Chemical formula: C₂₉H₄₁F₂N₅O Molecular mass: 513.666 g/mol PubChem compound: 3002977
Maraviroc interacts in the following cases:
Concomitant use of maraviroc and St. John’s Wort or products containing St. John’s Wort is not recommended.
Co-administration of maraviroc with St. John’s Wort is expected to substantially decrease maraviroc concentrations and may result in suboptimal levels and lead to loss of virologic response and possible resistance to maraviroc.
Maraviroc is metabolised by cytochrome P450 CYP3A4 and CYP3A5. Co-administration of maraviroc with medicinal products that induce CYP3A4 may decrease maraviroc concentrations and reduce its therapeutic effects. Dose adjustment of maraviroc is recommended when maraviroc is co-administered with potent CYP3A4 inducers.
Maraviroc is metabolised by cytochrome P450 CYP3A4 and CYP3A5. Co-administration of maraviroc with medicinal products that inhibit CYP3A4 may increase maraviroc plasma concentrations. Dose adjustment of maraviroc is recommended when maraviroc is co-administered with potent CYP3A4 inhibitors.
Limited data are available in adult patients with hepatic impairment and no data are available to recommend a specific dose for paediatric patients. Therefore, maraviroc should be used with caution in patients with hepatic impairment.
The safety and efficacy of maraviroc have not been specifically studied in patients with significant underlying liver disorders.
Cases of hepatotoxicity and hepatic failure with allergic features have been reported in association with maraviroc. In addition, an increase in hepatic adverse reactions with maraviroc was observed during studies of treatment-experienced subjects with HIV infection, although there was no overall increase in ACTG Grade ¾ liver function test abnormalities. Hepatobiliary disorders reported in treatment-naïve patients were uncommon and balanced between treatment groups. Patients with pre-existing liver dysfunction, including chronic active hepatitis, can have an increased frequency of liver function abnormalities during combination antiretroviral therapy and should be monitored according to standard practice.
Discontinuation of maraviroc should be strongly considered in any patient with signs or symptoms of acute hepatitis, in particular if drug-related hypersensitivity is suspected or with increased liver transaminases combined with rash or other systemic symptoms of potential hypersensitivity (e.g. pruritic rash, eosinophilia or elevated IgE).
There are limited data in patients with hepatitis B and/or C virus co-infection. Caution should be exercised when treating these patients. In case of concomitant antiviral therapy for hepatitis B and/or C, please refer to the relevant product information for these medicinal products.
There is limited experience in patients with reduced hepatic function, therefore maraviroc should be used with caution in this population.
In adult patients with a creatinine clearance of <80 mL/min, who are also receiving potent CYP3A4 inhibitors, the dose interval of maraviroc should be adjusted to 150 mg once daily.
Examples of agents/regimens with such potent CYP3A4-inhibiting activity are:
Maraviroc should be used with caution in adult patients with severe renal impairment (CLcr <30 mL/min) who are receiving potent CYP3A4 inhibitors.
There are no data available to recommend a specific dose in paediatric patients with renal impairment. Therefore, maraviroc should be used with caution in this population.
Effects on active substance levels – Geometric mean change if not stated otherwise:
Atazanavir 400 mg QD (maraviroc 300 mg BID):
Atazanavir concentrations not measured, no effect is expected.
Atazanavir/ritonavir 300 mg/100 mg QD (maraviroc 300 mg BID):
Atazanavir/ritonavir concentrations not measured, no effect is expected.
Lopinavir/ritonavir 400 mg/100 mg BID (maraviroc 300 mg BID):
Lopinavir/ritonavir concentrations not measured, no effect is expected.
Saquinavir/ritonavir 1000 mg/100 mg BID (maraviroc 100 mg BID):
Saquinavir/ritonavir concentrations not measured, no effect is expected.
Darunavir/ritonavir 600 mg/100 mg BID (maraviroc 150 mg BID):
Darunavir/ritonavir concentrations were consistent with historical data.
Tipranavir/ritonavir 500 mg/200 mg BID (maraviroc 150 mg BID):
Tipranavir/ritonavir concentrations were consistent with historical data.
Recommendations concerning co-administration in adults: Maraviroc dose should be decreased to 150 mg twice daily when co-administered with a Protease Inhibitors (PIs); except in combination with tipranavir/ritonavir where the maraviroc dose should be 300 mg BID.
Maraviroc dose should be increased to 600 mg twice daily when coadministered with carbamazepine, phenobarbital or phenytoin in the absence of a potent CYP3A4 inhibitor.
Not studied, but these are potent CYP3A4 inducers and would be expected to decrease maraviroc concentrations.
Maraviroc dose should be decreased to 150 mg twice daily when co-administered with clarithromycin and telithromycin.
Not studied, but both are potent CYP3A4 inhibitors and would be expected to increase maraviroc concentrations.
Effects on active substance levels – Geometric mean change if not stated otherwise: Interaction not studied. Cobicistat is a potent CYP3A inhibitor.
Recommendations concerning co-administration in adults: Maraviroc dose should be decreased to 150 mg twice daily when coadministered with cobicistat containing regimen.
Effects on active substance levels – Geometric mean change if not stated otherwise:
Efavirenz 600 mg QD + lopinavir/ritonavir 400mg/100 mg BID (maraviroc 300 mg BID):
Efavirenz, lopinavir/ritonavir concentrations not measured, no effect expected.
Efavirenz 600 mg QD + saquinavir/ritonavir 1000 mg/100 mg BID (maraviroc 100 mg BID):
Efavirenz, saquinavir/ritonavir concentrations not measured, no effect expected.
Efavirenz and atazanavir/ritonavir or darunavir/ritonavir:
Not studied. Based on the extent of inhibition by atazanavir/ritonavir or darunavir/ritonavir in the absence of efavirenz, an increased exposure is expected.
Recommendations concerning co-administration in adults: Maraviroc dose should be decreased to 150 mg twice daily when co-administered with efavirenz and a PI (except tipranavir/ritonavir where the dose should be 600 mg twice daily). Concomitant use of Maraviroc and fosamprenavir/ritonavir is not recommended.
Effects on active substance levels – Geometric mean change if not stated otherwise:
Etravirine and darunavir/ritonavir (maraviroc 150 mg BID):
| AUC12 | Cmax | C12 | |
| Maraviroc | ↑3.10 | ↑1.77 | - |
| Etravirine | ↔1.00 | ↔1.08 | ↓0.81 |
| Darunavir | ↓0.86 | ↔0.96 | ↓0.77 |
| Ritonavir | ↔0.93 | ↔1.02 | ↔0.74 |
Etravirine and lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir:
Not studied. Based on the extent of inhibition by lopinavir/ritonavir, saquinavir/ritonavir or atazanavir/ritonavir in the absence of etravirine, an increased exposure is expected.
Recommendations concerning co-administration in adults: Maraviroc dose should be decreased to 150 mg twice daily when co-administered with etravirine and a PI. Concomitant use of maraviroc and fosamprenavir/ritonavir is not recommended.
Maraviroc 300 mg twice daily should be administered with caution when co-administered with fluconazole.
Fluconazole is considered to be a moderate CYP3A4 inhibitor. Population PK studies suggest that a dose adjustment of maraviroc is not required.
Effects on active substance levels – Geometric mean change if not stated otherwise:
Fosamprenavir/ritonavir 700 mg/100 mg BID (maraviroc 300 mg BID):
| AUC12 | Cmax | C12 | |
| Maraviroc | ↑2.49 | ↑1.52 | ↑4.74 |
| Amprenavir | 0.65 | ↓0.66 | ↓0.64 |
| Ritonavir | ↓0.66 | ↓0.61 | ↔0.86 |
Recommendations concerning co-administration in adults: Concomitant use is not recommended. Significant reductions in amprenavir Cmin observed may result in virological failure in patients.
Limited data are available for coadministration with indinavir. Indinavir is a potent CYP3A4 inhibitor. Population PK analysis in phase 3 studies suggests dose reduction of maraviroc when co-administered with indinavir gives appropriate maraviroc exposure.
Maraviroc dose should be decreased to 150 mg twice daily when co-administered with itraconazole.
Not studied. Itraconazole, is a potent CYP3A4 inhibitor and would be expected to increase the exposure of maraviroc.
Effects on active substance levels – Geometric mean change if not stated otherwise:
Ketoconazole concentrations not measured, no effect is expected.
Recommendations concerning co-administration in adults: Maraviroc dose should be decreased to 150 mg twice daily when co-administered with ketoconazole.
Limited data are available for coadministration with nelfinavir. Nelfinavir is a potent CYP3A4 inhibitor and would be expected to increase maraviroc concentrations.
Maraviroc dose should be decreased to 150 mg twice daily when co-administered with rifabutin and a PI (except tipranavir/ritonavir where the dose should be 300 mg twice daily).
Not studied. Rifabutin is considered to be a weaker inducer than rifampicin. When combining rifabutin with protease inhibitors that are potent inhibitors of CYP3A4 a net inhibitory effect on maraviroc is expected.
Effects on active substance levels – Geometric mean change if not stated otherwise:
Rifampicin 600 mg QD (maraviroc 100 mg BID):
Rifampicin concentrations not measured, no effect expected.
Recommendations concerning co-administration in adults: Maraviroc dose should be increased to 600 mg twice daily when co-administered with rifampicin in the absence of a potent CYP3A4 inhibitor. This dose adjustment has not been studied in HIV patients.
Concomitant use of maraviroc and rifampicin + efavirenz is not recommended.
Combination with two inducers has not been studied. There may be a risk of suboptimal levels with risk of loss of virologic response and resistance development.
Although the aetiology is considered to be multifactorial (including corticosteroid use, alcohol consumption, severe immunosuppression, higher body mass index), cases of osteonecrosis have been reported particularly in patients with advanced HIV-disease and/or long-term exposure to combination antiretroviral therapy (CART). Patients should be advised to seek medical advice if they experience joint aches and pain, joint stiffness or difficulty in movement.
When maraviroc was administered in studies with healthy volunteers at doses higher than the recommended dose, cases of symptomatic postural hypotension were seen at a greater frequency than with placebo. Caution should be used when administering maraviroc in patients on concomitant medicinal products known to lower blood pressure. Maraviroc should also be used with caution in patients with severe renal insufficiency and in patients who have risk factors for, or have a history of postural hypotension. Patients with cardiovascular co-morbidities could be at increased risk of cardiovascular adverse reactions triggered by postural hypotension.
In HIV infected patients with severe immune deficiency at the time of institution of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic pathogens may arise and cause serious clinical conditions, or aggravation of symptoms. Typically, such reactions have been observed within the first few weeks or months of initiation of CART. Relevant examples are cytomegalovirus retinitis, generalised and/or focal mycobacterial infections, and pneumonia caused by Pneumocystis jiroveci (formerly known as Pneumocystis carinii). Any inflammatory symptoms should be evaluated and treatment initiated when necessary. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported to occur in the setting of immune reactivation; however, the reported time to onset is more variable and these events can occurmany months after initiation of treatment.
Limited data exist with the use of maraviroc in patients with severe cardiovascular disease, therefore special caution should be exercised when treating these patients with maraviroc. In the pivotal studies of treatment-experienced patients coronary heart disease events were more common in patients treated with maraviroc than with placebo (11 during 609 PY vs 0 during 111 PY of follow-up). In treatment-naïve patients such events occurred at a similarly low rate with maraviroc and control (efavirenz).
There are limited data from the use of maraviroc in pregnant women. The effect of maraviroc on human pregnancy is unknown. Studies in animals showed reproductive toxicity at high exposures. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied. Maraviroc should be used during pregnancy only if the expected benefit justifies the potential risk to the foetus.
It is unknown whether maraviroc is excreted in human milk. Available toxicological data in animals has shown extensive excretion of maraviroc in milk. Primary pharmacological activity (CCR5 receptor affinity) was limited in the species studied. A risk to the newborn/infants cannot be excluded.
It is recommended that mothers infected by HIV do not breast-feed their infants under any circumstances in order to avoid transmission of HIV.
There is no data on the effects of maraviroc on human fertility. In rats, there were no adverse effects on male or female fertility.
Maraviroc may have a minor influence on the ability to drive and use machines. Patients should be informed that dizziness has been reported during treatment with maraviroc. The clinical status of the patient and the adverse reaction profile of maraviroc should be borne in mind when considering the patient’s ability to drive, cycle or operate machinery.
Assessment of treatment related adverse reactions is based on pooled data from two Phase 2b/3 studies in treatment-experienced adult patients (MOTIVATE 1 and MOTIVATE 2) and one study in treatment-naïve adult patients (MERIT) infected with CCR5-tropic HIV-1.
The most frequently reported adverse reactions occurring in the Phase 2b/3 studies were nausea, diarrhoea, fatigue and headache. These adverse reactions were common (≥1/100 to <1/10).
The adverse reactions are listed by system organ class (SOC) and frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1,000), not known (cannot be estimated from the available data). The adverse reactions and laboratory abnormalities presented below are not exposure adjusted.
Adverse reactions observed in clinical trials or post-marketing:
Uncommon: Pneumonia, oesophageal candidiasis
Rare: Bile duct cancer, diffuse large B-cell lymphoma, Hodgkin’s disease, metastases to bone, metastases to liver, metastases to peritoneum, nasopharyngeal cancer, oesophageal carcinoma
Common: Anaemia
Rare: Pancytopenia, granulocytopenia
Common: Anorexia
Common: Depression, insomnia
Uncommon: Seizures and seizure disorders
Rare: Angina pectoris
Uncommon: Postural hypotension
Common: Abdominal pain, flatulence, nausea
Common: Alanine aminotransferase increased, aspartate aminotransferase increased
Uncommon: Hyperbilirubinaemia, gammaglutamyltransferase increased
Rare: Hepatitis toxic, hepatic failure, hepatic cirrhosis, blood alkaline phosphatase increased
Very rare: Hepatic failure with allergic features
Common: Rash
Rare/not known: Stevens-Johnson syndrome/Toxic epidermal necrolysis
Uncommon: Myositis, blood creatine phosphokinase increased
Rare: Muscle atrophy
Uncommon: Renal failure, proteinuria
Common: Asthenia
Common: Asthenia
Delayed type hypersensitivity reactions, typically occurring within 2-6 weeks after start of therapy and including rash, fever, eosinophilia and liver reactions have been reported. Skin and liver reactions can occur as single events, or in combination.
In HIV infected patients with severe immune deficiency at the time of initiation of combination antiretroviral therapy (CART), an inflammatory reaction to asymptomatic or residual opportunistic infections may arise. Autoimmune disorders (such as Graves' disease and autoimmune hepatitis) have also been reported; however, the reported time to onset is more variable and these events can occur many months after initiation of treatment.
Cases of osteonecrosis have been reported, particularly in patients with generally acknowledged risk factors, advanced HIV disease or long-term exposure to combination antiretroviral therapy (CART). The frequency of this is unknown.
Cases of syncope caused by postural hypotension have been reported.
Table 1 shows the incidence ≥1% of Grade 3-4 Abnormalities (ACTG Criteria) based on the maximum shift in laboratory test values without regard to baseline values.
Table 1. Incidence ≥1% of grade 3-4 abnormalities (ACTG criteria) based on maximum shift in laboratory test values without regard to baseline studies MOTIVATE 1 and MOTIVATE 2 (pooled analysis, up to 48 weeks):
| Laboratory parameter | Limit | Maraviroc 300 mg twice daily + OBT N=421* (%) | Placebo + OBT N=207* (%) |
|---|---|---|---|
| Hepatobiliary disorders | |||
| Aspartate aminotransferase | >5.0x ULN | 4.8 | 2.9 |
| Alanine aminotransferase | >5.0x ULN | 2.6 | 3.4 |
| Total bilirubin | >5.0x ULN | 5.5 | 5.3 |
| Gastrointestinal disorders | |||
| Amylase | >2.0x ULN | 5.7 | 5.8 |
| Lipase | >2.0x ULN | 4.9 | 6.3 |
| Blood and lymphatic system disorders | |||
| Absolute neutrophil count | <750/mm3 | 4.3 | 1.9 |
ULN: Upper Limit of Normal
OBT: Optimised Background Therapy
* Percentages based on total patients evaluated for each laboratory parameter
The MOTIVATE studies were extended beyond 96 weeks, with an observational phase extended to 5 years in order to assess the long term safety of maraviroc. The Long Term Safety/Selected Endpoints (LTS/SE) included death, AIDS-defining events, hepatic failure, Myocardial infarction/cardiac ischaemia, malignancies, rhabdomyolysis and other serious infectious events with maraviroc treatment. The incidence of these selected endpoints for subjects on maraviroc in this observational phase was consistent with the incidence seen at earlier timepoints in the studies.
In treatment-naïve patients, the incidence of grade 3 and 4 laboratory abnormalities using ACTG criteria was similar among the maraviroc and efavirenz treatment groups.
The adverse reaction profile in paediatric patients is based on 48 Week safety data from study A4001031 in which 103 HIV-1 infected, treatment-experienced patients aged 2 to <18 years received maraviroc twice-daily with optimised background therapy (OBT). Overall, the safety profile in paediatric patients was similar to that observed in adult clinical studies.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
