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Maraviroc

Pronunciation: (MAR-a-VIR-ok)
Class: Cellular chemokine receptor (CCR5) antagonist

Trade Names

Selzentry
- Tablets 150 mg, 300 mg

Celsentri (Canada)

Pharmacology

Selectively binds to CCR5 present on the cell membrane, preventing CCR5-tropic HIV-1 from entering cells.

Pharmacokinetics

Absorption

After oral dosing, C _max attained in 0.5 to 4 h. Bioavailability is 23% at a 100 mg dose and 33% at a 300 mg dose. Maraviroc is a substrate for the efflux transporter P-glycoprotein.

Distribution

Approximately 76% bound to human plasma protein and shows moderate affinity for albumin and alpha-1 acid glycoprotein. Vd is approximately 194 L.

Metabolism

Primarily metabolized by CYP3A to inactive metabolites.

Elimination

Terminal half-life is 14 to 18 h. Elimination is approximately 76% and 20% in the feces and urine, respectively, over 168 h. Maraviroc is the major component excreted; the remainder are metabolites.

Special Populations

Renal Function Impairment

In a single 300 mg dose study in patients with severe renal impairment (CrCl less than 30 mL/min) and ESRD, C _max 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. Contraindicated in patients with severe renal impairment or ESRD who are taking potent CYP3A4 inhibitors or inducers.

Hepatic Function Impairment

C _max and AUC were 11% and 25% higher, respectively, for patients with mild hepatic impairment, and 32% and 46% higher, respectively, for patients with moderate hepatic impairment. These changes do not warrant a dose adjustment.

Children

The pharmacokinetics have not been established.

Gender

Does not affect concentrations.

Race

Exposure was 26.5% higher in Asian patients compared with non-Asian patients. Dosage adjustment based on race is not needed.

Indications and Usage

In combination with other antiretroviral agents for treatment of adult patients infected only with CCR5-tropic HIV-1.

Contraindications

In patients with severe renal impairment or ESRD (CrCl less than 30 mL/min) who are taking potent CYP3A4 inhibitors or inducers.

Dosage and Administration

Concomitant Enfuvirtide, Nevirapine, All Nucleoside Reverse Transcriptase Inhibitors (NTRIs), Raltegravir, Tipranavir/Ritonavir
Adults and Adolescents 16 y of age and older

PO 300 mg twice daily.

Concomitant Potent CYP3A Inhibitors (Clarithromycin, Delavirdine, Itraconazole, Ketoconazole, Nefazodone, Protease Inhibitors [Except Tipranavir/Ritonavir], Telithromycin) With or Without a CYP3A Inducer
Adults and Adolescents 16 y of age and older

PO 150 mg twice daily.

Concomitant Potent CYP3A Inducers Without a Strong CYP3A Inhibitor (Carbamazepine, Efavirenz, Etravirine, Phenobarbital, Phenytoin, Rifampin)
Adults and Adolescents 16 y of age and older

PO 600 mg twice daily.

Renal Function Impairment
Concomitant Potent CYP3A Inhibitors (Clarithromycin, Delavirdine, Itraconazole, Ketoconazole, Nefazodone, Protease Inhibitors [Except Tipranavir/Ritonavir], Telithromycin) With or Without CYP3A Inducer Severe renal impairment (CrCl less than 30 mL/min) and ESRD on hemodialysis

Contraindicated.

Concomitant Enfuvirtide, Nevirapine, NRTIs, Raltegravir, Tipranavir/Ritonavir Severe renal impairment (CrCl less than 30 mL/min) and ESRD on hemodialysis

Reduce dosage to 150 mg twice daily if there are any symptoms of postural hypotension.

Concomitant Potent CYP3A Inducers (Carbamazepine, Efavirenz, Etravirine, Phenobarbital, Phenytoin, Rifampin) Without a Strong CYP3A Inhibitor Severe renal impairment (CrCl less than 30 mL/min) and ESRD on hemodialysis

Contraindicated.

General Advice

May be taken without regard to food.
Must be taken in combination with other antiretroviral agents.

Storage/Stability

Store at 59° to 86°F. Shelf life is 24 mo.

Drug Interactions

CYP3A and/or P-glycoprotein inducers (eg, efavirenz, nevirapine, rifampin)

Maraviroc concentrations may be reduced. Determine dosage selection based on concurrent medications.

CYP3A and/or P-glycoprotein inhibitors (eg, atazanavir, atazanavir/ritonavir, ketoconazole, lopinavir/ritonavir, ritonavir, saquinavir)

Maraviroc concentrations may be elevated. Determine dosage selection based on concurrent medications.

CYP3A and/or P-glycoprotein inhibitors plus inducers (eg, lopinavir/ritonavir plus efavirenz)

Maraviroc concentrations may be altered. Determine dosage selection based on concurrent medications.

Food

Coadministration of 300 mg tablet with a high-fat breakfast reduced maraviroc C _max and AUC by 33% in healthy volunteers; however, maraviroc can be taken with or without food.

Potent CYP3A inducers (eg, carbamazepine, efavirenz, etravirine, phenobarbital, phenytoin, rifampin) without a potent CYP3A inhibitor

Maraviroc plasma concentrations may be decreased. The recommended dosage is maraviroc 600 mg twice daily.

Potent CYP3A inhibitors (eg, clarithromycin, delavirdine, itraconazole, ketoconazole, nefazodone, protease inhibitors [except tipranavir/ritonavir], telithromycin) with or without a CYP3 inducer

Maraviroc plasma concentrations may be increased. The recommended dosage is maraviroc 150 mg twice daily. Patients with CrCl less than 50 mL/min may be at increased risk of adverse reactions (eg, dizziness, postural hypotension) related to elevated maraviroc concentrations. Administer maraviroc and a CYP3A inhibitor to patients with CrCl less than 50 mL/min only if the potential benefit outweighs the risk, and monitor patients for adverse reactions.

St. John's wort

Coadministration is not recommended. Maraviroc concentrations may be reduced, which may result in suboptimal levels of maraviroc and lead to loss of virologic response and possible resistance.

Adverse Reactions

Cardiovascular

Vascular hypotension disorders (3%); acute cardiac failure, cerebrovascular accident, coronary artery disease and occlusion, endocarditis, MI, myocardial ischemia, unstable angina (less than 2%).

CNS

Dizziness/postural dizziness (9%); disturbances in initiating and maintaining sleep (8%); paresthesias and dysesthesias (5%); anxiety symptoms, depressive disorders, disturbances in consciousness, peripheral nephropathies, sensory abnormalities (4%); convulsions and epilepsy, facial palsy, hemianopia, loss of consciousness, meningitis, tremor (excluding congenital), viral meningitis, visual field defect (less than 2%).

Dermatologic

Rash (11%); apocrine and eccrine gland disorders (5%); folliculitis, pruritus (4%); benign skin neoplasms, lipodystrophies (3%); erythemas (2%); basal cell carcinoma, squamous cell carcinoma of skin (less than 2%); Stevens-Johnson syndrome (postmarketing).

GI

Appetite disorder (8%); constipation (6%); abdominal neoplasm, anal cancer, Clostridium difficile colitis, esophageal carcinoma, tongue neoplasm (less than 2%).

Genitourinary

Bladder and urethral symptoms (5%); urinary tract signs and symptoms (3%); anogenital warts (2%).

Hepatic

Bile duct neoplasms malignant, cholestatic jaundice, hepatic cirrhosis or failure, hypertransaminasemia, jaundice, metastases to liver, portal vein thrombosis (less than 2%).

Hematologic-Lymphatic

Hypoplastic anemia, marrow depression (less than 2%).

Lab Tests

Elevated amylase or total bilirubin (6%); elevated AST or lipase (5%); decreased absolute neutrophil count (4%); elevated ALT (3%).

Musculoskeletal

Joint-related signs and symptoms (7%); muscle pains (3%); increased blood creatine kinase, myositis, osteonecrosis, rhabdomyolysis (less than 2%).

Respiratory

Upper respiratory tract infection (23%); coughing and associated symptoms (14%); bronchitis, sinusitis (7%); upper respiratory tract signs and symptoms (6%); breathing abnormalities, nasal congestion and inflammation (4%); paranasal sinus disorders (3%); pneumonia (2%).

Special Senses

Conjunctivitis, ocular infections (including inflammation and associated manifestations), otitis media (2%).

Miscellaneous

Pyrexia (13%); herpes infection (8%); pain and discomfort (4%); influenza (2%); anaplastic large cell lymphomas T- and null-cell types, Bowen disease, cholangiocarcinoma, diffuse large B-cell lymphoma, endocrine neoplasms malignant and unspecified, infective myositis, lymphoma, nasopharyngeal carcinoma, septic shock, squamous cell carcinoma, treponema infections (less than 2%).

Precautions

Warnings

Hepatotoxicity has been reported. Evidence of a systemic allergic reaction (eg, pruritic rash, eosinophilia, or elevated immunoglobulin E) prior to development of hepatotoxicity may occur. Evaluate patients with signs or symptoms of hepatitis or allergic reaction to the drug immediately.

Monitor

Monitor LFTs at baseline and periodically during treatment; monitor BP in patients with a history of postural hypotension or those on antihypertensive agents. Monitor patients for signs of infection.

Pregnancy

Category B .

Lactation

Undetermined; however, HIV-infected mothers should not breast-feed in order to avoid risking potential transmission of HIV to the infant.

Children

Safety and efficacy not established in patients younger than 16 y of age.

Elderly

Use with caution because of the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant diseases or other drug therapy.

Renal Function

If patients with severe renal impairment or ESRD not receiving a concomitant potent CYP3A inhibitor or inducer experience symptoms of postural hypotension, reduce dosage of maraviroc to 150 mg twice daily. Maraviroc is contraindicated in patients with severe renal impairment or ESRD cotreated with potent CYP3A inhibitors or inducers.

CV events

Use with caution in patients at increased risk of CV events and in patients with a history of postural hypotension or receiving medication known to lower BP.

Immune reconstitution syndrome

Has been reported; during initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium , cytomegalovirus, Mycobacterium tuberculosis ) and may require additional evaluation and treatment.

Infection

Because the CCR5 coreceptor located on some immune cells is antagonized, there can be an increased risk of developing infections.

Malignancy

May increase risk of malignancy.

Overdosage

Symptoms

Postural hypotension.

Patient Information

Advise patient to read the Medication Guide before using the product for the first time and with each refill.
Advise patients to stop treatment and seek immediate medical attention if they develop signs or symptoms of hepatitis or allergic reaction.
Inform patients that treatment is not a cure for HIV infection and that they may still develop illnesses associated with HIV infection, including opportunistic infections.
Inform patient that treatment does not reduce risk of transmission of HIV to others through sexual contact, sharing needles, or blood contamination.
Advise patient that it is important to remain under the care of a health care provider.
Advise patient to take the medication every day as prescribed and in combination with other antiretroviral drugs.
Instruct patient to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
Advise patient that if a dose is missed, to take the next dose as soon as possible and then take the next scheduled dose at its regular time. If it is less than 6 h before the next scheduled dose, advise patient not to take the missed dose and instead wait and take the next dose at the regular time.
Advise patients that if they experience dizziness while taking the medication to avoid driving or operating machinery.