Phentermine

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other sections: Primary pulmonary hypertension [see Warnings and Precautions (5.2) ] Valvular heart disease [see Warnings and Precautions (5.3) ] Effect on the ability to engage in potentially hazardous tasks [see Warnings and Precautions (5.5) ] Withdrawal effects following prolonged high dosage administration [see Drug Abuse and Dependence (9.3) ] The following adverse reactions to phentermine have been identified: Cardiovascular Primary pulmonary hypertension and/or regurgitant cardiac valvular disease, palpitation, tachycardia, elevation of blood pressure, ischemic events. Central Nervous System Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache, psychosis. Gastrointestinal Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Allergic Urticaria. Endocrine Impotence, changes in libido. Adverse events have been reported in the cardiovascular, central nervous, gastrointestinal, allergic, and endocrine systems. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

4 CONTRAINDICATIONS History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension) During or within 14 days following the administration of monoamine oxidase inhibitors Hyperthyroidism Glaucoma Agitated states History of drug abuse Pregnancy [see Use in Specific Populations (8.1) ] Nursing [see Use in Specific Populations (8.3) ] Known hypersensitivity, or idiosyncrasy to the sympathomimetic amines History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension) ( 4 ) During or within 14 days following the administration of monoamine oxidase inhibitors ( 4 ) Hyperthyroidism ( 4 ) Glaucoma ( 4 ) Agitated states. ( 4 ) History of drug abuse ( 4 ) Pregnancy ( 4 , 8.1 ) Nursing ( 4 , 8.3 ) Known hypersensitivity, or idiosyncrasy to the sympathomimetic amines ( 4 )

11 DESCRIPTION Phentermine hydrochloride is a sympathomimetic amine anorectic. Its chemical name is a,a,-dimethylphenethylamine hydrochloride. The structural formula is as follows: Phentermine hydrochloride is a white, odorless, hygroscopic, crystalline powder which is soluble in water and lower alcohols, slightly soluble in chloroform and insoluble in ether. Phentermine hydrochloride capsule USP is available as an oral capsule containing 15 mg or 30 mg phentermine hydrochloride (equivalent to 12 mg or 24 mg of phentermine base) Powder-filled capsules containing 15 mg phentermine hydrochloride (equivalent to 12 mg phentermine) or 30 mg phentermine hydrochloride (equivalent to 24 mg phentermine) and inactive ingredients: lactose monohydrate, magnesium stearate, iron oxide black, Shellac Glaze, N-Butyl alcohol, Isopropyl alcohol, propylene Glycol and Ammonium Hydroxide. In addition, the 15 mg capsules contain gelatin, titanium dioxide, D&C yellow # 10, FD&C yellow # 6, FD&C red # 40, FD&C blue # 1 and FD&C yellow # 5; the 30 mg capsules contain gelatin, titanium dioxide, iron oxide yellow and iron oxide red. Structural Formula

2 DOSAGE & ADMINISTRATION Dosage should be individualized to obtain an adequate response with the lowest effective dose. ( 2.1 ) Late evening administration should be avoided (risk of insomnia). ( 2.1 ) Phentermine hydrochloride Capsules can be taken with or without food. ( 2.1 ) Limit the dosage to 15 mg daily for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2 ) ( 2.2 ) 2.1 Exogenous Obesity Dosage should be individualized to obtain an adequate response with the lowest effective dose. The usual adult dose is 15 mg to 30 mg as prescribed by the physician, at approximately 2 hours after breakfast for appetite control. Administration of one 30 mg capsule daily has been found to be adequate in depression of the appetite for 12 to 14 hours. Phentermine is not recommended for use in pediatric patient’s≤16 years of age. Late evening medication should be avoided because of the possibility of resulting insomnia. With dry hands, gently remove the Phentermine Hydrochloride Capsule from the bottle. Immediately place the Phentermine Hydrochloride Capsule on top of the tongue where it will dissolve, then swallow with or without water. 2.2 Dosage in Patients with Renal Impairment The recommended maximum dosage of Phentermine Hydrochloride Capsule is 15 mg daily for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73m 2 ). Avoid use of Phentermine Hydrochloride Capsule in patients with eGFR less than 15 mL/min/1.73m 2 or end-stage renal disease requiring dialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ]

1 INDICATIONS & USAGE Phentermine hydrochloride Capsules are indicated as a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index greater than or equal to 30 kg/m 2 , or greater than or equal to 27 kg/m 2 in the presence of other risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia). Below is a chart of body mass index (BMI) based on various heights and weights. BMI is calculated by taking the patient’s weight, in kilograms (kg), divided by the patient’s height, in meters (m), squared. Metric conversions are as follows: pounds ÷ 2.2 = kg; inches x 0.0254 = meters. BODY MASS INDEX (BMI), kg/m 2 Height ( fe et , inches) Weight (pounds) 5’0” 5’3” 5’6” 5’9” 6’0” 6’3” 140 27 25 23 21 19 18 150 29 27 24 22 20 19 160 31 28 26 24 22 20 170 33 30 28 25 23 21 180 35 32 29 27 25 23 190 37 34 31 28 26 24 200 39 36 32 30 27 25 210 41 37 34 31 29 26 220 43 39 36 33 30 28 230 45 41 37 34 31 29 240 47 43 39 36 33 30 250 49 44 40 37 34 31 The limited usefulness of agents of this class, including phentermine, [see Clinical Pharmacology ( 12.1 , 12.2 ) ] should be measured against possible risk factors inherent in their use such as those described below. Phentermine hydrochloride is a sympathomimetic amine anorectic indicated as a short-term adjunct (a few weeks) in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity for patients with an initial body mass index greater than or equal to 30 kg/m2, or greater than or equal to 27 kg/m2 in the presence of other risk factors (e.g., controlled hypertension, diabetes, hyperlipidemia). ( 1 ) The limited usefulness of agents of this class, including Phentermine Hydrochloride Capsules USP, should be measured against possible risk factors inherent in their use. ( 1 )

9.2 Abuse Phentermine is related chemically and pharmacologically to the amphetamines. Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program.

9.1 Controlled Substance Phentermine is a Schedule IV controlled substance.

9.3 Dependence Abuse of amphetamines and related drugs may be associated with intense psychological dependence and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. A severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Phentermine is a Schedule IV controlled substance. 9.2 Abuse Phentermine is related chemically and pharmacologically to the amphetamines. Amphetamines and other stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. 9.3 Dependence Abuse of amphetamines and related drugs may be associated with intense psychological dependence and severe social dysfunction. There are reports of patients who have increased the dosage of these drugs to many times than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. A severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.

10 OVERDOSAGE 10.1 Acute Overdosage Manifestations of acute overdosage include restlessness, tremor, hyperreflexia, rapid respiration, confusion, assaultiveness, hallucinations, and panic states. Fatigue and depression usually follow the central stimulation. Cardiovascular effects include arrhythmia, hypertension or hypotension, and circulatory collapse. Gastrointestinal symptoms include nausea, vomiting, diarrhea and abdominal cramps. Overdosage of pharmacologically similar compounds has resulted in fatal poisoning usually terminates in convulsions and coma. Management of acute phentermine hydrochloride intoxication is largely symptomatic and includes lavage and sedation with a barbiturate. Experience with hemodialysis or peritoneal dialysis is inadequate to permit recommendations in this regard.Acidification of the urine increases phentermine excretion. Intravenous phentolamine (Regitine ® , CIBA) has been suggested on pharmacologic grounds for possible acute, severe hypertension, if this complicates overdosage. 10.2 Chronic Intoxication Manifestations of chronic intoxication with anorectic drugs include severe dermatoses, marked insomnia, irritability, hyperactivity and personality changes. The most severe manifestation of chronic intoxications is psychosis, often clinically indistinguishable from schizophrenia. See Drug Abuse and Dependence (9.3) .

7 DRUG INTERACTIONS Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis. · Monoamine oxidase inhibitors: Risk of hypertensive crisis. ( 4 , 7.1 ) · Alcohol: Consider potential interaction. ( 7.2 ) · Insulin and oral hypoglycemics: Requirements may be altered. ( 7.3 ) · Adrenergic neuron blocking drugs: Hypotensive effect may be decreased by phentermine. ( 7.4 ) 7.1 Monoamine Oxidase Inhibitors Use of phentermine is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors because of the risk of hypertensive crisis. 7.2 Alcohol Concomitant use of alcohol with phentermine may result in an adverse drug reaction. 7.3 Insulin and Oral Hypoglycemic Medications Requirements may be altered [see Warnings and Precautions (5.9) ]. 7.4 Adrenergic Neuron Blocking Drugs Phentermine may decrease the hypotensive effect of adrenergic neuron blocking drugs.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as “anorectics” or “anorexigenics.” It has not been established that the primary action of such drugs in treating obesity is one of appetite suppression since other central nervous system actions, or metabolic effects, may also be involved. 12.2 Pharmacodynamics Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for. 12.3 Pharmacokinetics Following the administration of phentermine, phentermine reaches peak concentrations (C max ) after 3 to 4.4 hours. Drug Interactions In a single-dose study comparing the exposures after oral administration of a combination capsule of 15 mg phentermine and 92 mg topiramate to the exposures after oral administration of a 15 mg phentermine capsule or a 92 mg topiramate capsule, there is no significant topiramate exposure change in the presence of phentermine. However in the presence of topiramate, phentermine C max and AUC increase 13% and 42%, respectively. Specific Populations Renal Impairment Cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions was 62% to 85%. Systemic exposure of phentermine may increase up to 91%, 45%, and 22% in patients with severe, moderate, and mild renal impairment, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6 )].

12.1 Mechanism of Action Phentermine is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d/l-amphetamine). Drugs of this class used in obesity are commonly known as “anorectics” or “anorexigenics.” It has not been established that the primary action of such drugs in treating obesity is one of appetite suppression since other central nervous system actions, or metabolic effects, may also be involved.

12.2 Pharmacodynamics Typical actions of amphetamines include central nervous system stimulation and elevation of blood pressure. Tachyphylaxis and tolerance have been demonstrated with all drugs of this class in which these phenomena have been looked for.

12.3 Pharmacokinetics Following the administration of phentermine, phentermine reaches peak concentrations (C max ) after 3 to 4.4 hours. Drug Interactions In a single-dose study comparing the exposures after oral administration of a combination capsule of 15 mg phentermine and 92 mg topiramate to the exposures after oral administration of a 15 mg phentermine capsule or a 92 mg topiramate capsule, there is no significant topiramate exposure change in the presence of phentermine. However in the presence of topiramate, phentermine C max and AUC increase 13% and 42%, respectively. Specific Populations Renal Impairment Cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions was 62% to 85%. Systemic exposure of phentermine may increase up to 91%, 45%, and 22% in patients with severe, moderate, and mild renal impairment, respectively [see Dosage and Administration (2.2) and Use in Specific Populations (8.6 )].

20190104

4

3 DOSAGE FORMS & STRENGTHS Capsules containing 15 mg or 30 mg phentermine hydrochloride (equivalent to 12 mg or 24 mg phentermine base respectively) 15 mg Capsules: white to off-white powder filled in Size ‘3’ gray opaque/yellow opaque capsules, imprinted with “U47” on cap and body in black ink. 30 mg Capsules: white to off-white powder filled in Size ‘3’ yellow opaque/yellow opaque capsules, imprinted with “U48” on cap and body in black ink. Capsules containing 15 mg or 30 mg phentermine Hydrochloride ( 3 )

Phentermine Phentermine Hydrochloride PHENTERMINE HYDROCHLORIDE PHENTERMINE LACTOSE MONOHYDRATE MAGNESIUM STEARATE GELATIN FD&C BLUE NO. 1 D&C YELLOW NO. 10 FD&C RED NO. 40 TITANIUM DIOXIDE FD&C YELLOW NO. 6 FD&C YELLOW NO. 5 SHELLAC FERROSOFERRIC OXIDE BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA Gray Opaque Yellow Opaque U;47 Phentermine Phentermine Hydrochloride PHENTERMINE HYDROCHLORIDE PHENTERMINE LACTOSE MONOHYDRATE MAGNESIUM STEARATE GELATIN FERRIC OXIDE RED FERRIC OXIDE YELLOW TITANIUM DIOXIDE SHELLAC FERROSOFERRIC OXIDE BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA Yellow Opaque U;48

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Studies have not been performed with phentermine to determine the potential for carcinogenesis, mutagenesis or impairment of fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility Studies have not been performed with phentermine to determine the potential for carcinogenesis, mutagenesis or impairment of fertility.

ANDA204318

Phentermine

Phentermine Hydrochloride

13107-106

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL –Phentermine Hydrochloride Capsules, USP 15 mg - 100 Capsules Label Text NDC 13107-105-30 Phentermine Hydrochloride Capsules, USP CIV 15 mg Rx only 30 Capsules phentermine3-fig1

17 PATIENT COUNSELING INFORMATION Patients must be informed that phentermine hydrochloride is a short-term (a few weeks) adjunct in a regimen of weight reduction based on exercise, behavioral modification and caloric restriction in the management of exogenous obesity, and that coadministration of phentermine with other drugs for weight loss is not recommended [see Indications and Usage (1) and Warnings and Precautions (5) ]. Patients must be instructed on how much phentermine to take, and when and how to take it [see Dosage and Administration (2) ]. Advise pregnant women and nursing mothers not to use phentermine [see Use in Specific Populations ( 8.1 , 8.3) ] . Patients must be informed about the risks of use of phentermine (including the risks discussed in Warnings and Precautions), about the symptoms of potential adverse reactions and when to contact a physician and/or take other action. The risks include, but are not limited to: Development of primary pulmonary hypertension [see Warnings and Precautions (5.2) ] Development of serious valvular heart disease [see Warnings and Precautions (5.3) ] Effects on the ability to engage in potentially hazardous tasks [see Warnings and Precautions (5.5) ] The risk of an increase in blood pressure [see Warnings and Precautions (5.8) and Adverse Reactions (6) ] The risk of interactions [see Contraindications (4) , Warnings and Precautions (5) and Drug Interactions (7) ] See also, for example, Adverse Reactions (6) and Use in Specific Populations (8) . The patients must also be informed about the potential for developing tolerance and actions if they suspect development of tolerance [see Warnings and Precautions (5.4) ] and the risk of dependence and the potential consequences of abuse [see Warnings and Precautions (5.6) , Drug Abuse and Dependence (9) , and Overdosage (10) ]. Tell patients to keep phentermine in a safe place to prevent theft, accidental overdose, misuse or abuse. Selling or giving away phentermine may harm others and is against the law. Revised:03/2017

14 CLINICAL STUDIES In relatively short-term clinical trials, adult obese subjects instructed in dietary management and treated with “anorectic” drugs lost more weight on the average than those treated with placebo and diet. The magnitude of increased weight loss of drug-treated patients over placebo-treated patients is only a fraction of a pound a week. The rate of weight loss is greatest in the first weeks of therapy for both drug and placebo subjects and tends to decrease in succeeding weeks. The possible origins of the increased weight loss due to the various drug effects are not established. The amount of weight loss associated with the use of an “anorectic” drug varies from trial to trial, and the increased weight loss appears to be related in part to variables other than the drugs prescribed, such as the physician-investigator, the population treated and the diet prescribed. Studies do not permit conclusions as to the relative importance of the drug and non-drug factors on weight loss. The natural history of obesity is measured over several years, whereas the studies cited are restricted to a few weeks’ duration; thus, the total impact of drug-induced weight loss over that of diet alone must be considered clinically limited.

8.5 Geriatric Use 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.3 Nursing Mothers It is not known if phentermine is excreted in human milk; however, other amphetamines are present in human milk. Because of the potential for serious adverse reactions in nursing infants, 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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Because pediatric obesity is a chronic condition requiring long-term treatment, the use of this product, approved for short-term therapy, is not recommended.

8.1 Pregnancy Pregnancy Category X Phentermine is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy. Phentermine has pharmacologic activity similar to amphetamine (d- and d/l-amphetamine) [see Clinical Pharmacology (12.1) ]. Animal reproduction studies have not been conducted with phentermine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

8 USE IN SPECIFIC POPULATIONS Nursing mothers: Discontinue drug or nursing taking into consideration importance of drug to mother. ( 4 , 8.3 ) Pediatric use: Safety and effectiveness not established. ( 8.4 ) Geriatric use: Due to substantial renal excretion, use with caution. ( 8.5 ) Renal Impairment: Avoid use in patients with eGFR less than 15 mL/min/m 2 or end-stage renal disease requiring dialysis) ( 8.6 ) 8.1 Pregnancy Pregnancy Category X Phentermine is contraindicated during pregnancy because weight loss offers no potential benefit to a pregnant woman and may result in fetal harm. A minimum weight gain, and no weight loss, is currently recommended for all pregnant women, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy. Phentermine has pharmacologic activity similar to amphetamine (d- and d/l-amphetamine) [see Clinical Pharmacology (12.1) ]. Animal reproduction studies have not been conducted with phentermine. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. 8.3 Nursing Mothers It is not known if phentermine is excreted in human milk; however, other amphetamines are present in human milk. Because of the potential for serious adverse reactions in nursing infants, 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Because pediatric obesity is a chronic condition requiring long-term treatment, the use of this product, approved for short-term therapy, is not recommended. 8.5 Geriatric Use 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. 8.6 Renal Impairment Based on the reported excretion of phentermine in urine, exposure increases can be expected in patients with renal impairment [see Clinical Pharmacology (12.3) ]. Use caution when administering Phentermine to patients with renal impairment. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73m 2 ), limit the dosage of Phentermine to 15 mg daily [see Dosage and Administration (2.2) ]. Phentermine has not been studied in patients with eGFR less than 15 mL/min/1.73m 2 , including end-stage renal disease requiring dialysis; avoid use in these populations.

16 HOW SUPPLIED/STORAGE AND HANDLING Phentermine Hydrochloride Capsules USP, 15 mg are white to off-white powder filled in Size ‘3’ gray opaque/yellow opaque capsules, imprinted with “U47” on cap and body in black ink. Bottles of 30 NDC 13107-105-30 Bottles of 100 NDC 13107-105-01 Phentermine Hydrochloride Capsules USP, 30 mg are white to off-white powder filled in Size ‘3’ yellow opaque/yellow opaque capsules, imprinted with “U48” on cap and body in black ink. Bottles of 30 NDC 13107-106-30 Bottles of 100 NDC 13107-106-01 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Protect from moisture. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). Keep out of the reach of children.