Pharmacological properties
Pharmacodynamics. Etset contains the active substance atorvastatin. Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of HMG-CoA to mevalonate, which is a precursor of sterols, in particular cholesterol. In the liver, TG and cholesterol are incorporated into VLDL molecules, enter the blood plasma and are transported to peripheral tissues. LDL is formed from VLDL and is catabolized mainly by interaction with high-affinity LDL receptors (LDL receptors).
Atorvastatin reduces plasma cholesterol and lipoprotein concentrations by inhibiting HMG-CoA reductase and subsequently cholesterol biosynthesis in the liver, and also increases the number of hepatic LDL receptors on the cell surface, leading to increased uptake and catabolism of LDL.
Atorvastatin reduces LDL formation and LDL particle number. Atorvastatin causes a marked and sustained increase in LDL receptor activity combined with favorable changes in the quality of circulating LDL particles. Atorvastatin effectively lowers LDL-C levels in patients with homozygous familial hypercholesterolemia, a group that has not always responded to lipid-lowering therapy.
In addition to its effect on plasma lipids, atorvastatin exhibits other effects that enhance its antiatherosclerotic effect. It inhibits the synthesis of isoprenoids - substances that act as growth factors on the proliferation of vascular smooth muscle cells, reduces plasma viscosity and the activity of some coagulation and aggregation factors. Due to this action, it improves hemodynamics and contributes to the normalization of blood clotting processes. In addition, HMG-CoA reductase inhibitors affect macrophage metabolism and, thus, inhibit activation, reduce the risk of rupture of atherosclerotic plaques.
Atorvastatin has been shown to reduce total cholesterol (30-46%), LDL-cholesterol (41-61%), apolipoprotein B (34-50%), and triglycerides (14-33%), while causing variable increases in HDL-cholesterol and apolipoprotein A in a dose-response study. These results are consistent with data from patients with heterozygous familial hypercholesterolemia, non-communicable forms of hypercholesterolemia, and mixed hyperlipidemia, including those with non-insulin-dependent diabetes mellitus.
It has been proven that lowering levels of total cholesterol, LDL cholesterol, and apolipoprotein B reduces the risk of cardiovascular complications and mortality from cardiovascular disease.
Pharmacokinetics. Absorption. Atorvastatin is rapidly absorbed after oral administration and reaches C max in blood plasma after 1-2 hours. The level of absorption and concentration of atorvastatin in blood plasma depend on the dose of atorvastatin. The bioavailability of atorvastatin in tablet form compared with the solution is 95 and 99%, respectively. The bioavailability of atorvastatin is approximately 14%, and the systemic availability of inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic clearance in the intestinal mucosa and biotransformation during the first pass through the liver. Food intake reduces the rate and extent of absorption of the drug by approximately 25 and 9%, respectively, which is confirmed by the level of C max and AUC, the reduction in LDL-C does not depend on the time of application. Plasma concentrations of atorvastatin after evening dosing are lower than those after morning dosing (approximately 30% higher for Cmax and AUC). Despite this, the reduction in LDL-C is independent of the time of day of dosing.
Distribution. The mean volume of distribution of atorvastatin is approximately 381 L. Plasma protein binding is 98%. A erythrocyte/plasma ratio of approximately 0.25 indicates low penetration of the drug into erythrocytes. Based on observations in rats, it is believed that atorvastatin is excreted in human milk (see Adverse Reactions, Use in Pregnancy and Lactation, and Precautions for Use).
Excretion. Atorvastatin and its metabolites are mainly excreted in the bile after hepatic and/or extrahepatic biotransformation, but are not subject to gastro-hepatic recirculation. T ½ of atorvastatin in humans is approximately 14 hours. Inhibitory activity against HMG-CoA reductase persists for 20-30 hours due to the presence of active metabolites. After administration, less than 2% of atorvastatin is determined in the urine.
Patient populations. Elderly. Plasma concentrations of atorvastatin in healthy elderly subjects (aged ≥65 years) are higher than in younger subjects (approximately 40% for Cmax and 30% for AUC). Available data suggest that efficacy and safety in the elderly do not differ from those in the general population.
Children: There are no data on the pharmacokinetics of atorvastatin in children.
Gender. Plasma concentrations of atorvastatin differ in women from those in men (Cmax is approximately 20% higher and AUC is approximately 10% lower). However, these differences are not clinically significant, and the heart rate of the drug in men and women is almost the same.
Renal insufficiency. The route of administration and dose do not affect the plasma concentration of atorvastatin and its hypolipidemic effect. Therefore, there is no need to adjust the dose of the drug.
Hemodialysis: Studies of the effect of atorvastatin in patients with end-stage renal disease have not been conducted. Since the drug is extensively bound to plasma proteins, hemodialysis cannot significantly increase the clearance of atorvastatin.
Hepatic insufficiency. In patients with alcoholic cirrhosis of the liver, the concentration of atorvastatin in the blood plasma is significantly increased (C max - approximately 16 times, AUC value - 11 times).
Indication
Prevention of cardiovascular disease. For adult patients without clinically apparent coronary artery disease but with multiple risk factors for coronary artery disease, such as age, smoking, hypertension, low HDL, or a family history of early coronary artery disease, etset is indicated to reduce the risk of:
occurrence of myocardial infarction; occurrence of stroke; carrying out revascularization procedures and angina.
For patients with type 2 diabetes and without clinically significant coronary artery disease, but with multiple risk factors for coronary artery disease, such as retinopathy, albuminuria, smoking, or hypertension, Etset is indicated to reduce the risk of:
myocardial infarction; stroke.
For patients with clinically significant coronary artery disease, Etset is indicated to reduce the risk of:
occurrence of non-fatal myocardial infarction; occurrence of fatal and non-fatal stroke; performance of revascularization procedures; hospitalization due to congestive heart failure; occurrence of angina pectoris.
hyperlipidemia:
as an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apolipoprotein B and triglycerides and to increase HDL cholesterol in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to Fredrickson classification); as an adjunct to diet to treat patients with elevated plasma TG levels (type IV according to Fredrickson classification); for the treatment of patients with primary dysbetalipoproteinemia (type III according to Fredrickson classification) when diet is not effective enough; to reduce total cholesterol and LDL cholesterol in patients with homozygous familial hypercholesterolemia as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or when such treatments are unavailable; as an adjunct to diet to reduce total cholesterol, LDL cholesterol and apolipoprotein B levels in boys and postmenarcheal girls aged 10 to 17 years with heterozygous familial hypercholesterolemia, if, after appropriate diet therapy, the test results are as follows:
a) LDL-C remains ≥190 mg/dL or
b) LDL-C remains ≥160 mg/dL and:
There is a family history of early cardiovascular disease; ≥2 other risk factors for cardiovascular disease are present in the patient as a child.
Application
Hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia (types IIa and IIb according to the Fredrickson classification). The recommended initial dose of Etset is 10 or 20 mg once a day. For patients who require a significant reduction in LDL-C (by 45%), therapy can be started with a dose of 40 mg once a day. The dosage range of Etset is from 10 to 80 mg once a day. The drug can be taken as a single dose at any time, regardless of the meal. The initial and maintenance doses of Etset should be selected individually, depending on the goal of treatment and response. After starting treatment and / or after titrating the dose of Etset, lipid levels should be analyzed during the period from 2 to 4 weeks and the dose adjusted accordingly.
Homozygous familial hypercholesterolemia. The dose of Etset for patients with homozygous familial hypercholesterolemia is 10 to 80 mg/day. Etset should be used as an adjunct to other lipid-lowering treatments (e.g. LDL apheresis) or if lipid-lowering treatments are unavailable.
Concomitant lipid-lowering therapy. Etset can be used with bile acid secretagogues. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution (see Precautions, Interactions).
Dosage in patients with renal impairment. Renal disease does not affect either the plasma concentration or the LDL-C reduction of Etset; therefore, no dose adjustment is required in patients with renal impairment (see Precautions, Excipients).
Dosage for patients taking cyclosporine, clarithromycin, itraconazole or certain protease inhibitors. Treatment with Etset should be avoided in patients taking cyclosporine or HIV protease inhibitors (tipranavir + ritonavir) or the hepatitis C protease inhibitor (telaprevir). Etset should be prescribed with caution to HIV patients taking lopinavir + ritonavir and used at the lowest necessary dose. In individuals taking clarithromycin, itraconazole, or in HIV patients taking saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir in combination, the therapeutic dose of Etset should be limited to 20 mg, and appropriate clinical evaluation is recommended to ensure that the lowest necessary dose of Etset is used. In patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, treatment with Etset should be limited to a dose of 40 mg, and appropriate clinical monitoring is recommended to ensure that Etset is used at the lowest necessary dose (see Precautions, Interactions).
Contraindication
Acute liver disease, which may include persistent elevations of hepatic transaminases of unknown etiology; hypersensitivity to any of the components of this medicinal product.
Side effects
Psychiatric: depression, sleep disturbances, including insomnia and nightmares.
Nervous system: headache, peripheral neuropathy, paresthesia, hypoesthesia, dizziness, dysgeusia, cognitive disorders (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with the use of statins, stroke.
From the side of the organs of hearing and labyrinth: tinnitus, ringing in the ears, hearing loss.
On the part of the organ of vision: blurred vision, blurred vision, visual impairment.
On the part of the digestive system: dyspepsia, nausea, vomiting, belching, diarrhea, constipation, flatulence, abdominal pain, pain in the upper and lower abdominal regions, stomach pain, gastrointestinal discomfort, pancreatitis.
Liver and gallbladder: hepatitis, cholestasis, cholestatic jaundice, fatal and non-fatal liver failure.
Metabolic disorders: hypoglycemia, hyperglycemia, anorexia, weight gain, diabetes mellitus.
Musculoskeletal and connective tissue disorders: myalgia, myopathy, including immunologically mediated necrotizing myopathy, myositis, cramps, muscle spasms, muscle weakness, fatigue, rhabdomyolysis, arthralgia, joint pain, back pain, pain in extremities, musculoskeletal pain, neck pain, joint swelling, tendinopathy (sometimes complicated by tendon rupture).
Skin and subcutaneous tissue disorders: alopecia, pruritus, skin rash, bullous rash (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis), urticaria, angioedema.
Respiratory system: nasopharyngitis, epistaxis, interstitial lung disease, sore throat and larynx.
From the genitourinary system: urinary tract infection, leukocyturia.
From the reproductive system and mammary glands: sexual dysfunction, impotence, gynecomastia.
General disorders: malaise, asthenia, pyrexia, chest pain, peripheral edema, fatigue, fever.
From the side of the circulatory and lymphatic system: thrombocytopenia.
Immune system disorders: allergic reactions, anaphylaxis (including anaphylactic shock).
Injury, poisoning and procedural complications: tendon rupture.
Infections and infestations: infections.
Changes in laboratory test results: increased levels of transaminases and liver enzymes, abnormal liver function tests, increased levels of alkaline phosphatase in the blood, increased blood CPK activity.
Children (ages 10-17 years). The frequency and nature of adverse reactions and laboratory abnormalities are comparable to those in adults. Experience with the safety of long-term use of atorvastatin in children is currently limited.
Lipid-modifying drug therapy should be one of the components of complex treatment for patients with a significantly increased risk of developing atherosclerotic vascular diseases due to hypercholesterolemia. Drug therapy is recommended as an adjunct to diet when the result of following a diet that limits the consumption of saturated fats and cholesterol, as well as from the use of other non-drug measures, is insufficient. In patients with coronary heart disease or with several risk factors for coronary heart disease, Etset can be started simultaneously with diet.
Skeletal Muscle: There have been isolated reports of rhabdomyolysis with acute renal failure secondary to myoglobinuria with atorvastatin and other drugs in this class. A history of renal impairment may be a risk factor for rhabdomyolysis. Such patients should be monitored closely for skeletal muscle events.
Atorvastatin, like other statins, has occasionally been associated with myopathy, defined as muscle pain or weakness in association with an elevation of CPK levels to >10 times the upper limit of normal (ULN). Concomitant use of high doses of atorvastatin with certain medicinal products, such as cyclosporine and potent CYP 3A4 inhibitors (e.g. clarithromycin, itraconazole and HIV protease inhibitors), increases the risk of myopathy/rhabdomyolysis.
There have been isolated reports of immunologically mediated necrotizing myopathy, an autoimmune myopathy associated with statin use. Immune-mediated necrotizing myopathy is characterized by the following features: proximal muscle weakness and elevated plasma CPK levels persisting despite discontinuation of statin treatment; muscle biopsy reveals necrotizing myopathy without significant inflammation; and positive dynamics are observed with immunosuppressive agents.
The possibility of myopathy should be considered in any patient with diffuse myalgia, muscle tenderness or weakness and/or marked elevations in CPK. Patients should be advised to promptly report unexplained muscle pain, tenderness or weakness, especially if accompanied by malaise or fever, or if signs and symptoms of muscle disease persist after discontinuation of Etset. Treatment with Etset should be discontinued if CPK levels are elevated or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs of this class increases with the simultaneous use of cyclosporine, fibric acid derivatives, erythromycin, clarithromycin, the hepatitis C protease inhibitor telaprevir, combinations of HIV protease inhibitors, including saquinavir + ritonavir, lopinavir + ritonavir, tipranavir + ritonavir, darunavir + ritonavir, fosamprenavir and fosamprenavir + ritonavir, as well as niacin or azole antifungals. Physicians considering the combination of Etset and fibric acid derivatives, erythromycin, clarithromycin, saquinavir + ritonavir, lopinavir + ritonavir, darunavir + ritonavir, fosamprenavir, fosamprenavir + ritonavir, azole antifungals, or lipid-modifying doses of niacin should carefully weigh the potential benefits and risks and closely monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, especially during the initial months of therapy and during any up-titration periods of either drug. Consideration should be given to the use of atorvastatin at low initial and maintenance doses when co-administered with the above drugs (see Interactions). In such situations, periodic CPK determination may be considered, but there is no guarantee that such monitoring will help prevent cases of severe myopathy.
Cases of myopathy, including rhabdomyolysis, have been reported with concomitant use of atorvastatin with colchicine, therefore atorvastatin with colchicine should be prescribed to patients with caution (see Interactions with other drugs).
Etset therapy should be temporarily interrupted or discontinued in any patient with an acute serious condition suggestive of myopathy or in the presence of a risk factor for renal failure secondary to rhabdomyolysis (e.g. severe acute infection, hypotension, surgery, trauma, severe metabolic, endocrine and electrolyte disturbances, and uncontrolled seizures).
Before initiating therapy with Etset, it is recommended to obtain liver enzyme test results and repeat the tests if clinically indicated. There have been isolated reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. In the event of severe liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice, Etset should be discontinued immediately. Unless other etiological factors for liver injury are identified, treatment with the drug should not be restarted.
Etset should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Etset is contraindicated in patients with acute liver disease or persistent elevations of hepatic transaminases of unknown etiology (see Adverse Reactions).
Endocrine function: Increases in HbA1c and fasting plasma glucose have been reported with HMG-CoA reductase inhibitors, including atorvastatin.
Statins inhibit cholesterol synthesis and theoretically may reduce adrenal and/or gonadal steroid secretion. Atorvastatin does not reduce basal plasma cortisol levels or impair adrenal reserve. The effect of statins on sperm fertilisation has not been studied in sufficient numbers of patients. It is not known how the drug affects or generally affects the gonadal-pituitary-hypothalamic system in premenopausal women. Caution should be exercised when co-administering statins with drugs that may reduce the level or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.
Use in patients with recent stroke or transient ischemic attack. There is clinical evidence that when atorvastatin 80 mg was used in patients without coronary artery disease who had a history of stroke or transient ischemic attack within the previous 6 months, a higher incidence of hemorrhagic stroke was observed compared with placebo. The increased risk was particularly pronounced in patients who had a hemorrhagic stroke or lacunar infarction at baseline.
For patients with a history of hemorrhagic stroke or lacunar infarction, the risk/benefit ratio of taking atorvastatin at a dose of 80 mg has not been determined, therefore, before starting treatment, the potential risk of hemorrhagic stroke should be carefully considered.
Elderly patients (65 years of age). No overall difference in safety and efficacy of the drug was found in elderly and younger subjects, however, a higher sensitivity in some older patients cannot be excluded. Since advanced age (65 years) is a predisposing factor for myopathy, Etset should be prescribed with caution in the elderly.
Hepatic impairment: Etset is contraindicated in patients with active liver disease, including persistent elevations of hepatic transaminases of unknown etiology (see Adverse Reactions and Excipients).
Before starting treatment. Atorvastatin should be prescribed with caution to patients with a predisposition to the development of rhabdomyolysis. Before starting treatment with statins in individuals prone to the development of rhabdomyolysis, the level of CPK should be determined in:
renal impairment; hypothyroidism; hereditary disorders of the muscular system in the family or personal history; previous cases of toxic effects of statins or fibrates on muscles; previous liver disease and/or alcohol consumption in large quantities.
For elderly patients (70 years of age), the need for these measures should be assessed taking into account the presence of other predisposing factors for the development of rhabdomyolysis.
An increase in the level of the drug in the blood plasma is possible, in particular, in the case of interaction and use in special patient populations, including those with hereditary diseases.
In such cases, it is recommended to assess the risk/benefit ratio of treatment and conduct clinical monitoring of the patient's condition. If the CPK level is significantly elevated (exceeds 5 times the upper limit of normal) before the start of therapy, treatment should not be started.
CPK measurement. CPK should not be measured after strenuous exercise or in the presence of any possible alternative causes of CPK elevation, as this may complicate interpretation of the results. If CPK is significantly elevated at baseline (5 times the upper limit of normal), a repeat measurement should be performed in 5-7 days to confirm the result.
During treatment. Patients should be advised to immediately report the development of muscle pain, cramps, or weakness, especially when accompanied by malaise or fever.
If these symptoms occur during treatment with atorvastatin, the patient's CPK level should be determined. If the CPK level is significantly elevated (exceeds 5 times the upper limit of normal), treatment should be discontinued.
After symptoms resolve and CPK levels normalize, consideration may be given to reinitiating atorvastatin treatment or initiating alternative statin therapy at the lowest possible dose and with close monitoring of the patient's health.
Atorvastatin treatment should be discontinued if a clinically significant increase in CPK levels (>10 times the upper limit of normal) is observed or if rhabdomyolysis is diagnosed (or suspected).
Concomitant use with other medicinal products. The risk of rhabdomyolysis is increased when atorvastatin is used concomitantly with certain medicinal products that may increase the plasma concentration of atorvastatin. Examples of such medicinal products include potent inhibitors of CYP 3A4 or the transport proteins cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir. Gemfibrozil and other fibric acid derivatives, erythromycin, niacin and ezetimibe also carry a risk of myopathy. Where possible, other medicinal products (that do not interact with atorvastatin) should be used instead of the above.
If concomitant treatment with atorvastatin and related drugs is necessary, the benefit/risk of the combined treatment should be carefully weighed. If patients are taking drugs that increase the concentration of atorvastatin in the blood plasma, it is recommended to reduce the dose of atorvastatin to the minimum. In addition, in the case of using potent CYP 3A4 inhibitors, it is necessary to consider the possibility of using atorvastatin in a low initial dose. It is also recommended to conduct appropriate clinical monitoring of the health status of these patients.
It is not recommended to use atorvastatin and fusidic acid simultaneously, therefore it is worth considering the possibility of temporarily withdrawing atorvastatin during treatment with fusidic acid.
Interstitial lung disease. Exceptional cases of interstitial lung disease have been reported with some statins, particularly with long-term therapy. Symptoms include dyspnea, nonproductive cough, and malaise (fatigue, weight loss, and fever). If interstitial lung disease is suspected, statin treatment should be discontinued.
Limitations of use. The possible consequences of using atorvastatin in conditions where the main deviation from the norm on the part of lipoproteins is an increase in the level of chylomicrons (types I and V according to the Fredrickson classification) have not been studied.
Excipients: This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Use during pregnancy and lactation. Etset is contraindicated in pregnant women and women who may become pregnant. Statins may cause fetal harm when used in pregnant women. Etset should be used in women of childbearing potential only if it is highly unlikely that such patients will become pregnant and who have been informed of the potential risk factors. If a woman becomes pregnant during treatment with Etset, the drug should be discontinued immediately and the patient should be re-counseled about the potential risk factors for the fetus and the lack of known clinical benefit from continued use of the drug during pregnancy.
During normal pregnancy, cholesterol and triglyceride levels in the blood plasma increase. The use of lipid-lowering drugs during pregnancy will not have a positive effect, since cholesterol and its derivatives are necessary for normal fetal development. Atherosclerosis is a chronic process, and therefore, a break in taking lipid-lowering drugs during pregnancy should not have a significant impact on the results of long-term treatment of primary hypercholesterolemia.
There are no adequate and well-controlled studies of atorvastatin use in pregnancy. There have been isolated reports of congenital anomalies following in utero exposure to statins.
Breastfeeding. It is not known whether atorvastatin is excreted in human milk, but small amounts of other drugs of this class are known to be excreted in human milk. Because statins have the potential to cause serious adverse reactions in nursing infants, women who require treatment with Etset should not breastfeed (see Adverse Reactions).
Ability to influence the reaction speed when driving vehicles or working with other mechanisms. Has a very slight influence on the reaction speed when driving vehicles or working with other mechanisms.
Patients aged 10-17 years with heterozygous familial hypercholesterolemia treated with atorvastatin (doses up to 20 mg) have been shown to have a similar adverse reaction profile to those treated with placebo. There was no significant effect of the drug on growth or puberty in boys or on menstrual cycle length in girls (see Adverse Reactions, Use). Adolescent girls should be counseled about appropriate methods of contraception during treatment with Etset (see Use in Pregnancy and Lactation).
Interactions
The risk of myopathy during statin treatment is increased by concomitant use of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or potent CYP 3A4 inhibitors (e.g. clarithromycin, HIV protease inhibitors, and itraconazole) (see Special warnings and pharmacological properties).
Potent CYP 3A4 inhibitors. Atorvastatin is metabolized by cytochrome P450 3A4. Concomitant use of Etset with potent CYP 3A4 inhibitors may lead to increased plasma concentrations of atorvastatin. The extent of interaction and potentiation of action depend on the variability of the effect on CYP 3A4. Concomitant use with potent CYP 3A4 inhibitors (e.g. cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir) should be avoided whenever possible. If concomitant use of these drugs with atorvastatin cannot be avoided, a lower initial and maximum dose of atorvastatin should be considered. Appropriate clinical monitoring of the patient is also recommended.
Moderate CYP 3A4 inhibitors (e.g. erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. Concomitant use of erythromycin and statins is associated with an increased risk of myopathy. Drug interaction studies to evaluate the effects of amiodarone or verapamil on atorvastatin have not been conducted. Amiodarone and verapamil are known to inhibit CYP 3A4 activity, and therefore, concomitant use of these drugs with atorvastatin may result in increased exposure to atorvastatin. Therefore, lower maximum doses of atorvastatin should be considered when atorvastatin is co-administered with these moderate CYP 3A4 inhibitors. Clinical monitoring of the patient is also recommended. Clinical monitoring of the patient is recommended after initiation of treatment with an inhibitor or after dose adjustment.
Grapefruit juice. Contains one or more components that inhibit CYP 3A4 and may increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (1.2 L/day).
Clarithromycin: Atorvastatin AUC was significantly increased when atorvastatin 80 mg was co-administered with clarithromycin (500 mg twice daily) compared to atorvastatin alone (see Pharmacology: Pharmacodynamics under Actions). Therefore, Etset 20 mg should be used with caution in patients receiving clarithromycin (see Precautions).
Combination of protease inhibitors. The AUC of atorvastatin was significantly increased when atorvastatin was co-administered with several combinations of HIV protease inhibitors and with the hepatitis C protease inhibitor telaprevir compared to atorvastatin alone (see Pharmacological properties). Therefore, concomitant use with Etset should be avoided in patients taking the HIV protease inhibitor tipranavir + ritonavir or the hepatitis C protease inhibitor telaprevir. The drug should be prescribed with caution to patients taking the HIV protease inhibitor lopinavir + ritonavir and used at the lowest necessary dose. In patients taking the HIV protease inhibitors saquinavir + ritonavir, darunavir + ritonavir, fosamprenavir or fosamprenavir + ritonavir, the dose of Etset should not exceed 20 mg and should be used with caution (see Features of use and administration). When used in patients taking the HIV protease inhibitor nelfinavir or the hepatitis C protease inhibitor boceprevir, the dose of Etset should not exceed 40 mg, and close clinical monitoring of patients is recommended.
Itraconazole. The AUC of atorvastatin was significantly increased when atorvastatin 40 mg was co-administered with itraconazole 200 mg (see Pharmacology: Pharmacodynamics under Actions). Thus, caution should be exercised in patients taking itraconazole if the dose of Etset exceeds 20 mg (see Special warnings and precautions for use).
