Phentermine is an oral sympathomimetic amine used as an adjunct for short-term (e.g., 8—12 weeks) treatment of exogenous  obesity. The pharmacologic effects of phentermine are similar to amphetamines. Phentermine resin complex was approved by  the FDA in 1959, but is no longer marketed in the US. Phentermine hydrochloride was FDA approved in 1973. In the mid-90s,  there was renewed interest in phentermine in combination with another anorectic, fenfluramine, for the treatment of obesity  and substance abuse, however, little scientific data support this practice. On July 8, 1997, the FDA issued a ‘Dear Health Care  Professional’ letter warning physicians about the development of valvular heart disease and pulmonary hypertension in women receiving the combination of fenfluramine and phentermine; fenfluramine was subsequently withdrawn from the US market in fall of 1997. Use of phentermine with other anorectic agents for obesity has not been evaluated and is not recommended. In May 2011, the FDA approved a phentermine hydrochloride orally disintegrating tablet (Suprenza) for the treatment of  exogenous obesity.

Limited data are available in reference texts regarding the mechanism of action of this drug. Phentermine is an analog of methamphetamine. Similar to the amphetamines, phentermine increases the release of norepinephrine and dopamine from nerve  terminals and inhibits their reuptake. Thus, phentermine is classified as an indirect sympathomimetic. Other effects include a weak ability to dose-dependently raise serotonin levels, although the effect on serotonin occurs is less potent than that of  methamphetamine itself.  

Clinical effects include CNS stimulation and elevation of blood pressure. Appetite suppression is believed to occur through direct  stimulation of the satiety center in the hypothalamic and limbic region. 

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism of  tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued  rather than the dose increased.

Phentermine is administered orally. The rate and extent of phentermine exposure under fasting conditions is equivalent regardless of oral formulation administered. Limited data exist on the pharmacokinetics of phentermine. Phentermine is primarily excreted by the kidneys. The elimination half-life ranges 19—24 hours and is influenced by urinary pH. Because the pKa of  phentermine is 9.84, the elimination half-life decreases to about 7—8 hours under acidic urinary conditions.

Route-Specific Pharmacokinetics: 

Oral Route: Following oral administration, most absorption of phentermine occurs from the small intestine. The duration of  action following administration of the 8 mg capsules or tablets is about 4 hours and 12—14 hours after administration of the  30 mg capsules or the 37.5 mg tablets. 

Phentermine oral disintegrating tablet (ODT) reaches peak concentrations (Cmax) 3—4.4 hours post-administration. Water  ingestion prior to swallowing the ODT did not affect the AUC. Despite a decrease in the Cmax (approximately 5%) and AUC  (approximately 12%) when phentermine ODT was administered after a high fat/high calorie breakfast, phentermine ODT can  be administered with or without food. The Cmax and AUC were decreased by approximately 7% and 8%, respectively, when  the ODT was swallowed without prior disintegration. 

Special Populations: 

Renal Impairment: Use with caution in patients with renal impairment. Cumulative urinary excretion of phentermine under  uncontrolled urinary pH conditions is 62—85%, and exposure increases can be expected in patients with renal impairment.

As a stimulant similar to some amphetamines, phentermine acts as an appetite suppressant by stimulating branches of the  sympathetic nervous system located within the central nervous system and is best used when used in conjunction with a  healthy lifestyle. Phentermine is indicated in the management of exogenous obesity as a short term (several weeks) adjunct in a regimen of weight reduction based on caloric restriction. It is often recommended for obese patients who possess greater risk  factors for high blood pressure, high cholesterol, or diabetes

Phentermine is contraindicated for use in any patient with a prior history of sympathomimetic amine hypersensitivity. According to the manufactures of phentermine capsules and tablets, its products are contraindicated in patients with cardiac disease,  advanced arteriosclerosis, moderate to severe hypertension, agitated states, or glaucoma. Likewise, orally disintegrating tablets are contraindicated in patients with a history of cardiac disease including coronary artery disease, stroke, cardiac arrhythmias, heart failure, and uncontrolled hypertension. Valvular heart disease has been reported in women receiving the combination of fenfluramine and phentermine; the safety and efficacy of combination therapy with phentermine and any other drug  products for weight loss, including selective serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, fluvoxamine, paroxetine),  have not been established. Therefore, coadministration of these drug products for weight loss is not recommended. Further,  primary pulmonary hypertension (PPH) has been reported to occur in patients receiving a combination of phentermine with  fenfluramine or dexfenfluramine. The possibility of an association between the use of phentermine alone and PPH or valvular  heart disease cannot be ruled out. The initial symptom of PPH is usually dyspnea. Other initial symptoms include: angina pec toris, 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. 

Because phentermine is a sympathomimetic agent, it is contraindicated in patients with hyperthyroidism. It should also be  used with caution in patients with thyroid disease. Phentermine is contraindicated for use during or within 14 days following  the use of MAOI therapy or other drugs with MAO-inhibiting activity. Monoamine oxidase inhibitors (MAOIs), or drugs that  possess MAO-inhibiting activity such as furazolidone or procarbazine, can prolong and intensify the cardiac stimulation and  vasopressor effects of phentermine.

Phentermine is contraindicated in patients with agitated states aggravate these effects or cause an adverse drug reaction. Symptoms of chronic intoxication include insomnia, irritability, change in personality, and psychotic symptoms that may  be clinically indistinguishable from other psychotic disorders, like schizophrenia. Phentermine could aggravate certain mental  conditions, such as those patients who exhibit highly nervous or agitated behavior, including psychosis, mania, or severe anxiety. 

The use of phentermine may cause dizziness, mask signs of fatigue or the need for rest, or impair the ability of a patient to participate in activities that require mental alertness. Advise patients to use caution when driving or operating machinery, or performing other tasks that require mental alertness until they are aware of how therapy will affect their mental and/or motor  performance. In general, ethanol ingestion may aggravate these effects or cause an adverse drug reaction. Advise patients to avoid alcohol while taking phentermine. 

Use phentermine cautiously in patients with diabetes mellitus. Insulin or other antidiabetic medication requirements may be  altered in these patients when using phentermine during weight loss and due to altered dietary regimens. Patients should  monitor their blood glucose regularly and follow the recommendations of their health care provider. 

Appetite suppressant therapy is not recommended for use in those patients with a history of anorexia nervosa or other eating  disorders. Use of phentermine is contraindicated in patients with a known history of drug or substance abuse. Phentermine is  chemically and pharmacologically related to the amphetamines which have been extensively abused. 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. The least amount reasonable should be prescribed or dispensed at one time in order to limit the potential for overuse or  drug diversion.

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and  are contraindicated during pregnancy. Safe use of phentermine during pregnancy has not been established; there is no known  indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who  may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards.

Phentermine is contraindicated during breast-feeding. It is not known whether phentermine and its metabolites are excreted  in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breast-feeding while taking  phentermine is not recommended. 

Safety and effectiveness of phentermine in children have not been established. Phentermine is not recommended for children  or adolescents 16 years of age and under. There is no established use of phentermine in infants or neonates. The debilitated or geriatric patient may be more susceptible to the CNS and sympathomimetic side effects of phentermine; use with caution in  elderly patients. Patients with renal impairment may also be more susceptible to side effects. Exposure increases can be expected in patients with renal impairment or renal failure. Use caution when administering phentermine to patients with renal  impairment. 

The use of inhalational anesthetics during surgery may sensitize the myocardium to the effects of sympathomimetic drugs.  Because of this, and its effects on blood pressure, in general, phentermine should be discontinued several days prior to surgery. Avoid abrupt discontinuation.

Phentermine products are now classified as FDA pregnancy risk category X, as are many anorexiants used for weight loss, and  are contraindicated during pregnancy.66 Safe use of phentermine during pregnancy has not been established; there is no  known indication for use of phentermine during pregnancy. Phentermine should not be taken by pregnant women or by women who may become pregnant unless, in the opinion of the physician, the potential benefits outweigh the possible hazards

Phentermine is contraindicated during breast-feeding.6 It is not known whether phentermine and its metabolites are excreted  in breast milk; however, because of the potential for serious adverse effects in the nursing infants, breast-feeding while taking  phentermine is not recommended 

The safety of phentermine when used with other anorexiant agents such as amphetamine, benzphetamine, dexfenfluramine,  dextroamphetamine, diethylpropion, ephedrine, fenfluramine, and sibutramine9 is controversial and concurrent use should  be avoided. The role of phentermine in the production of cardiac valvulopathy when combined with dexfenfluramine, fenfluramine, or other medications for weight loss is uncertain. The combined use of these agents may have the potential for additive side effects, such as hypertensive crisis or cardiac arrhythmias. Similarly, because phentermine is a sympathomimetic and  anorexic agent (i.e., psychostimulant) it should not be used in combination with other sympathomimetics or psychostimulants  for weight loss, including OTC preparations, and herbal products that may contain ephedra alkaloids or Ma huang. Phentermine, which increases catecholamine release, can increase blood pressure; this effect may be additive with the prolonged vasoconstriction caused by ergot alkaloids. Monitoring for cardiac effects during concurrent use of ergot alkaloids with phentermine may be advisable. 

Concurrent use of bromocriptine and some sympathomimetics such as phentermine should be approached with caution. One  case report documented worsening headache, hypertension, premature ventricular complexes, and ventricular tachycardia in  a post-partum patient receiving bromocriptine for lactation suppression who was subsequently prescribed acetaminophen;  dichloralphenazone; isometheptene for a headache. A second case involved a post-partum patient receiving bromocriptine  who was later prescribed phenylpropanolamine; guaifenesin and subsequently developed hypertension, tachycardia, seizures,  and cerebral vasospasm. 

In theory, an interaction is possible between cabergoline, an ergot derivative, and some sympathomimetic agents such as  phentermine. Use of the ergot derivative bromocriptine for lactation suppression in conjunction with a sympathomimetic (i.e., isometheptene or phenylpropanolamine) for other therapeutic uses has resulted in adverse effects such as worsening headache, hypertension, ventricular tachycardia, seizures, sudden loss of vision, and cerebral vasospasm. Concurrent use of  dronabinol, THC or nabilon with sympathomimetics may result in additive hypertension, tachycardia, and possibly cardiotoxicity.

Monoamine oxidase inhibitors (MAOIs), or drugs that possess MAO-inhibiting activity such as furazolidone, linezolid, or procarbazine, can prolong and intensify the cardiac stimulation and vasopressor effects of phentermine. Phenelzine and tranylcypromine appear to produce the greatest risk since these two MAOIs also have intrinsic amphetamine-like activity. In the presence of MAOIs, phentermine and other drugs that cause release of norepinephrine induce severe cardiovascular and cerebrovascular responses. It is unclear if selegiline, an inhibitor of MAO type B, can also predispose to this reaction. Phentermine  should not be administered during or within 14 days following the use of most MAOIs or drugs with MAO-inhibiting activity. Rasagiline is a selective MAO-B inhibitor at manufacturer recommended doses; therefore, serious reactions with sympathomimetics are not ordinarily expected. However, because a case of elevated blood pressure occurred during use of rasagiline and a sympathomimetic ophthalmic preparation, caution is advised when rasagiline is administered with sympathomimetics. The pressor response to some sympathomimetics is exaggerated in patients currently receiving tricyclic antidepressants. Concomitant use of tricyclic antidepressants with sympathomimetics, including phentermine, should be avoided whenever possible. 

Phentermine has vasopressor effects and may limit the benefit of antihypertensive agents particularly sympatholytic agents  such as guanadrel, guanethidine, methyldopa or reserpine. Phentermine may displace guanethidine from the neuron and  antagonize the neuronal blockade caused by guanethidine. Concomitant use of phentermine with methyldopa or reserpine  may antagonize the antihypertensive effects of these agents. Although leading drug interaction texts differ in the potential for an interaction between phentermine and this group of antihypertensive agents, these effects are likely to be clinically significant and have been described in hypertensive patients on these medications. 

Use caution in combining phentermine with antidiabetic agents. Phentermine exhibits sympathomimetic activity. Sympathomimetics may increase blood sugar via stimulation of beta2-receptors which leads to increased glycogenolysis. A pharmacody namic interaction with antidiabetic agents may occur. Diabetic patients may have decreased requirements of insulins, sulfonylureas, or other antidiabetic agents in association with the use of phentermine and the concomitant dietary regimen and weight loss. As long as blood glucose is carefully monitored to avoid hypoglycemia or hyperglycemia, it appears that phentermine can be used concurrently. 

Halogenated anesthetics may sensitize the myocardium to the effects of the sympathomimetics. Because of this, and its  effects on blood pressure, phentermine should be discontinued several days prior to surgery. Concurrent use of phentermine  and phenothiazines may antagonize the anorectic effects of phentermine. In addition, psychostimulants can aggravate psychotic states. Although not studied, the concomitant use of ethanol and phentermine may result in an adverse reaction and  should be avoided. 

Phentermine, like other sympathomimetics, is contraindicated in selected patients with thyroid disease; caution should be  used if co-administering thyroid hormones with phentermine. Atomoxetine has been reported to increase blood pressure and  heart rate, probably via inhibition of norepinephrine reuptake. Due to an additive pharmacodynamic effect, phentermine and  atomoxetine should be used together cautiously, particular in patients with a history of cardiac disease. Consider monitoring  heart rate and blood pressure at baseline and regularly throughout treatment if these agents must be used together. 

Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine or the  combination of phentermine; topiramate, may be associated with an increased seizure risk; therefore, seizures may be more  likely to occur in patients receiving these weight loss aides with bupropion or bupropion-containing combinations. Other side  effects might also occur, such as dizziness, blood pressure changes, or other side effects. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion;  naltrexone due to this risk and the duplication of therapy for weight loss. 

Due to the pharmacology of salmeterol, caution and close observation should also be used when fluticasone; salmeterol is  used concurrently with other adrenergic sympathomimetics, administered by any route, to avoid potential for increased cardiovascular effects based on the pharmacology of salmeterol. Use phentermine and selective serotonin reuptake inhibitors  (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs) together with caution;2 use together may be safe and efficacious for some patients based on available data, provided the patient is on a stable antidepressant regimen and receives close  clinical monitoring. Regular appointments to assess the efficacy of the weight loss treatment, the emergence of adverse  events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to  the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of  adverse reactions with phentermine and fluoxetine. However, recent data suggest that phentermine’s effect on MAO inhibitor and serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma  serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to  start therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants  (e.g., SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to  the initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression documented. In analyses of the results, therapy was generally  well tolerated, especially at lower phentermine doses, based on discontinuation rates and reported adverse events. Because  depression and obesity often coexist, the study data may be important to providing optimal co-therapies. 

Use phentermine and vortioxetine together with caution; use together may be safe and efficacious for some patients based  on available data, provided the patient is on a stable antidepressant regimen and receives close clinical monitoring. Regular  appointments to assess the efficacy of the weight loss treatment, the emergence of adverse events, and blood pressure monitoring are recommended. Watch for excessive serotonergic effects. Phentermine is related to the amphetamines, and there has been historical concern that phentermine might exhibit potential to cause serotonin syndrome or cardiovascular or pulmonary effects when combined with serotonergic agents. One case report has been received of adverse reactions with phen termine and the antidepressant fluoxetine. However, recent data suggest that phentermine’s effect on MAO inhibition and  serotonin augmentation is minimal at therapeutic doses, and that phentermine does not additionally increase plasma serotonin levels when combined with other serotonergic agents. In large controlled clinical studies, patients were allowed to start  therapy with phentermine or phentermine; topiramate extended-release for obesity along with their antidepressants (e.g.,  SSRIs or SNRIs, but not MAOIs or TCAs) as long as the antidepressant dose had been stable for at least 3 months prior to the  initiation of phentermine, and the patient did not have suicidal ideation or more than 1 episode of major depression docu mented. In analyses of the results, therapy was generally well tolerated, especially at lower phentermine doses, based on  discontinuation rates and reported adverse events. Because depression and obesity often coexist, the study data may be important to providing optimal co-therapies.

Central nervous system adverse reactions that have been reported in patients receiving phentermine include dizziness, dysphoria, euphoria, headache, insomnia, overstimulation, restlessness, and tremor. Psychosis at recommended doses may occur rarely in some patients. 

Primary pulmonary hypertension (PPH) and cardiac valvulopathy (regurgitant cardiac valvular disease) have been reported  with phentermine. The initial symptom of PPH is usually dyspnea; other initial symptoms include: angina pectoris, syncope, or peripheral 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 peripheral edema. Other cardiovascular adverse effects that have been reported include hypertension, ischemic events, palpitations, and sinus tachycardia. 

Reported adverse gastrointestinal effects of phentermine include constipation, diarrhea, dysgeusia, nausea, and xerostomia.  Impotence (erectile dysfunction), libido increase, and libido decrease have been reported in patients receiving phentermine.  Urticaria has been reported in patients receiving phentermine. 

Phentermine has not been systematically studied for its potential to produce dependence in obese patients treated with usu al recommended dose ranges. Phentermine is related chemically and pharmacologically to the amphetamines, and these  stimulant drugs have been extensively abused and the possibility of abuse of phentermine should be kept in mind when evaluating the desirability of including this drug product as part of a weight reduction program. Abuse of amphetamines and related drugs (e.g., phentermine) 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. Physical dependence (physiological dependence) is a state that develops as a result of physiological adaptation  in response to repeated drug use. Physical dependence manifests by drug-class-specific withdrawal symptoms after abrupt  discontinuation or a significant dose reduction of a drug. Limited data are available for phentermine. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on a sleep  electroencephalogram. Thus, in situations where rapid withdrawal is required, appropriate medical monitoring is recommend. Evidence-based data from the literature are relatively limited, and some experts suggest that long-term phentermine pharmacotherapy for obesity does not induce abuse or psychological dependence (addiction), drug craving, and that abrupt treatment cessation within the normal prescription dose range does not induce amphetamine-like withdrawal.32 More data are  needed to confirm the dependence potential of phentermine-containing obesity products. 

Tolerance to the anorexiant effects of phentermine usually develops within a few weeks of starting therapy. The mechanism  of tolerance appears to be pharmacodynamic in nature; higher doses of phentermine are required to produce the same response. When tolerance develops to the anorexiant effects, it is generally recommended that phentermine be discontinued  rather than the dose increased. The maximum recommended dose should not be exceeded.