Action and Clinical Uses:
Diltiazem is a calcium ion cellular influx inhibitor (calcium entry blocker or calcium ion antagonist).:
Mechanism of Action: 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.
Hypertension: The antihypertensive effect of diltiazem is believed to be brought about largely by its vasodilatory action on peripheral blood vessels with resultant decrease in peripheral vascular resistance.
Angina: The precise mechanism by which diltiazem relieves angina has not been fully determined, but it is believed to be brought about largely by its vasodilatory action.
In angina of effort it appears that the action of diltiazem is related to the reduction of myocardial oxygen demand. This is probably caused by a decrease in blood pressure brought about by the reduction of peripheral resistance and of heart rate.
Hemodynamic and Electrophysiologic Effects: 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 an increase, 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, i.v. diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. Chronic oral administration of diltiazem in doses up to 540 mg/day has resulted in small increases in PR interval. Second-degree and third-degree AV block have been observed (see Warnings). In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).
Pharmacokinetics: 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).
Diltiazem extended-release 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% C.I. 111 to 139%). The relative mean C max was 121%.
Pharmacodynamics: Hypertension: In a parallel-group, double-blind placebo-controlled study of 198 patients with mild to moderate essential hypertension, diltiazem extended-release 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 mm Hg, 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 diltiazem extended-release was reduced by -3.7 mm Hg with 120 mg/day vs -2.0 mm Hg with placebo, by -7.6 mm Hg after escalation to 240 mg/day vs -2.3 mm Hg with placebo, by -8.1 mm Hg after escalation to 360 mg/day versus -0.9 mm Hg 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 mm Hg (90% confidence interval -1.2 to 1.6 mm Hg). 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 diltiazem.
Diltiazem 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.
Indications And Clinical Uses :
Essential Hypertension: For the treatment of mild to moderate essential hypertension. Diltiazem 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.
Diltiazem can be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated, or in patients with medical conditions in which these drugs frequently cause serious adverse effects.
Safety of concurrent use of diltiazem with other antihypertensive agents has not been established.
Chronic Stable Angina: 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 these agents.
Diltiazem may be tried in combination with beta-blockers in chronic stable angina patients with normal ventricular function. When such concomitant therapy is introduced, patients must be monitored closely (see Warnings, Use with Beta-blockers).
Since the safety and efficacy of diltiazem in the management of unstable or vasospastic angina has not been substantiated, its use for these indications is not recommended.
Patients with sick sinus syndrome except in the presence of an implanted pacemaker; patients with second- or third-degree AV block except in the presence of an implanted pacemaker; patients with known hypersensitivity to diltiazem; patients with severe hypotension (less than 90Â mmÂ Hg systolic); myocardial infarction patients, who have left ventricular failure manifested by congestion.:
Pregnancy: 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.
Warnings in Clinical States:
Cardiac Conduction: Diltiazem 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 3 007 patients or 0.43%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction.
Congestive Heart Failure: 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 congestive cardiac failure (see also Contraindications).
Use With Beta-blockers: 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. Close medical supervision is recommended.
Generally diltiazem should not be given to patients with impaired left ventricular function while they receive beta-blockers. However 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.
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.
Hypotension: Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.
Patients With Myocardial Infarction: Use of immediate release diltiazem at 240 mg/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 sustained release formulations of diltiazem in acute myocardial infarction, their use may have effects similar to those of immediate release diltiazem in acute myocardial infarction.
Acute Hepatic Injury: In rare instances, significant elevations in alkaline phosphatase, CPK, LDH, AST, ALT and symptoms consistent with acute 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 Effects). As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.
Impaired Hepatic or Renal Function: Because diltiazem 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 impaired hepatic or renal function (see Adverse Effects).
Children: Safety and effectiveness in children have not been established.
Lactation: 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.
Geriatrics: 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.
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 1 200 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.
:Overall Diltiazem Safety Profile: In clinical trials with diltiazem involving over 3 300 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%).
In addition, the following events were reported with a frequency of less than 1%:
Cardiovascular: angina, arrhythmia, AV block (second-or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.
Nervous System: abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.
Gastrointestinal: anorexia, constipation, diarrhea, dry mouth, dysgeusia, mild evelations of AST, ALT, LDH, and alkaline phosphatase (see Warnings), thirst, vomiting, weight increase.
Dermatological: petechiae, photosensitivity, pruritus.
Other: 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, events 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.
Hypertension: A safety evaluation was carried out in placebo-controlled studies in which 345 hypertensive patients (diltiazem extended-release n=243; placebo n=102) were treated with diltiazem extended-release at doses up to 360Â 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: Cardiovascular: edema, including peripheral edema (5%), vasodilation, including hypotension, syncope and flushing (3%), palpitations (2%) and tachycardia (1%).
CNS: headache (13%), asthenia (3%), dizziness (3%), neck rigidity (1%), nervousness (1%), paresthesia (1%).
Gastrointestinal: gastrointestinal disease, including dyspepsia, nausea (5%), constipation (1%), anorexia (1%), dry mouth (1%).
Other: pain (4%), pharyngitis (2%), rhinitis (1%), dyspnea (1%), allergic reaction (1%), polyuria (1%), rash (1%).
The most common adverse effects for placebo treated patients in the above mentioned trials were: headache (17%), edema (3%), gastrointestinal disease (2%), pain (5%), vasodilation (1%), asthenia (6%), dizziness (4%), palpitations (2%), pharyngitis (2%), rhinitis (2%), dyspnea (1%), nervousness (2%), paresthesia (2%), tachycardia (2%).
Angina: The safety of diltiazem was evaluated in 158 patients with chronic stable angina pectoris treated with diltiazem at doses from 120 to 360 mg/day and in 50 patients treated with placebo. Thirty three percent of the diltiazem 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 diltiazem 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: Cardiovascular: edema, peripheral (1.8%), palpitations (1.2%), arrhythmia (1.2%).
CNS: headache (8.2%), asthenia (0.6%), dizziness (3.1%).
Gastrointestinal: constipation (1.2%), dyspepsia (1.2%).
Other: 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%).
Symptoms And Treatment Of Overdose :
OverdoseThere 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.
Dosage And Administration:
Diltiazem should not be chewed or crushed. Diltiazem has not been shown to be bioequivalent to other diltiazem formulations (see , Pharmacokinetics).
Hypertension: When used as monotherapy, usual starting doses are 180 to 240 mg once daily, although some patients may respond to 120 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 diltiazem or concomitant antihypertensive agents may need to be adjusted when adding one to the other. See Warnings and Precautions regarding use with beta-blockers.
Angina: Dosages for the treatment of angina should be adjusted to each patient’s needs, starting with a dose of 120 mg to 180 mg once daily. Individual patients may respond to higher doses of up to 360 mg once daily. When necessary, titration should be carried out over a 7- to 14-day period.
There is limited experience with doses above 360 mg. However, the incidence of adverse events increases as the dose increases with first-degree AV block, dizziness, and sinus bradycardia bearing the strongest realtionship to dose. Therefore, doses greater than 360 mg are not recommended.
Availability And Storage:
120 mg: 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 Green #3, FD&C Red #40, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.
180 mg: 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 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.
240 mg: 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.
300 mg: 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 Green #3, FD&C Red #40, gelatin, hydroxypropylmethylcellulose, magnesium stearate, microcrystalline cellulose, polysorbate, povidone, simethicone, sucrose stearate, talc and titanium dioxide. Bottles of 100.
360 mg: 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, 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.
Store between 15 to 30°C. Avoid excessive humidity.
TIAZAC® Crystaal Diltiazem HCI Antihypertensive-Antianginal