Expiration date: 06/2025

The composition and form of issue:

Tablets, film-coated. 1 tablet contains active substance:

rosuvastatin calcium 5.2, 10.4, 20.8 or 41,6 mg

(equivalent to the content of rosuvastatin 5, 10, 20, or 40 mg, respectively) 

other ingredients: microcrystalline cellulose 12 lactose monohydrate magnesium hydroxide crospovidone (type A) magnesium stearate 

shell film: Opadry II white (talc, macrogol 3350, titanium dioxide E171, polyvinyl alcohol) 

in packages the contour of the foil polyamide/aluminum/PVC and aluminum foil printed patent 10 PCs per cartons 3 packages contour.

Description pharmaceutical form:

Tablets 5 mg: round biconvex shaped, film-coated white or almost white, engraved with C33 on one side.

Tablets 10 mg: round biconvex shaped, film-coated white or almost white, with engraved inscription A34 on one side.

Tablet 20 mg: round biconvex shaped, film-coated white or almost white, engraved with C35 on one side.

Pills 40 mg: oval biconvex, film-coated white or almost white, with engraved inscription C36 on one side.

Pharmacokinetics:

Absorption

Cmax of rosuvastatin in plasma achieved in 5 hours after ingestion of the relevant dose. The absolute bioavailability is approximately 20%.

Distribution

Rosuvastatin is absorbed predominantly by the liver, which is the main site of cholesterol synthesis and clearance of cholesterol metabolism-LDL. Vd of rosuvastatin is approximately 134 L. 90% of rosuvastatin is associated with blood plasma proteins, mainly to albumin.

Metabolism

Undergoes limited metabolism (approximately 10%). Rosuvastatin is a fairly non-core substrate for the metabolic enzyme cytochrome P450. CYP2C9 is the principal isozyme involved in metabolism, while the CYP2C19 isoenzymes, CYP3A4 and CYP2D6 involved in the metabolism to a lesser extent. The main metabolite — N-desmethyl, which is 50% less active than rosuvastatin. Lactonase metabolites are pharmacologically inactive. More than 90% of the pharmacological activity for the inhibition of circulating HMG-COA reductase inhibitor rosuvastatin is provided, the rest of its metabolites.

Excretion

Approximately 90% of the received dose of rosuvastatin is excreted unchanged from the body through the intestines (including the absorbed and unabsorbed rosuvastatin), and the remainder is excreted unchanged by the kidneys. T1/2 is 19 hours and does not change with increasing doses of the drug. The geometric mean plasma clearance is approximately 50 l/h (coefficient of variation of 21.7%). As with other inhibitors of HMG-COA reductase in the process of hepatic capture of rosuvastatin involved membrane Transporter of cholesterol through the membrane transport protein With organic anions. This Transporter plays a major role in the excretion of rosuvastatin by the liver.

Linearity

Systemic exposure of rosuvastatin increases in proportion to the dose. Changes in pharmacokinetic parameters at the drug several times a day is not marked.

Age and gender

Gender and age do not have a clinically significant effect on the pharmacokinetic parameters of rosuvastatin.

Ethnic groups

A comparative study of the pharmacokinetics showed a two-fold increase in the average values of AUC and Tmax in plasma in patients of Asian origin (Japanese, Chinese, Filipinos, Vietnamese and Koreans) compared with parameters of members of the Caucasian race. The Indians were registered exceeding about 1.3 times the average value of AUC and Cmax. The analysis of pharmacokinetics for the entire study population did not reveal clinically important differences in the pharmacokinetics of the drug among the representatives of Caucasoid, Negroid races, Hispanics.

Renal failure

In patients with mild and moderate renal insufficiency, the plasma concentration of rosuvastatin or the N-desmethyl metabolite are not significantly changed. In patients with severe renal insufficiency (Cl creatinine <30 ml/min), the concentration of rosuvastatin in plasma is 3 times higher, and the concentration of the N-desmethyl metabolite 9-fold higher compared with healthy volunteers. The concentration of rosuvastatin in plasma of patients on hemodialysis were approximately 50% higher than in healthy volunteers.

Liver failure

In patients with various degrees of hepatic failure with grade 7 and lower for child-Pugh revealed no increase in T1/2 of rosuvastatin. However, 2 patients with scores of 8 and 9 on the scale of child-Pugh noted an elongation of T1/2, approximately in 2 times exceeding a similar indicator for patients with lower rates of child-Pugh. Experience with the use of rosuvastatin in patients with a score above 9 on a scale child-Pugh missing.

Description pharmacological action:

Rosuvastatin is a selective and competitive inhibitor of HMG-COA reductase, the enzyme that turns of Z-hydroxy-Z-methylglutarylcoenzyme a to mevalonate which is a precursor of cholesterol. The main target of action of rosuvastatin is the liver, where the synthesis of cholesterol (CH) and catabolism of LDL.

Rosuvastatin increases the number of hepatic LDL receptors on the cell surface, increasing the capture and catabolism of LDL.

It also inhibits the synthesis of cholesterol VLDL in the liver cells, thereby lowering the total content of LDL and VLDL.

Rosuvastatin lowers high cholesterol LDL (TC-LDL), total cholesterol and triglycerides (TG), increases the content of HDL cholesterol (HDL-C) and reduces the concentration of apolipoprotein b (Apob), HS-nelup (the total cholesterol minus the cholesterol in HDL-C, XC-VLDL), TG-VLDL and increases the level of apolipoprotein A-I (Apoa-1). Rosuvastatin reduces the ratio of cholesterol-LDL/ HDL-C, total cholesterol/HDL-C, HS-elpvp/HDL-C and Apob/Apoa-1.

The therapeutic effect can be achieved within one week after the start of treatment, after 2 weeks achieves 90% of the maximum possible effect. Usually the maximum possible therapeutic effect is achieved within 4 weeks and maintained upon further administration of the drug.

Clinical efficacy

Rosuvastatin is effective in the treatment of adult patients with hypercholesterolemia with or without hypertriglyceridemia symptoms, regardless of their race, gender or age, and in the treatment of special category patients with diabetes mellitus or the hereditary form of familial hypercholesterolemia.

Rosuvastatin is effective for the treatment of patients with hypercholesterolemia type IIA and IIb according to Fredrickson (average initial level of cholesterol-LDL is about 4.8 mmol/l). 80% of patients receiving 10 mg of rosuvastatin was achieved the target level of cholesterol-LDL, established by the European society for the study of atherosclerosis (less than 3 mmol/l).

In patients with heterozygous familial hypercholesterolemia who took rosuvastatin at doses from 20 to 80 mg according to the scheme of the forced titration of doses taken all doses had a significant effect on the variation of parameters characterizing a content of lipids, and the goal of therapy. The result of titration of doses up to 40 mg/day (12 weeks therapy) the content of cholesterol-LDL decreased by 53%. In 33% of patients was achieved values of cholesterol-LDL (below 3 mmol/l), the corresponding target standards manual of the European society for the study of atherosclerosis.

In patients with homozygous familial hypercholesterolemia who took rosuvastatin at doses of 20 and 40 mg, the average decrease in the content of cholesterol-LDL cholesterol was 22%. An additive effect was observed in combination with fenofibrate in relation to the content of TG and nicotinic acid (>1 g/day) in relation to the content of HDL-C. Studies on the effect of rosuvastatin on reducing the number of complications caused by lipid disorders such as coronary artery disease, has not yet been completed.

In patients with low-risk disease coronary artery disease (defined as Framingham risk less than 10% for more than 10 years), with the average content of cholesterol-LDL 4 mmol/l (154,5 mg/DL) rosuvastatin in a dose of 40 mg/day significantly slowed the increase in the maximum values characterizing the thickening of the wall of the carotid artery in 12 segments compared to placebo with speed ?Of 0.0145 mm/year (95% confidence interval (CI):?0,0196 to ?0,0093, p< 0.0001). A dose of 40 mg should be used only in patients with severe hypercholesterolemia and high risk of developing cardiovascular disease.

Indications:

hypercholesterolemia and combined (mixed) dyslipidemia state to reduce elevated concentrations of total cholesterol, LDL cholesterol, apolipoprotein b and triglycerides in serum as a Supplement to diet when diet and other non-pharmacological methods (e.g. exercise, weight reduction) are inadequate

family homozygous hypercholesterolemia as an adjunct to diet and other methods Lipetskaya therapy (e.g. LDL-apheresis) or when such therapies are not sufficiently effective.

Contraindications:

For tablets 5,10 and 20 mg:

• hypersensitivity to rosuvastatin or any component of the drug
  
• liver disease in the active phase, including a persistent increase in liver transaminases, as well as any increase in transaminaz in the serum of more than 3 times compared with CAH
  
• expressed by the human kidney (Cl creatinine <30 ml/min)
  
• myopathy
  
• concomitant use of cyclosporine
  
• patients predisposed to the development myotoxicity complications
  
• pregnancy and lactation
  
• women of childbearing age not using reliable contraception
  
• the age of 18 years (efficacy and safety not established)
  
• patients with hepatic impairment with a score above 9 on a scale child-Pugh
  
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption.
  

For tablets 40 mg:

• hypersensitivity to rosuvastatin or any component of the drug
  
• liver disease in the active phase, including a persistent increase in liver transaminases, as well as any increase in transaminaz in the serum of more than 3 times compared with CAH
  
• expressed by the human kidney (Cl creatinine <60 ml/min)
  
• myopathy
  
• concomitant use of cyclosporine
  
• patients predisposed to the development myotoxicity complications
  
• pregnancy and lactation
  
• hypothyroidism
  
• personal or family history of muscle disease
  
• myotoxicity on a background of reception of other inhibitors of HMG-COA reductase inhibitors or fibrates in history
  
• excessive alcohol consumption
  
• condition, which can lead to increase the concentration of rosuvastatin in plasma
  
• patients of Asian race
  
• concurrent administration of fibrates
  
• the age of 18 years (efficacy and safety not established)
  
• patients with hepatic impairment with a score above 9 on a scale child-Pugh
  
• lactose intolerance, lactase deficiency or glucose-galactose malabsorption.
  

With caution

For tablets 5,10 and 20 mg: the risk of myopathy/rhabdomyolysis — renal impairment, hypothyroidism, personal or family history of hereditary muscular diseases and previous history of muscular toxicity with other inhibitors of HMG-COA reductase inhibitors or fibrates excessive consumption of alcohol is a condition in which increased plasma concentrations of rosuvastatin the age of 70 liver disease history of sepsis, arterial hypotension, extensive surgical intervention, injury, severe metabolic, endocrine or electrolyte disorders uncontrolled epilepsy race (Asian race) concurrent administration of fibrates.

For tablets 40 mg: the risk of myopathy/rhabdomyolysis — renal failure age over 70 years liver disease history of sepsis with arterial hypotension, extensive surgical intervention, injury, severe metabolic, endocrine or electrolyte disorders, uncontrolled epilepsy.

Application of pregnancy and breast-feeding:

Martini contraindicated during pregnancy and lactation. Women of childbearing age should use reliable and adequate means of contraception.

As cholesterol and products of cholesterol biosynthesis are of great importance for the development of the fetus, the potential risk of inhibition of HMG-COA reductase exceeds the benefit from its use during pregnancy.

In case of pregnancy the drug should be discontinued immediately. Data on the allocation of the drug in breast milk is not available. If necessary, the appointment of the drug during lactation breastfeeding should be discontinued.

Side effects:

Side effects associated with the drug Martinel usually moderately severe and short term. During controlled clinical studies less than 4% of patients taking rosuvastatin, stopped treatment due to side effects.

About side effects in clinical trials and/or experience with the drug after its commercial implementation was reported with the following frequency:

Organs and systems	????? (&ge1/100, <1/10)	Sometimes (&ge1/1000, <1/100)	Rarely (&ge1/10000, <1 / 1000th)	Very rarely, including some messages (<1/10000)
Allergic reactions		Skin itching, rash, hives	Angioneurotic edema	The Stevens-Johnson Syndrome
CNS	Dizziness, headache, asthenic syndrome	Insomnia, mood change		Polyneuropathy, memory loss
The digestive tract	Constipation, abdominal pain, nausea
Hepatobiliary system				Jaundice, hepatitis
Musculoskeletal system	Myalgia		Myopathy (including myositis), rhabdomyolysis	Arthralgia
Urinary system				Hematuria
Laboratory parameters			The increase in liver transaminases

As the use of other inhibitors of HMG-COA reductase inhibitor, the incidence of side effects is dose dependent in nature.

The incidence of rhabdomyolysis, severe side effects from the kidney and liver increased in patients receiving rosuvastatin at a dose of 40 mg.

From the urinary system. When taking rosuvastatin were observed proteinuria, predominantly of tubular origin. Changes in the content of protein in the urine (absence or presence of trace quantities to the level of a ++ and higher) was found at less than 1% of patients taking 10 and 20 mg of rosuvastatin, about 3% of patients taking the drug at a dose of 40 mg.

The minimum change in the amounts of protein in the urine, expressed as a change from zero level or the presence of trace to + was observed with the drug at a dose of 20 mg. In most cases, proteinuria decreased, and independently held in the treatment process. In the analysis of clinical trial data revealed no causal relationship between proteinuria and acute or progressive renal disease. In some patients undergoing treatment with rosuvastatin was observed with a microscope, but clinical trials showed that the incidence of such cases is very low.

From the musculoskeletal system. Effect on skeletal muscles causing myalgia, myopathy (including myositis) and in rare cases, rhabdomyolysis with or without acute renal failure were observed in patients taking any dose of rosuvastatin, in particular the higher dose of 20 mg. the increase in the concentration of creatine phosphokinase (CPK) depending on the received dose detected in patients treated with rosuvastatin, but in most cases, these symptoms were minor, asymptomatic and transient. If the content of CPK 5 times the ULN, treatment should be discontinued (see "precautions").

In the liver. How and when taking other inhibitors of HMG-COA reductase, increased activity of hepatic transaminases, depending on the received dose was identified in a small number of patients taking rosuvastatin. In most cases, this increase was moderate, asymptomatic and transient.

Drug interactions:

Cyclosporine. The simultaneous administration of rosuvastatin and cyclosporine rosuvastatin AUC increased 7-fold compared to values obtained in healthy volunteers (see "Contraindications"). Joint application increases the concentration of rosuvastatin in plasma by 11 times. The simultaneous administration of drugs changes the concentration of cyclosporine in the blood plasma is not detected.

Antagonists of vitamin K. As in the case with other inhibitors of HMG-COA reductase, the beginning of rosuvastatin therapy or increasing the dose of the drug in patients receiving both vitamin K antagonists (e.g. warfarin or other cumarin anticoagulants) can lead to an increase in MHO. Cancellation or reduction of the dose of rosuvastatin may cause a decrease in MHO. In such cases, should be monitored MHO.

Ezetimib. The simultaneous administration of rosuvastatin and ezetimibe not observed changes in AUC or Cmax of both drugs. However, we cannot exclude a pharmacodynamic interaction of rosuvastatin and ezetimibe that can cause adverse events.

Gemfibrozil and other means that reduce lipid levels. Concomitant use of rosuvastatin and gemfibrozil leads to an increase 2 times the Cmax and AUC of rosuvastatin (see "precautions").

On the basis of the study the specific interactions are not anticipated, appropriate pharmacokinetic interaction fenofibrate, however, it is possible pharmacodynamic interaction. Gemfibrozil, fenofibrate, other fibrates and nicotinic acid in Lipetskaya doses (1 g/day or more) in concomitant administration with inhibitors of HMG-COA reductase inhibitors increased risk of myopathy, possibly due to the fact that they can cause myopathy and when used in monotherapy. Simultaneous administration of 40 mg of rosuvastatin and fibrates is contraindicated (see "Precautions," "Contraindications"). While taking the drug with gemfibrozil and other lipidnami means Mertenil initial dose should not exceed 5 mg.

The protease inhibitors. Although the exact mechanism of interaction is unknown, concomitant use of rosuvastatin with protease inhibitors can lead to a lengthening of T1/2 of rosuvastatin. In a pharmacokinetic study of the simultaneous administration of 20 mg rosuvastatin and a combination drug containing two protease inhibitors (400 mg lopinavir / 100 mg ritonavir) in healthy volunteers showed an increase of 2 times the AUC0--24 and 5 times Cmax of rosuvastatin, respectively. Therefore to appoint rosuvastatin and protease inhibitors in the treatment of patients with HIV is not recommended.

Antacids. Concomitant use of rosuvastatin and antacid suspension containing aluminum or magnesium hydroxide, can lead to a decrease in the concentration of rosuvastatin in plasma by about 50%. This effect is expressed weaker, if antacids are applied through 2 h after administration of rosuvastatin. The clinical significance of this interaction has not been studied.

Erythromycin. Concomitant use of rosuvastatin and erythromycin may lead to a decrease in AUC0–t rosuvastatin by 20% and rosuvastatin Cmax by 30%. This relationship may be caused by increased intestinal motility caused by erythromycin reception.

Oral contraceptives/hormone replacement therapy. Concomitant use of rosuvastatin and oral contraceptives may increase the AUC of ethinyl estradiol and norgestrel 26 and 34%, respectively. The increase in plasma concentrations should be considered when choosing the dose of oral contraceptives. Pharmacokinetic data on the simultaneous use of rosuvastatina and drugs hormone replacement therapy do not exist, therefore, we cannot exclude a similar effect when using this combination. However, such a combination of drugs widely used by women during clinical trials and was well tolerated.

Other medicines. Not expected to be clinically significant interaction in concomitant administration of digoxin and rosuvastatin.

The cytochrome P450 isoenzymes. The results of these studies in vitro and in vivo showed that rosuvastatin is neither an inhibitor nor inducer of cytochrome P450 isoenzymes. In addition, rosuvastatin is a relatively weak substrate for these enzymes. No clinically significant interaction between rosuvastatin and fluconazole (an inhibitor of isoenzymes CYP2C9 and CYP3A4) or ketoconazole (an inhibitor of isoenzymes CYP2A6 and CYP3A4). The combined use of Itraconazole (inhibitor of CYP3A4) and rosuvastatin increases rosuvastatin AUC by 28% (clinically not significant). Therefore, any interaction of drugs associated with metabolism by cytochrome P450 are not expected.

Method of application and dose:

Before treatment the patient should follow a standard diet with the use of products that are low in cholesterol, which should be continued during the entire treatment period. The dose should be selected individually in accordance with the purpose of treatment and therapeutic response of the patient to the therapy, given the current General recommendations for target levels of lipids.

Inside, at any time of the day, regardless of the meal, do not chew or crush, swallow whole with water.

The recommended starting dose is 5 or 10 mg 1 time per day for patients previously taking statins and for patients transferred to this drug after treatment with other inhibitors of HMG-COA reductase.

Selecting the start dose should take into account the level of cholesterol in each patient and the possible risk of cardiovascular complications and the potential risk of side effects. If necessary after 4 weeks to adjust the dose.

In connection with the possible development of side effects when taking doses of 40 mg compared with lower doses of the drug (see "Side effects"), a final titration to the maximum dose of 40 mg should only be performed in patients with severe hypercholesterolemia and high risk of cardiovascular complications (especially in patients with hereditary hypercholesterolemia), which in the dose of 20 mg was not achieved the target cholesterol level and who will be under medical supervision. At doses of 40 mg is recommended careful observation of a doctor. Not recommended administration of a dose of 40 mg to patients who previously did not apply to the doctor!

Elderly patients

For patients older than 70 years, the recommended starting dose is 5 mg. dose Adjustment in respect of age is required.

Patients with renal insufficiency

In patients with renal insufficiency mild or moderate severity dose adjustment is not required. The recommended starting dose is 5 mg for patients with renal failure of moderate severity (creatinine Cl <60 ml/min). The purpose of Mertenil at any dose is contraindicated in patients with severe renal disease (see "Contraindications"). Patients with renal insufficiency moderate use of the drug at a dose of 40 mg is contraindicated.

Patients with hepatic insufficiency

Increasing systemic concentrations of rosuvastatin in patients with a score of child-Pugh &le7 was not detected. However, the increase in systemic drug concentration have been observed in patients with scores of child-Pugh 8 and 9. These patients should monitor liver function during therapy. Information about the drug patients with a score of child-Pugh greater than 9 are missing. Patients with liver disease in the active phase Martinis contraindicated.

Ethnic groups

Patients of Asian race may increase systemic concentrations of rosuvastatin. When assigning doses 10 and 20 mg the recommended starting dose for patients of Asian origin is 5 mg. the drug is administered at a dose of 40 mg in such patients is contraindicated (see "Contraindications").

Patients predisposed to myopathy

When assigning doses 10 and 20 mg the recommended starting dose for patients with a predisposition to myopathy is 5 mg.

The use of the drug in a dose of 40 mg such patients is contraindicated.

Overdose:

Specific treatment in case of overdose does not exist.

In case of overdose recommended symptomatic treatment and supportive measures. Should monitor liver function and the degree of activity of KFK. Hemodialysis in this case is probably ineffective.

Precautions:

Proteinuria, primarily tubular in origin, was observed in patients with high doses of Mertenil, in particular 40 mg, but in most cases were recurrent or transient. It is shown that proteinuria does not mean the occurrence of acute or progression of existing renal diseases. The frequency of serious renal impairment is increased when taking 40 mg of rosuvastatin. It is recommended to monitor indicators of renal function during therapy with the drug Martini.

When applying Mertenil in all doses, and especially when the drug in doses exceeding 20 mg, revealed myalgia, myopathy and, in rare cases, rhabdomyolysis. Very rarely had rhabdomyolysis while receiving ezetimibe and inhibitors of HMG-COA reductase. In this case we cannot exclude a pharmacological interaction of drugs, so together Martinis and ezetimibe should be used with caution (see "Interactions").

The incidence of rhabdomyolysis when taking 40 mg of rosuvastatin is increased.

Determination of activity of KFK should not be after intense exercise causing an increase in ck, as this may hinder the interpretation of results. With the increase in CPK prior to therapy more than 5 times the ULN 5-7 days should be measured again. If the second measurement confirms the baseline CPK (in 5 times compared with CAH), therapy with Marttila should not even start.

Martini, like other inhibitors of HMG-COA reductase, should take special caution in patients with existing risk factors for myopathy/rhabdomyolysis. These factors include:

• renal failure
  
• hypothyroidism (doses of 40 mg see "Contraindications")
  
• a private or family history of muscle disease (for dose 40 mg see "Contraindications")
  
• a history of myotoxicity on a background of reception of other inhibitors of HMG-COA reductase inhibitors or fibrates (for dose 40 mg see "Contraindications")
  
• alcohol (for dose 40 mg see "Contraindications")
  
• over 70 years of age
  
• state, accompanied by an increase in the concentration of the drug in the blood plasma (see "Interactions") (for dose 40 mg see "Contraindications")
  
• concurrent administration of fibrates (for dose 40 mg see "Contraindications").
  

These patients should weigh the risks and potential benefits of therapy and provide clinical supervision throughout the course of therapy.

It is recommended to inform patients about the need to immediately inform the doctor about cases of sudden occurrence of muscle pain, muscle weakness or cramps, especially in combination with malaise or fever!

Such patients should be sure to monitor the activity of KFK. Treatment should be discontinued if the CPK level is more than 5 times the ULN or muscle symptoms are pronounced and cause daily discomfort throughout the day (even if the activity of KFK less than 5 times ULN). If the symptoms disappear and the activity of CPK returns to normal, you should consider re-appointment or appointment of Mertenil alternative inhibitor of HMG-COA reductase in smaller doses with careful monitoring of the patient. Regular monitoring of CPK activity in patients with no symptoms of rhabdomyolysis inappropriate.

However, the increase in the incidence of myositis and myopathy were identified in patients taking other inhibitors of HMG-COA reductase together with fibroevoy acid derivatives, including gemfibrozil, ciclosporin, nicotinic acid in lipid lowering doses, antifungals, protease inhibitors and macrolide antibiotics. Gemfibrozil increases risk of myopathy when combined administration of some inhibitors of HMG-COA reductase. Therefore, concomitant use of rosuvastatin and gemfibrozil is not recommended. Must be carefully evaluated the risks and potential benefits in the joint use of rosuvastatin with fibrates or nicotinic acid in Lipetskaya doses (more 1 g). Contraindicated concomitant use of rosuvastatin at a dose of 40 mg and fibrates (see "Interactions", "Side effects").

Martini should not be administered to patients with acute, severe disease, suggesting a myopathy or with possible development of secondary renal disease (such as sepsis, hypertension, surgery, trauma, metabolic syndrome, seizures, endocrine disorders, electrolyte disorders (see "Contraindications").

Like other inhibitors of HMG-COA reductase Martini should take special caution in patients with history of alcohol abuse or with a history of liver disease.

Recommended definition of indicators of liver function before and 3 months after start of treatment. If the activity of liver transaminases in the blood serum in 3 times the ULN, discontinue use Mertenil or reduce the amount you take (see "Method of application and dosage"). The frequency of the expressed violations of liver function (mainly related to the increase in liver transaminases), increase at 40 mg.