Phentermine Hydrochloride

1 INDICATIONS & USAGE Phentermine hydrochloride tablets USP 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 (feet, 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/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). ( 1 ) The limited usefulness of agents of this class, including phentermine hydrochloride tablets USP, should be measured against possible risk factors inherent in their use. ( 1 )

2 DOSAGE AND 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 can be taken with or without food. Error! Hyperlink reference not valid. • Limit the dosage to 15 mg daily for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73m 2 )- ( 2.2 ) 2.1Exogenous Obesity Dosage should be individualized to obtain an adequate response with the lowest effective dose. The usual adult dose is one capsule (37.5 mg) daily as prescribed by the physician, administered before breakfast or 1 to 2 hours after breakfast for appetite control. The usual adult dose is one tablet (37.5 mg) daily, as prescribed by the physician, administered before breakfast or 1 to 2 hours after breakfast. The dosage may be adjusted to the patient’s need. For some patients, half tablet (18.75 mg) daily may be adequate, while in some cases it may be desirable to give half tablets (18.75 mg) two times a day. Phentermine is not recommended for use in pediatric patients ≤ 16 years of age. Late evening medication should be avoided because of the possibility of resulting insomnia. 2.2 Dosage in Patients With Renal Impairment The recommended maximum dosage of phentermine hydrochloride is 15 mg daily for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73m 2 ). Avoid use of phentermine hydrochloride 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 )].

3 DOSAGE FORMS AND STRENGTHS Capsules containing 37.5 mg phentermine hydrochloride (equivalent to 30 mg phentermine base). Tablets with a functional score containing 37.5 mg phentermine hydrochloride (equivalent to 30 mg phentermine base). • Capsules containing 37.5 mg phentermine hydrochloride. ( Error! Hyperlink reference not valid. ) • Tablets with a functional score containing 37.5 mg phentermine hydrochloride. ( Error! Hyperlink reference not valid. )

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 ( Error! Hyperlink reference not valid. ) ] • 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) ( Error! Hyperlink reference not valid. ) • 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 , Error! Hyperlink reference not valid. ) • Known hypersensitivity, or idiosyncrasy to the sympathomimetic amines ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are described, or described in greater detail, in other section: 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 KVK-TECH, Inc., at 1-800-862-3895 or customerservice@kvktech.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 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 ) • 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.

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. ( Error! Hyperlink reference not valid. ) 8.1 Pregnancy Teratogenic Effects 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 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/m2, including end-stage renal disease requiring dialysis; avoid use in these populations.

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 )].

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).

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 tachycardia, 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 and 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 ) .

16 HOW SUPPLIED/STORAGE AND HANDLING Phentermine Hydrochloride Tablets, USP 37.5 mg are white with blue speckles, capsule-shaped tablets, bisected and debossed with "Є" to the left of bisect and "16" to the right of bisect on one side, and plain on the other side. NDC: 71335-0161-0 90 TABLET in a BOTTLE NDC: 71335-0161-1 30 TABLET in a BOTTLE NDC: 71335-0161-2 15 TABLET in a BOTTLE NDC: 71335-0161-3 28 TABLET in a BOTTLE NDC: 71335-0161-4 7 TABLET in a BOTTLE NDC: 71335-0161-5 14 TABLET in a BOTTLE NDC: 71335-0161-6 60 TABLET in a BOTTLE NDC: 71335-0161-7 45 TABLET in a BOTTLE NDC: 71335-0161-8 2 TABLET in a BOTTLE NDC: 71335-0161-9 21 TABLET in a BOTTLE Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP, with a child-resistant closure (as required). Keep out of the reach of children. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight container as defined in the USP, with a child-resistant closure (as required). Keep out of the reach of children.