Included in the formulation
АТХ:J.05.A.X.09 Maraviroc
Pharmacodynamics:It belongs to the class of antagonist drugs of chemokine receptors CCR5, necessary for binding HIV to the cell and for penetrating the virus into it. Selectively binding to chemokine receptors CCR5, maraviroc prevents penetration of tropic to the data receptors of HIV-1 inside the cell.
In the culture of cells with the combined use of maraviroc with other antiretroviral drugs, antagonism was not revealed.
Stability of the virus to maraviroc can develop in 2 ways: either by selecting a virus that can bind to the chemokine receptors of CXCR4 as a co-receptor for entry into the cell (CXCR4-tropic virus) or by selecting a virus that continues to use exclusively CCR5 (CCR5-tropic virus) in the presence of maraviroc .
Both ways of developing resistance were observed in clinical studies of maraviroc in both previously untreated and previously antiretroviral therapy patients.
The presence of CXCR4-tropic virus in the failure of treatment is due to its presence in the original viral population. Conducting a test to exclude the presence of this variant of HIV before the appointment of maraviroc reduces the risk of failure of therapy associated with this pathway of resistance development.
In pilot studies, 7.6% of patients who received antiretroviral therapy earlier, between the screening and the start of treatment (4-6 weeks), changed the tropism of the viruses from CCR5 to CXCR4, either double and / or mixed.
Pharmacokinetics:Absorption is variable and has multiple peaks.
Cmax in blood plasma is achieved on average after 2 hours with a single oral intake of 300 mg maraviroc. When oral administration of maraviroc in a dose exceeding 1200 mg, the pharmacokinetics of the drug are non-linear.
Absolute bioavailability in a dose of 100 mg is 23%, the estimated bioavailability at a dose of 300 mg is 33%. Maraviroc is a substrate for the transport P-glycoprotein, which ensures the release of substances from the cell.
Maraviroc can be taken at recommended doses regardless of the meal.
Distribution
It binds to human plasma proteins (about 76%) and weakly binds to albumin and alpha-1-acid glycoprotein. The volume distribution of maraviroc is approximately 194 liters.
Human studies and in vitro studies (using human liver microsomes and expressed enzymes) have shown that maraviroc mainly biotransformed by the cytochrome P 450 system to metabolites that are not active against HIV-1.In in vitro studies, it has been established that the main isoenzyme responsible for the metabolism of maraviroc is the isoenzyme CYP3A4.
Maraviroc is the main substance circulating after its single oral intake at a dose of 300 mg (approximately 42% of the radioactive fraction). The most significant circulating metabolite in humans is the secondary amine formed by N-dealkylation and not having significant pharmacological activity. Other metabolites are products of mono-oxidation.
Approximately 20% is excreted by the kidneys, 76% - through the intestine during 168 hours. Maraviroc is the main substance present in the urine (an average of 8% of the dose) and feces (an average of 25% of the dose). The rest was excreted in the form of metabolites. After intravenous administration (30 mg), the half-life of maraviroc was 13.2 hours, 22% of the dose was excreted unchanged by the kidneys, and the values of total clearance and renal clearance were 44.0 and 10.17 l / h, respectively.
The pharmacokinetics of maraviroc in children under 16 years of age has not been studied. Patients older than 65 years of age depend on pharmacokinetics from age.
The pharmacokinetics of maraviroc in patients with severe renal failure does not differ from that in patients with normal renal function.Therefore, there is no need for dose correction in such patients, but in the case that they do not take inhibitors of the CYP3A4 isoenzyme. Patients with renal failure receiving maraviroc together with powerful inhibitors of the CYP3A4 isoenzyme, a dose correction of maraviroc is necessary.
Pharmacokinetics (mean geometric values of Cmax and area under the concentration-time curve / AUClast) in patients with impaired liver function are higher than in patients with healthy liver: for mild degrees (class A according to Child-Pugh classification), respectively 11 and 25%, with an average degree (class B according to the Child-Pugh classification) - by 32 and 46%. In patients with severe impairment of liver function, the pharmacokinetics of maraviroc were not studied.
Indications:Treatment of HIV-infected patients who have not previously received or received antiretroviral therapy, infected with HIV-1 with tropism only with the CCR5-co-receptor in combination with other antiretroviral drugs.
I.B20-B24.B24 Disease caused by human immunodeficiency virus [HIV], unspecified
Contraindications:Hypersensitivity to maraviroc. Simultaneous reception with preparations containing St. John's Wort. Maraviroc is not recommended for use in children under the age of 18 due to lack of data on efficacy and safety.
Carefully:Use with caution in patients with an increased risk of developing cardiovascular disease, as well as in patients with cardiovascular disease.
In connection with the possibility of developing orthostatic hypotension, caution should be exercised in prescribing maraviroc for patients with orthostatic hypotension in the history or when taking medications that lead to a decrease in blood pressure.
Due to the lack of data on patients with concomitant hepatitis B or C, caution should be exercised in treating these patients with maraviroc.
Experience in the use of the drug in patients with impaired liver function is negligible, in connection with which maraviroc these patients should be used with caution.
There are limited data on the safety and effectiveness of maraviroc in patients with impaired renal function. The risk of orthostatic hypotension increases in patients with severe renal failure receiving HIV protease inhibitors and maraviroc. Patients with impaired renal function have a high risk of developing cardiovascular disease, which can be exacerbated by the presence of orthostatic hypotension.
Pregnancy and lactation:There are no clinical data on the use of maraviroc during pregnancy. Studies in animals showed no direct or indirect adverse effects on pregnancy, embryo / fetal development, childbirth, or postnatal development. Maraviroc should be used during pregnancy only if the potential benefit to the mother exceeds the potential risk to the fetus.
It is not known whether maraviroc with breast milk. HIV-infected women are advised not to breast-feed because of the risk of HIV transmission to the baby during breastfeeding. Women receiving maraviroc, it is recommended to refrain from breastfeeding because of the risk of developing unwanted phenomena in children.
Action category for the fetus by FDA - B
Dosing and Administration:At the beginning of treatment, consideration should be given to the need for a test for determining tropism for proper application.In patients with dual / mixed or CXCR4-tropic HIV-1, it is not recommended to apply (in this group of patients, efficacy in a Phase II clinical trial was not demonstrated). Assign inside regardless of food intake.
Adults
The dosage regimen depends on the concomitant use of antiretroviral or other drugs: at a dose of 150 mg 2 times / day - when administered with inhibitors of the isoenzyme CYP3A4 (with or without the inducer of the isoenzyme CYP3A4): 600 mg 2 times / day with CYP3A4 isoenzyme inducers without a potent inhibitor of the isoenzyme CYP3A4): 300 mg 2 / day - with other concomitant drugs that do not belong to potent inhibitors or powerful inducers of the CYP3A4 isoenzyme.
Children
The effectiveness and safety of the use of maraviroc in children under the age of 18 years are not established. In this regard, use in children is not recommended.
Elderly patients
The experience of use in patients over 65 years of age is limited, so caution should be exercised when appointing elderly patients.
Patients with impaired renal function.
Patients with renal failure receiving potent inhibitors of the isoenzyme CYP3A4, dosing regimen - 1 time / day.
Maraviroc should be used with caution in patients with severe renal failure (creatinine clearance less than 30 mL / min),taking potent inhibitors of the CYP3A4 isoenzyme. In patients with impaired renal function (creatinine clearance <80 ml / min), including terminal renal failure requiring hemodialysis, maraviroc should be taken at 150 mg every 24 hours, if it is administered in combination with inhibitors of the isoenzyme CYP3A4. In the absence of inhibitors of the isoenzyme CYP3A4, dose adjustment and the interval of administration of maraviroc is not required (300 mg every 12 hours). When combined with fosamprenavir + ritonavir maraviroc appoint 150 mg every 12 hours.
Patients with impaired liver function.
Dose adjustment is not required, however, in patients with hepatic insufficiency should be used with caution.
Side effects:Patients with previous experience of treatment and received maraviroc in combination with optimized basal therapy
Infectious and parasitic diseases: infrequently - pneumonia, candidiasis of the esophagus.
Benign, malignant and unspecified neoplasms (including cysts and polyps): rarely - bile duct cancer, diffuse large B-cell lymphoma, Hodgkin's disease, bone metastases, liver metastases, peritoneal metastases, nasopharyngeal cancer, esophageal cancer.
From the side of the blood and lymphatic system: often - anemia, rarely - pancytopenia, granulocytopenia.
From the side of metabolism: often - weight loss, anorexia.
Disorders of the psyche: often - depression, insomnia.
From the nervous system: often - peripheral neuropathy, dizziness, paresthesia, dysgeusia, drowsiness; infrequently - epileptic seizure, epilepsy.
From the cardiovascular system: rarely - angina.
From the respiratory system: often - a cough.
From the digestive tract: often - pain in the abdomen, bloating, constipation, indigestion.
From the hepatobiliary system: often - increased activity of transaminases (ALT, AST), activity of gamma-glutamyl transferase; infrequently hyperbilirubinemia; rarely - toxic hepatitis, hepatic insufficiency, liver cirrhosis, increased activity of alkaline phosphatase; very rarely - liver failure with allergic manifestations.
From the skin and subcutaneous tissues: often - a rash, alopecia; rarely Stevens-Johnson syndrome.
From the side of the musculoskeletal and connective tissue: often - spasms in the muscles, back pain, pain in the limbs, increased activity of creatine phosphokinase in the blood; rarely - muscle atrophy.
From the side of the kidneys and urinary tract: infrequently - renal failure, proteinuria.
Other: often - asthenia, fatigue.
Patients who were not previously treated
From the side of the blood and lymphatic system: often anemia.
From the side of metabolism: often - anorexia.
Disorders of the psyche: often - depression, unusual dreams, insomnia.
From the nervous system: often - dizziness, headache, drowsiness.
From the digestive tract: often - pain from the abdomen, constipation, indigestion, flatulence, nausea, diarrhea, vomiting.
From the hepatobiliary system: often - increased ALT activity, AST.
From the side of the musculoskeletal and connective tissue: often - pain in the neck.
Other: often - fatigue, asthenia.
In the post-registration observations in very rare cases, severe hypersensitivity reactions were observed (includes medication rash with eosinophilia and systemic symptoms), severe skin reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis), and hepatotoxicity, liver failure with allergic manifestations. In rare cases, reported orthostatic hypotension, leading to fainting.
Overdose:The maximum dose used in clinical trials was 1200 mg. Restrictive dose was an undesirable phenomenon was orthostatic hypotension.
There are no specific antidotes for an overdose of maraviroc. It is necessary to give the patient a horizontal position, carefully evaluate vital signs, measure blood pressure and make an ECG.
According to the indications for removal of the non-sucking active maraviroc, vomiting or gastric lavage can be induced. As an adjuvant can be considered Activated carbon. Because the maraviroc moderately binds to blood plasma proteins, dialysis can be used to remove it.
Interaction:Maraviroc is a substratum of the isoenzyme CYP3A4 cytochrome P 450. The concomitant use of maraviroc with LS-inducers of the isoenzyme CYP3A4 can reduce the concentration of maraviroc in the blood plasma and weaken its therapeutic effect. The combined use of maraviroc with drugs that depress the isoenzyme CYP3A4 can increase the concentration of maraviroc in the blood plasma. With the concomitant use of maraviroc with inhibitors and / or inducers of the CYP3A4 isoenzyme, dose adjustment is required.
Antiretroviral drugs
Nucleoside reverse transcriptase inhibitors (NRTIs)
Maraviroc does not affect the pharmacokinetics of zidovudine,lamivudine and tenofovir. Maraviroc in a dose of 300 mg 2 times / day and concomitant NRTIs can be used without dose adjustment.
Integrase inhibitors
Clinically significant interactions were not observed. Can be used together without dose adjustment.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
With the combined use of efavirenz in a dose of 600 mg 1 time / day and maraviroc at a dose of 100 mg 2 times / day AUC0-12 and Cmax maraviroc were reduced, the concentration of efavirenz was not measured. The dose of maraviroc with concomitant use with efavirenzem and in the absence of potent inhibitors of the isoenzyme CYP3A4 should be increased to 600 mg 2 times / day.
With the combined use of etravirine in a dose of 200 mg 2 times / day and maraviroc at a dose of 300 mg 2 times / day, AUC0-12 and Cmax maraviroc decreased, AUC0-12 and Cmax etravirine did not change significantly. The dose of maraviroc when used in conjunction with etravirine and in the absence of potent inhibitors of the isoenzyme CYP3A4 should be increased to 600 mg 2 times / day.
When combined use of nevirapine at a dose of 200 mg 2 times / day and maraviroc in a dose of 300 mg once AUC0-12 maraviroc did not change, and its Cmax increased. The concentration of nevirapine was not measured. The recommended dose of maraviroc when used with nevirapine is 300 mg 2 times / day.
HIV protease inhibitors (HIV-HIV)
HIV IP (atazanavir , atazanavir / ritonavir, lopinavir / ritonavir, saquinavir / ritonavir, darunavir / ritonavir, fosamprenavir / ritonavir) increase AUC12 and Cmax maraviroc. When the HIV is co-administered with HIV, the recommended dose of maraviroc is 150 mg 2 times / day, except for the combination with tipranavir / ritonavir, when a dose of 300 mg 2 times / day should be used. Maraviroc does not have a significant effect on HIV-specific HIV concentrations.
NNRTI + HIV + HIV
NNRTI + HIV VIVs increase AUC12 and Cmax maraviroc. When combined with efavirenz or etravirine and HIV, the recommended dose of maraviroc is 150 mg 2 times / day, except for fosamprenavir / ritonavir (when the dose of maraviroc should be 300 mg 2 times / day) or tprinavir / ritonavir (when the dose of maraviroc should be 600 mg 2 times / day).
Antibacterial drugs
Rifampicin reduces AUC12 and Cmax maraviroc. The recommended dose of maraviroc when used together with rifampicin is 600 mg 2 times / day in the absence of a potent inhibitor of isofermite CYP3A4 (this dose adjustment has not been studied in patients with HIV).
When combined with rifabutin and HIV, the recommended dose of maraviroc is 150 mg 2 times / day (except tipranavir / ritonavir, when it should be used at a dose of 300 mg 2 times / day).
When combined with clarithromycin, the recommended dose of maraviroc is 150 mg 2 times / day.
Antifungal medicines
Ketoconazole in increases AUC0-tau and Cmax maraviroc. When combined with ketoconazole, the recommended dose of maraviroc is 150 mg 2 times / day.
Itraconazole is a potent inhibitor of the CYP3A4 isoenzyme, it is expected that it will increase the C max of maraviroc. When combined with itraconazole, the recommended dose of maraviroc is 150 mg 2 times / day.
Fluconazole is a moderate inhibitor of the CYP3A4 isoenzyme. It is expected that when it is used together with maraviroc, dose adjustment of the latter will not be required. The recommended dose of maraviroc is 300 mg 2 times / day.
Antiviral drugs
Pegylated interferon alfa-2a or ribavirin can be used simultaneously with maraviroc without dose adjustment. The recommended dose of maraviroc is 300 mg 2 times / day.
Antiarrhythmic drugs
With the combined use of digoxin and maraviroc, AUCt and Cmax digoxin did not change significantly. The concentration of maraviroc was not expected to change. The recommended dose of maraviroc when used with digoxin is 300 mg 2 times / day.
Drug-induced drugs, statins, oral contraceptives, hypnotic drugs can be used concomitantly with marwiroc without dose adjustment.The recommended dose of maraviroc is 300 mg 2 times / day.
Preparations on plant basis
It is suggested that a joint application with St John's wort can partially reduce the concentration of maraviroc to a suboptimal level and lead to loss of virologic control and possible resistance to maraviroc. Joint use is not recommended.
Special instructions:Therapy should be performed by a physician with experience in the treatment of HIV infection. Maraviroc It should be used only when sensitive methods detect CCR5-tropic HIV-1 (ie, a virus with tropism is not detected for CXCR4 or has a double and / or mixed tropism). Tropism of the virus can not be determined on the basis of anamnesis of treatment or evaluation of the patient's stored blood samples. To estimate tropism, only the newly obtained patient blood sample can be used. In HIV-1-infected patients, changes in the tropism of the virus occur over time. Therefore, treatment should be started soon after the definition of tropism. Maraviroc should be used as part of a combination antiretroviral therapy regimen.
Patients should be informed that antiretroviral therapy, including the use of maraviroc, does not prevent the risk of HIV transmission to other people through sexual contact or through contact with blood. Patients should continue to observe all precautions. Maraviroc does not lead to eradication of HIV-1.
Doctors should make sure that the dose of maraviroc is correctly adjusted when it is used in conjunction with inhibitors and / or inducers of the CYP3A4 isoenzyme, since they can affect the concentration and therapeutic efficacy of maraviroc.
In HIV-infected patients with severe immunodeficiency, in the first few weeks or months of the onset of highly active antiretroviral therapy (HAART), symptoms of inflammatory reactions may occur as a result of exacerbation of secondary infections that have occurred in asymptomatic form. Such reactions can lead to a worsening of the patient's condition. Any symptoms of inflammation should be identified and, if necessary, appropriate treatment should be started.
Antagonists of chemokine receptors CCR5 can adversely affect the immune response in certain infections.This should be taken into account when treating infections such as active tuberculosis and invasive fungal infections.
Patients should be advised to consult a doctor if they are concerned about joint pain or joint movement, because of the frequent cases of osteonecrosis with HIV and / or prolonged use of HAART.
Dysfunction of the liver
The safety and effectiveness of maraviroc in patients with severe liver disease has not been studied. In a study on healthy volunteers, there was a case of hepatotoxicity with signs of an allergic reaction, possibly associated with the administration of maraviroc. In addition, during studies involving patients with experience of therapy against the background of taking maraviroc, there was an increase in the incidence of adverse reactions from the liver. In patients with liver disease, including chronic active hepatitis during combined antiretroviral therapy, the incidence of liver dysfunction may increase, so these patients should be monitored in accordance with standard practice.
All patients with signs or symptoms of acute hepatitis,especially when suspected to be hypersensitive to maraviroc, or with an increase in hepatic transaminase activity in combination with a rash or other symptoms of possible hypersensitivity (itching rash, eosinophilia or increased IgE concentration in plasma), the maraviroc should be discontinued.
Severe skin reactions and hypersensitivity reactions
In most cases, hypersensitivity reactions, including severe and potentially life-threatening, were noted in patients taking maraviroc together with other drugs that could cause such reactions. Immediately stop taking maraviroc and other drugs in case of signs and symptoms of a severe hypersensitivity reaction. After the appearance of the rash, the delay in stopping treatment with maraviroc and others presumably implicated in drugs can lead to a life-threatening reaction.
Disorders of the cardiovascular system
It should be used with caution maraviroc patients with a risk of developing cardiovascular complications.
Renal impairment
In patients with severe renal failure who are receiving HIV and maraviroc therapy,may increase the risk of orthostatic hypotension. This risk is associated with an increase in the maximum concentration of maraviroc.
Caution should be exercised in appointing maraviroc in patients with severe renal failure who have risk factors or episodes of orthostatic hypotension in the history or patients taking concomitant antihypertensive therapy. Patients with concomitant cardiovascular diseases are at increased risk of cardiovascular adverse events that may be exacerbated by orthostatic hypotension.
Influence on ability of driving of the car and management of mechanisms
Studies of the effect on the ability to drive a car or work with mechanisms have not been carried out. Patients should be warned about the possible development of symptoms associated with orthostatic hypotension, such as dizziness while taking maraviroc. When these symptoms occur, patients should avoid potentially dangerous activities, such as driving or working with machinery.