Tiazac

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect giving absolute bioavailability (compared to i.v. dosing) of about 40%. Therapeutic blood levels appear to be in the range of 50 to 200 ng/mL range and the plasma elimination half-life (beta-phase) following single or multiple drug administration is approximately 3.5 to 6 hours. In-vitro human serum binding studies revealed that 70 to 80% of diltiazem is bound to plasma proteins. Following extensive hepatic metabolism, only 2 to 4% of the drug appears unchanged in the urine and 6 to 7% appears as metabolites.

The metabolic pathways of diltiazem include N-and O-demethylation (via cytochrome P450), deacetylation (via plasma and tissue esterases), in addition to conjugation (via sulfation and glucuridonation). In vitro studies have demonstrated that CYP 3A4 is the principal CYP isoenzyme involved in N-demethylation. The major metabolite, desacetyl diltiazem, is present in the plasma at levels 10 to 20% of the parent drug and is 25 to 50% as potent as diltiazem in terms of coronary vasodilation.

TIAZAC Capsules: When compared to a regimen of immediate-release tablets at steady-state, approximately 93% of drug is absorbed from the TIAZAC formulation. When TIAZAC was coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected; T_max, however, occurred slightly earlier. Dose-dumping does not occur. The apparent elimination half-life after single or multiple dosing is 4 to 9.5 hours (mean 6.5 hours).

TIAZAC demonstrates nonlinear pharmacokinetics. As the dose of TIAZAC is increased from a daily dose of 120 to 240 mg, there is an increase in the AUC of 2.4 times. When the dose is increased from 240 mg to 360 mg there is an increase in AUC of 1.5 times.

In a study with 14 healthy subjects, the steady-state pharmacokinetics of TIAZAC were compared with Cardizem CD at a dose of 240 mg/day. The bioavailability of TIAZAC relative to Cardizem CD based on mean diltiazem AUC was 124% (90% CI=111 to 139%). The relative mean C_max was 121%.

Hypertension: In a parallel-group, double-blind placebo-controlled study of 198 patients with mild to moderate essential hypertension, TIAZAC was given for 4 weeks. The changes in diastolic blood pressure measured at trough (24 hours after the dose) for placebo, 90 mg, 180 mg and 360 mg were −5.4, −6.3, −6.2, −8.2 mmHg, respectively.

Another double-blind placebo-controlled clinical trial in 56 patients with mild to moderate essential hypertension treated for 8 weeks, followed a dose-escalation design. Supine diastolic blood pressure measured at trough following 2-week intervals of treatment with TIAZAC was reduced by −3.7 mmHg with 120 mg/day vs −2.0 mmHg with placebo, by −7.6 mmHg after escalation to 240 mg/day vs −2.3 mmHg with placebo, by −8.1 mmHg after escalation to 360 mg/day versus −0.9 mmHg with placebo.

In a double-blind, multicentre study, 181 patients with mild to moderate essential hypertension controlled with Cardizem CD monotherapy, were randomized to the same dose of either Cardizem CD or TIAZAC. The least squares mean for the difference in diastolic blood pressure at trough between TIAZAC and Cardizem CD groups pooled was 0.19 mmHg (90% CI=1.2 to 1.6 mmHg). Data based on same dose comparisons were supportive of this result.

Angina: In a double-blind, parallel group placebo-controlled trial, 158 patients with chronic stable angina were, after titration, treated for 2 weeks on their target maintenance dose of TIAZAC.

TIAZAC increased exercise tolerance times in a Bruce exercise protocol, at trough, 24 hours after dosing. Exercise tolerance times increased by 14, 26, 41 and 33 seconds for placebo, 120 mg, 240 mg, and 360 mg/day treated patient groups respectively. At peak, 8 hours after dosing, exercise tolerance times were increased by 13, 38, 64 and 53 seconds for placebo, 120 mg, 240 mg and 360 mg/day treated groups, respectively.

As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of diltiazem with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, terfenadine, theophylline.

Anesthetics: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Benzodiazepines: Diltiazem significantly increases peak plasma levels and the elimination half-life of triazolam and midazolam.

Beta-blockers: The concomitant administration of diltiazem with beta adrenergic blocking drugs warrants caution and careful monitoring. Such an association may have an additive effect on heart rate, on AV conduction or on blood pressure (see Warnings). Appropriate dosage adjustments may be necessary. A study in 5 normal subjects showed that diltiazem increased propranolol bioavailability by approximately 50%.

Carbamazepine: Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40 to 72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cimetidine: A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week course of cimetidine 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.

Cyclosporine: A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15 to 48% was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Digitalis: Diltiazem and digitalis glycosides may have an additive effect in prolonging AV conduction. In clinical trials, concurrent administration of diltiazem and digoxin have resulted in increases in serum digoxin levels with prolongation of AV conduction. This increase may result from a decrease in renal clearance of digoxin. Patients on concomitant therapy, especially those with renal impairment, should be carefully monitored. The dose of digoxin may need downward adjustment.

Rifampin: Administration of diltiazem with rifampin markedly reduced plasma diltiazem concentrations and the therapeutic effect of diltiazem.

Short- and Long-Acting Nitrates: Diltiazem may be safely coadministered with nitrates.

Other Calcium Antagonists: Limited clinical experience suggests that in certain severe conditions not responding adequately to verapamil or to nifedipine, using diltiazem in conjunction with either of these drugs may be beneficial.

Administration of diltiazem to elderly patients (over or equal to 65 years of age) requires caution. The incidence of adverse reactions is approximately 13% higher in this group. Those adverse reactions which occur more frequently include: peripheral edema, bradycardia, palpitation, dizziness, rash and polyuria. Therefore particular care in titration is advisable.

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

Safety and effectiveness in children have not been established.

Each lavender/white extended-release capsule imprinted, in black ink, with a maple leaf on one end and “BVF 300” on the other, contains: diltiazem HCI 300 mg. Nonmedicinal ingredients: black iron oxide, D&C Red #28, eudragit, FD&C Blue #1, FD&C Red #40, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.

Each bluish green/white extended-release capsule imprinted, in black ink, with a maple leaf on one end and “BVF 180” on the other, contains: diltiazem HCl 180 mg. Nonmedicinal ingredients: black iron oxide, D&C Red #28, eudragit, FD&C Green #3, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.

Each lavender/bluish green extended-release capsule imprinted, in white ink, with a maple leaf on one end and “BVF 240” on the other, contains: diltiazem HCI 240 mg. Nonmedicinal ingredients: black iron oxide, D&C Red #28, eudragit, FD&C Blue #1, FD&C Green #3, FD&C Red #40, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.

Each bluish green/bluish green extended-release capsule imprinted, in white ink, with a maple leaf on one end and “BVF 360” on the other, contains: diltiazem HCI 360 mg. Nonmedicinal ingredients: black iron oxide, eudragit, FD&C Green #3, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.

Store between 15 to 30°C. Avoid excessive humidity.

Each lavender/lavender extended-release capsule imprinted, in white ink, with a maple leaf on one end and “BVF 120” on the other, contains: diltiazem HCI 120 mg. Nonmedicinal ingredients: black iron oxide, D&C Red #28, eudragit, FD&C Blue #1, FD&C Red #40, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.

In pregnancy and in women of childbearing potential. Fetal malformations and adverse effects on pregnancy have been reported in animals. In repeated dose studies a high incidence of vertebral column malformations were present in the offspring of mice receiving more than 50 mg/kg of diltiazem orally.

In the offspring of mice receiving a single oral dose of 50 or 100 mg/kg on day 12 of gestation, the incidence of cleft palate and malformed extremities was significantly higher. Vertebral malformations were most prevalent when they received the drug on day 9. In rats, a significantly higher fetal death rate was present when 200 and 400 mg/kg were given orally on days 9 to 14 of gestation. Single oral dose studies in rats resulted in a significant incidence of skeletal malformations in the offspring of the group receiving 400 mg/kg on day 11. In rabbits, all pregnant dams receiving 70 mg/kg orally from day 6 to 18 of gestation aborted; at 35 mg/kg, a significant increase in skeletal malformations was recorded in the offspring.

constipation (1.2%), dyspepsia (1.2%).

abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.

pain (3.7%), pharyngitis (1.8%), cough increase (1.2%), gout (1.2%), rash (1.2%), hyperglycemia (1.2%), albuminuria (1.2%), crystalluria (1.2%), dyspnea (0.6%), infection (0.6%).

headache (8.2%), asthenia (0.6%), dizziness (3.1%).

The safety of TIAZAC was evaluated in 158 patients with chronic stable angina pectoris treated with TIAZAC at doses from 120 to 360 mg/day and in 50 patients treated with placebo. Thirty three percent of the TIAZAC treated patients had one or more adverse event compared to 18% in the placebo group. Discontinuation due to adverse events was required in 3 patients who were on TIAZAC 240 mg/day. The most common adverse events were: headache (8%), pain (4%), dizziness (3%) and peripheral edema (2%).

The following percentage of adverse effects, divided by system, were reported:

Hypertension: A safety evaluation was carried out in placebo-controlled studies in which 345 hypertensive patients (TIAZAC n=243; placebo n=102) were treated with TIAZAC at doses up to 360 mg/day. The most common adverse effects were: headache (13%); edema (5%); gastrointestinal disease (5%); pain (4%); vasodilation (3%); asthenia (3%); dizziness (3%) and palpitations (2%).

The following percentage of adverse effects, divided by system, were reported:

petechiae, photosensitivity, pruritus.

edema, peripheral (1.8%), palpitations (1.2%), arrhythmia (1.2%).

There have been reports of diltiazem overdose in doses ranging from less than 1 to 18 g. In cases with fatal outcome, the majority involved multiple drug ingestion.

Events observed following diltiazem overdose included bradycardia, hypotension, heart block and cardiac failure.

Most reports of overdose described some supportive medical measure and/or drug treatment. Bradycardia frequently responded favorably to atropine as did heart block, although cardiac pacing was also frequently utilized to treat heart block. Fluids and vasopressors were used to maintain blood pressure, and in cases of cardiac failure, inotropic agents were administered. In addition, some patients received treatment with ventilatory support, gastric lavage, activated charcoal, and i.v. calcium.

The effectiveness of i.v. calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received i.v. calcium. In some cases i.v. calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes, and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g/hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

In the event of overdosage or exaggerated response, appropriate supportive measures should be employed in addition to gastric lavage. The following measures may be considered:

Bradycardia: Administer atropine. If there is no response to vagal blockage, administer isoproterenol cautiously.

High-degree AV Block: Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure: Administer inotropic agents (isoproterenol, dopamine or dobutamine) and diuretics.

Hypotension: Vasopressors (e.g., dopamine or norepinephrine bitartrate). Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.