Summary of Product Characteristics Updated 23-May-2016 | Consilient Health Ltd
HypertensionLosartan and hydrochlorothiazide is not for use as initial therapy, but in patients whose blood pressure is not adequately controlled by losartan potassium or hydrochlorothiazide alone.Dose titration with the individual components (losartan and hydrochlorothiazide) is recommended.When clinically appropriate direct change from monotherapy to the fixed combination may be considered in patients whose blood pressure is not adequately controlled.The usual maintenance dose of Losartan Potassium/Hydrochlorothiazide is one tablet of Losartan Potassium/Hydrochlorothiazide 50 mg/12.5 mg (losartan 50 mg/HCTZ 12.5 mg) once daily. For patients who do not respond adequately to Losartan Potassium/Hydrochlorothiazide 50 mg/12.5 mg, the dosage may be increased to one tablet of Losartan Potassium/Hydrochlorothiazide 100 mg/25 mg (losartan 100 mg/ HCTZ 25 mg) once daily. The maximum dose is one tablet of Losartan Potassium/Hydrochlorothiazide 100 mg/25 mg once daily. In general, the antihypertensive effect is attained within three to four weeks after initiation of therapy. Losartan Potassium/Hydrochlorothiazide 100/12.5 (losartan 100 mg/ HCTZ 12.5 mg) is available for those patients titrated to 100 mg of losartan who require additional blood pressure control.
Use in patients with renal impairment and haemodialysis patientsNo initial dosage adjustment is necessary in patients with moderate renal impairment (i.e. creatinine clearance 30-50 ml/min). Losartan and hydrochlorothiazide tablets are not recommended for haemodialysis patients.Losartan/HCTZ tablets must not be used in patients with severe renal impairment (i.e. creatinine clearance <30 ml/min) (see section 4.3).
Use in patients with hepatic impairmentLosartan Potassium/Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see section 4.3.).
Use in patients with intravascular volume depletionVolume and /or sodium depletion should be corrected prior to administration of Losartan/HCTZ tablets.
Use in the elderlyDosage 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.
AngiooedemaPatients 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 depletionSymptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting.Such conditions should be corrected before the administration of Losartan Potassium/Hydrochlorothiazide (see sections 4.2. and 4.3.).
Electrolyte imbalancesElectrolyte 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 impairmentBased on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, Losartan Potassium/Hydrochlorothiazide should be used with caution in patients with a history of mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore Losartan Potassium/Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment (see sections 4.2, 4.3 and 5.2).
Renal function impairmentAs 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 transplantationThere is no experience in patients with recent kidney transplantation.
Primary hyperaldosteronismPatients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Losartan Potassium/Hydrochlorothiazide 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 cardiomyophathyAs with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Ethnic differencesAs 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.
PregnancyAIIRAs 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).
Hypotension and electrolyte/fluid imbalanceAs 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 effectsThiazide therapy may impair glucose tolerance. Dosage adjustment of antidiabetic agents, including insulin, may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.Thiazide therapy may precipitate hyperuricemia and/or gout in certain patients. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic- induced hyperuricemia.
Hepatic impairmentThiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as it may cause intrahepatic cholestasis, and since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.Losartan Potassium/Hydrochlorothiazide is contraindicated for patients with severe hepatic impairment (see section 4.3 and 5.2).In patients receiving thiazides, hypersensitivity reactions may occur with or without a history of allergy or bronchial asthma. Exacerbations or activation of systemic lupus erythematosus was reported after the use of thiazides.
ExcipientThe product contains lactose. Patients with rare congenital intolerance of galactose, Lapp lactase insufficiency and glucose-galactose malabsorption should not take this medicine (see section 6.1).
LosartanRifampicin and fluconazole have been reported to lower levels of active metabolites. 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 antiinflammatory drugs, including selective cyclooxygenase-2 inhibitors, the co-administration of angiotensin II receptor antagonists may result in a further deterioration of renal function. These effects are usually reversible.Other substances inducing hypotension like tricyclic antidepressants, antipsychotics, baclofene, amifostine: Concomitant use with these drugs that lower blood pressure, as main or side-effect, may increase the risk of hypotension.
HydrochlorothiazideWhen 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 drugsAdditive 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, ACTHIntensified 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.
LithiumDiuretic 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.
SalicylatesIn case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.
MethyldopaThere have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
CyclosporineConcomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout- type complications.
Digitalis glycosidesThiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis- induced cardiac arrhythmias.
Medicinal products affected by serum potassium disturbancesPeriodic 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, mizolastine, pentamidine, terfenadine, vincamine IV).
Calcium saltsThiazide 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 InteractionsBecause of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function (see section 4.4).
CarbamazepineRisk of symptomatic hyponatremia. Clinical and biological monitoring is required.
Iodine Contrast MediaIn 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 laxativesHydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.
|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 2nd and 3rd trimester of pregnancy (see section 4.3 and 4.4)|
LactationNo information is available regarding the use of Losartan Potassium/Hydrochlorothiazide during breastfeeding. Hydrochlorothiazide is excreted in human milk. Therefore, the use of Losartan Potassium/Hydrochlorothiazide during breastfeeding is not recommended. Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Hepato-biliary disordersRare: hepatitis.
InvestigationsRare: hyperkalaemia, elevated ALT.Additional adverse reactions that have been seen with one of the individual components and may be potential adverse reactions with Losartan Potassium/Hydrochlorothiazide are the following:
Blood and lymphatic system disordersUncommon: Anaemia, Henoch-Schönlein purpura, ecchymosis, haemolysis.
Immune system disordersRare: Anaphylactic reaction, angiooedema, urticaria.
Metabolism and nutrition disordersUncommon: Anorexia, gout.
Psychiatric disordersCommon: Insomnia.Uncommon: Anxiety, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorder, somnolence, memory impairment.
Nervous system disordersCommon: Headache, dizziness.Uncommon: Nervousness, paraesthesia, peripheral neuropathy, tremor, migraine, syncope.
Eye disordersUncommon: Blurred vision, burning/stinging in the eye, conjunctivitis, decrease in visual acuity.
Ear and labyrinth disordersUncommon: Vertigo, tinnitus.
Cardiac disordersUncommon: 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 disordersUncommon: Vasculitis.
Respiratory, thoracic and mediastinal disordersCommon: Cough, upper respiratory infection, nasal congestion, sinusitis, sinus disorder Uncommon: Pharyngeal discomfort, pharyngitis, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion
Gastrointestinal disordersCommon: Abdominal pain, nausea, diarrhoea, dyspepsiaUncommon: Constipation, dental pain, dry mouth, flatulence, gastritis, vomiting
Hepato-biliary disordersNot known: Liver function abnormalities
Skin and subcutaneous tissue disordersUncommon: Alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritus, rash, urticaria, sweating
Musculoskeletal and connective tissue disordersCommon: Muscle cramp, back pain, leg pain, myalgiaUncommon: Arm pain, joint swelling, knee pain, musculoskeletal pain, shoulder pain, stiffness, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weaknessNot known: Rhabdomyolysis
Renal and urinary disordersUncommon: Nocturia, urinary frequency, urinary tract infection
Reproductive system and breast disordersUncommon: Decreased libido, impotence
General disorders and administration site conditionsCommon: Asthenia, fatigue, chest pain. Uncommon: facial oedema, fever.
InvestigationsCommon: Hyperkalaemia, mild reduction of haematocrit and haemoglobinUncommon: Mild increase in urea and creatinine serum levelsVery rare: Increase in hepatic enzymes and bilirubin. Hydrochlorothiazide
Blood and lymphatic system disordersUncommon: Agranulocytosis, aplastic anaemia, haemolytic anaemia, leukopenia, purpura, thrombocytopenia.
Immune system disordersRare: Anaphylactic reaction
Metabolism and nutrition disordersUncommon: Anorexia, hyperglycaemia, hyperuricaemia, hypokalaemia, hyponatraemia
Psychiatric disordersUncommon: Insomnia
Nervous system disordersCommon: Cephalalgia.
Eye disordersUncommon: transient blurred vision, xanthopsia.
Vascular disordersUncommon: Necrotizing angiitis (vasculitis, cutaneous vasculitis)
Respiratory, thoracic and mediastinal disordersUncommon: Respiratory disturbances including pneumonitis and pulmonaryoedema.
Gastrointestinal disordersUncommon: Sialoadenitis, spasms, stomach irritation, nausea, vomiting, diarrhoea, constipation.
Hepato-biliary disordersUncommon: Icterus (intrahepatic cholestatis), pancreatitis
Skin and subcutaneous tissue disordersUncommon: Photosensitivity, urticaria, toxic epidermal necrolysis.
Musculoskeletal and connective tissue disordersUncommon: Muscle cramps.
Renal and urinary disordersUncommon: Glycosuria, interstitial nephritis, renal dysfunction, renal failure
General disorders and administration site conditionsUncommon: Fever, dizziness.
LosartanLimited data are available in regard to overdosage in humans. The most likely manifestation of overdosage 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 hemodialysis.
HydrochlorothiazideThe most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Losartan-HydrochlorothiazideThe components of Losartan Potassium/Hydrochlorothiazide have been shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone. This effect is thought to be a result of the complimentary actions of both components. Further, as a result of its diuretic effect, hydrochlorothiazide increases plasma renin activity, increases aldosterone secretion, decreases serum potassium, and increases the levels of angiotensin II. Administration of losartan blocks all the physiologically relevant actions of angiotensin II and through inhibition of aldosterone could tend to attenuate the potassium loss associated with the diuretic.Losartan has been shown to have a mild and transient uricosuric effect. Hydrochlorothiazide has been shown to cause modest increases in uric acid; the combination of losartan and hydrochlorothiazide tends to attenuate the diuretic- induced hyperuricemia.The antihypertensive effect of Losartan Potassium/Hydrochlorothiazide is sustained for a 24-hour period. In clinical studies of at least one year's duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of Losartan Potassium/Hydrochlorothiazide had no clinically significant effect on heart rate. In clinical trials, after 12 weeks of therapy with losartan 50 mg/hydrochlorothiazide 12.5 mg, trough sitting diastolic blood pressure was reduced by an average of up to 13.2 mmHg.Losartan Potassium/Hydrochlorothiazide 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.
LosartanLosartan is a synthetically produced oral angiotensin-II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormon of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone.Angiotensin II also stimulates smooth-muscle cell proliferation.Losartan selectively blocks the AT1 receptor. In vitro and in vivo losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, regardless of the source or route of its synthesis.Losartan does not have an agonist effect nor does it block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, there is thus no increase in bradykinin-mediated undesirable effects.During the administration of losartan the removal of the angiotensin II negative feedback on rennin secretion leads to increased plasma-renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of the plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After the discontinuation of losartan,PRA and angiotensin II values fell within 3 days to the baseline values.Both losartan and its principal active metabolite have a far greater affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10- to 40-times more active than losartan on a weight for weight basis.In a study specifically designed to assess the incidence of cough in patients treated with losartan as compared to patients treated with ACE inhibitors, the incidence of cough reported by patients receiving losartan or hydrochlorothiazide was similar and was significantly less than in patients treated with an ACE inhibitor. In addition, in an overall analysis of 16 double-blind clinical trials in 4131 patients, the incidence of spontaneously reported cough in patients treated with losartan was similar (3.1%) to that of patients treated with placebo (2.6%) or hydrochlorothiazide (4.1%), whereas the incidence with ACE inhibitors was 8.8%.In nondiabetic hypertensive patients with proteinuria, the administration of losartan potassium significantly reduces proteinuria, fractional excretion of albumin and IgG. Losartan maintains glomerular filtration rate and reduces filtration fraction. Generally losartan causes a decrease in serum uric acid (usually <0.4 mg/dL) which was persistent in chronic therapy.Losartan has no effect on autonomic reflexes and no sustained effect on plasma norepinephrine.In patients with left ventricular failure, 25 mg and 50 mg doses of losartan produced positive 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 StudiesIn controlled clinical studies, once-daily administration of Losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurements of blood pressure 24 hours post-dose relative to 5 6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70 80 % of the effect seen 5-6 hours postdose.Discontinuation of Losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, Losartan had no clinically significant effects on heart rate.Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.
LIFE StudyThe 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 ECGdocumented left ventricular hypertrophy. Patients were randomised to once daily losartan 50 mg or once daily atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, hydrochlorothiazide (12.5 mg) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. Other antihypertensives, with the exception of ACE inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach the goal blood pressure.The mean length of follow up was 4.8 years.The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95 % confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.
HydrochlorothiazideHydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.After oral use, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours the antihypertensive effect persists for up to 24 hours.
LosartanFollowing oral administration, losartan is well absorbed and undergoes first-pass metabolism, forming an active carboxylic acid metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. There was no clinically significant effect on the plasma concentration profile of losartan when the drug was administered with a standardized meal.
LosartanBoth losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 liters. Studies in rats indicate that losartan crosses the bloodbrain barrier poorly, if at all.
HydrochlorothiazideHydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
LosartanAbout 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.
LosartanPlasma 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 oncedaily dosing with 100 mg, neither losartan nor its active metabolite accumulates significantly in plasma.Both biliary and urinary excretion contribute to the elimination of losartan and its metabolites.Following an oral dose of 14C-labeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the feces.
HydrochlorothiazideHydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours.
Characteristics in Patients
Losartan-HydrochlorothiazideThe 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.
LosartanFollowing 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 hemodialysis.
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