( 2.6, 7.2) 7.1 Cyclosporine The risk of myopathy/rhabdomyolysis is increased with concomitant administration of cyclosporine. Limit pravastatin to 20 mg once daily for concomitant use with cyclosporine [see Dosage and Administration ( 2.5) , Warnings and Precautions ( 5.1) , and Clinical Pharmacology ( 12.3) ]. 7.2 Clarithromycin The risk of myopathy/rhabdomyolysis is increased with concomitant administration of clarithromycin. Limit pravastatin to 40 mg once daily for concomitant use with clarithromycin [see Dosage and Administration ( 2.6) , Warnings and Precautions ( 5.1) , and Clinical Pharmacology ( 12.3) ]. 7.3 Colchicine The risk of myopathy/rhabdomyolysis is increased with concomitant administration of colchicine [see Warnings and Precautions ( 5.1) ]. 7.4 Gemfibrozil Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are coadministered with gemfibrozil, concomitant administration of pravastatin sodium with gemfibrozil should be avoided [see Warnings and Precautions ( 5.1) ]. 7.5 Other Fibrates Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, pravastatin sodium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions ( 5.1) ]. 7.6 Niacin The risk of skeletal muscle effects may be enhanced when pravastatin is used in combination with niacin; a reduction in pravastatin sodium dosage should be considered in this setting [see Warnings and Precautions ( 5.1) ].

OVERDOSAGE

10. To date, there has been limited experience with overdosage of pravastatin. If an overdose occurs, it should be treated symptomatically with laboratory monitoring and supportive measures should be instituted as required.

DESCRIPTION

11. Pravastatin sodium is one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. Pravastatin sodium is designated chemically as 1-Naphthalene-heptanoic acid, 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-(2-methyl-1-oxobutoxy)-, monosodium salt, [1S-[1α(βS*,δS*),2α,6α,8β(R*),8aα]]-. Structural formula: Pravastatin sodium, USP is white to yellowish white powder or crystalline powder, hygroscopic in nature. It is a relatively polar hydrophilic compound with a partition coefficient (octanol/water) of 0.59 at a pH of 7. It is freely soluble in water and in methanol. Soluble in ethanol. Each pravastatin sodium tablet, USP intended for oral administration contains 10 mg or 20 mg or 40 mg or 80 mg of pravastatin sodium. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose anhydrous, magnesium stearate, microcrystalline cellulose, polyoxyl 35 castor oil and sodium carbonate anhydrous. Pravastatin Sodium Tablets, USP

CLINICAL STUDIES

14. 14.1 Prevention of Coronary Heart Disease In the Pravastatin Primary Prevention Study (WOS), 3 the effect of pravastatin sodium on fatal and nonfatal CHD was assessed in 6595 men 45 to 64 years of age, without a previous MI, and with LDL-C levels between 156 to 254 mg/dL (4 to 6.7 mmol/L). In this randomized, doubleblind, placebo-controlled study, patients were treated with standard care, including dietary advice, and either pravastatin sodium 40 mg daily (N=3302) or placebo (N=3293) and followed for a median duration of 4.8 years. Median (25 th, 75 th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −20.3 (−26.9, −11.7), −27.7 (−36, −16.9), −9.1 (−27.6, 12.5), and 6.7 (−2.1, 15.6), respectively. Pravastatin sodium significantly reduced the rate of first coronary events (either CHD death or nonfatal MI) by 31% (248 events in the placebo group [CHD death=44, nonfatal MI=204] versus 174 events in the pravastatin sodium group [CHD death=31, nonfatal MI=143], p=0.0001 [see figure below]). The risk reduction with pravastatin sodium was similar and significant throughout the entire range of baseline LDL cholesterol levels. This reduction was also similar and significant across the age range studied with a 40% risk reduction for patients younger than 55 years and a 27% risk reduction for patients 55 years and older. The Pravastatin Primary Prevention Study included only men, and therefore it is not clear to what extent these data can be extrapolated to a similar population of female patients. Pravastatin sodium also significantly decreased the risk for undergoing myocardial revascularization procedures (coronary artery bypass graft [CABG] surgery or percutaneous transluminal coronary angioplasty [PTCA]) by 37% (80 vs 51 patients, p=0.009) and coronary angiography by 31% (128 vs 90, p=0.007). Cardiovascular deaths were decreased by 32% (73 vs 50, p=0.03) and there was no increase in death from non-cardiovascular causes. Pravastatin Sodium Tablets, USP 14.2 Secondary Prevention of Cardiovascular Events In the LIPID4 study, the effect of pravastatin, 40 mg daily, was assessed in 9014 patients (7498 men; 1516 women; 3514 elderly patients [age ≥65 years]; 782 diabetic patients) who had experienced either an MI `(5754 patients) or had been hospitalized for unstable angina pectoris (3260 patients) in the preceding 3 to 36 months. Patients in this multicenter, double-blind, placebo-controlled study participated for an average of 5.6 years (median of 5.9 years) and at randomization had Total-C between 114 and 563 mg/dL (mean 219 mg/dL), LDL-C between 46 and 274 mg/dL (mean 150 mg/dL), TG between 35 and 2710 mg/dL (mean 160 mg/dL), and HDL-C between 1 and 103 mg/dL (mean 37 mg/dL). At baseline, 82% of patients were receiving aspirin and 76% were receiving antihypertensive medication. Treatment with pravastatin significantly reduced the risk for total mortality by reducing coronary death (see Table 5). The risk reduction due to treatment with pravastatin on CHD mortality was consistent regardless of age. Pravastatin significantly reduced the risk for total mortality (by reducing CHD death) and CHD events (CHD mortality or nonfatal MI) in patients who qualified with a history of either MI or hospitalization for unstable angina pectoris. Table 5 LIPID – Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=4512) Placebo (N=4502) Risk Reduction p-value Primary Endpoint CHD mortality 287 (6.4) 373 (8.3) 24% 0.0004 Secondary Endpoints Total mortality 498 (11.0) 633 (14.1) 23% <0.0001 CHD mortality or nonfatal MI 557 (12.3) 715 (15.9) 24% <0.0001 Myocardial revascularization procedures (CABG or PTCA) 584 (12.9) 706 (15.7) 20% <0.0001 Stroke All-cause 169 (3.7) 204 (4.5) 19% 0.0477 Non-hemorrhagic 154 (3.4) 196 (4.4) 23% 0.0154 Cardiovascular mortality 331 (7.3) 433 (9.6) 25% <0.0001 In the CARE5 study, the effect of pravastatin, 40 mg daily, on CHD death and nonfatal MI was assessed in 4159 patients (3583 men and 576 women) who had experienced a MI in the preceding 3 to 20 months and who had normal (below the 75th percentile of the general population) plasma total cholesterol levels. Patients in this double-blind, placebo-controlled study participated for an average of 4.9 years and had a mean baseline Total-C of 209 mg/dL. LDL-C levels in this patient population ranged from 101 to 180 mg/dL (mean 139 mg/dL). At baseline, 84% of patients were receiving aspirin and 82% were taking antihypertensive medications. Median (25th , 75th percentile) percent changes from baseline after 6 months of pravastatin treatment in Total-C, LDL-C, TG, and HDL-C were −22.0 (−28.4, −14.9), −32.4 (−39.9, −23.7), −11.0 (−26.5, 8.6), and 5.1 (−2.9, 12.7), respectively. Treatment with pravastatin significantly reduced the rate of first recurrent coronary events (either CHD death or nonfatal MI), the risk of undergoing revascularization procedures (PTCA, CABG), and the risk for stroke or TIA (see Table 6). Table 6 CARE – Primary and Secondary Endpoints Number (%) of Subjects Event Pravastatin 40 mg (N=2081) Placebo (N=2078) Risk Reduction p-value Primary Endpoint CHD mortality or nonfatal MI The risk reduction due to treatment with pravastatin was consistent in both sexes. 212 (10.2) 274 (13.2) 24% 0.003 Secondary Endpoints Myocardial revascularization procedures (CABG or PTCA) 294 (14.1) 391 (18.8) 27% 200 mg/dL and LDL-C 95 th percentile for age and sex and one parent with either a clinical or molecular diagnosis of familial hypercholesterolemia. The mean baseline LDL-C value was 239 mg/dL and 237 mg/dL in the pravastatin (range: 151 to 405 mg/dL) and placebo (range: 154 to 375 mg/dL) groups, respectively. Pravastatin significantly decreased plasma levels of LDL-C, Total-C, and ApoB in both children and adolescents (see Table 10). The effect of pravastatin treatment in the 2 age groups was similar. Table 10 Lipid-Lowering Effects of Pravastatin in Pediatric Patients with Heterozygous Familial Hypercholesterolemia: Least-Squares Mean % Change from Baseline at Month 24 (Last Observation Carried Forward: Intent-to-Treat) a Pravastatin 20 mg (Aged 8 to 13 years) N=65 Pravastatin 40 mg (Aged 14 to 18 years) N=41 Combined Pravastatin (Aged 8 to 18 years) N=106 Combined Placebo (Aged 8 to 18 years) N=108 95% CI of the Difference Between Combined Pravastatin and Placebo a The above least-squares mean values were calculated based on log-transformed lipid values. b Significant at p ≤ 0.0001 when compared with placebo. LDL-C −26.04 b −21.07 b −24.07 b −1.52 (−26.74, −18.86) TC −20.75 b −13.08 b −17.72 b −0.65 (−20.40, −13.83) HDL-C 1.04 13.71 5.97 3.13 (−1.71, 7.43) TG −9.58 −0.30 −5.88 −3.27 (−13.95, 10.01) ApoB (N) −23.16 b (61) −18.08 b (39) −21.11 b (100) −0.97 (106) (−24.29, −16.18) The mean achieved LDL-C was 186 mg/dL (range: 67 to 363 mg/dL) in the pravastatin group compared to 236 mg/dL (range: 105 to 438 mg/dL) in the placebo group. The safety and efficacy of pravastatin doses above 40 mg daily have not been studied in children. The long-term efficacy of pravastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established.

HOW SUPPLIED

16. /STORAGE AND HANDLING 16.1 How Supplied Pravastatin Sodium Tablets USP, 10 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC46’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-500-01 Pravastatin Sodium Tablets USP, 20 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC45’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-501-01 Pravastatin Sodium Tablets USP, 40 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC44’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-502-01 Pravastatin Sodium Tablets USP, 80 mg are white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC43’ on one side and plain on the other side and are supplied as follows: Unit dose packages of 30 (5 x 6) NDC 68084-746-25 16.2 Storage Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature]. Protect from light and moisture

GERIATRIC USE

8.5 Geriatric Use Two secondary prevention trials with pravastatin (CARE and LIPID) included a total of 6593 subjects treated with pravastatin 40 mg for periods ranging up to 6 years. Across these 2 studies, 36.1% of pravastatin subjects were aged 65 and older and 0.8% were aged 75 and older. The beneficial effect of pravastatin in elderly subjects in reducing cardiovascular events and in modifying lipid profiles was similar to that seen in younger subjects. The adverse event profile in the elderly was similar to that in the overall population. Other reported clinical experience has not identified differences in responses to pravastatin between elderly and younger patients. Mean pravastatin AUCs are slightly (25% to 50%) higher in elderly subjects than in healthy young subjects, but mean maximum plasma concentration (C max), time to maximum plasma concentration (T max), and half-life (t ½) values are similar in both age groups and substantial accumulation of pravastatin would not be expected in the elderly [see Clinical Pharmacology ( 12.3) ]. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, pravastatin sodium should be prescribed with caution in the elderly [see Warnings and Precautions ( 5.1) and Clinical Pharmacology ( 12.3) ].

DOSAGE FORMS AND STRENGTHS

3. Pravastatin sodium tablets, USP are supplied as: 10 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC46’ on one side and plain on the other side. 20 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC45’ on one side and plain on the other side. 40 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC44’ on one side and plain on the other side. 80 mg tablets: white to off-white, oval-shaped, biconvex uncoated tablets debossed with the logo of ‘ZC43’ on one side and plain on the other side. Tablets: 10 mg, 20 mg, 40 mg and 80 mg. ( 3)

MECHANISM OF ACTION

12.1 Mechanism of Action Pravastatin is a reversible inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, an early and rate limiting step in the biosynthetic pathway for cholesterol. In addition, pravastatin reduces VLDL and TG and increases HDL-C.

INDICATIONS AND USAGE

1. Therapy with lipid-altering agents should be only one component of multiple risk factor intervention in individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Drug therapy is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate. Pravastatin sodium tablet, USP is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to: Reduce the risk of MI, revascularization, and cardiovascular mortality in hypercholesterolemic patients without clinically evident CHD. ( 1.1) Reduce the risk of total mortality by reducing coronary death, MI, revascularization, stroke/TIA, and the progression of coronary atherosclerosis in patients with clinically evident CHD. ( 1.1) Reduce elevated Total-C, LDL-C, ApoB, and TG levels and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia. ( 1.2) Reduce elevated serum TG levels in patients with hypertriglyceridemia. ( 1.2) Treat patients with primary dysbetalipoproteinemia who are not responding to diet. ( 1.2) Treat children and adolescent patients ages 8 years and older with heterozygous familial hypercholesterolemia after failing an adequate trial of diet therapy. ( 1.2) Limitations of use: Pravastatin sodium tablets, USP have not been studied in Fredrickson Types I and V dyslipidemias. ( 1.3) 1.1 Prevention of Cardiovascular Disease In hypercholesterolemic patients without clinically evident coronary heart disease (CHD), pravastatin sodium tablets, USP are indicated to: reduce the risk of myocardial infarction (MI). reduce the risk of undergoing myocardial revascularization procedures. reduce the risk of cardiovascular mortality with no increase in death from non-cardiovascular causes. In patients with clinically evident CHD, pravastatin sodium tablet is indicated to: reduce the risk of total mortality by reducing coronary death. reduce the risk of MI. reduce the risk of undergoing myocardial revascularization procedures. reduce the risk of stroke and stroke/transient ischemic attack (TIA). slow the progression of coronary atherosclerosis. 1.2 Hyperlipidemia Pravastatin sodium tablet is indicated: as an adjunct to diet to reduce elevated total cholesterol (Total-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and triglyceride (TG) levels and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia and mixed dyslipidemia ( Fredrickson Types IIa and IIb). 1 as an adjunct to diet for the treatment of patients with elevated serum TG levels ( Fredrickson Type IV). for the treatment of patients with primary dysbetalipoproteinemia ( Fredrickson Type III) who do not respond adequately to diet. as an adjunct to diet and lifestyle modification for treatment of heterozygous familial hypercholesterolemia (HeFH) in children and adolescent patients ages 8 years and older if after an adequate trial of diet the following findings are present: LDL-C remains ≥ 190 mg/dL or LDL-C remains ≥ 160 mg/dL and: there is a positive family history of premature cardiovascular disease (CVD) or two or more other CVD risk factors are present in the patient. 1.3 Limitations of Use Pravastatin sodium has not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of pravastatin sodium in children and adolescents from 8 to 18 years of age have been evaluated in a placebo-controlled study of 2 years duration. Patients treated with pravastatin had an adverse experience profile generally similar to that of patients treated with placebo with influenza and headache commonly reported in both treatment groups. [See Adverse Reactions ( 6.4) .] Doses greater than 40 mg have not been studied in this population. Children and adolescent females of childbearing potential should be counseled on appropriate contraceptive methods while on pravastatin therapy [see Contraindications ( 4.3) and Use in Specific Populations ( 8.1) ]. For dosing information [see Dosage and Administration ( 2.3) .] Doubleblind, placebo-controlled pravastatin studies in children less than 8 years of age have not been conducted.

PREGNANCY

4.3 Pregnancy Atherosclerosis is a chronic process and discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hypercholesterolemia. Cholesterol and other products of cholesterol biosynthesis are essential components for fetal development (including synthesis of steroids and cell membranes). Since statins decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, they are contraindicated during pregnancy and in nursing mothers. PRAVASTATIN SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING AGE ONLY WHEN SUCH PATIENTS ARE HIGHLY UNLIKELY TO CONCEIVE AND HAVE BEEN INFORMED OF THE POTENTIAL HAZARDS. If the patient becomes pregnant while taking this class of drug, therapy should be discontinued immediately and the patient apprised of the potential hazard to the fetus [see Use in Specific Populations ( 8.1) ].

NUSRING MOTHERS

4.4 Nursing Mothers A small amount of pravastatin is excreted in human breastmilk. Because statins have the potential for serious adverse reactions in nursing infants, women who require pravastatin sodium treatment should not breastfeed their infants [see Use in Specific Populations ( 8.3) ].

WARNING AND CAUTIONS

5. WARNINGS AND PRECAUTIONS Skeletal muscle effects (e.g., myopathy and rhabdomyolysis): predisposing factors include advanced age (≥65), uncontrolled hypothyroidism, and renal impairment. Patients should be advised to promptly report to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness. Pravastatin therapy should be discontinued if myopathy is diagnosed or suspected. ( 5.1, 8.5) Liver enzyme abnormalities: persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. ( 5.2) 5.1 Skeletal Muscle Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with pravastatin and other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects. Uncomplicated myalgia has also been reported in pravastatin-treated patients [see Adverse Reactions (6)]. Myopathy, defined as muscle aching or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values to greater than 10 times the upper limit of normal (ULN), was rare ( 6 months) stable liver disease, due primarily to hepatitis C or non-alcoholic fatty liver disease, were treated with 80 mg pravastatin or placebo for up to 9 months. The primary safety endpoint was the proportion of subjects with at least one ALT ≥ 2 times the upper limit of normal for those with normal ALT (≤ the upper limit of normal) at baseline or a doubling of the baseline ALT for those with elevated ALT (> the upper limit of normal) at baseline. By Week 36, 12 out of 160 (7.5%) subjects treated with pravastatin met the prespecified safety ALT endpoint compared to 20 out of 160 (12.5%) subjects receiving placebo. Conclusions regarding liver safety are limited since the study was not large enough to establish similarity between groups (with 95% confidence) in the rates of ALT elevation. It is recommended that liver function tests be performed prior to the initiation of therapy and when clinically indicated. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of pravastatin [see Contraindications ( 4.2) ]. Caution should be exercised when pravastatin is administered to patients who have a recent (< 6 months) history of liver disease, have signs that may suggest liver disease (e.g., unexplained aminotransferase elevations, jaundice), or are heavy users of alcohol. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pravastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with pravastatin sodium, promptly interrupt therapy. If an alternate etiology is not found do not restart pravastatin sodium. 5.3 Endocrine Function Statins interfere with cholesterol synthesis and lower circulating cholesterol levels and, as such, might theoretically blunt adrenal or gonadal steroid hormone production. Results of clinical trials with pravastatin in males and post-menopausal females were inconsistent with regard to possible effects of the drug on basal steroid hormone levels. In a study of 21 males, the mean testosterone response to human chorionic gonadotropin was significantly reduced (p < 0.004) after 16 weeks of treatment with 40 mg of pravastatin. However, the percentage of patients showing a ≥ 50% rise in plasma testosterone after human chorionic gonadotropin stimulation did not change significantly after therapy in these patients. The effects of statins on spermatogenesis and fertility have not been studied in adequate numbers of patients. The effects, if any, of pravastatin on the pituitary-gonadal axis in pre-menopausal females are unknown. Patients treated with pravastatin who display clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if a statin or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., ketoconazole, spironolactone, cimetidine) that may diminish the levels or activity of steroid hormones. In a placebo-controlled study of 214 pediatric patients with HeFH, of which 106 were treated with pravastatin (20 mg in the children aged 8 to 13 years and 40 mg in the adolescents aged 14 to 18 years) for 2 years, there were no detectable differences seen in any of the endocrine parameters (ACTH, cortisol, DHEAS, FSH, LH, TSH, estradiol [girls] or testosterone [boys]) relative to placebo. There were no detectable differences seen in height and weight changes, testicular volume changes, or Tanner score relative to placebo.

INFORMATION FOR PATIENTS

17. PATIENT COUNSELING INFORMATION Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing pravastatin [see Warnings and Precautions ( 5.1) ]. It is recommended that liver enzyme tests be performed before the initiation of pravastatin sodium, and thereafter when clinically indicated. All patients treated with pravastatin sodium should be advised to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions ( 5.2) ]. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DOSAGE AND ADMINISTRATION

2. Adults: the recommended starting dose is 40 mg once daily. Use 80 mg dose only for patients not reaching LDL-C goal with 40 mg. ( 2.2) Significant renal impairment: the recommended starting dose is 10 mg once daily. ( 2.2) Children (ages 8 to 13 years, inclusive): the recommended starting dose is 20 mg once daily. ( 2.3) Adolescents (ages 14 to 18 years): the recommended starting dose is 40 mg once daily. ( 2.3) 2.1 General Dosing Information The patient should be placed on a standard cholesterol-lowering diet before receiving pravastatin sodium tablets and should continue on this diet during treatment with pravastatin sodium tablets [see NCEP Treatment Guidelines for details on dietary therapy]. 2.2 Adult Patients The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal impairment, a starting dose of 10 mg daily is recommended. Pravastatin sodium tablets can be administered orally as a single dose at any time of the day, with or without food. Since the maximal effect of a given dose is seen within 4 weeks, periodic lipid determinations should be performed at this time and dosage adjusted according to the patient’s response to therapy and established treatment guidelines. 2.3 Pediatric Patients Children (Ages 8 to 13 Years, Inclusive) The recommended dose is 20 mg once daily in children 8 to 13 years of age. Doses greater than 20 mg have not been studied in this patient population. Adolescents (Ages 14 to 18 Years) The recommended starting dose is 40 mg once daily in adolescents 14 to 18 years of age. Doses greater than 40 mg have not been studied in this patient population. Children and adolescents treated with pravastatin should be reevaluated in adulthood and appropriate changes made to their cholesterol-lowering regimen to achieve adult goals for LDL-C [see Indications and Usage ( 1.2) ]. 2.4 Concomitant Lipid-Altering Therapy Pravastatin sodium tablets may be used with bile acid resins. When administering a bile-acid-binding resin (e.g., cholestyramine, colestipol) and pravastatin, pravastatin sodium tablets should be given either 1 hour or more before or at least 4 hours following the resin. [See Clinical Pharmacology ( 12.3) .] 2.5 Dosage in Patients Taking Cyclosporine In patients taking immunosuppressive drugs such as cyclosporine concomitantly with pravastatin, therapy should begin with 10 mg of pravastatin sodium once-a-day at bedtime and titration to higher doses should be done with caution. Most patients treated with this combination received a maximum pravastatin sodium dose of 20 mg/day. In patients taking cyclosporine, therapy should be limited to 20 mg of pravastatin sodium once daily [see Warnings and Precautions ( 5.1) and Drug Interactions ( 7.1) ]. 2.6 Dosage in Patients Taking Clarithromycin In patients taking clarithromycin, therapy should be limited to 40 mg of pravastatin sodium once daily [see Drug Interactions ( 7.2) ].

HYDROcodone bitartrate 10 MG / acetaminophen 500 MG Oral Tablet

Generic Name: HYDROCODONE BITARTRATE AND ACETAMINOPHEN

Brand Name: Hydrocodone Bitartrate And Acetaminophen

Substance Name(s):
HYDROCODONE BITARTRATE
ACETAMINOPHEN

WARNINGS

Hepatotoxicity: Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4000 milligrams per day, and often involve more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4000 milligrams of acetaminophen per day, even if they feel well. Hypersensitivity/anaphylaxis: There have been post-marketing reports of hypersensitivity and anaphylaxis associated with use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Instruct patients to discontinue Hydrocodone Bitartrate and Acetaminophen Tablets, USP immediately and seek medical care if they experience these symptoms. Do not prescribe Hydrocodone Bitartrate and Acetaminophen Tablets, USP for patients with acetaminophen allergy. Respiratory Depression: At high doses or in sensitive patients, hydrocodone may produce dose-related respiratory depression by acting directly on the brain stem respiratory center. Hydrocodone also affects the center that controls respiratory rhythm, and may produce irregular and periodic breathing. Head Injury and Increased Intracranial Pressure: The respiratory depressant effects of narcotics and their capacity to elevate cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions or a preexisting increase in intracranial pressure. Furthermore, narcotics produce adverse reactions which may obscure the clinical course of patients with head injuries. Acute Abdominal Conditions: The administration of narcotics may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Misuse, Abuse, and Diversion of Opioids: Hydrocodone bitartrate and acetaminophen tablets contain hydrocodone, an opioid agonist, and is a Schedule III controlled substance. Opioid agonists have the potential for being abused and are sought by abusers and people with addiction disorders, and are subject to diversion. Hydrocodone bitartrate and acetaminophen tablets can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing hydrocodone bitartrate and acetaminophen tablets in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse or diversion (see DRUG ABUSE AND DEPENDENCE ).

DRUG INTERACTIONS

Drug Interactions: Patients receiving other narcotic analgesics, antihistamines, antipsychotics, antianxiety agents, or other CNS depressants (including alcohol) concomitantly with hydrocodone bitartrate and acetaminophen tablets may exhibit an additive CNS depression. When combined therapy is contemplated, the dose of one or both agents should be reduced. The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of either the antidepressant or hydrocodone.

OVERDOSAGE

Following an acute overdosage, toxicity may result from hydrocodone or acetaminophen. Signs and Symptoms: Hydrocodone: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. Acetaminophen: In acetaminophen overdosage: dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma and coagulation defects may also occur. Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. Treatment: A single or multiple drug overdose with hydrocodone and acetaminophen is a potentially lethal polydrug overdose, and consultation with a regional poison control center is recommended. Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Oxygen, intravenous fluids, vasopressors, and other supportive measures should be employed as indicated. Assisted or controlled ventilation should also be considered. For hydrocodone overdose, primary attention should be given to the reestablishment of adequate respiratory exchange through provision of a patent airway and the institution of assisted or controlled ventilation. The narcotic antagonist naloxone hydrochloride is a specific antidote against respiratory depression which may result from overdosage or unusual sensitivity to narcotics, including hydrocodone. Since the duration of action of hydrocodone may exceed that of the antagonist, the patient should be kept under continued surveillance, and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. A narcotic antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Gastric decontamination with activated charcoal should be administered just prior to N-acetylcysteine (NAC) to decrease systemic absorption if acetaminophen ingestion is known or suspected to have occurred within a few hours of presentation. Serum acetaminophen levels should be obtained immediately if the patient presents 4 hours or more after ingestion to assess potential risk of hepatotoxicity; acetaminophen levels drawn less than 4 hours post-ingestion may be misleading. To obtain the best possible outcome, NAC should be administered as soon as possible where impending or evolving liver injury is suspected. Intravenous NAC may be administered when circumstances preclude oral administration. Vigorous supportive therapy is required in severe intoxication. Procedures to limit the continuing absorption of the drug must be readily performed since the hepatic injury is dose dependent and occurs early in the course of intoxication.

DESCRIPTION

Hydrocodone bitartrate and acetaminophen is supplied in tablet form for oral administration. Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine, white crystals or as a crystalline powder. It is affected by light. The chemical name is 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula: Acetaminophen, 4′-hydroxyacetanilide, a slightly bitter, white, odorless, crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. It has the following structural formula: This is an image of the structural formula of Hydrocodone bitartrate. This is an image of the structural formula of Acetaminophen. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 2.5 mg/500 mg Each tablet contains: Hydrocodone Bitartrate …………. 2.5 mg Acetaminophen ……………………. 500 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, FD&C Red #3, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, stearic acid, and sucrose. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg Each tablet contains: Hydrocodone Bitartrate …………….. 5 mg Acetaminophen ……………………….. 325 mg In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, stearic acid and sugar spheres which are composed of starch derived from corn, FD&C Red #40, FD&C Yellow #6, and sucrose. Meets USP Dissolution Test 2. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/500 mg Each tablet contains: Hydrocodone Bitartrate …………. 5 mg Acetaminophen ……………………. 500 mg In addition each tablet contains the following inactive ingredients: hypromellose, lactose monohydrate, magnesium stearate, and sodium starch glycolate. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/325 mg Each tablet contains: Hydrocodone Bitartrate …………. 7.5 mg Acetaminophen ……………………. 325 mg In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Red #40 aluminum lake, FD&C Yellow #6 aluminum lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, sodium lauryl sulfate, and stearic acid. Meets USP Dissolution Test 2. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/500 mg Each tablet contains: Hydrocodone Bitartrate …………. 7.5 mg Acetaminophen ……………………. 500 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, FD&C Blue #1, FD&C Yellow #5, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, stearic acid, and sucrose. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/650 mg Each tablet contains: Hydrocodone Bitartrate …………. 7.5 mg Acetaminophen ……………………. 650 mg In addition each tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/750 mg Each tablet contains: Hydrocodone Bitartrate …………. 7.5 mg Acetaminophen ……………………. 750 mg In addition each tablet contains the following inactive ingredients: croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/325 mg Each tablet contains: Hydrocodone Bitartrate ………… 10 mg Acetaminophen ……………………. 325 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Yellow #10 lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/500 mg Each tablet contains: Hydrocodone Bitartrate ………… 10 mg Acetaminophen ……………………. 500 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 aluminum lake, D&C Red #30 aluminum lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/650 mg Each tablet contains: Hydrocodone Bitartrate ………… 10 mg Acetaminophen ……………………. 650 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, FD&C Blue #1 aluminum lake, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid. May also contain crospovidone. Meets USP Dissolution Test 1. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/660 mg Each tablet contains: Hydrocodone Bitartrate ………… 10 mg Acetaminophen ……………………. 660 mg In addition each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch, and stearic acid. May also contain crospovidone. Meets USP Dissolution Test 1.

HOW SUPPLIED

Hydrocodone Bitartrate and Acetaminophen Tablets, USP 2.5 mg/500 mg are supplied as white with bright pink specks, capsule-shaped, scored tablets, debossed “3591” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 100, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg are supplied as white with orange specks, capsule-shaped, scored tablets, debossed “3604” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 10, 30, 60, 90, 100, 120, 180, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/500 mg are supplied as white, capsule-shaped, scored tablets, debossed “3592” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 20, 30, 50, 60, 90, 100, 120, 180, 240, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/325 mg are supplied as light orange, oval-shaped, scored tablets, debossed “3605” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 10, 90, 100, 120, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/500 mg are supplied as white with green specks, capsule-shaped, scored tablets, debossed “3594” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 30, 60, 90, 100, 120, 180, 240, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/650 mg are supplied as white, modified capsule-shaped, scored tablets, debossed “3595” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 100, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/750 mg are supplied as white capsule-shaped, scored tablets, debossed “3596” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 60, 90, 100, 120, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/325 mg are supplied as light yellow, modified capsule-shaped, scored tablets, debossed “3601” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 60, 90, 100, 120, 150, 180, 240, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/500 mg are supplied as pink, capsule-shaped tablets, debossed “3600” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 30, 60, 90, 100, 120, 150, 180, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/650 mg are supplied as light blue, capsule-shaped, scored tablets, debossed “3597” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 30, 60, 90, 100, 120, 180, 500 and 1000. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/660 mg are supplied as white oval-shaped, scored tablets, debossed “3598” on one side and debossed “V” on the reverse side. The tablets are supplied in containers of 100, 500 and 1000. Storage: Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP/NF with a child-resistant closure. A Schedule CIII Narcotic.

GERIATRIC USE

Geriatric Use: Clinical studies of hydrocodone bitartrate and acetaminophen 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. Hydrocodone and the major metabolites of acetaminophen are known to be substantially excreted by the kidney. Thus the risk of toxic reactions may be greater in patients with impaired renal function due to the accumulation of the parent compound and/or metabolites in the plasma. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Hydrocodone may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of hydrocodone bitartrate and acetaminophen tablets and observed closely.

INDICATIONS AND USAGE

Hydrocodone bitartrate and acetaminophen tablets are indicated for the relief of moderate to moderately severe pain.

PEDIATRIC USE

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydrocodone bitartrate and acetaminophen tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Babies born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

NUSRING MOTHERS

Nursing Mothers: Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on nursing infants is not known. It is not known whether hydrocodone 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 hydrocodone and acetaminophen, 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

INFORMATION FOR PATIENTS

Information for Patients/Caregivers: Do not take Hydrocodone Bitartrate and Acetaminophen Tablets, USP if you are allergic to any of its ingredients. If you develop signs of allergy such as a rash or difficulty breathing stop taking Hydrocodone Bitartrate and Acetaminophen Tablets, USP and contact your healthcare provider immediately. Do not take more than 4000 milligrams of acetaminophen per day. Call your doctor if you took more than the recommended dose. Hydrocodone, like all narcotics, may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly. Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided. Hydrocodone may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to hydrocodone can develop with continued use and that the incidence of untoward effects is dose related. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 2.5 mg/500 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dosage should not exceed 8 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/325 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dosage should not exceed 12 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 5 mg/500 mg The usual adult dosage is one or two tablets every four to six hours as needed for pain. The total daily dosage should not exceed 8 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/325 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/500 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/650 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 7.5 mg/750 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 5 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/325 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/500 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/650 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets. Hydrocodone Bitartrate and Acetaminophen Tablets, USP 10 mg/660 mg The usual adult dosage is one tablet every four to six hours as needed for pain. The total daily dosage should not exceed 6 tablets.

LORazepam 0.5 MG Oral Tablet

Generic Name: LORAZEPAM

Brand Name: Lorazepam

Substance Name(s):
LORAZEPAM

WARNINGS

Lorazepam is not recommended for use in patients with a primary depressive disorder of psychosis. As with all patients on CNS-acting drugs, patients receiving lorazepam should be warned not to operate dangerous machinery or motor vehicles and that their tolerance for alcohol and other CNS depressants will be diminished.

OVERDOSAGE

In the management of overdosage with any drug, it should be borne in mind that multiple agents may have been taken. Manifestations of lorazepam overdosage include somnolence, confusion, and coma. Induced vomiting and/or gastric lavage should be undertaken, followed by general supportive care, monitoring of vital signs, and close observation of the patient. Hypotension, though unlikely, usually may be controlled with norepinephrine bitartrate injection. The usefulness of dialysis has not been determined. Flumazenil, a specific benzodiazepine receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be used in situations when an overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as a substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for re-sedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.

DESCRIPTION

Lorazepam, an antianxiety agent, has the chemical formula, (±)-7-Chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one: It is a nearly white powder almost insoluble in water. Each lorazepam tablet, to be taken orally, contains 0.5 mg, 1 mg or 2 mg of lorazepam. This product contains the following inactive ingredients: lactose, magnesium stearate, microcrystalline cellulose and polacrilin potassium. image of chemical structure

HOW SUPPLIED

Lorazepam tablets are available in the following dosage strengths: 0.5 mg: white, scored, round flat faced beveled edge, debossed with 240 over 0.5 on one side and WATSON on the other side, supplied in: Bottles of 10 NDC 54868-2145-0 Bottles of 20 NDC 54868-2145-2 Bottles of 30 NDC 54868-2145-3 Bottles of 50 NDC 54868-2145-5 Bottles of 60 NDC 54868-2145-6 Bottles of 90 NDC 54868-2145-9 Bottles of 100 NDC 54868-2145-4 1 mg: white, scored, round flat faced beveled edge, debossed with 241 over 1 on one side and WATSON on the other side, supplied in: Bottles of 03 NDC 54868-1338-6 Bottles of 10 NDC 54868-1338-7 Bottles of 15 NDC 54868-1338-0 Bottles of 20 NDC 54868-1338-1 Bottles of 30 NDC 54868-1338-3 Bottles of 60 NDC 54868-1338-4 Bottles of 90 NDC 54868-1338-8 Bottles of 100 NDC 54868-1338-2 Bottles of 120 NDC 54868-1338-9 2 mg: white, scored, round flat faced beveled edge, debossed with 242 over 2 on one side and WATSON on the other side, supplied in: Bottles of 30 NDC 54868-0061-3 Bottles of 60 NDC 54868-0061-5 Bottles of 90 NDC 54868-0061-4 Bottles of 100 NDC 54868-0061-2 Bottles of 120 NDC 54868-0061-6 Store at controlled room temperature 15°-30°C (59°-86°F). [See USP.] Dispense in a tight, light-resistant container as defined in the USP. Watson Laboratories, Inc. Corona, CA 92880 USA 30223-3 Rev: February 2004 Repackaging and Relabeling by: Physicians Total Care, Inc. Tulsa, OK 74146

INDICATIONS AND USAGE

Lorazepam is indicated for the management of anxiety disorders or for the short-term relief of the symptoms of anxiety or anxiety associated with depressive symptoms. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The effectiveness of lorazepam in long-term use, that is, more than 4 months, has not been assessed by systematic clinical studies. The physician should periodically reassess the usefulness of the drug for the individual patient.

DOSAGE AND ADMINISTRATION

Lorazepam is administered orally. For optimal results, dose, frequency of administration, and duration of therapy should be individualized according to patient response. To facilitate this, 0.5 mg, 1 mg, and 2 mg tablets are available. The usual range is 2 to 6 mg/day given in divided doses, the largest dose being taken before bedtime, but the daily dosage may vary from 1 to 10 mg/day. For anxiety, most patients require an initial dose of 2 to 3 mg/day given b.i.d. or t.i.d. For insomnia due to anxiety or transient situational stress, a single daily dose of 2 to 4 mg may be given, usually at bedtime. For elderly or debilitated patients, an initial dosage of 1 to 2 mg/day in divided doses is recommended, to be adjusted as needed and tolerated. The dosage of lorazepam should be increased gradually when needed to help avoid adverse effects. When higher dosage is indicated, the evening dose should be increased before the daytime doses.

SUMAtriptan succinate 100 MG Oral Tablet

Generic Name: SUMATRIPTAN SUCCINATE

Brand Name: IMITREX

Substance Name(s):
SUMATRIPTAN SUCCINATE

WARNINGS

IMITREX Tablets should only be used where a clear diagnosis of migraine headache has been established. Risk of Myocardial Ischemia and/or Infarction and Other Adverse Cardiac Events Sumatriptan should not be given to patients with documented ischemic or vasospastic coronary artery disease (CAD) (see CONTRAINDICATIONS). It is strongly recommended that sumatriptan not be given to patients in whom unrecognized CAD is predicted by the presence of risk factors (e.g., hypertension, hypercholesterolemia, smoker, obesity, diabetes, strong family history of CAD, female with surgical or physiological menopause, male over 40 years of age) unless a cardiovascular evaluation provides satisfactory clinical evidence that the patient is reasonably free of coronary artery and ischemic myocardial disease or other significant underlying cardiovascular disease. The sensitivity of cardiac diagnostic procedures to detect cardiovascular disease or predisposition to coronary artery vasospasm is modest, at best. If, during the cardiovascular evaluation, the patient’s medical history or electrocardiographic investigations reveal findings indicative of, or consistent with, coronary artery vasospasm or myocardial ischemia, sumatriptan should not be administered (see CONTRAINDICATIONS). For patients with risk factors predictive of CAD, who are determined to have a satisfactory cardiovascular evaluation, it is strongly recommended that administration of the first dose of sumatriptan tablets take place in the setting of a physician’s office or similar medically staffed and equipped facility unless the patient has previously received sumatriptan . Because cardiac ischemia can occur in the absence of clinical symptoms, consideration should be given to obtaining on the first occasion of use an electrocardiogram (ECG) during the interval immediately following IMITREX Tablets in these patients with risk factors. It is recommended that patients who are intermittent long-term users of sumatriptan and who have or acquire risk factors predictive of CAD, as described above, undergo periodic interval cardiovascular evaluation as they continue to use sumatriptan . The systematic approach described above is intended to reduce the likelihood that patients with unrecognized cardiovascular disease will be inadvertently exposed to sumatriptan . Drug-Associated Cardiac Events and Fatalities Serious adverse cardiac events, including acute myocardial infarction, life-threatening disturbances of cardiac rhythm, and death have been reported within a few hours following the administration of IMITREX® (sumatriptan succinate) Injection or IMITREX Tablets. Considering the extent of use of sumatriptan in patients with migraine, the incidence of these events is extremely low. The fact that sumatriptan can cause coronary vasospasm, that some of these events have occurred in patients with no prior cardiac disease history and with documented absence of CAD, and the close proximity of the events to sumatriptan use support the conclusion that some of these cases were caused by the drug. In many cases, however, where there has been known underlying coronary artery disease, the relationship is uncertain. Premarketing Experience With Sumatriptan : Of 6,348 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of oral sumatriptan, 2 experienced clinical adverse events shortly after receiving oral sumatriptan that may have reflected coronary vasospasm. Neither of these adverse events was associated with a serious clinical outcome. Among the more than 1,900 patients with migraine who participated in premarketing controlled clinical trials of subcutaneous sumatriptan, there were 8 patients who sustained clinical events during or shortly after receiving sumatriptan that may have reflected coronary artery vasospasm. Six of these 8 patients had ECG changes consistent with transient ischemia, but without accompanying clinical symptoms or signs. Of these 8 patients, 4 had either findings suggestive of CAD or risk factors predictive of CAD prior to study enrollment. Among approximately 4,000 patients with migraine who participated in premarketing controlled and uncontrolled clinical trials of sumatriptan nasal spray, 1 patient experienced an asymptomatic subendocardial infarction possibly subsequent to a coronary vasospastic event. Postmarketing Experience With Sumatriptan : Serious cardiovascular events, some resulting in death, have been reported in association with the use of IMITREX Injection or IMITREX Tablets. The uncontrolled nature of postmarketing surveillance, however, makes it impossible to determine definitively the proportion of the reported cases that were actually caused by sumatriptan or to reliably assess causation in individual cases. On clinical grounds, the longer the latency between the administration of IMITREX and the onset of the clinical event, the less likely the association is to be causative. Accordingly, interest has focused on events beginning within 1 hour of the administration of IMITREX. Cardiac events that have been observed to have onset within 1 hour of sumatriptan administration include: coronary artery vasospasm, transient ischemia, myocardial infarction, ventricular tachycardia and ventricular fibrillation, cardiac arrest, and death. Some of these events occurred in patients who had no findings of CAD and appear to represent consequences of coronary artery vasospasm. However, among domestic reports of serious cardiac events within 1 hour of sumatriptan administration, almost all of the patients had risk factors predictive of CAD and the presence of significant underlying CAD was established in most cases (see CONTRAINDICATIONS). Drug-Associated Cerebrovascular Events and Fatalities Cerebral hemorrhage, subarachnoid hemorrhage, stroke, and other cerebrovascular events have been reported in patients treated with oral or subcutaneous sumatriptan, and some have resulted in fatalities. The relationship of sumatriptan to these events is uncertain. In a number of cases, it appears possible that the cerebrovascular events were primary, sumatriptan having been administered in the incorrect belief that the symptoms experienced were a consequence of migraine when they were not. As with other acute migraine therapies, before treating headaches in patients not previously diagnosed as migraineurs, and in migraineurs who present with atypical symptoms, care should be taken to exclude other potentially serious neurological conditions. It should also be noted that patients with migraine may be at increased risk of certain cerebrovascular events (e.g., cerebrovascular accident, transient ischemic attack). Other Vasospasm-Related Events Sumatriptan may cause vasospastic reactions other than coronary artery vasospasm. Both peripheral vascular ischemia and colonic ischemia with abdominal pain and bloody diarrhea have been reported. Very rare reports of transient and permanent blindness and significant partial vision loss have been reported with the use of sumatriptan. Visual disorders may also be part of a migraine attack. Serotonin Syndrome Serotonin syndrome may occur with triptans, including IMITREX, particularly during combined use with selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms can occur within minutes to hours of receiving a new or a greater dose of a serotonergic medication. Treatment with IMITREX should be discontinued if serotonin syndrome is suspected. Increase in Blood Pressure Significant elevation in blood pressure, including hypertensive crisis, has been reported on rare occasions in patients with and without a history of hypertension. Sumatriptan is contraindicated in patients with uncontrolled hypertension (see CONTRAINDICATIONS). Sumatriptan should be administered with caution to patients with controlled hypertension as transient increases in blood pressure and peripheral vascular resistance have been observed in a small proportion of patients. Concomitant Drug Use In patients taking MAO-A inhibitors, sumatriptan plasma levels attained after treatment with recommended doses are 7-fold higher following oral administration than those obtained under other conditions. Accordingly, the coadministration of IMITREX Tablets and an MAO-A inhibitor is contraindicated (see CLINICAL PHARMACOLOGY and CONTRAINDICATIONS). Hypersensitivity Hypersensitivity (anaphylaxis/anaphylactoid) reactions have occurred on rare occasions in patients receiving sumatriptan. Such reactions can be life threatening or fatal. In general, hypersensitivity reactions to drugs are more likely to occur in individuals with a history of sensitivity to multiple allergens (see CONTRAINDICATIONS).

DRUG INTERACTIONS

Drug Interactions Monoamine Oxidase Inhibitors: Treatment with MAO-A inhibitors generally leads to an increase of sumatriptan plasma levels (see CONTRAINDICATIONS and PRECAUTIONS). Due to gut and hepatic metabolic first-pass effects, the increase of systemic exposure after coadministration of an MAO-A inhibitor with oral sumatriptan is greater than after coadministration of the monoamine oxidase inhibitors (MAOI) with subcutaneous sumatriptan. In a study of 14 healthy females, pretreatment with an MAO-A inhibitor decreased the clearance of subcutaneous sumatriptan. Under the conditions of this experiment, the result was a 2-fold increase in the area under the sumatriptan plasma concentration × time curve (AUC), corresponding to a 40% increase in elimination half-life. This interaction was not evident with an MAO-B inhibitor. A small study evaluating the effect of pretreatment with an MAO-A inhibitor on the bioavailability from a 25-mg oral sumatriptan tablet resulted in an approximately 7-fold increase in systemic exposure. Alcohol: Alcohol consumed 30 minutes prior to sumatriptan ingestion had no effect on the pharmacokinetics of sumatriptan.

OVERDOSAGE

Patients (N = 670) have received single oral doses of 140 to 300 mg without significant adverse effects. Volunteers (N = 174) have received single oral doses of 140 to 400 mg without serious adverse events. Overdose in animals has been fatal and has been heralded by convulsions, tremor, paralysis, inactivity, ptosis, erythema of the extremities, abnormal respiration, cyanosis, ataxia, mydriasis, salivation, and lacrimation. The elimination half-life of sumatriptan is approximately 2.5 hours (see CLINICAL PHARMACOLOGY), and therefore monitoring of patients after overdose with IMITREX Tablets should continue for at least 12 hours or while symptoms or signs persist. It is unknown what effect hemodialysis or peritoneal dialysis has on the serum concentrations of sumatriptan.

DESCRIPTION

IMITREX Tablets contain sumatriptan (as the succinate), a selective 5-hydroxytryptamine1 receptor subtype agonist. Sumatriptan succinate is chemically designated as 3-[2-(dimethylamino)ethyl]-N-methyl-indole-5-methanesulfonamide succinate (1:1), and it has the following structure: The empirical formula is C14H21N3O2S•C4H6O4, representing a molecular weight of 413.5. Sumatriptan succinate is a white to off-white powder that is readily soluble in water and in saline. Each IMITREX Tablet for oral administration contains 35, 70, or 140 mg of sumatriptan succinate equivalent to 25, 50, or 100 mg of sumatriptan, respectively. Each tablet also contains the inactive ingredients croscarmellose sodium, dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, and sodium bicarbonate. Each 100-mg tablet also contains hypromellose, iron oxide, titanium dioxide, and triacetin. Imitrex Tablets Chemical Structure

CLINICAL STUDIES

The efficacy of IMITREX Tablets in the acute treatment of migraine headaches was demonstrated in 3, randomized, double-blind, placebo-controlled studies. Patients enrolled in these 3 studies were predominately female (87%) and Caucasian (97%), with a mean age of 40 years (range, 18 to 65 years). Patients were instructed to treat a moderate to severe headache. Headache response, defined as a reduction in headache severity from moderate or severe pain to mild or no pain, was assessed up to 4 hours after dosing. Associated symptoms such as nausea, photophobia, and phonophobia were also assessed. Maintenance of response was assessed for up to 24 hours postdose. A second dose of IMITREX Tablets or other medication was allowed 4 to 24 hours after the initial treatment for recurrent headache. Acetaminophen was offered to patients in Studies 2 and 3 beginning at 2 hours after initial treatment if the migraine pain had not improved or worsened. Additional medications were allowed 4 to 24 hours after the initial treatment for recurrent headache or as rescue in all 3 studies. The frequency and time to use of these additional treatments were also determined. In all studies, doses of 25, 50, and 100 mg were compared to placebo in the treatment of migraine attacks. In 1 study, doses of 25, 50, and 100 mg were also compared to each other. In all 3 trials, the percentage of patients achieving headache response 2 and 4 hours after treatment was significantly greater among patients receiving IMITREX Tablets at all doses compared to those who received placebo. In 1 of the 3 studies, there was a statistically significant greater percentage of patients with headache response at 2 and 4 hours in the 50- or 100-mg group when compared to the 25-mg dose groups. There were no statistically significant differences between the 50- and 100-mg dose groups in any study. The results from the 3 controlled clinical trials are summarized in Table 1. Comparisons of drug performance based upon results obtained in different clinical trials are never reliable. Because studies are conducted at different times, with different samples of patients, by different investigators, employing different criteria and/or different interpretations of the same criteria, under different conditions (dose, dosing regimen, etc.), quantitative estimates of treatment response and the timing of response may be expected to vary considerably from study to study. Table 1. Percentage of Patients With Headache Response (No or Mild Pain) 2 and 4 Hours Following Treatment Placebo 2 hr 4 hr IMITREX Tablets 25 mg 2 hr 4 hr IMITREX Tablets 50 mg 2 hr 4 hr IMITREX Tablets 100 mg 2 hr 4 hr Study 1 27% 38% 52%a 67%a 61%ab 78%ab 62%ab 79%ab (N = 94) (N = 298) (N = 296) (N = 296) Study 2 26% 38% 52%a 70%a 50%a 68%a 56%a 71%a (N = 65) (N = 66) (N = 62) (N = 66) Study 3 17% 19% 52%a 65%a 54%a 72%a 57%a 78%a (N = 47) (N = 48) (N = 46) (N = 46) a P<0.05 in comparison with placebo. b P<0.05 in comparison with 25 mg. The estimated probability of achieving an initial headache response over the 4 hours following treatment is depicted in Figure 1. Figure 1. Estimated Probability of Achieving Initial Headache Response Within 240 Minutesa aThe figure shows the probability over time of obtaining headache response (no or mild pain) following treatment with sumatriptan. The averages displayed are based on pooled data from the 3 clinical controlled trials providing evidence of efficacy. Kaplan-Meier plot with patients not achieving response and/or taking rescue within 240 minutes censored to 240 minutes. For patients with migraine-associated nausea, photophobia, and/or phonophobia at baseline, there was a lower incidence of these symptoms at 2 hours (Study 1) and at 4 hours (Studies 1, 2, and 3) following administration of IMITREX Tablets compared to placebo. As early as 2 hours in Studies 2 and 3 or 4 hours in Study 1, through 24 hours following the initial dose of study treatment, patients were allowed to use additional treatment for pain relief in the form of a second dose of study treatment or other medication. The estimated probability of patients taking a second dose or other medication for migraine over the 24 hours following the initial dose of study treatment is summarized in Figure 2. Figure 2. The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatmenta aKaplan-Meier plot based on data obtained in the 3 clinical controlled trials providing evidence of efficacy with patients not using additional treatments censored to 24 hours. Plot also includes patients who had no response to the initial dose. No remedication was allowed within 2 hours postdose. There is evidence that doses above 50 mg do not provide a greater effect than 50 mg. There was no evidence to suggest that treatment with sumatriptan was associated with an increase in the severity of recurrent headaches. The efficacy of IMITREX Tablets was unaffected by presence of aura; duration of headache prior to treatment; gender, age, or weight of the patient; relationship to menses; or concomitant use of common migraine prophylactic drugs (e.g., beta-blockers, calcium channel blockers, tricyclic antidepressants). There were insufficient data to assess the impact of race on efficacy. Figure 1. Estimated Probability of Achieving Initial Headache Response Within 240 Minutes* Figure 2. The Estimated Probability of Patients Taking a Second Dose or Other Medication for Migraine Over the 24 Hours Following the Initial Dose of Study Treatment*

HOW SUPPLIED

IMITREX Tablets, 100 mg of sumatriptan (base) as the succinate. IMITREX Tablets, 100 mg, are pink, triangular-shaped, film-coated tablets debossed with “IMITREX 100” on one side and a chevron shape (^) on the other in blister packs of 9 tablets (NDC 54868-5118-0). Store between 36° and 86°F (2° and 30°C).

GERIATRIC USE

Geriatric Use The use of sumatriptan in elderly patients is not recommended because elderly patients are more likely to have decreased hepatic function, they are at higher risk for CAD, and blood pressure increases may be more pronounced in the elderly (see WARNINGS).

MECHANISM OF ACTION

Mechanism of Action Sumatriptan is an agonist for a vascular 5‑hydroxytryptamine1 receptor subtype (probably a member of the 5‑HT1D family) having only a weak affinity for 5‑HT1A, 5‑HT5A, and 5‑HT7 receptors and no significant affinity (as measured using standard radioligand binding assays) or pharmacological activity at 5‑HT2, 5‑HT3, or 5‑HT4 receptor subtypes or at alpha1‑, alpha2‑, or beta‑adrenergic; dopamine1; dopamine2; muscarinic; or benzodiazepine receptors. The vascular 5‑HT1 receptor subtype that sumatriptan activates is present on cranial arteries in both dog and primate, on the human basilar artery, and in the vasculature of human dura mater and mediates vasoconstriction. This action in humans correlates with the relief of migraine headache. In addition to causing vasoconstriction, experimental data from animal studies show that sumatriptan also activates 5‑HT1 receptors on peripheral terminals of the trigeminal nerve innervating cranial blood vessels. Such an action may also contribute to the antimigrainous effect of sumatriptan in humans. In the anesthetized dog, sumatriptan selectively reduces the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. In the cat, sumatriptan selectively constricts the carotid arteriovenous anastomoses while having little effect on blood flow or resistance in cerebral or extracerebral tissues.

INDICATIONS AND USAGE

IMITREX Tablets are indicated for the acute treatment of migraine attacks with or without aura in adults. IMITREX Tablets are not intended for the prophylactic therapy of migraine or for use in the management of hemiplegic or basilar migraine (see CONTRAINDICATIONS). Safety and effectiveness of IMITREX Tablets have not been established for cluster headache, which is present in an older, predominantly male population.

PEDIATRIC USE

Pediatric Use Safety and effectiveness of IMITREX Tablets in pediatric patients under 18 years of age have not been established; therefore, IMITREX Tablets are not recommended for use in patients under 18 years of age. Two controlled clinical trials evaluating sumatriptan nasal spray (5 to 20 mg) in pediatric patients aged 12 to 17 years enrolled a total of 1,248 adolescent migraineurs who treated a single attack. The studies did not establish the efficacy of sumatriptan nasal spray compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. Five controlled clinical trials (2 single attack studies, 3 multiple attack studies) evaluating oral sumatriptan (25 to 100 mg) in pediatric patients aged 12 to 17 years enrolled a total of 701 adolescent migraineurs. These studies did not establish the efficacy of oral sumatriptan compared to placebo in the treatment of migraine in adolescents. Adverse events observed in these clinical trials were similar in nature to those reported in clinical trials in adults. The frequency of all adverse events in these patients appeared to be both dose- and age-dependent, with younger patients reporting events more commonly than older adolescents. Postmarketing experience documents that serious adverse events have occurred in the pediatric population after use of subcutaneous, oral, and/or intranasal sumatriptan. These reports include events similar in nature to those reported rarely in adults, including stroke, visual loss, and death. A myocardial infarction has been reported in a 14-year-old male following the use of oral sumatriptan; clinical signs occurred within 1 day of drug administration. Since clinical data to determine the frequency of serious adverse events in pediatric patients who might receive injectable, oral, or intranasal sumatriptan are not presently available, the use of sumatriptan in patients aged younger than 18 years is not recommended.

PREGNANCY

Pregnancy Pregnancy Category C. In reproductive toxicity studies in rats and rabbits, oral treatment with sumatriptan was associated with embryolethality, fetal abnormalities, and pup mortality. When administered by the intravenous route to rabbits, sumatriptan has been shown to be embryolethal. There are no adequate and well-controlled studies in pregnant women. Therefore, IMITREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In assessing this information, the following findings should be considered. Embryolethality : When given orally or intravenously to pregnant rabbits daily throughout the period of organogenesis, sumatriptan caused embryolethality at doses at or close to those producing maternal toxicity. In the oral studies this dose was 100 mg/kg/day, and in the intravenous studies this dose was 2.0 mg/kg/day. The mechanism of the embryolethality is not known. The highest no-effect dose for embryolethality by the oral route was 50 mg/kg/day, which is approximately 9 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. By the intravenous route, the highest no-effect dose was 0.75 mg/kg/day, or approximately one tenth of the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. The intravenous administration of sumatriptan to pregnant rats throughout organogenesis at 12.5 mg/kg/day, the maximum dose tested, did not cause embryolethality. This dose is equivalent to the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Additionally, in a study in rats given subcutaneous sumatriptan daily prior to and throughout pregnancy at 60 mg/kg/day, the maximum dose tested, there was no evidence of increased embryo/fetal lethality. This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. Teratogenicity : Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in an increased incidence of blood vessel abnormalities (cervicothoracic and umbilical) at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose was approximately 60 mg/kg/day, which is approximately 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Oral treatment of pregnant rabbits with sumatriptan during the period of organogenesis resulted in an increased incidence of cervicothoracic vascular and skeletal abnormalities. The highest no-effect dose for these effects was 15 mg/kg/day, or approximately 3 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. A study in which rats were dosed daily with oral sumatriptan prior to and throughout gestation demonstrated embryo/fetal toxicity (decreased body weight, decreased ossification, increased incidence of rib variations) and an increased incidence of a syndrome of malformations (short tail/short body and vertebral disorganization) at 500 mg/kg/day. The highest no-effect dose was 50 mg/kg/day, or approximately 5 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. In a study in rats dosed daily with subcutaneous sumatriptan prior to and throughout pregnancy, at a dose of 60 mg/kg/day, the maximum dose tested, there was no evidence of teratogenicity. This dose is equivalent to approximately 6 times the maximum recommended single human oral dose of 100 mg on a mg/m2 basis. Pup Deaths: Oral treatment of pregnant rats with sumatriptan during the period of organogenesis resulted in a decrease in pup survival between birth and postnatal day 4 at doses of approximately 250 mg/kg/day or higher. The highest no-effect dose for this effect was approximately 60 mg/kg/day, or 6 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. Oral treatment of pregnant rats with sumatriptan from gestational day 17 through postnatal day 21 demonstrated a decrease in pup survival measured at postnatal days 2, 4, and 20 at the dose of 1,000 mg/kg/day. The highest no-effect dose for this finding was 100 mg/kg/day, approximately 10 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis. In a similar study in rats by the subcutaneous route there was no increase in pup death at 81 mg/kg/day, the highest dose tested, which is equivalent to 8 times the maximum single recommended human oral dose of 100 mg on a mg/m2 basis.

NUSRING MOTHERS

Nursing Mothers Sumatriptan is excreted in human breast milk following subcutaneous administration. Infant exposure to sumatriptan can be minimized by avoiding breastfeeding for 12 hours after treatment with IMITREX Tablets.

INFORMATION FOR PATIENTS

Information for Patients See PATIENT INFORMATION at the end of this labeling for the text of the separate leaflet provided for patients. Patients should be cautioned about the risk of serotonin syndrome with the use of sumatriptan or other triptans, especially during combined use with SSRIs or SNRIs.

DOSAGE AND ADMINISTRATION

In controlled clinical trials, single doses of 25, 50, or 100 mg of IMITREX Tablets were effective for the acute treatment of migraine in adults. There is evidence that doses of 50 and 100 mg may provide a greater effect than 25 mg (see CLINICAL TRIALS). There is also evidence that doses of 100 mg do not provide a greater effect than 50 mg. Individuals may vary in response to doses of IMITREX Tablets. The choice of dose should therefore be made on an individual basis, weighing the possible benefit of a higher dose with the potential for a greater risk of adverse events. If the headache returns or the patient has a partial response to the initial dose, the dose may be repeated after 2 hours, not to exceed a total daily dose of 200 mg. If a headache returns following an initial treatment with IMITREX Injection, additional single IMITREX Tablets (up to 100 mg/day) may be given with an interval of at least 2 hours between tablet doses. The safety of treating an average of more than 4 headaches in a 30-day period has not been established. Because of the potential of MAO-A inhibitors to cause unpredictable elevations in the bioavailability of oral sumatriptan, their combined use is contraindicated (see CONTRAINDICATIONS). Hepatic disease/functional impairment may also cause unpredictable elevations in the bioavailability of orally administered sumatriptan. Consequently, if treatment is deemed advisable in the presence of liver disease, the maximum single dose should in general not exceed 50 mg (see CLINICAL PHARMACOLOGY for the basis of this recommendation).

ethyl alcohol 70 % Topical Solution

Generic Name: ETHYL ALCOHL

Brand Name: Hand Sanitizer

Substance Name(s):
ALCOHOL

WARNINGS

Warnings For external use only-hands

INDICATIONS AND USAGE

Uses to decrease bacteria on the skin that could cause disease recommended for repeated use

INACTIVE INGREDIENTS

Inactive ingredients water, aloe barbadensis leaf juice, glyceryl caprylate/caprate, isopropyl myristate, tocopheryl acetate, acrylates/c10-30 alkyl acrylate crosspolymer, fragrance benzophenone-4, blue 1, yellow 5

PURPOSE

Purpose Antiseptic

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children If swallowed, get medical help or contact a Poison Control Center right away

DOSAGE AND ADMINISTRATION

Directions wet hands thoroughly with product and allow to dry without wiping for children under 6, use only under adult supervision not recommended for infants

STOP USE

Stop use and ask a doctor if skin irritation develops

ACTIVE INGREDIENTS

Active ingredient Ethyl alchol 70%

Paroxetine Hydrochloride 20 MG Oral Tablet

Generic Name: PAROXETINE

Brand Name: Paroxetine

Substance Name(s):
PAROXETINE HYDROCHLORIDE HEMIHYDRATE

WARNINGS

Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo 9,000 birth defect cases and >4,000 controls, found that maternal use of paroxetine during the first trimester of pregnancy was associated with a 2- to 3-fold increased risk of right ventricular outflow tract obstructions. In one study the odds ratio was 2.5 (95% confidence interval, 1 to 6, 7 exposed infants) and in the other study the odds ratio was 3.3 (95% confidence interval, 1.3 to 8.8, 6 exposed infants). Other studies have found varying results as to whether there was an increased risk of overall, cardiovascular, or specific congenital malformations. A meta-analysis of epidemiological data over a 16-year period (1992 to 2008) on first trimester paroxetine use in pregnancy and congenital malformations included the above-noted studies in addition to others (n = 17 studies that included overall malformations and n = 14 studies that included cardiovascular malformations; n = 20 distinct studies). While subject to limitations, this meta-analysis suggested an increased occurrence of cardiovascular malformations (prevalence odds ratio [POR] 1.5; 95% confidence interval 1.2 to 1.9) and overall malformations (POR 1.2; 95% confidence interval 1.1 to 1.4) with paroxetine use during the first trimester. It was not possible in this meta-analysis to determine the extent to which the observed prevalence of cardiovascular malformations might have contributed to that of overall malformations, nor was it possible to determine whether any specific types of cardiovascular malformations might have contributed to the observed prevalence of all cardiovascular malformations. If a patient becomes pregnant while taking paroxetine, she should be advised of the potential harm to the fetus. Unless the benefits of paroxetine to the mother justify continuing treatment, consideration should be given to either discontinuing paroxetine therapy or switching to another antidepressant (see PRECAUTIONS: Discontinuation of Treatment With Paroxetine Tablets). For women who intend to become pregnant or are in their first trimester of pregnancy, paroxetine should only be initiated after consideration of the other available treatment options. Animal Findings Reproduction studies were performed at doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during organogenesis. These doses are approximately 8 (rat) and 2 (rabbit) times the maximum recommended human dose (MRHD) on an mg/m2 basis. These studies have revealed no evidence of teratogenic effects. However, in rats, there was an increase in pup deaths during the first 4 days of lactation when dosing occurred during the last trimester of gestation and continued throughout lactation. This effect occurred at a dose of 1 mg/kg/day or approximately one-sixth of the MRHD on an mg/m2 basis. The no-effect dose for rat pup mortality was not determined. The cause of these deaths is not known. Nonteratogenic Effects Neonates exposed to paroxetine and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see : Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions ). Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk. There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs. When treating a pregnant woman with paroxetine during the third trimester, the physician should carefully consider both the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION ). Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

DRUG INTERACTIONS

Drug Interactions Tryptophan As with other serotonin reuptake inhibitors, an interaction between paroxetine and tryptophan may occur when they are coadministered. Adverse experiences, consisting primarily of headache, nausea, sweating, and dizziness, have been reported when tryptophan was administered to patients taking paroxetine. Consequently, concomitant use of paroxetine with tryptophan is not recommended (see WARNINGS: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions). Monoamine Oxidase Inhibitors See CONTRAINDICATIONS and WARNINGS . Pimozide In a controlled study of healthy volunteers, after paroxetine was titrated to 60 mg daily, co-administration of a single dose of 2 mg pimozide was associated with mean increases in pimozide AUC of 151% and Cmax of 62%, compared to pimozide administered alone. The increase in pimozide AUC and Cmax is due to the CYP2D6 inhibitory properties of paroxetine.Due to the narrow therapeutic index of pimozide and its known ability to prolong the QT interval, concomitant use of pimozide and paroxetine is contraindicated (see CONTRAINDICATIONS ). Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including paroxetine hydrochloride, and the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St. John’s Wort (see WARNINGS: Serotonin Syndrome of Neuroleptic Malignant Syndrome (NMS)-like Reactions) . The concomitant use of paroxetine with MAOIs (including linezolid) is contraindicated (see CONTRAINDICATIONS ). The concomitant use of paroxetine with other SSRIs, SNRIs or tryptophan is not recommended (see PRECAUTIONS: Drug Interactions: Tryptophan ). Thioridazine See CONTRAINDICATIONS and WARNINGS . Warfarin Preliminary data suggest that there may be a pharmacodynamic interaction (that causes an increased bleeding diathesis in the face of unaltered prothrombin time) between paroxetine and warfarin. Since there is little clinical experience, the concomitant administration of paroxetine and warfarin should be undertaken with caution (see PRECAUTIONS: Drugs That Interfere With Hemostasis ). Triptans There have been rare postmarketing reports of serotonin syndrome with the use of an SSRI and a triptan. If concomitant use of paroxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases (see WARNINGS: Seratonin Syndrome or Neuroleptic Malignant Syndrome (NMS) – like reactions ). Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug-metabolizing enzymes. Cimetidine Cimetidine inhibits many cytochrome P450 (oxidative) enzymes. In a study where paroxetine (30 mg once daily) was dosed orally for 4 weeks, steady-state plasma concentrations of paroxetine were increased by approximately 50% during coadministration with oral cimetidine (300 mg three times daily) for the final week. Therefore, when these drugs are administered concurrently, dosage adjustment of paroxetine after the 20 mg starting dose should be guided by clinical effect. The effect of paroxetine on cimetidine’s pharmacokinetics was not studied. Phenobarbital Phenobarbital induces many cytochrome P450 (oxidative) enzymes. When a single oral 30 mg dose of paroxetine was administered at phenobarbital steady state (100 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 25% and 38%, respectively) compared to paroxetine administered alone. The effect of paroxetine on phenobarbital pharmacokinetics was not studied. Since paroxetine exhibits nonlinear pharmacokinetics, the results of this study may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustment of paroxetine is considered necessary when coadministered with phenobarbital; any subsequent adjustment should be guided by clinical effect. Phenytoin When a single oral 30 mg dose of paroxetine was administered at phenytoin steady state (300 mg once daily for 14 days), paroxetine AUC and T½ were reduced (by an average of 50% and 35%, respectively) compared to paroxetine administered alone. In a separate study, when a single oral 300 mg dose of phenytoin was administered at paroxetine steady state (30 mg once daily for 14 days), phenytoin AUC was slightly reduced (12% on average) compared to phenytoin administered alone. Since both drugs exhibit nonlinear pharmacokinetics, the above studies may not address the case where the 2 drugs are both being chronically dosed. No initial dosage adjustments are considered necessary when these drugs are coadministered; any subsequent adjustments should be guided by clinical effect (see ADVERSE REACTIONS: Postmarketing Reports ). Drugs Metabolized by CYP2D6 Many drugs, including most drugs effective in the treatment of major depressive disorder (paroxetine, other SSRIs and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most patients (>90%), this CYP2D6 isozyme is saturated early during dosing with paroxetine. In 1 study, daily dosing of paroxetine (20 mg once daily) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T½ by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a CYP2D6 substrate has also been evaluated. In 1 study, daily dosing of paroxetine 20 mg in patients stabilized on risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9-hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine. Concomitant use of paroxetine with other drugs metabolized by cytochrome CYP2D6 has not been formally studied but may require lower doses than usually prescribed for either paroxetine or the other drug. Therefore, coadministration of paroxetine with other drugs that are metabolized by this isozyme, including certain drugs effective in the treatment of major depressive disorder (e.g., nortriptyline, amitriptyline, imipramine, desipramine, and fluoxetine), phenothiazines, risperidone, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. However, due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, paroxetine and thioridazine should not be coadministered (see CONTRAINDICATIONS and WARNINGS ). Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite (endoxifen) and hence reduced efficacy of tamoxifen (see PRECAUTIONS ). At steady state, when the CYP2D6 pathway is essentially saturated, paroxetine clearance is governed by alternative P450 isozymes that, unlike CYP2D6, show no evidence of saturation (see PRECAUTIONS: Tricyclic Antidepressants (TCAs)). Drugs Metabolized by Cytochrome CYP3A4 An in vivo interaction study involving the coadministration under steady-state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine. Based on the assumption that the relationship between paroxetine’s in vitro Ki and its lack of effect on terfenadine’s in vivo clearance predicts its effect on other CYP3A4 substrates, paroxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance. Tricyclic Antidepressants (TCAs) Caution is indicated in the coadministration of tricyclic antidepressants (TCAs) with paroxetine, because paroxetine may inhibit TCA metabolism. Plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced, if a TCA is coadministered with paroxetine (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6 ). Drugs Highly Bound to Plasma Protein Because paroxetine is highly bound to plasma protein, administration of paroxetine to a patient taking another drug that is highly protein bound may cause increased free concentrations of the other drug, potentially resulting in adverse events. Conversely, adverse effects could result from displacement of paroxetine by other highly bound drugs. Drugs That Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs or SNRIs are coadministered with warfarin. Patients receiving warfarin therapy should be carefully monitored when paroxetine is initiated or discontinued. Alcohol Although paroxetine does not increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine. Lithium A multiple-dose study has shown that there is no pharmacokinetic interaction between paroxetine and lithium carbonate. However, due to the potential for serotonin syndrome, caution is advised when paroxetine is coadministered with lithium. Digoxin The steady-state pharmacokinetics of paroxetine was not altered when administered with digoxin at steady state. Mean digoxin AUC at steady state decreased by 15% in the presence of paroxetine. Since there is little clinical experience, the concurrent administration of paroxetine and digoxin should be undertaken with caution. Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated. Procyclidine Daily oral dosing of paroxetine (30 mg once daily) increased steady-state AUC0-24, Cmax, and Cmin values of procyclidine (5 mg oral once daily) by 35%, 37%, and 67%, respectively, compared to procyclidine alone at steady state. If anticholinergic effects are seen, the dose of procyclidine should be reduced. Beta-Blockers In a study where propranolol (80 mg twice daily) was dosed orally for 18 days, the established steady-state plasma concentrations of propranolol were unaltered during coadministration with paroxetine (30 mg once daily) for the final 10 days. The effects of propranolol on paroxetine have not been evaluated (see ADVERSE REACTIONS: Postmarketing Reports ). Theophylline Reports of elevated theophylline levels associated with treatment with paroxetine have been reported. While this interaction has not been formally studied, it is recommended that theophylline levels be monitored when these drugs are concurrently administered. Fosamprenavir/Ritonavir Coadministration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy). Electroconvulsive Therapy (ECT) There are no clinical studies of the combined use of ECT and paroxetine.

OVERDOSAGE

Human Experience Since the introduction of paroxetine in the United States, 342 spontaneous cases of deliberate or accidental overdosage during paroxetine treatment have been reported worldwide (circa 1999). These include overdoses with paroxetine alone and in combination with other substances. Of these, 48 cases were fatal and of the fatalities, 17 appeared to involve paroxetine alone. Eight fatal cases that documented the amount of paroxetine ingested were generally confounded by the ingestion of other drugs or alcohol or the presence of significant comorbid conditions. Of 145 non-fatal cases with known outcome, most recovered without sequelae. The largest known ingestion involved 2,000 mg of paroxetine (33 times the maximum recommended daily dose) in a patient who recovered. Commonly reported adverse events associated with paroxetine overdosage include somnolence, coma, nausea, tremor, tachycardia, confusion, vomiting, and dizziness. Other notable signs and symptoms observed with overdoses involving paroxetine (alone or with other substances) include mydriasis, convulsions (including status epilepticus), ventricular dysrhythmias (including torsade de pointes), hypertension, aggressive reactions, syncope, hypotension, stupor, bradycardia, dystonia, rhabdomyolysis, symptoms of hepatic dysfunction (including hepatic failure, hepatic necrosis, jaundice, hepatitis, and hepatic steatosis), serotonin syndrome, manic reactions, myoclonus, acute renal failure, and urinary retention. Overdosage Management No specific antidotes for paroxetine are known.Treatment should consist of those general measures employed in the management of overdosage with any drugs effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, or exchange transfusion are unlikely to be of benefit. A specific caution involves patients who are taking or have recently taken paroxetine who might ingest excessive quantities of a tricyclic antidepressant. In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation (see PRECAUTIONS: Drugs Metabolized by Cytochrome CYP2D6 ). In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

DESCRIPTION

Paroxetine hydrochloride is an orally administered psychotropic drug. It is the hydrochloride salt of a phenylpiperidine compound identified chemically as (-)-trans-4R-(4′-fluorophenyl)-3S-[(3′,4′-methylenedioxyphenoxy) methyl] piperidine hydrochloride hemihydrate and has the molecular formula of C19H20FNO3•HCl•1/2H2O. The molecular weight is 374.8 (329.4 as free base). The structural formula of paroxetine hydrochloride is: Paroxetine hydrochloride USP is an odorless, off-white powder, having a melting point range of 120° to 138°C and a solubility of 5.4 mg/mL in water. Each film-coated tablet contains paroxetine hydrochloride equivalent to paroxetine as follows: 10 mg–yellow (scored); 20 mg–pink (scored); 30 mg–blue, 40 mg–pink. Inactive ingredients consist of dibasic calcium phosphate dihydrate, lactose monohydrate, sodium starch glycolate, dibasic calcium phosphate anhydrous, magnesium stearate, hypromellose, titanium dioxide, polyethylene glycol and polysorbate 80. In addition to this, 10 mg tablet contains D&C Yellow #10 AluminumLake and FD&C Yellow #6 AluminumLake. 20 mg and 40 mg tablets contain D&C Red #30 AluminumLake. 30 mg tablet contains FD&C Blue #2 AluminumLake. Paroxetine Chemical Structure

HOW SUPPLIED

Paroxetine Tablets USP, 10 mg are yellow colored film-coated modified capsule shaped, biconvex tablets debossed with ‘C 55’ on one side and a deep breakline on the other side. Paroxetine Tablets USP, 20 mgare pink colored film-coated modified capsule shaped, biconvex tablets debossed with ‘56’ on one side and ‘C’ with a deep breakline on the other side. NDC: 35356-892-30 Bottles of 30 NDC: 35356-892-60 Bottles of 60 NDC: 35356-892-90 Bottles of 90 Paroxetine Tablets USP, 30 mgare blue colored film-coated modified capsule shaped, biconvex tablets debossed with ‘F’ on one side and ‘12’ on the other side. Paroxetine Tablets USP, 40 mg are pink colored film-coated modified capsule shaped, biconvex tablets debossed with ‘A 59’ on one side and plain on the other side. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Manufactured by: Aurobindo Pharma LLCDayton, NJ08810 Manufactured for: Aurobindo Pharma USA, Inc.Dayton, NJ08810 Revised: 08/2011

GERIATRIC USE

Geriatric Use SSRIs and SNRIs, including paroxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event (see PRECAUTIONS: Hyponatremia ). In worldwide premarketing clinical trials with paroxetine, 17% of patients treated with paroxetine (approximately 700) were 65 years of age or older. Pharmacokinetic studies revealed a decreased clearance in the elderly, and a lower starting dose is recommended; there were, however, no overall differences in the adverse event profile between elderly and younger patients, and effectiveness was similar in younger and older patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

INDICATIONS AND USAGE

Major Depressive Disorder Paroxetine tablets, USP are indicated for the treatment of major depressive disorder. The efficacy of paroxetine in the treatment of a major depressive episode was established in 6-week controlled trials of outpatients whose diagnoses corresponded most closely to the DSM-III category of major depressive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials ). A major depressive episode implies a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: Change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation. The effects of paroxetine in hospitalized depressed patients have not been adequately studied. The efficacy of paroxetine in maintaining a response in major depressive disorder for up to 1 year was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials ). Nevertheless, the physician who elects to use paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. Obsessive Compulsive Disorder Paroxetine tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) as defined in the DSM-IV. The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning. The efficacy of paroxetine was established in two 12-week trials with obsessive compulsive outpatients whose diagnoses corresponded most closely to the DSM-IIIR category of obsessive compulsive disorder (see CLINICAL PHARMACOLOGY: Clinical Trials ). Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses, or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable. Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients assigned to paroxetine showed a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials ). Nevertheless, the physician who elects to use paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). Panic Disorder Paroxetine tablets, USP are indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV. Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks. The efficacy of paroxetine was established in three 10- to 12-week trials in panic disorder patients whose diagnoses corresponded to the DSM-IIIR category of panic disorder (see CLINICAL PHARMACOLOGY:Clinical Trials ). Panic disorder (DSM-IV) is characterized by recurrent unexpected panic attacks, i.e., a discrete period of intense fear or discomfort in which 4 (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself); (10) fear of losing control; (11) fear of dying; (12) paresthesias (numbness or tingling sensations); (13) chills or hot flushes. Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY:Clinical Trials ). Nevertheless, the physician who prescribes paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ). Generalized Anxiety Disorder Paroxetine tablets, USP are indicated for the treatment of Generalized Anxiety Disorder (GAD), as defined in DSM-IV. Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic. The efficacy of paroxetine in the treatment of GAD was established in two 8-week placebo-controlled trials in adults with GAD. Paroxetine has not been studied in children or adolescents with Generalized Anxiety Disorder (see CLINICAL PHARMACOLOGY: Clinical Trials ). Generalized Anxiety Disorder (DSM-IV) is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control. It must be associated with at least 3 of the following 6 symptoms: Restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, sleep disturbance. The efficacy of paroxetine in maintaining a response in patients with Generalized Anxiety Disorder, who responded during an 8-week acute treatment phase while taking paroxetine and were then observed for relapse during a period of up to 24 weeks, was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY: Clinical Trials ). Nevertheless, the physician who elects to use paroxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see DOSAGE AND ADMINISTRATION ).

PEDIATRIC USE

Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Clinical Worsening and Suicide Risk ). Three placebo-controlled trials in 752 pediatric patients with MDD have been conducted with paroxetine, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of paroxetine in a child or adolescent must balance the potential risks with the clinical need. Decreased appetite and weight loss have been observed in association with the use of SSRIs. Consequently, regular monitoring of weight and growth should be performed in children and adolescents treated with an SSRI such as paroxetine. In placebo-controlled clinical trials conducted with pediatric patients, the following adverse events were reported in at least 2% of pediatric patients treated with paroxetine and occurred at a rate at least twice that for pediatric patients receiving placebo: emotional lability (including self-harm, suicidal thoughts, attempted suicide, crying, and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia, and agitation. Events reported upon discontinuation of treatment with paroxetine in the pediatric clinical trials that included a taper phase regimen, which occurred in at least 2% of patients who received paroxetine and which occurred at a rate at least twice that of placebo, were: emotional lability (including suicidal ideation, suicide attempt, mood changes, and tearfulness), nervousness, dizziness, nausea, and abdominal pain (see DOSAGE AND ADMINISTRATION: Discontinuation of Treatment With Paroxetine Tablets ).

PREGNANCY

Pregnancy Pregnancy Category D. See WARNINGS: Usage in Pregnancy: Teratogenic Effects and Nonteratogenic Effects.

NUSRING MOTHERS

Nursing Mothers Like many other drugs, paroxetine is secreted in human milk, and caution should be exercised when paroxetine is administered to a nursing woman.

BOXED WARNING

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of paroxetine tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Paroxetine is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use.)

INFORMATION FOR PATIENTS

Information for Patients Paroxetine should not be chewed or crushed, and should be swallowed whole. Patients should be cautioned about the risk of serotonin syndrome with the concomitant use of paroxetine and triptans, tramadol, or other serotonergic agents. Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetine and should counsel them in its appropriate use. A patient Medication Guide is available for paroxetine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Patients should be cautioned about the concomitant use of paroxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding. Interference With Cognitive and Motor Performance Any psychoactive drug may impair judgment, thinking, or motor skills. Although in controlled studies paroxetine has not been shown to impair psychomotor performance, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that therapy with paroxetine does not affect their ability to engage in such activities. Completing Course of Therapy While patients may notice improvement with treatment with paroxetine in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication Patients should be advised to inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for interactions. Alcohol Although paroxetine has not been shown to increase the impairment of mental and motor skills caused by alcohol, patients should be advised to avoid alcohol while taking paroxetine. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see WARNINGS: Usage in Pregnancy: Teratogenic and Nonteratogenic Effects ). Nursing Patients should be advised to notify their physician if they are breastfeeding an infant (see PRECAUTIONS: Nursing Mothers ).

DOSAGE AND ADMINISTRATION

Major Depressive Disorder Usual Initial Dosage Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended initial dose is 20 mg/day. Patients were dosed in a range of 20 to 50 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of major depressive disorder. As with all drugs effective in the treatment of major depressive disorder, the full effect may be delayed. Some patients not responding to a 20 mg dose may benefit from dose increases, in 10 mg/day increments, up to a maximum of 50 mg/day. Dose changes should occur at intervals of at least 1 week. Maintenance Therapy There is no body of evidence available to answer the question of how long the patient treated with paroxetine tablets should remain on it. It is generally agreed that acute episodes of major depressive disorder require several months or longer of sustained pharmacologic therapy. Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown. Systematic evaluation of the efficacy of paroxetine tablets has shown that efficacy is maintained for periods of up to 1 year with doses that averaged about 30 mg. Obsessive Compulsive Disorder Usual Initial Dosage Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The recommended dose of paroxetine tablets in the treatment of OCD is 40 mg daily. Patients should be started on 20 mg/day and the dose can be increased in 10 mg/day increments. Dose changes should occur at intervals of at least 1 week. Patients were dosed in a range of 20 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets in the treatment of OCD. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy Long-term maintenance of efficacy was demonstrated in a 6-month relapse prevention trial. In this trial, patients with OCD assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials ). OCD is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Panic Disorder Usual Initial Dosage Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. The target dose of paroxetine tablets in the treatment of panic disorder is 40 mg/day. Patients should be started on 10 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. Patients were dosed in a range of 10 to 60 mg/day in the clinical trials demonstrating the effectiveness of paroxetine tablets. The maximum dosage should not exceed 60 mg/day. Maintenance Therapy Long-term maintenance of efficacy was demonstrated in a 3-month relapse prevention trial. In this trial, patients with panic disorder assigned to paroxetine demonstrated a lower relapse rate compared to patients on placebo (see CLINICAL PHARMACOLOGY: Clinical Trials ). Panic disorder is a chronic condition, and it is reasonable to consider continuation for a responding patient. Dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for continued treatment. Generalized Anxiety Disorder Usual Initial Dosage Paroxetine tablets should be administered as a single daily dose with or without food, usually in the morning. In clinical trials the effectiveness of paroxetine tablets was demonstrated in patients dosed in a range of 20 to 50 mg/day. The recommended starting dosage and the established effective dosage is 20 mg/day. There is not sufficient evidence to suggest a greater benefit to doses higher than 20 mg/day. Dose changes should occur in 10 mg/day increments and at intervals of at least 1 week. Maintenance Therapy Systematic evaluation of continuing paroxetine tablets for periods of up to 24 weeks in patients with Generalized Anxiety Disorder who had responded while taking paroxetine during an 8-week acute treatment phase has demonstrated a benefit of such maintenance (see CLINICAL PHARMACOLOGY: Clinical Trials ). Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment. Special Populations Treatment of Pregnant Women During the Third Trimester Neonates exposed to paroxetine and other SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding (see WARNINGS : Usage in Pregnancy ). When treating pregnant women with paroxetine during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. The physician may consider tapering paroxetine in the third trimester. Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment The recommended initial dose is 10 mg/day for elderly patients, debilitated patients, and/or patients with severe renal or hepatic impairment. Increases may be made if indicated. Dosage should not exceed 40 mg/day. Switching Patients to or From a Monoamine Oxidase Inhibitor At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with paroxetine tablets. Conversely, at least 14 days should be allowed after stopping paroxetine tablets before starting an MAOI antidepressant (see CONTRAINDICATIONS ). Use of Paroxetine Tablets With Reversible MAOIs Such as Linezolid or Methylene Blue Do not start paroxetine tablets in a patient who is being treated with linezolid or methylene blue because there is increased risk of serotonin syndrome or NMS-like reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient receiving therapy with paroxetine tablets may require urgent treatment with linezolid or methylene blue. If acceptable alternatives to linezolid or methylene blue treatment are not available and the potential benefits of linezolid or methylene blue treatment are judged to outweigh the risks of serotonin syndrome or NMS-like reactions in a particular patient, paroxetine tablets should be stopped promptly, and linezolid or methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome or NMS-like reactions for 2 weeks or until 24 hours after the last dose of linezolid or methylene blue, whichever comes first. Therapy with paroxetine tablets may be resumed 24 hours after the last dose of linezolid or methylene blue (see WARNINGS ). Discontinuation of Treatment With Paroxetine Tablets Symptoms associated with discontinuation of paroxetine have been reported (see PRECAUTIONS : Discontinuation of Treatment With Paroxetine Tablets ). Patients should be monitored for these symptoms when discontinuing treatment, regardless of the indication for which paroxetine tablets is being prescribed. A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

vortioxetine 10 MG Oral Tablet

DRUG INTERACTIONS

7 •Strong inhibitors of CYP2D6: Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) is coadministered (2.6 and 7.3). •Strong CYP Inducers: Consider increasing TRINTELLIX dose when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for more than 14 days. The maximum recommended dose should not exceed 3 times the original dose (2.7 and 7.3). 7.1 CNS Active Agents Monoamine Oxidase Inhibitors Adverse reactions, some of which are serious or fatal, can develop in patients who use MAOIs or who have recently been discontinued from an MAOI and started on a serotonergic antidepressant(s) or who have recently had SSRI or SNRI therapy discontinued prior to initiation of an MAOI [see Dosage and Administration (2.4), Contraindications (4) and Warnings and Precautions (5.2)]. Serotonergic Drugs Based on the mechanism of action of TRINTELLIX and the potential for serotonin toxicity, serotonin syndrome may occur when TRINTELLIX is coadministered with other drugs that may affect the serotonergic neurotransmitter systems (e.g., SSRIs, SNRIs, triptans, buspirone, tramadol, and tryptophan products etc.). Closely monitor symptoms of serotonin syndrome if TRINTELLIX is co-administered with other serotonergic drugs. Treatment with TRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if serotonin syndrome occurs [see Warnings and Precautions (5.2)]. Other CNS Active Agents No clinically relevant effect was observed on steady state lithium exposure following coadministration with multiple daily doses of TRINTELLIX. Multiple doses of TRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam. A clinical study has shown that TRINTELLIX (single dose of 20 or 40 mg) did not increase the impairment of mental and motor skills caused by alcohol (single dose of 0.6 g/kg). Details on the potential pharmacokinetic interactions between TRINTELLIX and bupropion can be found in Section 7.3. 7.2 Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin) Serotonin release by platelets plays an important role in hemostasis. Epidemiological studies of case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding. These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding. Altered anticoagulant effects, including increased bleeding, have been reported when SSRIs and SNRIs are coadministered with warfarin. Following coadministration of stable doses of warfarin (1 to 10 mg/day) with multiple daily doses of TRINTELLIX, no significant effects were observed in INR, prothrombin values or total warfarin (protein bound plus free drug) pharmacokinetics for both R- and S-warfarin [see Drug Interactions (7.4)]. Coadministration of aspirin 150 mg/day with multiple daily doses of TRINTELLIX had no significant inhibitory effect on platelet aggregation or pharmacokinetics of aspirin and salicylic acid [see Drug Interactions (7.4)]. Patients receiving other drugs that interfere with hemostasis should be carefully monitored when TRINTELLIX is initiated or discontinued [see Warnings and Precautions (5.3)]. 7.3 Potential for Other Drugs to Affect TRINTELLIX Reduce TRINTELLIX dose by half when a strong CYP2D6 inhibitor (e.g., bupropion, fluoxetine, paroxetine, quinidine) is coadministered. Consider increasing the TRINTELLIX dose when a strong CYP inducer (e.g., rifampicin, carbamazepine, phenytoin) is coadministered. The maximum dose is not recommended to exceed three times the original dose [see Dosage and Administration ( 2.5 and 2.6)] (Figure 1). Figure 1. Impact of Other Drugs on Vortioxetine PK Figure1.jpg 7.4 Potential for TRINTELLIX to Affect Other Drugs No dose adjustment for the comedications is needed when TRINTELLIX is coadministered with a substrate of CYP1A2 (e.g., duloxetine), CYP2A6, CYP2B6 (e.g., bupropion), CYP2C8 (e.g., repaglinide), CYP2C9 (e.g., S-warfarin), CYP2C19 (e.g., diazepam), CYP2D6 (e.g., venlafaxine), CYP3A4/5 (e.g., budesonide), and P-gp (e.g., digoxin). In addition, no dose adjustment for lithium, aspirin, and warfarin is necessary. Vortioxetine and its metabolites are unlikely to inhibit the following CYP enzymes and transporter based on in vitro data: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and P-gp. As such, no clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. In addition, vortioxetine did not induce CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A4/5 in an in vitro study in cultured human hepatocytes. Chronic administration of TRINTELLIX is unlikely to induce the metabolism of drugs metabolized by these CYP isoforms. Furthermore, in a series of clinical drug interaction studies, coadministration of TRINTELLIX with substrates for CYP2B6 (e.g., bupropion), CYP2C9 (e.g., warfarin), and CYP2C19 (e.g., diazepam), had no clinical meaningful effect on the pharmacokinetics of these substrates (Figure 2). Because vortioxetine is highly bound to plasma protein, coadministration of TRINTELLIX with another drug that is highly protein bound may increase free concentrations of the other drug. However, in a clinical study with coadministration of TRINTELLIX (10 mg/day) and warfarin (1 mg/day to 10 mg/day), a highly protein-bound drug, no significant change in INR was observed [see Drug Interactions (7.2)]. Figure 2. Impact of Vortioxetine on PK of Other Drugs Figure2.jpg

OVERDOSAGE

10 10.1 Human Experience There is limited clinical trial experience regarding human overdosage with TRINTELLIX. In pre-marketing clinical studies, cases of overdose were limited to patients who accidentally or intentionally consumed up to a maximum dose of 40 mg of TRINTELLIX. The maximum single dose tested was 75 mg in men. Ingestion of TRINTELLIX in the dose range of 40 to 75 mg was associated with increased rates of nausea, dizziness, diarrhea, abdominal discomfort, generalized pruritus, somnolence, and flushing. 10.2 Management of Overdose No specific antidotes for TRINTELLIX are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations.

DESCRIPTION

11 TRINTELLIX is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide (HBr), an antidepressant. Vortioxetine HBr is known chemically as 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine, hydrobromide. The empirical formula is C18 H22 N2 S, HBr with a molecular weight of 379.36 g/mol. The structural formula is: Vortioxetine HBr is a white to very slightly beige powder that is slightly soluble in water. Each TRINTELLIX tablet contains 6.355 mg, 12.71 mg or 25.42 mg of vortioxetine HBr equivalent to 5 mg, 10 mg, or 20 mg of vortioxetine, respectively. The inactive ingredients in TRINTELLIX tablets include mannitol, microcrystalline cellulose, hydroxypropyl cellulose, sodium starch glycolate, magnesium stearate and film coating which consists of hypromellose, titanium dioxide, polyethylene glycol 400, iron oxide red (5 mg and 20 mg) and iron oxide yellow (10 mg). chem structure.jpg

CLINICAL STUDIES

14 The efficacy of TRINTELLIX in treatment for MDD was established in six 6 to 8 week randomized, double-blind, placebo-controlled, fixed-dose studies (including one study in the elderly) and one maintenance study in adult inpatients and outpatients who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria for MDD. Adults (aged 18 years to 75 years) The efficacy of TRINTELLIX in patients aged 18 years to 75 years was demonstrated in five 6 to 8 week, placebo-controlled studies (Studies 1 to 5 in Table 4). In these studies, patients were randomized to TRINTELLIX 5 mg, 10 mg, 15 mg or 20 mg or placebo once daily. For patients who were randomized to TRINTELLIX 15 mg/day or 20 mg/day, the final doses were titrated up from 10 mg/day after the first week. The primary efficacy measures were the Hamilton Depression Scale (HAMD-24) total score in Study 2 and the Montgomery-Asberg Depression Rating Scale (MADRS) total score in all other studies. In each of these studies, at least one dose group of TRINTELLIX was superior to placebo in improvement of depressive symptoms as measured by mean change from baseline to endpoint visit on the primary efficacy measurement (see Table 4). Subgroup analysis by age, gender or race did not suggest any clear evidence of differential responsiveness. Two studies of the 5 mg dose in the U.S. (not represented in Table 4) failed to show effectiveness. Elderly Study (aged 64 years to 88 years) The efficacy of TRINTELLIX for the treatment of MDD was also demonstrated in a randomized, double-blind, placebo-controlled, fixed-dose study of TRINTELLIX in elderly patients (aged 64 years to 88 years) with MDD (Study 6 in Table 4). Patients meeting the diagnostic criteria for recurrent MDD with at least one previous major depressive episode before the age of 60 years and without comorbid cognitive impairment (Mini Mental State Examination score <24) received TRINTELLIX 5 mg or placebo. Table 4. Primary Efficacy Results of 6 Week to 8 Week Clinical Trials Study No. [Primary Measure] Treatment Group Number of Patients Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Placebo-subtracted Difference Difference (drug minus placebo) in least-squares mean change from baseline. (95% CI) Study 1 [MADRS] Non-US Study TRINTELLIX (5 mg/day)Doses that are statistically significantly superior to placebo after adjusting for multiplicity. 108 34.1 (2.6) -20.4 (1.0) -5.9 (-8.6, -3.2) TRINTELLIX (10 mg/day) 100 34.0 (2.8) -20.2 (1.0) -5.7 (-8.5, -2.9) Placebo 105 33.9 (2.7) -14.5 (1.0) — Study 2 [HAMD-24] Non-US Study TRINTELLIX (5 mg/day) 139 32.2 (5.0) -15.4 (0.7) -4.1 (-6.2, -2.1) TRINTELLIX (10 mg/day) 139 33.1 (4.8) -16.2 (0.8) -4.9 (-7.0, -2.9) Placebo 139 32.7 (4.4) -11.3 (0.7) — Study 3 [MADRS] Non-US Study TRINTELLIX (15 mg/day) 149 31.8 (3.4) -17.2 (0.8) -5.5 (-7.7, -3.4) TRINTELLIX (20 mg/day) 151 31.2 (3.4) -18.8 (0.8) -7.1 (-9.2, -5.0) Placebo 158 31.5 (3.6) -11.7 (0.8) — Study 4 [MADRS] US Study TRINTELLIX (15 mg/day) 145 31.9 (4.1) -14.3 (0.9) -1.5 (-3.9, 0.9) TRINTELLIX (20 mg/day) 147 32.0 (4.4) -15.6 (0.9) -2.8 (-5.1, -0.4) Placebo 153 31.5 (4.2) -12.8 (0.8) — Study 5 [MADRS] US Study TRINTELLIX (10 mg/day) 154 32.2 (4.5) -13.0 (0.8) -2.2 (-4.5, 0.1) TRINTELLIX (20 mg/day) 148 32.5 (4.3) -14.4 (0.9) -3.6 (-5.9, -1.4) Placebo 155 32.0 (4.0) -10.8 (0.8) — Study 6 (elderly) [HAMD-24] US and Non-US TRINTELLIX (5 mg/day) 155 29.2 (5.0) -13.7 (0.7) -3.3 (-5.3, -1.3) Placebo 145 29.4 (5.1) -10.3 (0.8) — SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval. Time Course of Treatment Response In the 6 to 8 week placebo-controlled studies, an effect of TRINTELLIX based on the primary efficacy measure was generally observed starting at Week 2 and increased in subsequent weeks with the full antidepressant effect of TRINTELLIX generally not seen until Study Week 4 or later. Figure 4 depicts time course of response in U.S. based on the primary efficacy measure (MADRS) in Study 5. Figure 4. Change from Baseline in MADRS Total Score by Study Visit (Week) in Study 5 Figure 5. Difference from Placebo in Mean Change from Baseline in MADRS Total Score at Week 6 or Week 8 †Results (point estimate and unadjusted 95% confidence interval) are from mixed model for repeated measures (MMRM) analysis. In Studies 1 and 6, the primary analysis was not based on MMRM and in Studies 2 and 6 the primary efficacy measure was not based on MADRS. Maintenance Study In a non-US maintenance study (Study 7 in Figure 6), 639 patients meeting DSM-IV-TR criteria for MDD received flexible doses of TRINTELLIX (5 mg or 10 mg) once daily during an initial 12 week open-label treatment phase; the dose of TRINTELLIX was fixed during Weeks 8 to 12. Three hundred ninety six (396) patients who were in remission (MADRS total score ≤10 at both Weeks 10 and 12) after open-label treatment were randomly assigned to continuation of a fixed dose of TRINTELLIX at the final dose they responded to (about 75% of patients were on 10 mg/day) during the open-label phase or to placebo for 24 to 64 weeks. Approximately 61% of randomized patients satisfied remission criterion (MADRS total score ≤10) for at least 4 weeks (since Week 8), and 15% for at least 8 weeks (since Week 4). Patients on TRINTELLIX experienced a statistically significantly longer time to have recurrence of depressive episodes than did patients on placebo. Recurrence of depressive episode was defined as a MADRS total score ≥22 or lack of efficacy as judged by the investigator. Figure 6. Kaplan-Meier Estimates of Proportion of Patients with Recurrence (Study 7) Figure 4 Figure 5 Figure 6

HOW SUPPLIED

16 /STORAGE AND HANDLING TRINTELLIX tablets are available as follows: Features Strengths 5 mg 10 mg 20 mg Color pink yellow red Debossment “5” on one side of tablet “TL” on other side of tablet “10” on one side of tablet “TL” on other side of tablet “20” on one side of tablet “TL” on other side of tablet Presentations and NDC Codes Bottles of 30 64764-720-30 64764-730-30 64764-750-30 Bottles of 90 64764-720-90 64764-730-90 64764-750-90 Bottles of 500 64764-720-77 64764-730-77 64764-750-77 Storage: Store at 77°F (25°C); excursions permitted to 59°F to 86°F (15°C to 30°C) [see USP Controlled Room Temperature].

GERIATRIC USE

8.5 Geriatric Use No dose adjustment is recommended on the basis of age (Figure 3). Results from a single-dose pharmacokinetic study in elderly (>65 years old) vs. young (24 to 45 years old) subjects demonstrated that the pharmacokinetics were generally similar between the two age groups. Of the 2616 subjects in clinical studies of TRINTELLIX, 11% (286) were 65 and over, which included subjects from a placebo-controlled study specifically in elderly patients [see Clinical Studies (14)]. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. Serotonergic antidepressants have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions (5.6)].

DOSAGE FORMS AND STRENGTHS

3 TRINTELLIX is available as immediate-release, film-coated tablets in the following strengths: •5 mg: pink, almond shaped biconvex film coated tablet, debossed with “5” on one side and “TL” on the other side •10 mg: yellow, almond shaped biconvex film coated tablet, debossed with “10” on one side and “TL” on the other side •20 mg: red, almond shaped biconvex film coated tablet, debossed with “20” on one side and “TL” on the other side TRINTELLIX is available as 5 mg, 10 mg and 20 mg immediate release tablets (3).

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of the antidepressant effect of vortioxetine is not fully understood, but is thought to be related to its enhancement of serotonergic activity in the CNS through inhibition of the reuptake of serotonin (5-HT). It also has several other activities including 5-HT3 receptor antagonism and 5-HT1A receptor agonism. The contribution of these activities to vortioxetine’s antidepressant effect has not been established.

INDICATIONS AND USAGE

1 TRINTELLIX is indicated for the treatment of major depressive disorder (MDD) (1, 14). 1.1 Major Depressive Disorder TRINTELLIX is indicated for the treatment of major depressive disorder (MDD). The efficacy of TRINTELLIX was established in six 6 to 8 week studies (including one study in the elderly) and one maintenance study in adults [see Clinical Studies (14)].

PEDIATRIC USE

8.4 Pediatric Use Clinical studies on the use of TRINTELLIX in pediatric patients have not been conducted; therefore, the safety and effectiveness of TRINTELLIX in the pediatric population have not been established.

PREGNANCY

8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of TRINTELLIX in pregnant women. Vortioxetine caused developmental delays when administered during pregnancy to rats and rabbits at doses 15 and 10 times the maximum recommended human dose (MRHD) of 20 mg, respectively. Developmental delays were also seen after birth in rats at doses 20 times the MRHD of vortioxetine given during pregnancy and through lactation. There were no teratogenic effects in rats or rabbits at doses up to 77 and 58 times, the MRHD of vortioxetine, respectively, given during organogenesis. The incidence of malformations in human pregnancies has not been established for TRINTELLIX. All human pregnancies, regardless of drug exposure, have a background rate of 2 to 4% for major malformations, and 15 to 20% for pregnancy loss. TRINTELLIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerations Neonates exposed to SSRIs or SNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or possibly, a drug discontinuation syndrome. It should be noted that in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions (5.2)]. When treating a pregnant woman with TRINTELLIX during the third trimester, the physician should carefully consider the potential risks and benefits of treatment. Neonates exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in one to two per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. Several recent epidemiologic studies suggest a positive statistical association between SSRI use in pregnancy and PPHN. Other studies do not show a significant statistical association. A prospective longitudinal study was conducted of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission. Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy. When treating a pregnant woman with TRINTELLIX, the physician should carefully consider both the potential risks of taking a serotonergic antidepressant, along with the established benefits of treating depression with an antidepressant. Animal Data In pregnant rats and rabbits, no teratogenic effects were seen when vortioxetine was given during the period of organogenesis at oral doses up to 160 and 60 mg/kg/day, respectively. These doses are 77 and 58 times, in rats and rabbits, respectively, the maximum recommended human dose (MRHD) of 20 mg on a mg/m2 basis. Developmental delay, seen as decreased fetal body weight and delayed ossification, occurred in rats and rabbits at doses equal to and greater than 30 and 10 mg/kg (15 and 10 times the MRHD, respectively) in the presence of maternal toxicity (decreased food consumption and decreased body weight gain). When vortioxetine was administered to pregnant rats at oral doses up to 120 mg/kg (58 times the MRHD) throughout pregnancy and lactation, the number of live-born pups was decreased and early postnatal pup mortality was increased at 40 and 120 mg/kg. Additionally, pup weights were decreased at birth to weaning at 120 mg/kg and development (specifically eye opening) was slightly delayed at 40 and 120 mg/kg. These effects were not seen at 10 mg/kg (5 times the MRHD).

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether vortioxetine is present in human milk. Vortioxetine is present in the milk of lactating rats. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from TRINTELLIX, 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

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a trend toward reduced risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.1)]. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)]. TRINTELLIX has not been evaluated for use in pediatric patients [see Use in Specific Populations (8.4)]. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.1). • Monitor for worsening and emergence of suicidal thoughts and behaviors (5.1). • TRINTELLIX has not been evaluated for use in pediatric patients (8.4).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS •Serotonin Syndrome has been reported with serotonergic antidepressants (SSRIs, SNRIs, and others), including with TRINTELLIX, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John’s Wort). If such symptoms occur, discontinue TRINTELLIX and initiate supportive treatment. If concomitant use of TRINTELLIX with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases (5.2). •Treatment with serotonergic antidepressants (SSRIs, SNRIs, and others) may increase the risk of abnormal bleeding. Patients should be cautioned about the increased risk of bleeding when TRINTELLIX is coadministered with nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, or other drugs that affect coagulation (5.3). •Activation of Mania/Hypomania can occur with antidepressant treatment. Screen patients for bipolar disorder (5.4). •Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.5) •Hyponatremia can occur in association with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) (5.6). 5.1 Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled studies of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a trend toward reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive-compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1. Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Age Range Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for MDD as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled studies) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that TRINTELLIX is not approved for use in treating bipolar depression. 5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with serotonergic antidepressants including TRINTELLIX, when used alone but more often when used concomitantly with other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of TRINTELLIX with MAOIs intended to treat psychiatric disorders is contraindicated. TRINTELLIX should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking TRINTELLIX. TRINTELLIX should be discontinued before initiating treatment with the MAOI [see Contraindications (4) and Dosage and Administration (2.4)]. If concomitant use of TRINTELLIX with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with TRINTELLIX and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. 5.3 Abnormal Bleeding The use of drugs that interfere with serotonin reuptake inhibition, including TRINTELLIX, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the increased risk of bleeding when TRINTELLIX is coadministered with NSAIDs, aspirin, or other drugs that affect coagulation or bleeding [see Drug Interactions (7.2)]. 5.4 Activation of Mania/Hypomania Symptoms of mania/hypomania were reported in <0.1% of patients treated with TRINTELLIX in pre-marketing clinical studies. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with other antidepressants. As with all antidepressants, use TRINTELLIX cautiously in patients with a history or family history of bipolar disorder, mania, or hypomania. 5.5 Angle Closure Glaucoma Angle Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs, including TRINTELLIX, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.6 Hyponatremia Hyponatremia has occurred as a result of treatment with serotonergic drugs. In many cases, hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). One case with serum sodium lower than 110 mmol/L was reported in a subject treated with TRINTELLIX in a pre-marketing clinical study. Elderly patients may be at greater risk of developing hyponatremia with a serotonergic antidepressant. Also, patients taking diuretics or who are otherwise volume-depleted can be at greater risk. Discontinuation of TRINTELLIX in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. More severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide) Advise patients and their caregivers about the benefits and risks associated with treatment with TRINTELLIX and counsel them in its appropriate use. Advise patients and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document. Suicide Risk Advise patients and caregivers to look for the emergence of suicidal ideation and behavior, especially early during treatment and when the dose is adjusted up or down [see Boxed Warning and Warnings and Precautions (5.1)]. Discontinuation of Treatment Patients who are on TRINTELLIX 15 mg/day or 20 mg/day may experience headache, muscle tension, mood swings, sudden outburst of anger, dizziness and runny nose if they abruptly stop their medicine. Advise patients not stopping TRINTELLIX without talking to their healthcare provider [see Adverse Reactions (6)]. Concomitant Medication Advise patients to inform their physicians if they are taking, or plan to take, any prescription or over-the-counter medications because of a potential for interactions. Instruct patients not to take TRINTELLIX with an MAOI or within 14 days of stopping an MAOI and to allow 21 days after stopping TRINTELLIX before starting an MAOI [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.2), and Drug Interactions (7.1)]. Serotonin Syndrome Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of TRINTELLIX and triptans, tricyclic antidepressants, fentanyl, Lithium, tramadol, tryptophan supplements, and St. John’s Wort supplements [see Warnings and Precautions (5.2) and Drug Interactions (7.1, 7.2)]. Abnormal Bleeding Caution patients about the increased risk of abnormal bleeding when TRINTELLIX is given with NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see Warnings and Precautions (5.3)]. Activation of Mania/Hypomania Advise patients and their caregivers to look for signs of activation of mania/hypomania [see Warnings and Precautions (5.4)]. Angle Closure Glaucoma Patients should be advised that taking TRINTELLIX can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.5)]. Hyponatremia Advise patients that if they are treated with diuretics, or are otherwise volume depleted, or are elderly, they may be at greater risk of developing hyponatremia while taking TRINTELLIX [see Warnings and Precautions (5.6)]. Nausea Advise patients that nausea is the most common adverse reaction, and is dose related. Nausea commonly occurs within the first week of treatment, then decreases in frequency but can persist in some patients. Alcohol A clinical study has shown that TRINTELLIX (single dose of 20 or 40 mg/day) did not increase the impairment of mental and motor skills caused by alcohol. Allergic Reactions Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing. Pregnancy Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy with TRINTELLIX [see Use in Specific Populations (8.1)]. Nursing Mothers Advise patients to notify their healthcare provider if they are breast-feeding an infant and would like to continue or start TRINTELLIX [see Use in Specific Populations (8.3)]. Distributed and marketed by: Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 Marketed by: Lundbeck Deerfield, IL 60015 TRINTELLIX is a trademark of H. Lundbeck A/S registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. ©2013-2016 Takeda Pharmaceuticals America, Inc. LUN205 R11 September 2016

DOSAGE AND ADMINISTRATION

2 •The recommended starting dose is 10 mg administered orally once daily without regard to meals (2.1). •The dose should then be increased to 20 mg/day, as tolerated (2.1). •Consider 5 mg/day for patients who do not tolerate higher doses (2.1). •TRINTELLIX can be discontinued abruptly. However, it is recommended that doses of 15 mg/day or 20 mg/day be reduced to 10 mg/day for one week prior to full discontinuation if possible (2.3). •The maximum recommended dose is 10 mg/day in known CYP2D6 poor metabolizers (2.6). 2.1 General Instruction for Use The recommended starting dose is 10 mg administered orally once daily without regard to meals. Dosage should then be increased to 20 mg/day, as tolerated, because higher doses demonstrated better treatment effects in trials conducted in the United States. The efficacy and safety of doses above 20 mg/day have not been evaluated in controlled clinical trials. A dose decrease down to 5 mg/day may be considered for patients who do not tolerate higher doses [see Clinical Studies (14)]. 2.2 Maintenance/Continuation/Extended Treatment It is generally agreed that acute episodes of major depression should be followed by several months or longer of sustained pharmacologic therapy. A maintenance study of TRINTELLIX demonstrated that TRINTELLIX decreased the risk of recurrence of depressive episodes compared to placebo. 2.3 Discontinuing Treatment Although TRINTELLIX can be abruptly discontinued, in placebo-controlled trials patients experienced transient adverse reactions such as headache and muscle tension following abrupt discontinuation of TRINTELLIX 15 mg/day or 20 mg/day. To avoid these adverse reactions, it is recommended that the dose be decreased to 10 mg/day for one week before full discontinuation of TRINTELLIX 15 mg/day or 20 mg/day [see Adverse Reactions (6)]. 2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of a MAOI intended to treat psychiatric disorders and initiation of therapy with TRINTELLIX to avoid the risk of Serotonin Syndrome [see Warnings and Precautions (5.2)]. Conversely, at least 21 days should be allowed after stopping TRINTELLIX before starting an MAOI intended to treat psychiatric disorders [see Contraindications (4)]. 2.5 Use of TRINTELLIX with Other MAOIs such as Linezolid or Methylene Blue Do not start TRINTELLIX in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered [see Contraindications (4)]. In some cases, a patient already receiving TRINTELLIX therapy may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, TRINTELLIX should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 21 days or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with TRINTELLIX may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue [see Warnings and Precautions (5.2)]. The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with TRINTELLIX is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use [see Warnings and Precautions (5.2)]. 2.6 Use of TRINTELLIX in Known CYP2D6 Poor Metabolizers or in Patients Taking Strong CYP2D6 Inhibitors The maximum recommended dose of TRINTELLIX is 10 mg/day in known CYP2D6 poor metabolizers. Reduce the dose of TRINTELLIX by one-half when patients are receiving a CYP2D6 strong inhibitor (e.g., bupropion, fluoxetine, paroxetine, or quinidine) concomitantly. The dose should be increased to the original level when the CYP2D6 inhibitor is discontinued [see Drug Interactions (7.3)]. 2.7 Use of TRINTELLIX in Patients Taking Strong CYP Inducers Consider increasing the dose of TRINTELLIX when a strong CYP inducer (e.g., rifampin, carbamazepine, or phenytoin) is coadministered for greater than 14 days. The maximum recommended dose should not exceed three times the original dose. The dose of TRINTELLIX should be reduced to the original level within 14 days, when the inducer is discontinued [see Drug Interactions (7.3)].

alendronate sodium 70 MG Oral Tablet

Generic Name: ALENDRONATE SODIUM

Brand Name: Alendronate Sodium

Substance Name(s):
ALENDRONATE SODIUM

DRUG INTERACTIONS

7 Calcium supplements, antacids, or oral medications containing multivalent cations interfere with absorption of alendronate. (2.6, 7.1) Aspirin and non-steroidal anti-inflammatory drug use may worsen GI irritation; use caution. (7.2, 7.3) 7.1 Calcium Supplements/Antacids Coadministration of alendronate sodium and calcium, antacids, or oral medications containing multivalent cations will interfere with absorption of alendronate sodium. Therefore, patients must wait at least one-half hour after taking alendronate sodium before taking any other oral medications. 7.2 Aspirin In clinical studies, the incidence of upper gastrointestinal adverse events was increased in patients receiving concomitant therapy with daily doses of alendronate sodium greater than 10 mg and aspirin-containing products. 7.3 Non-Steroidal Anti-Inflammatory Drugs Alendronate sodium may be administered to patients taking non-steroidal anti-inflammatory drugs (NSAIDs). In a 3 year, controlled, clinical study (n = 2027) during which a majority of patients received concomitant NSAIDs, the incidence of upper gastrointestinal adverse events was similar in patients taking alendronate sodium 5 or 10 mg/day compared to those taking placebo. However, since NSAID use is associated with gastrointestinal irritation, caution should be used during concomitant use with alendronate sodium.

OVERDOSAGE

10 Significant lethality after single oral doses was seen in female rats and mice at 552 mg/kg (3256 mg/m2) and 966 mg/kg (2898 mg/m2), respectively. In males, these values were slightly higher, 626 and 1280 mg/kg, respectively. There was no lethality in dogs at oral doses up to 200 mg/kg (4000 mg/m2). No specific information is available on the treatment of overdosage with alendronate sodium. Hypocalcemia, hypophosphatemia, and upper gastrointestinal adverse events, such as upset stomach, heartburn, esophagitis, gastritis, or ulcer, may result from oral overdosage. Milk or antacids should be given to bind alendronate. Due to the risk of esophageal irritation, vomiting should not be induced and the patient should remain fully upright. Dialysis would not be beneficial.

DESCRIPTION

11 Alendronate sodium is a bisphosphonate that acts as a specific inhibitor of osteoclast-mediated bone resorption. Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite found in bone. Alendronate sodium is chemically described as (4-amino-1-hydroxybutylidene) bisphosphonic acid monosodium salt trihydrate. The structural formula is: C4H12NNaO7P2•3H2O M.W. 325.12 Alendronate sodium is a white, crystalline, nonhygroscopic powder. It is soluble in water, very slightly soluble in alcohol, and practically insoluble in chloroform. Each tablet, for oral administration contains 6.53, 13.05, 45.68, 52.21 or 91.37 mg of alendronate monosodium salt trihydrate, which is the molar equivalent of 5, 10, 35, 40 and 70 mg, respectively, of free acid, and the following inactive ingredients: croscarmellose sodium, magnesium stearate, and microcrystalline cellulose. Alendronate sodium tablets USP meet USP Dissolution Test 2. chemical structure

CLINICAL STUDIES

14 14.1 Treatment of Osteoporosis in Postmenopausal Women Daily Dosing The efficacy of alendronate sodium 10 mg daily was assessed in four clinical trials. Study 1, a three-year, multicenter double-blind, placebo-controlled, U.S. clinical study enrolled 478 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 2, a three-year, multicenter double blind placebo controlled Multinational clinical study enrolled 516 patients with a BMD T-score at or below minus 2.5 with or without a prior vertebral fracture; Study 3, the Three-Year Study of the Fracture Intervention Trial (FIT) a study which enrolled 2027 postmenopausal patients with at least one baseline vertebral fracture; and Study 4, the Four-Year Study of FIT: a study which enrolled 4432 postmenopausal patients with low bone mass but without a baseline vertebral fracture. Effect on Fracture Incidence To assess the effects of alendronate sodium on the incidence of vertebral fractures (detected by digitized radiography; approximately one third of these were clinically symptomatic), the U.S. and Multinational studies were combined in an analysis that compared placebo to the pooled dosage groups of alendronate sodium (5 or 10 mg for three years or 20 mg for two years followed by 5 mg for one year). There was a statistically significant reduction in the proportion of patients treated with alendronate sodium experiencing one or more new vertebral fractures relative to those treated with placebo (3.2% vs. 6.2%; a 48% relative risk reduction). A reduction in the total number of new vertebral fractures (4.2 vs. 11.3 per 100 patients) was also observed. In the pooled analysis, patients who received alendronate sodium had a loss in stature that was statistically significantly less than was observed in those who received placebo (-3.0 mm vs. -4.6 mm). The Fracture Intervention Trial (FIT) consisted of two studies in postmenopausal women: the Three-Year Study of patients who had at least one baseline radiographic vertebral fracture and the Four-Year Study of patients with low bone mass but without a baseline vertebral fracture. In both studies of FIT, 96% of randomized patients completed the studies (i.e., had a closeout visit at the scheduled end of the study); approximately 80% of patients were still taking study medication upon completion. Fracture Intervention Trial: Three-Year Study (patients with at least one baseline radiographic vertebral fracture) This randomized, double-blind, placebo-controlled, 2027 patient study (alendronate sodium, n = 1022; placebo, n = 1005) demonstrated that treatment with alendronate sodium resulted in statistically significant reductions in fracture incidence at three years as shown in Table 6. Table 6: Effect of Alendronate Sodium on Fracture Incidence in the Three-Year Study of FIT (Patients With Vertebral Fracture at Baseline) Percent of Patients Alendronate Sodium (n = 1022) Placebo (n = 1005) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk % Patients with: Vertebral fractures (diagnosed by X-rayNumber evaluable for vertebral fractures: alendronate sodium, n = 984; placebo, n = 966 ≥ 1 new vertebral fracture 7.9 15.0 7.1 47p < 0.001 ≥ 2 new vertebral fractures 0.5 4.9 4.4 90 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture 13.8 18.1 4.3 26p = 0.007 ≥ 1 clinical (symptomatic) vertebral fracture 2.3 5.0 2.7 54p < 0.01 Hip fracture 1.1 2.2 1.1 51p < 0.05 Wrist (forearm) fracture 2.2 4.1 1.9 48 Furthermore, in this population of patients with baseline vertebral fracture, treatment with alendronate sodium significantly reduced the incidence of hospitalizations (25.0% vs. 30.7%). In the Three-Year Study of FIT, fractures of the hip occurred in 22 (2.2%) of 1005 patients on placebo and 11 (1.1%) of 1022 patients on alendronate sodium, p = 0.047. Figure 1 displays the cumulative incidence of hip fractures in this study. Figure 1: Cumulative Incidence of Hip Fractures in the Three-Year Study of FIT (Patients With Radiographic Vertebral Fracture at Baseline) Fracture Intervention Trial: Four-Year Study (patients with low bone mass but without a baseline radiographic vertebral fracture) This randomized, double-blind, placebo-controlled, 4432 patient study (alendronate sodium, n = 2214; placebo, n = 2218) further investigated the reduction in fracture incidence due to alendronate sodium. The intent of the study was to recruit women with osteoporosis, defined as a baseline femoral neck BMD at least two standard deviations below the mean for young adult women. However, due to subsequent revisions to the normative values for femoral neck BMD, 31% of patients were found not to meet this entry criterion and thus this study included both osteoporotic and non-osteoporotic women. The results are shown in Table 7 for the patients with osteoporosis. Table 7: Effect of Alendronate Sodium on Fracture Incidence in OsteoporoticBaseline femoral neck BMD at least 2 SD below the mean for young adult women Patients in the Four-Year Study of FIT (Patients Without Vertebral Fracture at Baseline) Percent of Patients Alendronate Sodium (n = 1545) Placebo (n = 1521) Absolute Reduction in Fracture Incidence Relative Reduction in Fracture Risk (%) Patients with: Vertebral fractures (diagnosed by X-ray)Number evaluable for vertebral fractures: Alendronate sodium, n = 1426; placebo, n = 1428 ≥ 1 new vertebral fracture 2.5 4.8 2.3 48p < 0.001 ≥ 2 new vertebral fractures 0.1 0.6 0.5 78p = 0.035 Clinical (symptomatic) fractures Any clinical (symptomatic) fracture 12.9 16.2 3.3 22p = 0.01 ≥ 1 clinical (symptomatic) vertebral fracture 1.0 1.6 0.6 41 (NS)Not significant. This study was not powered to detect differences at these sites. Hip fracture 1.0 1.4 0.4 29 (NS) Wrist (forearm) fracture 3.9 3.8 -0.1 NS Fracture Results Across Studies In the Three-Year Study of FIT, alendronate sodium reduced the percentage of women experiencing at least one new radiographic vertebral fracture from 15.0% to 7.9% (47% relative risk reduction, p < 0.001); in the Four-Year Study of FIT, the percentage was reduced from 3.8% to 2.1% (44% relative risk reduction, p = 0.001); and in the combined U.S./Multinational studies, from 6.2% to 3.2% (48% relative risk reduction, p = 0.034). Alendronate sodium reduced the percentage of women experiencing multiple (two or more) new vertebral fractures from 4.2% to 0.6% (87% relative risk reduction, p < 0.001) in the combined U.S./Multinational studies and from 4.9% to 0.5% (90% relative risk reduction, p < 0.001) in the Three-Year Study of FIT. In the Four-Year Study of FIT, alendronate sodium reduced the percentage of osteoporotic women experiencing multiple vertebral fractures from 0.6% to 0.1% (78% relative risk reduction, p = 0.035). Thus, alendronate sodium reduced the incidence of radiographic vertebral fractures in osteoporotic women whether or not they had a previous radiographic vertebral fracture. Effect on Bone Mineral Density The bone mineral density efficacy of alendronate sodium 10 mg once daily in postmenopausal women, 44 to 84 years of age, with osteoporosis (lumbar spine bone mineral density [BMD] of at least 2 standard deviations below the premenopausal mean) was demonstrated in four double-blind, placebo-controlled clinical studies of two or three years’ duration. Figure 2 shows the mean increases in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate sodium 10 mg/day relative to placebo-treated patients at three years for each of these studies. Figure 2: Osteoporosis Treatment Studies in Postmenopausal Women Increase in BMD Alendronate Sodium 10 mg/day at Three Years At three years significant increases in BMD, relative both to baseline and placebo, were seen at each measurement site in each study in patients who received alendronate sodium 10 mg/day. Total body BMD also increased significantly in each study, suggesting that the increases in bone mass of the spine and hip did not occur at the expense of other skeletal sites. Increases in BMD were evident as early as three months and continued throughout the three years of treatment. (See Figure 3 for lumbar spine results.) In the two-year extension of these studies, treatment of 147 patients with alendronate sodium 10 mg/day resulted in continued increases in BMD at the lumbar spine and trochanter (absolute additional increases between years 3 and 5: lumbar spine, 0.94%; trochanter, 0.88%). BMD at the femoral neck, forearm and total body were maintained. Alendronate sodium was similarly effective regardless of age, race, baseline rate of bone turnover, and baseline BMD in the range studied (at least 2 standard deviations below the premenopausal mean). Figure 3: Osteoporosis Treatment Studies in Postmenopausal Women Time Course of Effect of Alendronate Sodium 10 mg/day Versus Placebo: Lumbar Spine BMD Percent Change From Baseline In patients with postmenopausal osteoporosis treated with alendronate sodium 10 mg/day for one or two years, the effects of treatment withdrawal were assessed. Following discontinuation, there were no further increases in bone mass and the rates of bone loss were similar to those of the placebo groups. Bone Histology Bone histology in 270 postmenopausal patients with osteoporosis treated with alendronate sodium at doses ranging from 1 to 20 mg/day for one, two, or three years revealed normal mineralization and structure, as well as the expected decrease in bone turnover relative to placebo. These data, together with the normal bone histology and increased bone strength observed in rats and baboons exposed to long-term alendronate treatment, support the conclusion that bone formed during therapy with alendronate sodium is of normal quality. Effect on Height Alendronate sodium, over a three- or four-year period, was associated with statistically significant reductions in loss of height vs. placebo in patients with and without baseline radiographic vertebral fractures. At the end of the FIT studies the between-treatment group differences were 3.2 mm in the Three-Year Study and 1.3 mm in the Four-Year Study. Weekly Dosing The therapeutic equivalence of once weekly alendronate sodium 70 mg (n = 519) and alendronate sodium 10 mg daily (n = 370) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women with osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 5.1% (4.8, 5.4%; 95% CI) in the 70 mg once-weekly group (n = 440) and 5.4% (5.0, 5.8%; 95% CI) in the 10 mg daily group (n = 330). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers. Concomitant Use with Estrogen/Hormone Replacement Therapy (HRT) The effects on BMD of treatment with alendronate sodium 10 mg once daily and conjugated estrogen (0.625 mg/day) either alone or in combination were assessed in a two-year, double-blind, placebo-controlled study of hysterectomized postmenopausal osteoporotic women (n = 425). At two years, the increases in lumbar spine BMD from baseline were significantly greater with the combination (8.3%) than with either estrogen or alendronate sodium alone (both 6.0%). The effects on BMD when alendronate sodium was added to stable doses (for at least one year) of HRT (estrogen ± progestin) were assessed in a one-year, double-blind, placebo-controlled study in postmenopausal osteoporotic women (n = 428). The addition of alendronate sodium 10 mg once daily to HRT produced, at one year, significantly greater increases in lumbar spine BMD (3.7%) vs. HRT alone (1.1%). In these studies, significant increases or favorable trends in BMD for combined therapy compared with HRT alone were seen at the total hip, femoral neck, and trochanter. No significant effect was seen for total body BMD. Histomorphometric studies of transiliac biopsies in 92 subjects showed normal bone architecture. Compared to placebo there was a 98% suppression of bone turnover (as assessed by mineralizing surface) after 18 months of combined treatment with alendronate sodium and HRT, 94% on alendronate sodium alone, and 78% on HRT alone. The long-term effects of combined alendronate sodium and HRT on fracture occurrence and fracture healing have not been studied. figure 1 figure 2 figure 3 figure 3a 14.2 Prevention of Osteoporosis in Postmenopausal Women Daily Dosing Prevention of bone loss was demonstrated in two double-blind, placebo-controlled studies of postmenopausal women 40 to 60 years of age. One thousand six hundred nine patients (alendronate sodium 5 mg/day; n = 498) who were at least six months postmenopausal were entered into a two-year study without regard to their baseline BMD. In the other study, 447 patients (alendronate sodium 5 mg/day; n = 88), who were between six months and three years postmenopause, were treated for up to three years. In the placebo-treated patients BMD losses of approximately 1% per year were seen at the spine, hip (femoral neck and trochanter) and total body. In contrast, alendronate sodium 5 mg/day prevented bone loss in the majority of patients and induced significant increases in mean bone mass at each of these sites (see Figure 4). In addition, alendronate sodium 5 mg/day reduced the rate of bone loss at the forearm by approximately half relative to placebo. Alendronate sodium 5 mg/day was similarly effective in this population regardless of age, time since menopause, race and baseline rate of bone turnover. Figure 4: Osteoporosis Prevention Studies in Postmenopausal Women Bone Histology Bone histology was normal in the 28 patients biopsied at the end of three years who received alendronate sodium at doses of up to 10 mg/day. Weekly Dosing The therapeutic equivalence of once weekly alendronate sodium 35 mg (n = 362) and alendronate sodium 5 mg daily (n = 361) was demonstrated in a one-year, double-blind, multicenter study of postmenopausal women without osteoporosis. In the primary analysis of completers, the mean increases from baseline in lumbar spine BMD at one year were 2.9% (2.6, 3.2%; 95% CI) in the 35 mg once-weekly group (n = 307) and 3.2% (2.9, 3.5%; 95% CI) in the 5 mg daily group (n = 298). The two treatment groups were also similar with regard to BMD increases at other skeletal sites. The results of the intention-to-treat analysis were consistent with the primary analysis of completers. figure 4 figure 4a 14.3 Treatment to Increase Bone Mass in Men With Osteoporosis The efficacy of alendronate sodium in men with hypogonadal or idiopathic osteoporosis was demonstrated in two clinical studies. Daily Dosing A two-year, double-blind, placebo-controlled, multicenter study of alendronate sodium 10 mg once daily enrolled a total of 241 men between the ages of 31 and 87 (mean, 63). All patients in the trial had either a BMD T-score ≤ -2 at the femoral neck and ≤ -1 at the lumbar spine, or a baseline osteoporotic fracture and a BMD T-score ≤ -1 at the femoral neck. At two years, the mean increases relative to placebo in BMD in men receiving alendronate sodium 10 mg/day were significant at the following sites: lumbar spine, 5.3%; femoral neck, 2.6%; trochanter, 3.1%; and total body, 1.6%. Treatment with alendronate sodium also reduced height loss (alendronate sodium, -0.6 mm vs. placebo, -2.4 mm). Weekly Dosing A one-year, double-blind, placebo-controlled, multicenter study of once weekly alendronate sodium 70 mg enrolled a total of 167 men between the ages of 38 and 91 (mean, 66). Patients in the study had either a BMD T-score ≤ -2 at the femoral neck and ≤ -1 at the lumbar spine, or a BMD T-score ≤ -2 at the lumbar spine and ≤ -1 at the femoral neck, or a baseline osteoporotic fracture and a BMD T-score ≤ -1 at the femoral neck. At one year, the mean increases relative to placebo in BMD in men receiving alendronate sodium 70 mg once weekly were significant at the following sites: lumbar spine, 2.8%; femoral neck, 1.9%; trochanter, 2.0%; and total body, 1.2%. These increases in BMD were similar to those seen at one year in the 10 mg once-daily study. In both studies, BMD responses were similar regardless of age (≥ 65 years vs. < 65 years), gonadal function (baseline testosterone -2.5). 14.4 Treatment of Glucocorticoid-Induced Osteoporosis The efficacy of alendronate sodium 5 and 10 mg once daily in men and women receiving glucocorticoids (at least 7.5 mg/day of prednisone or equivalent) was demonstrated in two, one-year, double-blind, randomized, placebo-controlled, multicenter studies of virtually identical design, one performed in the United States and the other in 15 different countries (Multinational [which also included alendronate sodium 2.5 mg/day]). These studies enrolled 232 and 328 patients, respectively, between the ages of 17 and 83 with a variety of glucocorticoid-requiring diseases. Patients received supplemental calcium and vitamin D. Figure 5 shows the mean increases relative to placebo in BMD of the lumbar spine, femoral neck, and trochanter in patients receiving alendronate sodium 5 mg/day for each study. Figure 5: Studies in Glucocorticoid – Treated Patients Increase in BMD Alendronate Sodium 5 mg/day at One Year After one year, significant increases relative to placebo in BMD were seen in the combined studies at each of these sites in patients who received alendronate sodium 5 mg/day. In the placebo-treated patients, a significant decrease in BMD occurred at the femoral neck (-1.2%), and smaller decreases were seen at the lumbar spine and trochanter. Total body BMD was maintained with alendronate sodium 5 mg/day. The increases in BMD with alendronate sodium 10 mg/day were similar to those with alendronate sodium 5 mg/day in all patients except for postmenopausal women not receiving estrogen therapy. In these women, the increases (relative to placebo) with alendronate sodium 10 mg/day were greater than those with alendronate sodium 5 mg/day at the lumbar spine (4.1% vs. 1.6%) and trochanter (2.8% vs. 1.7%), but not at other sites. Alendronate sodium was effective regardless of dose or duration of glucocorticoid use. In addition, alendronate sodium was similarly effective regardless of age (< 65 vs. ≥ 65 years), race (Caucasian vs. other races), gender, underlying disease, baseline BMD, baseline bone turnover, and use with a variety of common medications. Bone histology was normal in the 49 patients biopsied at the end of one year who received alendronate sodium at doses of up to 10 mg/day. Of the original 560 patients in these studies, 208 patients who remained on at least 7.5 mg/day of prednisone or equivalent continued into a one-year double-blind extension. After two years of treatment, spine BMD increased by 3.7% and 5.0% relative to placebo with alendronate sodium 5 and 10 mg/day, respectively. Significant increases in BMD (relative to placebo) were also observed at the femoral neck, trochanter, and total body. After one year, 2.3% of patients treated with alendronate sodium 5 or 10 mg/day (pooled) vs. 3.7% of those treated with placebo experienced a new vertebral fracture (not significant). However, in the population studied for two years, treatment with alendronate sodium (pooled dosage groups: 5 or 10 mg for two years or 2.5 mg for one year followed by 10 mg for one year) significantly reduced the incidence of patients with a new vertebral fracture (alendronate sodium 0.7% vs. placebo 6.8%). figure 5 14.5 Treatment of Paget's Disease of Bone The efficacy of alendronate sodium 40 mg once daily for six months was demonstrated in two double-blind clinical studies of male and female patients with moderate to severe Paget’s disease (alkaline phosphatase at least twice the upper limit of normal): a placebo-controlled, multinational study and a U.S. comparative study with etidronate disodium 400 mg/day. Figure 6 shows the mean percent changes from baseline in serum alkaline phosphatase for up to six months of randomized treatment. Figure 6: Studies in Paget's Disease of Bone Effect on Serum Alkaline Phosphates of Alendronate Sodium 40 mg/day Versus Placebo or Etidronate 400 mg/day At six months the suppression in alkaline phosphatase in patients treated with alendronate sodium was significantly greater than that achieved with etidronate and contrasted with the complete lack of response in placebo-treated patients. Response (defined as either normalization of serum alkaline phosphatase or decrease from baseline ≥ 60%) occurred in approximately 85% of patients treated with alendronate sodium in the combined studies vs. 30% in the etidronate group and 0% in the placebo group. Alendronate sodium was similarly effective regardless of age, gender, race, prior use of other bisphosphonates, or baseline alkaline phosphatase within the range studied (at least twice the upper limit of normal). Bone histology was evaluated in 33 patients with Paget’s disease treated with alendronate sodium 40 mg/day for 6 months. As in patients treated for osteoporosis [see Clinical Studies (14.1)], alendronate sodium did not impair mineralization, and the expected decrease in the rate of bone turnover was observed. Normal lamellar bone was produced during treatment with alendronate sodium, even where preexisting bone was woven and disorganized. Overall, bone histology data support the conclusion that bone formed during treatment with alendronate sodium is of normal quality. figure 6

HOW SUPPLIED

16 /STORAGE AND HANDLING 70 mg – white to off-white, pillow-shaped, convex, unscored tablet debossed with “93” on one side and “5171” on the other side, in unit-of-use blister packages of 4. Storage 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, with a child-resistant closure (as required).

GERIATRIC USE

8.5 Geriatric Use Of the patients receiving alendronate sodium in the Fracture Intervention Trial (FIT), 71% (n = 2302) were ≥ 65 years of age and 17% (n = 550) were ≥ 75 years of age. Of the patients receiving alendronate sodium in the United States and Multinational osteoporosis treatment studies in women, osteoporosis studies in men, glucocorticoid-induced osteoporosis studies, and Paget’s disease studies [see Clinical Studies (14.1), (14.3), (14.4), (14.5)], 45%, 54%, 37%, and 70%, respectively, were 65 years of age or over. No overall differences in efficacy or safety were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

DOSAGE FORMS AND STRENGTHS

3 5 mg tablets are white to off-white, round flat-faced beveled-edge, unscored tablet debossed with “93” on one side and “5140” on the other. 10 mg tablets are white to off-white, round, convex, unscored tablet debossed with “93” on one side and “5141” on the other. 35 mg tablets are white to off-white, pillow-shaped, convex, unscored tablet debossed with “93” on one side and “5172” on the other. 40 mg tablets are white to off-white, oval convex, unscored tablet debossed with “93” on one side and “5142” on the other. 70 mg tablets are white to off-white, pillow-shaped, convex, unscored tablet debossed with “93” on one side and “5171” on the other side, 5 mg, 10 mg, 35 mg, 40 mg and 70 mg tablets (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Animal studies have indicated the following mode of action. At the cellular level, alendronate shows preferential localization to sites of bone resorption, specifically under osteoclasts. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Studies in mice on the localization of radioactive [3H]alendronate in bone showed about 10 fold higher uptake on osteoclast surfaces than on osteoblast surfaces. Bones examined 6 and 49 days after [3H]alendronate administration in rats and mice, respectively, showed that normal bone was formed on top of the alendronate, which was incorporated inside the matrix. While incorporated in bone matrix, alendronate is not pharmacologically active. Thus, alendronate must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Histomorphometry in baboons and rats showed that alendronate treatment reduces bone turnover (i.e., the number of sites at which bone is remodeled). In addition, bone formation exceeds bone resorption at these remodeling sites, leading to progressive gains in bone mass.

INDICATIONS AND USAGE

1 Alendronate sodium tablets USP are a bisphosphonate indicated for: Treatment and prevention of osteoporosis in postmenopausal women (1.1, 1.2) Treatment to increase bone mass in men with osteoporosis (1.3) Treatment of glucocorticoid-induced osteoporosis (1.4) Treatment of Paget’s disease of bone (1.5) Important limitations of use: The optimal duration of use has not been determined. The need for continued therapy should be re-evaluated on a periodic basis. (1.6) 1.1 Treatment of Osteoporosis in Postmenopausal Women Alendronate sodium tablets USP are indicated for the treatment of osteoporosis in postmenopausal women. In postmenopausal women, alendronate sodium tablets USP increase bone mass and reduces the incidence of fractures, including those of the hip and spine (vertebral compression fractures) [see Clinical Studies (14.1)]. 1.2 Prevention of Osteoporosis in Postmenopausal Women Alendronate sodium tablets USP are indicated for the prevention of postmenopausal osteoporosis [see Clinical Studies (14.2)]. 1.3 Treatment to Increase Bone Mass in Men With Osteoporosis Alendronate sodium tablets USP are indicated for treatment to increase bone mass in men with osteoporosis [see Clinical Studies (14.3)]. 1.4 Treatment of Glucocorticoid-Induced Osteoporosis Alendronate sodium tablets USP are indicated for the treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density [see Clinical Studies (14.4)]. 1.5 Treatment of Paget’s Disease of Bone Alendronate sodium tablets USP are indicated for the treatment of Paget’s disease of bone in men and women. Treatment is indicated in patients with Paget’s disease of bone who have alkaline phosphatase at least two times the upper limit of normal, or those who are symptomatic, or those at risk for future complications from their disease [see Clinical Studies (14.5)]. 1.6 Important Limitations of Use The safety and effectiveness of alendronate sodium tablets USP for the treatment of osteoporosis are based on clinical data of four years duration. The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.

PEDIATRIC USE

8.4 Pediatric Use Alendronate sodium is not indicated for use in pediatric patients. The safety and efficacy of alendronate sodium were examined in a randomized, double-blind, placebo-controlled two-year study of 139 pediatric patients, aged 4 to 18 years, with severe osteogenesis imperfecta (OI). One-hundred-and-nine patients were randomized to 5 mg alendronate sodium daily (weight < 40 kg) or 10 mg alendronate sodium daily (weight ≥ 40 kg) and 30 patients to placebo. The mean baseline lumbar spine BMD Z-score of the patients was -4.5. The mean change in lumbar spine BMD Z-score from baseline to Month 24 was 1.3 in the alendronate sodium-treated patients and 0.1 in the placebo-treated patients. Treatment with alendronate sodium did not reduce the risk of fracture. Sixteen percent of the alendronate sodium patients who sustained a radiologically-confirmed fracture by Month 12 of the study had delayed fracture healing (callus remodeling) or fracture non-union when assessed radiographically at Month 24 compared with 9% of the placebo-treated patients. In alendronate sodium-treated patients, bone histomorphometry data obtained at Month 24 demonstrated decreased bone turnover and delayed mineralization time; however, there were no mineralization defects. There were no statistically significant differences between the alendronate sodium and placebo groups in reduction of bone pain. The oral bioavailability in children was similar to that observed in adults. The overall safety profile of alendronate sodium in OI patients treated for up to 24 months was generally similar to that of adults with osteoporosis treated with alendronate sodium. However, there was an increased occurrence of vomiting in OI patients treated with alendronate sodium compared to placebo. During the 24 month treatment period, vomiting was observed in 32 of 109 (29.4%) patients treated with alendronate sodium and 3 of 30 (10%) patients treated with placebo. In a pharmacokinetic study, 6 of 24 pediatric OI patients who received a single oral dose of alendronate sodium 35 or 70 mg developed fever, flu-like symptoms, and/or mild lymphocytopenia within 24 to 48 hours after administration. These events, lasting no more than 2 to 3 days and responding to acetaminophen, are consistent with an acute-phase response that has been reported in patients receiving bisphosphonates, including alendronate sodium [see Adverse Reactions (6.2)].

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy category C There are no studies in pregnant women. Alendronate sodium should be used during pregnancy only if the potential benefit justifies the potential risk to the mother and fetus. Bisphosphonates are incorporated into the bone matrix, from which they are gradually released over a period of years. The amount of bisphosphonate incorporated into adult bone, and hence, the amount available for release back into the systemic circulation, is directly related to the dose and duration of bisphosphonate use. There are no data on fetal risk in humans. However, there is a theoretical risk of fetal harm, predominantly skeletal, if a woman becomes pregnant after completing a course of bisphosphonate therapy. The impact of variables such as time between cessation of bisphosphonate therapy to conception, the particular bisphosphonate used, and the route of administration (intravenous versus oral) on the risk has not been studied. Reproduction studies in rats showed decreased postimplantation survival and decreased body weight gain in normal pups at doses less than half of the recommended clinical dose. Sites of incomplete fetal ossification were statistically significantly increased in rats beginning at approximately 3 times the clinical dose in vertebral (cervical, thoracic, and lumbar), skull, and sternebral bones. No similar fetal effects were seen when pregnant rabbits were treated with doses approximately 10 times the clinical dose. Both total and ionized calcium decreased in pregnant rats at approximately 4 times the clinical dose resulting in delays and failures of delivery. Protracted parturition due to maternal hypocalcemia occurred in rats at doses as low as one tenth the clinical dose when rats were treated from before mating through gestation. Maternotoxicity (late pregnancy deaths) also occurred in the female rats treated at approximately 4 times the clinical dose for varying periods of time ranging from treatment only during pre-mating to treatment only during early, middle, or late gestation; these deaths were lessened but not eliminated by cessation of treatment. Calcium supplementation either in the drinking water or by minipump could not ameliorate the hypocalcemia or prevent maternal and neonatal deaths due to delays in delivery; intravenous calcium supplementation prevented maternal, but not fetal deaths. Exposure multiples based on surface area, mg/m2, were calculated using a 40 mg human daily dose. Animal dose ranged between 1 and 15 mg/kg/day in rats and up to 40 mg/kg/day in rabbits.

NUSRING MOTHERS

8.3 Nursing Mothers It is not known whether alendronate sodium is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when alendronate sodium is administered to nursing women.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Severe irritation of upper gastrointestinal (GI) mucosa can occur. Follow dosing instructions. Use caution in patients with active upper GI disease. Discontinue if new or worsening symptoms occur. (5.1) Hypocalcemia can worsen and must be corrected prior to use. (5.2) Severe bone, joint, muscle pain may occur. Discontinue use if severe symptoms develop. (5.3) Osteonecrosis of the jaw has been reported. (5.4) Atypical femur fractures have been reported. Evaluate new thigh or groin pain to rule out an incomplete femoral fracture. (5.5) 5.1 Upper Gastrointestinal Adverse Reactions Alendronate sodium, like other bisphosphonates administered orally, may cause local irritation of the upper gastrointestinal mucosa. Because of these possible irritant effects and a potential for worsening of the underlying disease, caution should be used when alendronate sodium are given to patients with active upper gastrointestinal problems (such as known Barrett’s esophagus, dysphagia, other esophageal diseases, gastritis, duodenitis, or ulcers). Esophageal adverse experiences, such as esophagitis, esophageal ulcers and esophageal erosions, occasionally with bleeding and rarely followed by esophageal stricture or perforation, have been reported in patients receiving treatment with oral bisphosphonates including alendronate sodium. In some cases these have been severe and required hospitalization. Physicians should therefore be alert to any signs or symptoms signaling a possible esophageal reaction and patients should be instructed to discontinue alendronate sodium and seek medical attention if they develop dysphagia, odynophagia, retrosternal pain or new or worsening heartburn. The risk of severe esophageal adverse experiences appears to be greater in patients who lie down after taking oral bisphosphonates including alendronate sodium and/or who fail to swallow oral bisphosphonates including alendronate sodium with the recommended full glass (6 to 8 oz) of water, and/or who continue to take oral bisphosphonates including alendronate sodium after developing symptoms suggestive of esophageal irritation. Therefore, it is very important that the full dosing instructions are provided to, and understood by, the patient [see Dosage and Administration (2.6)]. In patients who cannot comply with dosing instructions due to mental disability, therapy with alendronate sodium should be used under appropriate supervision. There have been postmarketing reports of gastric and duodenal ulcers with oral bisphosphonate use, some severe and with complications, although no increased risk was observed in controlled clinical trials [see Adverse Reactions (6.2)]. 5.2 Mineral Metabolism Hypocalcemia must be corrected before initiating therapy with alendronate sodium [see Contraindications (4)]. Other disorders affecting mineral metabolism (such as vitamin D deficiency) should also be effectively treated. In patients with these conditions, serum calcium and symptoms of hypocalcemia should be monitored during therapy with alendronate sodium. Presumably due to the effects of alendronate sodium on increasing bone mineral, small, asymptomatic decreases in serum calcium and phosphate may occur, especially in patients with Paget’s disease, in whom the pretreatment rate of bone turnover may be greatly elevated, and in patients receiving glucocorticoids, in whom calcium absorption may be decreased. Ensuring adequate calcium and vitamin D intake is especially important in patients with Paget’s disease of bone and in patients receiving glucocorticoids. 5.3 Musculoskeletal Pain In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking bisphosphonates that are approved for the prevention and treatment of osteoporosis [see Adverse Reactions (6.2)]. This category of drugs includes alendronate sodium. Most of the patients were postmenopausal women. The time to onset of symptoms varied from one day to several months after starting the drug. Discontinue use if severe symptoms develop. Most patients had relief of symptoms after stopping. A subset had recurrence of symptoms when rechallenged with the same drug or another bisphosphonate. In placebo-controlled clinical studies of alendronate sodium, the percentages of patients with these symptoms were similar in the alendronate sodium and placebo groups. 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing, and has been reported in patients taking bisphosphonates, including alendronate sodium. Known risk factors for osteonecrosis of the jaw include invasive dental procedures (e.g., tooth extraction, dental implants, boney surgery), diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids), poor oral hygiene, and co-morbid disorders (e.g., periodontal and/or other preexisting dental disease, anemia, coagulopathy, infection, ill-fitting dentures). For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ. Clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit/risk assessment. Patients who develop osteonecrosis of the jaw while on bisphosphonate therapy should receive care by an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of bisphosphonate therapy should be considered based on individual benefit/risk assessment. 5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical, low-energy, or low trauma fractures of the femoral shaft have been reported in bisphosphonate-treated patients. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with bisphosphonates. Atypical femur fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g., prednisone) at the time of fracture. Any patient with a history of bisphosphonate exposure who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients presenting with an atypical fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of bisphosphonate therapy should be considered, pending a risk/benefit assessment, on an individual basis. 5.6 Renal Impairment Alendronate sodium is not recommended for patients with creatinine clearance < 35 mL/min [see Dosage and Administration (2.8)]. 5.7 Glucocorticoid-Induced Osteoporosis The risk versus benefit of alendronate sodium for treatment at daily dosages of glucocorticoids less than 7.5 mg of prednisone or equivalent has not been established [see Indications and Usage (1.4)]. Before initiating treatment, the gonadal hormonal status of both men and women should be ascertained and appropriate replacement considered. A bone mineral density measurement should be made at the initiation of therapy and repeated after 6 to 12 months of combined alendronate sodium and glucocorticoid treatment.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Physicians should instruct their patients to read the Medication Guide before starting therapy with alendronate sodium and to reread it each time the prescription is renewed. 17.1 Osteoporosis Recommendations, Including Calcium and Vitamin D Supplementation Patients should be instructed to take supplemental calcium and vitamin D, if daily dietary intake is inadequate. Weight-bearing exercise should be considered along with the modification of certain behavioral factors, such as cigarette smoking and/or excessive alcohol consumption, if these factors exist. 17.2 Dosing Instructions Patients should be instructed that the expected benefits of alendronate sodium may only be obtained when it is taken with plain water the first thing upon arising for the day at least 30 minutes before the first food, beverage, or medication of the day. Even dosing with orange juice or coffee has been shown to markedly reduce the absorption of alendronate sodium [see Clinical Pharmacology (12.3)]. Patients should not chew or suck on the tablet because of a potential for oropharyngeal ulceration. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, patients should be instructed to swallow each tablet of alendronate sodium with a full glass of water (6 to 8 oz). Patients should be instructed not to lie down for at least 30 minutes and until after their first food of the day. Patients should be specifically instructed not to take alendronate sodium at bedtime or before arising for the day. Patients should be informed that failure to follow these instructions may increase their risk of esophageal problems. Patients should be instructed that if they develop symptoms of esophageal disease (such as difficulty or pain upon swallowing, retrosternal pain or new or worsening heartburn) they should stop taking alendronate sodium and consult their physician. Patients should be instructed that if they miss a dose of once weekly alendronate sodium, they should take one dose on the morning after they remember. They should not take two doses on the same day but should return to taking one dose once a week, as originally scheduled on their chosen day. TEVA PHARMACEUTICALS USA Sellersville, PA 18960 Rev. L 2/2012

DOSAGE AND ADMINISTRATION

2 Must be taken with 6 to 8 oz plain water at least 30 minutes before the first food, drink, or medication of the day; do not lie down for at least 30 minutes after taking alendronate sodium tablets USP and until after food. (2.6) Treatment of osteoporosis in postmenopausal women and in men: 10 mg daily or 70 mg (tablet or oral solution) once weekly. (2.1, 2.3) Prevention of osteoporosis in postmenopausal women: 5 mg daily or 35 mg once weekly. (2.2) Glucocorticoid-induced osteoporosis: 5 mg daily; or 10 mg daily in postmenopausal women not receiving estrogen. (2.4) Paget’s disease: 40 mg daily for six months. (2.5) 2.1 Treatment of Osteoporosis in Postmenopausal Women The recommended dosage is: one 70 mg tablet once weekly or one 10 mg tablet once daily 2.2 Prevention of Osteoporosis in Postmenopausal Women The recommended dosage is: one 35 mg tablet once weekly or one 5 mg tablet once daily 2.3 Treatment to Increase Bone Mass in Men With Osteoporosis The recommended dosage is: one 70 mg tablet once weekly or one 10 mg tablet once daily 2.4 Treatment of Glucocorticoid-Induced Osteoporosis The recommended dosage is one 5 mg tablet once daily, except for postmenopausal women not receiving estrogen, for whom the recommended dosage is one 10 mg tablet once daily. 2.5 Treatment of Paget’s Disease of Bone The recommended treatment regimen is 40 mg once a day for six months. Re-treatment of Paget’s Disease Re-treatment with alendronate sodium tablets USP may be considered, following a six-month post-treatment evaluation period in patients who have relapsed, based on increases in serum alkaline phosphatase, which should be measured periodically. Re-treatment may also be considered in those who failed to normalize their serum alkaline phosphatase. 2.6 Dosing Instructions Alendronate sodium tablets USP must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only [see Patient Counseling Information (17.2)]. Other beverages (including mineral water), food, and some medications are likely to reduce the absorption of alendronate sodium tablets USP [see Drug Interactions (7.1)]. Waiting less than 30 minutes, or taking alendronate sodium tablets USP with food, beverages (other than plain water) or other medications will lessen the effect of alendronate sodium tablets USP by decreasing its absorption into the body Alendronate sodium tablets USP should only be taken upon arising for the day. To facilitate delivery to the stomach and thus reduce the potential for esophageal irritation, alendronate sodium tablets USP should be swallowed with a full glass of water (6 to 8 oz). Patients should not lie down for at least 30 minutes and until after their first food of the day. Alendronate sodium tablets USP should not be taken at bedtime or before arising for the day. Failure to follow these instructions may increase the risk of esophageal adverse experiences [see Warnings and Precautions (5.1) and Patient Counseling Information (17.2)]. 2.7 Recommendations for Calcium and Vitamin D Supplementation Patients should receive supplemental calcium if dietary intake is inadequate [see Warnings and Precautions (5.2)]. Patients at increased risk for vitamin D insufficiency (e.g., over the age of 70 years, nursing home-bound, or chronically ill) may need vitamin D supplementation. Patients with gastrointestinal malabsorption syndromes may require higher doses of vitamin D supplementation and measurement of 25-hydroxyvitamin D should be considered. Patients treated with glucocorticoids should receive adequate amounts of calcium and vitamin D. 2.8 Dosing in Severe Renal Impairment Alendronate sodium tablets USP are not recommended for patients with creatinine clearance < 35 mL/min due to lack of experience in this population [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

EEMT DS Oral Tablet

Generic Name: ESTERIFIED ESTROGENS AND METHYLTESTOSTERONE

Brand Name: Esterified Estrogens and Methyltestosterone

Substance Name(s):
ESTROGENS, CONJUGATED
METHYLTESTOSTERONE

WARNINGS

See BOXED . Warnings Associated with Estrogens Cardiovascular Disorders Estrogen and estrogen/progestin therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogens should be discontinued immediately. Risk factors for arterial vascular disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (e.g., personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. Coronary Heart Disease and Stroke: In the Women’s Health Initiative (WHI) study, an increase in the number of myocardial infarctions and strokes was observed in women receiving CE compared to placebo. The CE-only substudy has concluded. The impact of those results are under review. (See CLINICAL PHARMACOLOGY, Clinical Studies .) In the CE/MPA substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE/MPA compared to women receiving placebo (37 versus 30 per 10,000 women-years). The increase in risk was observed in year 1 and persisted. In the same substudy of WHI, an increased risk of stroke was observed in women receiving CE/MPA compared to women receiving placebo (29 versus 21 per 10,000 women-years). The increase in risk was observed after the first year and persisted. In postmenopausal women with documented heart disease (n = 2,763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS) treatment with CE/MPA (0.625 mg/2.5 mg per day) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE/MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the CE/MPA-treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE/MPA group and the placebo group in HERS, HERS II, and overall. Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. Venous Thromboembolism (VTE.): In the Women’s Health Initiative (WHI) study, an increase in VTE was observed in women receiving CE compared to placebo. The CE-only substudy has concluded. The impact of those results are under review. (See CLINICAL PHARMACOLOGY, Clinical Studies.) In the CE/MPA substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CE/MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE/MPA group compared to 16 per 10,000 women-years in the placebo group. The increase in VTE risk was observed during the first year and persisted. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Malignant Neoplasms Endometrial Cancer: The use of unopposed estrogens in women with intact uteri has been associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. Clinical surveillance of all women taking estrogen/progestin combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Breast Cancer: The use of estrogens and progestins by postmenopausal women has been reported to increase the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women’s Health Initiative (WHI) substudy of CE/MPA. (See CLINICAL PHARMACOLOGY, Clinical Studies .) The results from observational studies are generally consistent with those of the WHI clinical trial and report no significant variation in the risk of breast cancer among different estrogens or progestins, doses, or routes of administration. The CE/MPA substudy of WHI reported an increased risk of breast cancer in women who took CE/MPA for a mean follow-up of 5.6 years. Observational studies have also reported an increased risk for estrogen/progestin combination therapy, and a smaller increased risk for estrogen alone therapy, after several years of use. In the WHI trial and from observational studies, the excess risk increased with duration of use. From observational studies, the risk appeared to return to baseline in about five years after stopping treatment. In addition, observational studies suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen/progestin combination therapy as compared to estrogen alone therapy. In the CE/MPA substudy, 26% of the women reported prior use of estrogen alone and/or estrogen/progestin combination hormone therapy. After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% confidence interval 1.01-1.54), and the overall absolute risk was 41 versus 33 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE/MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE/MPA compared with placebo. In the same substudy, invasive breast cancers were larger and diagnosed at a more advanced stage in the CE/MPA group compared with the placebo group. Metastatic disease was rare with no apparent difference between the two groups. Other prognostic factors such as histologic subtype, grade and hormone receptor status did not differ between the groups. The use of estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results. Dementia In the Women’s Health Initiative Memory Study (WHIMS), 4,532 generally healthy postmenopausal women 65 years of age and older were studied, of whom 35% were 70 to 74 years of age and 18% were 75 or older. After an average follow-up of 4 years, 40 women being treated with CE/MPA (1.8%, n = 2,229) and 21 women in the placebo group (0.9%, n = 2,303) received diagnoses of probable dementia. The relative risk for CE/MPA versus placebo was 2.05 (95% confidence interval 1.21 – 3.48), and was similar for women with and without histories of menopausal hormone use before WHIMS. The absolute risk of probable dementia for CE/MPA versus placebo was 45 versus 22 cases per 10,000 women-years, and the absolute excess risk for CE/MPA was 23 cases per 10,000 women-years. It is unknown whether these findings apply to younger postmenopausal women. (See CLINICAL PHARMACOLOGY, Clinical Studies and PRECAUTIONS, Geriatric Use .) The estrogen alone substudy of the Women’s Health Initiative Memory Study has concluded. It is unknown whether these findings apply to estrogen alone. Gallbladder Disease A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported. Glucose Tolerance A worsening of glucose tolerance has been observed in a significant percentage of patients on estrogen-containing oral contraceptives. For this reason, diabetic patients should be carefully observed while receiving estrogens. Hypercalcemia Estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level. Visual Abnormalities Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued. Warnings Associated with Methyltestosterone In patients with breast cancer, androgen therapy may cause hypercalcemia by stimulating osteolysis. In this case the drug should be discontinued. Prolonged use of high doses of androgens has been associated with the development of peliosis hepatis and hepatic neoplasms including hepatocellular carcinoma. [See PRECAUTIONS, Carcinogenesis (Androgens) .] Peliosis hepatis can be a life-threatening or fatal complication. Cholestatic hepatitis and jaundice occur with 17-alpha-alkylandrogens at a relatively low dose. If cholestatic hepatitis with jaundice appears or if liver function tests become abnormal, the androgen should be discontinued and the etiology should be determined. Drug-induced jaundice is reversible when the medication is discontinued. Edema with or without heart failure may be a serious complication in patients with preexisting cardiac, renal, or hepatic disease. In addition to discontinuation of the drug, diuretic therapy may be required.

OVERDOSAGE

Serious ill effects have not been reported following acute ingestion of large doses of estrogen-containing drug products by young children. Overdosage of estrogen may cause nausea and vomiting, and withdrawal bleeding may occur in females. There have been no reports of acute overdosage with the androgens.

DESCRIPTION

Esterified Estrogens and Methyltestosterone Tablets: Each green, oval, aqueous film coated tablet debossed “IP 78” on obverse and plain on the reverse contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP. Esterified Estrogens and Methyltestosterone Tablets H.S. (Half Strength): Each light blue, capsule-shaped, aqueous film coated tablet debossed “IP 77” on obverse and plain on the reverse contains: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP. Esterified Estrogens Esterified Estrogens, USP is a mixture of the sodium salts of the sulfate esters of the estrogenic substances, principally estrone, that are of the type excreted by pregnant mares. Esterified Estrogens contain not less than 75.0 percent and not more than 85.0 percent of sodium estrone sulfate, and not less than 6.0 percent and not more than 15.0 percent of sodium equilin sulfate, in such proportion that the total of these two components is not less than 90.0 percent. Methyltestosterone Methyltestosterone, USP is an androgen. Androgens are derivatives of cyclopentano-perhydrophenanthrene. Endogenous androgens are C-19 steroids with a side chain at C-17, and with two angular methyl groups. Testosterone is the primary endogenous androgen. Fluoxymesterone and methyltestosterone are synthetic derivatives of testosterone. Methyltestosterone is a white to light yellow crystalline substance that is virtually insoluble in water but soluble in organic solvents. It is stable in air but decomposes in light. Methyltestosterone structural formula: Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. contain the following inactive ingredients: Anhydrous Lactose, Colloidal Silicon Dioxide, D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, Magnesium Stearate, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinyl Alcohol, Sodium Bicarbonate, Talc and Titanium Dioxide. chemical structure

HOW SUPPLIED

Esterified Estrogens and Methyltestosterone Tablets, a combination of Esterified Estrogens and Methyltestosterone. Each green, oval, aqueous film coated tablet debossed “IP 78” on obverse and plain on the reverse contains: 1.25 mg of Esterified Estrogens, USP and 2.5 mg of Methyltestosterone, USP. Available in bottles of 100: NDC 13925-172-01 Esterified Estrogens and Methyltestosterone Tablets H.S. “Half Strength,” a combination of Esterifed Estrogens and Methyltestosterone. Each light blue, capsule- shaped, aqueous film coated tablet debossed “IP 77” on obverse and plain on the reverse contains: 0.625 mg of Esterified Estrogens, USP and 1.25 mg of Methyltestosterone, USP. Available in bottles of 100: NDC 13925-171-01 Keep Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. out of reach of children. Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] ‡ This product has not obtained FDA pre-market approval applicable for new drugs. Manufactured by: Amneal Pharmaceuticals of NY Hauppauge, NY 11788 Distributed by: Seton Pharmaceuticals Manasquan, NJ 08736 Rev. 04-2014

INDICATIONS AND USAGE

Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. are indicated in the: Treatment of moderate to severe vasomotor symptoms associated with the menopause in those patients not improved by estrogens alone. (There is no evidence that estrogens are effective for nervous symptoms or depression without associated vasomotor symptoms, and they should not be used to treat such conditions.) Esterified Estrogens and Methyltestosterone Tablets and Esterified Estrogens and Methyltestosterone Tablets H.S. have not been shown to be effective for any purpose during pregnancy and its use may cause severe harm to the fetus.

BOXED WARNING

ESTROGENS INCREASE THE RISK OF ENDOMETRIAL CANCER Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of “natural” estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. (See WARNINGS, Malignant Neoplasms, Endometrial Cancer.) CARDIOVASCULAR AND OTHER RISKS Estrogens with or without progestins should not be used for the prevention of cardiovascular disease. (See WARNINGS, Cardiovascular Disorders.) The Women’s Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (CE 0.625 mg) combined with medroxyprogesterone acetate (MPA 2.5 mg) relative to placebo. (See CLINICAL PHARMACOLOGY, Clinical Studies.) The Women’s Health Initiative Memory Study (WHIMS), a substudy of WHI, reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy. (See CLINICAL PHARMACOLOGY, Clinical Studies.) Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

DOSAGE AND ADMINISTRATION

When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. A woman without a uterus does not need progestin. Use of estrogen, alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman. Patients should be reevaluated periodically as clinically appropriate (e.g., 3-month to 6-month intervals) to determine if treatment is still necessary. (See BOXED WARNINGS and WARNINGS .) For women who have a uterus, adequate diagnostic measures, such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Given cyclically for short-term use only: For treatment of moderate to severe vasomotor symptoms associated with the menopause in patients not improved by estrogen alone. The lowest dose that will control symptoms should be chosen and medication should be discontinued as promptly as possible. Administration should be cyclic (e.g., three weeks on and one week off). Attempts to discontinue or taper medication should be made at three- to six-month intervals. Usual Dosage Range: 1 tablet of Esterified Estrogens and Methyltestosterone Tablets or 1 to 2 tablets of Esterified Estrogens and Methyltestosterone Tablets H.S. daily as recommended by the physician. Treated patients with an intact uterus should be monitored closely for signs of endometrial cancer and appropriate diagnostic measures should be taken to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding.