Losartan Comp Biotech 50/12,5 mg & 100/25 mg FC tablets.

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

Posology
The usual dose is one LOSARTAN COMP BIOTECH 50/12,5 film-coated tablet once daily, with or without food. The maximum dose is one LOSARTAN COMP BIOTECH 100/25 film-coated tablet once daily. The maximum antihypertensive effect is attained within three weeks after initiation of therapy.

Special populations
LOSARTAN COMP BIOTECH should not be initiated in patients with intravascular volume depletion (e.g., those treated with high-dose diuretics) (see section 4.3).
Elderly patients
No initial dosage adjustment is necessary for elderly patients.
Hepatic and renal impairment
LOSARTAN COMP BIOTECH is not recommended for patients with a history of hepatic or severe renal impairment (see sections 4.3 and 4.4).

Paediatric population
The safety and efficacy of LOSARTAN COMP BIOTECH have not been established in children (see section 4.3).

Method of administration
For oral administration. LOSARTAN COMP BIOTECH may be administered with other antihypertensive medicines, particularly calcium channel blockers and beta-blockers.

• Hypersensitivity to losartan potassium, other sulphonamide-derived medicines, due to the hydrochlorothiazide component, or to any of the excipients listed in section 6.1.
• A history of angioedema related to previous therapy with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Severe hepatic impairment, cholestasis and biliary obstructive disorders.
• Therapy resistant hypokalaemia or hypercalcaemia.
• Refractory hyponatraemia.
• Symptomatic hyperuricaemia/gout.
• Aortic stenosis.
• Concomitant therapy with potassium-sparing diuretics, such as spironolactone, triamterene or amiloride.
• Porphyria.
• Thiazide diuretics in combination with losartan, as contained in LOSARTAN COMP BIOTECH, should not be given to patients with Addisonu2019s disease.
• Anuria.
• Concomitant administration with lithium therapy may lead to toxic blood concentrations of lithium.
• Concomitant use of aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1,73 m2) (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The safety and efficacy of LOSARTAN COMP BIOTECH have not been established in children.
• Patients with a history of previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and lip.

Losartan potassium
Hypotension and intravascular volume depletion
Symptomatic hypotension, especially after the first dose, may occur in patients who are intravascularly volume- and/or sodium-depleted (e.g., those treated with high-dose diuretics, dietary salt restriction, or experiencing diarrhoea or vomiting). These conditions should be corrected prior to administration of LOSARTAN COMP BIOTECH, or a lower starting dose should be used (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. Since hypokalaemia may occur, serum potassium concentrations and creatinine clearance values should be closely monitored, especially in elderly patients and patients with heart failure or renal impairment (creatinine clearance 30 - 50 mL/min).

Hepatic impairment
LOSARTAN COMP BIOTECH is not recommended for patients with hepatic impairment. There is no therapeutic experience with LOSARTAN COMP BIOTECH in patients with severe hepatic impairment. Therefore, LOSARTAN COMP BIOTECH is contraindicated in patients with severe hepatic impairment (see sections 4.2 and 4.3).

Renal impairment
LOSARTAN COMP BIOTECH should not be used in patients with severe renal impairment (see section 4.3). Changes in renal function, including renal failure, have been reported due to inhibition of the renin-angiotensin system. These changes in renal function may be reversible upon discontinuation of therapy. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotaemia and (less frequently) with acute renal failure and/or death. Similar outcomes are likely with LOSARTAN COMP BIOTECH therapy. The blood urea and serum creatinine may be increased in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney during treatment with LOSARTAN COMP BIOTECH (see section 4.3). These changes in renal function may be reversible upon discontinuation of therapy.

Renal transplantation
There is no experience in patients with recent kidney transplantation.

Primary hyperaldosteronism
Patients with primary aldosteronism generally will not respond to antihypertensive medicines acting through inhibition of the renin-angiotensin system. Therefore, the use of LOSARTAN COMP BIOTECH is not recommended.

Coronary heart disease and cerebrovascular disease
As with any antihypertensive medicines, 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 medicines acting on the renin-angiotensin system, a risk of severe arterial hypotension, and (often acute) renal impairment.

Ethnic differences
As observed for ACE inhibitors, LOSARTAN COMP BIOTECH 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
Women of childbearing age should ensure adequate contraception. Should a woman become pregnant while receiving LOSARTAN COMP BIOTECH, the treatment should be stopped immediately and switched to a different class of antihypertensive medicine (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 4.3 and 4.5). 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 medicines, including insulin, may be required (see section 4.5). Hydrochlorothiazide in LOSARTAN COMP BIOTECH may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypocalcaemia may be evidence of hidden hyperparathyroidism. LOSARTAN COMP BIOTECH should be discontinued before carrying out tests for parathyroid function. Increases in cholesterol and triglyceride levels may be associated with hydrochlorothiazide in LOSARTAN COMP BIOTECH. LOSARTAN COMP BIOTECH therapy may precipitate hyperuricaemia and/or gout in certain patients.

Eye disorders
Choroidal effusion, acute myopia and secondary angle-closure glaucoma: Sulphonamide or sulphonamide-derived medicines 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 therapy initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue LOSARTAN COMP BIOTECH intake as soon 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 sulphonamide or penicillin allergy.

Hepatic impairment
Hydrochlorothiazide, as contained in LOSARTAN COMP BIOTECH, 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 COMP BIOTECH is contraindicated for patients with severe hepatic impairment (see section 4.3).

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. Photosensitising actions of hydrochlorothiazide could act as a possible mechanism for NMSC. Patients taking LOSARTAN COMP BIOTECH 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 or adequate protection in the case of exposure, should be advised to the patients in order to minimise the risk of skin cancer. Suspicious skin lesions should be promptly examined, potentially including histological examinations of biopsies. LOSARTAN COMP BIOTECH should not be used by patients who have had previous and/or current basal cell carcinomas and/or squamous cell carcinomas of the skin and/or lip (see section 4.3).

Other
In patients receiving LOSARTAN COMP BIOTECH, sensitivity reactions to thiazides 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 LOSARTAN COMP BIOTECH.

Excipient warning
LOSARTAN COMP BIOTECH contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take LOSARTAN COMP BIOTECH.

Losartan potassium
As with other medicines that block angiotensin II or its effects, concurrent use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium-containing medicines (e.g., trimethoprim-containing medicines), salt substitutes containing potassium or potassium supplements with LOSARTAN COMP BIOTECH may result in hyperkalaemia, since reduction of aldosterone production induced by LOSARTAN COMP BIOTECH may lead to elevation of serum potassium (see section 4.3 and 4.4).

As with other medicines which affect the excretion of sodium, lithium excretion may be reduced (see section 4.3).

Dual blockade of the 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 medicine (see sections 4.3 and 4.4).

The antihypertensive effects of LOSARTAN COMP BIOTECH may be potentiated by medicines that lower blood pressure (e.g., tricyclic antidepressants, antipsychotics, baclofen, amifostine). Rifampicin and fluconazole have been reported to reduce the levels of the active metabolite of losartan. Concurrent use with sympathomimetics may reduce the antihypertensive effects of LOSARTAN COMP BIOTECH. Nonsteroidal anti-inflammatory drugs (NSAIDs) may antagonise the antihypertensive effect of LOSARTAN COMP BIOTECH.

Hydrochlorothiazide
When administered concurrently, the following medicines may interact with thiazide diuretics:

• Lithium
  Should not be given with diuretics (see section 4.3). Diuretic medicines reduce the renal clearance of lithium and add a high risk of lithium toxicity.
• Alcohol, narcotics, barbiturates or antidepressants
  Potentiation of orthostatic hypotension may occur.
• Antidiabetic medicines (oral medicines and insulin)
  Treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicine 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 medicines
  May produce additive hypotensive 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: LOSARTAN COMP BIOTECH should be taken one hour before the intake of the resin.
• Corticosteroids or adrenocorticotropic hormone (ACTH)
  Concurrent use may intensify electrolyte depletion, particularly hypokalaemia.
• Sympathomimetics, such as noradrenaline (norepinephrine)
  May decrease the response to sympathomimetic medicines.
• Skeletal muscle relaxants, non-depolarising (e.g., tubocurarine)
  Possible increased responsiveness to the muscle relaxant.
• NSAIDs
  May reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.
• Medicines used in the treatment of gout (e.g., probenecid, sulfinpyrazone, allopurinol)
  Dosage adjustment of uricosuric medicines may be necessary, since hydrochlorothiazide may raise the level of serum uric acid. Increased dosage of probenecid or sulfinpyrazone may be necessary. The hydrochlorothiazide in LOSARTAN COMP BIOTECH may increase the incidence of hypersensitivity reactions to allopurinol.
• Anticholinergic medicines (e.g. atropine, biperiden)
  Increase of the bioavailability to hydrochlorothiazide, in LOSARTAN COMP BIOTECH, by decreasing gastrointestinal motility and stomach emptying rate.
• Cytotoxic medicines (e.g., cyclophosphamide, methotrexate)
  Hydrochlorothiazide, in LOSARTAN COMP BIOTECH, may reduce the renal excretion of cytotoxic medicines and potentiate their myelosuppressive effects.
• Salicylates
  In case of high dosages of salicylates, the hydrochlorothiazide in LOSARTAN COMP BIOTECH may enhance the toxic effect of the salicylates on the central nervous system.
• Methyldopa
  There have been reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide, as in LOSARTAN COMP BIOTECH, and methyldopa.
• Ciclosporin
  Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.
• Digoxin
  Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.
• Medicines affected by serum potassium disturbances (e.g., antiarrhythmic medicines, antipsychotic medicines and others)
  Periodic monitoring of serum potassium and electrocardiogram (ECG) is recommended when LOSARTAN COMP BIOTECH is administered with medicines affected by serum potassium disturbances (e.g., digoxin glycosides and antiarrhythmic medicines) and with the following torsades de pointes (ventricular tachycardia)- inducing medicines (including some antiarrhythmic medicines), hypokalaemia being a predisposing factor to torsades de pointes:
• Class IA antiarrhythmic medicines (e.g., quinidine, hydroquinidine, disopyramide).
• Class III antiarrhythmic medicines (e.g., amiodarone, sotalol, dofetilide, ibutilide).
• Some antipsychotic medicines (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
• Others (e.g., bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, terfenadine, vincamine IV).
• Calcium salts
  Hydrochlorothiazide, as in LOSARTAN COMP BIOTECH, may increase serum calcium levels due to decreased excretion. Serum calcium levels should be monitored and calcium dosage should be adjusted accordingly.
• Laboratory test interactions
  Because of their effects on calcium metabolism, hydrochlorothiazide may interfere with tests for parathyroid function (see section 4.4).
• Carbamazepine
  Risk of symptomatic hyponatraemia; clinical and biochemical monitoring is required.
• Iodine contrast media
  In case of 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.

Pregnancy
Safety in pregnancy has not been established (see section 4.3). When pregnancy is planned or confirmed, LOSARTAN COMP BIOTECH should be discontinued. Medicines affecting the renin-angiotensin system, such as LOSARTAN COMP BIOTECH, can cause embryonal toxicity, fetal and neonatal morbidity and mortality when administered to pregnant women. Women of childbearing age should ensure effective contraception.

Breastfeeding
No information is available regarding the use of LOSARTAN COMP BIOTECH during breastfeeding. Therefore, the safety of LOSARTAN COMP BIOTECH during breastfeeding has not been established (see section 4.3). Hydrochlorothiazide is excreted in human milk. Therefore, the use of LOSARTAN COMP BIOTECH during breastfeeding is contraindicated (see section 4.3).

There are no data to suggest that LOSARTAN COMP BIOTECH affects the ability to drive or use machines. However, when driving vehicles or operating machines, 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.

Tabulated summary of adverse reactions
The following adverse reactions have been reported with losartan-hydrochlorothiazide combination such as LOSARTAN COMP BIOTECH.

Immune system disorders
Frequency unknown: Angioedema (involving swelling of the face, lips, pharynx and/or tongue).

Nervous system disorders
Frequent: Dizziness.

Hepatobiliary disorders
Less frequent: Hepatitis.

General disorders and administration site conditions
Frequent: Asthenia/fatigue.

Investigations
Less frequent: Hyperkalaemia, elevation of alanine aminotransferase (ALT).

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

Blood and lymphatic system disorders
Less frequent: Symptomatic anaemia, Henoch-Schu00f6nlein purpura, ecchymosis, haemolysis. Frequency unknown: Decreased haemoglobin concentrations, neutropenia, thrombocytopenia.

Immune system disorders
Less frequent: 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), angioedema.

Endocrine disorders
Less frequent: Acute pancreatitis.

Metabolism and nutritional disorders
Less frequent: Anorexia, gout.

Psychiatric disorders
Frequent: Insomnia. Less frequent: Anxiety, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorder, somnolence, memory impairment.

Nervous system disorders
Frequent: Headache, dizziness. Less frequent: Nervousness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope.

Eye disorders
Less frequent: Blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity.

Ear and labyrinth disorders
Less frequent: Vertigo, tinnitus.

Cardiac disorders
Less frequent: Hypotension, orthostatic hypotension, sternalgia, angina pectoris, second degree atrioventricular (AV) block, cerebrovascular event, myocardial infarction, palpitations, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation).

Vascular disorders
Less frequent: Vasculitis. Frequency unknown: Dose-related orthostatic effects.

Respiratory, thoracic and mediastinal disorders
Frequent: Cough, nasal congestion, pharyngitis, upper respiratory infection, sinus disorder, sinusitis. Less frequent: Pharyngeal discomfort, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion.

Gastrointestinal disorders
Frequent: Abdominal pain, diarrhoea, dyspepsia, nausea. Less frequent: Taste disturbances or complete taste loss, constipation, dental pain, dry mouth, flatulence, gastritis, vomiting, obstipation.

Hepatobiliary disorders
Frequency unknown: Severe acute hepatotoxicity, cholestasis, liver function abnormalities.

Skin and subcutaneous tissue disorders
Less frequent: Urticaria, rash, atypical cutaneous lymphoid infiltrates, alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritis, sweating.

Musculoskeletal and connective tissue disorders
Frequent: Back pain, muscle cramps, leg pain, myalgia. Less frequent: Arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness. Frequency unknown: Rhabdomyolysis.

Renal and urinary disorders
Frequent: Impaired renal function, renal failure. Less frequent: Nocturia, urinary frequency, urinary tract infection.

Reproductive system and breast disorders
Less frequent: Decreased libido, erectile dysfunction/impotence.

General disorders and administration site conditions
Frequent: Asthenia/fatigue. Less frequent: Facial oedema, fever. Frequency unknown: Flu-like symptoms, malaise.

Investigations
Frequent: Hyperkalaemia, mild reduction of haematocrit and haemoglobin, hypoglycaemia. Less frequent: Mild increase in urea and creatinine serum levels, increase in hepatic enzymes and bilirubin. Frequency unknown: Hyponatraemia.

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

Neoplasms benign, malignant and unspecified (including cysts and polyps)
Frequency unknown: Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Blood and lymphatic system disorders
Less frequent: Leucopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, purpura.

Immune system disorders
Less frequent: Anaphylactic reactions.

Endocrine disorders
Less frequent: Pancreatitis.

Losartan potassium
Symptoms
The most likely manifestation of overdosage would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.

Treatment
If symptomatic hypotension should occur, supportive treatment should be instituted. Neither losartan nor the active metabolite can be removed by haemodialysis.

Hydrochlorothiazide
Symptoms
The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration resulting from excessive diuresis. If digoxin has also been administered, hypokalaemia may accentuate cardiac arrhythmias.

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