Tiazac XC

Diltiazem may be safely co-administered with nitrates.

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

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.

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.

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.

There was no increased risk of sudden cardiac death among users of amoxicillin.

There is no known diltiazem reaction with alcohol.

The concomitant administration of diltiazem with statin drugs warrants caution, and requires close medical supervision. Rhabdomyolysis and hepatitis have been reported in patients treated with atorvastatin or simvastatin in combination with diltiazem, and in the case of simvastatin-treated patients, deaths have occurred. If diltiazem is prescribed to a patient already taking a statin, consideration should be given to decreasing the dose of the statin.

In a published study of 10 healthy volunteers treated with simvastatin 20 mg, after 2 weeks of treatment with diltiazem 240 mg, the mean C_max (3.6-fold) and AUC (5-fold) of simvastatin were increased significantly.

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.

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

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

The use of erythromycin should be avoided in patients treated with CYP3A inhibitors, including diltiazem. An analysis reported in the literature indicates that the risk of sudden death is increased in current users of erythromycin (incidence-rate ratio=2.01; 95% CI=1.08 to 3.75), and this risk is further elevated in concurrent users of CYP3A inhibitors (5.35; 95% CI=1.72 to 16.64), including diltiazem. Cohort analysis revealed one death in 106 person—years in diltiazem-treated patients.

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

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

A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine 1200 mg per 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.

Dosage should be based on individual patient response. Treatment should start with 180 mg once daily; this may be increased at intervals of 7 to 14 days if adequate response is not obtained. Higher doses may not result in greater anti-anginal effect. The maximum dose is 360 mg once daily.

TIAZAC XC may be safely co-administered with short- and long-acting nitrates. Sublingual nitroglycerin may be taken as required to support acute anginal attacks during TIAZAC XC therapy.

When used as monotherapy, usual starting doses for hypertension are 180 to 240 mg once daily. Maximum antihypertensive effect is usually observed after approximately 2 to 4 weeks of therapy; therefore, dosage adjustments should be scheduled accordingly.

A maximum daily dose of 360 mg should not be exceeded. The dosage of TIAZAC XC or concomitant antihypertensive agents may need to be adjusted when adding one to the other. See Warnings and Precautions regarding use with beta-blockers.

TIAZAC XC has an extended-release delivery system designed to deliver maximum effect in the morning when administered at night-time. Accordingly, TIAZAC XC should be administered once daily at bedtime. TIAZAC XC should not be chewed or crushed. TIAZAC XC may be taken with or without food, but should be so taken consistently.

vitreous floaters, diplopia.

anorexia, constipation, diarrhea, dry mouth, dysgeusia, mild elevations of AST, ALT, LDH, and alkaline phosphatase (see Warnings and Precautions, Acute Hepatic Injury), thirst, vomiting, weight increase.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

feeling jittery, joint swelling, lethargy, neck swelling, oedema NOS, peripheral swelling, swelling NOS.

atrioventricular block first degree, palpitations.

Adverse Events >1%: Diltiazem Hydrochloride Extended-Release Formulation. Once-a-day Administration. Placebo-Controlled Angina Trial

The following data is divided into two sections. The first represents ADRs <1% in TIAZAC XC Clinical trials. The second reflects ADRs <1% in other diltiazem products.

The following treatment related adverse drug reactions were reported with <1% incidence in the TIAZAC XC clinical trial:

amblyopia, CPK increase, dyspnea, epistaxis, eye irritation, hyperglycemia, hyperuricemia, impotence, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties, dry mouth.

The following postmarketing events have been reported infrequently in patients receiving diltiazem: alopecia, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, angioedema, toxic epidermal necrolysis, extrapyramidal symptoms, gingival hyperplasia, hemolytic anemia, increased bleeding time, leukopenia, purpura, retinopathy, and thrombocytopenia. In addition, adverse reactions such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease in these patients. A number of well-documented cases of generalized rash, characterized as leukocytoclastic vasculitis, have been reported. However, a definitive cause and effect relationship between these events and diltiazem therapy is yet to be established.

dyspnoea NOS.

dizziness (exc vertigo), sinus headache.

urinary frequency.

petechiae, photosensitivity, pruritus.

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

dermatitis NOS, erythema NEC, face oedema, pruritus NOS, rash generalized.

flushing.

In addition, the following events were reported with a frequency of less than 1% in other diltiazem products:

In clinical trials with diltiazem, involving over 3300 patients the most common adverse reactions were headache (4.6%), edema (4.6%), dizziness (3.5%), asthenia (2.7%), first degree AV block (2.4%), bradycardia (1.7%), flushing (1.5%), nausea (1.4%), rash (1.2%), and dyspepsia (1.0%).

aspartate aminotransferase increased.

dyspepsia, nausea.

angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure (left ventricular dysfunction), ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

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.

For the management of chronic stable angina (effort-associated angina) without evidence of vasospasm in patients who remain symptomatic despite adequate doses of beta-blockers and/or organic nitrates or who cannot tolerate those agents.

TIAZAC XC may be tried in combination with beta-blockers in chronic stable angina in patients with normal ventricular function. When such concomitant therapy is introduced, these patients must be monitored closely (see Warnings and Precautions).

Since the safety and efficacy of TIAZAC XC in the management of unstable or vasospastic angina has not been substantiated, its use for these conditions is not recommended.

For the treatment of mild to moderate essential hypertension. It is to be administered once daily at bedtime.

TIAZAC XC should normally be used in those patients in whom treatment with diuretics or beta-blockers has been ineffective, or has been associated with unacceptable adverse effects.

The safety of concurrent use of TIAZAC XC with other antihypertensive agents has not been established.

No morbidity and mortality studies have been carried out to support the use of TIAZAC XC (see Action and Clinical Pharmacology, Pharmacodynamics).

Safety and efficacy in children has not been studied.

Atropine and intravenous fluids may suffice in patients with mild poisoning.

Calcium salts given intravenously (should be avoided in patients who may have coingested digoxin). Catecholamine pressors may be used to improve cardiac contractility (epinephrine, dopamine, dobutamine, isoproterenol) or vascular tone (norepinephrine, epinephrine, dopamine). High dose insulin together with glucose or glucagon may be effective in patients not responding to catecholamines.

Sustained release calcium channel blockers may cause delayed onset of toxicity and once established, toxicity may last for several days. Patients who have symptoms following a TIAZAC XC ingestion should be treated and monitored until all signs and symptoms of toxicity have resolved. Patients who remain asymptomatic with normal vital signs during a 24 hour period of observation in a monitored setting may be discharged.

Each white, film-coated, extended-release tablet, debossed with “B” on one side, and the strength on the other, contains: diltiazem HCl 300 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicone dioxide, croscarmellose sodium, eudragit, hydrogenated vegetable oil, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc and titanium dioxide. Bottles of 90.

Each white, film-coated, extended-release tablet, debossed with “B” on one side, and the strength on the other, contains: diltiazem HCl 180 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicone dioxide, croscarmellose sodium, eudragit, hydrogenated vegetable oil, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc and titanium dioxide. Bottles of 90.

Each white, film-coated, extended-release tablet, debossed with “B” on one side, and the strength on the other, contains: diltiazem HCl 360 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicone dioxide, croscarmellose sodium, eudragit, hydrogenated vegetable oil, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc and titanium dioxide. Bottles of 90.

Each white, film-coated, extended-release tablet, debossed with “B” on one side, and the strength on the other, contains: diltiazem HCl 240 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicone dioxide, croscarmellose sodium, eudragit, hydrogenated vegetable oil, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc and titanium dioxide. Bottles of 90.

Each white, film-coated, extended-release tablet, debossed with “B” on one side, and the strength on the other, contains: diltiazem HCl 120 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicone dioxide, croscarmellose sodium, eudragit, hydrogenated vegetable oil, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, microcrystalline wax, polydextrose, polyethylene glycol, polysorbate, povidone, pregelatinized starch, simethicone, sodium starch glycolate, sucrose stearate, talc and titanium dioxide. Bottles of 90.

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.

Use of immediate release diltiazem at 240 mg per day started 3 to 15 days after a myocardial infarction was associated with an increase in cardiac events in patients with pulmonary congestion with no overall effect on mortality. Although there has not been a study of a sustained-release formulation of diltiazem in acute myocardial infarction, their use may have effects similar to those of immediate-release dilitazem in acute myocardial infarction.

TIAZAC XC (diltiazem hydrochloride) prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13 of 3007 patients or 0.43%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction.

In rare instances, significant elevations in alkaline phosphatase, CPK, LDH, AST, ALT and symptoms consistent with hepatic injury have been observed. These reactions have been reversible upon discontinuation of drug therapy. Although a causal relationship to diltiazem has not been established in all cases, a drug induced hypersensitivity reaction is suspected (see Adverse Reactions). As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.

Decreases in blood pressure associated with diltiazem hydrochloride therapy may occasionally result in symptomatic hypotension.

Because diltiazem has a negative inotropic effect in vitro and it affects cardiac conduction, the drug should only be used with caution and under careful medical supervision in patients with cardiac failure (see also Contraindications).

Postinfarction patients with reduced ejection fraction are at particular risk for subsequent heart failure when treated with diltiazem. Accordingly, diltiazem should be avoided in patients with substantially reduced ejection fraction.

Because TIAZAC XC (diltiazem hydrochloride) is extensively metabolized by the liver and excreted by the kidney and in bile, monitoring of laboratory parameters and cautious dosage titration are recommended in patients with severe hepatic or renal function (see Adverse Reactions).

Generally, diltiazem should not be given to patients with impaired left ventricular function if they are already receiving beta-blockers. In exceptional cases, when in the opinion of the physician, concomitant use is considered essential, such use should be instituted gradually in a hospital setting under close medical supervision.

The combination of diltiazem and beta-blockers warrants caution since in some patients additive effects on heart rate, cardiac conduction, blood pressure or left ventricular function have been observed.

Diltiazem gives no protection against the dangers of abrupt beta-blocker withdrawal and such withdrawal should be done by the gradual reduction of the dose of beta-blocker.

Safety and effectiveness in children has not been studied.

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

Therapeutic blood levels appear to be in the range of 50-200 ng/mL. In vitro human serum binding studies revealed that 70 to 80% of diltiazem is bound to plasma proteins. The pharmacokinetics of diltiazem are non-linear.

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect giving absolute bioavailability (compared to intravenous dosing) of about 40%.

No studies are available that compare the relative bioavailability of TIAZAC XC tablets to TIAZAC capsules directly.

Following extensive hepatic metabolism, only 2-4% of the drug appears unchanged in the urine and 6-7% 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 active metabolite, desacetyl diltiazem, is present in the plasma at levels 10-20% of the parent drug and is 25-50% as potent as diltiazem in terms of coronary vasodilation.

In a double-blind study involving 311 patients with chronic stable angina, evening doses of 180, 360 and 420 mg clinical trial formulation of TIAZAC XC were compared to placebo and to 360 mg administered in the morning. The 420 mg dose is not approved for use in Canada. All doses administered at night increased exercise tolerance when compared with placebo after 21 hours, during the diltiazem trough period. The median effect, placebo-subtracted, was 20 to 28 seconds for all three doses; no dose-response was demonstrated, ie. use of the higher doses tested did not consistently result in increased exercise tolerance. The 360 mg dose given in the morning also improved exercise tolerance when measured 25 hours later. As expected, the effect was smaller than the effects measured only 21 hours following nighttime administration. TIAZAC XC had a larger effect in increasing exercise tolerance at peak serum concentrations than at trough.

In pharmacokinetic studies in healthy volunteers, there were no statistically significant differences between male and female subjects with respect to the AUC (p=0.099) and C_max (p=0.295).

Pharmacokinetic studies with TIAZAC XC in children have not been conducted.

Pharmacokinetic studies with TIAZAC XC in geriatrics have not been conducted. However it is known that 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.

No pharmacokinetic studies have been conducted with TIAZAC XC in patients with hepatic insufficiency.

The therapeutic effect of this group of drugs is believed to be related to their specific cellular action of selectively inhibiting transmembrane influx of calcium ions into cardiac muscle and vascular smooth muscle. The contractile processes of these tissues are dependent upon the movement of extracellular calcium into the cells through specific ion channels. Diltiazem blocks transmembrane influx of calcium through the slow channel without affecting, to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within cells of the above tissues. Diltiazem does not alter total serum calcium.

The effect of race in pharmacokinetic studies has not been evaluated.

No pharmacokinetic studies have been conducted with TIAZAC XC in patients with renal insufficiency.

Diltiazem produces antihypertensive effects both in the supine and standing positions. Resting heart rate is usually slightly reduced. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually unaffected. Heart rate at maximum exercise is reduced. Studies to date, primarily in patients with normal ventricular function, have shown that cardiac output, ejection fraction and left ventricular end-diastolic pressure have not been affected.

Chronic therapy with diltiazem produces no change, or a decrease, in circulating plasma catecholamines. However, no increased activity of the renin-angiotensin-aldosterone axis has been observed.

Diltiazem inhibits the renal and peripheral effects of angiotensin II.

In man, intravenous diltiazem in doses of 20 mg prolongs atrio-His conduction time and atrioventricular node functional and effective refractory periods by approximately 20%. Chronic oral administration of diltiazem in doses up to 540 mg per day has resulted in small increases in PR interval. Second degree and third degree AV block have been observed (see Warnings and Precautions). In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

In a double-blind clinical study, a diltiazem hydrochloride extended-release clinical trial formulation with the same bead coating as TIAZAC XC, administered daily at night for 7 weeks at doses of 120 mg, 240 mg, 360 mg and 540 mg was compared to administration of 360 mg in the morning. The 540 mg dose is not approved for use in Canada.

Group mean reductions in diastolic blood pressure between 6 AM and 12 NOON, as measured by ambulatory blood pressure monitoring (ABPM) for 120 mg, 240 mg, 360 mg and 540 mg taken at night were 4.7, 8.9, 10.2 and 14.8 mmHg, respectively, placebo-corrected. These reductions in diastolic blood pressure for all doses were significantly different from placebo and dose-related. Within this time period of 6 AM to 12 NOON, the 360 mg PM dose produced a statistically significant 3.3 mmHg greater reduction in diastolic blood pressure than the 360 mg AM dose.

When changes in mean seated office diastolic blood pressure from baseline were evaluated at 8 AM, the following decreases were noted: placebo 6.6 mmHg; 120 mg PM 10.5 mmHg; 240 mg PM 13.1 mmHg; 360 mg PM 15.5 mmHg; 540 mg PM 20.3 mmHg, with p<0.0001 for all comparisons with corresponding baseline measurements. For 360 mg AM, a mean decrease from baseline of 10.8 mmHg was seen, p<0.0001. When measured at 6 PM, the following decreases were noted: placebo 5.5 mmHg; 120 mg PM 5.2 mmHg; 240 mg PM 8.7 mmHg; 360 mg PM 10.3 mmHg; 540 mg PM 14.1 mmHg, with p<0.0001 for all comparisons with corresponding baseline measurements. For 360 mg AM, a mean decrease from baseline of 13.1 mmHg was seen, p<0.0001.

TIAZAC XC has an extended-release delivery system designed for night-time administration, resulting in maximum diltiazem plasma levels in the morning.

Administration of TIAZAC XC tablets in the fasted state at bedtime, in a single study, resulted in detectable dilitazem plasma levels after 3 to 4 hours, and peak plasma levels between 11 and 18 hours post dose. After single dosing, diltiazem bioavailability ranged from 2.5% to 16% over the first six hours. The apparent elimination half-life for TIAZAC XC after single or multiple dosing is 6 to 9 hours.

When a single dose of 360 mg TIAZAC XC tablets, administered at night, was compared to the same dose given in the morning, an 18% greater systemic exposure and 11% higher peak exposure were observed at night relative to morning. Under steady-state conditions, night-time administration resulted in 22% and 16% greater systemic and peak exposure, respectively, relative to morning administration.

When single doses of 360 mg TIAZAC XC tablets were given in the morning to assess potential food interaction, the observed ratios of means were AUC_τao 112.4% (90% C.I. 101.2-124.9) and C_max 104.0% (90% C.I. 92.9-116.5) for the fed/fasted comparison (see Dosage and Administration).

While both TIAZAC XC tablets and TIAZAC capsules possess the same immediate release diltiazem-containing bead cores, the release-controlling polymer bead coatings are different, resulting in different bioavailability profiles. Further, the TIAZAC beads are encapsulated in gelatin capsules to produce the TIAZAC formulation, while TIAZAC XC tablet beads are blended with inert wax beads and excipients, then compressed into tablets.

Diltiazem time course kinetics, as noted across studies in healthy volunteers that evaluated TIAZAC XC tablets and TIAZAC capsules respectively, are presented below in Figure 1.