Phentermine/topiramate Disease Interactions

Many amphetamines and amphetamine-like drugs are contraindicated in patients with advanced arteriosclerosis, symptomatic or unstable cardiac or cerebrovascular disease, moderate to severe hypertension, or hyperthyroidism. Like other sympathomimetic amines, amphetamines may cause cardiovascular adverse effects such as palpitation, tachycardia, cardiac arrhythmias, and elevation of blood pressure. Rarely, cardiomyopathy manifested as ventricular hypertrophy and/or congestive heart failure has been reported during chronic amphetamine use. In addition, sudden death has been reported in association with amphetamine therapy at usual dosages in children with structural cardiac abnormalities. In general, amphetamines should not be used in patients with structural cardiac abnormalities. If not otherwise contraindicated, therapy with amphetamines should be administered cautiously in patients with a current or past history of cardiovascular or cerebrovascular disease.

Some amphetamines and amphetamine-like drugs are contraindicated in patients with narrow-angle glaucoma or anatomically narrow angles. Like other sympathomimetic amines, amphetamines can induce transient mydriasis. In patients with narrow angles, pupillary dilation can provoke an acute attack of angle-closure glaucoma. If possible, these agents should also be avoided in patients with other forms of glaucoma since mydriasis may occasionally increase intraocular pressure.

Oligohidrosis (decreased sweating) and hyperthermia have been reported in association with the use of some carbonic anhydrase inhibitor anticonvulsants such as topiramate and zonisamide. Most of the reports have been in children. Caution and close monitoring of body temperature is advised when prescribing these drugs, especially in patients with a fever, in hot weather, or if combined with other drugs that predispose to heat related disorders. Zonisamide is not approved for use in pediatric patients in the U.S.

Some CNS stimulants are contraindicated in patients with marked agitation and/or anxiety since these symptoms may be aggravated. CNS stimulants may also exacerbate symptoms of behavior disturbance and thought disorder in psychotic patients, particularly children. Therapy with CNS stimulants should be administered cautiously in patients with a history of psychosis or a predisposition to agitated states.

Many CNS stimulants are contraindicated in patients with significant cardiovascular impairment such as uncompensated heart failure, severe coronary disease, severe hypertension (including that associated with hyperthyroidism or pheochromocytoma), cardiac structural abnormalities, serious arrhythmias, etc. Sudden death has been reported in patients with structural cardiac abnormalities or other serious cardiac disease who are treated with CNS stimulants at the recommended dosages for attention deficit hyperactivity disorder; use of these agents should be avoided in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmia, coronary artery disease, or other serious cardiac disease. Additionally, stroke, myocardial infarction, chest pain, syncope, arrhythmias, and other symptoms have been reported in adults under treatment. A careful assessment of the cardiovascular status should be done in patients being considered for treatment. This includes family history, physical exam, and further cardiac evaluation (EKG and echocardiogram). Patients who develop symptoms should have a detailed cardiac evaluation and if needed, treatment should be suspended.

The use of most CNS stimulants is contraindicated in patients with glaucoma, as these agents exhibit sympathomimetic activity and may induce mydriasis provoking an increase in intraocular pressure.

CNS stimulants increase blood pressure and heart rate; the use of some agents may be contraindicated in patients with severe/uncontrolled hypertension. Caution should be used when administering to patients with preexisting high blood pressure (even mild hypertension) and other cardiovascular conditions. All patients under treatment should be regularly monitored for potential tachycardia and hypertension.

The use of CNS stimulants can cause psychotic symptoms, suicidal ideation, and aggression, and can exacerbate symptoms of behavior disturbance and thought disorder; CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Psychiatric symptoms have been reported in patients with and without history of psychiatric disorders. All patients (particularly those with psychotic or bipolar disorders) should be monitored closely, especially during treatment initiation and at times of dose changes. Extreme caution should be exercised when CNS stimulants are given to patients with a history of psychosis, depression, mania, or bipolar disorder. Prior to initiating therapy, all patients should be screened for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disease, or depression). If any psychiatric symptoms emerge or are exacerbated, treatment suspension should be considered. Some CNS stimulants are contraindicated in patients with marked agitation or anxiety.

The use of some CNS stimulants has been associated with an increased risk of developing pulmonary hypertension, a rare but fatal disorder. The onset or aggravation of exertional dyspnea, or unexplained symptoms of angina pectoris, syncope, or lower extremity edema suggest the possibility of occurrence of pulmonary hypertension. Under these circumstances, treatment must be immediately discontinued, and the patient should be evaluated to confirm diagnosis. Caution should be exercised in patients with preexisting valvular heart disease or history of pulmonary hypertension. These drugs are not recommended in patients with known heart murmur or valvular heart disease.

CNS stimulants (especially amphetamines) have a high potential for abuse and misuse, which can lead to development of a substance use disorder, including addiction. Misuse and abuse of CNS stimulants can result in overdose and death; this risk is increased with higher doses or unapproved methods of administration (e.g., snorting, injection). Before prescribing a CNS stimulant, each patient's risk for abuse, misuse, and addiction should be assessed. Throughout therapy, it is recommended to reassess each patient's risk and frequently monitor for signs/symptoms of abuse, misuse, and addiction. Therapy with CNS stimulants should be administered cautiously, if at all, in patients with a history of alcohol or substance abuse. The use of some agents is contraindicated in patients with a history of drug abuse.

Antiepileptic drugs (AEDs) have been associated with an increased risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies involving the use of 11 different AEDs showed that patients receiving AEDs had approximately twice the risk of suicidal thinking or behavior compared to patients receiving placebo. AEDs should be administered cautiously in patients with depression or other psychiatric disorders; phentermine-topiramate should be avoided in patients with history of suicidal attempts or active suicidal ideation. The risk of suicidal thoughts and behavior should be carefully assessed against the risk of untreated illness, bearing in mind that epilepsy and many other conditions for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, caregivers, and families should be alert to the emergence or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior. If patients have symptoms of suicidal ideation or behavior, a dosage reduction or treatment discontinuation should be considered.

The major route of elimination of carbonic anhydrase inhibitors is through the kidney. These drugs should be administered cautiously in patients with reduced renal function and a dose adjustment might be required depending on the level of impairment.

Reduced plasma bicarbonate levels and, in some instances, elevated plasma chloride levels may result in metabolic acidosis during long-term therapy with carbonic anhydrase inhibitors. Therapy with carbonic anhydrase inhibitors should be administered cautiously in patients with metabolic or hyperchloremic acidosis or with conditions that predispose to acidosis (renal disease, severe respiratory disorders, diarrhea). The measurement of baseline and periodic serum bicarbonate is recommended. If metabolic acidosis develops (it may be corrected by administration of sodium bicarbonate), and persists, a dose reduction or treatment discontinuation should be considered.

Overall CNS stimulants should be administered with caution in patients with significantly impaired renal function as the reduction in the rate of elimination may alter the therapeutic response. The dosage should be adjusted accordingly in certain agents.

Obese, type 2 diabetic patients who achieve weight loss may demonstrate improved metabolic control of their disease as a result of their reduced weight. Therefore, patients with type 2 diabetes mellitus should be monitored during weight-reduction therapy (or therapy that may be expected to induce significant weight loss as a secondary effect) for hypoglycemia and reduced need for oral hypoglycemic medication or insulin, and the dosages of these agents adjusted accordingly. Patients should be apprised of the risk of hypoglycemia and be alert to potential signs and symptoms such as headache, dizziness, drowsiness, nervousness, confusion, tremor, hunger, weakness, perspiration, and palpitation.

Phentermine has not been studied in patients with end-stage renal disease on dialysis; therefore, this drug should be avoided in these patients.

Phentermine may be partially metabolized in the liver. After a single dose of phentermine 15 mg-topiramate 92 mg, mean phentermine systemic exposure (AUC) was 37% and 60% higher in patients with mild (Child-Pugh score 5 to 6) and moderate (Child-Pugh score 7 to 9) liver dysfunction, respectively, compared to healthy subjects. No dosage adjustment is necessary in patients with mild liver dysfunction. In patients with moderate liver dysfunction, a reduction in the starting and/or maintenance dosage may be necessary in accordance with the individual manufacturer product information. Phentermine pharmacokinetics have not been studied in patients with severe liver dysfunction (Child-Pugh score 10 to 15); therefore, use should be avoided.

A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients receiving topiramate. Symptoms include acute onset of decreased visual acuity and/or ocular pain. It typically occurs within 1 month of treatment initiation and it has been reported in both pediatric and adult patients. Caution is recommended when prescribing topiramate in patients with elevated intraocular pressure regardless of the etiology.

Topiramate is cleared by hemodialysis at a rate that is 4 to 6 times greater than that in a normal individual. To avoid rapid drops in topiramate plasma level during hemodialysis, a supplemental dose may be required. The actual adjustment should consider the duration of dialysis, the clearance rate of the dialysis system being used, and the effective renal clearance of topiramate in the patient being dialyzed.

Plasma clearance of topiramate decreased a mean of 26% in patients with moderate to severe liver dysfunction. After a single dose of phentermine 15 mg-topiramate 92 mg, pharmacokinetics of topiramate were not affected in patients with mild (Child-Pugh score 5 to 6) and moderate (Child-Pugh score 7 to 9) liver dysfunction when compared with healthy subjects. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at increased risk for hyperammonemia with or without encephalopathy. Although not studied, use of topiramate may exacerbate existing defects or unmask deficiencies in susceptible patients.

The use of topiramate increases the risk of kidney stones. The reported incidence was 1.5% during premarketing use, which is about 2 to 4 times that expected in a similar, untreated population. Topiramate is a carbonic anhydrase inhibitor and may promote stone formation by reducing urinary citrate excretion and increasing urinary pH. Therapy with topiramate should be administered cautiously with adequate hydration in patients, especially those with predisposing factors (e.g., history of nephrolithiasis), to minimize the risk of kidney stone formation. The concomitant use of topiramate with any other drug producing metabolic acidosis, or potentially in patients on a ketogenic diet, may create a physiological environment that increases the risk of kidney stone formation and should be avoided. Patients who are dehydrated may be at increased risk for the development of nephrolithiasis and should be encouraged to consume additional amounts of liquid during topiramate therapy.