February 1998

FDA Health Advisory Regarding Mibefradil
Labeling Changes: Severe Bradycardia, New Drug Interactions

On December 18, 1997, the FDA advised health professionals regarding new warnings in the labeling of mibefradil (Posicor7), a recently approved agent indicated for the treatment of hypertension and chronic stable angina. The FDA talk paper can be found at the following Internet address: www.fda.gov/bbs/topics/ANSWERS/ANS00841.html

Per the manufacturer=s Dear Health Professional Letter (December 1997), mibefradil has been associated with the suppression of sinoatrial node activity and severe bradycardia (as low as 30-40 bpm). Events have been reported primarily in the elderly on concurrent beta blocker therapy. Caution is advised when combining mibefradil with beta blockers. This combination should be avoided in the elderly when pretreatment sinus rate is below 55 bpm.

In addition, the manufacturer has received 7 U.S. reports of statin-induced rhabdomyolysis in patients receiving simvastatin and mibefradil possibly related to mibefradil=s inhibition of simvastatin metabolism via cytochrome P4503A4. This enzyme system is also responsible for lovastatin metabolism, thus the coadministration of mibefradil with either of these two drugs is contraindicated.

Health professionals are encouraged to read more complete information provided by the manufacturer summarizing these new warnings at the following Internet address: www.fda.gov/medwatch/safety/1997/posico.htm.

Mibefradil is currently not on the KUMC formulary.

FORMULARY ADDITIONS

Topiramate (Topamax7)
25 mg, 100 mg, 200 mg tablets
McNeil

Topiramate, a sulfamated monosaccharide, differs structurally from other carbonic anhydrase inhibitors or sulfonamide derivative. Topiramate is indicated as adjunctive therapy for the treatment of adults with partial onset seizures. The antiepileptic activity is contributed to three separate properties: state-dependent sodium channel blockade, antagonization of glutamate receptor activation , and potentiation of GABA activity. Topiramate is extensively excreted unchanged in the urine, however renally impaired patients (Creatinine Clearance <70 ml/min/1.73m²) require monitoring and a possible dosage adjustment of one-half the adult dose.

Some treatment-emergent adverse effects are fatigue, dizziness, ataxia, headache, somnolence, nystagmus, and diplopia. Due to the CNS associated side effects of topiramate, concurrent use of alcohol should be avoided.

Topiramate may increase phenytoin levels by approximately 13% with no effect on carbamzepine levels, however phenytoin and carbamazepine may decrease topiramate levels by approximately 48% and 40, respectively.

It is not necessary to monitor plasma levels to optimize therapy because plasma concentrations do not correlate with clinical efficacy.

The target maintenance dose of topiramate is 200-400 mg daily in two divided doses. Therapy should be initiated at 50 mg in two divided doses followed by a titration of 50 mg a week to a clinically effective dose. The required minimum dose is 200 mg/day and the maximum dose is 1600 mg/day. The daily cost of topiramate is $2.86-5.72.

Imiquimod Cream (Aldara7)
5% Cream (0.25 gm tube)
3M Pharmaceuticals

Imiquimod is an immune response modifier. Administered orally in humans, it induces interferon alpha. Imiquimod 5% cream is indicated for the treatment of external genital and perianal warts (condyloma acuminata) in adults. Imiquimod is not recommended for treatment of urethral, intra-vaginal, cervical, rectal or intra-anal human papilloma viral disease. The mechanism of action in condyloma auminata is unknown, but is presumed to be related to effects on immune response. Imiquimod has no direct antiviral effects and is not a cure. New warts may appear during imiquimod therapy. Sexual contact should be avoided while the cream is on the skin.

Common local skin reactions are erythema, erosion, excoriation/flaking and edema. Hand washing is recommended before and after applying imiquimod cream. The cream should be applied prior to bedtime and left on the skin for 6 to 10 hours, three times per week. Therapy should continue until there is total clearing of genital/perianal warts or for a maximum of 16 weeks. The cost of 0.25 gm is $7.52.

Carvedilol (Coreg7)
3.125mg, 6.25mg, 12.5mg, and 25mg tablets
Smith Kline Beecham Pharmaceuticals

Restricted to Cardiology

Carvedilol is a nonselective beta-blocker (with no intrinsic sympathomimetic activity) with alpha-1 blocking properties. Carvedilol appears to act in heart failure by reducing the effects of the sympathetic nervous system. Carvedilol increases left ventricular ejection fraction, decreases intracardiac and pulmonary vascular pressures, decreases heart rate and prevents progressive enlargement of the left ventricle with continued use.

Carvedilol is indicated for the treatment of mild to moderate (NYHA class II or III) heart failure of ischemic or cardiomyopathic origin, in conjunction with digitalis, diuretics, and ACE inhibitors to reduce the progression of disease as evidenced by cardiovascular death or hospitalization. It is also indicated for treatment of essential hypertension with or without other anti-hypertensives. This agent may be used in patients unable to tolerate ACE inhibitors and may be used in patients who are or are not receiving digitalis, hydralazine or nitrate therapy.

Carvedilol is contraindicated in patients with NYHA class IV decompensated cardiac failure requiring intravenous inotropic therapy, bronchial asthma or related bronchconstrictive conditions, second or third degree AV block, sick sinus syndrome (unless a permanent pacemaker is in place), cardiogenic shock or severe bradycardia.

The most frequently cited adverse events included dizziness, fatigue, upper respiratory tract infection, chest pain, hyperglycemia, and diarrhea. This drug has a FDA Pregnancy Category of C.

Carvedilol is extensively absorbed after oral administration with a bioavailability of approximately 25% to 35%. For congestive heart failure, the maximum recommended dose is 25 mg twice daily in patients <85 kg and 50 mg twice daily in patients > 85 kg. For hypertension, the recommended initial doses of carvedilol is 6.25 mg twice daily. The maximum daily dose is 50 mg.

Metronidazole Vaginal Gel (Metrogel V7)
0.75% Gel (70 gm tube)
Curatek Laboratories

Metronidazole vaginal gel is indicated for the treatment of bacterial vaginosis (BV).

MetroGel is contraindicated in patients with a prior history of sensitivity to metronidazole. Adverse events reported in clinical trials were primarily gastrointestinal and genitourinary in nature. Because metronidazole is contraindicated during the first trimester of pregnancy, clindamycin vaginal cream is the preferred treatment for BV during the first trimester. The recommended dose is one applicatorful (5 gm) vaginal gel twice daily for 5 days. The cost of full therapy is $21.78.

Pramipexole (Mirapex7)
0.125 mg, 0.25 mg, 1.0 mg, and 1.5 mg tablets
Pharmacia and Upjohn Laboratories

Pramipexole is indicated for the treatment of the signs and symptoms of idiopathic Parkinson=s Disease in early stage patients without levodopa and in advanced stage patients with levodopa. Pramipexole is a nonergot dopamine agonist with a high relative specificity and full intrinsic activity at the D₂ subfamily of dopamine receptors. It binds with a higher affinity to D₃ receptor subtypes compare to D₂ or D₄ receptor subtypes. The relevance of D₃ receptor binding in Parkinson=s Disease is unknown. The precise action of pramipexole in the treatment of Parkinson=s is not known, but may be related to stimulation of dopamine receptors in the striatum.

Pramipexole is rapidly absorbed reaching peak concentrations in approximately 2 hours. Renal insufficiency may require a dosage adjustment. In addition, pramipexole clearance is about 30% lower in women than in men.

The most common adverse reactions in patients with early disease were nausea, dizziness, somnolence, insomnia, and constipation. In patients with advanced disease, adverse reactions included dyskinesia, postural hypotension, extrapyramidal syndrome, insomnia, dizziness, accidental injury, and dream abnormalities. Hallucinations have occurred in approximately 9% of patients with early Parkinson=s disease and in 2.6% in patients with advanced disease. Since pramipexole is a dompamine agonist, dopamine antagonists (neuroleptics, phenothiazines, etc) may theoretically diminish the effectiveness of the drug. Pramipexole has an FDA pregnancy category rating of C.

Doses should be initiated at subtherapeutic levels to avoid intolerable side effects and orthostatic hypotension. Initial dosages should be gradually increased 0.375 mg daily ( in three divided dose) and should not be increased more frequently than every 5 to 7 days. If discontinued, pramipexole should be tapered over a period of one week.

Nilutamide (Nilandron7)
50 mg tablets
Hoechst Marion Roussel, Inc

Nilutamide is approved for the treatment of metastatic prostate cancer (Stage D₂) in combination with surgical castration. Nilutamide, a nonsteroidal antiandrogenic agent, has been used in combination with surgical orchiectomy or with LHRH analog therapy to improve inhibition of prostate cancer growth by blocking the action of residual adrenal androgens. Because it lacks progestational activity, it may increase levels of luteinizing hormone, follicle stimulating hormone, testosterone and estradiol.

Common adverse effects reported with nilutamide in the published clinical trials included nausea, vomiting, visual disturbances, alcohol intolerance, hot flushes, gynecomastia, diarrhea, interstitial pneumonitis and skin rash. Light-dark adaptation disorders are reported in up to 65% of patients treated with nilutamide. Alcohol intolerance was reported in 8% to 33% of patients treated with nilutamide. Coadministration of alcohol may result in facial flushing, malaise, and hypotension and is not recommended.

The FDA-approved adult dosing regimen is 300 mg once daily starting on the day of surgical castration or the next day. The manufacturer recommends all patients treated with nilutamide receive baseline liver function tests and chest X-rays with liver function tests monitored every 3 months thereafter. The cost of a typical therapy of nilutamide is $6.42.

Quetiapine (Seroquel7)
25 mg, 100 mg, 200 mg tablets
Zeneca Laboratories

Quetiapine is an antipsychotic drug that belongs to a unique chemical class called the dibenzothiazepines. Quetiapine is indicated for the management of manifestations of psychotic disorders. The commercial formulation is a fumarate salt, however doses and tablet strengths are expressed as milligrams of base.

Quetiapine is rapidly absorbed after oral administration and reaches peak plasma concentration within 1.5 hours. The mean terminal half-life of quetiapine is approximately 6 hours and steady state concentrations are achieved within two days of dosing. Because quetiapine is extensively metabolized by the liver, hepatic impairment may significantly increase serum concentrations and dosage adjustments are required. Dosage adjustment in renal impairment may not be needed.

The manufacturer recommended dosage is 25 mg twice daily initially, increased by 25-50 mg twice daily or three times daily on days 2 or 3 as tolerated. The total daily dosage range by day 4 should be 300 to 400 mg (given bid or tid). Further dosage adjustments (in increments of 25-50 mg bid) should be made at intervals of 2 days.

Quetiapine offers a reduced rate of EPS when compared to other atypical antipsychotics and does not appear to affect prolactin levels. The most frequently cited adverse reactions included dizziness, postural hypotension, dry mouth, and dyspepsia. Quetiapine has also been associated with neuroleptic malignant syndrome and somnolence. Quetiapine induced orthostatic hypotension may be accompanied by dizziness and tachycardia in some patients, particularly during the initial titration phase of the drug. This risk may be reduced by limiting the initial titration dose to 25 mg twice daily.

Patients should be counseled regarding the potential for orthostatic hypotension and somnolence during the initial titration phase (approximately 3 to 5 days) and when increasing the dose. The cost of daily therapy of quetiapine is $5.07.

FORMULARY ADDITION
Changes in the KUMC Formulary since 1997-1998 publications

*withdrawn from US market

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