Tikosyn Side Effects, and Drug Interactions - Dofetilide

Tikosyn Side Effects, and Drug Interactions - Dofetilide

SIDE EFFECTS

The TIKOSYN clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. TIKOSYN was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received TIKOSYN for up to three years.

In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials (see CLINICAL STUDIES: Safety in Patients with Structural Heart Disease DIAMOND Studies , for a description of these trials).

In studies of patients with supraventricular arrhythmias a total of 1346 and 677 patients were exposed to TIKOSYN and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness.

Serious Arrhythmias and Conduction Disturbances:   Torsade de pointes is the only arrhythmia that showed a dose-response relationship to TIKOSYN treatment. It did not occur in placebo treated patients. The incidence of torsade de pointes in patients with supraventricular arrhythmias was 0.8% (11/1346) (see WARNINGS ). The incidence of torsade de pointes in patients who were dosed according to the recommended dosing regimen (see DOSAGE AND ADMINISTRATION ) was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias.

In the DIAMOND trials a total of 1511 patients were exposed to TIKOSYN for 1757 patient years. The incidence of torsade de pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI.

Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials.

Other Adverse Reactions:   Table 8 presents other adverse events reported with a frequency of >2% on TIKOSYN and reported numerically more frequently on TIKOSYN than on placebo in the studies of patients with supraventricular arrhythmias.

Adverse events reported at a rate >2% but no more frequently on TIKOSYN than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia.

The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with TIKOSYN than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope.

The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on TIKOSYN and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium) or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters.

In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups.

Cimetidine:   (see CONTRAINDICATIONS ) Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with TIKOSYN (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires TIKOSYN and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of TIKOSYN.

Verapamil:   (see CONTRAINDICATIONS ) Concomitant use of verapamil is contraindicated. Co-administration of TIKOSYN with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of torsade de pointes.

Ketoconazole:   (see CONTRAINDICATIONS ) Concomitant use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum approved prescription dose) co-administered with TIKOSYN (500 mcg BID) for 7 days has been shown to increase dofetilide Cmax by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.

Trimethoprim Alone or in Combination with Sulfamethoxazole:   (see CONTRAINDICATIONS ) Concomitant use of trimethoprim alone or in combination with sulfamethoxazole is contraindicated. Trimethoprim 160 mg in combination with 800 mg sulfamethoxazole co-administered BID with TIKOSYN (500 mcg BID) for 4 days has been shown to increase dofetilide AUC by 103% and Cmax by 93%.

Potential Drug Interactions

Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with TIKOSYN. In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin and amiloride) should be co-administered with care as they might increase dofetilide levels.

Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochrome P450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously coadministered with TIKOSYN as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other cytochrome P450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4.

Other Drug Interaction Information

Digoxin:   Studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics of digoxin. In patients, the concomitant administration of digoxin with dofetilide was associated with a higher occurrence of torsade de pointes. It is not clear whether this represents an interaction with TIKOSYN or the presence of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication.

Other Drugs:   In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides) and theophylline did not affect the pharmacokinetics of TIKOSYN. In addition, studies in healthy volunteers have shown that TIKOSYN does not affect the pharmacokinetics or pharmacodynamics of warfarin, or the pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives.

Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide. Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P-glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport, respectively.