Phentermine Hydrochloride

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

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.

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 .

Patients must be informed that ADIPEX-P® 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 and WARNINGS AND PRECAUTIONS].

Patients must be instructed on how much ADIPEX-P® to take, and when and how to take it [see DOSAGE AND ADMINISTRATION].

Advise pregnant women and nursing mothers not to use ADIPEX-P® [see Use In Specific Populations ].

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]
• Development of serious valvular heart disease [see WARNINGS AND PRECAUTIONS]
• Effects on the ability to engage in potentially hazardous tasks [see WARNINGS AND PRECAUTIONS]
• The risk of an increase in blood pressure [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]
• The risk of interactions [see CONTRAINDICATIONS , WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]

See also, for example, ADVERSE REACTIONS and Use In Specific Populations .

The patients must also be informed about

• the potential for developing tolerance and actions if they suspect development of tolerance [see WARNINGS AND PRECAUTIONS] and
• the risk of dependence and the potential consequences of abuse [see WARNINGS AND PRECAUTIONS , Drug Abuse And Dependence and OVERDOSE].

Tell patients to keep ADIPEX-P® in a safe place to prevent theft, accidental overdose, misuse or abuse. Selling or giving away ADIPEX-P® may harm others and is against the law.

All trademarks are the property of their respective owners.

Suprenza is an orally disintegrating tablet (ODT) of phentermine hydrochloride, USP. Phentermine hydrochloride is a sympathomimetic amine anorectic. Its chemical name is α,α,dimethylphenethylamine hydrochloride. The structural formula is as follows:

C10H15N • HCl      M.W. 185.7

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.

Suprenza is available as an orally disintegrating tablet (ODT) containing 15 mg, 30 mg, or 37.5 mg of phentermine hydrochloride (equivalent to 12 mg, 24 mg, or 30 mg of phentermine base).

Suprenza contains the inactive ingredients mannitol powder, citric acid powder, Povidone CL, Povidone K 30, sucralose, magnesium stearate, peppermint flavor, talc, sodium lauryl sulfate, and mannitol pregranulated. Suprenza 15 mg ODT also contains FD&C Blue # 1 lake and FD&C Yellow # 5 lake. Suprenza 30 mg ODT also contains FD&C Yellow # 5 lake. Suprenza 37.5 mg ODT also contains FD&C Blue # 1 lake.

Mechanism of Action

Suprenza is a sympathomimetic amine with pharmacologic activity similar to the prototype drugs of this class used in obesity, amphetamine (d- and dll-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.

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.

Pharmacokinetics

In terms of rate and extent of exposure, phentermine orally disintegrating tablets are equivalent to phentermine capsules and tablets administered under fasting conditions.

Following the administration of the oral disintegrating tablet (ODT), phentermine reaches peak concentrations (Cmax) after 3.0 to 4.4 hours. Swallowing the ODT after disintegration with or without water did not affect the extent (AUC) of phentermine exposure.

Administration of the ODT after a high fat/high calorie breakfast decreased the Cmax of phentermine by approximately 5% and the AUC by approximately 12%. Despite the decrease in Cmax and AUC, phentermine ODT can be administered with or without food.

Swallowing the ODT without prior disintegration decreased the Cmax of phentermine by approximately 7% and the AUC by approximately 8% compared to swallowing the ODT after disintegration.

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 Cmax and AUC increase 13% and 42%, respectively.

Specific Populations

Suprenza was not studied in patients with renal impairment. The literature reported cumulative urinary excretion of phentermine under uncontrolled urinary pH conditions is 62%-85%. Exposure increases can be expected in patients with renal impairment. Use caution when administering Suprenza to patients with renal impairment.

Clinical Studies

No clinical studies have been conducted with Suprenza.

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.

Do not use phentermine if you have used an MAO inhibitor such as furazolidone (Furoxone), isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl, Emsam, Zelapar), or tranylcypromine (Parnate) in the last 14 days. A dangerous drug interaction could occur, leading to serious side effects.

Taking phentermine together with other diet medications such as fenfluramine (Phen-Fen) or dexfenfluramine (Redux) can cause a rare fatal lung disorder called pulmonary hypertension. Do not take phentermine with any other diet medications without your doctor's advice.

You should not take phentermine if you are allergic to it, or if you have:

• a history of heart disease (coronary artery disease, heart rhythm problems, congestive heart failure, pulmonary hypertension);
• severe or uncontrolled high blood pressure;
• overactive thyroid;
• glaucoma;
• if you are pregnant or breast-feeding;
• if you are in an agitated state;
• if you have a history of drug or alcohol abuse; or
• if you are allergic to other diet pills, amphetamines, stimulants, or cold medications.

To make sure you can safely take phentermine, tell your doctor if you have any of these other conditions:

• high blood pressure;
• diabetes;
• kidney disease; or
• a thyroid disorder.

FDA pregnancy category X. Weight loss during pregnancy can harm an unborn baby, even if you are overweight. Do not use phentermine if you are pregnant.

Phentermine can pass into breast milk and may harm a nursing baby. You should not breast-feed while taking phentermine.

Do not give this medication to a child younger than 16 years old.

Phentermine may be habit-forming and should be used only by the person it was prescribed for. Never share phentermine with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

General

• Teach patient to curtail overeating and consume a suitable diet to help induce and maintain weight loss.a

Administration

Oral Administration

Administer phentermine resin complex capsule before breakfast or 10–14 hours before retiring; swallow capsule whole.b

Administer phentermine hydrochloride 37.5-mg capsule or tablet (Adipex-P) before or 1–2 hours after breakfast; avoid late evening administration because of possible insomnia.c

Dosage

Available as phentermine resin complex; dosage expressed in terms of phentermine.a b Also available as phentermine hydrochloride; dosage expressed in terms of phentermine hydrochloride.a c

Adjust dosage according to individual response and tolerance; use the smallest dosage required to produce the desired response.c

Adults

Phentermine (as resin complex): Usual dosage is 15 or 30 mg once daily.a b

Phentermine hydrochloride: Usual dosage is 8 mg 3 times daily (given 30 minutes before meals)a or 15–37.5 mg once daily (in the morning).a c Alternatively, 18.75 mg twice daily.c

Special Populations

Geriatric Patients

Select dosage with caution, starting at lower end of dosage range.b \

Contraindications

• Symptomatic cardiovascular disease, hyperthyroidism, moderate to severe hypertension, glaucoma, or advanced arteriosclerosis.a b c

• Agitated state or history of drug abuse.a b c

• Within 14 days of MAO inhibitor therapy.a b c

• Known hypersensitivity or idiosyncrasy to sympathomimetic amines.a b c

Warnings/Precautions

Warnings

Avoid concomitant use with other drugs for weight loss, including anorexigenic agents (e.g., phendimetrazine), SSRI antidepressants (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline), and MAO inhibitors,154 165 168 169 b c since severe adverse reactions may occur.158 (See Specific Drugs under Interactions.)

Risk of primary pulmonary hypertension (frequently fatal) when used in combination with at least one other anorexigenic agent, including dexfenfluramine or fenfluramine (both no longer commercially available in the US) or phendimetrazine 165 167 or in those with a history of receiving at least one other anorexigenic agent.133 153 154 155 156 165 166 167 168

Risk with use of phentermine alone cannot be ruled out;154 168 169 primary pulmonary hypertension reported rarely in patients receiving phentermine alone.b c

Discontinue if new, unexplained symptoms of dyspnea, angina, syncope, or edema of the lower extremities occur,154 164 168 169 and evaluate for possible pulmonary hypertension.164

Risk of serious regurgitant valvular (principally mitral, aortic, and/or tricuspid; usually multivalvular) heart disease when used in combination with phendimetrazine165 167 or with dexfenfluramine or fenfluramine (both no longer commercially available in the US).114 115 116 118 122 125 127 128 129 130 131 132 133 134 158 166 167 168 169

Risk with use of phentermine alone cannot be ruled out;c valvular heart disease reported rarely in patients receiving phentermine alone.168 c

Medical history and cardiovascular examination are recommended for patients who received dexfenfluramine or fenfluramine alone or in combination with other anorexigenic drugs (e.g., phentermine). Perform echocardiogram in those with signs/symptoms suggestive of valvular heart disease and base subsequent testing and/or treatment on the specific valve lesions. Strongly consider performing echocardiographic evaluation in all patients exposed to these anorexigenic agents who are about to undergo invasive procedures for which anti-infective prophylaxis for bacterial endocarditis is indicated. In case of emergency procedures when cardiac evaluation cannot be performed, administer preventive anti-infective therapy.

Tolerance to anorexigenic effect usually develops within a few weeks.b c When it does, discontinue therapy; do not attempt to increase effect by exceeding recommended dosage.b c

Performance of activities requiring mental alertness or physical coordination may be impaired.b c

Potential for abuse; habituation or addiction reported with similar drugs (e.g., amphetamines).a b c

Manifestations of chronic intoxication may include psychosis resembling schizophrenia, severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes.b c

Abrupt discontinuance following prolonged high dosage may result in extreme fatigue, depression, and sleep EEG changes.b c

General Precautions

Prescribe and dispense in the smallest feasible quantity to minimize possibility of overdosage.b c

Use with caution in patients with mild hypertension; monitor BP closely.a b c Contraindicated in those with moderate or severe hypertension.a b c

Use with caution in patients with diabetes mellitus; insulin requirements may decrease in association with phentermine use and the concomitant dietary regimen and weight loss.a b c

Specific Populations

Category C.c d

Whether potential benefits outweigh risks is questionable; use during pregnancy (especially during the first trimester) probably should be considered a contraindication.a d

Not known whether phentermine is distributed into milk.d Discontinue nursing or the drug.c d

Safety and efficacy not established; use not recommended in children <16 years of age.a b c

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution, starting at lower end of dosage range, due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.b Monitoring of renal function may be useful.b

Use with caution; clearance may be decreased and risk of toxicity increased.b

Common Adverse Effects

Palpitation, tachycardia, increased BP, overstimulation, restlessness, insomnia, tremor, dizziness, headache, euphoria, dysphoria, dryness of the mouth, unpleasant taste, diarrhea, constipation, vomiting, other GI disturbances, urticaria, impotence, changes in libido.a b c

Storage

Oral

15–30°C.a c

25°C (may be exposed to 15–13°C).a b

• Produces anorexigenic effect and loss of weight.a b c

• Like other amphetamine derivatives, has no primary effect on appetite; anorexigenic action probably is secondary to CNS stimulation.a

• Inhibits uptake of norepinephrine and dopamine.a

• Combined therapy with serotoninergic fenfluramine (no longer commercially available in the US) may have provided complementary anorexigenic effects and had been used to manage obesity;100 103 111 however, fenfluramine hydrochloride (Pondimin) and dexfenfluramine hydrochloride (Redux) were withdrawn from the US market in 1997 because of adverse effects associated with the drugs.114 115 116 135 (See Warnings under Cautions.)