Asartan H Losartan Potassium and Hydrochlorothiazide

ASARTAN-H
LOSARTAN POTASSIUM AND HYDROCHLOROTHIAZIDE TABLETS

 

For the use only of a Registered Medical Practitioner or a Hospital or Laboratory.

 

COMPOSITION

Each film coated tablet contains:

Losartan Potassium BP 50mg

Hydrochlorothiazide BP 12.5mg

Excipients: q.s.

Colour: Lake Tartrazine

 

PHARMACOLOGY

Pharmacodynamic Properties

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics,
ATC code: C09DA01

Losartan-Hydrochlorothiazide

The 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 Tablets 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 Tablets 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.

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 on 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.

Loasrtan 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.

Hydrochlorothiazide

Hydrochlorothiazide 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.

 

Pharmacokinetics

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 standardized 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 t 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-Iabeled losartan in man, about 35% of radioactivity is recovered in the urine and 58% in the faeces.

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 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 Iosartan 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.

 

CLINICAL INFORMATION

Indications

Losartan Potassium and Hydrochlorothiazide tablet is indicated for the treatment of essential hypertension in patients whose blood pressure is not adequately controlled on Iosartan and hydrochlorothiazide alone.

 

Contraindications

Hypersensitivity to losartan, sulphonamide-derived substances (as hydrochlorothiazide) or to any of the excipients.

Therapy resistant hypokaleemia or hypercalcaemia.

Severe hepatic impairment; Cholestasis and biliary obstructive disorders.

Refractory hyponatraemia.

Symtomatic hyperuricaemia/gout.

Second and third trimester of pregnancy.

Severe renal impairment (i.e. creatinine clearance <30 ml/min)

Anuria.

 

Adverse effects

The adverse reactions below are classified where appropriate by system organ class and frequency according to the following convention:

Very common: ≤1/10, Common: ≥1/100 to <1/10, Uncommon: ≥1/1,000 to ≤1/100, Rare: ≥1/10,000 to ≤1/1,000, Very rare: ≤1/10,000 in clinical trials with losartan potassium salt and hydrochlorothiazide, no adverse reactions peculiar to this combination of substances were observed. 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.

 

Losartan

Blood and lymphatic system disorders

Uncommon: Anaemia, ecchymosis, haemolysis

Immune system disorders

Rare: Anaphylactic reactions, angioedema, urticaria

Metabolism and nutrition disorders

Uncommon: Anorexia, gout

Psychiatric disorders

Common: Insomnia

Uncommon: Anxiety, panic disorder, confusion, depression, abnormal dreams, sleep disorder.

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, sternalgia, angina pectoris, grade ll-AV block, cerebrovascular event, myocardial infarction, paIpitation, arrhythmias

Vascular disorders

Uncommon: Vasculitis

Respiratory, thoracic and mediastinal disorders

Common: Cough, upper respiratory infection, nasal congestion, sinustis, sinus disorder

Uncommon: Pharyngeal discomfort, pharyngitis, laryngitis, dyspnoea, bronchitis, epistaxis, rhinitis, respiratory congestion

GastrointestinaI disorders

Common: Abdominal pain, nausea, diarrhoea, dyspepsia

Uncommon: Constipation, dental pain, dry mouth, flatulence, gastritis, vomiting

Skin and subcutaneous tissue disorders

Uncommon: Alopecia, dermatitis, dry skin, erythema, flushing, photosensitivity, pruritus, rash

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 athralgia, 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

Hydrochlorothiazide

Blood and lymphatic system disorders

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

Immune system disorders

Rare: Anaphylactic reaction

Metabolism and nutrition disorders

Uncommon: Anorexia, hypergIycaemia, 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: Spasms, stomach irritation, nausea, vomiting, diarrhoea, constipation

Hepato-biliary disorders

Uncommon: lntrahepatic cholestatis, pancreatitis

Skin and subcutaneous tissue disorders

Uncommon: Photosensitivity, urticaria, toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Uncommon: Muscle cramps

Renal and urinary disorders

Uncommon: Glycosuria, interstitial nephritis, renal dysfunction, renal failure

 

Drug 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 co-administered with angiotensin II receptor antagonists.

When angiotensin II antagonists are administered simultaneously with NSAIDs (i.e. selective COX-2 inhibitors, acetylsalicylic acid at anti-inflammatory doses) and non-selective NSAIDs, attenuation of the antihypertensive effect may occur. Concomitant use of angiotensin II antagonist 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.

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, particulariy hypokalemia.

Preasor 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. Co-administration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

Anticholinergic agents (e.g. atropine, biperiden)

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

Cytotoxic agents (e.g. cyclophosphamide, methotrexate)

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

Salicylates

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

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 (e.g. quinidine, hydroquinidine, disopyramide).

– Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

– Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

– Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, terfenadine, vincamine IV).

Calcium salts

Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage should be adjusted accordingly.

Laboratory Test lnteractions

Because of their effects on calcium metabolism, thiazides may interfere with tests for parathyroid function.

Carbamazepine

Risk of symptomatic hyponatremia. Clinical and biological monitoring is required.

Iodine Contrast Media

In case of diuretic-induced dehydratlon, there is an increased risk of acute renal failure, especially with high doses of the iodine product.

Patients should be rehydrated before the administration.

Amphotericin B (parenteral), corticosteroids, ACTH, stimulant laxatives, or glycyrrhizin (found in liquorice)

Hydrochlorothiazide may intensify electrolyte imbalance, particularly hypokalaemia.

 

Dosage regimen

Losartan potasaium/Hydrochlorothiazide 100/25mg Film-coated Tablets may be administered with other antihypertensive agents.

Losartan potassium/Hydrochlorothiazide 100/25mg Film-coated Tablets should be swallowed with a glass of water.

Losartan potassium/Hydrochlorothiazide 100/25mg Film-coated Tablets may be administered with or without food.

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.

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 (Iosartan 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. Other tablets containing losartan 100 mg/ HCTZ 12.5 mg may be available for those patients titrated to 100mg of losartan who require additional blood pressure control.

Use in patients with renal impairment and haemodialysis patients

No initial dosage adjustment is necessary in patients with moderate renal impairment (i.e. creatinine clearance 30-50 ml/min). Losartan 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 mI/min).

Use in patients with intravascular volume depletion

Volume and /or sodium depletion should be corrected prior to administration of losartan/HCTZ tablets.

Use in patients with hepatic impairment

Losartan/HCTZ is contraindicated in patients with severe hepatic impairment.

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, Iosartan/hydrochlorothiazide should not be administered to children and adolescents.

 

Treatment of over dosage

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

Losartan

Limited data are available in regard to overdose in humans. The most likely manifestations of overdosing are hypotension and tachycardia; bradycardia can 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 electrolyte depletion (hypokalaemia, hypochloraemia, hyponatraemia) and dehydration as a result from excessive diuresis. If digitalis has also been ingested, hypokalaemia may enhance cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

 

PHARMACEUTICAL INFORMATION

Dosage forms and strengths of different dosage forms

Each film coated tablet contains:

Losartan Potassium BP 50mg

Hydrochlorothiazide BP 12.5mg

Excipients: q.s.

Colour: Lake Tartrazine

 

Storage conditions and shelf life (expiration date)

Store below 30oC in a dry place. Protect from direct sunlight, heat & moisture.

Keep all medicines out of reach of children.

 

Shelf Life

36 months
 

Package sizes

Alu-Alu pack of 10 tablets.

 

Description of the product e.g. tablet size, colour, markings etc

Yellow coloured, circular shaped, biconvex, film coated tablet plain on both side.

 

Manufactured by

Fredun Pharmaceuticals Ltd.

14,15,16, Zorabian Industrial Complex,

Veoor, Palghar (E). Dist. Thane – 401 404 INDIA.

 

Marketed by

Astranad Pharmaceuticals and Chemical Co. Ltd.

40, Oliyide Street, Mushin, Lagos.

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