Cozaar Comp 50 mg/12,5 mg/100 mg Tablets

COZAAR COMP is indicated for the treatment of hypertension in patients established on identical doses of the individual medicines.

The usual starting and maintenance dose of COZAAR COMP is one tablet of COZAAR COMP 50/12,5 (losartan 50 mg/hydrochlorothiazide 12,5 mg) once daily. For patients who do not respond adequately to COZAAR COMP 50/12,5 the dosage may be increased to two tablets of COZAAR COMP 50/12,5 once daily. The maximum dose is two tablets of COZAAR COMP 50/12,5 once daily. The maximum antihypertensive effect is attained within three weeks after initiation of therapy. COZAAR COMP 100/12,5 is available for those patients titrated to 100 mg of COZAAR who require additional blood pressure control. COZAAR COMP should not be initiated in patients who are intravascularly volume-depleted (e.g. those treated with high-dose diuretics). COZAAR COMP is not recommended for patients with severe renal impairment or for patients with hepatic impairment (see WARNINGS AND SPECIAL PRECAUTIONS and CONTRAINDICATIONS). No initial dosage adjustment of COZAAR COMP is necessary for elderly patients. A higher dose (100 mg losartan potassium and 25 mg hydrochlorothiazide) should not be used as initial therapy in elderly patients. COZAAR COMP may be administered with other antihypertensive agents, particularly calcium channel blockers and beta-blockers. COZAAR COMP may be administered with or without food.

• Hypersensitivity to losartan or hydrochlorothiazide or any of the components of COZAAR COMP.
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance < 30 ml/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see INTERACTIONS).
• Porphyria.
• Hydrochlorothiazide in combination with COZAAR COMP should not be given to patients with Addison's disease.
• COZAAR COMP is also contraindicated in patients with anuria, and hypersensitivity to other sulphonamide-derived medicines.
• Lithium therapy: Concomitant administration with COZAAR COMP may lead to toxic blood concentrations of lithium.
• Pregnancy and lactation (see PREGNANCY AND LACTATION).
• Use of medicines that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces foetal renal function and increases foetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with foetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure and death. When pregnancy is detected, discontinue COZAAR COMP as soon as possible (see PREGNANCY AND LACTATION).
• Hepatic impairment.
• The concomitant use of COZAAR COMP with aliskiren-containing products is contraindicated (see WARNINGS AND SPECIAL PRECAUTIONS and INTERACTIONS).

Should a woman become pregnant while receiving COZAAR COMP, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see CONTRAINDICATIONS and PREGNANCY AND LACTATION).

Hypersensitivity: Angioedema (see SIDE EFFECTS).

Hepatic and renal impairment: COZAAR COMP is not recommended for patients with hepatic impairment or severe renal impairment (see DOSAGE AND DIRECTIONS FOR USE and CONTRAINDICATIONS).

As a consequence of inhibiting the renin-angiotensin system, changes in renal function including renal failure have been reported. These changes in renal function may not be reversible upon discontinuation of therapy. COZAAR COMP may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney (see CONTRAINDICATIONS).

Increases in serum potassium: Concomitant use of other drugs that may increase serum potassium may lead to hyperkalaemia (see INTERACTIONS).

Hypotension and electrolyte/fluid imbalance: In patients who are intravascularly volume-depleted (e.g. those treated with high-dose diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of COZAAR COMP or a lower starting dose should be used (see DOSAGE AND DIRECTIONS FOR USE). Periodic determination of serum electrolytes should be performed at appropriate intervals.

Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see INTERACTIONS). Hydrochlorothiazide as in COZAAR COMP may decrease urinary calcium excretion and may cause an elevation of serum calcium. Marked hypercalcaemia may be evidence of occult hyperparathyroidism. COZAAR COMP should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with hydrochlorothiazide therapy. COZAAR COMP may precipitate hyperuricaemia and/or gout in certain patients.

Concomitant use with Lithium: Concomitant administration of lithium with COZAAR COMP may lead to toxic blood concentrations of lithium (see CONTRAINDICATIONS).

Other: In patients receiving hydrochlorothiazide as in COZAAR COMP, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazides.

Paediatric Use: Safety and efficacy in children has not been established.

Dual blockade of renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE inhibitors, ARBs or aliskiren may increase the risk of hypotension, hyperkalaemia and decrease renal function (including acute renal failure). Dual blockade of RAAS through the combined use of COZAAR COMP and aliskiren is therefore not recommended. COZAAR COMP should not be used concomitantly with aliskiren (see CONTRAINDICATIONS).

Losartan potassium: In clinical pharmacokinetic trials no interactions of clinical significance have been identified with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbitone (see Hydrochlorothiazide, Alcohol, barbiturates or narcotics below), ketoconazole and erythromycin. Rifampin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.

Concomitant use of medicines that block angiotensin II or its effects and potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium (e.g. trimethoprim-containing products) may lead to increases in serum potassium.

Lithium excretion may be reduced (see CONTRAINDICATIONS).

Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive medicines. Therefore, the antihypertensive effect of COZAAR COMP may be attenuated by NSAIDs including selective COX-2 inhibitors. In some patients with compromised renal function (e.g. elderly patients or patients who are volume-depleted, including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of COZAAR COMP may result in a further deterioration of renal function, including possible acute renal failure. Therefore, the combination should be administered with caution in patients with compromised renal function.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin receptor blockers such as COZAAR COMP, ACE inhibitors and/or aliskiren is associated with increased risks of hypotension, syncope, hyperkalaemia and changes in renal function (including acute renal failure) compared to monotherapy. Do not co-administer aliskiren with COZAAR COMP in patients with diabetes. Avoid use of aliskiren with COZAAR COMP in patients with renal impairment (GFR < 60 ml/min) (see CONTRAINDICATIONS and WARNINGS AND SPECIAL PRECAUTIONS).

Hydrochlorothiazide: When administered concurrently the following medication may interact with thiazide diuretics: Alcohol, barbiturates or narcotics: Potentiation of orthostatic hypotension may occur. Antidiabetic medicines (oral medicines and insulin): Dosage adjustment of the antidiabetic medicine may be required. Other antihypertensive medicines: Additive effect or potentiation. Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 %, respectively. COZAAR COMP should therefore be administered one hour before the intake of the resin. Corticosteroids, ACTH or glycyrrhizin (found in liquorice): Intensified electrolyte depletion, particularly hypokalaemia. Pressor amines (e.g. norepinephrine): Possible decreased response to pressor amines but not sufficient to preclude their use. Skeletal muscle relaxants, nondepolarising (e.g. pancuronium): Possible increased responsiveness to the muscle relaxant. Lithium: Should not be given with COZAAR COMP (see CONTRAINDICATIONS). Non-steroidal anti-inflammatory drugs including cyclooxygenase-2 inhibitors: The administration of a non-steroidal anti-inflammatory agent including a selective cyclooxygenase-2 inhibitor can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.

The use of COZAAR COMP is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take COZAAR COMP during pregnancy (see CONTRAINDICATIONS). 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 COZAAR COMP 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. COZAAR COMP 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 newborns, have been reported after administration of COZAAR COMP during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur (see CONTRAINDICATIONS).

Safety in pregnancy and lactation has not been established (see CONTRAINDICATIONS). When pregnancy is planned or confirmed COZAAR COMP should be discontinued. Medicines affecting the renin-angiotensin system, such as COZAAR COMP, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered to pregnant women. Women of childbearing age should ensure effective contraception. Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and foetus to unnecessary hazard including foetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions which have occurred in the adult. Diuretics do not prevent development of toxaemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxaemia.

Women of childbearing age should ensure adequate contraception. Lactation: Safety in breastfeeding has not been established. Thiazides appear in human milk.

There are no data to suggest that COZAAR COMP affects the ability to drive and use machines.

In controlled clinical trials for essential hypertension, the following adverse experiences were reported in patients treated with COZAAR COMP and are shown in decreasing order of frequency within body system: Very common (u2265 1/10), common (u2265 1/100, < 1/10), uncommon (u2265 1/1000, < 1/100); rare (u2265 1/10 000, < 1/1000); very rare (< 1/10 000), including isolated reports.

Nervous system disorders: Common: dizziness. General disorders and administration site conditions: Common: asthenia/fatigue.

Losartan Potassium: In controlled clinical trials for essential hypertension, the following adverse experiences were reported in patients treated with losartan potassium and are shown in decreasing order of frequency within body system: Very common (u2265 1/10), common (u2265 1/100, < 1/10), uncommon (u2265 1/1000, < 1/100); rare (u2265 1/10 000, < 1/1000); very rare (< 1/10 000), including isolated reports.

Psychiatric disorders: Common: insomnia. Nervous system disorders: Very common: headache. Common: dizziness. Cardiac disorders: Common: palpitation, tachycardia. Vascular disorders: Uncommon: orthostatic hypotension. Respiratory, thoracic and mediastinal disorders: Common: cough, pharyngitis, nasal congestion, sinus disorder, upper respiratory infection. Gastrointestinal disorder: Common: diarrhoea, nausea, abdominal pain, dyspepsia. Skin and subcutaneous tissue disorders: Uncommon: rash. Musculoskeletal, connective tissue and bone disorders: Common: back pain, muscle cramps. Reproductive system and breast disorders: Erectile dysfunction/impotence. General disorders and administration site conditions: Common: asthenia/fatigue, oedema/swelling, chest pain. Investigations: Common: hyperkalaemia, elevations of ALT.

Hydrochlorothiazide: In controlled clinical trials for essential hypertension, the following adverse experiences were reported in patients treated with hydrochlorothiazide and are shown in decreasing order of frequency within body system: Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: Very common (u2265 1/10), common (u2265 1/100, < 1/10), uncommon (u2265 1/1000, < 1/100); rare (u2265 1/10 000, < 1/1000); very rare (< 1/10 000), including isolated reports.

Blood and the lymphatic system disorders: Rare: thrombocytopenia. Very rare: leukopenia, agranulocytosis, haemolytic anaemia. Metabolic and nutrition disorders: Uncommon: anorexia, hyperuricaemia. Rare: hyperglycaemia. Nervous system disorders: Rare: paraesthesia, headache. Vascular disorders: Uncommon: hypotension, (including orthostatic hypotension). Respiratory, thoracic and mediastinal disorders: Very rare: respiratory distress including pneumonitis and pulmonary oedema. Gastrointestinal disorders: Uncommon: nausea, vomiting. Rare: diarrhoea, constipation. Very rare: pancreatitis. Hepatobiliary disorders: Rare: jaundice (intrahepatic cholestatic jaundice). Skin and subcutaneous tissue disorders: Uncommon: rash, urticaria. Rare: photosensitivity. Very rare: necrotising angiitis (vasculitis and cutaneous vasculitis).

Renal and urinary disorders: Rare: glycosuria.

Post-marketing data: Blood and the lymphatic system disorders: Aplastic anaemia, thrombocytopenia. Immune system disorders: Anaphylactic reactions, angioedema including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx and/or tongue have been reported rarely in patients treated with losartan; some of these patients previously experienced angioedema with other medicines including ACE inhibitors. Metabolic and nutrition disorders: Electrolyte imbalance including hyponatraemia and hypokalaemia. Psychiatric disorders: Restlessness. Nervous system disorders: Dysgeusia (reported with losartan). Eye disorders: Xanthopsia, transient blurred vision. Ear and labyrinth disorders: Vertigo. Vascular disorders: Hypotension, vasculitis, including Henoch-Schoenlein purpura. Respiratory, thoracic and mediastinal disorders: Cough. Gastrointestinal disorders: Gastric irritation, sialoadenitis, diarrhoea, vomiting. Hepatobiliary disorders: Hepatitis. Skin and subcutaneous tissue disorders: Purpura (including Henoch-Schoenlein purpura), pruritus, toxic epidermal necrolysis, cutaneous lupus erythematosus, urticaria, erythroderma have been reported with losartan, photosensitivity. Musculoskeletal, connective tissue and bone disorders: Cramping, muscle spasm, myalgia, arthralgia (reported with losartan). Renal and urinary disorders: Renal dysfunction, interstitial nephritis, renal failure. General disorders and administration site conditions: Fever, weakness, malaise. Investigations: Liver function abnormalities.

Losartan potassium: Limited data are available in regard to overdosage in humans. The most likely manifestation of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor the active metabolite can be removed by haemodialysis.

Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digoxin has also been administered, hypokalaemia may accentuate cardiac dysrhythmias. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.