LOSARTAN POTASSIUM/HYDROCHLOROTHIAZIDE 100/25 MG FILM-COATED TABLETS - summary of medicine characteristics

Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 100 mg losartan potassium and 25 mg hydrochlorothi­azide.

For the full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet. (Tablets)

Losartan potassium/Hydrochlo­rothiazide 100 mg/25 mg film-coated tablets: white, round, biconvex, 10mm film-coated tablets, scored on both sides, with side scores. Marked LH2 on one side.

The tablet can be divided into equal doses.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets 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 Losartan potassium/Hydrochlo­rothiazide is one tablet of Losartan potassium/Hydrochlo­rothiazide 50 mg/12.5 mg (losartan 50 mg/HCTZ 12.5 mg) once daily. For patients who do not respond adequately to Losartan potassium/Hydrochlo­rothiazide 50 mg/12.5 mg, the dosage may be increased to one tablet of Losartan potassium/Hydrochlo­rothiazide 100 mg/25 mg (losartan 100 mg/ HCTZ 25 mg) once daily. The maximum dose is one tablet of Losartan potassium/Hydrochlo­rothiazide 100 mg/25 mg once daily. In general, the antihypertensive effect is attained within three to four weeks after initiation of therapy. Other tablets containing losartan 100 mg/ HCTZ 12.5 mg may be available for those patients titrated to 100 mg of losartan 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

Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets may be administered with other antihypertensive agents.

Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets should be swallowed with a glass of water.

Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets may be administered with or without food.

4.3 Contraindications

– Hypersensitivity to the active substances, sulphonamide-derived substances 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

– Symtomatic hyperuricaemia/gout

– Second and third trimester of pregnancy (see section 4.4 and 4.6)

– Severe renal impairment (i.e. creatinine clearance <30 ml/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/1.73m2)(see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Angiooedema

Patients with a history of angiooedema (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 Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated 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 and potassium containing salt substitutes 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, Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated Tablets 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 Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated Tablets 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 Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated 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 nonblacks, possibly because of higher prevalence of low-renin states in the black hypertensive population.

Pregnancy

Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated Tablets should not be initiated during pregnancy. Unless continued losartan/hydrochlo­rothiazide 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 Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated Tablets 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 section 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.

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.

Losartan potassium/Hydrochlo­rothiazide 50/12.5mg Film-coated Tablets 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 (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ 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 HCTZ 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.

4.5 Interaction with other medicinal products and other forms of interactionLosartan

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 coadministered 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 preexisting 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.

Clinical trial data has 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).

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.

Cyclosporine:

Concomitant treatment with cyclosporine 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 contra-indicated during the second and third trimester of pregnancy (see section 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 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) (see also 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 section 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 the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for 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 losartan during breastfeeding, losartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothi­azide:

Hydrochlorothiazide is excreted in human milk in small amounts Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of hydrochlorothiazide during breastfeeding is not recommended. If hydrochlorothiazide is used during breast-feeding, doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

No studies on the effects 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 events below are classified where appropriate by system organ class and frequency according to the following convention:

Very common (> 1/10) Common (> 1/100 to < 1/10) Uncommon (> 1/1,000 to < 1/100) Rare (> 1/10,000 to < 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:

Hepato-biliary disorders

Rare: Hepatitis

Investigations

Rare: Hyperkalaemia, elevation of ALT

Additional 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

Blood and lymphatic system disorders

Uncommon: Anaemia, Henoch-Schonlein purpura, ecchymosis, haemolysis Not known: Thrombocytopenia

Immune system disorders

Rare: hypersensitivity: anaphylactic reactions, angiooedema 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 angiooedema had been reported in the past in connection with the administration of other medicines, including ACE inhibitors

Metabolism and nutrition disorders

Uncommon: Anorexia, gout

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

Not known: Dysgeusia

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

Not known: dose-related orthostatic effects

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

Not known: Pancreatitis

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

Musculoskeletal 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

Not known: Rhabdomyolysis

Renal and urinary disorders

Common: Renal failure and renal impairment

Uncommon: Nocturia, urinary frequency, urinary tract infection

Reproductive system and breast disorders

Uncommon: Decreased libido, erectile dysfunction/im­potence

General disorders and administration site conditions

Common: Asthenia, fatigue, chest pain

Uncommon: Facial oedema, oedema, fever

Not known: Flu-like symptoms and malaise

Investigations

Common: Hyperkalaemia, mild reduction of haematocrit and haemoglobin, hypoglycaemia

Uncommon: Mild increase in urea and creatinine serum levels

Very rare: Increase in hepatic enzymes and bilirubin.

Not known: Hyponatraemia

Hydrochlorothiazide

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

Not known: Non-melanoma skin cancer (Basal cell carcinoma and Squamous cell carcinoma)

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: Necrotizing 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 Not known: Cutaneous lupus erythematosus

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

Description of selected adverse reactions

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ 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: website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

No specific information is available on the treatment of overdose with Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets. Treatment is symptomatic and supportive. Therapy with Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets 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 manifestations of overdosing are hypotension and tachycardia; bradycardia can 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 electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration as a result from excessive diuresis. If digitalis has also been ingested, hypokalaemia may enhance cardiac arrhythmias.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

The components of Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets

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 Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets 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 Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets 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.

Losartan potassium/Hydrochlo­rothiazide 100/25mg Film-coated Tablets is effective in reducing blood pressure in males and females, blacks and nonblacks and in younger (<65 years) and older (>65 years) patients and is effective in all degrees of hypertension.

Losartan is a synthetically produced oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormon 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 doubleblind 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 hemodynamic 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.

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. Measurements 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 postdose.

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 effects on heart rate.

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

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.

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 pharmacodynamics 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 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 coadministration 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 HCTZ 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 HCTZ 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 HCTZ: 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 propertiesAbsorption

Losartan

Following oral administration, losartan is well absorbed and undergoes firstpass 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.

Losartan

Both losartan and its active metabolite are >99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres. 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.

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-labeled 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.

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-labeled 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.

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 hemodialysis.

5.3 Preclinical safety data

6   PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Core

Mannitol (E421)

Microcrystalline cellulose

Croscarmellose sodium

Povidone (K-30)

Magnesium stearate

Film-coating

Hypromellose (3cP, 50cP)

Hydroxypropyl­cellulose Titanium dioxide (E171) Macrogol 400

6.2 Incompatibilities

Not applicable

6.3 Shelf life

4 years

6.4 Special precautions for storage

Blister:

Store below 25°C.

Tablet container:

Store below 30°C.

6.5 Nature and contents of container

Blister pack (PVC/PVDC/Alu­minium) and HDPE-tablet container with LDPE-cap.

Blister: 10, 14, 20, 28, 30, 50, 56, 60, 98 or 100 film-coated tablets

Tablet container: 100, 250 or 500 film-coated tablets

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Actavis Group PTC ehf

Reykjavikurvegi 76–78

220 Hafnarfjordur

Iceland

8 MARKETING AUTHORISATION NUMBER(S)

PL 30306/0314