2.1 Exogenous Obesity

Dosage should be individualized to obtain an adequate response with the lowest effective dose.

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.

ADIPEX-P ®is not recommended for use in pediatric patients less than or equal to 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 ADIPEX-P ®is 15 mg daily for patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2). Avoid use of ADIPEX-P ®in patients with eGFR less than 15 mL/min/1.73 m 2or end-stage renal disease requiring dialysis [see Use in Specific Populations ( 8.6) and Clinical Pharmacology ( 12.3)] .

5.1 Coadministration with Other Drug Products for Weight Loss

ADIPEX-P ®is indicated only as short-term (a few weeks) monotherapy for the management of exogenous obesity. The safety and efficacy of combination therapy with ADIPEX-P ®and any other drug products for weight loss including prescribed drugs, over-the-counter preparations, and herbal products, or serotonergic agents such as selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine), have not been established. Therefore, coadministration of ADIPEX-P ®and these drug products is not recommended.

5.2 Primary Pulmonary Hypertension

Primary Pulmonary Hypertension (PPH) – a rare, frequently fatal disease of the lungs – has been reported to occur in patients receiving a combination of phentermine with fenfluramine or dexfenfluramine. The possibility of an association between PPH and the use of ADIPEX-P ®alone cannot be ruled out; there have been rare cases of PPH in patients who reportedly have taken phentermine alone. The initial symptom of PPH is usually dyspnea. Other initial symptoms may include angina pectoris, syncope or lower extremity edema. Patients should be advised to report immediately any deterioration in exercise tolerance. Treatment should be discontinued in patients who develop new, unexplained symptoms of dyspnea, angina pectoris, syncope or lower extremity edema, and patients should be evaluated for the possible presence of pulmonary hypertension.

5.3 Valvular Heart Disease

Serious regurgitant cardiac valvular disease, primarily affecting the mitral, aortic and/or tricuspid valves, has been reported in otherwise healthy persons who had taken a combination of phentermine with fenfluramine or dexfenfluramine for weight loss. The possible role of phentermine in the etiology of these valvulopathies has not been established and their course in individuals after the drugs are stopped is not known. The possibility of an association between valvular heart disease and the use of ADIPEX-P ®alone cannot be ruled out; there have been rare cases of valvular heart disease in patients who reportedly have taken phentermine alone.

5.4 Development of Tolerance, Discontinuation in Case of Tolerance

When tolerance to the anorectant effect develops, the recommended dose should not be exceeded in an attempt to increase the effect; rather, the drug should be discontinued.

5.5 Effect on the Ability to Engage in Potentially Hazardous Tasks

ADIPEX-P ®may impair the ability of the patient to engage in potentially hazardous activities such as operating machinery or driving a motor vehicle; the patient should therefore be cautioned accordingly.

5.6 Risk of Abuse and Dependence

ADIPEX-P ®is related chemically and pharmacologically to amphetamine (d- and d ll-amphetamine) and to other related stimulant drugs that have been extensively abused. The possibility of abuse of ADIPEX-P ®should be kept in mind when evaluating the desirability of including a drug as part of a weight reduction program. See Drug Abuse and Dependence ( 9) and Overdosage ( 10) .

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

5.7 Usage with Alcohol

Concomitant use of alcohol with ADIPEX-P ®may result in an adverse drug reaction.

5.8 Use in Patients with Hypertension

Use caution in prescribing ADIPEX-P ®for patients with even mild hypertension (risk of increase in blood pressure).

5.9 Use in Patients on Insulin or Oral Hypoglycemic Medications for Diabetes Mellitus

A reduction in insulin or oral hypoglycemic medications in patients with diabetes mellitus may be required.

7.1 Monoamine Oxidase Inhibitors

Use of ADIPEX-P ®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 ADIPEX-P ®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

ADIPEX-P ®may decrease the hypotensive effect of adrenergic neuron blocking drugs.

8.1 Pregnancy

ADIPEX-P ® 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 ll-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 ADIPEX-P ®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 ADIPEX-P ®to patients with renal impairment. In patients with severe renal impairment (eGFR 15 to 29 mL/min/1.73 m 2), limit the dosage of ADIPEX-P ®to 15 mg daily [see Dosage and Administration ( 2.2)] . ADIPEX-P ®has not been studied in patients with eGFR less than 15 mL/min/1.73 m 2, including end-stage renal disease requiring dialysis; avoid use in these populations.

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 that 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.

10.1 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 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) .

12.1 Mechanism of Action

ADIPEX-P ®is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and d ll-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 3.0 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 maxand 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)] .

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.