Celzentri^® (Tablets) Instructions for Use

ATC Code

J05AX09 (Maraviroc)

Active Substance

Maraviroc (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Systemic antiviral agents; direct-acting antiviral agents; other antiviral agents

Pharmacological Action

Maraviroc is an antiviral agent, an antagonist of the CCR5 chemokine receptors. The CCR5 receptor of the target cell is necessary for HIV binding to the cell and for virus entry into the cell. Maraviroc selectively binds to CCR5 chemokine receptors, preventing the entry of CCR5-tropic HIV-1 into the cell.

The inhibitory concentration at which pathogen activity in vitro is suppressed by 90% (EC₉₀) in 43 primary clinical isolates of CCR5-tropic HIV-1 was 0.57 (0.06-10.7) ng/ml, with no significant differences between the various subtypes tested.

When used in combination with other antiretroviral drugs in cell culture, no antagonism of maraviroc with nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), HIV protease inhibitors (PIs), or the fusion inhibitor enfuvirtide was observed.

Virus resistance to maraviroc can occur in two ways: by selection of a virus capable of binding to CXCR4 chemokine receptors as a co-receptor for cell entry (CXCR4-tropic virus), or by selection of a virus that continues to use CCR5 exclusively (CCR5-tropic virus) in the presence of maraviroc.

HIV-1 variants with reduced susceptibility to maraviroc were selected in cell culture from CCR5-tropic clinical virus isolates. Maraviroc-resistant viruses remained CCR5-tropic; conversion from CCR5-tropic virus to CXCR4-tropic virus did not occur.

Phenotypic resistance: The inhibitory concentration curves for maraviroc-resistant viruses did not reach 100% inhibition in assays using maraviroc dilution series.

Genotypic resistance: An accumulation of mutations in the envelope glycoprotein gp120 (the viral protein that binds to the CCR5 co-receptor) was detected. The location of these mutations in different isolates was not constant.

Cross-resistance: All clinical isolates of HIV-1 resistant to NRTIs, NNRTIs, HIV PIs, and enfuvirtide were sensitive to maraviroc in cell culture. Maraviroc-resistant viruses in cell culture remained sensitive to the fusion inhibitor enfuvirtide and to the HIV PI saquinavir.

Both pathways of resistance development were observed in clinical studies of maraviroc in both treatment-naive patients and those with prior antiretroviral therapy.

The presence of CXCR4-tropic virus at treatment failure is due to its presence at baseline. Performing a test to rule out the presence of this HIV variant before prescribing maraviroc reduces the risk of therapy failure associated with this resistance pathway.

In patients previously treated with antiretroviral therapy, the viral tropism sometimes changed from CCR5 to CXCR4 or dual/mixed during the period between screening and initiation of treatment (4-6 weeks).

Pharmacokinetics

When taken orally in a single 300 mg dose, C_max in blood plasma is reached on average after 2 hours. When maraviroc is taken orally at doses exceeding 1200 mg, the pharmacokinetics of the drug are nonlinear. The absolute bioavailability of maraviroc at a 100 mg dose is 23% and the estimated bioavailability at a 300 mg dose is 33%. Maraviroc is a substrate for the P-glycoprotein transporter, which mediates efflux of substances from cells. Maraviroc can be taken at recommended doses regardless of food intake.

Binding to human plasma proteins is about 76%, with weak binding to albumin and α₁-acid glycoprotein. The V_d of maraviroc is approximately 194 L.

Human studies and in vitro studies using human liver microsomes and expressed enzymes have demonstrated that maraviroc is primarily metabolized by CYP450 isoenzymes to metabolites that are not active against HIV-1. In vitro studies have shown that the CYP3A4 isoenzyme is the main isoenzyme responsible for 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, which does not possess significant pharmacological activity. Other metabolites are mono-oxidation products.

Approximately 20% is excreted by the kidneys, and 76% via the intestine over 168 hours. Maraviroc is the main substance present in urine (on average, 8% of the dose) and feces (on average, 25% of the dose). The remainder is excreted as metabolites. After IV administration (30 mg), the T_1/2 of maraviroc was 13.2 hours, 22% of the dose was excreted unchanged by the kidneys, and the total clearance and renal clearance values were 44.0 L/h and 10.17 L/h, respectively.

However, it has been shown that the additional administration of saquinavir/ritonavir (1000/100 mg twice daily) to patients with moderate renal insufficiency significantly alters the pharmacokinetics of maraviroc. In this patient group, the concentration of maraviroc was below the therapeutic level. Thus, patients with renal insufficiency receiving maraviroc concomitantly with potent CYP3A4 isoenzyme inhibitors require adjustment of the maraviroc dose.

Maraviroc is metabolized and excreted primarily by the liver. A study compared the pharmacokinetics of a single 300 mg dose of maraviroc in patients with mild (Child-Pugh class A, n=8) and moderate (Child-Pugh class B, n=8) hepatic impairment, compared to healthy patients. The geometric mean C_max and AUC_last values were 11% and 25% higher, respectively, for patients with mild hepatic impairment, and 32% and 46% higher for patients with moderate hepatic impairment compared to normal liver function. The pharmacokinetics of maraviroc in patients with severe hepatic impairment has not been studied.

Indications

Treatment of HIV-infected patients, previously treated with antiretroviral therapy, infected with CCR5 co-receptor tropic HIV-1 only, in combination with other antiretroviral drugs.

ICD codes

Dosage Regimen

Administer Celzentri^® tablets orally.

The standard dose is 300 mg twice daily.

Adjust the dose based on concomitant medications due to CYP3A4 interactions.

For patients taking potent CYP3A4 inhibitors (with or without a CYP3A4 inducer), reduce the dose to 150 mg twice daily.

Potent CYP3A4 inhibitors include: protease inhibitors (e.g., atazanavir, lopinavir, darunavir, saquinavir, all boosted with ritonavir), ketoconazole, and itraconazole.

For patients taking CYP3A4 inducers without a potent CYP3A4 inhibitor, increase the dose to 600 mg twice daily.

CYP3A4 inducers include: efavirenz, etravirine, rifampin, and carbamazepine.

Use a dose of 300 mg twice daily when co-administered with tipranavir/ritonavir or other drugs that are not potent CYP3A4 inhibitors or inducers.

For patients with renal impairment (CrCl less than 50 mL/min) receiving a potent CYP3A4 inhibitor, reduce the dose to 150 mg twice daily.

Perform viral tropism testing using a validated method prior to initiation to confirm CCR5-tropic HIV-1 only.

Initiate treatment soon after a confirmed CCR5-tropic result.

Do not use in patients with severe hepatic impairment; use with caution in patients with pre-existing liver dysfunction.

Monitor for orthostatic hypotension, especially in patients with renal impairment or those on concomitant medications that may lower blood pressure.

Adverse Reactions

Infections and infestations: Common – herpes infections, folliculitis, pneumonia, anogenital warts, influenza, bacterial infections, viral infections; Uncommon – esophageal candidiasis, septic shock.

Neoplasms: Common – benign skin neoplasms; Rare – abdominal tumors, cholangiocarcinoma, bone metastases, liver metastases, peritoneal metastases, anal tumors, nasopharyngeal cancer, esophageal cancer, tongue tumors (malignancy stage not established), Hodgkin’s disease, diffuse large B-cell lymphoma, basal cell carcinoma, Bowen’s disease, lymphoma, anaplastic large cell lymphoma T- and null-cell types, squamous cell carcinoma of the skin, endocrine malignant and unspecified tumors.

Blood and lymphatic system disorders: Common – anemia; Uncommon – pancytopenia, neutropenia, lymphadenopathy; Rare – granulocytopenia, hypoplastic anemia.

Metabolism and nutrition disorders: Common – hypertriglyceridemia, lipodystrophy; Rare – appetite disorder.

Endocrine system disorders: Rare – type 2 diabetes mellitus.

Psychiatric disorders: Common – anorexia, depression, abnormal dreams; Uncommon – agitation, hallucinations; Rare – mutism.

Nervous system disorders: Common – paresthesia, dysesthesia, hyperesthesia, insomnia, taste disorders, somnolence, peripheral neuropathy, headache, sensory disturbance, memory impairment, syncope; Uncommon – convulsions; Rare – loss of consciousness, epilepsy, petit mal epilepsy, facial paralysis, areflexia, meningitis (including viral), cerebrovascular disorders, tremor.

Eye disorders: Common – conjunctivitis, other manifestations of eye infections; Uncommon – cataract, hemianopia.

Ear and labyrinth disorders: Common – otitis media; Uncommon – dizziness.

Cardiac disorders: Common – flushing; Uncommon – coronary artery disease, myocardial infarction; Rare – deep vein thrombosis, decreased blood pressure, endocarditis.

Respiratory, thoracic and mediastinal disorders: Common – cough, upper and lower respiratory tract infections, sinusitis, bronchitis, nasal congestion; Uncommon – respiratory distress syndrome, bronchospasm; Rare – apnea.

Gastrointestinal disorders: Very common – nausea; Common – abdominal pain, dyspepsia, constipation, flatulence, abdominal distension, vomiting, diarrhea, intestinal atony and hypotension, gastroesophageal reflux; Uncommon – pancreatitis, rectal hemorrhage, pseudomembranous colitis.

Hepatobiliary disorders: Uncommon – liver cirrhosis; Rare – hepatic failure, toxic hepatitis, jaundice (including cholestatic), portal vein thrombosis; Very rare – hepatotoxicity and hepatic failure with allergic reactions have been reported in clinical and post-marketing studies.

Skin and subcutaneous tissue disorders: Common – rash, pruritus, dysfunction of apocrine and eccrine glands, erythema, acne, alopecia; Rare – Stevens-Johnson syndrome.

Musculoskeletal and connective tissue disorders: Common – muscle spasms, back pain, pain in extremity, neck pain, arthralgia; Uncommon – myositis; Rare – muscular atrophy, osteonecrosis, rhabdomyolysis.

Renal and urinary disorders: Common – ejaculation and erection disorders, nocturia; Uncommon – renal failure, proteinuria, polyuria.

Investigations: Common – increased ALT, increased AST.

General disorders and administration site conditions: Common – asthenia, fatigue, weight decreased, pyrexia, pain of undefined localization.

Contraindications

Children and adolescents under 18 years of age; concomitant use with preparations containing St. John’s wort (Hypericum perforatum); hypersensitivity to maraviroc.

Use in Pregnancy and Lactation

There are no clinical data on the use of maraviroc during pregnancy. Animal studies have not revealed direct or indirect adverse effects on pregnancy, embryonic/fetal development, childbirth or postnatal development. Maraviroc should be used during pregnancy only if the expected therapeutic benefit for the mother outweighs the potential risk to the fetus.

It is not known whether maraviroc is excreted in breast milk. HIV-infected women are recommended not to breast-feed due to the risk of HIV transmission to the breast-fed infant. Women taking maraviroc are advised to refrain from breast-feeding due to the risk of adverse events in children.

Special Precautions

Maraviroc should be used with caution in elderly patients; in patients with an increased risk of cardiovascular diseases, as well as in patients with cardiovascular diseases; in patients with a history of orthostatic hypotension or when taking drugs that can have a hypotensive effect; in such patients with impaired liver function; with particular caution – in patients with concomitant hepatitis B or C.

There are limited data on the safety and efficacy of maraviroc in patients with renal impairment, obtained from a comparative pharmacokinetic study. The study was conducted in patients with renal insufficiency and healthy volunteers taking maraviroc in combination with saquinavir/ritonavir. Overall, maraviroc was well tolerated, but patients with renal insufficiency had a higher frequency of adverse reactions (mostly mild).

The risk of orthostatic hypotension is increased in patients with severe renal insufficiency receiving boosted HIV protease inhibitors and maraviroc. The greatest risk can be expected with the concomitant use of maraviroc and HIV protease inhibitors such as saquinavir, darunavir, lopinavir – all in combination with ritonavir. Patients with renal impairment have a high risk of cardiovascular disease, which may be exacerbated by orthostatic hypotension. No studies have been conducted with maraviroc in patients with severe renal insufficiency receiving potent CYP3A4 isoenzyme inhibitors. Dose adjustment and dosing intervals are based on pharmacokinetic modeling and simulation programs.

Maraviroc should be used exclusively in cases where only CCR5-tropic HIV-1 is determined using an adequately validated and sensitive method (i.e., virus with CXCR4 tropism or dual/mixed tropism is not detected). Viral tropism cannot be determined based on treatment history or evaluation of stored patient blood samples.

In HIV-1-infected patients, viral tropism changes over time. Therefore, it is necessary to initiate treatment soon after tropism determination.

Antiretroviral therapy, including the use of maraviroc, does not prevent the risk of transmitting HIV to others through sexual contact or blood contact. Maraviroc does not lead to eradication of HIV-1.

It should be ensured that the maraviroc dose is correctly adjusted when used concomitantly with CYP3A4 isoenzyme inhibitors and/or inducers, as they can affect the concentration and therapeutic efficacy of maraviroc.

In HIV-infected patients with severe immunodeficiency, inflammatory reaction symptoms may appear during the first few weeks or months after initiation of highly active antiretroviral therapy (HAART) as a result of exacerbation of previously asymptomatic secondary infections. Such reactions can lead to deterioration of the patient’s condition. Examples are cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any symptoms of inflammation should be identified and appropriate treatment initiated if necessary.

CCR5 chemokine receptor antagonists may adversely affect the immune response to certain infections. This should be taken into account when treating infections such as active tuberculosis and invasive fungal infections.

Although the etiology of osteonecrosis is considered multifactorial (corticosteroid use, alcohol abuse, severe immunosuppression, high body mass index), cases of osteonecrosis are reported more frequently in HIV patients and/or with long-term use of HAART. Patients should be advised to consult a physician if they experience joint pain or stiffness or limited range of motion.

The safety and efficacy of maraviroc in patients with severe liver disease has not been studied.

In patients with liver disease, including chronic active hepatitis, during combination antiretroviral therapy, the frequency of liver function impairment may increase, so such patients should be monitored in accordance with standard practice for managing patients with liver disease. In all patients with signs or symptoms of acute hepatitis, especially if hypersensitivity to maraviroc is suspected or if liver transaminase elevations occur in combination with rash or other symptoms of possible hypersensitivity (pruritic rash, eosinophilia, or elevated plasma IgE levels), maraviroc should be discontinued.

In the absence of inhibitors of maraviroc metabolism, renal clearance accounts for approximately 23% of the total clearance of maraviroc and, therefore, renal impairment is not expected to significantly increase maraviroc serum concentrations. In patients with severe renal insufficiency receiving therapy with HIV protease inhibitors and maraviroc, there may be an increased risk of orthostatic hypotension. This risk is associated with an increase in the C_max of maraviroc. The maximum risk of orthostatic hypotension is observed with the concomitant use of maraviroc with HIV protease inhibitors that have the most potent inhibitory effect on the CYP3A4 isoenzyme (saquinavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir). Patients with renal impairment more often have concomitant cardiovascular diseases and are also at increased risk of cardiovascular adverse events, which may be exacerbated by orthostatic hypotension.

Effect on ability to drive and operate machinery

Maraviroc may cause dizziness. If patients experience dizziness, they should avoid potentially hazardous activities such as driving or operating machinery.

Drug Interactions

Concomitant use of maraviroc and St. John’s wort (Hypericum perforatum) preparations is expected to partially reduce the concentration of maraviroc to suboptimal levels, which may lead to loss of virological control and possible resistance to maraviroc.

Maraviroc is a substrate of the CYP3A4 isoenzyme. Concomitant use of maraviroc with medicinal products that are inducers of the CYP3A4 isoenzyme may reduce the plasma concentration of maraviroc and weaken its therapeutic effect. Concomitant use of maraviroc with medicinal products that inhibit the CYP3A4 isoenzyme may increase the plasma concentration of maraviroc. Dose adjustment is required when maraviroc is used concomitantly with CYP3A4 isoenzyme inhibitors and/or inducers.

When used concomitantly with efavirenz, a decrease in C_max and AUC₁₂ of maraviroc was observed. The concentration of efavirenz was not measured; no effect is expected. With this combination, the dose of maraviroc should be increased to 600 mg twice daily when used concomitantly with efavirenz and in the absence of potent CYP3A4 isoenzyme inhibitors.

When used concomitantly with etravirine, a decrease in C_max and AUC₁₂ of maraviroc was observed. The dose of maraviroc should be increased to 600 mg twice daily when used concomitantly with etravirine and in the absence of potent CYP3A4 isoenzyme inhibitors.

When used concomitantly with atazanavir or with the combinations atazanavir/ritonavir, lopinavir/ritonavir, darunavir/ritonavir, saquinavir/ritonavir, a significant increase in the C_max and AUC₁₂ of maraviroc was observed. When co-administered with HIV protease inhibitors, the dose of maraviroc should be reduced to 150 mg twice daily; with the exception of the combination with tipranavir/ritonavir, where a dose of 300 mg twice daily should be used. Maraviroc does not have a significant effect on the concentrations of HIV protease inhibitors.

Data on concomitant use with nelfinavir are limited. Nelfinavir is a potent inhibitor of the CYP3A4 isoenzyme, and it is expected to increase the concentration of maraviroc.

Data on concomitant use with indinavir are limited. Indinavir is a potent inhibitor of the CYP3A4 isoenzyme. Data from population pharmacokinetic analysis during phase 3 studies indicate that a dose reduction of maraviroc is required when co-administered with indinavir.

Fosamprenavir is a moderate inhibitor of the CYP3A4 isoenzyme. No adjustment of the maraviroc dose is anticipated to be required.

When used concomitantly with ketoconazole, an increase in the C_max and AUC₁₂ of maraviroc was observed. With this combination, the dose of maraviroc should be reduced to 150 mg twice daily.

Fluconazole is a moderate inhibitor of the CYP3A4 isoenzyme. No adjustment of the maraviroc dose is anticipated to be required. Caution should be exercised when co-administering maraviroc at a dose of 300 mg twice daily and fluconazole.

With higher maraviroc exposure, possible inhibition of the CYP2D6 isoenzyme cannot be ruled out.

When maraviroc is used without CYP3A4 isoenzyme inhibitors, its renal clearance is approximately 23%. Since both passive and active mechanisms are involved, there is a possibility of competition for renal excretion with other active substances eliminated by the kidneys.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.