Liprimar®
During treatment with HMG-CoA reductase inhibitors, with simultaneous use of cyclosporine, fibrates, nicotinic acid in lipid-lowering doses (more than 1 g / day) or inhibitors of the CYP3A4 isoenzyme / transport protein (for example, erythromycin, clarithromycin, antifungal agents - azole derivatives), the risk increases myopathy (see section “Special instructions”).
CYP3A4 isoenzyme inhibitors
Since atorvastatin is metabolized by the CYP3A4 isoenzyme, co-administration of atorvastatin with inhibitors of the CYP3A4 isoenzyme may lead to increased plasma concentrations of atorvastatin. The degree of interaction and potentiation effect is determined by the variability of the effect on the CYP3A4 isoenzyme.
It was found that potent inhibitors of the CYP3A4 isoenzyme lead to a significant increase in the concentration of atorvastatin in the blood plasma. The simultaneous use of strong inhibitors of the CYP3A4 isoenzyme (for example, cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided whenever possible. . If concomitant use of these drugs is necessary, initiating therapy at the lowest dose should be considered and the possibility of reducing the maximum dose of atorvastatin should be evaluated.
Moderate inhibitors of the CYP3A4 isoenzyme (for example, erythromycin, diltiazem, verapamil and fluconazole) may lead to increased plasma concentrations of atorvastatin. With the simultaneous use of HMG-CoA reductase inhibitors (statins) and erythromycin, an increased risk of developing myopathy was noted. Interaction studies between amiodarone or verapamil and atorvastatin have not been conducted. Both amiodarone and verapamil are known to inhibit the activity of the CYP3A4 isoenzyme, and simultaneous use of these drugs with atorvastatin may lead to increased exposure to atorvastatin. In this regard, it is recommended to reduce the maximum dose of atorvastatin and carry out appropriate monitoring of the patient's condition when used simultaneously with moderate inhibitors of the CYP3A4 isoenzyme. Monitoring should be carried out after the start of therapy and against the background of changing the dose of the inhibitor.
Gemfibrozil/fibrates
With the use of fibrates in monotherapy, adverse reactions, including rhabdomyolysis, affecting the musculoskeletal system were periodically noted. The risk of such reactions increases with simultaneous use of fibrates and atorvastatin. If the simultaneous use of these drugs cannot be avoided, the minimum effective dose of atorvastatin should be used, and the patient's condition should be regularly monitored.
Ezetimibe
The use of ezetimibe is associated with the development of adverse reactions, including rhabdomyolysis, from the musculoskeletal system. The risk of such reactions increases with simultaneous use of ezetimibe and atorvastatin. For such patients, careful monitoring is recommended.
Erythromycin/clarithromycin
With the simultaneous use of atorvastatin and erythromycin (500 mg 4 times a day) or clarithromycin (500 mg 2 times a day), inhibitors of the CYP3A4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma was observed (see sections "Special instructions" and "Pharmacokinetics" ).
Protease inhibitors
The simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, is accompanied by an increase in the concentration of atorvastatin in the blood plasma.
Diltiazem
The combined use of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma (see section “Pharmacokinetics”).
Cimetidine
No clinically significant interaction of atorvastatin with cimetidine was detected (see section “Pharmacokinetics”).
Itraconazole
The simultaneous use of atorvastatin in doses from 20 mg to 40 mg and itraconazole in a dose of 200 mg led to an increase in the AUC value of atorvastatin (see section "Pharmacokinetics").
Grapefruit juice
Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, its excessive consumption (more than 1.2 L per day) may cause an increase in the concentration of atorvastatin in the blood plasma (see section "Pharmacokinetics").
Transport protein inhibitors
Atorvastatin is a substrate of liver enzyme transporters (see section "Pharmacokinetics").
Co-administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in increased atorvastatin exposure (AUC ratio: 8.7) (see Pharmacokinetics section). Cyclosporine is an inhibitor of organic anion transport polypeptide 1B1 (OATP1B1), OATP1B3, multidrug resistance-associated protein 1 (MDR1) and breast cancer resistance protein, as well as CYP3A4, and therefore increases the exposure of atorvastatin. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and Administration”).
Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein, and therefore increase the exposure of atorvastatin. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and Administration”).
Co-administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased atorvastatin exposure (AUC ratio: 3.29) (see Pharmacokinetics section).
Letermovir is an inhibitor of the transporters P-gp, BCRP, MRP2, OAT2 and the hepatic transporter OATP1B1/1B3, thus increasing the level of exposure to atorvastatin. The daily dose of atorvastatin should not exceed 20 mg (see section “Dosage and Administration”). The magnitude of indirect drug interactions between CYP3A and OATP1B1/1B3 on co-administration of drugs may differ when letermovir is co-administered with cyclosporine. It is not recommended to use atorvastatin in patients receiving letermovir therapy in combination with cyclosporine.
Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein and therefore increase the exposure of atorvastatin. Should be used with caution and at the lowest dose required (see section "Dosage and Administration").
Inducers of the CYP3A4 isoenzyme
The combined use of atorvastatin with inducers of the CYP3A4 isoenzyme (for example, efavirenz, rifampicin or St. John's wort preparations) may lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma (see section “Pharmacokinetics”). However, the effect of rifampicin on the concentration of atorvastatin in hepatocytes is unknown and if concomitant use cannot be avoided, the effectiveness of this combination should be carefully monitored during therapy.
Antacids
Simultaneous oral administration of a suspension containing magnesium hydroxide and aluminum hydroxide reduced the concentration of atorvastatin in the blood plasma (change in AUC: 0.66), but the degree of reduction in the concentration of LDL-C did not change.
Phenazone
Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.
Colestipol
With simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased (change in AUC: 0.74); however, the lipid-lowering effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.
Digoxin
With repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when digoxin was used in combination with atorvastatin at a dose of 80 mg/day, digoxin concentrations increased (AUC change: 1.15). Patients receiving digoxin in combination with atorvastatin require appropriate monitoring.
Azithromycin
With simultaneous use of atorvastatin at a dose of 10 mg 1 time per day and azithromycin at a dose of 500 mg 1 time per day, the concentration of atorvastatin in the blood plasma did not change.
Oral contraceptives
With simultaneous use of atorvastatin and oral contraceptives containing norethisterone and ethinyl estradiol, increased concentrations of norethisterone (AUC change 1.28) and ethinyl estradiol (AUC change 1.19) were observed. This effect should be taken into account when choosing an oral contraceptive for a woman taking atorvastatin.
Terfenadine
With simultaneous use of atorvastatin and terfenadine, no clinically significant changes in the pharmacokinetics of terfenadine were detected.
Warfarin
In a clinical study in patients regularly receiving warfarin therapy, concomitant use of atorvastatin at a dose of 80 mg per day resulted in a slight increase in prothrombin time of approximately 1.7 s during the first 4 days of therapy. The indicator returned to normal within 15 days of atorvastatin therapy.
Although significant interactions affecting anticoagulant function have been observed only in rare cases, the prothrombin time should be determined before initiating atorvastatin therapy in patients receiving coumarin anticoagulant therapy and frequently enough during therapy to prevent a significant change in the prothrombin time. Once stable prothrombin time values are observed, its monitoring can be carried out in the same way as recommended for patients receiving coumarin anticoagulants.
When changing the dose of atorvastatin or discontinuing therapy, prothrombin time should be monitored according to the same principles as described above.
Atorvastatin therapy was not associated with bleeding or changes in prothrombin time in patients not receiving anticoagulant treatment.
Colchicine
Although studies have not been conducted on the simultaneous use of colchicine and atorvastatin, there are reports of the development of myopathy when using this combination. Caution should be exercised when atorvastatin and colchicine are used concomitantly.
Amlodipine
In a drug interaction study in healthy subjects, coadministration of atorvastatin 80 mg and amlodipine 10 mg resulted in a clinically nonsignificant increase in atorvastatin concentrations (AUC change: 1.18)
Fusidic acid
During post-marketing studies, cases of rhabdomyolysis have been reported in patients taking concomitant statins, including atorvastatin and fusidic acid. The mechanism of this interaction is unknown. In patients for whom the use of fusidic acid is considered necessary, statin treatment should be discontinued for the entire period of use of fusidic acid. Statin therapy can be resumed 7 days after the last dose of fusidic acid. In exceptional cases where long-term systemic therapy with fusidic acid is necessary, for example for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision. The patient should seek immediate medical attention if symptoms of muscle weakness, tenderness, or pain occur.
Other concomitant therapy
In clinical studies, atorvastatin was used in combination with antihypertensive agents and estrogens as part of hormone replacement therapy. There were no signs of clinically significant adverse interactions; No interaction studies with specific drugs have been conducted.
In addition, an increase in the concentration of atorvastatin was observed when used simultaneously with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C protease inhibitors (boceprevir, elbasvir/grazoprevir, simeprevir) , clarithromycin and itraconazole.
Caution should be exercised when using these drugs together and the lowest effective dose of atorvastatin should be used.
Liprimar
From the nervous system: more often 2% - insomnia, dizziness; less often 2% - headache, asthenia, malaise, drowsiness, unusual dreams, amnesia, paresthesia, peripheral neuropathy, amnesia, emotional lability, ataxia, facial paralysis, hyperkinesis, depression, hyperesthesia, loss of consciousness.
From the senses: less often 2% - amblyopia, tinnitus, dry conjunctiva, impaired accommodation, hemorrhage in the eyes, deafness, glaucoma, parosmia, loss of taste, taste perversion.
From the cardiovascular system: more often 2% - chest pain; less than 2% - palpitations, vasodilation, migraine, postural hypotension, increased blood pressure, phlebitis, arrhythmia, angina pectoris.
From the hematopoietic system: less than 2% - anemia, lymphadenopathy, thrombocytopenia.
From the respiratory system: more often 2% - bronchitis, rhinitis; less often 2% - pneumonia, dyspnea, bronchial asthma, nosebleeds.
From the digestive system: more often 2% - nausea; less than 2% - heartburn, constipation or diarrhea, flatulence, gastralgia, abdominal pain, anorexia, decreased or increased appetite, dry mouth, belching, dysphagia, vomiting, stomatitis, esophagitis, glossitis, erosive and ulcerative lesions of the oral mucosa, gastroenteritis, hepatitis, biliary colic, cheilitis, duodenal ulcer, pancreatitis, cholestatic jaundice, liver dysfunction, rectal bleeding, melena, bleeding gums, tenesmus.
From the musculoskeletal system: more often than 2% - arthritis; less than 2% - leg muscle cramps, bursitis, tenosynovitis, myositis, myopathy, arthralgia, myalgia, rhabdomyolysis, torticollis, muscle hypertonicity, joint contractures.
From the genitourinary system: more often than 2% - urogenital infections, peripheral edema; less often 2% - dysuria (including pollakiuria, nocturia, urinary incontinence or urinary retention, imperative urge to urinate), nephritis, hematuria, vaginal bleeding, nephrourolithiasis, metrorrhagia, epididymitis, decreased libido, impotence, ejaculation disorder.
From the skin: more often than 2% - alopecia, xeroderma, increased sweating, eczema, seborrhea, ecchymosis, petechiae.
Allergic reactions to the components of the drug: less often 2% - skin itching, skin rash, contact dermatitis, rarely - urticaria, angioedema, facial edema, photosensitivity, anaphylaxis, exudative erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).
Laboratory indicators: less than 2% - hyperglycemia, hypoglycemia, increased serum CPK, albuminuria.
Other: less than 2% - weight gain, gynecomastia, mastodynia, exacerbation of gout.
Overdose. Treatment: there is no specific antidote; symptomatic therapy is carried out. Hemodialysis is ineffective.
