4.1. Therapeutic indications

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

Use in patients with hepatic impairment

Losartan Potassium and Hydrochlorothiazide 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 potassium and hydrochlorothiazide should not be administered to children and adolescents.

Method of administration

Losartan Potassium and Hydrochlorothiazide may be administered with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).

Losartan Potassium and Hydrochlorothiazide should be swallowed whole with a glass of water.

Losartan Potassium and Hydrochlorothiazide may be administered with or without food.

4.3. Contraindications

• Hypersensitivity to losartan potassium, 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 Losartan Potassium and Hydrochlorothiazide 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

Intestinal angioedema

Intestinal angioedema has been reported in patients treated with angiotensin II receptor antagonists, including Losartan Potassium (see section 4.8). These patients presented with abdominal pain, nausea, vomiting and diarrhoea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Losartan Potassium should be discontinued and appropriate monitoring should be initiated until complete resolution of symptoms has occurred.

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 Losartan Potassium and Hydrochlorothiazide 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 potassium and hydrochlorothiazide is not recommended (see section 4.5).

Liver function impairment

Based on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan potassium in cirrhotic patients, Losartan Potassium and Hydrochlorothiazide should be used with caution in patients with a history of mild to moderate hepatic impairment. There is no therapeutic experience with losartan potassium in patients with severe hepatic impairment. Therefore Losartan Potassium and Hydrochlorothiazide 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 potassium 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 and Hydrochlorothiazide 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 potassium 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, hyponatraemia, hypochloraemic alkalosis, hypomagnesaemia or hypokalaemia 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 hypercalcaemia 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 hyperuricaemia and/or gout in certain patients. Because losartan potassium decreases uric acid, losartan potassium in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricaemia.

Acute Respiratory Toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS) have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after hydrochlorothiazide intake. At the onset, symptoms include dyspnoea, fever, pulmonary deterioration and hypotension. If diagnosis of ARDS is suspected, Losartan Potassium and Hydrochlorothiazide should be withdrawn and appropriate treatment given.

Hydrochlorothiazide should not be administered to patients who previously experienced ARDS following hydrochlorothiazide intake.

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 and Hydrochlorothiazide 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).

Eye disorders

Choroidal effusion, acute myopia and secondary angle-closure glaucoma:

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy

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 Potassium

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, baclofen, amifostine: Concomitant use with these drugs that lower blood pressure, as main or side-effect, may increase the risk of hypotension.

Grapefruit juice contains components that inhibit CYP450 enzymes and may lower the concentration of the active metabolite of losartan which may reduce the therapeutic effect. Consumption of grapefruit juice should be avoided while taking losartan/HCTZ tablets.

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 hypokalaemia.

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 potassium and 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 antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide).

• Class III antiarrhythmics (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 hyponatraemia. 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 fetotoxicity (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 feto-placental perfusion and may cause fetal 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 Potassium and Hydrochlorothiazide during breastfeeding, Losartan Potassium and Hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Losartan Potassium and Hydrochlorothiazide during breastfeeding is not recommended. If Losartan Potassium and Hydrochlorothiazide 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 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 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 potassium 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/hydrocholorthiazide are the following:

Losartan potassium :

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

System organ class

Adverse reaction

Frequency

Blood and lymphatic system disorder

anaemia, Henoch-Schönlein purpura, ecchymosis, haemolysis

uncommon

Thrombocytopenia

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, diarrhoea, dyspepsia

common

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

uncommon

Intestinal angioedema

rare

Pancreatitis

not known

General disorders and administration site condition

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, angio-oedema 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 angio-oedema 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, thrombocytopenia

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

choroidal effusion, acute myopia, acute angle-closure galucoma

not known

Vascular disorders

Necrotizing angiitis (vasculitis, cutaneous vasculitis)

uncommon

Respiratory, thoracic and mediastinal disorders

Respiratory disorders including pneumonitis and pulmonary oedema

uncommon

acute respiratory distress syndrome (ARDS)

(see section 4.4)

Very rare

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 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 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 Losartan Potassium and Hydrochlorothiazide Tablets. Treatment is symptomatic and supportive. Therapy with Losartan Potassium and Hydrochlorothiazide 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 potassium

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 (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalaemia may accentuate cardiac arrhythmias.

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