Amlozaar-H

Amlozaar-H

Manufacturer:

Brown & Burk Phils

Distributor:

Brown & Burk Phils
Full Prescribing Info
Contents
Losartan potassium, hydrochlorothiazide, amlodipine besilate.
Description
Each film-coated tablet contains: Losartan Potassium 50 mg, Hydrochlorothiazide 12.5 mg, Amlodipine Besilate equivalent to Amlodipine 5 mg.
Action
Pharmacology: Pharmacodynamics: Amlodipine: Amlodipine inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both Dihydropyridines and non-Dihydropyridines binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa = 8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Hemodynamic: Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pre-treatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in the glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Electrophysiological Effects: Amlodipine does not change sino-atrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with hypertension, no adverse effects on electrocardiographic parameters were observed.
Losartan: Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). Both losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Neither losartan nor its active metabolite inhibits the angiotensin converting enzyme [ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin)]; nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the press or effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following losartan administration. In spite of the effect of losartan on aldosterone secretion, very little effect on serum potassium was observed.
Hydrochlorothiazide: The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure.
Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy.
Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
Pharmacokinetics: Amlodipine: After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Special Population: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment. Patients with renal failure may, therefore, receive the usual initial dose. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in the area under the plasma concentration time curve (AUC) of approximately 40-60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.
Pediatric Patients: Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
Losartan: Absorption: 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.
Distribution: Both losartan and its active metabolite are ≥99% bound to plasma proteins, primarily albumin. The volume of distribution of losartan is 34 litres.
Metabolism: 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 1% of individuals studied. In addition to the active metabolite, inactive metabolites are formed.
Elimination: 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 excretions contribute to the elimination of losartan and its metabolites. Following an oral dose/intravenous administration of 14C-labeled losartan in man, about 35%/43% of radioactivity is recovered in the urine and 58%/50% in the faeces.
Special Populations: Pediatric: Pharmacokinetics of losartan and its active metabolite were generally similar across the studied age groups and similar to historical pharmacokinetic data in adults.
Geriatrics and Gender: Losartan pharmacokinetics has been investigated in the elderly (65-75 years) and in both genders. Plasma concentrations of losartan and its active metabolite are similar in elderly and young hypertensive. Plasma concentrations of losartan were about twice as high in female hypertensive as male hypertensive, but concentrations of the active metabolite were similar in males and females. No dosage adjustment is necessary.
Renal impairment: Following oral administration, plasma concentrations and AUCs of losartan and its active metabolite are increased by 50-90% in patients with mild (creatinine clearance of 50-74 mL/min) or moderate (creatinine clearance 30-49 mL/min) renal insufficiency. In this study, renal clearance was reduced by 55-85% for both losartan and its active metabolite in patients with mild or moderate renal insufficiency. Neither losartan nor its active metabolite can be removed by hemodialysis. No dosage adjustment is necessary for patients with renal impairment unless they are volume-depleted.
Hepatic impairment: 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 times and about 1.7 times those in young male volunteers. Compared to normal subjects, the total plasma clearance of losartan in patients with hepatic insufficiency was about 50% lower and the oral bioavailability was about two times higher. A lower starting dose is recommended for patients with a history of hepatic impairment.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5-6 and 14.8 hours. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. The elimination half-life is between 5.8 and 18.9 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
Indications/Uses
It is indicated for the treatment of essential hypertension. It may be used alone or in combination with other antihypertensive agents, including diuretics.
Dosage/Direction for Use
The usual recommended dose of Amlozaar-H is once daily.
No dose adjustment of amlodipine is required upon concomitant administration of thiazide diuretics, beta blockers, and angiotensin-converting enzyme inhibitors, or as prescribed by the physician.
Overdosage
Amlodipine: Available data suggest that gross over dosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption.
In humans, experience with intentional overdose is limited. Gastric lavage may be worthwhile in some cases. Clinically significant hypotension due to amlodipine over dosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.
Losartan: Symptoms of intoxication: Limited data are available with regard to overdose in humans. The most likely manifestation of overdose would be hypotension and tachycardia. Bradycardia could occur from parasympathetic (vagal) stimulation.
Treatment of intoxication: If symptomatic hypotension should occur, supportive treatment should be instituted. Measures are depending on the time of medicinal product intake and kind and severity of symptoms. Stabilization of the cardiovascular system should be given priority. After oral intake, the administration of a sufficient dose of activated charcoal is indicated. Afterwards, close monitoring of the vital parameters should be performed. Vital parameters should be corrected if necessary. Neither Losartan nor the active metabolite can be removed by hemodialysis.
Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremic, 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.
Contraindications
Losartan: It is contraindicated in patients who are hypersensitive to any component of this product. Do not co-administer aliskiren with Losartan in patients with diabetes.
Amlodipine: Amlodipine besylate tablets are contraindicated in patients with known sensitivity to amlodipine.
Hydrochlorothiazide: Anuria, Hypersensitivity to this product or to other sulfonamide-derived drugs.
Special Precautions
Losartan: Angiooedema: Patients with a history of angiooedema (swelling of the face, lips, throat, and/or tongue) should be closely monitored.
Hypotension and Intravascular volume depletion: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume- and/or sodium-depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Losartan Potassium/Hydrochlorothiazide tablets.
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.
Liver function impairment: Based-on pharmacokinetic data which demonstrate significantly increased plasma concentrations of losartan in cirrhotic patients, Losartan Potassium/Hydrochlorothiazide tablets should be used with caution in patients with a history of mild to moderate hepatic impairment. There is no therapeutic experience with losartan in patients with severe hepatic impairment. Therefore Losartan Potassium/Hydrochlorothiazide tablets are contraindicated in patients with severe hepatic impairment.
Renal function impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function, including renal failure, have been reported (in particular, in patients whose renal function is dependent on the renin-angiotensin-aldosterone system, such as those with severe cardiac insufficiency or pre-existing renal dysfunction).
As with other drugs that affect the renin-angiotensin-aldosterone system, increases in blood urea and serum creatinine have also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney; these changes in renal function may be reversible upon discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.
Renal transplantation: There is no experience in patients with recent kidney transplantation.
Primary hyperaldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Losartan Potassium/Hydrochlorothiazide tablets is not recommended.
Coronary heart disease and cerebrovascular disease: As with any antihypertensive agents, excessive blood pressure decrease in patients with ischaemic cardiovascular and cerebrovascular disease could result in a myocardial infarction or stroke.
Heart failure: In patients with heart failure, with or without renal impairment, there is - as with other drugs acting on the renin-angiotensin system - a risk of severe arterial hypotension, and (often acute) renal impairment.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Ethnic differences: As observed for angiotensin converting enzyme inhibitors, losartan 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.
Amlodipine: Use in patients with heart failure: In a long term, placebo controlled study, in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
Use in patients with impaired hepatic function: As with all calcium antagonists, amlodipine half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. The drug should therefore be administered with caution in these patients.
There are no data to support the use of amlodipine alone, during or within one month of a myocardial infarction.
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
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, hypomagnesaemia 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 Hyponatremia may occur in edematous patients in hot weather.
Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. Dosage adjustment of Antidiabetic agents, including insulin, may be required. 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 hyperkalaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.
Thiazide therapy may precipitate hyperuricemia and/or gout in certain patients. Because losartan decreases uric acid, losartan in combination with hydrochlorothiazide attenuates the diuretic-induced hyperuricemia.
Hepatic impairment: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as it may cause intrahepatic cholestasis, and since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Losartan Potassium/Hydrochlorothiazide tablets are contraindicated for patients with severe hepatic impairment.
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 erythematous has been reported with the use of thiazides.
According to the CMD (h) discussion in June 2008 each member state should decide whether or not to include the doping warning statement in the national text: Anti-doping test: Hydrochlorothiazide could produce a positive analytical result in an anti-doping test.
Special warnings regarding excipients: Losartan Potassium/Hydrochlorothiazide contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use In Pregnancy & Lactation
Use in Pregnancy: Losartan: The use of losartan is not recommended during the first trimester of pregnancy. The use of losartan is contra-indicated during the 2nd and 3rd trimester of pregnancy.
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 medicinal products. 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 losartan 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, and hyperkalemia). Should exposure to losartan have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Amlodipine: Although some Dihydropyridines compounds have been found to be teratogenic in animals, data if the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in pregnancy. Accordingly, amlodipine should not be administered during pregnancy or to women of childbearing potential unless effective contraception is used.
Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during second and third trimesters may compromise foeto-placental perfusion and may cause foetal or neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the increased risk of decreased plasma volume and placental hypo perfusion, 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 alternative treatment could be used.
Use in Lactation: Amlodipine: Although some Dihydropyridines compounds have been found to be teratogenic in animals, data if the rat and rabbit for amlodipine provide no evidence for a teratogenic effect. There is, however, no clinical experience with the preparation in lactation. Accordingly, amlodipine should not be administered during lactation.
Losartan: Because no information is available regarding the use of losartan during breastfeeding, losartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense dieresis can inhibit the milk production. Therefore, the use of losartan/hydrochlorothiazide during breastfeeding is not recommended. If losartan/hydrochlorothiazide is used during breastfeeding, doses should be kept as low as possible.
Adverse Reactions
Losartan: Blood and lymphatic system disorders: Uncommon: Anemia, Henoch-Schonlein purpura, ecchymosis, hemolysis.
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.
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, stemalgia, angina pectoris, grade II-AV block, cerebrovascular event, myocardial infarction, and palpitation, arrhythmias (atrial fibrillations, sinus Bradycardia, tachycardia, ventricular tachycardia, and ventricular fibrillation).
Vascular disorders: Uncommon: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Uncommon: Decreased libido, impotence.
General disorders and administration site conditions: Common: Asthenia, fatigue, chest pain. Uncommon: Facial oedema.
Amlodipine: The most commonly reported side effects of amlodipine are headache, oedema, rash, fatigue, nausea, flushing and dizziness.
Other reported side effects are: Blood and the lymphatic system disorders: Very rare: thrombocytopenia, Leukocytopenia.
Immune system disorders: Very rare: allergic reaction.
Metabolic and nutrition disorders: Very rare: hyperglycemia.
Psychiatric disorders: Uncommon: mood changes, insomnia.
Nervous system disorders: Common: somnolence, dizziness, headache. Uncommon: tremor, taste perversion, syncope, hypoaesthesia, paraesthesia. Very rare: peripheral neuropathy.
Eye disorders: Uncommon: visual disturbances.
Ear and Labyrinth disorders: Uncommon: tinnitus.
Cardiac disorders: Common: Palpitations. Rare: syncope. Very rare: Myocardial infarction, arrhythmia, ventricular tachycardia and atrial fibrillation.
Vascular disorders: Common: flushing. Uncommon: hypotension. Very rare: Vasculitis.
Respiratory, thoracic and mediastinal disorders: Uncommon: dyspnoea, rhinitis. Very rare: coughing.
Gastrointestinal disorders: Common: Abdominal pain. Uncommon: Vomiting, dyspepsia, altered bowel habits, dry mouth. Very rare: pancreatitis, gastritis, gingival hyperplasia.
Hepato-biliary disorders: Very rare: abnormal liver function tests (mostly consistent with cholestasis), hepatitis, and jaundice.
Skin and subcutaneous tissue disorders: Uncommon: alopecia, pruritus, purpura, skin discoloration, increased sweating, rash. Very rare: erythema multiform, angioedema and urticaria.
Musculoskeletal, connective tissue and bone disorders: Uncommon: myalgia, arthralgia, muscle cramps and back pain.
Renal and urinary disorders: Uncommon: increased urinary frequency, micturition disorder, nocturia.
Reproductive Disorders: Uncommon: impotence, Gynaecomastia.
General disorders and administration site conditions: Common: oedema, fatigue. Uncommon: chest pain, asthenia, pain, malaise.
Hydrochlorothiazide: The following adverse reactions have been reported and, within each category, are listed in order of decreasing severity.
Body as a Whole: Weakness.
Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs).
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, Sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.
Hypersensitivity: Anaphylactic reactions, necrotizing angiitis (Vasculitis and cutaneous Vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.
Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, hyperuricemia.
Drug Interactions
Losartan/Hydrochlorothiazide: No drug interaction studies have been conducted between losartan/hydrochlorothiazide and other drugs. The following interactions are based on drug interactions involving each component of the losartan/hydrochlorothiazide combination.
ACE inhibitors (e.g., captopril, ramipril): Concurrent use may be associated with an increased risk of renal dysfunction and hyperkalemia. Consider monotherapy.
Alcohol, barbiturates, narcotics: Potentiation of orthostatic hypotension may occur.
Aliskiren: Renal excretion of potassium may be decreased, resulting in hyperkalemia, particularly in diabetic patients. Co administration is contraindicated in diabetic patients and should be avoided in patients with moderate to severe renal impairment. If co administration is undertaken, closely monitor serum potassium concentrations and renal function.
Antihypertensive agents (e.g., propranolol): Additive or potentiation of hypotension effects may occur.
Antineoplastic agents (e.g., cyclophosphamide): Hydrochlorothiazide may prolong antineoplastic-induced myelosuppression. If co administration cannot be avoided, use with caution.
Cholestyramine, colestipol resins: Hydrochlorothiazide absorption may be impaired. Single doses of either cholestyramine or colestipol resins bind hydrochlorothiazide, reducing GI absorption up to 85% and 43%, respectively. Separate the administration times by at least 4 h. Adjust diuretic dose as needed.
Corticosteroids, corticotrophin: Coadministation may cause intensified electrolyte depletion, particularly hypokalemia.
Cyclo-oxygenase 2 inhibitors (e.g., Celecoxib), NSAIDs (e.g., ibuprofen, indomethacin, ketorolac [nasal]): The diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide and the antihypertensive effects of losartan may be reduced. In addition, concomitant use may further deteriorate renal function, especially in volume-depleted patients, patients with renal impairment, or elderly patients. The risk of hyperkalemia may also be increased. Monitor BP, renal function, and serum potassium. If an interaction is suspected, it may be necessary to discontinue the NSAID.
Amlodipine: CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or Diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers. Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
C09DX - Angiotensin II receptor blockers (ARBs), other combinations ; Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab 30's.
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