Maraviroc (Selzentry) - Drug Class, Uses, MOA

Maraviroc (Selzentry) is an orally available antiretroviral drug that acts as a CCR5 receptor antagonist. It is used in the treatment of HIV-1 infection in combination with other antiviral drugs.

Maraviroc (Selzentry) Uses:

  • HIV-1 infection:

    • Treatment of only CCR5-tropic HIV-1 infection in patients 2 years and older and weighing ≥10 kg, in combination with other antiretroviral agents.

Maraviroc (Selzentry) use in COVID-19 infection:

Since no effective drugs have been found to treat patients with COVID-19 infection. Many drugs have been hypothesized to be effective. Maraviroc is thought to act as an antiviral molecule targeting SARS-CoV-2 Mpro [Ref].


Maraviroc (Selzentry) Dose in Adults:

Maraviroc (Selzentry) Dose in the treatment of HIV-1 infection:

  • Oral:
    • 300 mg BD;
    • The dose recommended when maraviroc administered concomitantly with other medications that are not potent CYP3A inhibitors or inducers, including 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 BD;
      • The 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, and boceprevir.
    • CYP3A inducers (without a potent CYP3A inhibitor):

      • 600 mg BD;
      • The dose recommended when maraviroc administered concomitantly with potent CYP3A inducers including (but not limited to) efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, and phenytoin

Maraviroc (Selzentry) Dose in Children:

  • Use in combination with other antiretroviral agents.

Maraviroc (Selzentry) Dose in the treatment of HIV-1 infection:

  • Administration without potent CYP3A inhibitors or inducers:

    • Children ≥2 years and Adolescents:

      • Weight <30 kg: Not recommended
      • Weight ≥30 kg: Oral: 300 mg BD
  • Administration with potent CYP3A inhibitors or inducers:

    • Children ≥2 years (weighing ≥10 kg) and Adolescents:
      • See dosage adjustment for concomitant therapy

Dosing adjustment for concomitant CYP3A4 inhibitors/inducers:

  • Children ≥2 years and Adolescents:

    • CYP3A inhibitors (with or without a CYP3A4 inducer):

      • The dose recommended when maraviroc administered concomitantly with strong CYP3A inhibitors including (but not limited to):
        • Protease inhibitors (excluding tipranavir/ritonavir), boceprevir, delavirdine, elvitegravir/ritonavir, ketoconazole, itraconazole, clarithromycin, nefazodone, and telithromycin
      • 10 to <20 kg: Oral: 50 mg BD
      • 20 to <30 kg: Oral: 75 mg BD (tablets) or 80 mg BD (oral solution)
      • 30 to <40 kg: Oral: 100 mg BD
      • ≥40 kg: Oral: 150 mg BD
    • CYP3A inducers (without a strong CYP3A4 inhibitor):

      • In pediatric patients, maraviroc not recommended
      • In adults, dosage adjustment recommended when maraviroc administered concomitantly with CYP3A inducers including (but not limited to):

Maraviroc Pregnancy Risk Category: B

  • Maraviroc shows moderate transfer to the human placenta.
  • The data from the antiretroviral pregnancy registry do not provide sufficient information to assess human teratogenic risks.
  • Although maternal antiretroviral treatment (ART) may increase preterm births, the information available is inconsistent due to variability in maternal factors (disease severity and gestational age at the initiation of therapy),
  • Some studies have shown an increased risk of stillbirth and low birth weight in infants under gestational age. However, not all studies have confirmed this.
  • Maternal ART is an important treatment option that has clear benefits.
  • Avoid delay if you are concerned about adverse neonatal outcomes.
  • All infants who have been exposed to antiretroviral medication should be followed up for a long time
  • Potential mitochondrial dysfunction should be considered for children who have significant organ abnormalities of unknown origin (especially the heart or CNS).
  • Due to insufficient data, the Health and Human Services (HHS), Perinatal HIV Guidelines don't recommend maraviroc for HIV-infected pregnant women who are antiretroviral naive.
  • Maraviroc is not recommended for pregnant women who have received ART therapy in the previous but are starting again, or who need a new regimen due to poor tolerance of poor virologic response.
  • If the viral suppression is effective and the regimen is well tolerated, females who are pregnant while taking maraviroc might continue to take it.
  • Pregnancy does not require dosage adjustments.
  • To keep HIV-positive pregnant women under the control and to reduce the chance of perinatal transmission, it is generally recommended that ART be performed.
  • Monitoring during pregnancy is more common than monitoring in adults who are not pregnant.
  • All HIV-positive women should continue ART after giving birth. ART can also be modified once the baby is born.

Maraviroc use during breastfeeding:

  • It is unknown if maraviroc can be found in breast milk.
  • Postnatal HIV transmission is not completely eliminated by infant or maternal antiretroviral treatment.
  • A multiclass-resistant virus was also detected in breastfed infants, despite maternal therapy.
  • To reduce the possibility of HIV transmission, women with HIV should not breastfeed in the US. The formula is affordable, safe and easily accessible.

Maraviroc (Selzentry) Dose in Kidney Disease:

  • CrCl ≥30 mL/minute:

    • No dosage adjustment necessary
  • CrCl <30 mL/minute:

    • Concomitant potent CYP3A inhibitors (with or without a potent CYP3A inducer) or concomitant potent CYP3A inducer (without a potent CYP3A inhibitor):
      • Use is contraindicated
    • Other concomitant medications (eg, tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, enfuvirtide, and other medications that are not potent CYP3A inhibitors or inducers):
      • No dosage adjustment necessary, unless postural hypotension occurs; then, reduce dose to 150 mg BD
  • ESRD requiring intermittent hemodialysis (IHD):

Note: Hemodialysis has minimal effect on clearance

  • Concomitant potent CYP3A inhibitors (with or without a potent CYP3A inducer) or concomitant potent CYP3A inducer (without a potent CYP3A inhibitor):
    • Use is contraindicated
  • Other concomitant medications (eg, tipranavir/ritonavir, nevirapine, raltegravir, all NRTIs, enfuvirtide, and other medications that are not potent CYP3A inhibitors or inducers):
    • No dosage adjustment necessary, unless postural hypotension occurs; then, reduce dose to 150 mg BD.

Maraviroc (Selzentry) Dose in Liver disease:

  • 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 cautiously.
  • Moderate impairment (with concomitant potent CYP3A inhibitor):
    • There are no dosage adjustments provided in the manufacturer's labeling
    • However, maraviroc concentrations are increased moderate impairment
    • Use cautiously and monitor closely for adverse events.
  • Severe impairment:
    • There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

  • Includes data from both treatment-naive and treatment-experienced patients.
  • Unless otherwise noted, the frequency of adverse events is as reported in adults receiving combination antiretroviral therapy.

Common Side Effects of Maraviroc (Selzentry):

  • Dermatologic:

    • Skin rash
  • Gastrointestinal:

    • Vomiting
  • Infection:

    • Infection
  • Respiratory:

    • Upper respiratory tract infection
    • Cough
  • Miscellaneous:

    • Fever

Less Common Side Effects of Maraviroc (Selzentry):

  • Cardiovascular:

    • Hypertension
    • Cardiac Failure
    • Cerebrovascular Accident
    • Coronary Artery Disease
    • Coronary Occlusion
    • Endocarditis
    • Myocardial Infarction
    • Portal Vein Thrombosis
    • Septic Shock
    • Unstable Angina Pectoris
  • Central Nervous System:

    • Dizziness
    • Insomnia
    • Paresthesia
    • Dysesthesia
    • Anxiety
    • Impaired Consciousness
    • Depression
    • Peripheral Neuropathy
    • Malaise
    • Pain
    • Sensory Disturbance
    • Memory Impairment
    • Epilepsy
    • Loss Of Consciousness
    • Meningitis
    • Facial Paralysis
    • Seizure
  • Dermatologic:

    • Nail Disease
    • Sweat Gland Disease
    • Folliculitis
    • Pruritus
    • Tinea
    • Acne Vulgaris
    • Alopecia
    • Erythema
    • Condyloma Acuminatum
  • Endocrine & Metabolic:

    • Lipodystrophy
  • Gastrointestinal:

    • Abdominal Distension
    • Bloating
    • Flatulence
    • Decreased Gastrointestinal Motility
    • Change In Appetite
    • Constipation
    • Abdominal Pain
    • Diarrhea
    • Nausea
    • Carcinoma In Situ Of Esophagus
    • Colitis
  • Genitourinary:

    • Genitourinary Complaint
    • Ejaculatory Disorder
    • Erectile Dysfunction
  • Hematologic & Oncologic:

    • Anemia
    • Neutropenia
    • Benign Skin Neoplasm
    • Basal Cell Carcinoma
    • Bone Marrow Depression
    • Bowen Disease
    • Carcinoma
    • Hypoplastic Anemia
    • Liver Metastases
    • Malignant Lymphoma
    • Malignant Neoplasm
    • Malignant Neoplasm Of Bile Duct
    • Malignant Neoplasm Of Tongue
    • Neoplasm
    • Squamous Cell Carcinoma
    • Squamous Cell Carcinoma Of Skin
  • Hepatic:

    • Increased Serum AST
    • Cholestatic Jaundice
    • Hepatic Cirrhosis
    • Hepatic Failure
    • Jaundice
  • Infection:

    • Herpes Virus Infection
    • Bacterial Infection
    • Herpes Zoster
    • Varicella Zoster Infection
    • Meningococcal Infection Viral Infection
    • Influenza
    • Bacterial Infection
  • Neuromuscular & Skeletal:

    • Arthropathy
    • Myalgia
    • Increased Creatine Phosphokinase
    • Myositis
    • Osteonecrosis
    • Rhabdomyolysis
    • Tremor
  • Ophthalmic:

    • Conjunctivitis
    • Eye Disease
    • Hemianopia
    • Visual Field Defect
  • Otic:

    • Otitis Media
  • Respiratory:

    • Bronchitis
    • Upper Respiratory Complaint
    • Sinusitis
    • Irregular Breathing
    • Nasal Congestion
    • Rhinitis
    • Lower Respiratory Tract Infection
    • Pulmonary Infection
    • Paranasal Sinus Disease
    • Pneumonia

Rare side effects of Maraviroc (Selzentry):

  • Hepatic:

    • Hepatitis
    • Hepatotoxicity
  • Immunologic:

    • Immune Reconstitution Syndrome

Contraindications to Maraviroc (Selzentry):

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

Canadian labeling: Additional contraindications not in US labeling

  • Hypersensitivity to maraviroc and any component of the formulation

Warnings and precautions

  • CNS effects

    • May cause dizziness.
    • CNS symptoms can cause patients to avoid driving and operating machinery.
  • Hepatotoxicity: [US Boxed Warning]

    • Reports have suggested that drug-induced liver toxicities could be caused by allergic-type symptoms.
    • Severe rash and other symptoms may precede hepatotoxicity.
    • Patients with pre-existing HBV/HCV infection or hepatic dysfunction should be cautious. However, symptoms can occur even if there are no pre-existing conditions.
    • Monitor your liver function at baseline, and as indicated by your doctor during treatment.
    • Patients with hepatitis, elevated transaminases or systemic allergic reactions should be considered for discontinuation.
    • It is not recommended to engage in a battle with maraviroc.
  • Immune reconstitution syndrome:

    • The immune reconstitution syndrome may occur in patients who have received HIV treatment.
    • This can lead to an inflammatory response to an indolent, residual opportunistic virus.
    • Additional evaluation and treatment may still be necessary.
  • Infections

    • Pay attention to any signs or symptoms that indicate the possibility of developing infection.
    • Clinical trials have shown that there was a slight increase in certain upper respiratory tract infections as well as herpes virus infection.
  • Malignancy

    • The pharmacologic mechanism may cause an increase in malignancy and affect immune surveillance.
    • There has not been an increase in malignancy.
    • This risk requires long-term monitoring.
  • Postural hypotension:

    • Hypotension symptoms have been diagnosed.
    • Patients at high risk for the condition should be treated with caution if they are taking medication or have a history of it.
    • Patients with severe renal impairment or ESRD may be at greater risk for postural hypotension.
    • Patients suffering from severe renal dysfunction or ESRD should be given a lower dose.
  • Hypersensitivity and skin reactions

    • Patients who have received concomitant medications with these reactions have reported severe and life-threatening skin reactions and hypersensitivity reactions.
    • These reports have been accompanied by rash and other constitutional findings (eg, fevers, muscle aches, conjunctivitis or oral lesions), as well as organ dysfunction (including hepatic impairment).
    • If hypersensitivity symptoms develop, discontinue use of maraviroc or any other suspected agent.
    • As appropriate, monitor hepatic function.
  • Cardiovascular disease

    • Patients with heart disease or patients who have a history or are currently at risk for postural hypotension or those taking concomitant medications that lower blood pressure should be cautious.
    • Postural hypotension can lead to cardiac adverse events in patients with cardiovascular comorbidities.
    • Trials revealed that there was a slight increase in the number of cardiovascular events in patients treated with therapy (myocardial infarction and/or myocardial ischemia) compared to placebo.
    • However, it is not known if this relationship is related to therapy.
    • Not to be overlooked, most patients who experience cardiac events had previously experienced risk factors or cardiac disease.
  • Hepatic impairment

    • Patients with HBV/or HCV coinfection, mild-to-moderate liver impairment or HCV coinfection should be cautious. Maraviroc concentrations may increase.
    • Patients with mild hepatic impairment receive concomitant potent CYP3A inhibits.
    • Maraviroc concentrations may be increased further. Monitor closely for any adverse reactions.
    • It has not been tested in patients with severe liver impairment.
  • Renal impairment

    • Maraviroc concentrations may be affected by renal impairment.
    • Patients with moderate-to-severe renal impairment should be cautious.
    • Patients with severe renal impairment and those with ESRD may be at greater risk for postural hypotension.
    • Patients with severe renal disease or ESRD should be given a lower dose.
    • Patients with severe renal impairment or ESRD are not recommended to use this drug.

Maraviroc: Drug Interaction

Risk Factor C (Monitor therapy)

Aprepitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Bosentan

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Clofazimine

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

CYP3A4 Inducers (Moderate)

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

CYP3A4 Inhibitors (Moderate)

May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).

Deferasirox

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Delavirdine

May increase the serum concentration of Maraviroc.

Duvelisib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Erdafitinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Erdafitinib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Fosaprepitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Fosnetupitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Ivosidenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Larotrectinib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Netupitant

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Orlistat

May decrease the serum concentration of Antiretroviral Agents.

Palbociclib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Sarilumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Siltuximab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Simeprevir

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Tocilizumab

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).

Risk Factor D (Consider therapy modification)

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.

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.

Dabrafenib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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).

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.

Enzalutamide

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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.

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.

Lorlatinib

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.

MiFEPRIStone

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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.

Mitotane

May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.

Stiripentol

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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.

Risk Factor X (Avoid combination)

Conivaptan

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Fusidic Acid (Systemic)

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

Idelalisib

May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).

St John's Wort

May decrease the serum concentration of Maraviroc.

 

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)

How to administer Maraviroc (Selzentry)?

  • Oral:
    • Administer without regard to meals.
    • Stable immunologic parameters and virologic suppression have been reported following the administration of crushed tablets.
    • However, an oral solution is commercially available.

Mechanism of action of Maraviroc (Selzentry):

  • Maraviroc, an antagonist of CCR5, selectively and reversibly binds the chemokine C-C motif receptor 5, [CCR5]) coreceptors on human CD4 cells.
  • CCR5 antagonism is a block in interaction between the human CCR5 cortexor and the gp120 unit of the viral envelope glycoprotein.
  • This inhibits gp120 conformational changes required for CCR5tropic HIV-1 fusion to the CD4 cells and subsequent cell entry.

Notification:

    • Pediatric patients with Maraviroc were >=30kg and received non-interacting concomitant medication.
    • These parameters were comparable to those in adults.

Protein binding:

  • ~76%

Metabolism:

  • Hepatic, via CYP3A to inactive metabolites

Bioavailability:

  • 23% to 33% (maraviroc is a substrate for the efflux transporter P-gp)

Half-life elimination:

  • 14 to 18 hours

Time to peak, plasma:

  • 0.5 to 4 hours

Excretion:

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

International Brands of Maraviroc:

  • Selzentry
  • Celsentri

Maraviroc Brand Names in Pakistan:

No Brands Available in Pakistan.