Indapamide/ Amlodipine

Registered South African indications:

• Substitution therapy for treatment of essential hypertension
  - In adult patients already controlled with indapamide and amlodipine given concurrently at the same dose level

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other sulfonamides, to dihydropyridine derivatives
• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl <30ml/min)
• Severe hepatic impairment (Child-Pugh C)
• Hepatic encephalopathy
• Hypokalaemia
• Severe hypotension
• Shock
  - Including cardiogenic shock
• Obstruction of the outflow tract of the left ventricle
  - High grade aortic stenosis
• Haemodynamically unstable heart failure after acute myocardial infarction

South African recommendations

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Sun or artificial UVA (Ultraviolet A) exposure
• Cirrhotic patients with oedema and ascites
• Hypertensive crisis
• Water and electrolyte imbalance
• Diabetes mellitus
  - In the presence of hypokalemia
• Cardiac failure
  - Severe heart failure (NYHA class III and IV)
• Congestive cardiac failure
• Coronary artery disease
• Prolonged QT interval
  - Congenital
  - Iatrogenic
• Pre-existing dysrhythmia
  - Bradycardia
  - Ventricular tachycardia
  - Atrial fibrillation
• Malignant hyperthermia
• Gout
• Hyperuricaemia
• Hyperparathyroidism
• Malnourished and/or polymedicated
• Coadministration with digoxin
• Coadministration with torsades de points inducing agents and those associated with risk of ventricular dysrhythmias
• Coadministration with verapamil and dantrolene (See additional prescribing points)
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

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

South African registered indications and dosages

Substitution therapy for treatment of essential hypertension
- In adult patients already controlled with indapamide and amlodipine given concurrently at the same dose level

Indapamide/ Amlodipine

1.5/5 (mg)
1.5/10 (mg)

• Oral (tab): 1 tab, daily as single dose, preferably taken in the morning, to be swallowed whole with water and not chewed

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Fixed dose combination not suitable for initiation therapy

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If a change of the posology is required, titration should be done with the individual components

Not established for use in children below 18 years

Pregnancy 

South African recommendations

• Contraindicated

Indapamide

• There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women
• Prolonged exposure to a thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause foeto-placental ischaemia and growth retardation
• Cases of hypoglycaemia and thrombocytopenia in neonates have been reported following exposure to a thiazide near term
• Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity

Amlodipine

• The safety of amlodipine in human pregnancy has not been established
• In animal studies, reproductive toxicity was observed at high doses
• Reproductive studies in mice and rats have shown prolongation of pregnancy, prolonged duration of labour and decreased pup survival at dosages approximately 50 times the maximum recommended mg/kg human dose

Breastfeeding

South African recommendations

• Contraindicated

Indapamide

• There is insufficient information on the excretion of indapamide/metabolites in human milk
• Hypersensitivity to sulfonamide derived medicines and hypokalaemia might occur. A risk to the newborns/ infants cannot be excluded
• Indapamide is closely related to thiazide diuretics which have been associated, with a decrease or even suppression of milk secretion in women breastfeeding their babies

Amlodipine

• It is not known whether amlodipine is excreted in breast milk

Fertility

South African recommendations

Indapamide

• Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated

Amlodipine

• Reversible biochemical changes in the head of spermatozoa have been reported in patients treated by calcium channel blockers such as contained in indapamide/ amlodipine
• Clinical data are insufficient regarding the potential effect of amlodipine on fertility
• In one rat study with mg/kg doses of amlodipine comparable with the human therapeutic dose, adverse reactions were found on male fertility which included a decrease in plasma follicle stimulating hormone (FSH), a decrease in testosterone, a decrease in sperm density and a decrease in the number of mature spermatids and Sertoli cells

South African recommendations

• Mild to moderate (CrCl≥30ml/min): Caution; no dose adjustment recommended 
• Severe (CrCl<30ml/min): Contraindicated 
  Safety of indapamide/ amlodipine has not been established in patients with renal dysfunction. In renal impairment, indapamide/ amlodipine doses should be in accordance with recommended doses of the individual components taken individually

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended 
  Dosage recommendations of amlodipine have not been established in patients with mild to moderate hepatic impairment, therefore dose selection should be cautious and should start at the lower end of the dosing range
• Severe: Contraindicated 
  When liver function is impaired, thiazide-related diuretics may cause hepatic encephalopathy, particularly in the case of electrolyte imbalance. Due to the presence of indapamide in this combination, administration must be stopped immediately if this occurs

South African recommendations

• Caution; no dose adjustment recommended 
  Dose indapamide/ amlodipine according to renal function

Central Nervous System Disorders

• Insomnia
• Altered mood
• Anxiety 
• Depression
• Confusional state
• Fatigue
• Headache
• Paraesthesia
• Somnolence
• Tremor
• Dysgeusia
• Hypoaesthesia
• Paraesthesia
• Peripheral neuropathy
• Extrapyramidal syndrome
• Pain

Cardiovascular Disorders

• Dysrhythmia
  - Bradycardia
  - Ventricular tachycardia
  - Atrial fibrillation
• Syncope
• Torsade de pointes (potentially fatal)
• Flushing
• Hypotension
• Vasculitis
• Palpitations
• Myocardial infarction
• Prolonged QT electrocardiogram

Respiratory Disorders

• Dyspnoea
• Rhinitis
• Cough
• Chest pain
• Pulmonary oedema

Gastrointestinal Disorders

• Abdominal pain
• Nausea and vomiting
• Dyspepsia
• Change of bowel habit
• Diarrhoea
• Constipation
• Dry mouth
• Pancreatitis
• Gastritis
• Gingival hyperplasia

Hepatobiliary Disorders

• Abnormal hepatic function
• Hepatic encephalopathy (in case of hepatic insufficiency)
• Hepatitis
• Jaundice
• Increased hepatic enzyme

Genitourinary Disorders

• Renal failure
• Micturition disorder
• Nocturia
• Pollakiuria
• Erectile dysfunction

Endocrine and Metabolic Disorders

• Hypercalcaemia
• Hypokalaemia
• Hyponatraemia with hypovolemia
  - Dehydration
  - Orthostatic hypotension
• Hyperglycaemia
• Gynaecomastia
• Decreased weight
• Increased weight
• Increased blood glucose

Musculoskeletal Disorders

• Ankle swelling
• Arthralgia
• Myalgia
• Muscle spasm
• Back pain
• Hypertonia

Skin and Subcutaneous Tissue Disorders

• Rash
• Maculopapular rash
• Purpura
• Alopecia
• Skin discolouration
• Hyperhidrosis
• Pruritus
• Urticaria
• Toxic epidermal necrolysis
• Stevens-Johnson Syndrome
• Erythema multiforme
• Exfoliative dermatitis
• Exanthema
• Possible worsening of pre-existing acute disseminated lupus erythematosus
• Photosensitivity

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Agranulocytosis
• Aplastic anaemia
• Haemolytic anaemia
• Leukopenia
• Thrombocytopenia
• Oedema
  - Angioedema
  - Quincke's oedema
• Increased blood uric acid
• Secondary compensatory metabolic alkalosis

Sensory Disorders

• Myopia
• Diplopia
• Blurred vision
• Visual impairment
• Tinnitus
• Vertigo

• Lithium
• Agents that increase risk for Torsades de pointes
• Class Ia antidysrhythmics
• Quinidine
• Hydroquinidine
• Disopyramide
• Class III antidysrhythmics
• Amiodarone
• Sotalol
• Dofetilide
• Ibutilide
• Antipsychotic agents
• Phenothiazine
• Chlorpromazine
• Cyamemazine
• Levomepromazine
• Thioridazine
• Trifluoperazine
• Benzamide agents
• Amisulpride
• Sulpiride
• Sultopride
• Tiapride
• Butyrophenone agents
• Droperidol
• Haloperidol
• Bepridil
• Cisapride
• Diphemanil
• Halofantrine
• Mizolastine
• Pentamidine
• Sparfloxacin
• Moxifloxacin
• Vincamine
• Non-steroidal anti-inflammatory drugs
• Cyclooxygenase-2 (COX-2) selective inhibitors
• Salicylic acid
• Allopurinol
• Angiotensin-converting enzyme (ACE) inhibitors
• Agents causing hypokalemia
• Amphotericin B
• Mineralocorticoid agents
• Glucocorticoid agents
• Tetracosactide
• Stimulant laxatives
• Baclofen
• Digitalis preparations
• Digoxin
• Potassium-sparing diuretics
• Amiloride
• Spironolactone
• Triamterene
• Metformin
• Iodinated contrast media
• Imipramine-like antidepressants
• Imipramine-like neuroleptics
• Calcium salts
• Ciclosporin
• Tacrolimus
• Corticosteroids
• Strong to moderate CYP3A4 inhibitors
• Protease inhibitors
• Azole antifungals
• Macrolides
• Erythromycin
• Clarithromycin
• Verapamil
• Diltiazem
• Dantrolene
• CYP3A4 inducers
• Rifampicin
• Simvastatin

Other interactions

• Grapefruit
• Grapefruit juice
• Hypericum perforatum (St John's Wort)

• Serum electrolytes
• Hepatic function
• Renal function
• Blood pressure

None routine. Specific cases may require

• Blood uric acid
• Blood glucose
• Electrocardiogram
• Parathyroid function
• Serum levels
  - Digoxin
  - Lithium
  - Tacrolimus
  - Ciclosporin
• Cardiac function
• Respiratory function

Additional observations

• Weight

Special precautions for use

Hepatic encephalopathy

• When liver function is impaired, thiazide-related diuretics such as contained in indapamide/ amlodipine may cause hepatic encephalopathy, particularly in case of electrolyte imbalance. Treatment  must be stopped immediately if this occurs

Photosensitivity

• Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics such as contained in indapamide/ amlodipine
• If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment
• If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA (Ultraviolet A)

Water and electrolyte balance

• Plasma sodium 
  - This must be measured before starting treatment, then at regular intervals subsequently
  - The fall in plasma sodium may be asymptomatic initially and regular monitoring is therefore essential, and should be even more frequent in the elderly and cirrhotic patients
  - Diuretic treatment may cause hyponatraemia, with serious consequences
  - Hyponatraemia with hypovolaemia may cause dehydration and orthostatic hypotension
  - Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis
• Plasma potassium
  - Potassium depletion with hypokalaemia is a major risk with the use of thiazide and thiazide related diuretics
  - Hypokalaemia (<3,4mmol/l) must be prevented in certain high risk populations, i.e. the elderly, malnourished and/or polymedicated, cirrhotic patients with oedema and ascites, coronary artery disease, long QT interval (congenital or iatrogenic) and cardiac failure patients
  - Hypokalaemia increases the cardiac toxicity of digoxin and the risk of dysrhythmias
  - Hypokalaemia, as well as bradycardia, are predisposing factors to the onset of severe dysrhythmias, in particular, torsades de pointes which may be fatal
  - Plasma potassium should be measured before initiating treatment and in the first week of treatment and frequently thereafter especially in the above mentioned categories of patients
  - Hypokalaemia should be corrected
• Plasma calcium
  - Thiazide and thiazide related diuretics may decrease urinary calcium excretion and cause a rise in plasma calcium
  - Hyperparathyroidism should be excluded as a cause of hypercalcaemia
  - Treatment with indapamide/ amlodipine should be withdrawn before the investigation of parathyroid function

Dantrolene (infusion)

• In animals, lethal ventricular fibrillation and cardiovascular collapse were observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene
• Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as contained in this combination be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia

Indapamide
Indapamide is a sulfonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, which acts by inhibiting the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.

Amlodipine
Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle.

COMBINATION PREPARATIONS

Indapamide/ Amlodipine

Tablet 1.5mg/5mg

• Natrixam (Servier Laboratories SA) originator

Tablet 1.5mg/10mg

• Natrixam (Servier Laboratories SA) originator