Composition, form of production and packaging
The tablets covered with a film membrane of blue color, capsular, biconcave, with engraving "150 MVC" on one side of the tablet; On the cross-section two layers are visible, the core of the tablet is white.
1 tab.
maraviroc 150 mg
Additives: microcrystalline cellulose 282 mg, calcium hydrophosphate 142.5 mg, sodium carboxymethyl starch 18 mg, magnesium stearate 7.5 mg, opadrai blue (85G20583) (polyvinyl alcohol 10.56 mg, talc 4.8 mg, titanium dioxide 4.63 mg, macrogol 3350 2.96 mg, soy lecithin 0.84 mg, aluminum lignol based on indigocarmine 0.21 mg) 24 mg.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
180 pcs. - bottles (1) - packs of cardboard.
The tablets covered with a film membrane of blue color, capsular, biconcave, with engraving "300 MVC" on one side of the tablet; On the cross-section two layers are visible, the core of the tablet is white.
1 tab.
maraviroc 300 mg
Additives: microcrystalline cellulose 564 mg, calcium hydrophosphate 258 mg, sodium carboxymethyl starch 36 mg, magnesium stearate 15 mg, opadrai blue (85G20583) (polyvinyl alcohol 21.12 mg, talc 9.6 mg, titanium dioxide 9.26 mg, macrogol 3350 5.92 mg, soy lecithin 1.68 mg, aluminum lignol based on indigocarmine 0.42 mg) 48 mg.
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
10 pieces. - blisters (9) - packs of cardboard.
180 pcs. - bottles (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2013.
PHARMACHOLOGIC EFFECT
Mechanism of action
Maraviroc belongs to a class of drugs - antagonists of chemokine receptors CCR5. The target cell receptor CCR5 is required for binding HIV to the cell and for penetrating the virus into the cell. Maraviroc selectively binds to the chemokine receptors of CCR5, preventing the entry of HIV-1, tropic to these receptors, inside the cell.
Antiviral activity in cell culture
The inhibitory concentration at which the activity of the pathogen in vitro is inhibited by 90% (EC 90 ), in 43 primary clinical isolates of CCR5-tropic HIV-1 was 0.57 (0.06-10.7) ng / ml, without significant changes between the different tested subtypes.
When combined with other antiretroviral drugs in cell culture, maraviroc has not demonstrated antagonism with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), HIV protease inhibitors (HIV), and enfuvirtide fusion inhibitors.
Resistance
The viability of the virus to maraviroc can be manifested in two ways: by selecting a virus that is capable of binding to the chemokine receptors of CXCR4 as a co-receptor for entry into the cell (CXCR4-tropic virus) or selecting a virus that continues to use exclusively CCR5 (CCR5-tropic virus) in the presence of maraviroc.
Resistance in cell culture
Variants of HIV-1, which have a reduced sensitivity to maraviroc, were selected in the culture of CCR5-tropic clinical viral isolates. Maraviroc resistant viruses remained CCR5-tropic, no conversion of CCR5-tropic virus into CXCR4-tropic virus occurred.
Phenotypic resistance: the curves of the inhibitory concentrations for maraviroc resistant viruses did not reach 100% oppression in the trials using the maraviroc dilution series.
Genotypic resistance: an accumulation of mutations in the enveloped glycoprotein gp120 (a viral protein that binds to the CCR5 co-receptor) has been found. The position of these mutations in different isolates was not constant.
Cross-resistance: All clinical isolates of HIV-1 resistant to NRTI, NNRTI, HIV-IP and enfuvirtide, were susceptible to maraviroc in cell culture. Maraviroc resistant viruses in cell culture remained sensitive to the inhibitor of enfuvirtide fusion and to the HIV of saquinavir.
In vivo
Both ways of developing resistance were observed in clinical studies of maraviroc in both previously untreated patients and previous antiretroviral therapy.
The presence of CXCR4-tropic virus in the failure of treatment is due to its presence initially. 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.
Resistance in patients with prior antiretroviral therapy
In pilot studies, 7.6% of patients who received antiretroviral therapy earlier, between the screening and treatment start (4-6 weeks), changed the tropism of viruses with CCR5 to CXCR4 or double / mixed.
PHARMACOKINETICS
Suction
The maximum concentration (C max ) in blood plasma is reached on average after 2 hours with a single oral intake of 300 mg of maraviroc. When oral administration of maraviroc in a dose exceeding 1200 mg, the pharmacokinetics of the drug are non-linear. The absolute bioavailability of the maraviroc in a dosage of 100 mg is 23% and the estimated bioavailability at a dosage of 300 mg is 33%. Maraviroc is a substrate for the transport P-glycoprotein, which provides the release of substances from the cell. Maraviroc can be taken at recommended doses regardless of the meal.
Distribution
It binds (approximately 76%) to human plasma proteins and weakly binds to albumin and? 1- acid glycoprotein. V d of maraviroc is approximately 194 liters.
Metabolism
Human studies and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviros are mainly metabolized by the cytochrome P450 system to metabolites that are not active against HIV-1. In vitro studies have shown that the isoenzyme CYP3A4 is the main isoenzyme responsible for the metabolism of maraviroc. At the same time, the polymorphic isoenzymes CYP2C9, CYP2D6 and CYP2C19 are not significantly associated with the metabolism of maraviroc.
Maraviroc is the main circulating substance after a single oral dose of 300 mg. The most significant circulating metabolite in humans is a secondary amine formed by N-dealkylation, and does not have significant pharmacological activity. Other metabolites are products of mono-oxidation.
Excretion
Approximately 20% is excreted by the kidneys, and 76% by the intestine during 168 hours. Maraviroc is the main substance present in the urine (on average, 8% of the dose) and feces (on average, 25% of the dose). The rest was excreted in the form of metabolites. After intravenous administration (30 mg), T 1/2 of maraviroc was 13.2 chv, 22% of the dose was excreted unchanged by the kidneys, and the values ​​of total clearance and renal clearance were 44.0 l / h and 10.17 l / h, respectively.
Pharmacokinetics in special clinical cases
The pharmacokinetics of maraviroc in children has not been studied.
Dependence of pharmacokinetics on age was not revealed.
It was shown that the pharmacokinetics of maraviroc in patients with severe renal insufficiency does not differ from pharmacokinetics in patients with normal renal function. In this regard, there is no need to adjust the dose of the drug in patients with renal insufficiency in the absence of inhibitors of the isoenzyme CYP3A4.
However, it has been shown that the addition of saquinavir / ritonavir (1000/100 mg x 2 r / day) to patients with moderate renal insufficiency significantly alters the pharmacokinetics of maraviroc. In this group of patients, the concentration of maraviroc was lower than the therapeutic concentration. Thus, patients with renal insufficiency and receiving maraviroc together with potent inhibitors of the CYP3A4 isoenzyme need a dosage correction of maraviroc.
Maraviroc is metabolized and excreted mainly by the liver. The study compared the pharmacokinetics of a single dose of 300 mg of maraviroc in patients with mild (Class A Child-Pugh classification, n = 8) and mean (class B in the Child-Pugh classification, n = 8) degrees of severity of hepatic impairment compared to healthy patients. The mean geometric values ​​of Cmax and the area under the concentration-time curve (AUC last ) were 11% and 25%, respectively, higher for patients with mild liver function impairment, and 32% and 46% higher for middle-infraction patents function of the liver in comparison with normal liver function. In patients with severe impairment of liver function, the pharmacokinetics of maraviroc were not studied.
INDICATIONS
- treatment of HIV-infected patients who had previously received antiretroviral therapy, infected with HIV-1 with tropism only to the CCR5 co-receptor in combination with other antiretroviral drugs.
DOSING MODE
Inside, regardless of food intake.
The recommended dose is 150 mg, 300 mg or 600 mg 2 times / day, depending on the concomitant use of antiretroviral drugs or other medicines.
Tab.1. The dosage regimen of Celzentri in combination with other medicines.
Complementary medications The recommended dose of Celzentri
Inhibitors of the isoenzyme CYP3A4 (with or without an inducer of CYP3A4 isoenzyme), including: HIV IP (other than tipranavir / ritonavir), ketoconazole, itraconazole, clarithromycin and other potent inhibitors of the isoenzyme CYP3A4 (nefazodone, telithromycin) 150 mg 2 times / day
Other concomitant medications, including tipranavir / ritonavir, nevirapine, all NRTIs and enfuvirtide 300 mg 2 times / day
Inductors of the isoenzyme CYP3A4 (without the powerful inhibitor of the isoenzyme CYP3A4), including: efavirenz, rifampin, carbamazepine, phenobarbital and phenytoin 600 mg 2 times / day
Patients with a dysfunction of the liver dose adjustment is not required.
A dose adjustment is required in patients with impaired renal function receiving potent inhibitors of the CYP3A4 isoenzyme, such as the HIV IP (other than tipranavir / ritonavir), ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin.
Maraviroc should be used with caution in patients with renal insufficiency (CC less than 30 ml / min), taking potent inhibitors of the isoenzyme CYP3A4. Inpatients with impaired renal function (CC <80 ml / min) , including terminal renal failure requiring hemodialysis, the dosage interval of maraviroc should be modified 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 are not required.
Table 2 shows the recommendations for correcting the intervals between doses of the drug. It is necessary to closely monitor the clinical response to the treatment of patients with impaired renal function.
Tab.2 . Multiplicity of dosing correction for patients with impaired renal function.
Complementary medicinal preparations KK (ml / min) <80
Without potent inhibitors of the isoenzyme CYP3A4 or in conjunction with tipranavir / ritonavir There are no recommendations for modifying the dose and the interval of intake of 300 mg every 12 hours
When combined with potent inhibitors of the isoenzyme CYP3A4, for example, with lopinavir / ritonavir, darunavir / ritonavir, saquinavir / ritonavir atazanavir / ritonavir, ketoconazole 150 mg 1 time every 24 h
When combined with fosamprenavir / ritonavir 150 mg every 12 h
SIDE EFFECT
The undesirable phenomena presented below are listed according to the body systems and in accordance with the frequency of occurrence. Frequency of occurrence is defined as follows: very often (? 1/10), often (? 1/100 and <1/10), infrequently (? 1/1 000 and <1/100), rarely (? 1/10 000 and <1/1 000), very rarely (<1/10 000, including individual cases). Frequency categories were formed on the basis of clinical studies of the drug and post-registration surveillance.
Infections and infestations: often - herpetic infections, folliculitis, pneumonia, anogenital warts, influenza, bacterial infections, viral infections; infrequently - candidiasis of the esophagus, septic shock.
Neoplasms: often - benign neoplasm of the skin; rarely - abdominal tumors, cholangiocarcinoma, bone metastases, liver metastases, peritoneal metastases, anal tumor, nasopharyngeal cancer, esophageal cancer, language tumors (malignancy stage not established), Hodgkin's disease, diffuse large B-cell lymphoma, basal cell carcinoma, Bowen's disease, lymphoma, anaplastic large-cell T- and zero-cell lymphomas, squamous cell carcinoma of the skin, endocrine malignant and unspecified tumors.
On the part of the system of blood and blood-forming organs: often - anemia; infrequently - pancytopenia, neutropenia, lymphadenopathy; rarely - granulocytopenia, hypoplastic anemia.
From the side of metabolism and nutrition: often - hypertriglyceridemia, lipodystrophy; rarely - an upset of appetite.
From the endocrine system: rarely - diabetes mellitus type 2.
Mental disorders: often - anorexia, depression, pathological dreams; infrequent excitation, hallucinations; rarely - mutism.
From the side of the nervous system: often - paresthesia, dysesthesia, hyperesthesia, insomnia, taste disorders, drowsiness, peripheral neuropathy, headache, impaired sensation, memory loss, fainting; infrequently - convulsions; rarely - loss of consciousness, epilepsy, small epileptic seizures, paralysis of the facial nerve, areflexia, meningitis (including viral), cerebral circulatory disorders, tremor.
From the side of the organ of vision: often - conjunctivitis, other manifestations of eye infections; infrequently - cataract, hemianopia.
On the part of the hearing organs and labyrinthine disorders: often - otitis media; infrequently - dizziness.
From the cardiovascular system: often - hot flashes; infrequently - ischemic heart disease, myocardial infarction; rarely - deep vein thrombosis, lowering of blood pressure, endocarditis.
From the respiratory system: often - cough, upper and lower respiratory tract infections, sinusitis, bronchitis, nasal congestion; infrequently - respiratory distress syndrome, bronchospasm; rarely - apnea.
From the gastrointestinal tract: very often - nausea; often - abdominal pain, indigestion, constipation, flatulence, bloating, vomiting, diarrhea, atony and hypotension of the intestine, gastroesophageal reflux; infrequently - pancreatitis, rectal bleeding, pseudomembranous colitis.
From the hepatobiliary system: infrequently - cirrhosis of the liver; rarely - liver failure, toxic hepatitis, jaundice (including cholestatic), portal vein thrombosis; very rarely - hepatotoxicity and hepatic insufficiency with allergic reactions have been registered in clinical and post-registration studies.
From the skin: often - a rash, itching of the skin, a violation of the function of apocrine and eccrine glands, erythema, acne, alopecia; rarely Stevens-Johnson syndrome.
From the musculoskeletal system: often - spasms in the muscles, back pain, pain in the extremities, neck pain, arthralgia; infrequently - myositis; rarely - muscular atrophy, osteonecrosis, rhabdomyolysis.
From the genitourinary system: often - violation of ejaculation and erection, nocturia; infrequently - renal failure, proteinuria, polyuria.
Other: often - asthenia, fatigue, weight loss, fever, pain of unclear localization.
On the part of laboratory indicators: often - increased activity of ALT, AST.
CONTRAINDICATIONS
- hypersensitivity to maraviroc or to one of the excipients;
- 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.
With caution: there is little experience of use in patients older than 65 years, so care should be taken when prescribing maraviroc to elderly patients.
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 when using maraviroc in patients with orthostatic hypotension in anamnesis or when taking medications that lead to a decrease in blood pressure.
Because there is insufficient data on patients with concomitant hepatitis B or C, caution should be exercised in treating these patients with maraviroc.
The experience of using the drug in patients with impaired liver function is negligible, and therefore maraviroc in these patients should be used with caution.
There are limited data on the safety and effectiveness of maraviroc in patients with impaired renal function, obtained in a comparative pharmacokinetic study. The study was conducted in patients with renal insufficiency and healthy volunteers taking maraviroc in combination with saquinavir / ritonavir. Overall, the maraviroc was well tolerated, but in patients with renal insufficiency, the incidence of adverse events (mostly unexpressed) was higher.
The risk of orthostatic hypotension increases in patients with severe renal failure who receive boosted HIV from HIV and maraviroc. The greatest risk can be expected with the joint administration of maraviroc and HIV-specific HIV, such as saquinavir, darunavir, lopinavir - all in combination with ritonavir. Patients with impaired renal function have a high risk of developing cardiovascular disease, which can be exacerbated by the presence of orthostatic hypotension. Studies with maraviroc in patients with severe renal failure receiving potent inhibitors of the isoenzyme CYP3A4 have not been performed. Correction dose and receiving intervals are based on pharmacokinetic modeling and simulation programs.
PREGNANCY AND LACTATION
Clinical data on the use of maraviroc during pregnancy are not available. Studies in animals did not reveal any direct or indirect adverse effect on pregnancy, embryo / fetal development, birth or postnatal development. Maraviroc should be used during pregnancy only if the potential benefit to the mother outweighs the potential risk to the fetus.
It is not known whether maraviroc is excreted in breast milk. HIV-positive women are advised not to breastfeed because of the risk of HIV transmission to the baby during breastfeeding. Women taking maraviroc, it is recommended not to breastfeed because of the risk of adverse events in children.
APPLICATION FOR FUNCTIONS OF THE LIVER
Dosage adjustment is necessary in patients with impaired renal function receiving potent inhibitors isoenzyme CYP3A4, such as HIV-PI (except tipranavir / ritonavir), ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin.
Maraviroc should be used cautiously in patients with renal impairment (creatinine clearance less than 30 mL / min) receiving potent inhibitors isoenzyme CYP3A4. In patients with impaired renal function (creatinine clearance <80 mL / min)Including terminal renal insufficiency requiring hemodialysis, should be modified maraviroc dosing interval if it is administered in combination with inhibitors of isoenzyme CYP3A4. In the absence of inhibitors of CYP3A4 isoenzyme correction interval and dose receiving maraviroc not required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Patients with impaired liver function dose adjustment is required.
APPLICATION FOR CHILDREN
Maraviroc is not recommended for use in children under the age of 18 years due to lack of efficacy and safety data
APPLICATION IN ELDERLY PATIENTS
There is little experience of use in patients older than 65 years, so you need to be careful in appointing maraviroc elderly patients.
SPECIAL INSTRUCTIONS
Therapy should be performed by physicians with experience in the treatment of HIV infection.
Before treatment should take into account:
- the appointment Tselzentri patient is carried out after studying the tropism, viral resistance and treatment history;
- application maraviroc not recommended for patients with dual / mixed or CXCR4-tropic HIV-1.
Maraviroc should only be used in cases when using adequately validated and sensitive method defined only CCR5-tropic HIV-1 (i.e., not detected virus with a tropism to CXCR4 or having a dual / mixed tropism). The tropism of the virus can not be determined based on the history of treatment or evaluation is stored patient blood samples.
In HIV-1 infected patients over time there is a change of tropism of the virus. It is therefore necessary to start treatment soon after the determination of tropism.
Information for Patients
Patients should be informed that antiretroviral therapy, including the use of maraviroc, does not prevent the risk of transmission of HIV to others through sexual contact or through contact with blood. Patients should continue to take all precautionary measures. Maraviroc does not lead to the eradication of HIV-1.
Correction of dose
Make sure that the correct dose of maraviroc adjusted when used together with inhibitors and / or inducers isoenzyme CYP3A4, as they may affect the concentration and therapeutic efficacy of maraviroc.
Immune reconstitution syndrome
in HIV-infected patients with severe immune deficiency in the first few weeks or months of starting highly active antiretroviral therapy (HAART) may appear symptoms of inflammatory reactions as a result of acute secondary infection, occurring in an asymptomatic form. Such reactions can lead to poor patient. Examples are cytomegalovirus retinitis, generalized and / or focal mycobacterial infections and pneumonia caused by Pneumocystis jiroveci (formerly known asCarinii of Pneumocystis) . It is necessary to detect any symptoms of inflammation and to begin appropriate treatment if necessary.
Effects on immunity
antagonists of chemokine CCR5 receptors can negatively affect the immune response in certain infection. This should be considered when treating infections such as active tuberculosis and invasive fungal infections.
osteonecrosis
Despite the fact that the nature of osteonecrosis is considered multifactorial (corticosteroids, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis observed more frequently in patients with HIV and / or long-term use of HAART. Patients should be advised to consult a doctor in cases where they are concerned about the pain in the joints or joint movement difficult.
Abnormal liver function
Safety and efficacy of maraviroc in patients with severe liver disease has not been studied.
In a study in healthy volunteers was observed hepatotoxicity is the case with the signs of an allergic reaction, possibly associated with taking maraviroc. In addition, during studies involving patients experienced in patients receiving therapy maraviroc was an increase in adverse reactions in the liver, while no increased incidence of liver function test abnormalities in general to a level of 3-4 severity scale ACTG (AIDS clinical trial group - a group conducting clinical trials in the treatment of AIDS, US).
An even smaller number of cases of hepatobiliary system observed in previously untreated patients therapy. The frequency of side effects of the liver and liver function tests deviation degree on the scale 3-4 ACTGbyli comparable between groups receiving maraviroc and efavirenz. Patients with liver disease, including chronic active hepatitis during combination antiretroviral therapy may increase the frequency of liver function abnormalities, therefore, these patients should be monitored in accordance with standard practice, the management of patients with liver disease.
All patients with signs or symptoms of acute hepatitis, especially in cases of suspected hypersensitivity to the drug or increasing the activity of hepatic transaminases in combination with a rash or other symptoms possible hypersensitivity (itchy rash, or eosinophilia IgEv increased concentration of plasma) should stop reception of maraviroc.
Renal dysfunction .
In the absence of maraviroc metabolic inhibitors, renal clearance is about 23% of the total clearance of maraviroc and hence is not expected that renal dysfunction could significantly increase the concentration in the blood serum of maraviroc.
In patients with severe renal insufficiency receiving therapy with PI HIV drug maraviroc, may increase the risk of orthostatic hypotension. This risk is associated with an increase in the maximum concentration of maraviroc. Maximal risk orthostatic hypotension observed with simultaneous application maraviroc SP with HIV, with the most potent inhibitory effect against isozyme CYP3A4 (saquinavir / ritonavir, darunavir / ritonavir, lopinavir / ritonavir). Patients with impaired renal function often suffer concomitant cardiovascular diseases, as well as an increased risk of cardiovascular adverse events, which may be exacerbated by orthostatic hypotension.
Impact on the ability to drive vehicles and manage mechanisms
Studies of the effect on the ability to drive or operate machinery has not been. Maraviroc may cause dizziness. Patients should be warned that if they experience dizziness, they should avoid potentially hazardous activities such as driving or using machinery.
OVERDOSE
The maximum dose used in clinical trials was 1200 mg. Dose-limiting adverse effect was orthostatic hypotension.
Specific antidotes overdose maraviroc not. It is necessary to give the patient a horizontal position, to carefully assess vital signs, measuring blood pressure and make an electrocardiogram.
According to the testimony can cause vomiting or gastric lavage hold. Purpose of activated carbon can be considered as auxiliary means. Since maraviroc moderately bound to plasma proteins, with the aim of deducing maraviroc dialysis may be used.
DRUG INTERACTION
Maraviroc is a substrate isoenzyme CYP3A4. Concomitant use with medicinal maraviroc isoenzyme inducers of CYP3A4 may decrease maraviroc concentration in the blood plasma, and reduce its therapeutic effect. Sharing maraviroc with drugs, depressing isoenzyme CYP3A4, maraviroc can increase the concentration in plasma. With concomitant use maraviroc inhibitors and / or inducers of CYP3A4 isoenzyme require dosage adjustment.
Further details regarding concomitant medication use are presented below (see. Chart 3).
Maraviroc has no inhibitory activity against any of the major cytochrome P450 isoenzymes at clinically relevant concentrations (CYP1A2, CYP2B6, CYP2C8, CYP2C9 , CYP2C19, CYP2D6 and CYP3A4).
Maraviroc no clinically significant effect on the pharmacokinetics of midazolam, oral contraceptives (ethinyl estradiol and levonorgestrel), or the ratio of 6? -gidroksikortizol / cortisol in urine, suggesting lack of inhibition or induction of isoenzyme CYP3A4 in vivo . At higher exposure maraviroc can not exclude possible inhibition isozyme CYP2D6. Based on data obtained in vitro and in clinical studies, likely to affect the pharmacokinetics of maraviroc concomitant drugs is low.
When using maraviroc without inhibitors isoenzyme CYP3A4, its renal clearance is about 23%. So how involved and passive and active mechanisms, there is a possibility of competition for elimination with other active substances that are excreted by the kidneys.
However, maraviroc concomitant use of tenofovir and co-trimoxazole (trimethoprim comprises inhibitor of cationic renal transport) has no effect on the pharmacokinetics of maraviroc.
In addition, concomitant use with maraviroc lamivudine / zidovudine showed no effect on the pharmacokinetics of lamivudine maraviroc (derived mainly kidneys) or zidovudine (not associated with cytochrome P450 metabolism and renal clearance). Maraviroc inhibits in vitro P-glycoprotein (EC 50is 183 .mu.mol / l). Systemic effect of this inhibition has not been studied.
Inhibit P-glycoprotein in the intestine, maraviroc may affect the bioavailability of certain drugs.
Chart 3. Interaction with other drugs and their recommended dosage.
Pharmaceutical formulations (dosage maraviroc used in study) Changing the geometric mean AUC 12 (mcg x h / ml) C max (mcg / ml) relative to the initial value: - - no changes; ^ - rises; v- reduced Recommendations regarding sharing
Antivirals
NRTIs
Lamivudine, 150 mg of 2 times / day; maraviroc, 300 mg of 2 times / day AUC 12 lamivudine: - 1.13; Cmax lamivudine: - 1.16 maraviroc concentration was not determined, maraviroc effect is not expected at a dose of 300 mg of 2 times / day and related nucleoside analogs can be used without dose adjustment.
Tenofovir 300 mg one time / day maraviroc, 300 mg of 2 times / day AUC 12 maraviroc: - 1.03; The C max maraviroc: - 1.03; The concentration of tenofovir was not determined, the influence is not expected.
Zidovudine, 300 mg of 2 times / day maraviroc, 300 mg of 2 times / day AUC 12 zidovudine: - 0.98 C max zidovudine: - 0.93 maraviroc concentration was not determined, the influence is expected.
NNRTIs
Efavirenz, 600 mg 1 time / day maraviroc, 100 mg of 2 times / day AUC 12 maraviroc: v C 0.55 maxmaraviroc: v 0.49 Efavirenz concentrations not measured, the influence is not expected. Maraviroc dose should be increased to 600 mg of 2 times / day to day with concomitant use with efavirenz and absence potent inhibitors isoenzyme CYP3A4. For combination with efavirenz and IPVICH cm. Below.
Nevirapine 200 mg of 2 times / day single dose of maraviroc, 300 mg AUC 12 maraviroc: - compared with the control; The C max maraviroc: ^ in comparison with the control. The concentration of nevirapine has not been measured, the influence is not expected. Maraviroc at a dose of 300 mg of 2 times / day and nevirapine may be used together without dose adjustment.
Etravirine 200 mg of 2 times / day 300 mg maraviroc 2 times / day AUC Maraviroc 12 : v 0.47; maraviroc the C max: V 0.40; etravirine AUC 12 : - 1.06; etravirine the C max : - 1.05; etravirine C 12 - 1.08. Maraviroc dose should be increased to 600 mg of 2 times / day when used together with etravirine and absence potent inhibitors isoenzyme CYP3A4. For combination with etravirine and HIV SP
SP HIV
atazanavir 400 mg of 2 times / day 300 mg maraviroc 2 times / day AUC 12 maraviroc: ^ C 3.57 maxmaraviroc: 2.09 ^ concentration of atazanavir was not determined, the influence is not expected. When co-administered with SP HIV maraviroc dose should be reduced to 150 mg of 2 times / day; except in combination with tipranavir / ritonavir when to use a dose of 300 mg of 2 times / day. Maraviroc has no significant effect on HIV-PI concentrations.
Atazanavir / ritonavir, 300 mg / 100 mg 1 time / day maraviroc, 300 mg of 2 times / day AUC 12 maraviroc ^ C 4.88 max maraviroc: Concentration ^ 2.67 atazanavir / ritonavir was not measured, no effect is expected.
Lopinavir / ritonavir, 400 mg / 100 mg, 2 times / day maraviroc, 300 mg of 2 times / day AUC 12 maraviroc: ^ C 3.95 maxmaraviroc: ~ 1.97 Concentration of lopinavir / ritonavir has not been measured, the influence is not expected. When co-administered with SP HIV maraviroc dose should be reduced to 150 mg 2 times a day; except in combination with tipranavir / ritonavir when to use a dose of 300 mg 2 times a day. Maraviroc has no significant effect on HIV-PI concentrations.
Saquinavir / ritonavir 1000 mg / 100 mg, 2 times / day 100 mg maraviroc 2 times / day AUC 12 maraviroc ^ C 9.77 max maraviroc ^ 4.78 Concentration of saquinavir / ritonavir was not measured, no effect is expected.
Darunavir / ritonavir, 600 mg / 100 mg, 2 times / day maraviroc, 150 mg of 2 times / day AUC 12 maraviroc: ^ C 4.05 maxmaraviroc: 2.29 ^ concentrations of darunavir / ritonavir consistent with historical data.
Nelfinavir data sharing with nelfinavir limited. Nelfinavir is a potent inhibitor of isozyme CYP3A4, and it is expected that it will increase the concentration of maraviroc.
