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Maraviroc

Pronunciation

(mah RAV er rock)

Index Terms

  • UK-427,857

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Selzentry: 150 mg, 300 mg [contains fd&c blue #2 aluminum lake, soybean lecithin]

Brand Names: U.S.

  • Selzentry

Pharmacologic Category

  • Antiretroviral, CCR5 Antagonist (Anti-HIV)

Pharmacology

Maraviroc, a CCR5 antagonist, selectively and reversibly binds to the chemokine (C-C motif receptor 5 [CCR5]) coreceptors located on human CD4 cells. CCR5 antagonism prevents interaction between the human CCR5 coreceptor and the gp120 subunit of the viral envelope glycoprotein, thereby inhibiting gp120 conformational change required for CCR5-tropic HIV-1 fusion with the CD4 cell and subsequent cell entry.

Distribution

Vd: ~194 L

Metabolism

Hepatic, via CYP3A to inactive metabolites

Excretion

Urine (~20%, 8% as unchanged drug); feces (76%, 25% as unchanged drug)

Time to Peak

Plasma: 0.5 to 4 hours

Half-Life Elimination

14 to 18 hours

Protein Binding

~76%

Special Populations: Renal Function Impairment

In a single 300 mg dose study in patients with severe renal impairment (CrCl <30 mL/minute) and ESRD, Cmax and AUC were 2.4- and 3.2-fold higher, respectively, for patients with severe renal impairment, and 1.7- and 2-fold higher, respectively, for ESRD patients.

Use: Labeled Indications

HIV infection: Treatment of only CCR5-tropic HIV-1 infection, in combination with other antiretroviral agents

Contraindications

Patients with severe renal impairment (CrCl <30 mL/minute) or end-stage renal disease (ESRD) who are taking potent CYP3A inhibitors or inducers

Canadian labeling: Additional contraindications (not in U.S. labeling): Hypersensitivity to maraviroc or any component of the formulation

Dosage

Oral:

Manufacturer labeling: Adults: 300 mg twice daily (when administered concomitantly with tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs and enfuvirtide)

Alternate dosing: Adolescents ≥16 years (HHS [pediatric], 2014): 300 mg twice daily (when administered concomitantly with tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs and enfuvirtide)

Dosage adjustment for concomitant CYP3A inhibitors/inducers:

CYP3A inhibitors (with or without a potent CYP3A inducer): 150 mg twice daily; dose recommended when maraviroc administered concomitantly with potent CYP3A inhibitors including (but not limited to) protease inhibitors (excluding tipranavir/ritonavir), delavirdine, elvitegravir/ritonavir, ketoconazole, itraconazole, clarithromycin, nefazodone, telithromycin, or boceprevir.

CYP3A inducers (without a potent CYP3A inhibitor): 600 mg twice daily; dose recommended when maraviroc administered concomitantly with potent CYP3A inducers including (but not limited to) efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, and phenytoin

Dosage adjustment in renal impairment:

CrCl ≥30 mL/minute:

CrCl ≥30 mL/minute and concomitant potent CYP3A inhibitors (with or without a potent CYP3A inducer): 150 mg twice daily

CrCl ≥30 mL/minute and concomitant potent CYP3A inducer (without a potent CYP3A inhibitor): 600 mg twice daily

CrCl ≥30 mL/minute and other concomitant medications (eg, tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide): 300 mg twice daily

CrCl <30 mL/minute:

CrCl <30 mL/minute and concomitant potent CYP3A inhibitors (with or without a potent CYP3A inducer) or concomitant potent CYP3A inducer (without a potent CYP3A inhibitor): Use is contraindicated

CrCl <30 mL/minute and other concomitant medications (eg, tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide): 300 mg twice daily. If postural hypotension occurs, reduce dose to 150 mg twice daily

CrCl <30 mL/minute and experiencing postural hypotension: Reduce dose to 150 mg twice daily

ESRD requiring intermittent hemodialysis (IHD): Note: Hemodialysis has minimal effect on clearance

With concomitant potent CYP3A inhibitors (with or without a potent CYP3A inducer) or concomitant potent CYP3A inducer (without a potent CYP3A inhibitor): Use is contraindicated.

With other concomitant medications (eg, tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, and enfuvirtide): 300 mg twice daily. If postural hypotension occurs, reduce dose to 150 mg twice daily.

Dosage adjustment in hepatic impairment:

Mild to moderate impairment: There are no dosage adjustments provided in the manufacturer's labeling; however, maraviroc concentrations are increased in mild to moderate impairment; use caution.

Moderate impairment (with concomitant potent CYP3A inhibitor): There are no dosage adjustments provided in the manufacturer's labeling; however, maraviroc concentrations are increased in moderate impairment; use caution and monitor closely for adverse events.

Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Administration

Administer without regards to meals.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Maraviroc. Management: Increase maraviroc adult dose to 600 mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Do not use maraviroc with strong CYP3A4 inducers in patients with CrCl less than 30 mL/min. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Efavirenz: May decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with efavirenz. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Etravirine: May decrease the serum concentration of Maraviroc. Of note, this effect only applies in the absence of a strong CYP3A4 inhibitor Management: Increase maraviroc adult dose to 600 mg twice daily if used with etravirine. This does not apply to patients also receiving strong CYP3A4 inhibitors. This combination is contraindicated in patients with CrCl less than 30 mL/min. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Mifepristone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Osimertinib: May increase the serum concentration of CYP3A4 Substrates. Osimertinib may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St Johns Wort: May decrease the serum concentration of Maraviroc. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Fever (13%)

Dermatologic: Skin rash (11%)

Respiratory: Upper respiratory tract infection (23%), cough (14%)

2% to 10%:

Cardiovascular: Vascular hypertensive disorder (3%)

Central nervous system: Dizziness (9%; including postural dizziness), insomnia (8%), paresthesia (5%), anxiety (4%), impaired consciousness (4%), depression (4%), pain (4%), peripheral neuropathy (4%), sensory disturbance (4%), amnesia (3%)

Dermatologic: Folliculitis (4%), pruritus (4%), acne vulgaris (3%), skin neoplasm (benign; 3%), alopecia (2%), erythema (2%), tinea (4%)

Endocrine & metabolic: Lipodystrophy (4%)

Gastrointestinal: Decreased gastrointestinal motility (9%), change in appetite (8%), constipation (6%)

Genitourinary: Genitourinary complaint (urinary tract/bladder symptoms, 3% to 5%), warts (genital, 2%)

Hematologic & oncologic: Neutropenia (grades 3/4: 4%)

Hepatic: Increased serum AST (grades 3/4: 5%), increased serum ALT (grades 3/4: 3%), increased serum bilirubin (grades 3/4: 6%)

Infection: Herpes infection (8%), bacterial infection (3%), Neisseria, (3%),

Neuromuscular & skeletal: Arthralgia (7%), myalgia (3%)

Ophthalmic: Conjunctivitis (2%), eye infection (2%)

Otic: Otitis media (2%)

Respiratory: Bronchitis (7%), sinusitis (7%), paranasal sinus disease (3% to 6%), irregular breathing (4%), nasal congestion (4%), lower respiratory tract infection (3%)

Miscellaneous: Sweat gland disturbances (5%), flu-like symptoms (2%)

<2% (Limited to important or life-threatening): Anal cancer, angina pectoris, basal cell carcinoma, bile duct neoplasm, bone marrow depression, carcinoma in situ of esophagus, cardiac failure, cerebrovascular accident, cholestatic jaundice, coronary artery disease, coronary artery occlusion, endocarditis, endocrine neoplasm, hepatic cirrhosis, hepatic failure, hepatotoxicity, hypoplastic anemia, immune reconstitution syndrome, increased creatine kinase, ischemic heart disease, liver metastases, lymphoma, meningitis (viral), multiorgan hypersensitivity, myocardial infarction, myositis, osteonecrosis, pneumonia, portal vein thrombosis, rhabdomyolysis, seizure, septic shock, squamous cell carcinoma, Stevens-Johnson syndrome, syncope, T-cell lymphoma, tongue neoplasm, toxic epidermal necrolysis, tremor

ALERT: U.S. Boxed Warning

Hepatotoxicity:

Hepatotoxicity has been reported with maraviroc use. Severe rash or evidence of a systemic allergic reaction (eg, eosinophilia, elevated immunoglobulin E [Ige], fever) prior to the development of hepatotoxicity may occur. Immediately evaluate patients with signs or symptoms of hepatitis or allergic reactions following use of maraviroc.

Warnings/Precautions

Concerns related to adverse effects:

• CNS effects: May cause dizziness. If this occurs, patients should avoid driving or operating machinery.

• Hepatotoxicity: [US Boxed Warning]: Possible drug-induced hepatotoxicity with allergic type features has been reported; hepatotoxicity may be preceded by severe rash or other signs of systemic allergic reactions (eg, pruritic rash, eosinophilia, fever, and/or increased IgE, excluding rash alone or Stevens-Johnson syndrome (HHS [adult], 2015) and/or hepatic adverse events (transaminase increases or signs/symptoms of hepatitis); some cases have been life-threatening; immediately evaluate patients with signs and symptoms of allergic reaction or hepatitis (with or without allergy symptoms). Use with caution in patients with pre-existing hepatic dysfunction or coinfection with HBV and/or HCV, however symptoms have occurred in the absence of pre-existing hepatic conditions. Monitor hepatic function at baseline and as clinically indicated during treatment. Consider discontinuation in any patient with possible hepatitis or with elevated transaminases combined with systemic allergic events. Rechallenge with maraviroc is not recommended (HHS [pediatric], 2014).

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Infections: Monitor closely for signs/symptoms of developing infections; use associated with a small increase of certain upper respiratory tract infections and herpes virus infections during clinical trials.

• Malignancy: May affect immune surveillance and lead to an increased risk of malignancy due to pharmacologic mechanism of action. No increase in malignancy has been observed. Long term follow up needed to assess this risk.

• Postural hypotension: Symptomatic postural hypotension has occurred; use caution in patients at risk due to concomitant medication or history of condition. An increased risk of postural hypotension may occur in patients with severe renal insufficiency or in those with ESRD. Patients with severe renal dysfunction or ESRD who experience postural hypotension should have dose reduced.

• Skin and hypersensitivity reactions: Severe and life-threatening skin and hypersensitivity reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and drug rash with eosinophilia with systemic symptoms (DRESS), have been reported with use, predominately in patients also receiving concomitant agents associated with these reactions. Rash and constitutional findings (eg, fever, muscle aches, conjunctivitis, oral lesions), with or without organ dysfunction (including hepatic failure), have also accompanied these reports. Discontinue maraviroc and any other suspected agent immediately if symptoms or signs of hypersensitivity occur. Monitor liver function tests and clinical status as appropriate.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with cardiovascular disease, or in patients with a history of or current cardiac risk factors for postural hypotension, or receiving concomitant medication known to lower blood pressure. Patients who have cardiovascular comorbidities could be at risk for cardiac adverse events prompted by postural hypotension. During trials, a small increase in cardiovascular events (myocardial ischemia and/or infarction) occurred in treated patients compared to placebo, although a contributory relationship relative to therapy is unknown. Of note, patients experiencing events generally had cardiac disease/risk factors prior to therapy.

• Hepatic impairment: Use caution in patients with HBV and/or HCV coinfection or with mild-to-moderate hepatic impairment; maraviroc concentrations are increased. Maraviroc concentrations are further increased in patients with moderate hepatic impairment receiving concomitant potent CYP3A inhibitors; monitor closely for adverse events. Use in patients with severe hepatic impairment has not been studied.

• Renal impairment: Renal impairment may increase maraviroc concentrations. Use with caution in patients with mild-to-moderate renal impairment. An increased risk of postural hypotension may occur in patients with severe renal impairment or in those with ESRD. Patients with severe renal dysfunction or ESRD who experience postural hypotension should have dose reduced. Do not use maraviroc in patients with severe renal impairment or ESRD who are receiving CYP3A inhibitors or inducers unless no alternative treatment options are available.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Prior to therapy, coreceptor tropism testing should be performed for presence of CCR5-tropic only virus HIV-1 infection. Therapy not recommended for use in patients with CXCR4- or dual/mixed tropic HIV-1 infection; efficacy not demonstrated in this population. In studies with treatment-naive patients, virologic failure and emergent lamivudine resistance was more common in maraviroc-treated patients compared to patients receiving efavirenz.

Monitoring Parameters

Viral load, CD4 count, transaminases and bilirubin (prior to initiation and periodically during treatment); signs/symptoms of infection, rash, severe skin reactions, hepatitis and/or allergic reaction; postural hypotension; tropism testing (prior to initiation)

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse effects have not been observed in animal reproduction studies. Maraviroc has minimal to low transfer across the human placenta. The DHHS Perinatal HIV Guidelines note there are insufficient data to recommend use in pregnancy.

Regardless of CD4 count or HIV RNA copy number, all HIV-infected pregnant women should receive a combination antiretroviral (ARV) drug regimen. A combination of antepartum, intrapartum, and infant ARV prophylaxis is recommended. ARV therapy should be started as soon as possible in women with symptomatic infection. Although earlier initiation may be more effective in reducing the perinatal transmission of HIV, initiation may be delayed until after 12 weeks gestation in women who do not require immediate treatment after careful consideration of maternal conditions (eg, nausea and vomiting) and the potential risks of first trimester fetal exposure for specific agents. A scheduled cesarean delivery at 38 weeks gestation is recommended for all women with HIV RNA >1000 copies/mL or unknown concentrations near delivery in order to decrease transmission. If ARV therapy must be interrupted for <24 hours during the peripartum period, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to ARV medications. In couples who want to conceive, the HIV-infected partner should attain maximum viral suppression prior to conception.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal], 2014).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, diarrhea, rhinorrhea, rhinitis, dyspepsia, flatulence, arthralgia, or insomnia. Have patient report immediately to prescriber signs of infection, severe dizziness, syncope, paresthesia, angina, urinary retention, oliguria, considerable asthenia, edema of extremities, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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