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Candiflu ® Neo – capsules 50 mg

INSTRUCTIONS FOR MEDICAL USE

CANDIFLU NEO

Trade name of the drug: Candiflu® Neo

Active substance (INN): Fluconazole

Package name: 50 mg capsules

Contents:

1 capsule contains:

active substance: Fluconazole – 50 mg;

Excipients: sugar, lactose, aerosil, potato or corn starch, calcium stearate or magnesium stearate

Description: Solid white gelatin capsules with white or almost white color powder, odorless.

Pharmacotherapeutic group: Antifungal agent.

ATX code: J02AC01

Pharmacological properties

Fluconazole, a representative of a new class of triazole antifungal agents. It has a highly specific action by inhibiting the activity of cytochrome P450-dependent fungal enzymes. It blocks the conversion of fungal cell lanosterol into ergosterol; it increases cell membrane permeability, disrupts cell growth and replication. Fluconazole, being highly selective for cytochrome P450 of fungi, practically does not inhibit these enzymes in humans (in comparison with itraconazole, clotrimazole, econazole and ketoconazole it inhibits cytochrome P450 dependent oxidative processes in human liver microsomes to a lesser extent). It does not have antiadrogenic activity.

It is active in opportunistic mycoses, including those caused by Candida spp. (including generalized candidiasis against immunosuppression), Cryptococcus neoformans and Coccidioides immitis (including intracranial infections), Microsporum spp. and Trichophyton spp.; in endemic mycoses caused by Blastomyces dermatidis, Histoplasma capsulatum (including immunosuppression).

Pharmacokinetics

Absorption

After oral administration, fluconazole is well absorbed. Simultaneous intake of food has no effect on the absorption rate (absorption) of the drug when taken orally. Time of maximum concentration achievement ( ТСmax) after oral use on an empty stomach of fluconazole 150 mg – 0.5-1.5 hours, and makes 90% of concentration in plasma in intravenous division of 2.5-3.5 mg/l.

Distribution

Plasma concentration is in direct relation to the dose. Equilibrium plasma concentration (Css) of the drug is reached by day 4-5 of administration (when taken once daily). Administration of “shock” dose (on the first day), 2 times higher than the usual daily dose, allows achieving a concentration corresponding to 90% of Css by the second day.

Good penetration into all body fluids. Active substance concentrations in breast milk, joint fluid, saliva, sputum and peritoneal fluid are similar to those in plasma. Constant values in vaginal secretion are reached 8 hours after oral administration and are maintained at this level for at least 24 hours. It penetrates well into the cerebrospinal fluid (CSF); in fungal meningitis, the concentration in the CSF is about 85% of that in plasma. In sweat fluid, dermis and stratum corneum (selective accumulation) high concentrations exceeding serum concentrations are achieved. When administered at a dose of 50 mg once daily, fluconazole concentrations were 73 µg/g after 12 days and 5.8 µg/L after 7 days of discontinuation of treatment. After oral administration of 150 mg once a week. – on day 7, the concentration of fluconazole in the stratum corneum of the skin was 23.4 µg/g, and 7 days after the second dose was 7.1 µg/g.

Concentrations in the nails after 4 months of use at a dose of 150 mg once a week were: 4.05 µg/g in healthy nails and 1.8 µg/g in affected nails. Six months after completion of therapy, fluconazole was still detected in the nails.

The apparent volume of distribution (Vd) approached the total extracellular fluid content in the body. The binding to plasma proteins is low – 11-12%.

Metabolism and excretion

The elimination half-life (T1/2) is 30 hours. It is an inhibitor of CYP2C9 isoenzyme in the liver. It is eliminated mainly by the kidneys (80% – unchanged, 11% – as metabolites). Clearance of fluconazole is proportional to creatinine clearance.

Fluconazole pharmacokinetics depends significantly on the functional state of the kidneys, and there is an inverse relationship between T1/2 and creatinine clearance ( Cc). After hemodialysis, within 3 hours, plasma concentration of fluconazole decreases by 50%.

Fluconazole pharmacokinetics is similar when administered intravenously and when taken orally, which allows to easily switch from one type of administration to another.

Indications for use

Mucosal candidiasis: oral cavity, pharynx, esophagus, non-invasive bronchopulmonary candidiasis, candiduria, cutaneous-mucosal and chronic oral atrophic candidiasis (associated with wearing dentures).

Genital candidiasis: vaginal (acute and recurrent). Candida balanitis. Prophylactic use to reduce the frequency of recurrent vaginal candidiasis (three or more episodes per year).

Prophylaxis of fungal infections in patients with malignant tumors against the background of chemo- or radiation therapy; prevention of relapse of oropharyngeal candidiasis in AIDS patients.

Mycosis of the skin: feet, body, inguinal area, onychomycosis, pityriasis, cutaneous candida infections.

Dosage and administration

Inside

In cases of oropharyngeal andidosis, usually 50-100 mg once daily, treatment should be continued for 7-14 days. If necessary, in patients with severe immune impairment, treatment may be longer. For prophylaxis of oropharyngeal candidiasis relapses in AIDS patients after full course of primary therapy, the drug may be prescribed 150 mg once a week.

For vaginal candidiasis, fluconazole is taken once orally in a dose of 150 mg. To reduce the recurrence rate of vaginal candidiasis, the drug may be used in a dose of 150 mg. 1 time per month. The duration of therapy is determined individually; it varies from 4 to 12 months. Some patients may require more frequent use.

For balanitis caused by Candida spp., fluconazole is prescribed once in a dose of 150 mg orally. For prophylaxis of candidiasis, the recommended dose of fluconazole is 50-400 mg once daily, depending on the risk of fungal infection. If there is a high risk of generalized infection, such as in patients with expected severe or prolonged neutropenia, the recommended dose is 400 mg once daily. Fluconazole is administered several days before the expected appearance of neutropenia; after an increase in neutrophil count over 1000/mm for another 7 days.

For mycoses of the skin, including mycoses of the feet, skin of the groin, and candidiasis of the rut, the recommended dose is 150 mg once a week or 50 mg once a day. Duration of therapy in common cases is 2-4 weeks, but in case of mycoses of feet a longer therapy (up to 6 weeks) may be required.

For pityriasis – 300 mg once a week for 2 weeks, some patients need a third dose of 300 mg per week, while in some cases a single dose of 300 mg to 400 mg is sufficient; an alternative treatment regimen is 50 mg once a day for 2-4 weeks.

For onychomycosis, the recommended dose is 150 mg once a week. Treatment should be continued until the infected nail is replaced (uninfected nail grows back). It takes 3-6 months and 6-12 months, respectively, for the nails on the fingers and toes to re-grow. However, the rate of growth can vary widely from person to person and also depending on age.

For esophageal candidiasis in children, fluconazole is prescribed once in a daily dose of 3 mg/kg, in the following average doses: ages 3-6 years (body weight 15-20 kg) – 50 mg; ages 7-9 years (body weight 21-29 kg) – 50-100 mg; ages 10-12 years (body weight 30-40 kg) – 100-150 mg; ages 12-15 years (body weight 40-50 kg) – 100-150 mg. Duration of therapy – at least 3 weeks and for 2 more weeks after symptoms have regressed.

Forchildren with mucous membrane candidiasis, fluconazole is prescribed once in a daily dose of 3 mg/kg, in the following average doses: 3-6 years old (body weight 15-20 kg) – 100-150 mg on the 1st day, then – 50 mg; 7-9 years old (body weight 21-29 kg) – 100-200 mg on the 1st day, then – 100 mg: at the age of 10-12 years (body weight 30-40 kg) – on the 1st day 100-150 mg, then – by 50-100 mg; at the age of 12-15 years (body weight 40-50 kg) – on the 1st day 250-300 mg, then – by 100-150 mg. The therapy duration is at least 3 weeks.

For generalized candidiasis and cryptococcal infection (including meningitis) in children, fluconazole is indicated in a single daily dose of 6-12 mg/kg, with the following average doses: 3-6 years old (body weight 15-20 kg) – 100-250 mg; 7-9 years old (body weight 21-29 kg) – 100-300 mg; 10-12 years old (body weight 30-40 kg) – 200-350 mg; 12-15 years old (body weight 40-50 kg) – 250-400 mg. Duration of therapy – for 10-12 weeks (until laboratory confirmation of the absence of pathogens in the cerebrospinal fluid).

For prevention of fungal infections in immunocompromised children, in whom the risk of infection is associated with neutropenia, developed as a result of cytotoxic chemotherapy or radiotherapy, fluconazole is administered by 3-12 mg/kg/day, depending on the severity and duration of induced neutropenia, in the following average doses ages 3-6 years (body weight 15-20 kg) – 50-250 mg; ages 7-9 years (body weight 21-29 kg) – 50-300 mg; ages 10-12 years (body weight 30-40 kg) – 100-350 mg; ages 12-15 years (body weight 40-50 kg) – 100-400 mg. Duration of therapy – until elimination of induced neutropenia.

For children with impaired renal function, the daily dose of the drug should be reduced (in the same proportional relationship as in adults), according to the degree of renal failure.

For elderly patients with no renal impairment, the usual dosing regimen of the drug should be followed. In patients with renal failure (creatinine clearance less than 50 ml/min) the dosage regimen should be adjusted as described below.

Administration of the drug for patients with impaired renal function. Fluconazole is mainly excreted unchanged in the urine. It is not necessary to change the dose if it is administered once. In re-administration of the drug in patients with impaired renal function a “shock” dose of 50 mg to 400 mg should be given first. If creatinine clearance (CK) is 50 ml/min, the usual dose of the drug (100% of the recommended dose) is used once daily. If CK is 11 to 50 ml/min, a dose equal to 50% of the recommended dose is used. If patients are regularly on dialysis, one dose of the drug is administered after each session of hemodialysis.

Side effects

Digestive system disorders: change of taste, vomiting, nausea, diarrhea, flatulence, abdominal pain, liver disorders (jaundice, hyperbilirubinemia, increased alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase activity, hepatitis, hepatocellular necrosis), including with lethal outcome.

Nervous system disorders: headache, dizziness, seizures.

Cardiovascular system: prolongation of the QT interval, ventricular fibrillation/rattling.

Blood organs: leukopenia, thrombocytopenia, neutropenia, agranulocytosis.

Allergic reactions: skin rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome), anaphylactoid reactions (including angioedema, facial edema, urticaria, skin itching).

Other: impaired renal function, alopecia, hypercholesterolemia, hypertriglyceridemia, hypokalemia.

Contraindications

Concomitant use of terfenadine (concomitantly with fluconazole at a dose of 400 mg/day or more), astemizole and other drugs that prolong the Q-T interval.

Concomitant use of cisapride.

Hypersensitivity to the drug or similar azole compounds.

Lactose intolerance, lactase deficiency or glucose-galactase malabsorption.

Children under 3 years of age (for this dosage form).

With caution: hepatic and/or renal insufficiency, the appearance of rash against the background of fluconazole administration in patients with superficial fungal infection and invasive/systemic fungal infections, potentially proarrhythmogenic conditions in patients with multiple risk factors (organic heart disease, electrolyte balance disorders, simultaneous use of drugs that cause arrhythmias), simultaneous use of potentially hepatotoxic agents, alcoholism. Simultaneous use of terfenadine and fluconazole in dose less than 400 mg/day.

Drug interactions

Anticoagulants. Fluconazole increases prothrombin time of coumarin anticoagulants (e.g., warfarin) by 12% on average, therefore it is necessary to monitor prothrombin time of patients receiving fluconazole and coumarin anticoagulants carefully.

Sulfonylureas. When concomitant administration of fluconazole and oral sulfonylurea drugs (chlorpropamide, glibenclamide, glipizide and tolbutamide) the elimination half-life of the latter is prolonged, which may lead to hypoglycemia. Blood glucose concentration should be periodically monitored and, if necessary, the dose of hypoglycemic drugs should be adjusted.

Hydrochlorothiazide increases fluconazole plasma concentration by 40%, but it does not require changing the dosing regimen of fluconazole in patients receiving concomitant diuretics.

Phenytoin. Concomitant administration of fluconazole and phenytoin is accompanied by an increase in concentrations of the latter to a clinically significant degree. Therefore, it is necessary to monitor phenytoin levels and dose selection to ensure therapeutic concentration in serum.

Oral contraceptives. Repeated use of fluconazole (in doses of 50-200 mg) has no effect on the effectiveness of the combined contraceptive.

Rifampicin. Concomitant use of fluconazole and rifampicin decreased the area under the curve “concentration – time” by 25% and the half-life of fluconazole by 20%. It is necessary to increase fluconazole dose if they are concomitantly administered.

Cyclosporine. When treating with fluconazole at a dose of 200 mg/day, cyclosporine blood concentrations are increased.

Theophylline. Fluconazole prolongs the half-life of theophylline and increases the risk of intoxication (its dose should be corrected).

Terfenadine. Concomitant administration of fluconazole in doses of 400 mg/day or more with terfenadine is contraindicated. Treatment with fluconazole in doses less than 400 mg/day. In combination with terfenadine should be performed under close medical supervision.

Cisapride. When concomitant administration of fluconazole and cisapride, adverse cardiac reactions, including paroxysms of ventricular tachycardia (torsades depointes).

Nifabutin. Cases of uveitis have been described.

Tacrolimus. Increases the concentration of tacrolimus, therefore increasing the risk of nephrotoxic effects.

Zidovudine. In patients receiving a combination of fluconazole and zidovudine, an increase in zidovudine concentration is observed, which is caused by a decrease in conversion of the latter to its main metabolite, so an increase in side effects of zidovudine should be expected.

Midazolam. Increases the concentration of midazolam, and therefore, the risk of psychomotor effects increases (most pronounced when fluconazole is administered orally than intravenously).

Special indications

Treatment should be continued until clinical and hematological remission occurs. Premature discontinuation of treatment leads to relapses.

Treatment can be started in the absence of results of culture or other laboratory tests, but if they are available, appropriate correction of fungicidal therapy is recommended.

Blood counts, kidney and liver function should be monitored during treatment. If renal and liver function abnormalities occur, the drug should be discontinued. In rare cases, the use of fluconazole was accompanied by toxic liver changes. In the case of hepatotoxic effects associated with fluconazole, no clear dependence on the total daily dose, duration of therapy, sex, and age of the patient was noted. Hepatotoxic effects of fluconazole are usually reversible; their signs disappeared after discontinuation of therapy. If clinical signs of liver damage appear, which may be associated with fluconazole, the drug should be discontinued.

AIDS patients are more prone to develop severe skin reactions when using many drugs. In cases where patients with superficial fungal infection develop a rash and it is considered to be definitely related to fluconazole, the drug should be discontinued. If rash appears in patients with invasive/systemic fungal infections, they should be closely monitored and fluconazole should be discontinued if bullous changes or erythema multiforme appear.

Use in pregnancy and during breastfeeding

It is not advisable to use the drug in pregnant women, with the exception of severe or life-threatening forms of fungal infections, if the anticipated benefits to the mother exceed the possible risks to the fetus.

Fluconazole is in breast milk at the same concentration as in plasma, therefore its administration during lactation is not recommended.

Influence on the ability to drive motor transport and operate machinery

In case of adverse reactions on the nervous system side, patients are recommended to refrain from driving a vehicle and other mechanisms as well as to be cautious while carrying out activities requiring high concentration and quick psychomotor reactions.

Overdose

There was described a case of hallucinations and paranoid behavior after 8.2 g of drug administration. The patient was hospitalized and his condition normalized within 48 hours. In case of overdose, gastric lavage, forced diuresis and symptomatic treatment should be administered. After 3-hour session of hemodialysis the drug concentration in plasma is decreased by 50%.

Form of production

Capsules of 50 mg in a contour cellular pack.

Storage conditions

Store in a dry, dark place at a temperature not exceeding 25°C.

Keep out of the reach of children!

Shelf life

3 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies.

Reliased by a doctor’s prescription

Potassium and Magnesium Asparaginate- infusion solution

INSTRUCTIONS FOR MEDICAL USE

POTASSIUM AND MAGNESIUM ASPARAGINATE

Trade name of the drug: Potassium and Magnesium Asparaginate.

Active ingredients (INN): potassium hydroxide, magnesium oxide, L-aspartic acid.

Dosage form: solution for infusion.

Contents:

1000 ml of the solution contains:

Active ingredients: potassium hydroxide – 3.854 g, magnesium oxide – 1.116 g, L-aspartic acid – 15.16 g.

excipients: xylitol, water for injection.

Description: clear, almost colorless liquid.

Pharmacotherapeutic group: Mineral drug, trace element.

ATX code: B05XA31.

Pharmacological properties

Source of potassium and magnesium ions. Prevents or eliminates hypokalemia. Improves metabolism in the myocardium. Improves tolerance to cardiac glycosides. Has antiarrhythmic activity. Asparaginate carries potassium and magnesium ions and promotes their penetration into the intracellular space. Asparaginate enters cells, it is involved in metabolic processes. Magnesium ion plays an important role in maintaining potassium and calcium homeostasis, has the properties of a calcium channel blocker, and participates in many enzymatic reactions, protein and carbohydrate metabolism.

Pharmacokinetics

Potassium asparaginate and magnesium asparaginate are intensively absorbed in intestine, mainly in small intestine. Excreted by the kidneys.

Indications for use

Potassium and magnesium deficiency therapy as combination therapy in various forms of CHD (including acute myocardial infarction), chronic heart failure, cardiac arrhythmias (including arrhythmias caused by overdose of cardiac glycosides).

Dosage and administration

Oral and intravenous (slow trickle or intravenous drop). Dosage and regimen of administration are determined individually depending on indications, clinical situation and dosage form.

Side effects

Digestive system: nausea, vomiting, diarrhea, discomfort or burning in the epigastrium (in patients with anacid gastritis or cholecystitis).

Cardiovascular system: AV-blockade; when administered intravenously – paradoxical reaction in the form of increased number of extrasystoles, BP decrease.

Metabolism: hyperkalemia (nausea, vomiting, diarrhea, paresthesia), hypermagnesemia (facial hyperemia, thirst, bradycardia, BP decrease, muscle weakness, fatigue, paresis, coma, areflexia, respiratory depression, seizures).

Local reactions: when administered intravenously – phlebitis, venous thrombosis.

Contraindications

Hypersensitivity to potassium asparaginate and magnesium asparaginate; children and teenagers under 18 years of age. Oral administration: acute and chronic renal failure, hyperkalemia, hypermagnesemia, Addison’s disease, AV-blockade of degree I-III, shock, including cardiogenic shock (BP less than 90 mm Hg), amino acid metabolism disorders, severe myasthenia, hemolysis, acute metabolic acidosis, dehydration state.

Caution: pregnancy (especially I trimester), breast-feeding.

For intravenous administration: hyperkalemia, hypermagnesemia, acute renal insufficiency, insufficiency of the adrenal cortex, AV-blockade of II and III degree, amino acid metabolism disorders, hemolysis, severe myasthenia, dehydration; Addison’s disease.

Caution: expressed liver dysfunction, metabolic acidosis, danger of edema development, chronic renal insufficiency – if it is impossible to monitor regularly the magnesium content in serum (danger of cumulation, toxic magnesium content), cardiogenic shock (systolic blood pressure less than 90 mm Hg), hypophosphatase. st), hypophosphatemia, urolithiasis associated with impaired calcium, magnesium and ammonium phosphate metabolism, AV-blockade of degree I.

Special indications

Strophantine or preparations of foxglove can be administered together with potassium and magnesium asparaginate, if necessary. Hyperkalemia and hypermagnesemia are possible during rapid I/V administration.

As part of a polarizing mixture (combined with dextrose and insulin) normalize the heart rhythm in myocardial infarction, ectopic arrhythmias and overdose of cardiac glycosides.

Use during pregnancy and lactation

Administration of this medicine orally during pregnancy (especially during the first trimester) is possible only if the potential benefit to the mother exceeds the possible risk to the fetus. Potassium and magnesium asparaginate penetrate into breast milk. If it is necessary to take this medicine during lactation, breastfeeding should be discontinued.

It is contraindicated by intravenous administration during pregnancy and lactation (breast-feeding). Caution should be exercised when using by mouth in patients with significant liver dysfunction. Use in renal dysfunction Contraindicated for oral administration in acute and chronic renal failure.

Contraindicated for intravenous administration in acute renal failure. Caution is required for chronic renal failure if it is not possible to monitor the magnesium content in serum on a regular basis (risk of cumulation and toxic levels of magnesium).

Administration for children

Administration for children and adolescents under 18 years of age is contraindicated.

Drug interactions

Simultaneous use with antiarrhythmic drugs increases the negative dromo- and batmotropic effects of antiarrhythmic drugs.

When concomitant use of beta-adrenoblockers, cyclosporine, ACE inhibitors, NSAIDs, potassium-saving diuretics, table salt substitutes containing potassium increase the risk of hyperkalemia.

Concomitant use with astringents and coagulants decreases absorption from the gastrointestinal tract, with anesthetics – possible increase in deprivative effect on the CNS, with atracurium besylate, suxamethonium chloride – possible increase in neuromuscular blockade.

Co-administration with potassium-saving diuretics (triamterene, spironolactone), beta-adrenoblockers, cyclosporine, heparin, ACE inhibitors, NSAIDs increases the risk of hyperkalemia up to arrhythmia and asystole.

Magnesium reduces the effects of neomycin, polymyxin B, tetracycline and streptomycin.

Overdose

Symptoms: conduction disorders (especially with previous pathology of cardiac conduction system).

Treatment: drug withdrawal, symptomatic therapy (intravenous injection of calcium chloride), if necessary – hemodialysis and peritoneal dialysis.

Form of production

Infusion solution 100 ml, 200 ml, 250 ml (vials).

Storage conditions

Store in a dry, dark place at temperatures not exceeding 25ºC. Keep out of the reach of children! Do not heat or freeze!

Shelf life

2 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by a doctor’s prescription.

Drolaket- injection

INSTRUCTIONS FOR MEDICAL USE

DROLAKET

Trade name of the drug: Drolaket

Active ingredients (INN): ketorolaca tromethamine, dimedrol (diphenhydramide hydrochloride)

Dosage form: solution for injection.

Contents:

2 ml of the solution contains:

Active ingredients: ketorolac tromethamine – 30.0 mg; dimedrol (diphenhydramide hydrochloride) – 1 mg

Excipients: ethyl alcohol, sodium chloride, sodium hydroxide, water for injection.

Description: pale yellow transparent solution.

Pharmacotherapeutic group: Nonsteroidal anti-inflammatory agent.

ATX code: M01AB15

Pharmacological properties

Pharmacodynamics

It is a combined preparation, the action of which is related to the constituent components of the drug.

Ketorolac is a non-steroidal anti-inflammatory drug (NSAID), has a pronounced analgesic effect, also has anti-inflammatory and moderate antipyretic effects. The mechanism of action is associated with non-selective inhibition of COX1 and COX2 activity, which catalyzes the formation of prostaglandins from arachidonic acid, which play an important role in the pathogenesis of pain, inflammation and fever. It is comparable with morphine in strength of analgesic effect and is significantly superior to other NSAIDs.

Dimedrol. A 1st generation blocker of H1-histamine receptors eliminates the effects of histamine mediated through this type of receptors. Its action on the CNS is due to blockade of H3-histamine receptors in the brain and inhibition of central cholinergic structures. It has pronounced antihistamine activity, reduces or prevents histamine-induced smooth muscle spasms, increased capillary permeability, tissue edema, itching and hyperemia. It has the effect of local anesthesia (when ingested, there is a short-term numbness of the oral mucous membranes), blocks the cholinoreceptors of the ganglia (reduces BP) and the CNS, has sedative, hypnotic, anti-Parkinsonian and antiemetic effects. Antagonism with histamine is more in relation to local vascular reactions in inflammation and allergy than systemic reactions, i.e. BP reduction. However, when parenterally administered to patients with circulating blood volume deficiency, a decrease in BP and an increase in existing hypotension due to ganglioblocating action are possible.

Pharmacokinetics

Ketorolac after injection/injection causes the onset of analgesic effect in 0.5 hours, maximum effect is achieved after 1 – 2 hours. Bioavailability is 80-100%, absorption by intramuscular injection is complete and rapid. After intramuscular administration of 30 mg, maximum blood plasma concentration (Cmax) is 1.74-3.1 µg/ml, 60 mg – 3.23-5.77 µg/ml, time to reach maximum concentration is 15-73 minutes and 30-60 minutes, respectively; Cmax after intravenous infusion of 15 mg is 1.96-2.98 µg/ml, 30 mg – 3.69-5.61 µg/ml. Time to reach equilibrium concentrations (Css) when parenterally administered – 24 h when administered 4 times a day (above subtherapeutic) and is 0.65-1.13 mcg/ml, 1.29-2.47 mcg/ml for intramuscular administration of 15 mg, 1.29-2.47 mcg/ml for 30 mg, 0.79-1.39 mcg/ml for intravenous infusion of 15 mg, 1.68-2.76 mcg/ml for 30 mg.

99% of the drug is bound to plasma proteins, and in case of hypoalbuminemia the amount of free substance in blood increases.

The volume of distribution is 0.15-0.33 l/kg. In patients with renal insufficiency the distribution volume of the drug may increase 2-fold, and the distribution volume of its R-enantiomer – by 20%. It passes poorly through the blood-brain barrier, penetrates through the placenta (10%). Small amounts are detected in breast milk.

More than 50% of the administered dose is metabolized in the liver to form pharmacologically inactive metabolites. The main metabolites are glucuronides, which are excreted by the kidneys and p-hydroxyketorolac.

It is excreted 91% by the kidneys (40% as metabolites), 6% – through the intestine.

The elimination half-life (T1/2) in patients with normal renal function is on average 5.3 hours (3.5-9.2 hours after 30 mg IM, 4-7.9 hours after 30 mg IM). The T1/2 is longer in elderly patients and shorter in younger patients. Liver function has no effect on T1/2. In patients with impaired renal function in creatinine concentration in plasma 19-50 mg/l (168-442 µmol/l) the T1/2 is 10.3-10.8 hours, in more severe renal failure – more than 13.6 hours.

Total clearance is 0.023 l/kg/h (0.019 l/kg/h in elderly patients), intravenous infusion of 30 mg – 0.03 l/kg/h; in patients with renal insufficiency with creatinine concentration in blood plasma of 19-50 mg/l, intravenous infusion of 30 mg – 0.015 l/kg/h.

Not excreted by hemodialysis.

Dimedrol. Binding to plasma proteins is 98-99%. Most of it is metabolized in the liver, a smaller part is excreted unchanged in the urine within 24 hours. The elimination half-life (T1/2) is 1-4 hours. It is well distributed in the body, penetrates through the blood-brain barrier.

It is metabolized mainly in the liver by hydroxylation and conjugation to glucuronides; the products of biotransformation are eliminated in the urine. It is excreted with mother’s milk and may cause sedation in infants. Maximum activity occurs after 1 hour, duration of action – from 4 to 6 hours.

Indications for use

  • Pain relief during postoperative period (including dental treatment)
  • Pain management in muscles and joints
  • post-traumatic pain syndrome
  • renal colic.

Administration and dosages.

It is administered deep into the muscle, slowly at least 15 seconds in minimum effective doses selected according to the pain intensity and patient’s reaction. If necessary, opioid analgesics in reduced doses may be administered simultaneously.

Single dose when administered intramuscularly:

  • Adults under 65 years of age and children over 16 years of age – 10-30 mg, depending on the severity of the pain syndrome;
  • Adults over 65 years of age or with impaired renal function: 10-15 mg.

Doses for multiple parenteral intramuscular administration:

  • Adults under 65 years of age and children over 16 years of age are given 10-60 mg on the first administration, followed by 10-30 mg every 6 hours (usually 30 mg every 6 hours);
  • Adults over 65 years of age or with impaired renal function: 10-15 mg every 4-6 hours.

The maximum daily dose for adults under 65 years of age and children over 16 years of age should not exceed 90 mg, and for adults over 65 years of age or with impaired renal function, 60 mg when administered intramuscularly.

When parenteral administration the duration of treatment should not exceed 5 days.

Side effects

Often – more than 3%, less often – 1-3%, rarely – less than 1%.

Side effects associated with the use of ketorolac.

The digestive system: frequently – gastralgia, diarrhea; less frequently – stomatitis, flatulence, constipation, vomiting, feeling of stomach fullness; rarely – decreased appetite, nausea, gastrointestinal erosive and ulcerative lesions (including with perforation and/or bleeding – abdominal pain, epigastric spasm or burning, blood in stool or melena, vomiting with blood or “coffee grounds” type, nausea, heartburn, etc.), cholestatic jaundice, hepatitis, hepatomegaly, acute pancreatitis.

Urinary system disorders: rare – acute renal failure, lower back pain, hematuria, azotemia, hemolytic-uremic syndrome (hemolytic anemia, renal failure, thrombocytopenia, purpura), increased frequency of urination, increased or decreased volume of urine, nephritis, edema of renal genesis.

Sensory system: rare: decreased hearing, tinnitus, visual impairment (including blurred vision).

Respiratory system: rarely – bronchospasm or dyspnea, rhinitis, pulmonary edema, laryngeal edema (shortness of breath, difficulty in breathing).

The central nervous system: often – headache, dizziness, somnolence, rarely – aseptic meningitis (fever, severe headache, cramps, neck and/or back stiffness), hyperactivity (mood changes, anxiety), hallucinations, depression, psychosis, fainting states.

Cardiovascular system: less frequently – increase in blood pressure.

Blood organs: rarely – anemia, eosinophilia, leukopenia.

Hemostasis: rarely – bleeding from the postoperative wound, nasal bleeding, rectal bleeding.

Skin: less common – skin rash (including maculopapular rash), purpura, rarely – exfoliative dermatitis (fever with or without chills, hyperemia, thickening or peeling of the skin, enlargement and/or pain of the palatine tonsils), urticaria, erythema malignant exudative (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell syndrome).

Local reactions: less frequent – burning or pain at the injection site.

Allergic reactions: rare – anaphylaxis or anaphylactoid reactions (changes in complexion, skin rash, urticaria, skin itching, tachypnea or dyspnea, eyelid edema, periorbital edema, shortness of breath, difficulty in breathing, heaviness in the chest, wheezing).

Other: often – edema (face, shins, ankles, fingers, feet, weight gain); less often – increased sweating, rarely – tongue swelling, fever.

Side effects associated with the use of dimedrol

Nervous system and sense organs: general weakness, fatigue, sedative effect, decreased attention, dizziness, drowsiness, headache, impaired coordination of movements, decreased speed of psychomotor reactions, anxiety, increased excitability, irritability, nervousness, insomnia, euphoria, fear of death, confusion, tremor, neuritis, seizures, paresthesias; dilated pupils, increased intraocular pressure, visual disturbances, diplopia, acute labyrinthitis, tinnitus. Patients with local brain lesions or epilepsy have activated (even when using low doses of dimedrol) convulsive discharges on EEG and this may provoke an epileptic seizure, tachycardia, extrasystole.

Blood system: agranulocytosis, thrombocytopenia, hemolytic anemia.

Gastrointestinal tract: dry mouth, transient numbness of the oral mucosa, anorexia, nausea, pain in the epigastric region, vomiting, diarrhea, constipation.

Urinary system: frequent and/or difficult urination, urinary retention, early menstruation.

Respiratory system: dry mucous membranes of the nose and throat, nasal congestion, thickening of bronchial secretion, a feeling of compression in the chest, difficulty in breathing, shortness of breath.

Skin and skin derivatives: hyperemia, itching, polymorphic rash, cyanosis of skin and mucous membranes.

Allergic reactions: rash, urticaria, anaphylactic shock.

Reactions at the injection place: local necrosis during subcutaneous and intradermal injection.

Others: increased sweating, chills, fever, hyperthermic syndrome, photosensitization.

Contraindications

Hypersensitivity to the components of the drug or other antihistamines, “aspirin” triad (combination of bronchial asthma, recurrent polyposis of the nose and sinuses, and intolerance to acetylsalicylic acid and medicines of pyrazolone series), hypovolemia (regardless of the cause), pheochromocytoma, epilepsy, prolonged Q-T interval syndrome or long-term use of drugs that may prolong the Q-T interval. Porphyria. Closed-angle glaucoma, prostatic hyperplasia, stenotic peptic ulcer disease of the stomach and duodenum, stenosis of the bladder neck, bradycardia, heart rhythm disorders. Ulcerative lesions of the gastrointestinal tract in the acute stage, hypocoagulation (including hemophilia), bleeding or high risk of bleeding, severe renal insufficiency (plasma creatinine > 50 mg/l), severe hepatic insufficiency or active liver disease, conditions after coronary artery bypass grafting, confirmed hyperkalemia, pregnancy (III trimester), inflammatory bowel disease, childbirth, lactation, children under 16 years (safety and effectiveness of use are not established).

Caution

Hypersensitivity to other NSAIDs, bronchial asthma; presence of factors that increase gastrointestinal toxicity: Alcoholism, tobacco smoking and cholecystitis; postoperative period; chronic heart failure, coronary heart disease; edema syndrome; arterial hypertension; impaired renal function (plasma creatinine below 50 mg/L); cholestasis; active hepatitis; sepsis; systemic lupus erythematosus; concomitant use with other NSAIDs, long-term use of NSAIDs, cerebrovascular disease, dyslipidemia/hyperlipidemia, diabetes, peripheral artery disease, history of peptic ulcers, presence of H. pylori, severe somatic diseases, concomitant use of oral GCS (including prednisolone), anticoagulants (including warfarin), antiplatelet agents (including clopidogrel), selective serotonin reuptake inhibitors (including citalopram, fluoxetine, paroxetine, sertraline), older age (over 65 years), pregnancy.

Interaction with other drugs

Ketorolac. Co-administration of ketorolac with paracetamol increases nephrotoxicity of ketorolac.

Administration with other NSAIDs, glucocorticosteroids, ethanol, corticotropin, calcium preparations increases the risk of gastrointestinal mucosal ulceration and gastrointestinal bleeding.

Concomitant administration with anticoagulant drugs – coumarin and indandion derivatives, heparin, thrombolytics (alteplase, streptokinase, urokinase), antiplatelet drugs, cephalosporins, valproic acid and acetylsalicylic acid increases the risk of bleeding.

Reduces the effect of hypotensive and diuretic drugs (reduces the synthesis of prostaglandins in the kidneys).

Administration together with methotrexate increases hepato- and nephrotoxicity (coadministration is possible only when using low doses of the latter and monitoring its plasma concentrations).

Administration with other nephrotoxic drugs (including gold drugs) increases the risk of nephrotoxicity.

Medicinal products that block tubular secretion reduce the clearance of ketorolac and increase its plasma concentrations.

Increases the effect of narcotic analgesics.

Myelotoxic drugs increase the manifestation of hematotoxicity of the drug.

Dimedrol potentiates the effects of anesthetics, sleeping pills, sedatives, narcotic analgesics and local anesthetics. When used with tricyclic antidepressants, it may increase the cholin-blocking and depressing effect on the central nervous system.

Possible risk of seizures when used with analeptics. Concomitant use of MAO inhibitors and dimedrol may lead to increased blood pressure and affect the central nervous and respiratory systems. The use of dimedrol together with hypotensive drugs may increase the feeling of fatigue. The drug increases the effect of ethanol, reduces the effectiveness of apomorphine as a vomiting agent in the treatment of poisoning. It should not be administered concomitantly with drugs containing dimedrol, including those for topical use.

Incompatibility. Do not mix with other drugs in the same container.

Use only the recommended solvent.

Special indications

Before prescribing the medicinal product, the question of previous allergy to the drug or to other NSAIDs should be ascertained. Due to the risk of allergic reactions, the first dose should be administered under close medical supervision.

Hypovolemia increases the risk of nephrotoxic adverse reactions.

If necessary, it may be administered in combination with narcotic analgesics.

It is not recommended to use as a drug for premedication, maintenance of anesthesia.

When coadministration with other NSAIDs, fluid retention, decompensation of cardiac activity, increased blood pressure may be observed. The effect on platelet aggregation stops after 24 – 48 hours. Do not use simultaneously with paracetamol for more than 5 days.

For patients with blood coagulation disorders, prescribe only with continuous monitoring of platelet count, especially important for post-operative patients who require careful hemostasis control.

The risk of drug complications increases with prolongation of treatment (in patients with chronic pain) and increasing the oral dose of the drug more than 40 mg/day.

Antacids, misoprostol, omeprazole are prescribed to reduce the risk of NSAID gastropathy.

Alcoholic beverages are contraindicated during treatment with the drug, exposure to UV radiation should be avoided. The use of diphenhydramine as an antiemetic may complicate the diagnosis of appendicitis and recognition of symptoms of overdose of other drugs.

Use in pregnancy and lactation

Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system, ketorolac should not be used during pregnancy (especially in the third trimester).

The use of ketorolac is contraindicated during pregnancy, during labor and delivery.

Do not use during breastfeeding due to possible adverse effects of prostaglandin synthesis inhibitors on infants.

Influence on the ability to drive a car and operate complex mechanisms

It is recommended to avoid work requiring high attention and quick reaction (driving a vehicle, operating mechanisms and so on).

Overdose.

Symptoms: Abdominal pain, nausea, vomiting, peptic ulcer of the stomach and duodenum, erosive gastritis, impaired renal function, metabolic acidosis, dry mouth, difficulty breathing, mydriasis, face redness, CNS oppression or agitation, tachycardia, arrhythmia, depressed cardiovascular function and respiration, depression, hyperkinesia, confusion, delirium; in children – development of convulsions. A case of rhabdomyolysis after diphenhydramine overdose has been described.

Treatment: symptomatic and supportive therapy with careful control of respiratory function and blood pressure. Gastric lavage, administration of adsorbents (activated charcoal), parenterally administer diazepam if convulsions and CNS agitation symptoms develop. I/V drip administration of plasma substitute fluids, oxygen therapy. Epinephrine and analeptics should not be used. As an antidote in case of diphenhydramine overdose, physostigmine 0.02-0.06 mg/kg body weight may be administered intravenously several times if the severity of anticholinergic symptoms increases

Form of production

Solution for injection in 2 ml ampoules.

Storage conditions

Store in a dark place at temperatures not exceeding 25 C.

Keep out of reach of children!

Shelf life

2 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

 Released by a doctor’s prescription.

Abenol® Neo- injection

INSTRUCTIONS FOR MEDICAL USE

ABENOL NEO

Trade name of the drug: Abenol® Neo

Active substance (INN): Ketoprofen

Pharmaceutical form: Solution for injection.

Contents:

2 ml of the solution (1 ampoule) contains:

active substance: ketoprofen 100 mg;

Excipients: propylene glycol, 96% ethyl alcohol, benzyl alcohol, sodium metabisulfite, sodium hydroxide, sodium hydroxide 1M solution, water for injection.

Description: Clear, colorless or slightly yellowish solution.

Pharmacotherapeutic group: Nonsteroidal anti-inflammatory drug.

ATX code: M01AB15.

Pharmacological properties

Ketoprofen is a non-steroidal anti-inflammatory agent, a derivative of propionic acid. It has analgesic, anti-inflammatory and antipyretic effects. Mechanism of action is related to inhibition of cyclooxygenase-1 and cyclooxygenase-2 activity and decrease in prostaglandin biosynthesis, which play the major role in pathogenesis of inflammation, pain and fever.

Ketoprofen has a pronounced analgesic effect due to two mechanisms: peripheral – mediated by inhibition of prostaglandin synthesis in tissues, and central – due to inhibition of prostaglandin synthesis in central and peripheral nervous system and also due to the effect on biological activity of other neurotropic substances which play a key role in release of pain mediators in the spinal cord. In addition, ketoprofen has anti-bradykinin activity, stabilizes lysosomal membranes, causes significant inhibition of neutrophil activity in patients with rheumatoid arthritis. Inhibits platelet aggregation.

Pharmacokinetics

Bioavailability is 90%. Maximum concentration (Cmax) in blood is reached within 30 minutes. The degree of binding to proteins, mainly to albumin, is 99%. Volume of distribution (Vd) is 0.1 – 0.2 l/kg.

Ketoprofen penetrates rapidly through the blood-brain barrier and into the synovial fluid. Concentration of ketoprofen in synovial fluid is lower than in blood, but it stays there for a longer time, which determines the long-term action of the drug.

After intramuscular (I/m) introduction of 100 mg, after 3 hours the drug concentration in blood plasma is 3 µg/ml, and in synovial fluid – 1.5 µg/ml; after 4 hours the concentration in blood plasma is 0.3 µg/ml, and in synovial fluid – 0.8 µg/ml.

Significant levels of concentrations in synovial fluid are reached 15 min after a single intravenous injection of ketoprofen at a dose of 100 mg.

Ketoprofen is mainly metabolized in the liver via microsomal oxidation reactions to form conjugates.

The elimination half-life (T½ ) of ketoprofen is 2 hours. It is eliminated mainly in the urine (more than 50% as metabolites), 1% is eliminated in the faeces.

INDICATIONS FOR USE

Symptomatic therapy of painful inflammatory processes of different genesis:

  • rheumatoid arthritis;
  • ankylosing spondylitis;
  • psoriatic arthritis;
  • reactive arthritis;
  • gout, pseudopodagra;
  • osteoarthritis;
  • Extra-articular rheumatism (tendinitis, bursitis, shoulder capsulitis).

Pain syndrome (including post-operative and post-traumatic pain, algodysmenorrhea, pain from tumor metastases).

Dosage and administration

The drug is administered parenterally (intramuscular (IV/m) and intravenously (IV)).

For treating acute pain syndrome the drug is administered 2 ml (100 mg) 1 to 2 times a day in a car. The duration of parenteral therapy is usually several days. After achieving the desired effect, the drug is prescribed in the form of capsules, tablets or suppositories.

Infusion of the drug is administered only in hospitals.

For an intermittent IV infusion of 100-200 mg of ketoprofen is diluted in 100 ml of isotonic solution (0.9%) of sodium chloride for injection and given for 0.5-1 hours; after 8 hours the injection is repeated. Maximum daily dose is 300 mg.

For continuous intravenous infusion 100-200 mg of ketoprofen is diluted in 500 ml of infusion solution (0.9% sodium chloride solution for injection, Ringer’s solution with lactate, dextrose (glucose) solution) and infused for 8 hours; after 8 hours the preparation is repeated.

Ketoprofen can be combined with centrally acting analgesics.

Ketoprofen solution must not be mixed with tramadol in the same vial, as this produces a precipitate.

The bottle with infusion solution containing ketoprofen should be wrapped in dark paper or aluminum foil because ketoprofen decomposes in light.

Side effects

Digestive system: dyspepsia, nausea, flatulence, abdominal pain, diarrhea, constipation, anorexia, vomiting, stomatitis. There are separate reports on the development of colitis, intestinal perforation (as a complication of diverticulitis), exacerbation of ulcerative colitis and Crohn’s disease. Less than 0.1% have enteropathy with perforation, adhesions, intestinal ulcers; in enteropathy bleeding is possible; in 1% of patients after 3-6 months of treatment and in 2-4% of patients after 12 months of treatment there were cases of GI ulcers, bleeding, small intestine perforation. There are some reports of hepatitis development, marked liver function abnormalities with jaundice. Changes in liver function tests values were observed in 15% of patients; sometimes (less than 1% of patients) significant increase of ALT or AST is noted.

CNS: 1-3% – depression, nervousness, nightmares, somnolence; 0.1% – disorientation, delirium with visual and auditory hallucinations, speech disorders; asthenia, weakness, dizziness, headache.

Sensory organs: 1-3% – visual impairment, conjunctivitis (after oral administration), tinnitus.

Respiratory system: rarely – hemoptysis, dyspnea, rhinitis, bronchospasm, increased attacks of bronchial asthma.

Cardiovascular system: edema (2%); sometimes (1%) – congestive heart failure, arterial hypertension.

Blood system: less than 1% – agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia. When using the drug in high doses – inhibition of platelet aggregation, prolongation of bleeding time, bruising, hemorrhage. Dermatological reactions: 1-3% – skin rash; less than 1% – alopecia, eczema, exfoliative dermatitis, erythema multiforme, lichenoid dermatitis, photosensitivity reactions. There are reports of the development of Stevens-Johnson syndrome and toxic epidermal necrolysis.

Urinary system: acute renal failure, interstitial nephritis, nephrotic syndrome, acute pyelonephritis.

Allergic reactions: rarely – urticaria, angioedema. Local reactions: at the injection site, a reaction in the form of burning and/or pain.

Contraindications

  • Gastrointestinal erosive and ulcerative lesions in the acute phase;
  • Severe heart failure;
  • Severe liver dysfunction;
  • Severe renal dysfunction;
  • susceptibility to bleeding;
  • Chronic dyspepsia in anamnesis;
  • Bronchial asthma, rhinitis;
  • pregnancy;
  • lactation (breast-feeding);
  • Children under 15 years of age;
  • Hypersensitivity to ketoprofen, acetylsalicylic acid or other NSAIDs.

Drug interactions

When used concomitantly, ketoprofen may reduce the effect of diuretics and antihypertensive drugs.

Concomitant use of ketoprofen and diuretics or ACE inhibitors increases the risk of impaired renal function.

When concomitant use of ketoprofen and cardiac glycosides, lithium drugs, cyclosporine and methotrexate their toxicity increases due to decreased excretion. Ketoprofen can decrease the effect of mifepristone, so there should be at least 8-12 days between mifepristone treatment and initiation of ketoprofen therapy. Acetylsalicylic acid reduces the degree of binding of ketoprofen to plasma proteins. Combined use of ketoprofen with other salicylates should be avoided.

Special indications

Caution should be exercised when prescribing the drug in patients with a history of gastrointestinal diseases due to the risk of gastrointestinal bleeding or gastrointestinal perforation. Caution should be exercised when prescribing to patients with blood clotting disorders, hemophilia, Willebrand’s disease, severe thrombocytopenia, renal and hepatic insufficiency.

Ketoprofen may mask the symptoms of infectious diseases.

Caution should be exercised when prescribing ketoprofen to patients with arterial hypertension and cardiovascular diseases, which are characterized by fluid retention in the body. BP should be monitored regularly (especially in patients with cardiovascular disease).

During long-term treatment with ketoprofen, especially in elderly patients, systematic monitoring of blood count, as well as liver and kidney function, is necessary. If creatinine clearance is less than 0.33 ml/s (20 ml/min), the dose of ketoprofen should be adjusted.

Ketoprofen should be discontinued before surgical intervention.

The solution for injection contains ethanol. Each ampoule (2 ml) contains 200 mg of ethanol, which should be taken into account when prescribing the drug to patients who abuse alcohol, patients with trauma or with brain diseases. Alcohol intake should be avoided during treatment with ketoprofen.

When using the drug, caution should be exercised by persons whose activities require quick psychomotor reactions (driving a car, working with mechanisms), because the drug may cause drowsiness and dizziness.

Overdose

There are few data on overdose of parenteral forms of the drug.

The following symptoms are possible: headache, dizziness, nausea, vomiting, epigastric pain, bloody vomiting, darkened stool, confusion, difficulty in breathing, convulsions, renal failure and renal failure.

Treatment: No specific antidote exists. Symptomatic therapy, histamine H2-receptor blockers, proton pump inhibitors and prostaglandins are used.

Form of production

Solution for injection 100 mg/2 ml in 2 ml ampoules.

Storage conditions

Store in a dark place at temperatures not exceeding 25°C. Keep out of the reach of children!

Shelf life

3 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by a doctor’s prescription.

Metolan- injection

INSTRUCTIONS FOR MEDICAL USE

METOLAN

Trade name of the drug: Metolan

Active substance (INN): Meldonium

Dosage form: Solution for injection.

Contents:

5 ml of the solution (1 ampoule) contains:

The active substance: Meldonium – 500 mg.

Excipients: Water for injection.

Description: Colorless, transparent liquid.

Pharmacotherapeutic group: Metabolic agents.

ATX code: C01EB22

Pharmacological properties

Meldonium is a structural analogue of gamma-butyrobetaine, a substance that is found in every cell of the human body.

Under increased stress, the drug restores the balance between supply and demand of cells for oxygen, eliminates the accumulation of toxic products of metabolism in the cells, protecting them from damage; it also has a tonic effect. As a result of its use, the body acquires the ability to withstand the load and quickly restore energy reserves. Due to these properties, the drug is used to treat various disorders of the cardiovascular system, blood supply to the brain, as well as to increase physical and mental performance. In acute ischemic myocardial damage, the drug slows down the formation of the necrotic zone and shortens the rehabilitation period. In heart failure, it increases myocardial contractility, increases exercise tolerance, reduces the frequency of angina attacks. In acute and chronic ischemic cerebral circulatory disorders improves blood circulation in the focus of ischemia, contributes to the redistribution of blood in favor of the ischemic area. It is effective in case of vascular and dystrophic ocular pathology. The drug eliminates the functional disorders of the nervous system in patients with chronic alcoholism during withdrawal syndrome.

Pharmacokinetics

Bioavailability of the drug after intravenous (IV) injection is 100%. Maximal concentration (Cmax) in blood plasma is reached immediately after administration. The drug is metabolized in the body to form two main metabolites, which are excreted by the kidneys. The elimination half-life (T1/2) is 3-6 hours.

Indications for use

As part of the complex therapy of coronary heart disease (angina pectoris, myocardial infarction), chronic heart failure and dyshormonal cardiomyopathy, and as part of the complex therapy of acute and chronic blood circulation disorders of the brain (stroke and cerebrovascular insufficiency).

Hemophthalmus and retinal hemorrhages of various etiologies, central retinal vein thrombosis and its branches, retinopathies of various etiologies (diabetic, hypertensive).

Reduced work capacity, physical overexertion, including in athletes. Withdrawal syndrome in chronic alcoholism (in combination with specific therapy).

Dosage and administration

Because of the possible development of the excitatory effect it is recommended to use in the morning.

Cardiovascular diseases

As part of the complex therapy of 0.5-1 g per day by IV (5-10 ml of a solution for injection 500 mg/5 ml), applying the entire dose at once or dividing it into 2 times. The course of treatment is 4-6 weeks.

Impaired cerebral circulation

Acute phase – 0.5 g 1 time a day v/v for 10 days, then switch to oral dosage form. The total course of treatment is 4-6 weeks.

Chronic disorders

  • Oral dosage form is used. Repeated courses (usually 2-3 times a year) are possible after consultation with the doctor.

Vascular pathology and dystrophic retinal diseases

  • Parabulbar 0.5 ml of 500 mg/5 ml solution for 10 days.

Mental and physical overload, including in athletes:

  • Adults 0.5 g v/v (5-10 ml of 500 mg/5 ml solution for injection) once daily. The course of treatment is 10-14 days. If necessary, treatment should be repeated in 2-3 weeks.

Chronic alcoholism.

IV – 0.5 g 2 times a day. The course of treatment – 7-10 days.

Side effects

The cardiovascular system: rare – tachycardia, changes in blood pressure.

The central nervous system (CNS): rare – psychomotor agitation.

The digestive system: rare – dyspeptic symptoms.

Allergic reactions: rare – skin itching, redness, rash, swelling.

Contraindications

  • Increased intracranial pressure (including with impaired venous outflow, intracranial tumors);
  • Organic CNS lesions;
  • pregnancy, lactation;
  • hypersensitivity to the drug;
  • under 18 years of age.

Drug interactions

Increases the effect of coronadilators, some hypotensive drugs, cardiac glycosides. It can be combined with antianginal drugs, anticoagulants, antiaggregants, antiarrhythmic drugs, diuretics and bronchodilators. Caution must be exercised when combining with nitroglycerin, nifedipine, alpha-adrenoblockers, hypotensive agents and peripheral vasodilators because of possible development of moderate tachycardia and arterial hypotension.

Special indications

Caution should be exercised in patients with chronic liver and renal diseases during long-term use of the drug. There are no sufficient data on the use of meldonium in children.

Many years of experience in the treatment of acute myocardial infarction and unstable angina in cardiology departments show that meldonium is not a first-line drug for acute coronary syndrome.

Use during pregnancy and lactation.

The safety of using the drug during pregnancy has not been proven.

To avoid possible adverse effects on the fetus, it is not prescribed during pregnancy.

It is not known whether the drug is excreted with the milk of the mother. If the drug treatment for the mother is necessary, breastfeeding of the child is stopped.

Effect on the ability to drive vehicles and operate other mechanisms.

There are no data on adverse effects of the drug on the speed of psychomotor reactions.

Form of production

Solution for injection 500 mg/5 ml in 5 ml ampoules N5(1×5), N10(2×5)

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25°C. Keep out of the reach of children! Do not freeze!

Shelf life

4 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by doctor’s prescription.

Lignova- powder for preparation of oral solution

INSTRUCTIONS FOR MEDICAL USE

LIGNOVA

Trade name of the drug: Lignova

Active substance (INN): hydrolysis lignin

Dosage form: powder for preparation of oral solution.

Contents: hydrolyzed lignin

Description: dark brown to black amorphous powder without odor.

Pharmacotherapeutic group: medicine for detoxification of the body.

ATX code: A07BC

Pharmacological properties

Pharmacodynamics

The drug is a natural enterosorbent consisting of products of hydrolysis of cotton fiber components – lignin polymer, whose structural elements are derivatives of phenylpropane and hydrocellulose.

It has high sorption activity and non-specific detoxifying effect.

It binds and removes from the body pathogenic bacteria and their endotoxins, drugs, poisons, salts of heavy metals, alcohol, allergens, as well as excess of certain metabolic products, including bilirubin, cholesterol, urea, metabolites responsible for the development of endogenous toxicity.

Non-toxic, not absorbed, completely eliminated from the intestine within 24 hours.

Indications for use

As a detoxifying agent in adults and children in exogenous and endogenous intoxications of various origins:

  • Drug poisoning, alkaloids, salts of heavy metals, alcohol and other harmful substances;
  • complex treatment of food poisoning, such as salmonellosis, dysentery, dyspepsia;
  • purulent inflammatory diseases that are clearly indicative of poisoning;
  • Hyperbilirubinemia and hyperazotemia associated with hepatic and renal failure;
  • food and drug allergies;
  • For the prevention of chronic diseases in personnel working in hazardous conditions.

Dosage and administration

The drug is taken orally an hour before a meal and taking medications, stirring 5 grams in 100 ml of boiled and cooled water.

The daily dose depends on the severity of the disease, body weight and age of the patient and is 0.5-1.0 g / kg body weight in 2-4 times a day. Average single doses: for children aged 7-14 years old – 5 g 2-4 times daily; for children over 14 years old and adults – 5-10 g 3-4 times daily. Duration of intake in acute conditions of 3-5 days, with allergic diseases and chronic intoxications – up to 14 days. Repeated courses are carried out after 2 weeks on the doctor’s recommendation.

Possible gastric lavage of patients with acute poisoning with a probe using the drug.

Side effects

The drug is well tolerated. Use of the drug may cause stool coloring in black, which is not a contraindication for the drug use. Allergic reactions and constipation are rare. Prolonged use may lead to impaired absorption of vitamins, calcium, in connection with which preventive administration of multivitamins and calcium preparations is recommended.

Contraindications

Individual intolerance to the drug. It is not advisable to use the drug in acute gastric and 12 duodenal ulcer, bowel atony.

Drug interactions

Because of the adsorptive properties, the drug is able to reduce the effectiveness of simultaneously taken drugs, so it is not recommended to take other drugs 2 hours before and 2 hours after taking the drug.

Special indications

Not described.

Overdose

It has not been described.

Form of production

Powder for preparation of solution for oral administration 5 g №10 (1х10), №20 (2х10), №30 (3х10) in sachets or 10 g, 35 g, 50 g, 70 g, 105 g, 200 g in vials.

Storage conditions

Store in a dry, dark place at temperatures under 25 ° C. Keep out of the reach of children!

Shelf life

2 years. Do not use after the expiration date.

Conditions for dispensing from pharmacies

Released without a prescription.

Mamakarit- film-coated tablets

INSTRUCTIONS FOR MEDICAL USE

MAMACARIT

Trade name of the drug: Mamacarit

Active substance (INN): Capecitabine

Dosage form: film-coated tablets

Contents:

1 film-coated tablet contains:

Active ingredient: Capecitabine 150 mg or 500 mg

Excipients: lactose (anhydrous), croscarmellose sodium, polyvinylpolypyrrolidone, microcrystalline cellulose, magnesium stearate.

Excipients in film coating: hydroxypropyl methylcellulose, polyethylene glycol 4000, titanium dioxide.

Description: Round, biconvex film-coated tablets, white or almost white.

Pharmacotherapeutic group: Antineoplastic agent

ATX code: L01BC06

Pharmacological properties

Pharmacodynamics

Capecitabine is a fluoropyrimidine carbamate derivative, an oral cytostatic agent that is activated in tumor tissue and has a non-selective cytotoxic effect. In vitro capecitabine has no cytotoxic effect, in vivo it is converted into -fluorouracil (FU), which undergoes further metabolism. PV formation occurs mainly in tumor tissue under the action of tumor angiogenic factor – thymidine phosphorylase (dTdPhase), which minimizes the systemic effect of PV on healthy body tissues. Sequential enzymatic biotransformation of capecitabine into FP creates higher concentrations of the drug in tumor tissues than in the surrounding healthy tissues.

The metabolism of FP into 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP) occurs in both healthy and tumor cells. These metabolites damage cells through two different mechanisms. First, FDUMF and the folate cofactor N5-10-methyltetrahydrofolate bind to thymidylate synthase (TS) to form a covalently bound tertiary complex, which leads to the inhibition of thymidylate formation from uracil. Thymidylate is an essential precursor of thymidine triphosphate, an important component of DNA synthesis. Second, during RNA synthesis, nucleus transcriptional enzymes can mistakenly incorporate FUTP instead of uridine triphosphate (UTP). This metabolic “mistake” disrupts the RNA process and protein synthesis.

Pharmacokinetics

After oral administration, capecitabine is absorbed rapidly and completely, after which it is transformed into its metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCT) and 5′-deoxy-5-fluoruridine (5′-DFUR). Concomitant ingestion decreases the absorption rate of capecitabine, but the area under the concentration-time curve (AUC) of 5′-DFTCT and the next metabolite, 5-fluorouracil (5-FU), are not significantly affected. Capecitabine, 5′-DFCT, 5′-DFUR and 5-FU bind to proteins, less than 60%, and is independent of concentration (mainly with albumin, about 35%).

Liver carboxylesterase performs the first metabolic conversion of capecitabine to 5′-DPCT, which is then transformed to 5′-DFUR by cytidine deaminase, which is mainly found in the liver and tumor tissues. The AUC for 5-FU is 6-22 times lower than after intravenous 5-FU jet injection at a dose of 600mg/m2. Capecitabine metabolites become cytotoxic only after conversion to 5-FU and 5-FU anabolites. The 5-FU is further catabolized to form inactive metabolites, dihydro-5-fluorouracil (FUN2), 5-fluorourareidopropionic acid (FUPC), and alpha-fluoro-beta-alanine (FBAL); this pseudo-coenzyme is controlled by dihydropyrimidine dehydrogenase (DPD), the activity of which limits the rate of reaction.

The half-life T1/2 of capecitabine, 5′-DPCR, 5′-DFUR, 5-FU, and FBAL is 0.85, 1.11, 0.66, 0.76, and 3.23 hours, respectively. In the range of therapeutic doses, pharmacokinetic parameters of capecitabine and its metabolites, except for 5-FU, are dose-dependent. Urinary excretion is 95.5%, fecal excretion is 2.6%. The main metabolite in the urine is F-BAL, which accounts for 57% of the dose taken. About 3% of the administered dose is excreted unchanged in the urine.

Pharmacokinetics in patients of special groups

Gender, presence or absence of liver metastases before treatment, patient’s general condition index, concentration of total bilirubin, serum albumin, activity of ALT and AST in patients with colorectal cancer had no significant effect on pharmacokinetics of 5′-DFUR, 5-FU and FBL.

Patients with metastatic liver damage. In patients with mild to moderate hepatic dysfunction due to metastasis, there is no clinically significant change in the pharmacokinetics of capecitabine. There are no data on pharmacokinetics in patients with severe hepatic impairment.

Patients with impaired renal function. The results of pharmacokinetic study, conducted in cancer patients with different (from mild to severe) degree of renal failure, indicate that the pharmacokinetics of unchanged drug and 5-FU does not depend on creatinine clearance (CK). CK affects the AUC of 5′-DFUR (35% increase in AUC when CK decreases by 50%) and FBL (114% increase in AUC when CK decreases by 50%). FBAL is a metabolite that has no antiproliferative activity.

Elderly patients. Age has no effect on the pharmacokinetics of 5′-DFUR and 5-FU. AUC of FBL increased in patients aged 65 years and older (20% increase in age was accompanied with 15% increase in AUC of FBL), which is probably due to changes in renal function.

Indications for use

Breast cancer

  • Combination therapy with docetaxel for locally advanced or metastatic breast cancer when chemotherapy including anthracyclines has failed.
  • monotherapy of locally advanced or metastatic breast cancer resistant to chemotherapy with taxanes or anthracycline-type drugs or in the presence of contraindications to them.

Colorectal cancer

  • Adjuvant therapy for colorectal cancer.
  • Therapy for metastatic colorectal cancer.

Gastric cancer

First-line therapy for advanced gastric cancer.

Dosage and administration

Orally with water, not later than 30 minutes after a meal.

Monotherapy

1250 mg/m2 twice daily, morning and evening (2500 mg/m2 per day), for 2 weeks, followed by a 7-day break.

Combination therapy

Breast cancer

1250 mg/m2 twice daily for 2 weeks followed by a one-week break in combination with docetaxel (75 mg/m2 as a 1-hour intravenous infusion once every 3 weeks).

Premedication is given before administration of docetaxel according to the instructions for its use

Colorectal cancer and gastric cancer

As part of combination therapy, the recommended dose of capecitabine is 800-1000 mg/m² 2 times per day for two weeks followed by a seven-day break, or 625 mg/m² 2 times per day for a continuous regimen. The addition of immunobiologic agents to combination therapy does not affect the dose of capecitabine. Hyperhydration when using cisplatin and antiemetics premedication when using cisplatin or oxaliplatin in combination with capecitabine is performed according to the instructions for their medical use.

The recommended duration of adjuvant therapy for colorectal cancer is 6 months.

Calculation of total daily dose of capecitabine is carried out depending on body surface area.

Table 1. Standard and reduced doses of the drug calculated for 1250 mg/m2 of body surface area

 Dose of 1250 mg/m2 (2 times/day)
Full dose 1250 mg/m2Number of tablets 150 mg and/or 500 mg per dose (morning and evening)75% of the dose 950 mg/m250% of the dose 625 mg/m2
Body surface area (m2)Dose per administration (mg)  150 mg  500 mgDose per administration (mg)Dose per administration (mg)
≤1.26150031150800
1.27-1.381650131300800
1.39-1.521800231450950
1.53-1.662000415001000
1.67-1.7821501416501000
1.79-1.9223002418001150
1.93-2.062500519501300
2.07-2.1826501520001300
≥2.1928002521501450

Table 2. Standard and reduced doses of the drug calculated for 1000 mg/m2 body surface area

 Body surface area (m2)Dose of 1000 mg/m2 (2 times/day)
 Full dose 1000 mg/m2Number of tablets 150 mg and/or 500 mg per dose (morning and evening)  75% of the dose 750 mg/m2  50% of the dose 500 mg/m2
Dose per administration (mg)  150 mg  500 mgDose per 1 administration (mg)Dose per 1 administration (mg)
≤1.26115012800600
1.27-1.381300221000600
1.39-1.521450321100750
1.53-1.661600421200800
1.67-1.781750521300800
1.79-1.921800231400900
1.93-2.062000415001000
2.07-2.1821501416001050
≥2.1923002417501100

Dose adjustment during treatment

Toxic effects during treatment with capecitabine can be eliminated by symptomatic therapy and/or by changing the dose of capecitabine (by interrupting treatment or reducing the dose of the drug). In case of grade 1 toxicity the dose is not changed. In case of grade 2 and 3 toxicity the use of capecitabine should be interrupted until its disappearance or reduction of toxicity to grade 1. Capecitabine can be resumed at the full dose or with adjustments, according to the recommendations given in Table 3.

If signs of grade 4 toxicity develop, treatment should be stopped or temporarily interrupted until the symptoms subside or decrease to grade 1, after which the drug can be resumed at a dose equal to 50% of the previous dose.

Capecitabine should be discontinued immediately in case of severe or moderate toxicity. If several doses of capecitabine have been missed due to toxicity, these doses are not replenished, but simply the planned cycles of therapy are continued. If the dose has had to be reduced, it should not be increased afterwards. The following are recommendations for dose changes in case of toxic events (according to the National Cancer Institute of Canada Clinical Trials Group Common Toxicity Criteria, NCIC CTG, version 1 or the US National Cancer Institute Common Criteria for Adverse Events, CTCAE, version 3).

 Toxicity levelChanging the dose over the course of a therapy cycleDose adjustment during the next therapy cycle (% of initial dose)
Level 1Continue with the same doseContinue with the same dose
Level 2
at 1st appearanceInterrupt therapy until resolution to level 0-1100%
at 2nd appearanceInterrupt therapy until resolution to level 0-175%
at 3rd appearanceInterrupt therapy until resolution to level 0-150%
at 4th appearanceDiscontinue therapy completely 
Level 3
at 1st appearanceInterrupt therapy until resolution to level 0-175%
at 2nd appearanceInterrupt therapy until resolution to level 0-150%
at 3rd appearanceDiscontinue therapy completelyNot applicable
Level 4
at 1st appearanceDiscontinue therapy completely OR, if the physician believes it is in the patient’s best interest to continue treatment, interrupt therapy until resolution to level 0-150%
at 2nd appearanceDiscontinue therapy completelyNot applicable
Table 3. Dose Variation of Capecitabine with Monotherapy

Hematological toxicity

If during therapy with capecitabine a decrease in neutrophils <1.5 x 109/l and/or platelets <100 x 109/l is observed, treatment should be interrupted.

General recommendations for combination therapy

If toxicity occurs during combination therapy, the recommendations for capecitabine dose adjustment in Table 3 above and the corresponding recommendations in the instructions for use of other drugs should be followed.

At the beginning of the therapy cycle, if the administration of capecitabine or other drug(s) is expected to be delayed, all drugs should be delayed until conditions for resuming therapy with all drugs are met.

If, during the combination therapy cycle, toxicity does not appear to be related to the use of capecitabine, the therapy with capecitabine should be continued and the dose of the other drug should be adjusted according to the recommendations in the drug’s instructions for medical use.

If the other drug(s) must be discontinued, treatment with capecitabine can be continued if the requirements for resumption of therapy with capecitabine are met. These recommendations apply for all indications and all special patient groups.

Dose adjustment in special cases

Impaired liver function in patients with liver metastases

There is no need to change the starting dose in patients with liver metastases and mild to moderate hepatic dysfunction. However, these patients should be closely monitored. The use of the drug in patients with severe hepatic impairment has not been studied.

Renal dysfunction

In patients with baseline moderate renal failure (Cockroft- Gault formula, 30-50 ml/min) it is recommended to reduce initial single dose of 1250 mg/m2 by 25%, while initial single dose of 1000 mg/m2 in moderate renal failure does not need to be corrected. In patients with mild renal failure (CKD 51-80 ml/min) correction of the initial dose is not required. In severe renal failure capecitabine is contraindicated.

In case of 2nd, 3rd or 4th degree undesirable phenomenon the patient should be closely monitored and the therapy should be immediately stopped with the purpose of further dose adjustment according to the recommendations stated in table 3. If calculated creatinine clearance decreased during therapy to less than 30 ml/min, therapy with Capecitabine should be discontinued. Recommendations to adjust the dose of the drug in moderate renal failure apply to both monotherapy and combination therapy.

Elderly and senile patients

Correction of the initial dose during monotherapy with capecitabine is not required. However, taking into account the fact that the 3rd and 4th degree adverse events when using capecitabine both in monotherapy and in combination with other drugs developed more often in patients over 60 years old than in younger patients, close monitoring of elderly patients is recommended.

When treated in combination with docetaxel, it is recommended to reduce the starting dose of the drug

Capecitabine to 75% (950 mg/m2 twice daily).

When treated in combination with irinotecan in patients aged 65 or older it is recommended to reduce initial dose of Capecitabine to 800 mg/m2 twice daily.

Side effects

Digestive system: diarrhea, nausea, vomiting, stomatitis, abdominal pain, constipation, epigastric pain, dyspepsia, dry mouth, flatulence, soft stool, anorexia, appetite impairment, oral candidiasis, hyperbilirubinemia, taste disorders.

Nervous system disorders: increased fatigue, weakness, pronounced somnolence, headache, paresthesia, dizziness, sleep disturbances, asthenia.

Skin and subcutaneous tissues: palmar-subcutaneous syndrome, dermatitis, dry skin, alopecia, itching, focal peeling, hyperpigmentation of the skin, skin cracking.

Other: increased lacrimation, fever, possible dehydration, weight loss, possible dyspnea, cough, pain in extremities, lower back pain, myalgia, cardiotoxic effect (most likely in patients with IHD), edema of lower extremities, anemia.

Contraindications

Hypersensitivity to capecitabine and other fluoropyrimidine derivatives or any drug components.

Established DPD (dihydropyrimidine dehydrogenase) deficiency as for other fluoropyrimidines. Concomitant use of sorivudine or its structural analogues, such as brivudine. Severe renal insufficiency (creatinine clearance below 30 ml/min).

Severe hepatic insufficiency.

Initial neutrophil count <1.5 x 109/l and/or platelets <100 x 109/l

Pregnancy and lactation period.

Age under 18 years (effectiveness and safety of use have not been established).

Caution: in case of CHD, liver or kidney function abnormality, age over 60 years old, concomitant use with coumarin-type oral anticoagulants.

Drug interactions

Substrates of cytochrome Р450 2С9. Studies on the interaction of capecitabine and other drugs metabolized by 2C9 isoenzyme of cytochrome Р450 system have not been conducted. Caution should be exercised when prescribing capecitabine concomitantly with these drugs.

Coumarin anticoagulants: Capecitabine enhances the effects of indirect anticoagulants, which may lead to clotting disorders and bleeding in a few days or months from the beginning of therapy with capecitabine; in several cases such phenomena were observed a month after treatment completion. Increases the area under the concentration-time curve (AUC) of warfarin by 57% and the international normalized ratio (INR) by 91%.

Phenytoin: Capecitabine increases the plasma concentration of phenytoin, which is presumably due to inhibition of CYP2C9 isoenzyme by capecitabine. In patients taking capecitabine concomitantly with phenytoin, it is recommended to monitor phenytoin plasma concentrations regularly.

Antacids containing aluminum and magnesium hydroxide: slightly increase plasma concentrations of capecitabine and one metabolite (5′-DPCR); the three main metabolites (5′-DFUR, FU and FBAL) of capecitabine are not affected.

Calcium folinate (leucovorin) does not affect the pharmacokinetics of capecitabine and its metabolites. However, the toxic effect of capecitabine may be enhanced due to the effect of calcium folinate on the pharmacodynamics of the drug.

Sorivudine and its analogues: potentially can lead to fatal enhancement of toxicity of fluoropyrimidines due to inhibition of dihydropyrimidine dehydrogenase by sorivudine. Capecitabine should not be administered simultaneously with sorivudine or its structural analogues such as brivudin, and at least a four-week interval between the end of therapy with sorivudine or its structural analogues (including brivudin) and the beginning of treatment with capecitabine should be observed. Allopurinol: due to a possible decrease in the effectiveness of fluorouracil, concomitant administration of allopurinol with capecitabine should be avoided.

Interferon alfa: The maximum tolerated dose (MTD) of capecitabine in combination with interferon alfa-2a is 2000 mg/m2 per day, while the MTD of capecitabine is 3000 mg/m2 for monotherapy.

Radiation therapy: the MPD of capecitabine in combination with radiation therapy is 34% lower than the MPD of capecitabine used in monotherapy.

Oxaliplatin: no clinically significant difference in exposure to capecitabine or its metabolites, free platinum or total platinum was observed with the combined use of capecitabine and oxaliplatin, regardless of the presence of bevacizumab.

Bevacizumab: No clinically significant effect of bevacizumab on the pharmacokinetics of capecitabine or its metabolites has been noted.

Cyclophosphamide: increases cytotoxicity of capecitabine due to increased thymidine phosphorylase activity.

Special indications

Patients taking capecitabine should be closely monitored for signs of toxicity. Most adverse events are reversible and do not require permanent withdrawal of capecitabine, although it may be necessary to reduce the dose or temporarily discontinue it. The spectrum of cardiotoxicity during treatment with capecitabine is similar to that of other fluoropyrimidines. Administration of fluoropyrimidines may be accompanied by cardiotoxicity, including ECG changes, myocardial infarction, angina pectoris, arrhythmias, cardiogenic shock, sudden death. These adverse events are more common in patients with coronary heart disease (CHD).

In rare cases during treatment with fluorouracil unexpected severe toxicity in the form of stomatitis, diarrhea, neutropenia and neurotoxicity due to insufficient activity of dihydropyrimidine dehydrogenase have been observed.

Treatment with capecitabine may cause diarrhea, sometimes severe. The average time before the first signs of grade 2-4 diarrhea was 31 days. Patients with severe diarrhea should be monitored closely, with fluid and electrolyte replacement if dehydrated. Grade 2 diarrhea is defined as increased frequency of stools up to 4-6 times per day, or stools at night; grade 3 diarrhea – as increased stools up to 7-9 times per day, or incontinence and malabsorption syndrome; grade 4 diarrhea – as increased stools up to 10 or more times per day, or blood macro-appearance in stool, or necessity of parenteral maintenance therapy. If stage 2, 3, or 4 diarrhea occurs, therapy with capecitabine should be discontinued until diarrhea has disappeared or has reduced to stage 1. For grade 3 and 4 diarrhea, treatment with capecitabine should be resumed with dose reduction. Standard anti-diarrheal medications (e.g., loperamide) are recommended. Frequency of gastrointestinal toxic events during capecitabine treatment in patients aged 60-79 years old was the same as in general population of patients. In patients aged 80 years and older reversible gastrointestinal disorders of the 3rd and 4th grades, such as diarrhea, nausea and stomatitis, developed more frequently. The drug capecitabine may cause palmar plantar syndrome (palmar plantar erythrodysesthesia, or chemotherapy-induced acral erythema), which is characterized by numbness, paresthesias, tingling, swelling, redness, scaling, blistering and severe pain syndrome. Grade 2 palm plantar syndrome is characterized by painful redness and swelling of the hands and/or feet, and the discomfort caused by these symptoms interferes with the patient’s daily activities. Grade 3 palm plantar syndrome is defined as moist desquamation, ulceration, blistering and severe pain in the hands and/or feet, as well as severe discomfort that makes it impossible for the patient to do any kind of daily activity. If grade 2 or 3 palmar-todermal syndrome occurs, the use of capecitabine should be interrupted until the symptoms disappear or are reduced to grade 1; if grade 3 syndrome occurs, subsequent doses of capecitabine should be reduced. Patients with mild to moderate impairment of liver function due to metastases should be closely monitored. If serum bilirubin level rises >3.0 x IUF (upper limit of normal) or liver aminotransferase activity (ALT, AST) rises >2.5 x IUF, the drug capecitabine should be stopped immediately until toxicity disappears or is reduced to grade 1.

Caution should be exercised when prescribing capecitabine to patients with renal insufficiency. As in fluorouracil treatment, the incidence of therapy-related adverse events of 3rd and 4th degree severity was higher in patients with moderate renal insufficiency (CK 30-50 ml/min). In patients taking coumarin (indirect) anticoagulants and capecitabine it is necessary to monitor blood clotting system regularly. Appointment of coumarin anticoagulants is possible not earlier than 1 month after termination of therapy with capecitabine because of possible hypocoagulation and bleeding development.

The safety and efficacy of capecitabine in children has not been studied.

During therapy with capecitabine and for at least 3 months after its completion, reliable contraceptive methods should be used. If pregnancy occurs during the therapy, the patient should be aware of the potential threat to the fetus.

Influence on the ability to drive a car and operate complex mechanisms

During therapy with capecitabine it is necessary to observe caution while driving motor transport and engaging in other potentially dangerous activities requiring high concentration and quick psychomotor reactions.

Overdose

Symptoms: nausea, vomiting, diarrhea, mucous membrane inflammation (mucositis), gastrointestinal tract irritation and bleeding, as well as bone marrow suppression.

Treatment: symptomatic. An antidote to capecitabine is not known.

Form of production

150 mg or 500 mg film-coated tablets in carton packs

Storage conditions

Store in a dry place, protected from light, at a temperature not more than 25°C. Keep out of the reach of children!

Shelf life

3 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by a doctor’s prescription.

Nifustal – oral suspension

INSTRUCTIONS FOR MEDICAL USE

NIFUSTAL

Trade name of the drug: Nifustal

Active substance (INN): Nifuroxazide

Dosage form: oral suspension

Contents:

5 ml of the suspension contains:

active substance: nifuroxazide 220 mg;

Excipients: carbomer, sucrose, citric acid, sodium hydroxide, methylparaben (E219), simethicone emulsion 30%, banana essence, purified water.

Description: light yellow coloured suspension with banana odour; during storage it slightly settles, but after shaking returns to the homogeneous suspension without leaving a thick sediment at the bottom of the bottle.

Pharmacotherapeutic group: Antibacterial synthetic drug (gr. nitrofuran).

ATX code: A07AX03

Pharmacological properties

Pharmacodynamics

Nifuroxazide is a derivative of 5-nitrofuran. It has antibacterial action in intestine lumen against some species of Gram-positive bacteria of Staphylococcus genus and some species of Gram-negative bacteria of Yersinia spp, Escherichia spp, Citrobacter spp, Enterobacter spp, Klebsiella spp, Salmonella spp. Nifuroxazide does not exhibit antibacterial activity against bacteria of Proteus vulgaris, Proteus mirabilis and Pseudomonas aeruginosa species.

Nifuroxazid does not destroy saprophytic intestinal flora. It does not cause emergence of strains resistant to nifuroxazide. The exact mechanism of action is not known. Nifuroxazide can inhibit dehydrogenase activity and disrupt protein synthesis in bacterial cells. Efficacy is independent of the pH in the intestinal lumen.

Pharmacokinetics

Nifuroxazide is practically not absorbed from the gastrointestinal tract after oral administration. It is excreted unchanged in the feces.

Indications for use

Treatment of acute bacterial diarrhea caused by susceptible strains of Staphylococcus spp., Salmonella spp., Escherichia coli in the absence of signs of invasion (e.g., deterioration of general condition, fever, toxicoin infection, etc.).

The dose and rehydration method (oral or intravenous) are determined according to the severity of the diarrhea, patient’s age, state of health, presence of concomitant diseases.

Dosage and administration method

The drug is administered orally. Shake the bottle thoroughly before use until a homogeneous suspension is obtained. If necessary, the suspension can be taken with water. The drug is taken regardless of meals.

Doses for children:

  • 2 to 6 months – 1 to 2 measuring spoons for 2.5 ml 2 times a day, every 12 hours;
  • From 7 months to 6 years of age – 1 measuring spoon for 5 ml 3 times a day, every 8 hours;
  • Adults and children over 7 years of age – 1 scoop of 5 ml 4 times a day, every 6 hours.

Nifuroxazide should not be taken for more than 3 days without a physician’s consultation. If after that the symptoms do not disappear, a more thorough diagnosis to determine the cause of the symptoms is necessary, and antibiotic therapy should be considered.

During the treatment of acute diarrhea, constant oral replenishment of fluid deficiency in the body is mandatory, depending on the overall condition of the patient.

A measuring spoon for 2.5 ml contains 110 mg of nifuroxazide.

A measuring spoon for 5 ml contains 220 mg of nifuroxazide.

Side effects

Hepatopoietic and lymphatic system disorders: One case of granulocytopenia has been described.

Gastrointestinal tract:

In cases of individual hypersensitivity to nifuroxazide, abdominal pain, nausea and exacerbation of diarrhea may appear. In the case of such symptoms of minor intensity, there is no need for special therapy or discontinuation of nifuroxazide. If the above symptoms of significant intensity develop, the drug should be discontinued. In the future, the patient should not take nitrofuran derivatives.

Skin and subcutaneous tissue:

Skin reactions in the form of skin rash are rare (1/10,000 to <1/1,000). One case of pustulosis in an elderly person and one case of nodular scabies due to contact allergy to nifuroxazide has been described.

Nifuroxazide is usually well tolerated and has virtually no side effects.

Contraindications

Nifuroxazid is contraindicated for use in hypersensitivity to any of its components, as well as in allergy to 5-nitrofuran derivatives. The drug should not be used in premature infants and children under 2 months of age.

Drug interactions

Alcohol consumption during treatment with nifuroxazide may cause disulfiram-like reactions. During administration of Nifuroxazide, concomitant administration of other oral medications should be avoided due to the strong adsorptive properties of the drug.

Special indications

If diarrhea persists after 3 days of treatment, a physician should be consulted. The physician should determine the cause of the symptoms and consider prescribing antibiotic therapy.

The drug is used with the obligatory observance of a diet, excluding juices, raw vegetables and fruits, as well as spicy and hard-to-digest foods.

During treatment with nifuroxazide, the use of alcoholic beverages is contraindicated, because the drug increases the body’s sensitivity to alcohol and may provoke a reaction expressed as an exacerbation of diarrhea, vomiting, abdominal pain, hyperemia of the skin, a feeling of heat in the face and upper torso, noise in the head, difficulty in breathing, tachycardia, a feeling of fear.

Due to the presence of sucrose in the drug, patients with rare hereditary diseases associated with fructose intolerance, impaired glucose-galactose absorption or sucrose-isomaltose deficiency should not take this drug.

Administration of the drug during pregnancy and lactation

The use of nifuroxazide during pregnancy:

There are no clinical data regarding the use of nifuroxazide during pregnancy.

Animal studies show no direct or indirect effects on the course of pregnancy, the development of the embryo or fetus, the course of labor, or the development of the child after delivery. Nifuroxazide is preferably not used in pregnant women. Before prescribing the drug, the treating physician should carefully weigh the expected benefit/risk of its use.

Nifuroxazide use during lactation:

Nifuroxazide is not absorbed in the gastrointestinal tract. Nevertheless, due to the lack of sufficient clinical data, caution should be exercised when prescribing nifuroxazide to breastfeeding women.

It is necessary to consult a physician for breast-feeding women before taking nifuroxazide.

Effect of the drug on the ability to drive vehicles and operate machinery

Nifuroxazide has no effect on the ability to drive vehicles and operate machinery.

Overdose

One case of overdose of Nifuroxazid in form of oral suspension has been described in a child aged 2 years old who took unspecified quantity of the drug. The overdose manifested as drowsiness and diarrhea, which passed on their own. In case of overdose, gastric lavage and symptomatic treatment are recommended.

Form of production

Oral suspension 220 mg/5 ml 90 ml (bottles with measuring spoon or cup).

Storage conditions

Store in a dry, dark place at a temperature not exceeding 25 ° C. Keep out of the reach of children!

Shelf life

3 years.

After opening the bottle shelf life of the suspension – 14 days. Do not use after the expiration date.

Conditions for dispensing from pharmacies

Released by doctor’s prescription.

Despiron- suspension granules

INSTRUCTIONS FOR MEDICAL USE

DESPIRON

Trade name of the drug: Despirone

Active substance (INN): Spiramycin

Form release: granules for preparation of suspension for oral administration.

Contents:

Each 5 ml of the suspension contains:

active substance: spiramycin – 1.5 million IU (333 mg).

Excipients: crosspovidone, sodium benzoate, xanthan gum, sucrose, sucralose, flavoring (vanilla multicomponent).

Description: almost white or slightly yellowish pellets with a smell of vanillin.

Pharmacotherapeutic group: Antibiotics (gr. macrolides)

ATX code: J01FA02

Pharmacological properties

It is an antibiotic of macrolide group. The mechanism of antibacterial action is caused by inhibition of protein synthesis in a microbial cell at the expense of binding to 50S-subunit of ribosome.

Sensitive microorganisms (MAC<1 mg/l): Gram-positive aerobes – Bacillus cereus, Corynebacterium diphtheriae, Enterococcus spp., Rhodococcus equi, Staphylococcus spp. (methicillin-sensitive and methicillin-resistant strains), Streptococcus B, unclassified Streptococcus, Streptococcus pneumoniae, Streptococcus pyogenes; Gram-negative aerobes – Bordetella pertussis, Branhamella catarrhalis, Campylobacter spp, Legionella spp., Moraxella spp.; anaerobes – Actinomyces spp., Bacteroides spp., Eubacterium spp., Mobiluncus spp., Peptostreptococcus spp., Porphyromonas spp., Prevotella spp, Propionibacterium acnes; different – Borrelia burgdorferi, Chlamydia spp., Coxiella spp., Leptospiria spp., Mycoplasma pneumoniae, Treponema pallidum, Toxoplasma gondii.

Moderately susceptible microorganisms (antibiotic is moderately active in vitro at antibiotic concentrations in the focus of inflammation ≥ 1 mg/L, but < 4 mg/L): Gram-negative aerobes – Neisseria gonorrhoeae; aerobes – Clostridium perfringens; various – Ureaplasma urealyticum.

Resistant microorganisms (MPC>4 mg/l; at least 50% of strains are resistant): Gram-positive aerobes – Corynebacterium jekeium, Nocardia asteroides; Gram-negative aerobes – Acinetobacter spp., Enterobacter spp., Haemophilus spp., Pseudomonas spp.; anaerobes – Fusobacterium spp.; miscellaneous – Mycoplasma hominis.

Pharmacokinetics

Absorption

Absorption of spiramycin is rapid but incomplete, with wide variability (10% to 60%). After an oral dose of 6 million IU, the Cmax of spiramycin in plasma is about 3.3 µg/ml. Absorption is not affected by food intake.

Distribution

Binding to plasma proteins is low (approximately 10%). Vd about 383 l. The drug penetrates well into saliva and tissues (concentration in lungs is 20-60 µg/g, in tonsils

  • 20-80 µg/g, in infected sinuses 75-110 µg/g, in bones 5-100 µg/g). 10 days after the end of treatment, spiramycin concentration in spleen, liver, kidney is 5-7 µg/g.

Penetrates through the placental barrier (fetal blood concentrations are approximately 50% of those in maternal serum). Concentrations in placental tissue are 5 times higher than the corresponding concentrations in blood serum. It is excreted with breast milk. Spiramycin does not penetrate the cerebrospinal fluid.

Metabolism and excretion

Spiramycin is metabolized in the liver to form active metabolites with an unspecified chemical structure.

T1/2 from plasma is about 8 hours. It is mainly excreted in the bile (concentration is 15-40 times higher than in serum). Renal excretion is about 10% of the administered dose. The amount of drug excreted in the intestine (with feces) is very low.

INDICATIONS FOR USE

Infectious-inflammatory diseases caused by microorganisms sensitive to the drug:

  • Acute and chronic pharyngitis caused by beta-haemolytic streptococcus A (as an alternative to treatment with beta-lactam antibiotics, especially in case of contraindications to their use);
  • acute sinusitis (given the sensitivity of the most common microorganisms that cause this pathology, the use of the drug is indicated if there are contraindications to the use of beta-lactam antibiotics)
  • acute and chronic tonsillitis caused by spiramycin-sensitive microorganisms;
  • acute bronchitis caused by a bacterial infection that developed after acute viral bronchitis;
  • exacerbation of chronic bronchitis;
  • community-acquired pneumonia in patients without risk factors for adverse outcome, severe clinical symptoms, and clinical signs of pneumococcal etiology of pneumonia;
  • pneumonia caused by atypical pathogens (such as Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, Legionella spp.) or suspected (regardless of severity and presence or absence of risk factors for adverse outcome);
  • skin and subcutaneous tissue infections, including impetigo, impetiginosis, ecthyma, infectious dermohypodermitis (especially rye), secondary infectious dermatoses, erythrasma;
  • Oral infections (including stomatitis, glossitis);
  • Non-nococcal genital infections;
  • Toxoplasmosis, including in pregnancy;
  • Infections of the musculoskeletal system and connective tissue, including periodontal. Prevention of rheumatism recurrence in patients allergic to beta-lactam antibiotics. Eradication of Neisseria meningitidis from the nasopharynx (when contraindicated to take rifampicin) for prevention (but not treatment) of meningococcal meningitis:
  • In patients after treatment and before leaving quarantine;
  • in patients who have been in contact with persons who have excreted Neisseria meningitidis with saliva into the environment for 10 days before hospitalization.

Administration and dosages

The drug is taken orally.

Method of suspension preparation: suspension is prepared immediately before use. Pellets are shaken in vial, boiled water cooled to room temperature is added to the mark and mixed to get a homogeneous suspension.

Adults are prescribed 6-9 million IU per day. The daily dose is divided into 2 or 3 doses. The maximum daily dose is 9 million IU.

A daily dose of only 1.5 million IU should be used in children and adolescents aged 6 to 18 years.

In children over 6 years of age the daily dose is from 150,300,000 ME per kg of body weight, which is divided into 2 or 3 doses to 6 to 9 million ME. Maximum daily dose in children is 300,000 ME per kg of body weight, but if a child weighs more than 30 kg, it should not exceed 9 million ME.

For prevention of meningococcal meningitis in adults we use 3 million ME twice a day for 5 days, in children – 75000 ME/kg of body weight twice a day for 5 days. Patients with impaired renal function due to insignificant renal excretion of spiramycin do not require dose adjustment.

Side effects

The following classification was used to indicate the incidence of adverse reactions: very common (≥10%), common (≥1%, <10); infrequent (≥0.1%, <1%); rare (≥0.01%, <0.1%), very rare, including some reports (<0.01%), the incidence is unknown (according to available data the frequency cannot be determined).

Digestive system: nausea, vomiting, diarrhea; very rare – pseudomembranous colitis (<0.01%); frequency unknown – ulcerative esophagitis, acute colitis, acute intestinal mucosal damage in patients with AIDS while using spiramycin in high doses for cryptosporidiosis (only 2 cases).

Liver and biliary tract: very rare (<0.01%) – deviation of liver function tests from normal values; cholestatic or mixed hepatitis.

Nervous system: very rare (isolated cases) – transient paresthesia.

Blood system: very rare (<0.01%) – acute hemolysis.

Cardiovascular system: very rare – prolongation of QT interval on ECG.

Immune system: skin rash, urticaria, itching, very rare (<0.01%) – angioedema, anaphylactic shock, in some cases – vasculitis, including Schoenlein-Henoch purpura.

Skin and subcutaneous tissue: very rare – acute generalized exanthematous pustulosis.

Contraindications

  • lactation period;
  • glucose-6-phosphate dehydrogenase deficiency (risk of acute hemolysis);
  • Hypersensitivity to the drug components.

Caution is exercised when bile duct obstruction and hepatic insufficiency are prescribed.

Patients with impaired renal function due to low renal excretion of spiramycin a dose change is not required.

Drug interactions

Spiramycin inhibits absorption of carbidopa with a decrease in plasma concentrations of levodopa. Clinical monitoring and dose adjustment of levodopa is required when spiramycin is concomitantly administered.

Numerous cases of increased activity of indirect anticoagulants in patients taking antibiotics have been reported. The type of infection or severity of the inflammatory reaction, age, and general condition of the patient are predisposing risk factors. In such circumstances, it is difficult to determine the extent to which the infection itself or its treatment plays a role in MHO changes. However, this effect is observed more frequently with certain groups of antibiotics, in particular with fluoroquinolones, macrolides, cyclines, sulfamethoxazole+trimethoprim combination, some cephalosporins.

Special indications

During treatment with the drug in patients with liver diseases, liver function should be periodically monitored.

If generalized erythema and pustules with high body temperature occur at the beginning of treatment, acute generalized exanthematous pustulosis should be suspected; if such a reaction occurs, treatment should be stopped, and further use of spiramycin, both in monotherapy and in combination, is contraindicated.

Effect on the ability to drive vehicles and operate machinery

There is no information about the negative effect of the drug on the ability to drive vehicles and engage in other potentially dangerous activities. However, the severity of the patient’s condition should be taken into account, which may affect attention and speed of psychomotor reactions. Therefore, the decision about the possibility of driving a car or engaging in other potentially hazardous activities in a particular patient should be made by the attending physician.

Pregnancy and lactation

The drug may be administered during pregnancy when indicated.

There is a wide experience of using the drug during pregnancy. Risk of transmitting toxoplasmosis to fetus during pregnancy is decreased from 25% to 8% if the drug is used in the first trimester, from 54% to 19% – in the second trimester, and from 65% to 44% – in the third trimester. No teratogenic or fetotoxic effects were observed.

Breast-feeding should be discontinued if the drug is administered during lactation, because penetration of spiramycin into the breast milk is possible.

Overdose

There are no known cases of spiramycin overdose.

Symptoms: nausea, vomiting, diarrhea are possible. Cases of prolongation of the QT interval, which is resolved on withdrawal of the drug, have been observed in infants receiving high doses of spiramycin or after IV administration of spiramycin in patients predisposed to QT interval prolongation.

Treatment: in case of spiramycin overdose ECG-monitoring is recommended with determination of QT interval duration, especially in the presence of risk factors (hypokalemia, congenital prolongation of the QT interval, simultaneous use of drugs that prolong the QT interval and cause development of ventricular tachycardia of “pirouette” type). There is no specific antidote. Symptomatic therapy is recommended in case of suspected spiramycin overdose.

Form of production

Granules for preparation of suspension 1.5 ml/5 ml 75 ml (vials with or without measuring spoon or cup).

Storage conditions

Store in a dry, dark place at a temperature not exceeding 25 ° C. Period of storage of suspension after dilution at a temperature not exceeding 25 ° C for a maximum of 7 days, at 4 ° C for a maximum of 14 days.

Keep out of the reach of children!

Shelf life

2 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by a doctor’s prescription.

Encerta- film-coated tablets

INSTRUCTIONS FOR MEDICAL USE

ENCERTA

Trade name of the drug: Encerta

Active substance (INN): Entecavir

Dosage form: film-coated tablets.

Contents:

Each film-coated tablet contains:

Active ingredient: entecavir 0.5 mg or 1.0 mg.

Excipients: lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinylpyrrolidone K-30, corn starch, talc;

Contents of the shell: talc, hydroxypropyl methylcellulose, polyethylene glycol 4000 (macrogoal-4000), castor oil, titanium dioxide, tween 80 (polysorbate-80).

Description: Round, biconvex film-coated tablets, white or almost white.

Pharmacotherapeutic group: Antiviral medicine.

ATX code: J05AF10.

Pharmacological properties

Entecavir is a guanosine nucleoside analogue with potent and selective activity against HBV polymerase. Entecavir is phosphorylated to form active triphosphate (TR), which has an intracellular half-life of 15 hours. The intracellular concentration of TP is directly related to the extracellular level of entecavir, with no significant accumulation of the drug after the initial “plateau” level. By competing with its natural substrate, deoxyguanosine-TR, entecavir-TR inhibits all 3 functional activities of viral polymerase: (1) HUV polymerase priming, (2) reverse transcription of negative strand from pregenomic iRNA, and (3) synthesis of positive strand HBV DNA. Entecavira-TR is a weak inhibitor of cellular DNA polymerases a, ft, and 5 with Ki 18- 40 μm. In addition, at high concentrations of entecavir-TP and entecavir, no adverse effects have been noted with respect to polymerase and DNA synthesis in the mitochondria of HepG2 cells.

Pharmacokinetics

Absorption

In healthy subjects, entecavir is rapidly absorbed and the maximum plasma concentration is determined after 0.5-1.5 hours. When entecavir is taken repeatedly at doses of 0.1 to 1 mg, a dose-proportional increase in maximum concentration (Cmax) and area under the concentration-time curve (AUC) is noted. The equilibrium state is reached after 6-10 days of oral administration once daily, with a plasma concentration increase of about 2-fold. The maximum (Cmax) and minimum (Cmin) equilibrium plasma concentrations were 4.2 and 0.3 ng/ml, respectively, when taking 0.5 mg, and 8.2 and 0.5 ng/ml, respectively, when taking 1 mg. When comparing the bioavailability in healthy subjects, the bioavailability of tablets and oral solution was 100%, i.e., the two dosage forms were interchangeable. Minimal delay in absorption (1-1.5 hours with food and 0.75 hours with fasting), a 44-46% decrease in Cmax and 18-20% decrease in AUC were observed when taking entecavir orally with a high-fat or light meal.

Distribution

The estimated volume of distribution of entecavir exceeded total body water, indicating good tissue penetration of the drug. Entecavir is approximately 13% bound to human serum proteins in vitro.

Metabolism and excretion

Entecavir is not a substrate, inhibitor or inducer of CYP450 enzymes. No oxidized or acetylated metabolites were detected after administration of labeled 14C entecavir in humans and rats, and few phase II metabolites (glucuronides and sulfates) were detected.

After reaching maximum levels, the plasma concentration of entecavir decreased bi-exponentially, with a half-life of 128-149 hours. When administered once daily, there was a 2-fold increase in concentration (cumulation) of the drug, i.e. the effective half-life was approximately 24 hours.

Entecavir is excreted primarily by the kidneys, with 62% to 73% of the dose determined in the urine unchanged in the equilibrium state. Renal clearance is independent of dose and ranges from 360 to 471 mL/min, indicating glomerular filtration and tubular secretion of the drug.

Indications for use

Chronic hepatitis B in adults with signs of viral replication and elevated serum transaminase activity (ALT or ACT) or in presence of histological signs of inflammatory process in liver.

Dosage and administration

Entecavir should be taken orally on an empty stomach (i.e. at least 2 hours after a meal and at least 2 hours before the next meal). The recommended dose of entecavir for patients with compensated liver damage is 0.5 mg once daily. In lamivudine-resistant patients (i.e., patients with a history of hepatitis B virus viremia persisting on lamivudine therapy or patients with confirmed lamivudine resistance), it is recommended that 1 mg of entecavir once daily. In patients with decompensated liver damage, it is recommended to prescribe 1.0 mg entecavir once daily.

Patients with renal impairment

The clearance of entecavir decreases with decreased creatinine clearance. A dose adjustment for entecavir is recommended for patients with creatinine clearance <50 mL/min, including those on hemodialysis and long-term outpatient peritoneal dialysis, according to Table 1.

Table 1: Recommended doses of entecavir in patients with renal impairment.

  Creatinine clearance (ml/min)  Patients who have not previously received nucleoside drugsLamivudine-resistant patients and patients with decompensated liver damage
≥ 500,5 mg once a day1,0 mg once a day
30 – ˂ 500,5 mg every 48 hours1,0 мг mg every 48 hours
10 – ˂ 300,5 mg every 72 hours1,0 mg every 72 hours
  ˂ 10 Hemodialysis* or long-term outpatient perinatal dialysis  0,5 mg every 5-7 days  1,0 mg every 5-7 days

*Entecavir should be taken after hemodialysis.

No dose adjustment of entecavir is required in patients with hepatic impairment. No dose adjustment of entecavir is required in elderly patients.

Side effects

Digestive system disorders: rare (> 1/1000, < 1/100): diarrhea, dyspepsia, nausea, vomiting;

Central nervous system: common (> 1/100, < 1/10): headache, fatigue; rare (> 1/1000, < 1/100): insomnia, dizziness, somnolence;

Immune system: anaphylactoid reaction;

Skin and subcutaneous tissue: alopecia, rash;

Liver: increased transaminase activity;

Metabolism: lactoacidosis (general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness), especially in patients with decompensated liver damage;

Besides, in patients with decompensated liver damage, the following side effects were additionally observed: frequent – decrease of bicarbonate concentration in blood, increase of ALT and bilirubin concentration more than 2 times in comparison with IGN, albumin concentration less than 2.5 g/dl, increase of lipase activity more than 3 times versus normal, platelet concentration less than 50000/mm3; rare – renal failure.

Contraindications

  • Hypersensitivity to entecavir or any other component of the drug.
  • Childhood age under 18 years.

Drug interactions

Because entecavir is mainly excreted by the kidneys, concomitant administration of entecavir and drugs that reduce renal function or compete at the level of tubular secretion may increase the serum concentration of entecavir or these drugs. No significant drug interactions have been identified when concomitant administration of entecavir with lamivudine, adefovir dipivoxil or tenofovir disoproxil fumarate. Interactions of entecavir with other drugs that are excreted by the kidneys or affect renal function have not been studied. Patients should be monitored closely if entecavir is concomitantly prescribed with such drugs.

Special indications

During treatment with nucleoside analogues as monotherapy and in combination with antiretroviral drugs, cases of lactoacidosis and marked hepatomegaly with steatosis, sometimes leading to patient’s death, have been described.

Symptoms that may indicate the development of lactoacidosis: general fatigue, nausea, vomiting, abdominal pain, sudden weight loss, shortness of breath, rapid breathing, muscle weakness. Risk factors include female sex, obesity, long-term use of nucleoside analogues, hepatomegaly. If the above symptoms appear or the laboratory confirmation of lactoacidosis is obtained, treatment with the drug should be discontinued.

There have been described cases of hepatitis exacerbation after discontinuation of antiviral therapy, including entecavir. Most of these cases have passed without treatment. However, severe exacerbations, including fatal ones, may develop. The causal relationship of these exacerbations to withdrawal of therapy is unknown. Liver function should be monitored periodically after treatment discontinuation. If necessary, antiviral therapy may be resumed.

Patients with hepatitis B/HIV co-infection

Note that when entecavir is administered to HIV co-infected patients who are not receiving antiretroviral therapy, there may be a risk of developing resistant strains of HIV.

Patients with hepatitis B/hepatitis C/hepatitis D co-infection

There are no data on the efficacy of entecavir in patients with hepatitis B/hepatitis C/hepatitis D co-infection.

Patients with decompensated liver damage

There is a high risk of serious adverse liver effects, particularly in patients with decompensated liver disease of grade C according to the Child-Pugh classification. These patients are also at higher risk of lactoacidosis and specific renal side effects such as hepatorenal syndrome. Therefore, patients should be closely monitored for clinical signs of lactoacidosis and renal dysfunction, and appropriate laboratory tests should be performed in this group of patients (liver enzyme activity, blood lactic acid concentration, serum creatinine concentration).

Lamivudine resistant patients

The presence of resistance mutations in hepatitis B virus to lamivudine increases the risk of developing resistance to entecavir. Therefore, frequent monitoring of viral load in lamivudine-resistant patients and, if necessary, appropriate testing for the detection of resistance mutations is required.

Patients with impaired renal function

For patients with impaired renal function, a dosing regimen adjustment is recommended.

Patients who have undergone liver transplantation

The safety and efficacy of entecavir in liver transplant patients is unknown. Renal function should be carefully monitored before and during treatment with entecavir in liver transplant patients receiving immunosuppressants that may affect renal function, such as cyclosporine and tacrolimus.

General information for patients

Patients should be informed that entecavir therapy does not reduce the risk of hepatitis B transmission and therefore appropriate precautions should be taken. Each tablet of the drug contains 120.5 mg (0.5 mg tablets) or 241 mg (1 mg tablets) of lactose. In this regard, patients with rare hereditary lactose intolerance, lactase deficiency or glucose-galactose malabsorption are not recommended to take the drug.

Pregnancy and lactation

Adequate and well-controlled studies in pregnant women have not been conducted. The drug should be taken during pregnancy only if the potential benefit of use exceeds the potential risk to the fetus.

There are no data on the penetration of entecavir into the female milk. Breast-feeding during the use of the drug is not recommended.

Overdose

Cases of overdose of entecavir have not been registered. In case of overdose the patient should be under close medical supervision and if necessary – standard supportive therapy.

Form of production

Filmed film-coated tablets 0.5 mg and 1.0 mg in shrink-wrapped packages.

Storage conditions

Store in a dry, dark place at a temperature not exceeding 25°C. Keep out of the reach of children!

Shelf life

2 years. Do not use after the expiration date.

Conditions of dispensing from pharmacies

Released by a doctor’s prescription.

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