Liprimar, 10 mg 100 pcs
€17.42 €14.51
Liprimar is hypolipidemic, hypocholesterolemic.
Pharmacodynamics
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, a key enzyme that converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate, a precursor of steroids, including cholesterol, a synthetic hypolipidemic agent.
. In patients with homozygous and heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces plasma levels of total cholesterol (CHs), chs-LDL and apo-B (apo-B), as well as chs-LBP and triglycerides (TG), causes unstable increase in HDL-C.
Atorvastatin reduces plasma cholesterol and lipoprotein concentrations by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to increased capture and catabolism of hs-LDL.
Atorvastatin decreases formation of LDL-C and the number of LDL particles, causes a pronounced and sustained increase in LDL receptor activity in combination with favorable qualitative changes in LDL particles, and reduces LDL-C levels in patients with homozygous hereditary familial hypercholesterolemia resistant to therapy with other hypolipidemic agents.
Atorvastatin in doses from 10 to 80 mg reduces total cholesterol by 30-46%, LDL-C by 41-61%, apolipoprotein-B by 34-50% and TG by 14-33%. Results of therapy are similar in patients with heterozygous familial hypercholesterolemia, nonfamilial forms of hypercholesterolemia and mixed hyperlipidemia, including patients with insulin-independent diabetes.
In patients with isolated hypertriglyceridemia, atorvastatin decreases total cholesterol, chs-LDL, chs-LDLNP, apo-B and TG and increases chs-LDL.
In patients with dysbetalipoproteinemia, atorvastatin decreases intermediate-density lipoprotein cholesterol.
In patients with hyperlipoproteinemia of type IIa and IIb according to Frederickson mean increase of HDL-C content during treatment with atorvastatin (10-80 mg) in comparison with baseline is 5.1-8.7% and it is not dose dependent. There are significant dose-dependent reductions in the values of ratios: total cholesterol/Hs-LDL and hs-LDL/Hs-LDL by 29-44% and 37-55%, respectively.
Liprimar® in a dose of 80 mg significantly reduced the risk of coronary complications and mortality by 16% after 16-week course, and the risk of re-hospitalization for angina with signs of myocardial ischemia by 26%. In patients with different baseline concentrations of CHD Liprimar® causes a decrease in the risk of coronary complications and mortality (in patients with myocardial infarction without Q-wave and unstable angina, regardless of gender, age of the patient).
The decrease in plasma HDL-C correlates better with the drug dose than with its plasma concentration. The dose is adjusted according to the therapeutic effect (see section “Dosage and administration”).
Therapeutic effect is achieved 2 weeks after the start of therapy, reaches a maximum after 4 weeks and lasts for the duration of therapy.
Prevention of cardiovascular complications
. In the Anglo-Scandinavian Study of Cardiovascular Complications (lipid-lowering branch (ASCOT-LLA) the effect of atorvastatin on fatal and nonfatal outcomes of CHD was found that the effect of atorvastatin therapy at 10 mg dose was significantly greater than that of placebo, so it was decided to terminate the study early after 3.3 years instead of the intended 5 years.
Diabetes
The pooled study of the effect of atorvastatin on fatal and nonfatal cardiovascular outcomes in type 2 diabetes (CARDS) showed that atorvastatin therapy reduced the risk of the following cardiovascular complications regardless of gender, patient age or baseline CH-LD level.
Atherosclerosis
In a study of the reversal of coronary atherosclerosis with intensive lipid-lowering therapy (REVERSAL) with atorvastatin at a dose of 80 mg in patients with CHD, we found that the mean reduction in total atheroma volume (the primary efficacy criterion) since the start of the study was 0.4%.
Recurrent Stroke
. The Intensive Cholesterol Lowering Program (SPARCL) found that atorvastatin at a dose of 80 mg/day reduced the risk of recurrent fatal or nonfatal stroke in patients who had a stroke or transient ischemic attack (TIA) without a history of CHD by 15% compared with placebo. The risk of major cardiovascular complications and revascularization procedures was significantly reduced. Reduction of risk of cardiovascular disorders during atorvastatin therapy was observed in all groups except for the group including patients with primary or recurrent hemorrhagic stroke (7 in atorvastatin group versus 2 in placebo group).
Hemorrhagic stroke
The incidence of hemorrhagic or ischemic stroke (265 versus 311) or CHD (123 versus 204) was lower in patients treated with atorvastatin at a dose of 80 mg than in the control group.
Secondary prevention of cardiovascular complications
The New Target Trial (TNT) compared the effect of atorvastatin at doses of 80 and 10 mg/day on the risk of cardiovascular complications in patients with clinically confirmed CHD. Atorvastatin at a dose of 80 mg significantly reduced the development of the following complications.
Pharmacokinetics
Intake. Atorvastatin is quickly absorbed after oral administration: Tmax in blood plasma – in 1-2 hours. In women Cmax is 20% higher and AUC is 10% lower than in men. The degree of absorption and plasma concentration increase in proportion to the dose. Absolute bioavailability is about 14%, and systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to presystemic metabolism in the gastrointestinal mucosa and/or during first passage through the liver. Food slightly reduces rate and degree of drug absorption (by 25 and 9%, respectively, as evidenced by the results of Cmax and AUC determination, but decrease of low-density lipoprotein cholesterol (LDL-C) is similar to that during atorvastatin administration on an empty stomach. Despite the fact that after Atorvastatin administration in the evening its concentration in plasma is lower (Cmax and AUC, approximately by 30%) than after administration in the morning, decrease of HDL-C levels does not depend on the time of day, when the drug is taken.
Distribution. The average Vd of atorvastatin is about 381 l. The binding to plasma proteins is at least 98%. The ratio of content in erythrocytes/plasma is about 0.25, i.e. atorvastatin poorly penetrates into erythrocytes.
Metabolism. Atorvastatin is largely metabolized with the formation of ortho- and para-hydroxylated derivatives and various β-oxidation products. In vitro ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable with that of atorvastatin. Approximately 70% of the decrease of HMG-CoA reductase activity is due to the action of active circulating metabolites. Results of in vitro studies suggest that hepatic cytochrome CYP3A4 isoenzyme plays an important role in atorvastatin metabolism. This fact is supported by increased plasma concentrations of the drug in concomitant administration of erythromycin, which is an inhibitor of this isoenzyme. In vitro studies have also shown that atorvastatin is a weak inhibitor of cytochrome CYP3A4 isoenzyme. Atorvastatin has no clinically significant effect on plasma concentrations of terfenadine, which is metabolized primarily with the participation of cytochrome CYP3A4 isoenzyme, therefore its significant effect on pharmacokinetics of other substrates of cytochrome CYP3A4 isoenzyme is unlikely (see section “Interaction”).
Elimination. Atorvastatin and its metabolites are excreted mainly with bile after hepatic and/or extrahepatic metabolism (atorvastatin does not undergo marked hepatic recirculation). T1/2 of preparation is approximately 14 h, hereby the inhibitory effect of the preparation with regard to HMG-CoA reductase is determined by activity of circulating metabolites approximately by 70% and lasts for about 20-30 h due to their presence. After oral administration, less than 2% of the administered dose of the drug is detected in the urine.
Particular groups of patients
Elderly patients. Atorvastatin concentrations in plasma of patients older than 65 years old are higher (Cmax – approximately by 40%, AUC – approximately by 30%) than those of adult patients of young age. No differences in efficacy and safety of the drug or achievement of hypolipidemic therapy goals were found in elderly patients compared to general population.
Children. No studies of pharmacokinetics of the drug in children have been conducted.
Inadequate renal function. Renal dysfunction does not influence atorvastatin concentration in plasma or its effect on lipid metabolism parameters, therefore there is no need to change the dose in patients with impaired renal function (see “Dosage and administration”).
Atorvastatin is not excreted during hemodialysis due to intense binding to plasma proteins.
Hepatic function insufficiency. Concentration of the drug is significantly increased (Cmax – approximately 16 times, AUC – approximately 11 times) in patients with alcoholic cirrhosis (stage B according to Child-Pugh classification).
Indications
Active ingredient
Composition
Active substance:
atorvastatin (in the form of calcium salt) 10 mg;
Auxiliary substances:
Calcium carbonate;
MCC;
Lactose monohydrate;
Croscarmellose sodium;
Polysorbate 80;
Hydroxypropylcellulose;
Magnesium stearate;
Opadry White YS-1-7040 (contains hypromellose, polyethylene glycol, titanium dioxide, talc); simethicone emulsion (contains simethicone, stearic emulsifier, sorbic acid, water); candelilla wax
How to take, the dosage
Ingestion, at any time of day, regardless of meals.
Before initiating treatment with Liprimar®, an attempt should be made to achieve control of hypercholesterolemia through diet, exercise and weight loss in obese patients, as well as therapy of the underlying disease.
A standard hypocholesterolemic diet should be recommended to the patient when prescribing the drug and the patient should adhere to it during the whole period of therapy.
The dose of the drug varies from 10 to 80 mg once daily and is titrated taking into account the baseline level of CHD, the goal of therapy and the individual effect on the therapy.
The maximum daily dose of the drug for single administration is 80 mg.
At the beginning of treatment and/or during dose escalation of Liprimar® it is necessary to monitor plasma lipid levels every 2-4 weeks and adjust the drug dose accordingly.
Primary hypercholesterolemia and combined (mixed) hyperlipidemia. For most patients – 10 mg once daily; the therapeutic effect is manifested within 2 weeks and usually reaches a maximum within 4 weeks. With long-term treatment, the effect is maintained.
Homozygous familial hypercholesterolemia. In most cases, 80 mg once a day is prescribed (reduction of CH-LDL content by 18-45%).
Inadequate liver function. In liver function insufficiency, the Liprimar® dose should be decreased, with constant monitoring of liver transaminases AST and ALT activity.
Inadequate renal function. Impaired renal function does not affect the plasma concentration of atorvastatin or the degree of reduction of HDL-C level during therapy with Liprimar® , therefore no dose adjustment is required.
Elderly patients. No differences in efficacy, safety or therapeutic effect of Liprimar® have been found in elderly patients compared to the general population and no dose adjustment is required (see “Pharmacokinetics”).
The use in combination with other drugs. If coadministration with cyclosporine is necessary, the dose of Liprimar® should not exceed 10 mg (see “Cautionary Note”).
Interaction
Cytochrome CYP3A4 isoenzyme inhibitors. Since atorvastatin is metabolized by CYP3A4 cytochrome isoenzyme, co-administration of atorvastatin with CYP3A4 cytochrome isoenzyme inhibitors may lead to an increase in plasma concentration of atorvastatin. The degree of interaction and potentiation effect are determined by the variability of effects on cytochrome CYP3A4 isoenzyme.
OATP1B1 transport protein inhibitors. Atorvastatin and its metabolites are substrates of OATP1B1 transport protein. OATP1B1 inhibitors (e.g., cyclosporine) may increase bioavailability of atorvastatin. Thus, co-administration of Atorvastatin at dose of 10 mg and cyclosporine at dose of 5.2 mg/kg/day leads to 7.7-fold increase of Atorvastatin concentration in blood plasma (see “Dosage and administration”).
Eritromycin/clarithromycin. In concurrent administration of atorvastatin and erythromycin (500 mg 4 times per day) or clarithromycin (500 mg 2 times per day), which inhibit CYP3A4 cytochrome isoenzyme, increased Atorvastatin concentration in plasma was observed (see “Caution”).
Protease inhibitors. Concomitant administration of atorvastatin with protease inhibitors, known as inhibitors of cytochrome CYP3A4 isoenzyme, is accompanied with increase of concentration of atorvastatin in plasma (in concurrent usage with erythromycinCmax of atorvastatin is increased by 40%).
Diltiazem. Concomitant administration of atorvastatin in dose of 40 mg with diltiazem in dose of 240 mg leads to increased concentration of atorvastatin in plasma.
Cimetidine. No clinically significant interaction of atorvastatin with cimetidine has been found.
Itraconazole. Concomitant administration of atorvastatin in doses from 20 to 40 mg and itraconazole in dose 200 mg led to increase of AUC value of atorvastatin.
Grapefruit juice. Since grapefruit juice contains one or more components that inhibit cytochrome CYP3A4 isoenzyme, its excessive consumption (more than 1.2 liters per day) may cause increase of atorvastatin concentration in plasma.
CYP3A4 cytochrome isoenzyme inducers. Concomitant use of atorvastatin with inducers of cytochrome CYP3A4 isoenzyme (e.g. efavirenz or rifampicin) may lead to decreased concentration of atorvastatin in plasma. Due to dual mechanism of interaction with rifampicin (inducer of cytochrome CYP3A4 isoenzyme and inhibitor of hepatocyte transport protein OATP1B1) it is recommended to use atorvastatin and rifampicin simultaneously, because delayed administration of atorvastatin after rifampicin administration leads to significant decrease of plasma concentration of atorvastatin.
Antacids. Simultaneous oral administration of suspension containing magnesium hydroxide and aluminum hydroxide decreased plasma concentration of atorvastatin by approximately 35%, but the degree of decrease in HDL-C concentration did not change.
Phenazone. Atorvastatin has no effect on the pharmacokinetics of phenazone, so no interaction with other drugs metabolized by the same cytochrome isoenzymes is expected.
Colestipol. Concomitant use of colestipol decreased plasma concentrations of atorvastatin by approximately 25%; however, the hypolipidemic effect of combining atorvastatin and colestipol was superior to that of each drug alone.
Digoxin. When digoxin and atorvastatin were repeatedly administered at a dose of 10 mg, plasma Css of digoxin did not change. However, when using digoxin in combination with atorvastatin at a dose of 80 mg/day, digoxin concentration increased by approximately 20%. Patients receiving digoxin in combination with atorvastatin require appropriate monitoring.
Asithromycin. Concomitant administration of atorvastatin in dose of 10 mg once daily and azithromycin in dose of 500 mg once daily did not change concentration of atorvastatin in plasma.
Peroral contraceptives. In concomitant use of atorvastatin and oral contraceptives containing norethisterone and ethinylestradiol, a significant increase in AUC of norethisterone and ethinylestradiol by approximately 30 and 20%, respectively, was observed. This effect should be considered when choosing an oral contraceptive for a woman taking atorvastatin.
Terfenadine. No clinically significant changes in pharmacokinetics of terfenadine have been observed with concomitant use of atorvastatin and terfenadine.
Warfarin. No evidence of clinically significant interaction of atorvastatin with warfarin has been found.
Amlodipine. Concomitant administration of atorvastatin at a dose of 80 mg and amlodipine at a dose of 10 mg did not change pharmacokinetics of atorvastatin in equilibrium.
Other concomitant therapy. In clinical trials atorvastatin was used in combination with antihypertensive agents and estrogens in substitution therapy; no signs of clinically significant adverse interactions were observed; no studies of interaction with other specific drugs were conducted.
Special Instructions
Action on the liver. As with other hypolipidemic agents of this class, after Liprimar® treatment a moderate (more than 3 times as compared to HBV) increase in liver transaminases AST and ALT was observed. A persistent increase in serum hepatic transaminases (more than 3-fold compared to IGN) was observed in 0.7% of patients treated with Liprimar®. The frequency of similar changes was 0.2; 0.2; 0.6 and 2.3% when using 10, 20, 40 and 80 mg, respectively. Increased liver transaminase activity was not usually accompanied by jaundice or other clinical manifestations. When the dose was reduced or when Liprimar® was temporarily or completely discontinued, hepatic transaminase activity returned to the baseline level. Most patients continued Liprimar® at the reduced dose without any clinical sequelae.
Hepatic function should be monitored before therapy, at 6 and 12 weeks after the start of Liprimar® or after increasing doses, and during the entire course of treatment. Liver function should also be monitored when clinical signs of liver damage appear. If liver transaminases are elevated, their activity should be monitored until they normalize. If the increase of AST or ALT activity more than 3 times of GHB persists, it is recommended to reduce the dose or discontinue Liprimar® (see “Side effects”).
Liprimar® should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Active liver disease or persistently elevated plasma hepatic transaminases of unclear genesis are contraindications to the use of Liprimar® (see section “Contraindications”).
Action on skeletal muscles. Myalgia has been reported in patients treated with Liprimar® (see “Side effects”). The diagnosis of myopathy (muscle pain or muscle weakness accompanied by an increase in CPK activity of more than 10 times that of IGN) should be considered in patients with diffuse myalgia, muscle soreness or weakness and/or marked increase in CPK activity. Liprimar® therapy should be discontinued in case of marked elevation of CPK activity, in the presence of confirmed or suspected myopathy. Risk of myopathy during treatment with other drugs of this class was increased with concomitant use of cyclosporine, fibrates, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g) or azole antifungals. Many of these drugs inhibit cytochrome CYP3A4 isoenzyme-mediated metabolism and/or drug transport. Cytochrome CYP3A4 isoenzyme is known to be the main liver isoenzyme involved in the biotransformation of atorvastatin. When prescribing Liprimar® in combination with fibrates, erythromycin, immunosuppressants, azole antifungals or lipid-lowering doses of nicotinic acid, the physician should carefully weigh the expected benefits of treatment against the possible risks. Patients should be monitored regularly to detect muscle pain or weakness, especially during the first months of therapy and during the period of increasing the dose of any of the aforementioned agents. If combination therapy is necessary, lower initial and maintenance doses of the above agents should be considered. Periodic monitoring of CPK activity may be recommended in such situations, although such monitoring does not prevent the development of severe myopathy (see “Interactions”).
Liprimar®, like other statins, has described rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria. If there are symptoms of possible myopathy or if there is a risk factor for renal failure with rhabdomyolysis (e.g. severe acute infection, arterial hypotension, major surgery, trauma, metabolic, endocrine or electrolyte disturbances and uncontrolled convulsions) Liprimar® should be suspended or completely stopped.
Patients should be advised to seek immediate medical attention if they have unexplained pain or muscle weakness, especially if accompanied by malaise or fever.
The effect on the ability to drive a car or perform work requiring increased speed of physical and mental reactions. There are no data on the effect of atorvastatin on the ability to drive a car and engage in potentially hazardous activities requiring increased concentration and rapid psychomotor reactions.
Contraindications
With caution: alcohol abuse; history of liver disease.
Side effects
CNS disorders: insomnia, headache, asthenic syndrome.
Gastrointestinal disorders: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal and connective tissue disorders: myalgia.
CNS and peripheral nervous system disorders: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.
Gastrointestinal system disorders: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.
Musculoskeletal and connective tissue disorders: back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.
Allergic reactions: urticaria, skin itching, rash, anaphylactic reactions, bullous rash, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell’s syndrome).
Metabolic disorders: hypoglycemia, hyperglycemia, increased serum creatine phosphokinase (CPK).
Hematopoietic disorders: thrombocytopenia.
Others: impotence, peripheral edema, weight gain, chest pain, secondary renal failure, alopecia, tinnitus, increased fatigue.
Overdose
Treatment: There is no specific antidote for the treatment of Liprimar® overdose.
In case of overdose symptomatic treatment should be given as required. Since the drug is actively bound to blood plasma proteins, hemodialysis is ineffective.
Similarities
Weight | 0.047 kg |
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Shelf life | 3 years |
Conditions of storage | At a temperature not exceeding 25 °C |
Manufacturer | Pfizer, Puerto Rico |
Medication form | pills |
Brand | Pfizer |
Other forms…
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