Diltiazem hydrochloride (Diltiazem CD)

1. Health Canada Product Monograph — Diltiazem hydrochloride

• Used to manage chronic stable (effort-associated) angina in patients who remain symptomatic despite adequate beta-blocker or nitrate therapy, or who cannot tolerate those agents.
• May be combined with beta-blockers for chronic stable angina in patients with normal heart pumping function, under close monitoring.
• Used to treat mild to moderate essential hypertension.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Contraindicated in pregnancy and in women of childbearing potential.
• Animal studies showed a higher rate of vertebral, skeletal, and cleft palate malformations, and increased fetal death, at doses well above the human therapeutic range.
• Pregnancy should be ruled out before starting this medication in women of childbearing potential.

• Contraindicated during breastfeeding.
• Diltiazem passes into breast milk at concentrations that may approach those in the mother's blood, and safety in nursing infants has not been established.

• Use with caution in patients 65 years of age and older, since adverse reactions are reported meaningfully more often in this group.
• Peripheral swelling, slow heart rate, palpitations, dizziness, rash, and increased urination are reported more frequently in older adults, so gradual, careful dose titration is advised.
• Pharmacokinetics in elderly patients have not been fully studied, but a lower starting dose may be needed.

• Safety and effectiveness in patients under 18 years of age have not been established, and Health Canada has not authorized this medication for pediatric use.

• For angina, the usual starting dose is 120 to 180 mg once daily, titrated over 7 to 14 days as needed up to a maximum of 360 mg once daily.
• For hypertension, the usual starting dose is 180 to 240 mg once daily as monotherapy, with the full antihypertensive effect typically seen after 2 to 4 weeks; the maximum dose is 360 mg once daily.
• Capsules must be swallowed whole and should not be chewed or crushed, since this could release the full dose at once.
• If a dose is missed, take it as soon as remembered, but if it is almost time for the next dose, skip the missed one and resume the regular schedule; do not double up.
• Lower starting doses and gradual, careful adjustment are used in patients with impaired liver or kidney function.

• Headache may occur.
• Swelling of the ankles or feet (edema) may occur.
• Dizziness may occur.
• Slow heart rate (bradycardia) may occur.
• First-degree AV block (a mild slowing of the heart's electrical conduction) may occur.
• Weakness (asthenia) may occur.
• Flushing may occur.
• Nausea may occur.
• Constipation or upset stomach (dyspepsia) may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Diltiazem may cause significant slowing of the heart rate or high-degree heart block, particularly in patients with underlying conduction problems.
• Worsening heart failure may occur, since diltiazem can reduce the heart's pumping strength.
• Severe drops in blood pressure (hypotension) may occur, especially when starting therapy or increasing the dose.
• Liver injury with elevated liver enzymes has occurred rarely and is usually reversible after stopping the drug.
• Serious skin reactions, including erythema multiforme, exfoliative dermatitis, and rarely Stevens-Johnson syndrome or toxic epidermal necrolysis, have been reported.
• Bronchospasm, including worsening of asthma, may occur, particularly after a dose increase.
• Blood disorders such as low platelet count, low white blood cell count, or hemolytic anemia have been reported rarely.
• Mood changes, including new or worsening depression, may occur.
• Seek prompt medical attention for fainting, severe dizziness, a very slow or irregular heartbeat, new swelling, difficulty breathing, or a spreading skin rash.

• Use with caution in patients with congestive heart failure, since diltiazem can further reduce heart pumping strength.
• Use with caution when combined with beta-blockers, digitalis, or amiodarone, because of additive effects on heart rate and conduction.
• Use with caution in patients with impaired liver or kidney function, with gradual dose titration and monitoring.
• Use with caution in patients at risk of intestinal obstruction, since diltiazem can slow bowel motility.
• Use with caution in patients with pre-existing bronchial hyperactivity or asthma.
• Use with caution in patients with diabetes, since diltiazem may raise blood glucose.
• Use with caution in elderly patients, who experience more frequent adverse effects.

• Contraindicated in patients with sick sinus syndrome, unless a functioning ventricular pacemaker is in place.
• Contraindicated in second- or third-degree AV block.
• Contraindicated in patients with known hypersensitivity to diltiazem or any ingredient in the capsule.
• Contraindicated in significant hypotension (systolic blood pressure below 90 mmHg).
• Contraindicated in severe bradycardia (heart rate below 40 beats per minute).
• Contraindicated in patients with a recent heart attack complicated by lung congestion from heart failure.
• Contraindicated in pregnancy and in women of childbearing potential.
• Contraindicated during breastfeeding.
• Contraindicated with concurrent use of intravenous dantrolene.
• Contraindicated with concurrent use of ivabradine.
• Contraindicated with concurrent use of lomitapide, due to a large increase in lomitapide blood levels.

• Combining diltiazem with beta-blockers, digitalis, or amiodarone can have additive effects on heart rate and conduction, increasing the risk of severe bradycardia or heart block.
• Diltiazem is a moderate inhibitor of CYP3A4 and can raise blood levels of many other drugs metabolized by this enzyme, including certain benzodiazepines such as midazolam and triazolam, cyclosporine, and statins like lovastatin.
• Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, ritonavir, and clarithromycin can raise diltiazem blood levels and may require dose adjustment.
• CYP3A4 inducers such as rifampin, carbamazepine, or phenytoin can lower diltiazem blood levels and reduce its effectiveness.
• Diltiazem can increase blood levels of direct oral anticoagulants such as apixaban, rivaroxaban, and dabigatran, raising the risk of serious bleeding.
• Diltiazem may raise digoxin blood levels, requiring closer monitoring and possible dose reduction of digoxin.
• Combining diltiazem with acetylsalicylic acid or other antiplatelet drugs may increase bleeding risk.
• Concomitant use with dantrolene infusion, ivabradine, or lomitapide is contraindicated due to serious interaction risks.
• Alcohol may add to the blood-pressure-lowering effect of diltiazem, increasing the risk of dizziness or fainting, especially early in treatment.

• Grapefruit and grapefruit juice may raise diltiazem blood levels and should be avoided or used cautiously, watching for signs of excess effect such as headache, irregular heartbeat, swelling, or chest pain.
• Taking the capsule with a high-fat meal delays but does not reduce the amount of drug absorbed, so it can be taken with or without food.
• Calcium-containing supplements may reduce the effectiveness of diltiazem.

• Taken once daily at a consistent time, with or without food, swallowing the capsule whole without chewing or crushing it.

• Store at room temperature between 15 and 30 degrees C, and keep out of the reach and sight of children.

• This medication relaxes blood vessels and reduces the heart's workload to treat high blood pressure and chronic angina.
• Take one capsule once daily at the same time each day, swallowed whole, and do not stop or change the dose without talking to the prescriber.
• Common effects include headache, ankle swelling, dizziness, flushing, and a slow heart rate.
• Contact the prescriber's office right away for fainting, a very slow or irregular heartbeat, worsening swelling, shortness of breath, or a spreading skin rash.
• Avoid grapefruit and grapefruit juice, which can increase the drug's effects, and mention any new medications, including over-the-counter products, to the pharmacist.
• Store the capsules at room temperature, away from children; this medication must not be used during pregnancy or breastfeeding.