LOCARD

APPROVED

by Order of the Ministry of Health

of Ukraine

as of 01.09.10 No. 750

Registration Certificate

No. UA/10963/01/01

 

INSTRUCTION

For Medical Application of Drug

LOCARD

 

Formulation:

active substances: losartan, hydrochlorothiazide;

1 tablet contains potassium losartan 50 mg, hydrochlorothiazide  12.5 mg;

adjuvants: lactose monohydrate, microcrystalline cellulose, gelatinized starch, nonaqueous colloid silicon dioxide, magnesium stearate, hypromellose, talc, titanium dioxide (E 171), yellow iron oxide (E 172), polyethylene glycol 6000.

Dosage Form. Tablets coated with membrane.

Pharmacotherapeutic Group. Combined drugs of angiotensin II antagonists. Losartan and Diuretics.

ATC Code C09D A01.

Clinical Characteristics.

Indications.

Treatment of arterial hypertension in patients with indications for combined therapy.

Contraindications.

  • Hypersensitivity to any components of the drug.
  • Hypersensitivity to other drugs which are sulphonamide derivatives.
  • Anuria.
  • Severe kidneys function impairment (creatinine clearance < 30 ml/min).
  • Severe liver function impairment.
  • Pregnancy.
  • Breast-feeding period.
  • Children’s age.

Method of Application and Dosage.

Ordinary initial and maintaining dose of the drug is 1 tablet of Locard once a day. In patients without adequate therapeutic response to 1 tablet of Locard (50 mg of losartan/12.5 mg of hydrochlorothiazide) during 2-4 weeks the drug dose can be increased to 2 tablets of Locard 50/12.5 mg once a day. Maximum dose is 2 tablets of Locard 50/12.5 mg once a day. As a rule, anti-hypertension effect is reached within 3 weeks after the beginning of treatment. Adjustment of initial dose of Locard for elderly patients is not required, although it is better to start treatment of patients above 75 with dose of 25 mg of losartan. Locard in dosage of 2 tablets 50/12.4 mg should not be applied as initial therapy in elderly patients.

Dosage in case of impaired kidneys function:

Patients with moderate kidneys function impairment (creatinine clearance over 0.5ml/sec or 30 ml/min) can take usual doses of Locard. Patients with severe kidneys function impairment that undergo haemodialysis should not take Locard. Recommended initial losartan dose for patients with hypovolemia is 25 mg once a day, therefore, it is not recommended to start application of drug until diuretics taking is finished and hypovolemia is eliminated.

It is not recommended to apply Locard in patients with impaired liver function.

Patients can take Locard both after meals and on an empty stomach. It is recommended to take Locard at one and the same time of the day. In case of missing of drug taking patient should not double the dose. In such a case he shall take the next dose at the same time. Duration of treatment is not limited.

Side effects.

The most common side effects associated with drug taking are dizziness, general weakness, and fatigability.

There is information about the following undesirable reactions.

Hypersensitivity: anaphylactic reactions, angioneurotic oedema, including laryngeal and glottis oedema followed by development of respiratory obstruction and/or oedema of face, lips, larynx and/or tongue; some of these patients had development of angioneurotic oedema in past history in course of taking of other drugs including ACE inhibitors. There are several records of development of vasculitis, including Schönlein-Henoch disease, in course of losartan taking.

Digestive tract: there are records of rare cases of hepatitis development, as well as diarrhoea in patients treated with losartan.

Respiratory system: reports of coughing in course of treatment with losartan.

Cutaneous coverings: urticaria.

Additional side effects in course of taking of each of the components of the drug which may be potential side effects of Locard are as follows:

Losartan. Rash, dose-dependent orthostatic effects, abdominal pain, asthenia/fatigue, chest pain, oedemas, heartbeats, tachycardia, dyspepsia, nausea, back pain, muscle cramps, headache, insomnia, cough, nose congestion, pharyngitis, sinus disorders, infections of upper airways, migraine, liver function impairment, anaemia, myalgia, pruritus.

Hydrochlorothiazide. Anorexia, irritation of stomach, nausea, vomiting, cramps, diarrhoea, constipations, jaundice (intrahepatic cholestatic jaundice), pancreatitis, sialadenitis, vertigo, paraesthesia, headache, xanthopsia, leukopenia, agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, purpura, photosensitivity, fever, necrotizing angiitis (vasculitis) (cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary oedema), toxic epidermal necrolysis, hyperglycaemia, carbohydrate metabolism disturbance, glycosuria, hyperuricemy, electrolyte imbalance, including hyponatremia and hypokaliemia, kidneys function impairment, interstitial nephritis, renal insufficiency, muscle cramps, weakness, temporary loss of visual acuity.

Laboratory research data. Hyperkaliemia (potassium level in serum > 5.5 mg-equivalents/litre) is observed in 0.7 % of patients, but is not the reason to stop the treatment with Locard. ALT increase is rarely observed and usually disappears after treatment cessation.

 Overdosage.

Overdosage data is limited. The most probable consequence of overdose is arterial hypotension and tachycardia; there also may occur bradycardia due to parasympathetic (vagal) stimulation. The main symptoms of hydrochlorothiazide overdosage are excessive diuresis, significant hypotension with bradycardia, other cardiac rhythm disturbances, reduction of level of electrolytes in blood serum and acid-base balance disturbance. In case of drug overdosage the treatment shall be immediately stopped. In case of recent overdosage gastric lavage is recommended. It is necessary to control patient’s vital functions and, if necessary, to perform symptomatic treatment. Losartan and its active metabolite are not excreted by means of haemodialysis.

Application during Pregnancy and Breast-Feeding Periods.

Taking of the drug during pregnancy and breast-feeding periods is not recommended. If taking of the drug is required during lactation period, breast-feeding shall be stopped.

Children.

Locard safety and effectiveness for children have not been established, therefore, the drug is not applied in paediatrics.

Peculiarities of Application.

With care should be prescribed to the following groups of patients.

  • With water-electrolytic balance disturbance (dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokaliemia) which may develop against intercurrent diarrhoea or vomiting.
  • With bilateral renal arteries stenosis or single-kidney artery stenosis; pancreatic diabetes, with hypercalcemia, hyperuricemy and/or grout; with complicated allergic history and bronchial asthma; as well as systemic diseases of connective tissue (including systemic lupus erythematosus); hypovolemia (including against high doses of diuretics); and in cases of simultaneous application of non-steroid anti-inflammatory drugs (NSAD), including cyclooxygenase-II inhibitors.

It is not recommended to apply Locard for treatment of patients with severely impaired liver and renal functions (creatinine clearance over 0.5 ml/sec or 30 ml/min). In some patients treatment with hydrochlorothiazide may cause increase in concentration of uric acid in blood serum and/or grout. Due to inhibition of renin-angiotensin functions, in some patients changes of renal functions including renal insufficiency took place; these changes can have reversible character and disappear after treatment cessation.

Losartan reduces concentration of uric acid in blood serum. Application of losartan in combination with hydrochlorothiazide decreases hyperuricemy caused by hydrochlorothiazide.

The drug should be carefully applied in patients with bilateral stenosis of renal artery or single-kidney artery stenosis. It is necessary to regularly control the concentration of creatinine in blood serum.

Losartan should be carefully applied in treatment of patients who had angioneurotic oedema of any origin in past history. In case of angioneurotic oedema it is required to stop drug application and turn to the doctor.

In course of hydrochlorothiazide application in patients with allergy or bronchial asthma, as well as in patients without allergy or asthma, hypersensitivity reactions are possible. Symptoms of systemic lupus erythematosus were also observed.

As in case of application of other hypotensive drugs, treatment with hydrochlorothiazide may cause symptomatic hypotension.  In patients with uncomplicated arterial hypertension it occurs rarely, and is more often observed in patients with hypovolemia or electrolyte balance disturbance.

In course of treatment it is recommended to control the level of potassium and calcium in blood serum, especially in patients with impaired renal function and in elderly people. Increase in level of calcium in blood serum in course of treatment with hydrochlorothiazide can be the symptom of latent hyperparathyroidism. Before parathyroid functional tests it is necessary to stop application of hydrochlorothiazide.

Hyperkaliemia, which sometimes occurs in course of treatment with losartan, is not clinically significant due to combination of losartan with hydrochlorothiazide and does not require cessation of treatment.

Metabolic and endocrine effects. Treatment with thiazides may disturb glucose tolerance. In some cases adjustment of dose of hypoglycemic agents including insulin may be required. Therefore, during the treatment of patients with pancreatic diabetes it is required to carry out thorough observation and if necessary to adjust the dosage of hypoglycemic agents. Increase in level of cholesterol and blood triglycerides may also be connected with application of thiazide diuretics.

Other effects. In patients that receive thiazide diuretics hypersensitivity reactions may be observed even in case of absence of indications of allergy or bronchial asthma in past history. Development of exacerbation or progression of systemic lupus erythematosus against taking of thiazide diuretics is possible (See Section Interaction with Other Drugs and Other Types of Interaction).

Ability to Affect the Rate of Reactions when Driving or Operating Other Mechanisms.

Studies of drug effect on ability to drive and operate mechanisms are absent. However, when driving or operating mechanisms it is necessary to remember that treatment with antihypertensive drugs may sometimes cause dizziness or insomnia, in particular at the beginning of treatment or in case of dose increase.

Interaction with Other Drugs and Other Types of Interaction.

Locard may be applied with other hypotensive drugs. Clinically significant interaction of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine, phenobarbital, ketoconazole, and erythromycin has not been observed.

Simultaneous application of losartan and rifampicin may accelerate metabolic breakdown of losartan and its active metabolites, which leads to reduction of losartan effectiveness.

Simultaneous taking of losartan and spironolactone, amiloride or triamterene and/or potassium drugs may result in hyperkaliemia.

As in case of other hypotensive drugs, the hypotensive effect of losartan may decrease in case of simultaneous application of non-steroid anti-inflammatory drugs (e.g., indomethacin), or sympathomimetic agents.

Hydrochlorothiazide reduces lithium excretion. Simultaneous application of losartan with lithium drugs may cause intensification of lithium side effects due to increase in reabsorption of lithium in proximal tubules. Therefore, it is recommended to control concentration of lithium in blood serum, and, as far as possible, to avoid simultaneous application of hydrochlorothiazide and lithium drugs. Simultaneous taking of barbiturates, narcotic drugs (morphine) or alcohol drinks may intensify hypotensive effect of hydrochlorothiazide. Moreover, hypotensive effect of hydrochlorothiazide may also be increased in case of simultaneous application of other hypotensive drugs.

Hydrochlorothiazide may reduce effects of antidiabetic agents, including insulin. In case of such simultaneous treatment it is required to adjust the dose of antidiabetic agent if necessary. Simultaneous application of hydrochlorothiazide and colestipol or cholestyramine  results in reduction of hydrochlorothiazide absorption by 43% and 85%, respectively.

Parallel application of hydrochlorothiazide and corticosteroids (including adrenocorticotropic hormone) may cause hypokaliemia.

During simultaneous application of hydrochlorothiazide and pressor amines the relevant reaction to pressor amines may be decreased, but not as much as to stop their application.

During general anesthesia or application of non-depolarizing muscle relaxants (e.g., tubocurarin chloride) the risk of hypotension is increased. Combined application of amiodarone and hydrochlorothiazide increases risk of development of arrhythmia connected with hypokaliemia.

Non-steroid anti-inflammatory drugs may reduce diuretic and hypotensive effect of hydrochlorothiazide. Diflunisal increases concentration of hydrochlorothiazide in plasma and reduces its hyperuricemic action. Simultaneous application of the drug with foxglove glycosides increases possibility of toxic effects of glycosides.

Drug Influence on Laboratory Research results

Due to influence of thiazides on calcium metabolism, their application may distort the results of study of parathyroid glands function.

Pharmacological Properties.

Pharmacodynamics.

Locard is a combination of losartan and hydrochlorothiazide.

Losartan is an antihypertensive drug, selective antagonist of angiotensin II (AT1 type) receptors. It bonds with AT1 type receptors located in different tissues including vascular plain muscles, adrenal cortex, kidneys and heart, blocks development of angiotensin II effects, namely decreases arterial vasoconstriction and aldosterone release, reduces wedge pressure in pulmonary vessels, decreases general peripheral resistance which results in reduction of systemic arterial pressure. Losartan does not inhibit activity of kinase II, enzyme which catalyzes breakdown of bradykinin. Losartan maximum effect is observed in 6 hours after intake. This effect lasts for 24 hours, therefore, taking the drug once a day is enough. Hypotensive effect is stabilized during the first week of treatment, and maximum hypotensive effect is reached in 3-6 weeks.

Hydrochlorothiazide is a diuretic agent. Thiazide diuretics inhibit reabsorption of Na+ and Cl- in distal tubules intensifying excretion of sodium, potassium, chlorine, and water. The beginning of treatment with hydrochlorothiazide is characterized by reduction of circulating plasma volume with further decrease in cardiac output and significant reduction of arterial tension. In response to reduction of arterial pressure and cardiac output the liquid from interstitial space is redistributed to intravascular stream, and in 3-4 months the plasma volume gradually becomes normal. In case of long-term application of the drug the cardiac output returns to initial value, and peripheral vascular resistance is decreased to lower levels as compared to the initial value. Diuresis mainly begins in 2 hours after hydrochlorothiazide taking, reaches its maximum in 3-4 hours, and lasts for 6-12 hours. Hypotensive effect is observed in 3-4 days of treatment and reaches its maximum in 3-4 weeks. Duration of hypotensive effect: 12-18 hours.

Combined application of losartan with hydrochlorothiazide ensures additive hypotensive effect which lasts for more than 24 hours and is preserved for the long-lasting period of treatment.

Pharmacokinetics.

Losartan. After having been taken orally, losartan is rapidly absorbed in gastrointestinal tract. It undergoes significant primary metabolism followed by formation of active metabolites of carboxylic acid and other inactive metabolites. Systemic bioavailability is approximately 33%. Maximum concentration of losartan in blood serum is reached within 1 hour, and of its active metabolite – within 3-4 hours after application. Over 99% of losartan and active metabolite are bound with proteins, mainly albumin.

Losartan and its active metabolite clearance from plasma is about 600 ml/min and 50ml/min, respectively. Losartan and its active metabolite clearance from kidneys is about 75 ml/min and 26 ml/min, respectively. When taken orally, 5% of applied dose of losartan is excreted with urine unchanged, and 6% – in form of active metabolite. Period of half-excretion is 1.5-2 hours and 6-9 hours, respectively. About 35% is excreted with urine, and approximately 65% – with faeces.

Hydrochlorothiazide. After having been taken orally, hydrochlorothiazide is quickly absorbed. Its bioavailability is 70%. Maximum concentration in blood plasma is reached in 1.5-5 hours. It is bound with proteins by approximately 40%. 95% of hydrochlorothiazide is excreted by kidneys in unchanged form. It is the result of tubulous excretion. Period of half-excretion is 5.6-14.8 hours.

Specific Groups of Patients.

Elderly Patients.

Losartan-hydrochlorothiazide. Concentrations of losartan and its active metabolite in blood plasma as well as the rate of hydrochlorothiazide absorption in elderly patients with arterial hypertension do not differ much from the same indices in young patients with arterial hypertension.

Losartan and its active metabolite cannot be removed by means of haemodialysis.

Pharmaceutical Characteristics.

Main Physicochemical Properties: yellow, round-shaped, biconvex tablets coated with membrane.

Effective Period.

3 years.

Storage Conditions.

Store under the temperature below 25°C out of reach of children.

Packaging.

10 tablets in blister, 3 blisters in carton box.

Category of Selling.

On prescription.

 

Manufacturer.

Bioveeta Laboratories Pvt. Ltd.

Location.

India, B705, Vardhaman vatika, G.B. Road, Manpada, Thane (W).

Date of Last Revision.