Angiotensin II antagonists (angiotensin II receptor antagonists) / thiazide diuretics (thiazides).

Losartan, hydrochlorothiazide

Cozaar Comp 50 mg/12.5 mg film-coated tablets Cozaar Comp 100 mg/12.5 mg film-coated tablets Cozaar Comp 100 mg/25 mg film-coated tablets

Film coated tablets Cozaar Comp 50 mg/12.5 mg Yellow, oval film-coated tablets marked 717 on one side and plain or scored on the other. The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses. Cozaar Comp 100 mg/12.5 mg White, oval film-coated tablets marked 745 on one side and plain on the other. Cozaar Comp 100 mg/25 mg Light yellow, oval film-coated tablets marked 747 on one side and plain on the other.

Cozaar Comp is indicated for the treatment of essential hypertension in patients whose blood pressure is not adequately controlled on losartan or hydrochlorothiazide alone.

Cozaar Comp may be administered with other antihypertensive agents.

Cozaar Comp tablets should be swallowed with a glass of water.

Cozaar Comp may be administered with or without food.

Hypertension

Losartan and hydrochlorothiazide is not for use as initial therapy, but in patients whose blood pressure is not adequately controlled by losartan potassium or hydrochlorothiazide alone.

Dose titration with the individual components (losartan and hydrochlorothiazide) is recommended.

When clinically appropriate, direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled.

The usual maintenance dose of Cozaar Comp is one tablet of Cozaar Comp 50 mg/12.5 mg (losartan 50 mg/HCTZ 12.5 mg) once daily. For patients who do not respond adequately to Cozaar Comp 50 mg/12.5 mg, the dosage may be increased to one tablet of Cozaar Comp 100 mg/25 mg (losartan 100 mg/ HCTZ 25 mg) once daily. The maximum dose is one tablet of Cozaar Comp 100 mg/25 mg once daily. In general, the antihypertensive effect is attained within three to four weeks after initiation of therapy. Cozaar Comp 100/12.5 (losartan 100 mg/ HCTZ 12.5 mg) is available for those patients titrated to 100 mg of Cozaar Comp who require additional blood pressure control.

Use in patients with renal impairment and haemodialysis patients

No initial dosage adjustment is necessary in patients with moderate renal impairment (i.e. creatinine clearance 30-50 ml/min). Losartan and hydrochlorothiazide tablets are not recommended for haemodialysis patients. Losartan/HCTZ tablets must not be used in patients with severe renal impairment (i.e. creatinine clearance <30 ml/min).

Use in patients with intravascular volume depletion

Volume and /or sodium depletion should be corrected prior to administration of Losartan/HCTZ tablets.

Use in patients with hepatic impairment

Losartan/HCTZ is contraindicated in patients with severe hepatic impairment.

Use in the elderly

Dosage adjustment is not usually necessary for the elderly.

Use in children and adolescents (< 18 years)

There is no experience in children and adolescents. Therefore, losartan/hydrochlorothiazide should not be administered to children and adolescents.

Not recommended.

• Hypersensitivity to losartan, sulphonamide-derived substances (as hydrochlorothiazide) or to any of the excipients
• Therapy resistant hypokalaemia or hypercalcaemia
• Severe hepatic impairment; Cholestasis and biliary obstructive disorders
• Refractory hyponatraemia
• Symtomatic hyperuricaemia/gout
• 2nd and 3rd trimester of pregnancy
• Lactation
• Severe renal impairment (i.e. creatinine clearance <30 ml/min)
• Anuria.

Losartan

Angiooedema

Patients with a history of angiooedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored.

Hypotension and Intravascular volume depletion

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Cozaar Comp tablets.

Electrolyte imbalances

Electrolyte imbalances are common in patients with renal impairment, with or without diabetes, and should be addressed. Therefore, the plasma concentrations of potassium and creatinine clearance values should be closely monitored; especially patients with heart failure and a creatinine clearance between 30-50 ml/ min should be closely monitored.

The concomitant use of potassium sparing diuretics, potassium supplements and potassium containing salt substitutes with losartan/ hydrochlorothiazide is not recommended.

Liver function impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, Cozaar Comp should be used with caution in patients with a history of mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore Cozaar Comp is contraindicated in patients with severe hepatic impairment.

Renal function impairment

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function, including renal failure, have been reported (in particular, in patients whose renal function is dependent on the renin-angiotensin-aldosterone system, such as those with severe cardiac insufficiency or pre-existing renal dysfunction).

As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Renal transplantation

There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism

Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Cozaar Comp tablets is not recommended.

Coronary heart disease and cerebrovascular disease:

As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.

Heart failure:

In patients with heart failure, with or without renal impairment, there is - as with other drugs acting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyophathy

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Ethnic differences

As observed for angiotensin converting enzyme inhibitors, losartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Pregnancy

Cozaar Comp should not be initiated during pregnancy. Unless continued Losartan/HTCZ 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 Cozaar Comp should be stopped immediately, and, if appropriate, alternative therapy should be started.

Hydrochlorothiazide

Hypotension and electrolyte/fluid imbalance

As with all antihypertensive therapy, symptomatic hypotension may occur in some patients. Patients should be observed for clinical signs of fluid or electrolyte imbalance, e.g., volume depletion, hyponatremia, hypochloremic alkalosis, hypomagnesemia or hypokalemia which may occur during intercurrent diarrhea or vomiting. Periodic determination of serum electrolytes should be performed at appropriate intervals in such patients. Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Metabolic and endocrine effects

Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Thiazide therapy may precipitate hyperuricemia and/or gout in certain patients. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as it may cause intrahepatic cholestasis, and since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Cozaar Comp is contraindicated for patients with severe hepatic impairment.

Other

In patients receiving thiazides, 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.

Excipient

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Losartan

Rifampicin and fluconazole have been reported to reduce levels of active metabolite. The clinical consequences of these interactions have not been evaluated.

As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. Co-medication is not advisable.

As with other medicines which affect the excretion of sodium, lithium excretion may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be co-administered with angiotensin II receptor antagonists.

When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses) and non-selective NSAIDs, attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists may result in a further deterioration of renal function. These effects are usually reversible.

Other substances inducing hypotension like tricyclic antidepressants, antipsychotics, baclofene, amifostine: Concomitant use with these drugs that lower blood pressure, as main or side-effect, may increase the risk of hypotension.

Hydrochlorothiazide

When given concurrently, the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, narcotics or antidepressants:

Potentiation of orthostatic hypotension may occur.

Antidiabetic drugs (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic drug may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Other antihypertensive drugs

Additive effect.

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 percent, respectively.

Corticosteroids, ACTH

Intensified electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., adrenaline)

Possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine)

Possible increased responsiveness to the muscle relaxant.

Lithium

Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity; concomitant use is not recommended.

Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)

Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g. atropine, biperiden)

Increase of the bioavailability to thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Cytotoxic agents (eg cyclophosphamide, methotrexate)

Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

Salicylates

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Ciclosporin

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

Medicinal products affected by serum potassium disturbances

Periodic monitoring of serum potassium and ECG is recommended when Losartan/hydrochlorothiazide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):

• Class Ia antiarrythmics (eg quinidine, hydroquinidine, disopyramide).
• Class III antiarrythmics (eg amiodarone, sotalol, dofetilide, ibutilide).
• Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
• Others (eg bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, terfenadine, vincamine IV).

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage should be adjusted accordingly.

Laboratory Test Interactions

Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function.

Carbamazepine

Risk of symptomatic hyponatremia. Clinical and biological monitoring is required.

Iodine Contrast Media

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of the iodine product.

Patients should be rehydrated before the administration.

Amphotericin B (parenteral), corticosteroids, ACTH or stimulant laxatives

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

The adverse events below are classified where appropriate by system organ class and frequency according to the following convention:

Very common: 1/10

Common: 1/100, < 1/10

Uncommon: 1/1,000, 1/100

Rare: 1/10,000, 1/1,000

Very rare: 1/10,000

Not known: 1/10,000

(cannot be estimated from the available data)

In clinical trials with losartan potassium salt and hydrochlorothiazide, no adverse events peculiar to this combination of substances were observed. The adverse events were restricted to those which were formerly observed with losartan potassium salt and/or hydrochlorothiazide.

In controlled clinical trials for essential hypertension, dizziness was the only adverse experience reported as substance-related that occurred with an incidence greater than placebo in 1% or more of patients treated with losartan and hydrochlorothiazide.

Next to these effects, there are further adverse reactions reported after the introduction of the product to the market as follows:

Hepato-biliary disorders

Rare: Hepatitis

Investigations

Rare: Hyperkalaemia, elevation of ALT

Additional adverse events that have been seen with one of the individual components and may be potential adverse events with losartan potassium/ hydrochlorothiazide are the following:

Losartan

Blood and lymphatic system disorders

Uncommon: Anaemia, Henoch-Schönlein purpura, ecchymosis, haemolysis

Immune system disorders

Rare: Anaphylactic reactions, angioedema, urticaria

Metabolism and nutrition disorders

Uncommon: Anorexia, gou

Psychiatric disorders

Common: Insomnia

Uncommon: Anxiety, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorder, somnolence, memory impairment

Nervous system disorders

Common: Headache, dizziness

Uncommon: Nervousness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope

Eye disorders

Uncommon: Blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity

Ear and labyrinth disorders

Uncommon: Vertigo, tinnitus

Cardiac disorders

Uncommon: Hypotension, orthostatic hypotension, sternalgia, angina pectoris, grade II-AV block, cerebrovascular event, myocardial infarction, palpitation, arrhythmias (atrial fibrillations, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation)

Vascular disorders

Uncommon: Vasculitis

Respiratory, thoracic and mediastinal disorders

Common: Cough, upper respiratory infection, nasal congestion, sinusitis, sinus disorder

Uncommon: Pharyngeal discomfort, pharyngitis, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion

Gastrointestinal disorders

Common: Abdominal pain, nausea, diarrhoea, dyspepsia

Uncommon: Constipation, dental pain, dry mouth, flatulence, gastritis, vomiting

Hepato-biliary disorders

Not known: Liver function abnormalities

Skin and subcutaneous tissue disorders

Uncommon: Alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritus, rash, urticaria, sweating

Musculoseletal and connective tissue disorders

Common: Muscle cramp, back pain, leg pain, myalgia

Uncommon: Arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness

Renal and urinary disorders

Uncommon: Nocturia, urinary frequency, urinary tract infection

Reproductive system and breast disorders

Uncommon: Decreased libido, impotence

General disorders and administration site conditions

Common: Asthenia, fatigue, chest pain

Uncommon: Facial oedema, fever

Investigations

Common: Hyperkalaemia, mild reduction of haematocrit and haemoglobin

Uncommon: Mild increase in urea and creatinine serum levels

Very rare: Increase in hepatic enzymes and bilirubin.

Hydrochlorothiazide

Blood and lymphatic system disorders

Uncommon: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leukopenia, purpura, thrombocytopenia

Immune system disorders

Rare: Anaphylactic reaction

Metabolism and nutrition disorders

Uncommon: Anorexia, hyperglycaemia, hyperuricaemia, hypokalaemia, hyponatraemia

Psychiatric disorders

Uncommon: Insomnia

Nervous system disorders

Common: Cephalalgia

Eye disorders

Uncommon: Transient blurred vision, xanthopsia

Vascular disorders

Uncommon: Necrotising angiitis (vasculitis, cutaneous vasculitis)

Respiratory, thoracic and mediastinal disorders

Uncommon: Respiratory distress including pneumonitis and pulmonary oedema

Gastrointestinal disorders

Uncommon: Sialoadenitis, spasms, stomach irritation, nausea, vomiting, diarrhoea, constipation

Hepato-biliary disorders

Uncommon: Icterus (intrahepatic cholestatis), pancreatitis

Skin and subcutaneous tissue disorders

Uncommon: Photosensitivity, urticaria, toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Uncommon: Muscle cramps

Renal and urinary disorders

Uncommon: Glycosuria, interstitial nephritis, renal dysfunction, renal failure

General disorders and administration site conditions

Uncommon: Fever, dizziness

Merck Sharp & Dohme Limited

(POM)