This information is intended for use by health professionals

1. Name of the medicinal product

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

2. Qualitative and quantitative composition

Cozaar Comp 50 mg/12.5 mg

Each tablet contains 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide (HCTZ).

Cozaar Comp 100 mg/12.5 mg

Each tablet contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide (HCTZ).

Cozaar Comp 100 mg/25 mg

Each tablet contains 100 mg of losartan potassium and 25 mg of hydrochlorothiazide (HCTZ).

Cozaar Comp 50 mg/12.5 mg: each tablet contains 63.13 mg lactose monohydrate.

Cozaar Comp 100 mg/12.5 mg: each tablet contains 88.40 mg lactose monohydrate.

Cozaar Comp 100 mg/25 mg: each tablet contains 126.26 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film coated tablet

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 score line is not intended for breaking the tablet.

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.

4. Clinical particulars
4.1 Therapeutic indications

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

4.2 Posology and method of administration

Posology

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 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) (see section 4.3).

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 (see section 4.3).

Use in the elderly

Dosage adjustment is not usually necessary for the elderly.

Paediatric population

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.

Method of administration

Cozaar Comp may be administered with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).

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

Cozaar Comp may be administered with or without food.

4.3 Contraindications

• Hypersensitivity to losartan, sulphonamide-derived substances (as hydrochlorothiazide) or to any of the excipients listed in section 6.1;

• Therapy resistant hypokalaemia or hypercalcaemia;

• Severe hepatic impairment; cholestasis and biliary obstructive disorders;

• Refractory hyponatraemia;

• Symptomatic hyperuricaemia/gout;

• 2nd and 3rd trimesters of pregnancy (see sections 4.4 and 4.6);

• Severe renal impairment (i.e. creatinine clearance <30 ml/min);

• Anuria;

• The concomitant use of Cozaar Comp with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Losartan

Angioedema

Patients with a history of angioedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored (see section 4.8).

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 (see sections 4.2 and 4.3).

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, potassium containing salt substitutes, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) with losartan/hydrochlorothiazide is not recommended (see section 4.5).

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 (see sections 4.2, 4.3 and 5.2).

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 cardiomyopathy

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

AIIRAs should not be initiated during pregnancy. Unless continued AIIRA 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 AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia, and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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 diarrhoea 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 (see section 4.5). 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 (see section 4.3 and 5.2).

Non-melanoma skin cancer

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of hydrochlorothiazide could act as a possible mechanism for NMSC.

Patients taking hydrochlorothiazide should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of hydrochlorothiazide may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

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

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

4.5 Interaction with other medicinal products and other forms of interaction

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, salt substitutes containing potassium, or other drugs that may increase serum potassium (e.g., trimethoprim-containing products) 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.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia, and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4, and 5.1).

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 (e.g. 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.

Cyclosporin

Concomitant treatment with cyclosporin 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 (e.g. quinidine, hydroquinidine, disopyramide).

• Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

• Others (e.g. 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 (see section 4.4).

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, stimulant laxatives, or glycyrrhizin (found in liquorice)

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

4.6 Fertility, pregnancy and lactation

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs):

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the 2nd and 3rd trimesters of pregnancy (see sections 4.3 and 4.4).

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 drugs. Unless continued AIIRA 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 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 foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

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 (see sections 4.3 and 4.4).

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 thrombocytopaenia.

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

Angiotensin II Receptor Antagonists (AIIRAs):

Because no information is available regarding the use of Cozaar Comp during breastfeeding, Cozaar Comp is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a new-born 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 Cozaar Comp during breastfeeding is not recommended. If Cozaar Comp is used during breastfeeding, doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

No studies on the reactions on the ability to drive and use machines have been performed. However, when driving vehicles or operating machinery it must be borne in mind that dizziness or drowsiness may occasionally occur when taking antihypertensive therapy, in particular during initiation of treatment or when the dose is increased.

4.8 Undesirable effects

The adverse reactions 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 (cannot be estimated from the available data).

In clinical trials with losartan potassium salt and hydrochlorothiazide, no adverse reactions peculiar to this combination of substances were observed. The adverse reactions 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 reaction 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:

System organ class

Adverse reaction

Frequency

Hepato-biliary disorders

hepatitis

rare

Investigations

hyperkalaemia, elevation of ALT

rare

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

Losartan:

The following adverse reactions have been reported for losartan in clinical studies and in post-marketing experience:

System organ class

Adverse reaction

Frequency

Blood and lymphatic system disorders

anaemia, Henoch-Schönlein purpura, ecchymosis, haemolysis

uncommon

thrombocytopaenia

not known

Cardiac disorders

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)

uncommon

Ear and labyrinth disorders

vertigo, tinnitus

uncommon

Eye disorders

blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity

uncommon

Gastrointestinal disorders

abdominal pain, nausea, diarrhea, dyspepsia

common

constipation, dental pain, dry mouth, flatulence, gastritis, vomiting, obstipation

uncommon

pancreatitis

not known

General disorders and administration site conditions

asthenia, fatigue, chest pain

common

facial oedema, oedema, fever

uncommon

flu-like symptoms, malaise

not known

Hepatobiliary disorders

liver function abnormalities

not known

Immune system disorders

hypersensitivity: anaphylactic reactions, angioedema including swelling of the larynx and glottis causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue; in some of these patients angioedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors;

rare

Metabolism and nutrition disorders

anorexia, gout

uncommon

Musculoskeletal and connective tissue disorders

muscle cramp, back pain, leg pain, myalgia

common

arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness

uncommon

rhabdomyolysis

not known

Nervous system disorders

headache, dizziness

common

nervousness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope

uncommon

dysgeusia

not known

Psychiatric disorders

insomnia

common

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

uncommon

Renal and urinary disorders

renal impairment, renal failure

common

nocturia, urinary frequency, urinary tract infection

uncommon

Reproductive system and breast disorders

decreased libido, erectile dysfunction/impotence

uncommon

Respiratory, thoracic and mediastinal disorders

cough, upper respiratory infection, nasal congestion, sinusitis, sinus disorder

common

pharyngeal discomfort, pharyngitis, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion

uncommon

Skin and subcutaneous tissue disorders

alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritus, rash, urticaria, sweating

uncommon

Vascular disorders

vasculitis

uncommon

dose-related orthostatic effects

not known

Investigations

hyperkalaemia, mild reduction of haematocrit and haemoglobin, hypoglycaemia

common

mild increase in urea and creatinine serum levels

uncommon

increase in hepatic enzymes and bilirubin

very rare

hyponatraemia

non known

Hydrochlorothiazide

System organ class

Adverse reaction

Frequency

Blood and lymphatic system disorders

agranulocytosis, aplastic anaemia, haemolytic anaemia, leukopenia, purpura, thrombocytopaenia

uncommon

Immune system disorders

anaphylactic reaction

rare

Metabolism and nutrition disorders

anorexia, hyperglycaemia, hyperuricaemia, hypokalaemia, hyponatraemia

uncommon

Psychiatric disorders

insomnia

uncommon

Nervous system disorders

cephalalgia

common

Eye disorders

transient blurred vision, xanthopsia

uncommon

Vascular disorders

necrotizing angiitis (vasculitis, cutaneous vasculitis)

uncommon

Respiratory, thoracic and mediastinal disorders

respiratory distress including pneumonitis and pulmonary oedema

uncommon

Gastrointestinal disorders

sialoadenitis, spasms, stomach irritation, nausea, vomiting, diarrhoea, constipation

uncommon

Hepato-biliary disorders

icterus (intrahepatic cholestasis), pancreatitis

uncommon

Skin and subcutaneous tissue disorders

photosensitivity, urticaria, toxic epidermal necrolysis

uncommon

cutaneous lupus erythematosus

not known

Musculoskeletal and connective tissue disorders

muscle cramps

uncommon

Neoplasms benign, malignant and unspecified (incl. cysts and polyps)

Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma)

not known

Renal and urinary disorders

glycosuria, interstitial nephritis, renal dysfunction, renal failure

uncommon

General disorders and administration site conditions

fever, dizziness

uncommon

Description of Selected Adverse Reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose dependent association between hydrochlorothiazide and NMSC has been observed (see also sections 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

No specific information is available on the treatment of overdose with Cozaar Comp. Treatment is symptomatic and supportive. Therapy with Cozaar Comp should be discontinued and the patient observed closely. Suggested measures include induction of emesis if ingestion is recent, and correction of dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.

Losartan

Limited data are available in regard to overdose in humans. The most likely manifestation of overdose 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 (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, ATC code: C09DA01

Losartan-Hydrochlorothiazide

The components of Cozaar Comp have been shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone. This effect is thought to be a result of the complimentary actions of both components. Further, as a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, decreases serum potassium, and increases the levels of angiotensin II. Administration of losartan blocks all the physiologically relevant actions of angiotensin II and through inhibition of aldosterone could tend to attenuate the potassium loss associated with the diuretic.

Losartan has been shown to have a mild and transient uricosuric effect. Hydrochlorothiazide has been shown to cause modest increases in uric acid; the combination of losartan and hydrochlorothiazide tends to attenuate the diuretic-induced hyperuricemia.

The antihypertensive effect of Cozaar Comp is sustained for a 24-hour period. In clinical studies of at least one year's duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of Cozaar Comp had no clinically significant effect on heart rate. In clinical trials, after 12 weeks of therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg, trough sitting diastolic blood pressure was reduced by an average of up to 13.2 mmHg.

Cozaar Comp is effective in reducing blood pressure in males and females, blacks and non-blacks and in younger (<65 years) and older (≥65 years) patients and is effective in all degrees of hypertension.

Losartan

Losartan is a synthetically produced oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. Angiotensin II also stimulates smooth-muscle cell proliferation.

Losartan selectively blocks the AT1 receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.

Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is thus no increase in bradykinin-mediated undesirable effects.

During the administration of losartan the removal of the angiotensin II negative feedback on renin secretion leads to increased plasma-renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of the plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After the discontinuation of losartan, PRA and angiotensin II values fell within 3 days to the baseline values.

Both losartan and its principal active metabolite have a far greater affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10- to 40-times more active than losartan on a weight for weight basis.

In a study specifically designed to assess the incidence of cough in patients treated with losartan as compared to patients treated with ACE inhibitors, the incidence of cough reported by patients receiving losartan or hydrochlorothiazide was similar and was significantly less than in patients treated with an ACE inhibitor. In addition, in an overall analysis of 16 double-blind clinical trials in 4131 patients, the incidence of spontaneously reported cough in patients treated with losartan was similar (3.1%) to that of patients treated with placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence with ACE inhibitors was 8.8%.

In nondiabetic hypertensive patients with proteinuria, the administration of losartan potassium significantly reduces proteinuria, fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate and reduces filtration fraction. Generally losartan causes a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy.

Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.

In patients with left ventricular failure, 25 mg and 50 mg doses of losartan produced positive haemodynamic and neurohormonal effects characterized by an increase in cardiac index and decreases in pulmonary capillary wedge pressure, systemic vascular resistance, mean systemic arterial pressure and heart rate and a reduction in circulating levels of aldosterone and norepinephrine, respectively. The occurrence of hypotension was dose related in these heart failure patients.

Hypertension Studies

In controlled clinical studies, once-daily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurement of blood pressure 24 hours post-dose relative to 5-6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70 – 80% of the effect seen 5-6 hours post-dose.

Discontinuation of losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, losartan had no clinically significant effect on heart rate.

Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.

LIFE Study

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study was a randomised, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG-documented left ventricular hypertrophy. Patients were randomised to once daily losartan 50 mg or once daily atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. Other antihypertensives, with the exception of ACE inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach the goal blood pressure.

The mean length of follow up was 4.8 years.

The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95% confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001, 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.

Dual Blockade of the renin-angiotensin-aldosterone system (RAAS)

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.

After oral use, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours the antihypertensive effect persists for up to 24 hours.

Non-melanoma skin cancer:

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥50,000 mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also section 4.4).

5.2 Pharmacokinetic properties

Absorption

Losartan

Following oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.

Distribution

Losartan

Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Studies in rats indicate that losartan crosses the blood-brain barrier poorly, if at all.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Biotransformation

Losartan

About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labelled losartan potassium, circulating plasma radioactivity primarily is attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was seen in about one percent of individuals studied.

In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl side chain and a minor metabolite, an N-2 tetrazole glucuronide.

Elimination

Losartan

Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is about 74 ml/min and 26 ml/min, respectively. When losartan is administered orally, about 4% of the dose is excreted unchanged in the urine, and about 6% of the dose is excreted in the urine as active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral losartan potassium doses up to 200 mg.

Following oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with a terminal half-life of about 2 hours and 6-9 hours, respectively. During once-daily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.

Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites. Following an oral dose of 14C-labelled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the faeces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours.

Characteristics in Patients

Losartan-Hydrochlorothiazide

The plasma concentrations of losartan and its active metabolite and the absorption of hydrochlorothiazide in elderly hypertensives are not significantly different from those in young hypertensives.

Losartan

Following oral administration in patients with mild to moderate alcoholic cirrhosis of the liver, plasma concentrations of losartan and its active metabolite were, respectively, 5-fold and 1.7-fold greater than those seen in young male volunteers.

Pharmacokinetic studies showed that the AUC of losartan in Japanese and non-Japanese healthy male subjects is not different. However, the AUC of the carboxylic acid metabolite (E-3174) appears to be different between the two groups, with an approximately 1.5 fold higher exposure in Japanese subjects than in non-Japanese subjects. The clinical significance of these results is not known.

Neither losartan nor the active metabolite can be removed by haemodialysis.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of general pharmacology, genotoxicity and carcinogenic potential. The toxic potential of the combination of losartan/hydrochlorothiazide was evaluated in chronic toxicity studies for up to six months duration in rats and dogs after oral administration, and the changes observed in these studies with the combination were mainly produced by the losartan component. The administration of the losartan/hydrochlorothiazide combination induced a decrease in the red blood cell parameters (erythrocytes, haemoglobin, haematocrit), a rise in urea-N in the serum, a decrease in heart weight (without a histological correlate) and gastrointestinal changes (mucous membrane lesions, ulcers, erosions, haemorrhages).

There was no evidence of teratogenicity in rats or rabbits treated with the losartan/hydrochlorothiazide combination. Foetal toxicity in rats, as evidenced by a slight increase in supernumerary ribs in the F1 generation, was observed when females were treated prior to and throughout gestation. As observed in studies with losartan alone, adverse foetal and neonatal reactions, including renal toxicity and foetal death, occurred when pregnant rats were treated with the losartan/hydrochlorothiazide combination during late gestation and/or lactation.

6. Pharmaceutical particulars
6.1 List of excipients

Cozaar Comp 50 mg/12.5 mg, Cozaar Comp 100 mg/12.5 mg and Cozaar Comp 100 mg/25 mg:

microcrystalline cellulose (E460),

lactose monohydrate,

pregelatinised maize starch,

magnesium stearate (E572),

hydroxypropyl cellulose (E463),

hypromellose (E464).

Cozaar Comp 50 mg/12.5 mg contains 4.24 mg (0.108 mEq) of potassium.

Cozaar Comp 100 mg/12.5 mg contains 8.48 mg (0.216 mEq) of potassium.

and Cozaar Comp 100 mg/25 mg contains 8.48 mg (0.216 mEq) of potassium.

Cozaar Comp 50 mg/12.5 mg and Cozaar Comp 100 mg/25 mg also contains: titanium dioxide (E171), quinoline yellow aluminium lake (E104) and carnauba wax (E903).

Cozaar Comp 100 mg/12.5 mg also contains: titanium dioxide (E171) and carnauba wax (E903).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Blisters

Do not store above 30°C. Store in the original package in order to protect from light and moisture.

HDPE bottle

Do not store above 25°C. Store in the original container in order to protect from light. Keep the bottle tightly closed in order to protect from moisture.

6.5 Nature and contents of container

Cozaar Comp 50 mg/12.5 mg - PVC/PE/PVDC blister packages with aluminium foil lidding in cartons containing 4, 7, 10, 14, 20, 28, 30, 50, 56, 84, 98, or 280 tablets and unit-dose packages of 28, 56 and 98 tablets for hospital use. HDPE bottles of 100 tablets.

Cozaar Comp 100 mg/12.5 mg - PVC/PE/PVDC blister packages with aluminium foil lidding in cartons containing 14, 15, 28, 30, 50, 56, 84, 90, 98, 280 tablets. HDPE bottles of 100 tablets.

Cozaar Comp 100 mg/25 mg - PVC/PE/PVDC blister packages with aluminium foil lidding in cartons containing 7, 14, 28, 30, 50, 56, 84, 90, 98, or 280 tablets and unit-dose packages of 28, 56 and 98 tablets for hospital use. HDPE bottles of 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU

8. Marketing authorisation number(s)

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

PL 00025/0338

PL 00025/0473

PL 00025/0374

9. Date of first authorisation/renewal of the authorisation

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

12 April 1996/15 March 2010

17 October 2007/30 October 2013

22 December 1999/15 March 2010

10. Date of revision of the text

28 December 2018

© Merck Sharp & Dohme Limited 2018. All rights reserved.

SPC.HYZ.18.UK.6641.WS-327