Atorvastatin

When ATH:
C10AA05

Characteristic.

Lipid-lowering agents of the statin. HMG-CoA reductase.

Atorvastatin calcium - white or almost white crystalline powder, insoluble in aqueous solutions at pH values 4 and lower; slightly soluble in distilled water, phosphate buffer pH 7,4 and acetonitrile; slightly soluble in ethanol, easily soluble in methanol. Molecular weight 1209,42.

Pharmacological action.
Hypolipidemic.

Application.

Primary Hypercholesterolemia (heterozygous familial hypercholesterolemia and non-family, according to Fredrickson type IIa), combined (mixed) hyperlipidemia (Fredrickson type IIb on and III), disbetalipoproteinemiya (according to Fredrickson type III) (as an adjunct to diet), familial endogenous hypertriglyceridemia (according to Fredrickson type IV), resistant to dietary treatments. Homozygous Familial Hypercholesterolemia (as a supplement to the lipid-lowering therapy, incl. autotransfusion blood cleaned of LDL). Diseases of the cardiovascular system (incl. in patients without clinical manifestations of coronary heart disease, but with increased risk factors for its occurrence - age over 55 years, Nicotine addiction, arterial hypertension, genetic predisposition), incl. against the background of dyslipidemia - secondary prevention to reduce the overall risk of death, myocardial infarction, stroke, rehospitalization for angina and the need for revascularization.

Contraindications.

Hypersensitivity, liver disease in active phase (incl. chronic active hepatitis, chronic alcoholic hepatitis), increase in liver transaminases (more than 3 fold compared with the upper limit of normal) unknown origin, hepatic failure, cirrhosis of any etiology, pregnancy and lactation.

Restrictions apply.

History of liver disease, severe electrolyte imbalance, endocrine and metabolic disorders, alcoholism, hypotension, severe acute infection (sepsis), Uncontrolled seizures, extensive surgery, injury, Age to 18 years (efficacy and safety have not been established).

Pregnancy and breast-feeding.

Atorvastatin crosses the placenta and reaches the fetal liver level, equivalent level in maternal plasma. Atorvastatin showed no teratogenicity in rats at doses up using 300 mg / kg / day and in rabbits at doses up to 100 mg / kg / day. These doses creating exposure, in 30 (rats) and 20 (Rabbits) times the exposure in humans (based on body surface area, in mg / m²).

Studies in rats, atorvastatin doses 20, 100 and 225 mg / kg / day from day 7 of pregnancy up 21 days of lactation, marked decline in survival of pups at birth, Newborn, and maturation of young females, receiving doses of atorvastatin 225 mg / kg / day. Registered a decline in body weight 4 and 21 day young females, receiving atorvastatin 100 mg / kg / day; reduction in body weight at birth, on 4, 21 and 91 day - at a dose 225 mg / kg / day. Developmental delay is observed at a dose of 100 mg / kg / day (Rotary Activity) and 225 mg / kg / day (fright at the sound of, Disturbances of the pinna, the opening of the eyes). These doses correspond to AUC values, in 6 (100 mg / kg) and 22 times (225 mg / kg) AUC greater than in humans at a dose 80 mg / day. Rare cases of congenital anomaly were observed following intrauterine exposure of HMG-CoA reductase.

Cholesterol and other substances, synthesized from cholesterol, important for fetal development (including the synthesis of steroids and cell membranes). As inhibitors of HMG-CoA reductase inhibitors reduce the synthesis of cholesterol and, perhaps, the synthesis of other biologically active substances - derivatives of cholesterol, These drugs can cause adverse fetal effects when taking pregnant women. In this regard, inhibitors of HMG-CoA reductase inhibitors are contraindicated during pregnancy and breastfeeding.

There is one report of severe congenital bony deformity, tracheo-esophageal fistula, and anal atresia (FATHER ассоциация) a child, born mother, which took lovastatin with dextroamphetamine sulfate in the I trimester of pregnancy.

The safety of atorvastatin in pregnant women has not been established.

Category actions result in FDA - X. (Animal tests or clinical trials revealed a violation of the fetus and / or there is evidence of the risk of adverse effects on the human fetus, obtained in research or practice; risk, associated with the use of drugs in pregnancy, greater than the potential benefits.)

Women of childbearing age atorvastatin can be taken only if they use reliable contraceptive measures. If the patient plans pregnancy, she should stop taking the drug for at least 1 months before the planned pregnancy. In case of pregnancy during treatment with atorvastatin should be discontinued immediately. The patient should be informed of the potential risk to the fetus.

In animal experiments found, that atorvastatin passes into breast milk of rats. Levels of drug in plasma and liver of young lactating animals comprise from those in breast milk 50 and 40% respectively.

Unknown, if atorvastatin is secreted into breast milk in humans. Since it is possible serious adverse effect on the baby, while taking atorvastatin is necessary to stop breastfeeding.

Side effects.

In controlled clinical trials, (n=2502) less 2% patients discontinued treatment due to side effects, caused by atorvastatin. The most frequent adverse effects, associated with atorvastatin, were constipation, flatulence, dyspepsia, and abdominal pain.

From the nervous system and sensory organs: ≥2% - headache, asthenic syndrome, insomnia, dizziness; <2% - Malaise, drowsiness, nightmares, amnesia, paresthesia, peripheral neuropathy, emotional lability, dystaxia, Bell's paralysis, hyperkinesia, depression, giperesteziya, amblyopia, dryness of the conjunctiva, ccomodation eye, bleeding in the eye, glaucoma, noise yshah, deafness, parosmija, loss of taste, dysgeusia.

Cardio-vascular system: ≥2% - chest pain; <2% - Palpitations, vasodilation, fainting, migraine, postural hypotension, increased blood pressure, phlebitis, arrhythmia, angina, anemia, lymphadenopathy, thrombocytopenia.

From the respiratory system: ≥2% - sinusitis, pharyngitis, bronchitis, rhinitis; <2% - Pneumonia, dyspnoea, bronchial asthma, nose bleed.

From the digestive tract: ≥2% - abdominal pain, constipation or diarrhea, dyspepsia, flatulence, nausea; <2% - Anorexia or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, gastritis, enteritis, colitis, cheilitis, duodenal ulcer, gastric ulcer, pancreatitis, želčnaâ how, cholestatic jaundice, abnormal liver function, hepatitis, rectal bleeding, ground, krovotochivosty right, tenesmus.

On the part of the musculoskeletal system: ≥2% - arthralgia, myalgia, arthritis; <2% - Stiff neck, cramping of the leg muscles, ʙursit, tendosynovyt, myasthenia, myositis, Kryvosheya, Muscle hypertonicity, joint contractures.

With the genitourinary system: ≥2% - urogenital infections, peripheral edema; <2% - Gematuriya, albuminuria, increased urination, cystitis, dizurija, nocturia, nephrolithiasis, urinary incontinence or urinary retention, urgent need to urinate, jade, vaginal bleeding, uterine bleeding, metrorragija, epididymitis, decreased libido, impotence, abnormal ejaculation.

For the skin: <2% - Alopecia, dermatoxerasia, increased perspiration, acne, eczema, seborrhea, skin ulcer, ecchymosis, petechiae.

Allergic reactions: ≥2% - skin rash; <2% - Swelling of the face, generalized edema, itching, contact dermatitis, hives.

Other: ≥2% - infection, accidental injury, flu-like symptoms, backache; <2% - Fever, photosensitivity, weight gain, breast enlargement, giperglikemiâ, gipoglikemiâ, increased serum creatinine phosphokinase, Alkaline phosphatase, increase in ALT or AST, worsening of gout.

Side effects, noted in post-marketing studies with atorvastatin: anaphylaxis, angioedema, bullous rash (incl. erythema multiforme exudative, Stevens-Johnson syndrome, toxic epidermal necrolysis), raʙdomioliz, tendon rupture.

Cooperation.

The risk of myopathy increase tacrolimus, fibrates, Erythromycin, a nicotinic acid, antifungal agents (azole). Antacids reduce the concentration of atorvastatin on 35% (effect on LDL cholesterol did not change). Repeated dose of digoxin and atorvastatin equilibrium concentration of digoxin increased by about 20% (for patients, receiving digoxin, must be monitored). In a joint application of atorvastatin and oral contraceptives AUC of norethindrone and ethinyl estradiol increased by about 30 and 20%. At simultaneous reception with erythromycin (CYP3A4 inhibitor) plasma concentrations of atorvastatin increased by about 40%. Lipid-lowering effect of the combination of atorvastatin with colestipol than that for either agent alone. The simultaneous use of medicines, reducing the concentration or activity of endogenous steroid hormones (incl. ketoconazole, spironolactone, cimetidine), increases the risk of reducing the production of endogenous steroid hormones (Caution should be exercised).

Overdose.

Treatment: symptomatic and supportive therapy. No specific antidote. Hemodialysis nyeeffyektivyen.

Dosing and Administration.

Inside, regardless of the meal. The recommended starting dose for adults - 10 mg 1 once a day. Further dose picked individually. The dose may be increased every 4 weeks to a maximum - 80 mg / day.

Precautions.

Before the start of the whole period of treatment must adhere to a standard cholesterol-lowering diet.

Abnormal liver function. The use of inhibitors of HMG-CoA reductase to reduce the level of lipids in the blood can lead to changes in biochemical parameters, reflecting liver function. In clinical trials in patients, treated with atorvastatin, the frequency of persistent increase in serum transaminase levels (more than 3 times higher than the upper limit of normal, observed in 2 or more cases) was 0,7%. The frequency of these disturbances at doses 10, 20, 40 and 80 mg was 0,2; 0,2; 0,6 and 2,3%. One patient developed jaundice. Liver function should be monitored before treatment, through 6 Sun, 12 weeks after the start of ingestion and after each dose escalation, and periodically, for example, every 6 Months. Changes in the activity of liver enzymes are usually observed within the first 3 months after initiation of therapy. Patients, in which there is an increase in transaminase levels, must be controlled before returning to normal enzyme levels. In that case, if AST or ALT values ​​over 3 times higher than the level of the upper permissible limit, it is recommended to reduce the dose or stop treatment.

The effect on muscles. In some cases, during treatment with atorvastatin in patients observed myalgia, does not lead to complications. Patients with diffuse myalgia, lethargy or weakness of the muscles and / or a significant increase in creatine are at risk for the development of myopathy (defined as pain in the muscle with a concomitant increase in CPK in more than 10 times compared with the upper limit of normal). With the development of myopathy (or the assumption that it exists) necessary to determine the activity of creatine phosphokinase; If a significant increase in its level persists, it is recommended to reduce the dose of atorvastatin or cancel.

In the appointment of atorvastatin combination therapy with cyclosporine, fibric acid derivatives, Erythromycin, clarithromycin, immunosuppressants and azole antifungals structure, and nicotinic acid in dosages, causing lowering lipids, necessary to compare the potential benefits and the risks and monitor patients, who show signs or symptoms of muscle pain, lethargy or weakness, especially during the first few months of treatment and at higher doses of any of the preparations.

The drug should be immediately canceled when the signs and risk factors of acute renal failure due to rhabdomyolysis (eg acute severe infection, hypotension, major surgery, injury, severe metabolic and endocrine disorders, and electrolyte imbalance).

It is necessary to immediately consult a doctor if you have unexplained pain or weakness in muscles, especially if accompanied by malaise and fever.