Lisinopril/ Hydrochlorothiazide

Registered South African indications:

• Hypertension - mild to moderate

Contraindications

South African recommendations

• Hypersensitivity to the active substances or any of the excipients
• Hypersensitivity to any component of lisinopril/hydrochlorothiazide
• History of anaphylactic/anaphylactoid reactions or angio-oedema related to previous treatment with an angiotensin-converting enzyme (ACE) inhibitor
• Hereditary or idiopathic angio-oedema
• Hypersensitivity to other sulphonamide-derived medicines
• Anuria
• Lisinopril/hydrochlorothiazide should not be given to patients with aortic stenosis or hypertrophic cardiomyopathy
• Pregnancy
• Nursing mothers
• Coadministration with sacubitril/valsartan therapy; lisinopril/hydrochlorothiazide must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan
• Concomitant use of lisinopril/hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m2)

Recommendations in other jurisdictions 

• Hypersensitivity to the active substances or any of the excipients
• Hypersensitivity to any other ACE inhibitor
• Hypersensitivity to any sulphonamide-derived drugs
• History of angioedema associated with previous ACE inhibitor therapy
• Hereditary or idiopathic angioedema
• Concomitant use with sacubitril/valsartan therapy; lisinopril/hydrochlorothiazide must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan
• Second and third trimesters of pregnancy
• Severe renal impairment (CrCl<30ml/min)
• Anuria
• Severe hepatic impairment
• Concomitant use of lisinopril/hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73 m²)

Cautions 

• Pregnancy in first trimester (Recommendations in other jurisdictions​​​​​​)
• Breastfeeding (Recommendations in other jurisdictions​​​​​​)
• Renal impairment (South African recommendations)
• Mild to moderate renal impairment (Recommendations in other jurisdictions​​​​​​)
• Hepatic impairment (South African recommendations)
• Mild to moderate hepatic impairment (Recommendations in other jurisdictions​​​​​​)
• Volume depleted patients
• Ischaemic heart disease
• Cerebrovascular disease
• Cardiac failure
• Fixed cardiac output states
• Dual blockade of renin-angiotension-aldosterone system
• Renal transplant
• Haemodialysis 
• Low density lipoprotein apheresis
• Surgery
• Diabetes mellitus
• Gout
• Black patients
• May impair ability to drive and operate machinery

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

Dosages below include:

• South African registered indications and dosages

South African registered indications and dosages

Hypertension - mild to moderate
- In those who have been stabilised on their individual components given in the same proportions

Lisinopril/ Hydrochlorothiazide
10/12.5 (mg)
20/12.5 (mg)

• Oral (tab): 1 tab, dly; If desired therapeutic effect is not achieved in 2-4 weeks, dosage may be increased to a max of 2 tab, dly; Max: 2 tab/24hrs

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Lisinopril/hydrochlorothiazide tablets should be taken approximately at the same time each day

Not established for use in children

Pregnancy

South African recommendations

• Contraindicated
• Should a woman become pregnant while receiving an ACE inhibitor the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy the doctor should institute alternative medication
• When pregnancy is detected, lisinopril/ hydrochlorothiazide should be discontinued as soon as possible
• ACE-inhibitors can cause foetal and neonatal morbidity and mortality when administered to pregnant women during the second and third trimesters. ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regulatory mechanisms
• Oligohydramnios, which may result in limb contractures, craniofacial deformations and hypoplastic lung development, as well as hypotension, renal failure, hyperkalaemia, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors. Cases of defective skull ossification have been observed
• Prematurity and low birth mass can occur
• Hydrochlorothiazide hazards include foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which occur in the adult. Infants should be closely observed for hypotension, oliguria and hyperkalaemia
• Lisinopril, which crosses the placenta, has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit
• There is no experience with the removal of hydrochlorothiazide, which also crosses the placenta, from the neonatal circulation. A retrospective epidemiological study has suggested that maternal exposure to an ACE inhibitor during the first trimester of pregnancy may lead to an increased risk of malformations, particularly of the cardiovascular and central nervous systems

Recommendations in other jurisdictions 

• First trimester: Caution; positive evidence of risk
• Second and third trimester: Contraindicated
• ACE-inhibitors: The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimester of pregnancy
• ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started
• Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Unless continued ACE inhibitors therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started
• ACE inhibitor therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). Should exposure to ACE inhibitors have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension
• Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient
• Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia
• Hydrochlorothiazide should not be used for 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
• Hydrochlorothiazide should not be used for primary hypertension in pregnant women except in rare situations where no other treatment could be used

Breastfeeding

South African recommendations

• Contraindicated
• It is not known whether lisinopril is secreted in human milk; however, the thiazides do appear in human milk
• Lisinopril/hydrochlorothiazide is not recommended for nursing mothers

Recommendations in other jurisdictions 

• Caution; not recommended
• ACE-inhibitors: Because no information is available regarding the use of lisinopril/hydrochlorothiazide during breastfeeding, lisinopril/hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant
• Hydrochlorothiazide: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of lisinopril/hydrochlorothiazide during breastfeeding is not recommended. If lisinopril/hydrochlorothiazide is used during breastfeeding, doses should be kept as low as possible

Renal Impairment

South African recommendations

• CrCl>30 and <80ml/min: Caution; no dose adjustment recommended
  Lisinopril/hydrochlorothiazide may be used, but only after titration of the individual components
  Lisinopril/hydrochlorothiazide is not to be used as initial therapy in any patient with renal insufficiency
• CrCl≤30ml/min: Caution; not recommended
  Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at CrCl≤30ml/min (i.e. moderate or severe renal insufficiency)

Recommendations in other jurisdictions 

• CrCl>30 and <80ml/min: Caution; dose adjustment recommended
  Lisinopril/hydrochlorothiazide may be used, but only after titration of the individual components
  Lisinopril/hydrochlorothiazide is not to be used as initial therapy in any patient with renal insufficiency
  Recommended dose of lisinopril, when used alone, in mild renal insufficiency, is 5-10mg
• CrCl<30ml/min: Contraindicated
  Thiazides may not be appropriate diuretics for use in patients with renal impairment and are ineffective at creatinine clearance values of 30 ml/min or below

Hepatic Impairment

South African recommendations

• Caution; no dose adjustment recommended
  Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma

Recommendations in other jurisdictions 

• Mild to moderate: Caution; no dose adjustment recommended
  Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma
• Severe: Contraindicated

Elderly

• No dose adjustment recommended

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Prohibited - At all times

Central Nervous System Disorders

• Weakness
• Lethargy
• Drowsiness
• Restlessness
• Seizures
• Headache
• Paraesthesia
• Dizziness
• Vertigo
• Sleep disturbances
• Hallucinations
• Mental confusion
• Depressive symptoms
• Syncope

Cardiovascular Disorders

• Postural hypotension
• Myocardial infarction
• Cerebrovascular accident
• Palpitations
• Tachycardia
• Raynaud's phenomenon

Respiratory Disorders

• Cough
• Rhinitis
• Bronchospasm
• Sinusitis
• Allergic alveolitis
• Eosinophilic pneumonia

Gastrointestinal Disorders

• Nausea and vomiting
• Constipation
• Diarrhoea
• Intestinal ulceration
• Abdominal pain 
• Indigestion
• Dry mouth
• Pancreatitis
• Intestinal angioedema

Hepatobiliary Disorders

• Cholestatic jaundice
• Pancreatitis
• Hepatitis
• Hepatic failure

Genitourinary Disorders

• Renal dysfunction
• Uraemia
• Acute renal failure
• Oliguria/anuria
• Impotence

Endocrine and Metabolic Disorders

• Hypochloraemic alkalosis
• Hyponatremia
• Hypokalaemia
• Hyperglycaemia
• Hyperuricaemia
• Gout
• Hypomagnesaemia
• Anorexia
• Hypoglycaemia
• Syndrome of inappropriate antidiuretic hormone secretion
• Gynaecomastia

Musculoskeletal Disorders

• Muscle pain
• Cramps

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity reactions
• Rash
• Pruritus
• Urticaria
• Alopecia
• Psoriasis
• Angioneurotic oedema
• Sweating
• Pemphigus
• Toxic epidermal necrolysis
• Stevens-Johnson Syndrome
• Erythema multiforme
• Cutaneous pseudolymphoma

Immune, Blood and Lymphatic System Disorders

• Thrombocytopaenia
• Granulocytopaenia
• Leucopenia
• Aplastic anaemia
• Haemolytic anaemia
• Decreases in haematocrit
• Bone marrow depression
• Neutropenia
• Agranulocytosis
• Lymphadenopathy
• Autoimmune disease

Sensory Disorders

• Dry mouth
• Thirst
• Yellow vision
• Taste disturbance

• Aliskiren-containing agents
• Sacubitril/valsartan
• Digoxin
• Neuromuscular blocking agents
• Colestyramine
• Colestipol
• Trimethoprim
• Sotalol
• Central nervous system depressants
• Amphotericin B
• Allopurinol 
• Procainamide 
• Agents that increase/decrease serum potassium 
• Lithium 
• Antihypertensive agents 
• Nitrates
• Ciclosporin
• Lovastatin
• Cytostatic agents
• Immunosuppressive agents
• Amantadine
• Non-steroidal anti-inflammatory drugs
• Gold
• Tricyclic antidepressants
• Antipsychotics
• Anaesthetic agents
• Sympathomimetics
• Antidiabetic agents
• Calcium salts

• Serum potassium
• Renal function

Specific cases may require

• Hepatic function
• Full blood count
• Serum glucose

Lisinopril
Lisinopril is a potent angiotensin-converting enzyme (ACE) inhibitor. This enzyme functions to convert angiotensin I to angiotensin II which is involved in vascular control and function through many different mechanisms, including stimulation of aldosterone secretion. By inhibiting the ACE, lisinopril thus prevents the downstream vasopressor activity and aldosterone secretion effected by angiotensin II.

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

Lisinopril/ Hydrochlorothiazide

Tablet 10mg/12.5mg 

• Adco-Zetomax Co (Adcock)
• Auro Lisinopril Co (Actor)
• Hexal-Lisinopril Co (Sandoz)
• Lisinopril Co Unicorn (Unicorn)
• Lisinozide (Novagen)
• Lisoretic (Pharma Dynamics)
• Lisozide (Austell)
• Zestoretic (AstraZeneca) originator

Tablet 20mg/12.5mg

• Adco-Zetomax Co (Adcock)
• Auro Lisinopril Co (Actor)
• Diace Co (Zydus)
• Hexal-Lisinopril Co (Sandoz)
• Lisinopril Co Unicorn (Unicorn)
• Lisinozide (Novagen)
• Lisoretic (Pharma Dynamics)
• Lisozide (Austell)
• Zestoretic (AstraZeneca) originator
• Zestozide (Xixia)