Teva-Diltiazem Xc Product Monograph

1 INDICATIONS

• Essential Hypertension

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

  TEVA-DILTIAZEM XC (diltiazem hydrochloride) 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 diltiazem hydrochloride extended-release tablets with other antihypertensive agents has not been established.

  No morbidity and mortality studies have been carried out to support the use of diltiazem hydrochloride (see 10 CLINICAL PHARMACOLOGY, Pharmacodynamics section).

• 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 those agents.

  TEVA-DILTIAZEM XC (diltiazem hydrochloride) 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 7 WARNINGS AND PRECAUTIONS).

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

1.1 Pediatrics

Safety and efficacy in children have not been studied.

1.2 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.

2 CONTRAINDICATIONS

TEVA-DILTIAZEM XC (diltiazem hydrochloride) is contraindicated:

• In patients with sick sinus syndrome, except in the presence of an implanted pacemaker;

• In patients with second or third-degree AV block, except in the presence of an implanted

  • pacemaker;
• In patients with known hypersensitivity to diltiazem;
• In patients with severe hypotension (less than 90 mm Hg systolic);
• In patients with severe bradycardia (below 40 beats per minute);
• In myocardial infarction patients, who have left ventricular failure manifested by pulmonary congestion;
• In pregnancy and in women of child-bearing potential. Fetal malformations and adverse effects on pregnancy have been reported in animals.
• Concomitant use of dantrolene.
• Concomitant use of ivabradine.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

N/A

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

TEVA-DILTIAZEM XC (diltiazem hydrochloride) has an extended-release delivery system designed to deliver maximum effect in the morning when administered at night-time. Accordingly, TEVA-DILTIAZEM XC should be administered once daily at bedtime. TEVA-DILTIAZEM XC may be taken with or without food, but should be so taken consistently.

4.2 Recommended Dose and Dose Adjustment

Hypertension

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 TEVA-DILTIAZEM XC or concomitant antihypertensive agents may need to be adjusted when adding one to the other. See 7 WARNINGS AND PRECAUTIONS regarding use with beta-blockers.

Angina

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.

TEVA-DILTIAZEM 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 TEVA-DILTIAZEM XC therapy.

4.4 Dosing Considerations

TEVA-DILTIAZEM XC should not be chewed or crushed.

4.5 Missed Dose

If you miss a dose, take it as soon as possible. However, if it is almost time for the next dose, skip the missed dose and take your next dose as scheduled. Do not take two doses at the same time.

5 OVERDOSAGE

Significant diltiazem overdose causes cardiovascular and systemic toxicity and may be fatal. The onset of toxicity may be delayed in patients who have ingested a sustained release preparation such as TEVA-DILTIAZEM XC. The clinical effects of acute overdose can involve pronounced hypotension possibly leading to collapse and acute kidney injury, sinus bradycardia with or without isorhythmic dissociation, sinus arrest, atrioventricular conduction disturbances and cardiac arrest. Mental status will often be preserved although patients with hypotension may be drowsy or comatose. Hypoxia may be due to non-cardiogenic lung injury caused by precapillary vasodilation. Impaired gut motility may result in ileus. Patients are often hyperglycemic due to impaired insulin release. Fatalities may occur with large overdoses and in patients with co-existing cardiac disease or with cardiotoxic co-ingestants.

Severely symptomatic patients poisoned with diltiazem should receive supplemental oxygen and be stabilized in the usual fashion with attention to maintaining the airway and restoring circulation. An electrocardiogram and routine blood analysis including electrolytes, glucose, and the usual search for co-ingestants should be performed.

Induced emesis is contraindicated. Patients who present within an hour of a significant overdose of diltiazem should have gastric lavage followed by activated charcoal. Lavage is not indicated for patients with delayed presentations. Whole bowel irrigation may be considered in patients with significant ingestions of sustained-release diltiazem.

In the event of overdose or exaggerated response, appropriate supportive measures should be employed in addition to gastric lavage.

The following measures may be considered:

Bradycardia

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

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

Calcium salts given intravenously should be avoided in patients who may have co-ingested 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 TEVA-DILTIAZEM 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Dosage Forms, Strengths, Composition and Packaging

TEVA-DILTIAZEM XC tablets are available in 180 mg, 240 mg, 300 mg and 360 mg strengths.

TEVA-DILTIAZEM XC tablets are available in the following strengths.

TEVA-DILTIAZEM XC 180 mg tablets are white capsule-shaped tablets debossed with “180” on one side and “ ” and code “691” on the other side.

TEVA-DILTIAZEM XC 240 mg tablets are white capsule-shaped tablets debossed with “240” on one side and “ ” and code “692” on the other side.

TEVA-DILTIAZEM XC 300 mg tablets are white capsule-shaped tablets debossed with “300” on one side and “ ” and code “693” on the other side.

TEVA-DILTIAZEM XC 360 mg tablets are white capsule-shaped tablets debossed with “360” on one side and “ ” and code “694” on the other side.

TEVA-DILTIAZEM XC 180 mg tablets are supplied in bottles of 30, 100 and 1000 tablets.

TEVA-DILTIAZEM XC 240 mg tablets are supplied in bottles of 30, 100 and 1000 tablets.

TEVA-DILTIAZEM XC 300 mg tablets are supplied in bottles of 30, 100 and 1000 tablets.

TEVA-DILTIAZEM XC 360 mg tablets are supplied in bottles of 30, 100 and 1000 tablets.

7 WARNINGS AND PRECAUTIONS

Cardiovascular

Cardiac Conduction

TEVA-DILTIAZEM 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.

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 cardiac failure (see also 2 CONTRAINDICATIONS).

Cases of acute renal failure have been reported in patients using diltiazem at therapeutic dosages. Patients at greater risk appear to have reduced left ventricular function, severe bradycardia or severe hypotension.

Prior to general anesthesia, the anesthetist must be informed of ongoing diltiazem treatment. Depression of cardiac contractility, conductivity and automaticity, as well as the vascular dilatation associated with anesthetics may be potentiated by calcium channel blockers.

Post-infarction 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.

Hypotension

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

Patients with Myocardial Infarction

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 diltiazem in acute myocardial infarction.

Use with Beta-Blockers

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.

Endocrine and Metabolism

Patients with Diabetes

Careful monitoring is necessary to detect new onset of diabetes or in patients with diabetes mellitus (type 1 or type 2) due to an increase in blood glucose.

Hepatic/Biliary/Pancreatic

Acute Hepatic Injury

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 8 ADVERSE REACTIONS). As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.

Because diltiazem hydrochloride extended-release tablets are 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 8 ADVERSE REACTIONS).

7.1 Special Populations

7.1.1 Pregnant Women

Fetal malformations and adverse effects on pregnancy have been reported in animals.

7.1.2 Breast-feeding

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

It is unknown if the drug is excreted in human milk. Because many drugs are excreted in human milk, precaution should be exercised.

7.1.3 Pediatrics

Safety and effectiveness in children has not been studied.

7.1.4 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.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

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%).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real world use.

Hypertension

Table 2 presents the most common adverse reactions reported in the placebo-controlled hypertension trials in patients receiving a diltiazem hydrochloride extended-release formulation (once-a-day dosing) up to 360 mg.

Table 2 Adverse Events >1%: Diltiazem Hydrochloride Extended-Release Formulation Once-a-day PM Administration Placebo-Controlled Hypertension Trials

Angina

In the angina clinical study, the adverse event profile of diltiazem hydrochloride extended-release tablets was consistent with that previously described for diltiazem hydrochloride extended-release tablets and other formulations of diltiazem hydrochloride. The most frequent adverse effects experienced by diltiazem hydrochloride extended-release tablet patients are presented in Table 3.

Table 3 Adverse Events >1%: Diltiazem Hydrochloride Extended-Release Formulation Once-a-day Administration Placebo-Controlled Angina Trial

Adverse Reactions

8.3 Less Common Clinical Trial Adverse Drug Reactions

The following treatment related adverse drug reactions were reported with < 1% incidence in the diltiazem hydrochloride extended-release tablets clinical trial:

• Cardiac disorders: atrioventricular block (first degree), palpitations.
• Eye disorders: vitreous floaters, diplopia.
• Gastrointestinal disorders: dyspepsia, nausea.
• General disorders and administration site conditions: feeling jittery, joint swelling, lethargy, neck swelling, oedema NOS, peripheral swelling, swelling NOS.
• Investigations: aspartate aminotransferase increased.
• Nervous system and psychiatric disorders: dizziness (vertigo), sinus headache.
• Renal and urinary disorders: urinary frequency.
• Respiratory, thoracic and mediastinal disorders: dyspnoea NOS.
• Skin and subcutaneous disorders: dermatitis NOS, erythema NEC, face oedema, pruritus NOS, rash generalized.
• Vascular disorders: flushing.

The following adverse events were reported with a frequency < 1% in other diltiazem products:

• Cardiovascular: 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.
• Dermatological: Petechiae, photosensitivity, pruritus, urticaria.
• Eye disorders: Amblyopia, eye irritation.
• Gastrointestinal disorders: Anorexia, constipation, diarrhea, dry mouth, dysgeusia, thirst, vomiting, weight increase.
• General disorders and administration site conditions: Malaise (reported as common adverse reaction), osteoarticular pain.
• Investigations: Mild elevations of AST, ALT, LDH, and alkaline phosphatase (see 7 WARNINGS AND PRECAUTIONS, Hepatic / Biliary / Pancreatic), CPK increase.
• Metabolism and nutrition disorders: Hyperglycemia, hyperuricemia.
• Nervous System and psychiatric disorders: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.
• Renal and urinary disorders: Nocturia, polyuria.
• Respiratory, thoracic and mediastinal disorders: Dyspnea, epistaxis, nasal congestion.
• Sexual dysfunction disturbances and gender identity disorders: Impotence, sexual difficulties.
• Vascular disorders: Orthostatic hypotension

8.5 Post-Market Adverse Reactions

Adverse reactions reported during post marketing experience are derived from spontaneous reports and therefore, the frequency of these adverse reactions is not known.

• Blood and lymphatic system disorders: Thrombocytopenia, hemolytic anemia, increased bleeding time, leukopenia
• Nervous system and psychiatric disorders: Mood changes including depression, extrapyramidal symptoms
• Cardiac disorders: Sinoatrial block, congestive heart failure, sinus arrest, cardiac arrest (asystole)
• Respiratory, thoracic and mediastinal disorders: Bronchospasm (including asthma aggravation)
• Gastrointestinal disorders: Gingival hyperplasia
• Metabolism and nutrition disorders: Hyperglycaemia, diabetes (new onset), worsening of existing diabetes (type 1 or type 2)
• Skin and subcutaneous tissue disorders: Photosensitivity (including lichenoid keratosis at sun exposed skin areas), angioneurotic oedema, erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), sweating, exfoliative dermatitis (see 7 WARNINGS AND PRECAUTIONS), acute generalized exanthematous pustulosis, occasionally desquamative erythema with or without fever, allergic reactions, alopecia, purpura
• Vascular disorders: A number of well-documented cases of generalized rash, some characterized as leukocytoclastic vasculitis
• Hepatobiliary disorders: Hepatitis
• Renal disorders: Acute kidney injury/failure
• Reproductive system and breast disorders: Gynecomastia
• Eye disorders: Detached retina, retinopathy
• Musculoskeletal and connective tissue disorders: Myopathy

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty. 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. However, a definitive cause and effect relationship between these events and diltiazem hydrochloride extended-release tablet therapy is yet to be established.

9 DRUG INTERACTIONS

9.2 Drug Interactions Overview

As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Co-administration 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.

9.3 Drug-Behavioural Interactions

Alcohol

Alcohol can exhibit hypotensive effects. Coadministration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis. Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, light-headedness, syncope, orthostasis, or tachycardia.

Sexual dysfunction disturbances and gender identity disorders

Impotence, sexual difficulties.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

Table 4 Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

9.5 Drug-Food Interactions

Alcohol

Alcohol can exhibit hypotensive effects. Co-administration with antihypertensive agents including diltiazem may result in additive effects on blood pressure and orthostasis. Patients should be advised that alcohol may potentiate the hypotensive effects of diltiazem, especially during the initiation of therapy and following a dosage increase. Caution should be exercised when rising from a sitting or recumbent position, and patients should notify their physician if they experience dizziness, light-headedness, syncope, orthostasis, or tachycardia.

Grapefruit Juice

Grapefruit Juice may increase the plasma concentrations of orally administered diltiazem in some patients. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Patients who regularly consume grapefruit or grapefruit juice should be monitored for increased adverse effects of diltiazem such as headache, irregular heartbeat, edema, unexplained weight gain, and chest pain. Grapefruit and grapefruit juice should be avoided if an interaction is suspected.

Multivitamins with minerals

Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity. Monitoring of the effectiveness of calcium channel blocker therapy is advised during co-administration with calcium products.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

TEVA-DILTIAZEM XC (diltiazem hydrochloride) is a calcium ion cellular influx inhibitor (calcium channel blocker or calcium channel antagonist) of the benzothiazepine (non-dihydropyridine) class.

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 vasodilator action.

In angina due to coronary spasm, diltiazem increases myocardial oxygen delivery by dilating both large and small coronary arteries and by inhibiting coronary spasm at drug levels which cause little negative inotropic effect. The resultant increases in coronary blood flow are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.

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.

10.2 Pharmacodynamics

Hypertension

In a double-blind clinical study, a diltiazem hydrochloride extended-release clinical trial formulation with the same bead coating as diltiazem hydrochloride extended-release tablets, 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 6AM 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 mm Hg, 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 mm Hg 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.

Angina

In a double-blind study involving 311 patients with chronic stable angina, evening doses of 180, 360 and 420 mg clinical trial formulation of diltiazem hydrochloride extended-release tablets 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, i.e., 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. diltiazem hydrochloride extended-release tablets had a larger effect in increasing exercise tolerance at peak serum concentrations than at trough.

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 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 7 WARNINGS AND PRECAUTIONS). In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

In Vitro Observations

Initial experimental work revealed that diltiazem was a coronary and peripheral vasodilator. Subsequent work substantiated that diltiazem’s smooth muscle relaxant effect, as well as negative inotropic effect, resulted from the drug’s ability to block excitation-contraction coupling by inhibiting slow calcium channel conduction. In a muscle bath study with isolated human coronary artery segments obtained at the time of cardiac transplantation, diltiazem produced nearly complete relaxation of potassium-contracted segments.

Studies in various experimental models have confirmed the negative inotropic effect of diltiazem. At low doses (1.1 x 10^-7 M), diltiazem caused a reduction in contractile force of guinea pig papillary muscle with no demonstrable effect on the action potential. However, at higher concentrations (1.1 x 10^-5 M), both a decrease in contractile tension and a lowering of maximum dp/dt were seen. Studies done in isolated perfused rat hearts showed that diltiazem (10^-6 M) decreases contractility without affecting action potential duration or resting membrane potential. In several experimental models, it has been shown that the concentration of diltiazem required to produce smooth muscle relaxation and vasodilation is significantly less than the concentration required to produce a negative inotropic effect.

In Vivo Observations

Experiments in both open and closed chest dog models indicate that diltiazem increases coronary blood flow and reduces coronary vascular resistance. Intravenous diltiazem (100 mcg/kg) increased coronary blood flow by 90%, with a predominant effect on large coronary arteries and collaterals. Increase in coronary blood flow has also been shown following diltiazem administration in both the epicardial and subendocardial regions in ischemic and non-ischemic models. There was also a dose-related decrease in mean aortic pressure and systemic vascular resistance with an increase in stroke volume and cardiac output. No significant change was noted in determinants of LV function such as LVEDP or LV dp/dt.

The reduction in blood pressure that is seen with diltiazem is due to a direct vasodilatory effect on the blood vessels and is not mediated by sympathetic alpha receptor blockade, beta receptor stimulation, or ganglionic blockade. Diltiazem has been shown to inhibit the pressor responses induced by norepinephrine and angiotensin II.

In animal studies, the negative inotropic effect of diltiazem appears to be offset by its ability to decrease afterload and induce a mild reflex adrenergic response.

10.3 Pharmacokinetics

Absorption

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%.

Distribution

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.

Metabolism

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.

Excretion

Following extensive hepatic metabolism, only 2-4% of the drug appears unchanged in the urine and 6-7% appears as metabolites.

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

Administration of diltiazem hydrochloride extended-release tablets in the fasted state at bedtime, in a single study, resulted in detectable diltiazem 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 diltiazem hydrochloride extended-release tablets after single or multiple dosing is 6 to 9 hours.

When a single dose of 360 mg diltiazem hydrochloride extended-release 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 diltiazem hydrochloride extended-release tablets were given in the morning to assess potential food interaction, the observed ratios of means were AUCτao 112.4% (90% C.I. 101.2 - 124.9) and Cmax 104.0% (90% C.I. 92.9 - 116.5) for the fed/fasted comparison (see 4 DOSAGE AND ADMINISTRATION).

While both diltiazem hydrochloride extended-release tablets and diltiazem hydrochloride extended-release 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 diltiazem hydrochloride extended-release capsule beads are encapsulated in gelatin capsules to produce the diltiazem hydrochloride extended-release capsules formulation, while diltiazem hydrochloride extended-release 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 diltiazem hydrochloride extended-release tablets and diltiazem hydrochloride extended-release capsules respectively, are presented below in Figure 1.

Figure 1: 24- hour diltiazem plasma concentration time course at steady-state¹

Diltiazem Hydrochloride Extended-Release Tablets 360 mg	Diltiazem Hydrochloride Extended-Release Capsules 360 mg
Diltiazem Hydrochloride Extended-Release Tablets -10PM Dosing Diltiazem Hydrochloride Extended-Release Tablets -8AM Dosing	Diltiazem Hydrochloride Extended-Release Capsules 8AM Dosing Diltiazem Hydrochloride Extended-Release Capsules 10PM Dosing

¹ Data for each graph were obtained from separate studies.

No studies are available that compare the relative bioavailability of diltiazem hydrochloride extended-release tablets to diltiazem hydrochloride extended-release capsules directly.

Special Populations and Conditions

• Pediatrics: Pharmacokinetic studies with diltiazem hydrochloride extended-release tablets in children have not been conducted.
• Geriatrics: Pharmacokinetic studies with diltiazem hydrochloride extended-release tablets 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.
• Sex: 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 Cmax (p=0.295).
• Race: The effect of race in pharmacokinetic studies has not been evaluated.
• Hepatic Insufficiency: No pharmacokinetic studies have been conducted with diltiazem hydrochloride extended-release tablets in patients with hepatic insufficiency.
• Renal Insufficiency: No pharmacokinetic studies have been conducted with diltiazem hydrochloride extended-release tablets in patients with renal insufficiency.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15 -30^oC)

12 SPECIAL HANDLING INSTRUCTIONS

N/A

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Diltiazem Hydrochloride

Chemical name: Diltiazem Hydrochloride is: 1,5-Benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride, (+)-cis

Molecular formula: C22H26N2 O4 S ∙HCl

Molecular mass: 450.98 g/mol

Structural formula:

Physicochemical properties: Diltiazem hydrochloride is highly soluble in formic acid, freely soluble in water, methanol and chloroform. It is slightly soluble in absolute ethanol and acetic anhydride, and practically insoluble in benzene. The pKa value is 7.7. Melting point is 210°C to 215°C.

TEVA-DILTIAZEM XC tablets are a modified release dosage that contain 180 mg, 240 mg 300 mg or 360 mg of diltiazem hydrochloride.

14 CLINICAL TRIALS

14.1 Trial Design and Study Demographics

One clinical study was conducted in subjects with mild to moderate hypertension, and another clinical study was conducted in subjects with chronic stable angina.

Table 5

14.2 Study Results

Hypertension

In a double-blind clinical study, a diltiazem hydrochloride extended-release clinical trial formulation with the same bead coating as diltiazem hydrochloride extended-release tablets, 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 mm Hg, 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 mm Hg 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.

Angina

In a double-blind study involving 311 patients with chronic stable angina, evening doses of 180, 360 and 420 mg clinical trial formulation of diltiazem hydrochloride extended-release tablets 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, i.e., 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. Diltiazem hydrochloride extended-release tablets had a larger effect in increasing exercise tolerance at peak serum concentrations than at trough.

Comparative Bioavailability

Diltiazem hydrochloride extended-release tablets have an extended-release delivery system designed for night-time administration, resulting in maximum diltiazem plasma levels in the morning.

Administration of diltiazem hydrochloride extended-release tablets in the fasted state at bedtime, in a single study, resulted in detectable diltiazem 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 diltiazem hydrochloride extended-release tablets after single or multiple dosing is 6 to 9 hours.

When a single dose of 360 mg diltiazem hydrochloride extended-release 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 diltiazem hydrochloride extended-release tablets were given in the morning to assess potential food interaction, the observed ratios of means were AUCτao 112.4% (90% C.I. 101.2 - 124.9) and Cmax 104.0% (90% C.I. 92.9 - 116.5) for the fed/fasted comparison (see 2 DOSAGE AND ADMINISTRATION).

Comparative Bioavailability Studies:

A single-dose, randomized, double-blinded, crossover, pivotal, comparative oral bioavailability study of TEVA-DILTIAZEM XC (diltiazem hydrochloride) 360 mg Extended-Release Tablets (Cobalt Pharmaceuticals Company) and Tiazac^® XC (diltiazem hydrochloride) 360 mg Extended- Release Tablets (Biovail Pharmaceuticals Canada) was conducted in 35 healthy male and female volunteers under fasting conditions. Data from 35 subjects is summarized in Table 6.

A single-dose, randomized, double-blinded, crossover, pivotal, comparative oral bioavailability study of TEVA-DILTIAZEM XC (diltiazem hydrochloride) 360 mg Extended-Release Tablets (Cobalt Pharmaceuticals Company) and Tiazac^® XC (diltiazem hydrochloride) 360 mg Extended- Release Tablets (Biovail Pharmaceuticals Canada) was conducted in 29 healthy male and female volunteers under fed conditions. Data from 29 subjects is summarized in Table 7.

Table 6: Comparative Bioavailability Data for TEVA-DILTIAZEM XC (Diltiazem Hydrochloride) 360 mg Extended-Release Tablets vs. Tiazac^® XC 360 mg Extended- Release Tablets Administered under Fasting Conditions

^* TEVA-DILTIAZEM XC (diltiazem hydrochloride) Extended-Release Tablets, 360 mg, manufactured by Watson Laboratories Inc., Florida for Cobalt Pharmaceuticals Company, Canada.

^† Tiazac^® XC (diltiazem HCl) Extended-Release Tablets, 360 mg, manufactured by Biovail Pharmaceuticals Canada, Canada, purchased in Canada.

^§ Expressed as the median (range) only.

^€ Expressed as the arithmetic mean (CV%) only

# N=34

Table 7: Comparative Bioavailability Data for Teva-Diltiazem XC (Diltiazem Hydrochloride) 360 mg Extended-Release Tablets vs. Tiazac^® XC 360 mg Extended- Release Tablets Administered under Fed Conditions

^* TEVA-DILTIAZEM XC (diltiazem hydrochloride) Extended-Release Tablets, 360 mg, manufactured by Watson Laboratories Inc., Florida for Cobalt Pharmaceuticals Company, Canada.

^† Tiazac^® XC (diltiazem HCl) Extended-Release Tablets, 360 mg, manufactured by Biovail Pharmaceuticals Canada, Canada, purchased in Canada.

^§ Expressed as the median (range) only.

^€ Expressed as the arithmetic mean (CV%) only.

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

Acute Toxicity

Toxic effects appeared rapidly, and toxicity included reduction of spontaneous activity, ptosis, piloerection, ataxia, loss of muscle tone and loss of righting reflex. Gross autopsy of animals who died, as well as, the survivors revealed no abnormalities.

Tolerance was evaluated in rabbits and dogs. Dogs received oral doses of 12.5, 25, 50 or 100 mg/kg. Ataxia, disorientation, decreased activity, diuresis and mydriasis were noted at 25 mg/kg. In addition, heavy sedation and emesis were seen at 50 mg/kg. At 100 mg/kg, convulsions occurred, and one of the two animals died. Rabbits received 100, 200, 300, 400 mg/kg. The major symptoms were decreased activity, increased respiration, salivation and opisthotonos. One of the two rabbits died at 300 mg/kg and the two rabbits in the 400 mg/kg group died.

Subacute Toxicity

In rats, oral doses of 10, 20, 50, 100, 250 or 500 mg/kg/day of diltiazem were administered for 28 or 30 days. The relative liver weights of animals receiving 250 mg/kg/day and 500 mg/kg/day were increased. Microscopic examination revealed drug related degeneration of hepatic and renal cells in the highest dose group.

When the drug was given to rats intraperitoneally at 25 mg/kg/day for 30 days, hepatic and renal cell degeneration was seen. Macular hyaloid degeneration of the heart also was seen in 50% of the rats in this study.

Thirty day subacute studies in dogs revealed hepatic and renal cell degeneration when diltiazem was given at doses of 25 mg/kg/day orally and 5 mg/kg/day intravenously. Two dogs out of 5 receiving 50 mg/kg/day orally, died.

Chronic Toxicity/Carcinogenicity

In mice, diltiazem was administered at doses of 5, 15 or 30 mg/kg/day for a period of 21 months in females. Because of a lower survival, males were terminated at 20 months. Gross and histopathological examination failed to reveal any treatment-related increase in the incidence of either neoplastic or other toxic lesions.

Rats received 6.25, 25 or 100 mg/kg/day of diltiazem for 24 months. An additional group received 200 mg/kg for 12 months. Treatment was terminated at 23 months in females receiving 100 mg/kg because of the low survival. Females had increased weight gain at 100 and 200 mg/kg, food consumption was increased among both sexes at these dose levels. Organ weight data revealed a significant increase in liver weight for rats of both sexes given 200 mg/kg. Microscopic evaluation revealed some evidence of dose dependent hepatic cytoplasmic vacuolization in rats treated with doses of 100 and 200 mg/kg/day and killed at 12 months. At 24 months, there were similar findings in control and treated animals. There was no increase in the incidence of neoplastic or other toxic lesions in rats treated with diltiazem.

Diltiazem was administered orally to dogs for 12 months at doses of 5, 10, 20 mg/kg/day. A dose related suppression of body weight gain became noticeable after 6 months.

Mutagenicity

No mutagenic changes were observed in the recombination test and two Ames reverse mutagenicity assays.

Reproduction Studies

Results in Mice

Results in Rats

Results in Rabbits

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.

In fertility studies, female rats received doses of 12.5, 25, 50 and 100 mg/kg p.o. In the 100 mg/kg group, there was a reduction in the number showing a positive mating. However, the overall pregnancy rates and the average pre-coital time were comparable.

In peri- and post-natal studies, rats received diltiazem in doses of 10, 30 or 100 mg/kg/day from day 14 of gestation through day 21 post-partum. Diltiazem was associated with a reduction in early individual weights and survival rates of the pups. At 100 mg/kg/day, dystocia was evident.

Retinal and tongue malformations were more frequent in the offspring of the 30 and 100 mg/kg/day group.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. TIAZAC^® XC (Diltiazem Hydrochloride Extended-Release Tablets). Bausch Health Canada Inc. Submission Control Number 247563. June 3 2021.