Pro-Diltiazem CD Product Monograph

1 INDICATIONS

PRO-DILTIAZEM CD (Diltiazem Hydrochloride) is indicated for:

Angina

PRO-DILTIAZEM CD is indicated 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. PRO-DILTIAZEM CD 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 7 WARNINGS AND PRECAUTIONS).

Hypertension

PRO-DILTIAZEM CD is indicated for the treatment of mild to moderate essential hypertension. Safety of concurrent use of diltiazem with other antihypertensive agents has not been established.

1.1 Pediatrics

Pediatrics (< 18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of PRO-DILTIAZEM CD in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (> 65 years of age): Pharmacokinetics of diltiazem in elderly patients has not been fully elucidated. Preliminary results in elderly patients (over 65 years old) suggest that a lower dosage might be required in this age group (see 7 WARNINGS AND PRECAUTIONS).

2 CONTRAINDICATIONS

PRO-DILTIAZEM CD is contraindicated:

• In patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker.
• In patients with second or third-degree AV block.
• In patients with known hypersensitivity to diltiazem or to any of the excipients.
• In patients with 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 childbearing potential.
• Breast-feeding.
• With concomitant use of dantrolene infusion.
• With concomitant use of ivabradine.
• With concomitant use of lomitapide mesylate as it may result in increased concentrations of lomitapide mesylate due to CYP3A4 inhibition (see 9.4 Drug-Drug Interactions).

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• Geriatrics (see 4.2 Recommended Dose and Dose Adjustment and 7.1.4 Geriatrics).

• Renal disease (see 4.2 Recommended Dose and Dose Adjustment and 7 WARNINGS AND

  PRECAUTIONS).

• Hepatic disease (see 4.2 Recommended Dose and Dose Adjustment and 7 WARNINGS AND

  PRECAUTIONS).

• Rule out pregnancy (see 2 CONTRAINDICATIONS and 7.1.1 Pregnant Women).

• Concomitant therapy with drugs metabolized by the CYP450 system (see 9.1 Serious Drug

  Interactions, 9.2 Drug Interactions Overview, and 9.4 Drug-Drug Interactions).

4.2 Recommended Dose and Dosage Adjustment

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.

Patients controlled on diltiazem alone or in combination with other medications may be safely switched to PRO-DILTIAZEM CD capsules at the nearest equivalent total daily dose. Subsequent titration to higher or lower doses may be necessary and should be initiated as clinically warranted.

There is limited experience with doses above 360 mg, however, the incidence of adverse reactions increases as the dose increases with first degree AV block, dizziness, and sinus bradycardia bearing the strongest relationship to dose. Therefore, doses greater than 360 mg are not recommended.

Hypertension

Dosage should be individualized depending on patient's tolerance and responsiveness to PRO-DILTIAZEM CD capsules. 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. The usual dosage range studied in clinical trials was 240 to 360 mg once daily.

A maximum daily dose of 360 mg once daily should not be exceeded.

The dosage of PRO-DILTIAZEM CD 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.

Dosage in elderly patients

Pharmacokinetics of diltiazem in elderly patients has not been fully elucidated. Preliminary results in elderly patients (over 65 years old) suggest that a lower dosage might be required in this age group (see 7 WARNINGS AND PRECAUTIONS).

There are few available data concerning dosage requirements in patients with impaired renal or hepatic function. If diltiazem must be used in these patients, the dosage should be carefully and gradually adjusted depending on patient tolerance and response (see 7 WARNINGS AND PRECAUTIONS).

4.4 Administration

PRO-DILTIAZEM CD capsules should not be chewed or crushed.

4.5 Missed Dose

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule.

5 OVERDOSAGE

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

Events observed following diltiazem overdose included sinus bradycardia with or without isorhythmic dissociation, pronounced hypotension possibly leading to collapse, and acute kidney injury, sinus arrest, heart block, atrioventricular conduction disturbance, cardiac arrest, and cardiac failure.

The effectiveness of intravenous 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 intravenous calcium. In some cases, intravenous 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 administrated as a continuous infusion at a rate of 2 g per 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. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination. The following measures may be considered:

• Bradycardia: Administer atropine. If there is no response to vagal blockade, 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: Administer fluids and vasopressors (e.g., dopamine or noradrenaline).

  Actual treatment and dosage should depend on the severity of the clinical situation.

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada’s toll-free number, 1-844 POISON-X (1-844-764-7669).

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1: Dosage Forms, Strengths, Composition and Packaging

Description

PRO-DILTIAZEM CD 120 mg: Light turquoise blue opaque body, light turquoise blue opaque cap, hard gelatin capsules, imprinted “APO 120”, with white spheroidal bead fill.

PRO-DILTIAZEM CD 180 mg: Light turquoise blue opaque body, light blue opaque cap, hard gelatin capsules, imprinted “APO 180”, with white spheroidal bead fill.

PRO-DILTIAZEM CD 240 mg: Light blue opaque body, light blue opaque cap, hard gelatin capsules, imprinted “APO 240”, with white spheroidal bead fill

PRO-DILTIAZEM CD 300 mg: Light grey opaque body, light blue opaque cap, hard gelatin capsules, imprinted “APO 300”, with white spheroidal bead fill.

Packaging

PRO-DILTIAZEM CD 120 mg, 180 mg, 240 mg and 300 mg capsules are supplied in bottles of 100 and 500 capsules.

7 WARNINGS AND PRECAUTIONS

Cardiovascular

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 (6 of 1208 patients or 0.5%).

First degree AV block was observed in 5.8% of patients receiving diltiazem (see 8 ADVERSE REACTIONS).

Concomitant use of diltiazem with agents known to affect cardiac conduction (such as beta-blockers, digitalis or amiodarone) may result in additive effects on cardiac conduction (see 7 WARNINGS AND PRECAUTIONS and 9 DRUG INTERACTIONS).

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 (see 9 DRUG INTERACTIONS).

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 2 CONTRAINDICATIONS).

Hypotension

Since diltiazem lowers peripheral vascular resistance, decreases in blood pressure may occasionally result in symptomatic hypotension. In patients with angina or arrhythmias using antihypertensive drugs, the additional hypotensive effect of diltiazem should be taken into consideration.

Use with Beta-blockers

The combination of diltiazem and beta-blockers warrants caution since in some patients additive effects on heart rate, AV 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.

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, and no overall effect on mortality. Although there has not been a study of diltiazem in acute myocardial infarction reported, their use may have effects similar to those of immediate release diltiazem in acute myocardial infarction.

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.

Gastrointestinal

Diltiazem has an inhibitory effect on intestinal motility. Therefore, it should be used with caution in patients at risk of developing an intestinal obstruction.

Hepatic/biliary/pancreatic

Acute Hepatic Injury

In rare instances, significant elevations in alkaline phosphatase, CPK, LDH, SGOT, SGPT 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 8 ADVERSE REACTIONS). As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.

Impaired Hepatic Function

Diltiazem should be used with caution in patients with hepatic impairment. Because diltiazem is extensively metabolized by the liver and excreted in bile, the monitoring of laboratory parameters of hepatic function is recommended, and cautious dosage titration are recommended in patients with impaired hepatic function (see 8 ADVERSE REACTIONS).

Neurologic

Calcium channel blocking agents, such as diltiazem, may be associated with mood changes, including depression (see 9 DRUG INTERACTIONS and 8 ADVERSE REACTIONS).

Renal

Acute Kidney Injury

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.

Impaired Renal Function

Diltiazem should be used with caution in patients with renal impairment. Because diltiazem is excreted by the kidney, the monitoring of laboratory parameters of renal function is recommended, and cautious dosage titration are recommended in patients with impaired renal function (see 8 ADVERSE REACTIONS).

Respiratory

The use of diltiazem may induce bronchospasm, including asthma aggravation, especially in patients with pre-existing bronchial hyper-activity. Cases have been reported after dose increase. Patients should be monitored for signs and symptoms of respiratory impairment during diltiazem therapy.

Skin

Dermatological events (see 8 ADVERSE REACTIONS) may be transient and may disappear despite continued use of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.

7.1 Special Populations

7.1.1 Pregnant Women

PRO-DILTIAZEM CD is contraindicated in pregnancy and in women of child-bearing potential. Fetal malformations and adverse effects on pregnancy have been reported in animals. In repeated dose studies a high incidence of vertebral column malformations was present in the offspring of mice receiving more than 50 mg/kg of diltiazem HCl 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 6-18 of gestation aborted; at 35 mg/kg, a significant increase in skeletal malformations was recorded in the offspring (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

7.1.2 Breast-feeding

Diltiazem has been reported to be excreted in human milk. One report with oral diltiazem suggests that concentrations in breast milk may approximate serum levels. Since diltiazem safety in newborns has not been established, it should not be given to nursing mothers.

7.1.3 Pediatrics

Pediatrics (<18 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of PRO-DILTIAZEM CD in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (> 65 years of age): 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 (see 4 DOSAGE AND ADMINISTRATION).

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

Angina

In controlled trials, adverse events were reported in 21.1% of patients and required discontinuation in 2.2% of patients. The most common adverse effects reported were: first degree AV block (5.8%), dizziness (3.0%), headache (3.0%), asthenia (2.7%), bradycardia (2.5%), and angina pectoris (1.6%).

Hypertension

In controlled trials, adverse effects were reported in 30.7% of patients and required discontinuation of therapy in 2.1%. The most common adverse effects were headache (8.7%); edema (4.0%); bradycardia (3.7%); dizziness (3.4%), ECG abnormality (2.9%); asthenia (2.6%), and first-degree AV block (2.1%).

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 for identifying and approximating rates of adverse drug reactions in real-world use.

Angina

The safety of diltiazem hydrochloride controlled delivery capsules, administered at doses up to 360 mg a day, was evaluated in 365 patients with chronic stable angina treated in controlled and open-label clinical trials. Adverse events were reported in 21.1% of patients and required discontinuation in 2.2% of patients.

The most common adverse effects reported were: first degree AV block (5.8%), dizziness (3.0%), headache (3.0%), asthenia (2.7%), bradycardia (2.5%), and angina pectoris (1.6%).

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

Cardiovascular: First degree AV block (5.8%), bradycardia (2.5%), angina pectoris (1.6%), peripheral edema (1.4%), palpitations (1.1%), and ventricular extrasystoles (0.8%).

Central Nervous System: Dizziness (3.0%), headache (3.0%), asthenia (2.7%), insomnia (1.1%), nervousness (0.8%).

Dermatological: Rash (0.8%).

Gastrointestinal: Nausea (1.4%), diarrhea (0.5%).

Other: Amblyopia (0.5%).

The following additional adverse effects have occurred with an incidence of less than 0.5% in clinical trials: bundle branch block, ventricular tachycardia, ECG abnormality, supraventricular extrasystoles, chest pain, syncope, postural hypotension, paresthesia, tremor, depression, mental confusion, impotence, abdominal pain, constipation, GI disorder, epistaxis, nuchal rigidity, myalgia.

Hypertension

A safety evaluation was carried out in controlled studies in 378 hypertensive patients treated with diltiazem hydrochloride-controlled delivery capsules at doses up to 360 mg a day. Adverse effects were reported in 30.7% of patients and required discontinuation of therapy in 2.1%.

The most common adverse effects were headache (8.7%); edema (4.0%); bradycardia (3.7%); dizziness (3.4%), ECG abnormality (2.9%); asthenia (2.6%), and first-degree AV block (2.1%).

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

Blood and lymphatic system disorders: Leukopenia (1.1%).

Cardiovascular: Edema peripheral (4.0%), bradycardia (3.7%), ECG abnormalities (2.9%), first degree AV block (2.1%), arrhythmia (1.6%), vasodilation (flushing) (1.6%), bundle branch block (0.8%), cardiomegaly (0.5%), hypotension (0.5%).

Gastrointestinal: Constipation (1.3%), dyspepsia (1.3%), diarrhea (0.6%).

Investigations: ALT increase (0.8%).

Nervous System and psychiatric disorders: Headache (8.7%), dizziness (3.4%), asthenia (2.6%), somnolence (1.3%), nervousness (1.1%).

Renal and urinary disorders: Nocturia (0.5%).

The following additional adverse effects have occurred with an incidence of less than 0.5% in clinical trials: systolic murmur, supraventricular extra systoles, migraine, tachycardia, increased appetite, increase in weight, albuminuria, bilirubinemia, hyperuricemia, thirst, insomnia, vertigo, nausea, pruritus, rash, increased perspiration, polyuria, amblyopia, tinnitus, and elevations in creatine kinase, alkaline phosphatase, and AST.

Overall Diltiazem safety profile

In clinical trials of 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%).

The following events were reported with a frequency of less than 1.0%.

Cardiovascular: Angina, arrhythmia, bundle branch block, tachycardia, ventricular extra systoles, congestive heart failure, syncope, palpitations, AV block (second- or third- degree), hypotension, ECG abnormalities.

Dermatological: Petechiae, pruritus, photosensitivity, urticarial.

Eye disorders: Amblyopia, eye irritation.

Gastrointestinal disorders: Anorexia, diarrhea, dysgeusia, dyspepsia, vomiting, weight increase, thirst, constipation.

General disorders and administration site conditions: Malaise (reported as common adverse reaction), osteoarticular pain.

Investigations: Elevations of AST, ALT, LDH, and alkaline phosphatase (see 7 WARNINGS AND PRECAUTIONS), CPK increase.

Metabolism and nutrition disorders: hyperglycemia, hyperuricemia.

Nervous System and psychiatric disorders: Amnesia, depression, gait abnormality, nervousness, somnolence, hallucinations, paresthesia, personality change, tinnitus, tremor, abnormal dreams, insomnia.

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 therapy is yet to be established.

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

Serious Drug Interactions

• Concomitant use of dantrolene infusion
• Concomitant use of ivabradine
• Concomitant use of lomitapide mesylate
• Concomitant use of Direct Oral Anticoagulants (DOACs; e.g. apixaban, rivaroxaban, dabigatran, see 9.4 Drug-Drug Interactions)

9.2 Drug Interactions Overview

Cytochrome P450 System

As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem undergoes biotransformation mainly by the CYP3A4 isoenzyme of the cytochrome P450 system and is a substrate of the P-glycoprotein (P-gp). Diltiazem has also been shown to be an inhibitor of CYP3A4 (moderate) and P-gp.

Co-administration of diltiazem with other drugs which follow the same route of biotransformation or are inhibitors or inducers of these enzymes may result in altered bioavailability of diltiazem or these drugs. Dosages of similarly metabolized drugs, particularly those of low therapeutic index, and especially in patients with renal and/or hepatic impairment, may require adjustment, or discontinuation, when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.

9.3 Drug-Behavioural 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.

9.4 Drug-Drug Interactions

PRO-DILTIAZEM CD is contraindicated with co-administration of lomitapide mesylate as it may increased concentrations of lomitapide mesylate due to inhibition of CYP3A4 (see 9 DRUG INTERACTIONS).

Co-administration of diltiazem with other drugs which follow the same route of biotransformation or are inhibitors or inducers of these enzymes may result in altered bioavailability of diltiazem or these drugs. 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.

Table 2 : Established or Potential Drug-Drug Interactions

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

Calcium Antagonists (verapamil, nifedipine)

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.

9.5 Drug-Food Interactions

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 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

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.

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.

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.

10.2 Pharmacodynamics

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 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 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).

10.3 Pharmacokinetics

Diltiazem is considered to be a moderate inhibitor of CYP3A4, increasing the exposure of oral midazolam, a selective substrate of CYP3A4, by 3.8-fold. In an in vitro study, diltiazem was both a substrate and inhibitor of the efflux transporter, P-glycoprotein (P-gp). Co-administration of diltiazem with the P-gp probe substrate, digoxin, increased plasma concentrations and exposure of digoxin by approximately 20% and 40%, respectively.

Single oral doses of 30 to 120 mg of diltiazem hydrochloride immediate release tablets result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. There is a departure from linearity of accumulation of diltiazem when diltiazem tablets are administered to steady-state in normal subjects. A 240 mg daily dose (60 mg QID) gave plasma levels 2.3 times higher than a 120 mg daily dose (30 mg QID) and a 360 mg daily dose (90 mg QID) had levels 1.7 times higher than the 240 mg daily dose.

More than 95% of drug is absorbed from the diltiazem hydrochloride-controlled delivery capsules formulation. A single 360 mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours. When diltiazem hydrochloride-controlled delivery capsules were taken with a high fat content breakfast, the extent of diltiazem absorption was not affected but was delayed. Dose-dumping does not occur.

A departure from linearity similar to that seen with diltiazem hydrochloride tablets is observed. As the dose of diltiazem hydrochloride-controlled delivery capsules is increased from a daily dose of 120 mg to 240 mg, there is an increase in the area under the curve (AUC) of 2.7 times. When the dose is increased from 240 mg to 360 mg there is an increase in AUC of 1.6 times.

A study which compared patients with normal hepatic function to liver cirrhosis patients noted an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single dose study in patients with severely impaired renal function showed no difference in the half-life of diltiazem as compared to patients with normal renal function (see 7 WARNINGS AND PRECAUTIONS and 4 DOSAGE AND ADMINISTRATION).

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 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 6.0 hours. In vitro human serum binding studies revealed that 70 to 80% of diltiazem is bound to plasma proteins.

Metabolism

The metabolic pathways of diltiazem include N- and O-demethylation (via cytochrome P-450), deacetylation (via plasma and tissue esterases), in addition to conjugation (via sulfation and glucuronidation). 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.

Elimination

Diltiazem undergoes extensive hepatic metabolism in which only 2 to 4% of the drug appears unchanged in the urine and 6 to 7% appears as metabolites. The apparent elimination half-life after single or multiple dosing is 5 to 8 hours.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15°C to 30°C.

Keep out of reach and sight of children.

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Diltiazem Hydrochloride

Chemical name: Chemically, 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 and molecular mass: C₂₂H₂₆N₂O₄S.HCl, 450.98 g/mol

Structural formula:

Physicochemical properties:

Description: The compound is a white crystalline substance or powder having a bitter taste or odour.

Solubility: Diltiazem is considered freely soluble in water, methanol, or chloroform, slightly soluble in absolute ethanol and barely soluble in benzene.

14 CLINICAL TRIALS

14.2 Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of PRO-DILTIAZEM CD 300 mg controlled-delivery capsules (Pro Doc Ltée.) with CARDIZEM^® CD 300 mg controlled-delivery capsules (Nordic Laboratories Inc.) was conducted in healthy, adult, male subjects under fed conditions. Comparative bioavailability data from the 15 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ PRO-DILTIAZEM CD (diltiazem hydrochloride) controlled-delivery capsules, 300 mg (Pro Doc Ltée.)

² CARDIZEM^® CD (diltiazem hydrochloride) controlled-delivery capsules, 300 mg (Nordic Laboratories Inc.) ³ Expressed as the arithmetic mean (CV %) only

A randomized, two-way, single-dose, crossover comparative bioavailability study of PRO-DILTIAZEM CD 300 mg controlled-delivery capsules (Pro Doc Ltée.) with CARDIZEM^® CD 300 mg controlled-delivery capsules (Nordic Laboratories Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from the 16 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ PRO-DILTIAZEM CD (diltiazem hydrochloride) controlled-delivery capsules, 300 mg (Pro Doc Ltée.)

² CARDIZEM^® CD (diltiazem hydrochloride) controlled-delivery capsules, 300 mg (Nordic Laboratories Inc.) ³ Expressed as the arithmetic mean (CV %) only

A randomized, two-way, multiple-dose, crossover comparative bioavailability study of PRO-DILTIAZEM CD 300 mg controlled-delivery capsules (Pro Doc Ltée.) with CARDIZEM^® CD 300 mg controlled-delivery capsules (Nordic Laboratories Inc.), administered as 1 x 300 mg controlled-delivery capsules once a day for seven days, was conducted in healthy, adult, male subjects. Comparative bioavailability data from the 16 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ PRO-DILTIAZEM CD (diltiazem hydrochloride) controlled-delivery capsules, 300 mg (Pro Doc Ltée.)

² CARDIZEM^® CD (diltiazem hydrochloride) controlled-delivery capsules, 300 mg (Nordic Laboratories Inc.) ³ Expressed as the arithmetic mean (CV %) only

A randomized, two-way, multiple-dose, crossover comparative bioavailability study of PRO-DILTIAZEM CD 120 mg controlled-delivery capsules (Pro Doc Ltée.) with CARDIZEM^® CD 120 mg controlled-delivery capsules [Marion Merrell Dow (Canada) Inc.], administered as 1 x 120 mg controlled-delivery capsules once a day for seven days, was conducted in healthy, adult, male subjects. Comparative bioavailability data from the 16 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ PRO-DILTIAZEM CD (diltiazem hydrochloride) controlled-delivery capsules, 120 mg (Pro Doc Ltée.)

² CARDIZEM^® CD (diltiazem hydrochloride) controlled-delivery capsules, 120 mg [Marion Merrell Dow (Canada) Inc.] ³ Expressed as the arithmetic mean (CV %) only

16 NON-CLINICAL TOXICOLOGY

General Toxicology

Table 3: 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 that 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.

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.

Reproductive and Developmental Toxicology

Table 4: Results in mice

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 postpartum. 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.

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^-6M) 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

Pharmacodynamics

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.

Pharmacokinetics

The effect of diltiazem on the pharmacokinetics of phenytoin was investigated in rats. Animals were given 20 mg/kg i.p. phenytoin alone or phenytoin together with 5 mg/kg i.p. diltiazem and the plasma samples were collected at different time intervals. The study showed that diltiazem significantly (p<0.05) increased phenytoin AUC (4-fold), C_max (2-fold), and elimination half-life (t_½ from 1.1h to 2.0h), in the rat.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1.

   CARDIZEM® CD (Diltiazem Hydrochloride Controlled Delivery Capsules, 120 mg, 180 mg,

   240 mg and 300 mg), submission control 291522, Product Monograph, Bausch Health, Canada Inc. (MAR 25, 2025)