Phentermine Hydrochloride

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 ) ] 1. • 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 (see WARNINGS ), palpitation, tachycardia, elevation of blood pressure. Central Nervous System: Overstimulation, restlessness, dizziness, insomnia, euphoria, dysphoria, tremor, headache; rarely psychotic episodes at recommended doses. Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Allergic: Urticaria. Endocrine: Impotence, changes in libido.

11 DESCRIPTION Phentermine Hydrochloride USP has the chemical name of α, α -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, an anorectic agent for oral administration, is available as: a) 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: corn starch, gelatin, lactose monohydrate and magnesium stearate. In addition, the 15 mg capsules contain D&C Yellow #10, FD&C Blue #1, FD&C Red #3, FD&C Red #40, titanium dioxide and the 30 mg capsules contain D&C Yellow #10, FD&C Red #3, titanium dioxide. b) bead-filled capsules containing 30 mg Phentermine hydrochloride (equivalent to 24 mg Phentermine) and inactive ingredients: corn starch, sucrose, hypromellose, povidone, and talc. In addition, the capsule contains FD&C blue #1/Brilliant blue FCF Aluminum Lake, D&C red #28 and gelatin. 91cf84db-figure-02

1 INDICATIONS AND USAGE Phentermine Hydrochloride, USP 15 mg and 30 mg is 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 ≥30 kg/m 2 , or≥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. The limited usefulness of agents of this class, including Phentermine hydrochloride, [ see CLINICAL PHARMACOLOGY ( 12.1 , 12.2 ) ] should be measured against possible risk factors inherent in their use such as those described below. 91cf84db-figure-01

10 OVERDOSAGE The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of 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 ) .

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 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 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 (Cmax) after 3 to 4.4 hours. Specific Populations Renal Impairment Phentermine was not studied in patients with renal impairment. The literature reported cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62% to 85%. Exposure increases can be expected in patients with renal impairment. Use caution when administering phentermine to patients with renal impairment. 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.

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Phentermine Hydrochloride Phentermine Hydrochloride PHENTERMINE HYDROCHLORIDE PHENTERMINE STARCH, CORN GELATIN, UNSPECIFIED LACTOSE MONOHYDRATE D&C YELLOW NO. 10 FD&C BLUE NO. 1 FD&C RED NO. 3 FD&C RED NO. 40 TITANIUM DIOXIDE MAGNESIUM STEARATE K;26

ANDA040886

Phentermine Hydrochloride

Phentermine Hydrochloride

63187-512

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL – 15 mg Bottle Label NDC 63187-512-30 PHENTERMINE HYDROCHLORIDE CAPSULES, USP 15 mg 30 CAPSULES Rx Only 63187-512-30

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Phentermine Hydrochloride Capsules, USP safely and effectively. See full prescribing information for Phentermine Hydrochloride Capsules, USP. Phentermine Hydrochloride Capsules, USP CIV for oral use INDICATIONS AND USAGE 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 ≥ 30 kg/m 2 , or ≥ 27 kg/m 2 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, should be measured against possible risk factors inherent in their use. ( 1 ) DOSAGE AND ADMINISTRATION Dosage should be individualized to obtain an adequate response with the lowest effective dose. DOSAGE FORMS AND STRENGTHS • Capsules containing 15 mg and 30 mg Phentermine Hydrochloride. ( 3 ) CONTRAINDICATIONS • • History of cardiovascular disease (e.g., coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension) ( 4 ) 1. • 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 ) WARNINGS AND PRECAUTIONS • • Co-administration with other drugs for weight loss is not recommended (safety and efficacy of combination not established). ( 5.1 ) 1. • Rare cases of primary pulmonary hypertension have been reported. Phentermine should be discontinued in case of new, unexplained symptoms of dyspnea, angina pectoris, syncope or lower extremity edema. ( 5.2 ) 2. • Rare cases of serious regurgitant cardiac valvular disease have been reported. ( 5.3 ) 3. • Tolerance to the anorectic effect usually develops within a few weeks. If this occurs, phentermine should be discontinued. The recommended dose should not be exceeded. ( 5.4 ) 4. • Phentermine may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle. ( 5.5 ) 5. • Risk of abuse and dependence. The least amount feasible should be prescribed or dispensed at one time in order to minimize the possibility of overdosage. ( 5.6 ) • Concomitant alcohol use may result in an adverse drug reaction. ( 5.7 ) • • Use caution in patients with even mild hypertension (risk of increase in blood pressure). ( 5.8 ) 6. • A reduction in dose of insulin or oral hypoglycemic medication may be required in some patients. ( 5.9 ) ADVERSE REACTIONS Adverse events have been reported in the cardiovascular, central nervous, gastrointestinal, allergic, and endocrine systems. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact KVK-TECH, Inc., at 215-579-1842 or customerservice@kvktech.com ; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . DRUG INTERACTIONS • 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 ) 1. • Adrenergic neuron blocking drugs: Hypotensive effect may be decreased by phentermine. ( 7.4 ) 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 ) • • Use caution when administering phentermine to patients with renal impairment ( 8.6 ) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/2012 FULL PRESCRIBING INFORMATION: CONTENTS * * Sections or subsections omitted from the full prescribing information are not listed 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Co-administration With Other Drug Products for Weight Loss 5.2 Primary Pulmonary Hypertension 5.3 Valvular Heart Disease 5.4 Development of Tolerance, Discontinuation in Case of Tolerance 5.5 Effect on the Ability to Engage in Potentially Hazardous Tasks 5.6 Risk of Abuse and Dependence 5.7 Usage With Alcohol 5.8 Use in Patients With Hypertension 5.9 Use in Patients on Insulin or Oral Hypoglycemic Medications for Diabetes Mellitus 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 7.1 Monoamine Oxidase Inhibitors 7.2 Alcohol 7.3 Insulin and Oral Hypoglycemic Medications 7.4 Adrenergic Neuron Blocking Drugs 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 10.1 Acute Overdosage 10.2 Chronic Intoxication 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION FULL PRESCRIBING INFORMATION

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.

16 HOW SUPPLIED Phentermine Hydrochloride capsules, USP are available as follows: Phentermine Hydrochloride capsules, USP 15 mg are supplied as gray opaque cap, rich yellow opaque body with black imprint “K 26” on both the cap and body, filled with powder. Bottles of 07, NDC 63187-512-07 Bottles of 30, NDC 63187-512-30 Bottles of 60, NDC 63187-512-60 Bottles of 90, NDC 63187-512-90 Store at 20° to 25°C (68° to 77°F) with excursions permitted between 15° to 30°C (59° to 86°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). Protect from moisture. Keep out of the reach of children