Diltiazem

Registered South African indications:

• Prophylaxis of angina pectoris, including Prinzmetal's angina
• Hypertension - mild to moderate

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Women of childbearing age
• Severe renal impairment
• Severe hepatic impairment
• Porphyria
• Children
• Decompensated cardiac insufficiency
• Sick sinus syndrome
• Conduction disturbances (sino-atrial or atrioventricular block)
• Bradycardia (pulse rate <55/min)

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Breastfeeding
• Sick sinus syndrome
  - 2nd or 3rd degree AV block in patients without a functioning pacemaker
• Severe bradycardia (<50 beats/min)
• Left ventricular failure with pulmonary stasis
• Decompensated cardiac failure
• Coadministration with dantrolene infusion
• Coadministration with ivabradine
• Coadministration with lomitapide
• Coadministration with asunaprevir

Cautions

South African recommendations

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Bradycardia
• Pre-existing hypotension
• Impaired left ventricular function
• Congestive heart failure
• Anaesthesia
• Coadministration with digitalis glycosides

Recommendations in other jurisdictions

• Pregnancy
• Women of childbearing age not using contraception
• Renal impairment
• Hepatic impairment
• Elderly
• Acute porphyria
• Reduced left ventricular function
• Bradycardia
• First degree AV block
• Prolonged PR interval
• Severe hypotension
• General anaesthesia
• Those predisposed to mood changes and/or depression
• Patients at risk of intestinal obstruction
• Diabetes mellitus
• Pre-existing bronchial hyper-reactivity
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab, src

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Prophylaxis of angina pectoris, including Prinzmetal's angina
Hypertension - mild to moderate

60mg tab

• Oral (tab): Initial: 30-60mg, 6-8hrly; Titrate by 30-60mg, 6-8hrly if an acceptable clinical response has not been obtained; Maintenance: 90-360mg, dly; Max: 360mg/24hrs
  OR

90mg tab

• Oral (tab): Initial: 90-180mg, 12hrly; Titrate by 90mg, 12hrly; Maintenance: 180-360mg, dly; Max: 360mg/24hrs
  OR

180mg & 240mg tab

• Oral (src): 180mg, 12-24hrly OR 240mg, dly; Max: 360mg/24hrs

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See additional prescribing points for further dosing instructions

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Capsules should be swallowed intact with some liquid

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Indications and dosages registered in other jurisdictions

Prevention and long term treatment of angina pectoris (NOT indicated for acute attacks of angina)
Arterial hypertension - mild to moderate

• Oral (tab): Initial: 60mg, 8hrly; Titrate up to 360mg, dly, depending on patient response; Higher doses of up to 480mg, dly have been used with benefit in some patients, especially in unstable angina. There is no evidence of any decrease in efficacy at these high doses

OR

• Oral (cap): Initial: 90mg, 12hrly; Titrate up to 120mg, 12hrly OR 240mg, dly; Titrate up to 300mg, dly; Titrate up to 180mg, 12hrly, if required; Maintenance: 180-360mg, dly; Max: 360mg/24hrs 

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Tablets should be swallowed whole with a little water

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Tablet formulations may contain hydrogenated castor oil. This may cause stomach upset and diarrhoea

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The capsules should be swallowed whole and not chewed. Dosage may be taken with or without food

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Residues from slow release formulations of the product may pass into the patient's stools

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In order to avoid confusion, it is suggested that patients once titrated to an effective dose should remain on this treatment and should not be changed between different presentations

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• Since teratogenic effects were noted in animals, diltiazem should not be administered to pregnant women or to women of childbearing age

Recommendations in other jurisdictions

• Caution; not recommended
• There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have reproductive toxicity in certain animal species (rat, mice and rabbit). Diltiazem is therefore not recommended during pregnancy or in women of childbearing potential not using effective contraception

Breastfeeding

South African recommendations

• Contraindicated
• Diltiazem is excreted in human milk, and therefore should not be administered to breastfeeding women

Recommendations in other jurisdictions

• Contraindicated
• As this agent is excreted in breast milk, breastfeeding whilst taking diltiazem is contraindicated

Fertility

• No information available

Renal Impairment

South African recommendations

• Mild (eGFR≥60ml/min/1.73m²): No dose adjustment recommended
• Moderate (eGFR 30-59 ml/min/1.73m²): Caution; dose adjustment recommended
  Use with caution. There is no exact dosage adjustment information provided in the manufacturer’s labeling. Monitor serum creatinine and eGFR during therapy. Consider dose reduction by up to 25% (for both immediate- and sustained-release preparations) when deterioration of renal function parameters is observed during chronic therapy
• Severe (eGFR<30ml/min/1.73m²): Contraindicated

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Monitor heart rate closely; Increase in dose is not recommended at heart rate <50 beats/min
  Initial: 60mg, 12hrly; Titrate up to 240mg, dly, if necessary

Hepatic Impairment

South African recommendations

• Mild (Child-Pugh class A): No dose adjustment recommended
• Moderate (Child-Pugh class B): Caution; dose adjustment recommended
  Use with caution. There is no exact dosage adjustment information provided in the manufacturer’s labeling. Hepatic function during chronic therapy. Consider dose reduction by up to 25% (for immediate-release preparation) and up to 50% (for sustained-release preparations) when changes in hepatic function parameters (≥2x above normal limit) are observed during chronic therapy 
• Severe (Child-Pugh class C): Contraindicated
  Contraindicated in active liver disease or compensated liver disease

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Monitor heart rate closely; Increase in dose is not recommended at heart rate <50 beats/min
  Initial: 60mg, 12hrly; Titrate up to 240mg, dly, if necessary

Elderly

South African recommendations

• Caution; no dose adjustment recommended
  No dose adjustment is recommended by the manufacturer. Consider using the lowest [recommended] therapeutic dose when initiating therapy
  Use with caution in elderly with renal or hepatic impairment

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Monitor heart rate closely; Increase in dose is not recommended at heart rate <50 beats/min
  Initial: 60mg, 12hrly; Titrate up to 240mg, dly, if necessary

Porphyria Information

• Probably porphyrinogenic (PRP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Nervousness
• Insomnia
• Mood changes
• Depression
• Headache
• Dizziness
• Extrapyramidal syndrome
• Malaise

Cardiovascular Disorders

• Atrioventricular block
  - First, second or third degree
  - Bundle branch block
• Palpitations
• Bradycardia
• Sinoatrial block
• Congestive heart failure
• Sinus arrest
• Cardiac arrest (asystole)
• Flushing
• Orthostatic hypotension
• Vasculitis
  - Leukocytoclastic vasculitis

Respiratory Disorders

• Bronchospasm
  - Asthma aggravation

Gastrointestinal Disorders

• Constipation
• Dyspepsia
• Gastric pain
• Nausea and vomiting
• Diarrhoea
• Dry mouth
• Gingival hyperplasia

Hepatobiliary Disorders

• Increased hepatic enzymes
  - Increased aspartate transaminase (AST)
  - Increased alanine transaminase (ALT)
  - Increased lactate dehydrogenase (LDH)
  - Increased alkaline phosphatase (ALP)
• Hepatitis

Endocrine and Metabolic Disorders

• Gynaecomastia
• Hyperglycaemia

Skin and Subcutaneous Tissue Disorders

• Erythema
• Urticaria
• Photosensitivity
  - Lichenoid keratosis (sun-exposed skin areas)
• Angioneurotic oedema
• Rash
• Erythema multiforme
  - Steven-Johnson's syndrome
  - Toxic epidermal necrolysis
• Sweating
• Exfoliative dermatitis
• Acute generalized exanthematous pustulosis
• Desquamative erythema (with or without fever)

Immune, Blood and Lymphatic System Disorders

• Thrombocytopenia
• Peripheral oedema

• Dantrolene
• Ivabradine
• Lomitapide
• Asunaprevir
• Alpha-antagonists
• Beta-blockers
• Amiodarone
• Digoxin
• Antiarrhythmic agents
• Nitrate derivatives
• Ciclosporin
• Phenytoin
• Carbamazepine
• Theophylline
• Anti-H2 agents
• Cimetidine
• Ranitidine
• Rifampicin
• Lithium
• Antiplatelet agents
• Strong CYP3A4 inhibitors
• CYP3A4 substrates
• CYP3A4 inducers
• Statins
• Atorvastatin
• Fluvastatin
• Simvastatin
• Cilostazol
• Benzodiazepines
• Midazolam
• Triazolam
• Corticosteroids
• Methylprednisolone
• Agents that affect cardiac contractility and/or conduction

Other interactions

• Alcohol
• X-ray contrast media
• Grapefruit juice

• Hepatic function
• Renal function
• Electrocardiogram (ECG)
• Blood pressure
• Heart rate

Specific cases may require

• Blood sugar

Additional observations

• Mood changes
• Signs and symptoms of respiratory impairment

Further dosing instructions

• The daily dosage for diltiazem ranges from 90mg to 360mg per day. The total daily dosage should be titrated upward from 90mg per day to a maximum of 360mg per day to meet the requirements of the individual patient. For daily dosages above 90mg per day, it may be possible to decrease the dosage after 2 to 3 months. Once the daily dosage has been optimised, the most appropriate preparation may be selected
• The dosage of diltiazem should be titrated with an immediate release preparation to meet the needs of the individual patient. Once the daily dosage has been optimised, the sustained release capsules may be substituted, where appropriate

Diltiazem is a calcium antagonist. It restricts the slow channel entry of calcium into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction of the amount of available intracellular calcium reducing myocardial oxygen consumption. It increases exercise capacity and improves all indices of myocardial ischaemia in the angina patient. It also relaxes large and small coronary arteries and relieves the spasm of vasospastic (Prinzmetal's) angina and the response to catecholamines but has little effect on the peripheral vasculature. There is therefore no possibility of reflex tachycardia. A small reduction in heart rate occurs which is accompanied by an increase in cardiac output, improved myocardial perfusion and reduction of ventricular work.

Tablet 60mg

• Adco-Zildem (Adcock Ingram)
• Dilatam (Pharmacare) (Discontinued: 01/04/2018)
• Sandoz Diltiazem HCI 60 (Sandoz SA) (Discontinued: 01/04/2018)

Tablet 90mg

• Adco-Zildem (Adcock Ingram)

Slow release capsule 180mg

• Adco-Zildem SR (Adcock Ingram)
• Tilazem 180 CR (Pfizer Laboratories) originator (Discontinued: 01/04/2018)

Slow release capsule 240mg

• Adco-Zildem SR (Adcock Ingram)
• Tilazem 240 CR (Pfizer Laboratories) originator (Discontinued: 01/04/2018)