Enalapril/ Hydrochlorothiazide

Registered South African indications:

• Hypertension
  - In patients stabilised on the individual components administered at the same dosages

Safety in pregnancy and lactation has not been established. Should a woman become pregnant while receiving enalapril/ hydrochlorothiazide, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine

 

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other sulphonamide derived medicines
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): Such patients must never again be given these medicines
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Severe renal function impairment (CrCl < 30ml/min) or anuria
• Bilateral renal artery stenosis
• Patients with severe hepatic impairment
• Renal artery stenosis in patients with a single kidney or aortic stenosis
• Concomitant therapy with potassium sparing diuretics such as eplerenone, spironolactone, triamterene and amiloride
• Patients with Addison’s disease
• Coadministration with lithium therapy may lead to toxic blood concentrations of lithium
• Coadministration with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) is contraindicated
• Coadministration of fluoroquinolone with ACE inhibitors, such as enalapril/ hydrochlorothiazide is contraindicated in patients with moderate renal impairment (CrCl ≤ 30ml/min) and in elderly patients
• Combination with sacubitril/valsartan due to the increased risk of angioedema. Do not administer enalapril/ hydrochlorothiazide within 36 hours of switching to or from sacubitril/valsartan, a medicine containing a neprilysin inhibitor
• History of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip
• Pregnancy
• Breastfeeding
• Porphyria

• Renal impairment (CrCl >30ml/min)
• Mild to moderate hepatic impairment
• Volume depletion
• Cardiogenic shock
• Ischaemic heart disease
• Cerebrovascular disease
• Cardiac failure
• Dual blockade of renin-angiotensin-aldosterone system
• Left ventricular outflow tract obstruction
• Haemodialysis
• Kidney transplantation
• Collagen vascular disease
• Risk factors for hyperkalaemia
• Diabetes mellitus
• Black patients
• Surgery
• Anaesthesia
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

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

South African registered indications and dosages

Hypertension
- In patients stabilised on the individual components administered at the same dosages

Enalapril/ Hydrochlorothiazide
20/12.5 (mg)

• Oral (tab): 1 tab, once dly; Max: 2 tab/24hrs

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Missed dose

Advise patients who forget to take enalapril/ hydrochlorothiazide to take a dose as soon as possible and then continue with the normal dose. Patients should not take a double dose to compensate for the missed dose

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• ACE inhibitors, such as enalapril, including enalapril/ hydrochlorothiazide, should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy
• Safety in pregnancy and lactation has not been established. Should a woman become pregnant while receiving enalapril/ hydrochlorothiazide, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine

Enalapril maleate

• Pregnant women should be informed of the potential hazards to the foetus and must not take enalapril/ hydrochlorothiazide during pregnancy
• Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with enalapril/ hydrochlorothiazide should be stopped immediately and if appropriate, alternative therapy should be started
• Foetal exposure to ACE inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spina bifida) and of kidney malformations
• Enalapril/ hydrochlorothiazide passes through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms. Oligohydramnios, as well as hypotension, oliguria and anuria in new-borns have been reported after administration of enalapril/ hydrochlorothiazide during the second and third trimester and may result in limb contractures, craniofacial deformations and hypoplastic lung development. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur
• Should exposure to enalapril have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended

Hydrochlorothiazide

• Hydrochlorothiazide crosses the placental barrier and appears in cord blood. Hazards include foetal and neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occur in the adult. There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester
• Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester may compromise foetal-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia
• In gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease, enalapril/ hydrochlorothiazide should not be administered. Enalapril/ hydrochlorothiazide should not be used for essential hypertension in pregnant woman
• Infants whose mothers have taken enalapril/ hydrochlorothiazide should be closely observed for hypotension, oliguria and hyperkalaemia. There is no experience with the removal of the combination product, enalapril/ hydrochlorothiazide, from the neonatal circulation. Enalapril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit

Breastfeeding

South African recommendations

• Contraindicated
• Mothers breastfeeding their infants should not be treated with enalapril/ hydrochlorothiazide
• Both enalapril maleate and hydrochlorothiazide appear in human milk. If use of enalapril/ hydrochlorothiazide is deemed essential, the patient should stop nursing
• Hydrochlorothiazide, as in enalapril/ hydrochlorothiazide, in high doses causing intense diuresis can inhibit the milk production

Fertility

South African recommendations

• No information available

• CrCl >30ml/min: Caution; no dose adjustment recommended
  May be used only after the individual components have been successfully titrated. Do not use as initial therapy in any patient with renal insufficiency
• CrCl ≤30 ml/min or anuria or when coadministered with fluoroquinolones: Contraindicated
• Bilateral renal artery stenosis: Contraindicated
• Renal artery stenosis in patients with a single kidney: Contraindicated
• GFR <60ml/min/1.73m² (when coadministered with aliskiren-containing products): Contraindicated

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

• No dose adjustment recommended

Central Nervous System Disorders

• Headache
• Depression
• Syncope
• Confusion
• Somnolence
• Insomnia
• Nervousness
• Paresthesia
• Sleep disorders
• Dizziness
• Fatigue

Cardiovascular Disorders

• Chest pain
• Flushing
• Palpitations
• Myocardial infarction
• Cerebrovascular accident
• Raynaud's phenomenon

Respiratory Disorders

• Cough
• Dyspnoea
• Rhinorrhoea
• Sore throat
• Hoarseness
• Bronchospasm
• Pulmonary infiltrates
• Pneumonitis
• Pulmonary oedema
• Rhinitis
• Allergic alveolitis
• Eosinophilic pneumonia

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Ileus
• Dyspepsia
• Constipation
• Anorexia
• Dry mouth
• Peptic ulcer
• Flatulence
• Stomatitis
• Aphthous ulcerations
• Glossitis
• Intestinal angiooedema

Hepatobiliary Disorders

• Pancreatitis
• Hepatic failure
• Hepatic necrosis
• Hepatitis
• Jaundice
• Cholecystitis 
• Increased bilirubin
• Increased liver enzymes

Genitourinary Disorders

• Decreased libido
• Renal failure
• Proteinuria
• Oliguria
• Interstitial nephritis
• Impotence

Endocrine and Metabolic Disorders

• Syndrome of inappropriate antidiuretic hormone secretion 
• Hypokalaemia
• Increased cholesterol
• Increased of triglycerides
• Hyperuricaemia
• Hypoglycaemia
• Hypomagnesaemia
• Gout
• Increased blood glucose
• Hypercalcaemia
• Gynecomastia
• Hyperkalaemia
• Increased serum creatinine
• Increased serum urea
• Hyponatraemia

Musculoskeletal Disorders

• Muscle cramps
• Arthralgia

Skin and Subcutaneous Tissue Disorders

• Rash
• Hypersensitivity
• Angioneurotic oedema
• Diaphoresis
• Pruritus
• Urticaria
• Alopecia
• Erythema multiforme
• Stevens-Johnson syndrome
• Exfoliative dermatitis
• Toxic epidermal necrolysis
• Purpura
• Cutaneous lupus erythematosus
• Erythroderma
• Pemphigus

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Neutropenia
• Decreased haemoglobin
• Decreased haematocrit
• Thrombocytopenia
• Agranulocytosis
• Bone marrow depression
• Leukopenia
• Pancytopenia
• Lymphadenopathy
• Autoimmune diseases

Sensory Disorders

• Taste alteration
• Vertigo
• Blurred vision
• Tinnitus

• Potassium sparing diuretics
• Eplerenone
• Spironolactone
• Triamterene
• Amiloride
• Sacubitril/valsartan
• Angiotensin-converting enzyme inhibitors
• Angiotensin II receptor blockers
• Aliskiren
• Antihypertensives
• Lithium
• Non-steroidal anti-inflammatory drugs
• Agents that increase serum potassium
• Central nervous system depressants
• Gold
• MTOR inhibitors
• Antidiabetics
• Non-depolarizing muscle relaxants
• Cholestyramine
• Colestipol
• Quinidine
• Procainamide
• Amiodarone
• Sotalol
• Digoxin
• Corticosteroids
• Adrenocorticotropic hormone
• Furosemide
• Carbenoxolone
• Pressor amines
• Cytostatics
• Laxatives

None routine. Specific cases may require

• Renal function
• Serum potassium
• Full blood count

Enalapril
Enalapril is hydrolysed to enalaprilat which is a specific, long-acting, non-sulfhydryl angiotensin-converting enzyme inhibitor. Angiotensin-converting enzyme inhibitor is a peptidyl dipeptidase which catalyses the conversion of angiotensin I to the pressor substance angiotensin II. This results in reduced plasma renin activity and decreased aldosterone secretion. The blood pressure lowering effect of enalapril is primarily through suppression of the renin- angiotensin- aldosterone system.

Hydrochlorothiazide
Hydrochlorothiazide acts primarily in the distal convoluted tubule where it inhibits sodium chloride transport. It competes for the chloride site and affects the electrolyte reabsorption by increasing sodium and chloride excretion. This reduces plasma volume indirectly and increases plasma renin activity, aldosterone secretion and urinary potassium loss.

COMBINATION PREPARATIONS

Enalapril/ Hydrochlorothiazide

Tablet 20mg/12.5mg

• Co-Renitec (MSD) originator
• Enap Co (Pharma Dynamics)
• Pharmapress Co (Pharmacare)