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Losartan/Hydrochlorothiazide Bluefish

Document: Losartan_Hydrochlorothiazide Bluefish film-coated tablet ENG SmPC change

1. NAME OF THE MEDICINAL PRODUCT


Losartan/Hydrochlorothiazide Bluefish 50 mg/12.5 mg film-coated tablets

Losartan/Hydrochlorothiazide Bluefish 100 mg/25 mg film-coated tablets


2. QUALITATIVE AND QUANTITATIVE COMPOSITION


Losartan/Hydrochlorothiazide Bluefish 50 mg/12.5 mg film-coated tabletcontains: 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide.


Losartan/Hydrochlorothiazide Bluefish 100 mg/25 mg film-coated tabletcontains: 100 mg of losartan potassium and 25 mg of hydrochlorothiazide.


Excipient:

Losartan/Hydrochlorothiazide Bluefish 50 mg/12.5 mg film-coated tabletcontains155.00 mg lactose monohydrate.

Losartan/Hydrochlorothiazide Bluefish 100 mg/25 mg film-coated tabletcontains310.00 mg lactose monohydrate.


For a full list of excipients, see section 6.1.


3. PHARMACEUTICAL FORM


Film-coated tablet.

Losartan/Hydrochlorothiazide Bluefish 50 mg/12.5 mg film-coated tablets are yellow and oblong with a score line.


Losartan/Hydrochlorothiazide Bluefish 100 mg/25 mg film-coated tablets are yellow and round with a score line.


The score-line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.


4. Clinical particulars


4.1 Therapeutic indications


Losartan/Hydrochlorothiazide Bluefish is indicated for 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


This medicinal product is available in 2 strengths: 50 mg/12.5 mg and 100 mg/25 mg


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/Hydrochlorothiazide Bluefishis one tablet of Losartan/Hydrochlorothiazide Bluefish50 mg/12.5 mg (losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. For patients who do not respond adequately to Losartan/Hydrochlorothiazide Bluefish50 mg/12.5 mg, the dosage may be increased to one tablet of Losartan/Hydrochlorothiazide Bluefish100 mg/25 mg (losartan 100 mg/Hydrochlorothiazide25 mg) once daily. The maximum dose is one tablet of Losartan/Hydrochlorothiazide Bluefish100 mg/25 mg once daily. In general, the antihypertensive effect is attained within three to four weeks after initiation of therapy.


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/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/Hydrochlorothiazide tablets.


Use in patients with hepatic impairment


Losartan/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.


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

Losartan/Hydrochlorothiazide Bluefishshould be swallowed with a glass of water.

Losartan/Hydrochlorothiazide Bluefish may be administered with or without food.


4.3 Contraindications



4.4. Special warnings and precautions for use


Losartan


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/Hydrochlorothiazide Bluefish (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/Hydrochlorothiazide Bluefish 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/Hydrochlorothiazide Bluefish 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/Hydrochlorothiazide Bluefishis 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

AIIRAs should not be initiated during pregnancy. Unless continued AIIRAtherapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).


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

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

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

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


Hydrochlorothiazide


Hypotension and electrolyte/fluid imbalance


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


Metabolic and endocrine effects


Thiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (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 decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricaemia.


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/Hydrochlorothiazide Bluefish is contraindicated for patients with severe hepatic impairment (see section 4.3 and 5.2).


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 monohydrate.

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


4.5. Interaction with other medicinal products and other forms of interaction


Losartan


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


As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, 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 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 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).

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


Hydrochlorothiazide


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


Alcohol, barbiturates, narcotics or antidepressants:


Potentiation of orthostatic hypotension may occur.


Antidiabetic drugs (oral agents and insulin):


The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the

antidiabetic drug may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.


Other antihypertensive drugs:


Additive effect.


Cholestyramine and colestipol resins:


Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.


Corticosteroids, ACTH:


Intensified electrolyte depletion, particularly hypokalemia.


Pressor amines (e.g., adrenaline):


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


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


Possible increased responsiveness to the muscle relaxant.


Lithium:


Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity;

concomitant use is not recommended.


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


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


Anticholinergic agents (e.g. atropine, biperiden):


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


Cytotoxic agents (eg cyclophosphamide, methotrexate):


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


Salicylates:


In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the

salicylates on the central nervous system.


Methyldopa:


There have been isolated reports of haemolytic anaemia occurring with concomitant use of

hydrochlorothiazide and methyldopa.


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 (eg quinidine, hydroquinidine, disopyramide).

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

• Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine,

cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

• Others (eg bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin,

pentamidine, terfenadine, vincamine IV).


Calcium salts:


Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium

supplements must be prescribed, serum calcium levels should be monitored and calcium dosage should be adjusted accordingly.


Laboratory Test Interactions:


Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (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 or stimulant laxatives:


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 AIIRAs 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 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).

Hydrochlothiazide


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.

Breast-feeding

Angiotensin II Receptor Antagonists (AIIRAs)

Because no information is available regarding the use of losartan during breastfeeding, Losartan/Hydrochlorothiazide Bluefish 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 Losartan/Hydrochlorothiazide Bluefish during breast feeding is not recommended. If Losartan/Hydrochlorothiazide Bluefish is used during breast feeding, doses should be kept as low as possible.


4.7. Effects on ability to drive and usemachines


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 events peculiar to this combination of substances were observed. The adverse events were restricted to those which were formerly observed with losartan potassium salt and/or hydrochlorothiazide.


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


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


Hepato-biliary disorders

Rare: Hepatitis


Investigations

Rare: Hyperkalaemia, elevation of ALT


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


Losartan


Blood and lymphatic system disorders

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


Immune system disorders

Rare: Anaphylactic reactions, angioedema, urticaria


Metabolism and nutrition disorders

Uncommon: Anorexia, 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


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


Renal and urinary disorders

Uncommon: Nocturia, urinary frequency, urinary tract infection


Reproductive system and breast disorders

Uncommon: Decreased libido, impotence


General disorders and administration site conditions

Common: Asthenia, fatigue, chest pain

Uncommon: Facial oedema, fever


Investigations

Common: Hyperkalaemia, mild reduction of haematocrit and haemoglobin

Uncommon: Mild increase in urea and creatinine serum levels

Very rare: Increase in hepatic enzymes and bilirubin.


Hydrochlorothiazide


Blood and lymphatic system disorders

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

Thrombocytopenia


Immune system disorders

Rare: Anaphylactic reaction


Metabolism and nutrition disorders

Uncommon: Anorexia, hyperglycaemia, hyperuricaemia, hypokalaemia, hyponatraemia


Psychiatric disorders

Uncommon: Insomnia


Nervous system disorders

Common: Cephalalgia


Eye disorders

Uncommon: Transient blurred vision, xanthopsia


Vascular disorders

Uncommon: 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


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 national reporting system listed in Appendix V*.


4.9. Overdose


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


Losartan


Limited data are available in regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

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


Hydrochlorothiazide


The most common signs and symptoms observed are those caused by electrolyte depletion (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.


5. PHARMACOLOGICAL PROPERTIES


5.1. Pharmacodynamic properties


Pharmacotherapeutic group: Angiotensin II antagonists and diuretics

ATC code: C09DA01


Losartan – Hydrochlorothiazide


The components of Losartan/Hydrochlorothiazide Bluefish 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 hyperuricaemia.


The antihypertensive effect of losartan and hydrochlorothiazide 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 and hydrochlorothiazide 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 mm Hg.


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


Losartan


Losartan is a synthetically produced oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1receptor 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 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 angiotensin-II negative feedback on renin secretion leads to increased plasma-renin activity (PRA). Increases in PRA lead to an increases 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 AT2receptor. The active metabolite is 10- to 40-times more active than losartan on a weight for weight basis.


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


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


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


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.


Hypertension Studies


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


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


LIFE Study


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


The mean length of follow up was 4.8 years.


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


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

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

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

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

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

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


Hydrochlorothiazide


Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazides 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.


5.2. Pharmacokinetic properties


Absorption


Losartan


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


Distribution


Losartan


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


Biotransformation


Losartan


About 14% of an intravenously- or orally-administered dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-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.


Elimination


Losartan


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


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


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


Hydrochlorothiazide


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


Characteristics in Patients


Losartan-Hydrochlorothiazide


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


Losartan


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

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


5.3. Preclinical Safety Data


Preclinical data reveal no special hazard for humans based on conventional studies of general

pharmacology, genotoxicity and carcinogenic potential. The toxic potential of the combination of losartan/hydrochlorothiazide was evaluated in chronic toxicity studies for up to six months duration in rats and dogs after oral administration, and the changes observed in these studies with the combination were mainly produced by the losartan component. The administration of the losartan/hydrochlorothiazide combination induced a decrease in the red blood cell parameters (erythrocytes, haemoglobin, haematocrit), a rise in urea-N in the serum, a decrease in heart weight (without a histological correlate) and gastrointestinal changes (mucous membrane lesions, ulcers, erosions, haemorrhages).

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


6. PHARMACEUTICAL PARTICULARS


6.1. List of Excipients

Tablet core:

Lactose monohydrate

Pregelatinised maize starch

Microcrystalline cellulose

Magnesium stearate


Film-coating:

Hydroxypropylcellulose

Hypromellose

Titanium dioxide

Talc

Yellow iron oxide


6.2. Incompatibilities

Not applicable.


6.3. Shelf life

3 years


6.4. Special precautions for storage

This medicinal product does not require any special storage conditions.


6.5. Nature and contents of container

PVC/PE/PVDC aluminium blister

Pack sizes:

50/12.5 mg : 14, 28, 56, 90 and 98 tablets

100/25 mg : 28, 56, 90 and 98 tablets


Not all pack sizes may be marketed.


6.6 Special precautions for disposal and other handling

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


7. MARKETING AUTHORIZATION HOLDER


Bluefish Pharmaceuticals AB

P.O. Box 49013

100 28 Stockholm

Sweden


8. MARKETING AUTHORISATION NUMBER(S)


<[To be completed nationally]>


9. DATE OF FIRST REGISTRATION/RENEWAL OF REGISTRATION



<[To be completed nationally]>


10. DATE OF REVISION OF THE TEXT



2016-05-27