Losartan/ Hydrochlorothiazide

Registered South African indications:

• Hypertension

Should a woman become pregnant while receiving losartan/hydrochlorothiazide, the treatment should 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 medicine (when given in combination with thiazide diuretics as with losartan/hydrochlorothiazide)
• Pregnancy
• Lactation
• Severe renal function impairment (CrCl<30ml/min)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic stenosis
• Severe hepatic impairment; cholestasis and biliary obstructive disorders
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs)
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Porphyria
• Thiazide diuretics in (fixed dose) combination as with losartan/hydrochlorothiazide, should not be given to patients with Addison's disease
• Anuria or severe renal impairment
• Therapy resistant hypokalaemia or hypercalcaemia
• Refractory hyponatraemia
• Symptomatic hyperuricaemia/gout
• The concomitant use of losartan/hydrochlorothiazide with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73 m²)
• Concomitant therapy with potassium-sparing diuretics such as spironolactone, triamterene, amiloride
• Coadministration with lithium

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Hypersensitivity to other sulphonamide-derived medicine
• Therapy resistant hypokalaemia or hypercalcaemia
• Severe hepatic impairment; cholestasis and biliary obstructive disorders
• Refractory hyponatraemia
• Symptomatic hyperuricaemia/gout
• 2nd and 3rd trimesters of pregnancy
• Severe renal impairment (CrCl<30ml/min)
• Anuria
• The concomitant use of losartan/hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73 m²)

• Pregnancy 1st trimester (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Renal impairment (CrCl≥30ml/min)
• Mild to moderate hepatic impairment
• Elderly
• History of angioedema 
• Hypotension in volume-depleted patients 
• Primary aldosteronism 
• Heart failure 
• Coronary heart disease
• Cerebrovascular disease
• Fixed cardiac output states
• Black patients
• Diabetes mellitus
• Dual blockade of the renin-angiotensin-aldosterone system
• Renal artery stenosis
• Asthma
• Systemic lupus erythematosus
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

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

South African registered indications and dosages

Hypertension
- In in patients established on identical doses of the individual medicines

Losartan/ Hydrochlorothiazide

• Oral (fct, tab): Usual starting dose: 50/12.5mg tab, once daily; For those not responding adequately, may be increased to one 100/25mg tab, once daily; Max: 100/25mg tab/24hrs

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The losartan/ hydrochlorothiazide 100/12.5mg tablet is available for those patients titrated to 100mg of losartan who require additional blood pressure control

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The maximum antihypertensive effect is attained within three weeks after initiation of therapy

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Losartan/ hydrochlorothiazide may be administered with other antihypertensive agents such as calcium channel blockers and beta-blockers

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Losartan/ hydrochlorothiazide should not be initiated in patients who are intravascularly volume-depleted (e.g., those treated with high-dose diuretics)

Not established for use in children and adolescents

Pregnancy

South African recommendations

• Contraindicated
• Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 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 AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started
• Women of childbearing age should ensure adequate barrier contraception
• When pregnancy is planned or confirmed, losartan/ hydrochlorothiazide should be discontinued
• Medicines affecting the renin-angiotensin system, such as losartan/hydrochlorothiazide, can cause foetal and neonatal morbidity and mortality when administered to pregnant women

Recommendations in other jurisdictions

• Caution; not recommended: 1st trimester
• Contraindicated: 2nd and 3rd trimester
• The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the 2nd and 3rd trimester of pregnancy
• 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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II Receptor Inhibitors (AIIRAs), similar risks may exist for this class of medicines. Unless continued ARB therapy is considered essential, 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 AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started
• Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).  Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken AIIRAs 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 second and third trimesters 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 essential hypertension in pregnant women except in rare situations where no other treatment could be used

Breastfeeding

South African recommendations

• Contraindicated
• Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. Women taking losartan/hydrochlorothiazide should not breastfeed their infants

Recommendations in other jurisdictions

• Caution; not recommended
• Angiotensin II Receptor Antagonists (AIIRAs): Because no information is available regarding the use of losartan/ hydrochlorothiazide during breastfeeding, losartan/ 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 is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of losartan/ hydrochlorothiazide during breastfeeding is not recommended. If losartan/ hydrochlorothiazide is used during breastfeeding, doses should be kept as low as possible

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• No information available

South African recommendations

• CrCl≥30ml/min: Caution; no dose adjustment recommended
• CrCl<30ml/min: Contraindicated
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated

Recommendations in other jurisdictions

• CrCl≥30ml/min: Caution; no dose adjustment recommended
• CrCl<30ml/min: Contraindicated
• Haemodialysis: Caution; not recommended
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated

South African recommendations

• Mild to moderate: Caution; not recommended
• Severe: Contraindicated

Recommendations in other jurisdictions

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

South African recommendations

• Caution; no dose adjustment recommended
  Losartan/hydrochlorothiazide should not be used as initial therapy in elderly patients

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended

Central Nervous System Disorders 

• Depression
• Dizziness
• Somnolence
• Sleep disorders
• Paraesthesia
• Migraine
• Insomnia
• Dysgeusia
• Malaise
• Fatigue
• Weakness
• Restlessness
• Seizures
• Headache

Cardiovascular Disorders 

• Palpitations
• Angina pectoris
• Syncope
• Atrial fibrillation
• Cerebrovascular accident
• Orthostatic hypotension

Respiratory Disorders

• Dyspnoea
• Cough

Gastrointestinal Disorders 

• Abdominal pain
• Obstipation
• Diarrhoea
• Nausea and vomiting
• Dyspepsia
• Intestinal ulceration

Hepatobiliary Disorders 

• Pancreatitis
• Hepatitis
• Liver function abnormalities
• Cholestatic jaundice

Genitourinary Disorders 

• Renal failure
• Erectile dysfunction
• Oliguria

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Hypoglycaemia
• Hypochloraemic alkalosis
• Hyponatremia
• Hypokalaemia
• Hyperglycaemia
• Hyperuricaemia
• Gout
• Hypomagnesaemia
• Anorexia

Musculoskeletal Disorders 

• Myalgia
• Arthralgia
• Rhabdomyolysis
• Cramps

Skin and Subcutaneous Tissue Disorders 

• Urticaria
• Pruritus
• Rash
• Photosensitivity

Immune, Blood and Lymphatic System Disorders 

• Thrombocytopenia
• Hypersensitivity reactions
• Anaphylactic reactions
• Angioedema
• Vasculitis
• Granulocytopenia
• Leucopenia
• Aplastic anaemia
• Haemolytic anaemia

Sensory Disorders  

• Visual disturbance
• Tinnitus
• Dry mouth
• Thirst
• Yellow vision

• Aliskiren-containing products
• Spironolactone
• Triamterene
• Amiloride
• Rifampicin
• Fluconazole
• Lithium
• Potassium supplements
• Potassium sparing diuretics
• Non-steroidal anti-inflammatory drugs
• Angiotension-converting enzyme inhibitors
• Tricyclic antidepressants
• Antipsychotics
• Baclofen
• Amifostine
• Central nervous system depressants
• Antidiabetic agents
• Antihypertensive agents
• Cholestyramine
• Colestipol
• Adrenaline
• Digoxin
• Neuromuscular blocking agents
• Corticosteroids
• Corticotrophin
• Probenecid
• Sulfinpyrazone
• Allopurinol
• Atropine
• Biperiden
• Methotrexate
• Cyclophosphamide
• Salicylates
• Methyldopa
• Cyclosporin
• Calcium salts
• Carbamazepine
• Iodine contrast media
• Amphotericin B 
• Stimulant laxatives

• Serum potassium
• Renal function

None routine. Specific cases may require

• Hepatic function 
• ECG

Losartan
Losartan selectively binds to the angiotensin II AT receptors found in the vascular smooth muscle, adrenal gland, kidneys and the heart; this inhibits vasoconstriction and aldosterone secretion which results in a decrease in vascular resistance and blood pressure 

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

Losartan/ Hydrochlorothiazide

Tablet 50mg/12.5mg 

• Austell Losartan Co (Austell)
• Co-normoten (Trinity)
• Cozaar Comp (MSD) originator
• Hytenza Co fct (Abex)
• Lohype Plus (Ranbaxy)
• Losaar Plus (Accord)
• Losacar Co (Zydus)
• Losartan Co Unicorn (Ranbaxy)
• Lozaan Co (Thebe)
• Losartan Comp Biotech 50/12,5 (Biotech Lab)
• Netrasol Co (Specpharm)
• Sartoc Co (Pharmacare)
• Zartan Co (Pharma Dynamics)

Losartan/ Hydrochlorothiazide

Tablet 100mg/12.5mg

• Cozaar Comp (MSD) originator

Losartan/ Hydrochlorothiazide

Tablet 100mg/25mg

• Co-normoten (Trinity)
• Fortzaar (Organon) originator
• Hytenza Co fct (Abex)
• Lohype Plus (Ranbaxy)
• Losaar Plus (Accord)
• Losartan Co Unicorn (Ranbaxy)
• Losartan Comp Biotech 100/25 (Biotech Lab)
• Lozaan Co (Thebe)
• Netrasol Co (Specpharm)
• Sartoc Co 100/25 (Pharmacare)
• Zartan Co (Pharma Dynamics)