Selzentry (maraviroc)

Dosage of maraviroc is based on different concomitant drugs.

Maraviroc is available as oral tablets and an oral solution. Administer maraviroc orally twice daily without regard to food. Administer maraviroc in combination with other antiretroviral agents.

Swallow maraviroc tablets whole; do not chew. Assess children for the ability to swallow tablets; use the oral solution instead of tablets in those unable to reliably swallow tablets.

Administer maraviroc oral solution containing 100 mg/5 mL using the press-in bottle adapter and appropriate oral dosing syringe supplied by the manufacturer; use the 3-mL oral syringe for doses <=2.5 mL and the 10-mL oral syringe for doses >2.5 mL. Exercise care when measuring neonate doses due to the small volumes of oral solution required. Consult the manufacturer's instructions for more specific information regarding administration of the oral solution.

Store maraviroc tablets and oral solution at 20-25oC (excursions permitted to 15-30oC). Discard any unused oral solution 60 days after first opening the bottle.

There is no enhanced messaging for this drug.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Anti-Retrovirals/Atidarsagene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Atidarsagene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of atidarsagene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the medication) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of atidarsagene autotemcel therapy.(1)

Anti-Retrovirals/Elivaldogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Elivaldogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of elivaldogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of elivaldogene autotemcel therapy.(1)

Anti-Retrovirals/Etuvetidigene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Etuvetidigene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating HIV-based lentiviral vector. Antiretrovirals may interfere with the manufacturing of the apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of etuvetidigene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients should not take antiretrovirals for at least one month prior to mobilization and until at least 7 days after etuvetidigene autotemcel infusion.(1) If a patient requires antiretroviral agents for HIV post-exposure prophylaxis, etuvetidigene autotemcel treatment should be delayed until HIV testing is negative at 6 months post-exposure.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of etuvetidigene autotemcel therapy.(1)

Anti-Retrovirals/Lovotibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Lovotibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of lovotibeglogene autotemcel.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization and until all cycles of apheresis are completed.(1) There are some long-acting antiretroviral medications that may require a longer duration of discontinuation for elimination of the medication. If a patient is taking anti-retrovirals for HIV prophylaxis, confirm a negative test for HIV before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of lovotibeglogene autotemcel therapy.(1)

Anti-Retrovirals; Hydroxyurea/Betibeglogene Autotemcel

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Betibeglogene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of apheresed cells. Hydroxyurea may interfere with hematopoietic stem cell (HSC) mobilization of CD34+ cells.(1)

CLINICAL EFFECTS: Use of hydroxyurea before mobilization may result in unsuccessful stem cell mobilization. Use of antiretrovirals before mobilization and apheresis may interfere with the production of betibeglogene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals and hydroxyurea for at least one month prior to mobilization and until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.

DISCUSSION: Antiretroviral medications and hydroxyurea may interfere with the manufacturing of betibeglogene autotemcel therapy.(1)

Maraviroc/St. John's Wort

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: St. John's wort may induce the metabolism of maraviroc by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of St. John's wort may result in decreased levels of, effectiveness of, and resistance to maraviroc.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of maraviroc states that patients receiving maraviroc should not use St. John's wort.(1)

DISCUSSION: Concurrent use of St. John's wort is expected to substantially decrease maraviroc levels.(1)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Anti-Retrovirals/Marnetegragene Autotemcel

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Marnetegragene autotemcel is prepared from apheresed cells that are transduced with a replication defective, self-inactivating lentiviral vector. Antiretrovirals may interfere with the manufacturing of transduced cells.

CLINICAL EFFECTS: Use of antiretrovirals before mobilization and apheresis may interfere with the production of marnetegragene autotemcel.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discontinue antiretrovirals for at least one month prior to mobilization (or the expected duration of time needed for elimination of the antiretrovirals) until all cycles of apheresis are completed. If a patient requires antiretrovirals for HIV prophylaxis, then confirm a negative HIV test before beginning mobilization and apheresis of CD34+ cells.(1)

DISCUSSION: Antiretroviral medications may interfere with the manufacturing of marnetegragene autotemcel.(1)

Maraviroc/Etravirine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Etravirine may induce the metabolism of maraviroc by CYP3A4. This effect may be overcome by the concurrent administration of an inhibitor of CYP3A4(1-4)

CLINICAL EFFECTS: Concurrent use of etravirine without a strong inhibitor of CYP3A4 may result in decreased levels and effectiveness of maraviroc and the development of resistance. Concurrent use of etravirine with a strong inhibitor of CYP3A4 may result in increased levels of maraviroc and the development of toxicity.(1-4)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal impairment.(3)

PATIENT MANAGEMENT: In adults, the recommended dosage of maraviroc in combination with etravirine in the absence of a strong CYP3A4 inhibitor is 600 mg twice daily. The recommended dosage of maraviroc in combination with etravirine and a CYP3A4 inhibitor (except tipranavir/ritonavir) is 150 mg twice daily.(2,3,5) In adults, maraviroc should not be used with a strong CYP3A4 inducer in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease.(3) In children aged 2 years and older weighing at least 10 kg, maraviroc in combination with etravirine is not recommended.(3) No dosage adjustments are recommended for etravirine.(5)

DISCUSSION: In a study in 28 healthy subjects, concurrent use of etravirine (200 mg twice daily) with maraviroc (300 mg twice daily) decreased maraviroc area-under-curve (AUC), maximum concentration (Cmax), and minimum concentration (Cmin) by 53%, 60%, and 39%, respectively, when compared to the use of maraviroc (300 mg twice daily) alone.(1-4) There were no significant changes in etravirine pharmacokinetics.(5) The concurrent use of etravirine (200 mg twice daily), darunavir/ritonavir (600/100 mg twice daily), and maraviroc (150 mg twice daily) increased maraviroc AUC, Cmax, and Cmin by 210%, 77%, and 427%, respectively, when compared to the administration of maraviroc (150 mg twice daily) alone.(1-4) There were no significant changes in etravirine pharmacokinetics.(5)

Maraviroc/Selected Protease Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Some protease inhibitors may inhibit the metabolism of maraviroc by CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of protease inhibitors without a dosage adjustment of maraviroc may result in elevated levels of and toxicity from maraviroc.(1-3)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal and/or hepatic impairment.(1)

PATIENT MANAGEMENT: The US manufacturer of maraviroc states that adult patients receiving concurrent therapy with strong inhibitors of CYP3A4 such as protease inhibitors (except for tipranavir/ritonavir) should receive a dose of 150 mg maraviroc twice daily. This is the recommended dose in patients receiving strong CYP3A4 inhibitors regardless of whether or not the patient is also receiving a strong inducer of CYP3A4.(1) In adults, maraviroc should not be used with a potent CYP3A4 inhibitor in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease. Patients with hepatic impairment should be closely monitored for maraviroc-related side effects.(1) In adults, patients receiving tipranavir/ritonavir should receive 300 mg maraviroc twice daily.(1) In pediatric patients aged 2 years and older weighing at least 10 kg, patients receiving concurrent therapy with strong inhibitors of CYP3A4 such as protease inhibitors (except for tipranavir/ritonavir) regardless of whether or not the patient is also receiving a strong inducer of CYP3A4 should receive the following maraviroc dose based on tablet or oral solution (20 mg/ml): - 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily - 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily - 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily - >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily In pediatric patients aged 2 years and older weighing at least 10 kg, no dose recommendations are available with mild to moderate renal impairment. Maraviroc is contraindicated in pediatric patients with severe renal impairment or end-stage renal disease who are on concurrent therapy with strong CYP3A4 inhibitors.(1)

DISCUSSION: In a study in 12 subjects, concurrent atazanavir (400 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 4.19-fold, 3.57-fold, and 2.09-fold, respectively.(1) In a study in 12 subjects, concurrent atazanavir/ritonavir (300/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 6.67-fold, 4.88-fold, and 2.67-fold, respectively.(1) In a study in 12 subjects, concurrent darunavir/ritonavir (600/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice daily) by 8.00-fold, 4.05-fold, and 2.29-fold, respectively.(1) In a study in 10 subjects, concurrent darunavir/ritonavir (600/100 mg twice daily) and etravirine (200 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice daily) by 5.27-fold, 3.10-fold, 1.77-fold, respectively.(1) In a study in 12 subjects, concurrent ketoconazole (400 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 3.75-fold, 5.00-fold, and 3.38-fold, respectively.(1) In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 9.24-fold, 3.95-fold, and 1.97-fold, respectively.(1) In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 6.29-fold, 2.53-fold, 1.25-fold, respectively.(1) In a study in 8 subjects, concurrent ritonavir (100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 4.55-fold, 2.61-fold, and 1.28-fold, respectively.(1) In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 11.3-fold, 9.77-fold, 4.78-fold, respectively.(1) In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax, of maraviroc (100 mg twice daily) by 8.42-fold, 5.00-fold, and 2.26-fold, respectively.(1) In a study in 12 subjects, concurrent tipranavir/ritonavir (500/200 mg twice daily) increased the Cmin and AUC of maraviroc (150 mg twice daily) by 80% and 2%, respectively. The Cmax of maraviroc decreased by 14%.(1) Selected protease inhibitors include: amprenavir, atazanavir, darunavir, ensitrelvir, fosamprenavir, indinavir, lopinavir, nelfinavir, nirmatrelvir/ritonavir, ritonavir, saquinavir, and tipranavir.

Maraviroc/Strong Cyp3a4 Inducers

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong CYP3A4 inducers may increase the metabolism of maraviroc.(1)

CLINICAL EFFECTS: Concurrent use of strong inducers of CYP3A4 in the absence of an inhibitor of CYP3A4 and without a dosage adjustment of maraviroc may result in decreased levels and effectiveness of maraviroc.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal impairment.(1) Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of maraviroc states that adult patients receiving therapy with inducers of CYP3A4 who are not also receiving an inhibitor of CYP3A4 should receive a dose of 600 mg maraviroc twice daily.(1) The US manufacturer of maraviroc states that adult patients receiving therapy with inducers of CYP3A4 who are also receiving a strong inhibitor of CYP3A4 should receive a dose of 150 mg maraviroc twice daily.(1) In adults, maraviroc should not be used with a strong CYP3A4 inducer in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease.(1) In children aged 2 years and older weighing at least 10 kg, patients receiving therapy with strong CYP3A4 inducers who are not also receiving an inhibitor of CYP3A4 is not recommended.(1) In children aged 2 years and older weighing at least 10 kg, patients receiving therapy with a strong CYP3A4 inducer and a strong CYP3A4 inhibitor should receive the following maraviroc dose based on tablet or oral solution (20 mg/ml): - 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily - 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily - 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily - >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily In pediatric patients aged 2 years and older weighing at least 10 kg, no dose recommendations are available with mild to moderate renal impairment. Maraviroc is contraindicated in pediatric patients with severe renal impairment or end-stage renal disease who are on concurrent therapy with strong CYP3A4 inhibitors.(1)

DISCUSSION: In a study in 12 subjects, concurrent efavirenz (600 mg daily) decreased the minimum concentration (Cmin), area-under-curve (AUC), and maximum concentration (Cmax) of maraviroc (100 mg twice daily) by 45%, 44.8%, and 51.4%, respectively.(1) In a study in 12 subjects, concurrent efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (200 mg twice daily) by 9%, 15%, and 16%, respectively, when compared to the administration of maraviroc (100 mg twice daily) alone.(1) In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 78%, 63%, and 66%, respectively.(1) In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased the Cmin and Cmax of maraviroc (200 mg twice daily) by 34% and 4%, respectively, when compared to the administration of maraviroc (100 mg twice daily) alone. The AUC of maraviroc increased by 3%.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, efavirenz, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.

Maraviroc/Strong Cyp3a4 Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Strong inhibitors of CYP3A4 may inhibit the metabolism of maraviroc.(1)

CLINICAL EFFECTS: Concurrent use of a strong inhibitor of CYP3A4 without a dosage adjustment of maraviroc may result in elevated levels of and toxicity from maraviroc. (1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal and/or hepatic impairment.(1)

PATIENT MANAGEMENT: The US manufacturer of maraviroc states that adult patients receiving concurrent therapy with strong inhibitors of CYP3A4 should receive a dose of 150 mg maraviroc twice daily. This is the recommended dose in patients receiving strong CYP3A4 inhibitors regardless of whether or not the patient is also receiving a strong inducer of CYP3A4.(1) In adults, maraviroc should not be used with a strong CYP3A4 inhibitor in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease.(1) Adult patients with hepatic impairment should be closely monitored for maraviroc-related side effects.(1) In pediatric patients aged 2 years and older weighing at least 10 kg, patients receiving concurrent therapy with strong inhibitors of CYP3A4 should receive the following maraviroc dose based on tablet or oral solution (20 mg/ml): - 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily - 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily - 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily - >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily In pediatric patients aged 2 years and older weighing at least 10 kg, no dose recommendations are available with mild to moderate renal impairment. Maraviroc is contraindicated in pediatric patients with severe renal impairment or end-stage renal disease who are on concurrent therapy with strong CYP3A4 inhibitors.(1) NIH guidelines recommend a dose reduction of 150 mg maraviroc twice daily with itraconazole and posaconazole. Dose reduction should also be considered with concurrent isavuconazole and voriconazole.(2)

DISCUSSION: In a study in 12 subjects, concurrent atazanavir (400 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 4.19-fold, 3.57-fold, and 2.09-fold, respectively.(1) In a study in 12 subjects, concurrent atazanavir/ritonavir (300/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 6.67-fold, 4.88-fold, and 2.67-fold, respectively.(1) In a study in 12 subjects, concurrent darunavir/ritonavir (600/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice daily) by 8.00-fold, 4.05-fold, and 2.29-fold, respectively.(1) In a study in 10 subjects, concurrent darunavir/ritonavir (600/100 mg twice daily) and etravirine (200 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (150 mg twice daily) by 5.27-fold, 3.10-fold, 1.77-fold, respectively.(1) In a study in 12 subjects, concurrent ketoconazole (400 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 3.75-fold, 5.00-fold, and 3.38-fold, respectively.(1) In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 9.24-fold, 3.95-fold, and 1.97-fold, respectively.(1) In a study in 11 subjects, concurrent lopinavir/ritonavir (400/100 mg twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (300 mg twice daily) by 6.29-fold, 2.53-fold, 1.25-fold, respectively.(1) In a study in 8 subjects, concurrent ritonavir (100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 4.55-fold, 2.61-fold, and 1.28-fold, respectively.(1) In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg twice daily) increased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 11.3-fold, 9.77-fold, 4.78-fold, respectively.(1) In a study in 11 subjects, concurrent saquinavir/ritonavir (1000/100 mg twice daily) and efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax, of maraviroc (100 mg twice daily) by 8.42-fold, 5.00-fold, and 2.26-fold, respectively.(1) In a study in 12 subjects, concurrent tipranavir/ritonavir (500/200 mg twice daily) increased the Cmin and AUC of maraviroc (150 mg twice daily) by 80% and 2%, respectively. The Cmax of maraviroc decreased by 14%.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, delavirdine, idelalisib, isavuconazonium, itraconazole, josamycin, ketoconazole, lonafarnib, mibefradil, mifepristone, nefazodone, relacorilant, ribociclib, posaconazole, telaprevir, telithromycin, tucatinib, and voriconazole.(2)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Selected Antiretrovirals/Orlistat

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: The exact mechanism is unknown. Orlistat may reduce the absorption of lipophilic antiretroviral HIV drugs by retention in the gastrointestinal tract or reduced gastrointestinal tract transit time.

CLINICAL EFFECTS: The concurrent administration of orlistat and atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, or tenofovir may result in a decrease in the levels and clinical effects of the antiretroviral, including loss of virological control.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: HIV RNA levels should be frequently monitored in patients taking orlistat while being treated for HIV infection. If there is a confirmed increase in HIV viral load, orlistat should be discontinued.(1)

DISCUSSION: Loss of virological control has been reported in HIV-infected patients taking orlistat concomitantly with lipophilic antiretroviral drugs.(1) There are three case reports of patients having an increased HIV viral load after taking orlistat concomitantly with their HIV therapy.(2-4) Antiretrovirals included in this monograph are atazanavir, efavirenz, emtricitabine, maraviroc, ritonavir, and tenofovir.

Selected Sensitive Cyp3a4 Substrates/Oral Lefamulin

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Lefamulin is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,3)

CLINICAL EFFECTS: Concurrent use of oral lefamulin may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(1)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: If oral lefamulin must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor for adverse effects of the CYP3A4 substrate.(1) Drug-specific recommendations: The manufacturer of abemaciclib recommends monitoring for adverse reactions and considering a dose reduction of abemaciclib in 50 mg decrements as detailed in prescribing information (based on starting dose, previous dose reductions, and combination or monotherapy use) with concurrent use of moderate CYP3A4 inhibitors.(2)

DISCUSSION: In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) Sensitive CYP3A4 substrates linked to this monograph include: abemaciclib, acalabrutinib, alprazolam, atorvastatin, brotizolam, budesonide, buspirone, cobimetinib, darifenacin, ebastine, eletriptan, elvitegravir, everolimus, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, paritaprevir, sildenafil, simvastatin, ticagrelor, triazolam, and ulipristal.(1,3,5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Maraviroc/Tecovirimat

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tecovirimat may induce the metabolism of maraviroc by CYP34.(1-4)

CLINICAL EFFECTS: Concurrent use of CYP3A4 inducers in the absence of an inhibitor of CYP3A4 and without a dosage adjustment of maraviroc may result in decreased levels and effectiveness of maraviroc.(1)

PREDISPOSING FACTORS: This interaction may be more severe in patients with renal impairment.(1)

PATIENT MANAGEMENT: Coadministration of maraviroc with tecovirimat should be approached with caution. In adults, consider increasing maraviroc to 600 mg twice daily when coadministered with tecovirimat in the absence of a protease inhibitor or other strong CYP3A4 inhibitors. When coadministered with tecovirimat in presence of a protease inhibitor or strong CYP3A4 inhibitor, consider decreasing maraviroc to 150 mg twice daily. These dose adjustments should be considered during and for approximately 2 weeks after the end of tecovirimat treatment.(1-4) In adults, maraviroc should not be used with a strong CYP3A4 inducer in patients with a creatinine clearance less than 30 ml/min or end-stage renal disease.(1) In children aged 2 years and older weighing at least 10 kg, patients receiving therapy with strong CYP3A4 inducers who are not also receiving an inhibitor of CYP3A4 is not recommended.(1) In children aged 2 years and older weighing at least 10 kg, patients receiving therapy with a strong CYP3A4 inducer and a strong CYP3A4 inhibitor should receive the following maraviroc dose based on tablet or oral solution (20 mg/ml): - 10 - <20 kg: 50 mg twice daily or 50 mg (2.5ml) twice daily - 20 - <30 kg: 75 mg twice daily or 80 mg (4 ml) twice daily - 30 - <40 kg: 100 mg twice daily or 100 mg (5 ml) twice daily - >= 40 kg: 150 mg twice daily or 150 mg (7.5 ml) twice daily In pediatric patients aged 2 years and older weighing at least 10 kg, no dose recommendations are available with mild to moderate renal impairment. Maraviroc is contraindicated in pediatric patients with severe renal impairment or end-stage renal disease who are on concurrent therapy with strong CYP3A4 inhibitors.(1)

DISCUSSION: In a study in 12 subjects, concurrent efavirenz (600 mg daily) decreased the minimum concentration (Cmin), area-under-curve (AUC), and maximum concentration (Cmax) of maraviroc (100 mg twice daily) by 45%, 44.8%, and 51.4%, respectively.(1) In a study in 12 subjects, concurrent efavirenz (600 mg daily) increased the Cmin, AUC, and Cmax of maraviroc (200 mg twice daily) by 9%, 15%, and 16%, respectively, when compared to the administration of maraviroc (100 mg twice daily) alone.(1) In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased the Cmin, AUC, and Cmax of maraviroc (100 mg twice daily) by 78%, 63%, and 66%, respectively.(1) In a study in 12 subjects, concurrent rifampin (600 mg daily) decreased the Cmin and Cmax of maraviroc (200 mg twice daily) by 34% and 4%, respectively, when compared to the administration of maraviroc (100 mg twice daily) alone. The AUC of maraviroc increased by 3%.(1) In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of midazolam by 39% and 32%, respectively.(2-3)

Selected Sensitive Cyp3a4 Substrates/Schisandra

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Schisandra is considered a moderate inhibitor of CYP3A4. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate by 2- to 5-fold.(1,2)

CLINICAL EFFECTS: Concurrent use of Schisandra may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP3A4 pathway.(3-7)

PREDISPOSING FACTORS: With darifenacin, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(8)

PATIENT MANAGEMENT: If Schisandra must be coadministered with a sensitive CYP3A4 substrate, it is recommended to closely monitor the CYP3A4 substrate and adjust its dose as appropriate.(3-7) The US manufacturer of sirolimus protein-bound injection (Fyarro) states a dose reduction to 56 mg/m2 is recommended when used concurrently with moderate or weak CYP3A4 inhibitors. Concurrent use with strong CYP3A4 inhibitors should be avoided.(8)

DISCUSSION: A study in 12 healthy volunteers found that Schisandra led to an increase in midazolam area-under-curve (AUC) and maximum concentration (Cmax) of 2.05- and 1.65-fold, respectively, compared to midazolam administered alone.(3) In a study of 18 healthy volunteers, sirolimus AUC and Cmax increased by 2.07-fold and 1.96-fold, respectively when given with Schisandra compared to sirolimus administered alone.(4) The effect of Schisandra on tacrolimus has been examined in several small pharmacokinetic studies in healthy volunteers as well as liver and kidney transplant patients. Compared to tacrolimus given alone, tacrolimus AUC when administered with Schisandra was consistently increased by 2.1-fold, while the increase in Cmax varied between 1.83- and 2.11-fold in the transplant studies(5-6) and 3-fold in the study on healthy subjects.(7) In the study with kidney transplant patients, a decrease in tacrolimus dose of 40.9 % was required to bring tacrolimus levels into the therapeutic range.(5)

*Patients with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease (ESRD) who are receiving concomitant therapy with a potent cytochrome P-450 (CYP) isoenzyme 3A inhibitor or inducer.

• Lactation

• Acute myocardial infarction
• Chronic hepatitis B
• Chronic hepatitis C
• Disease of liver
• Drug-induced hepatitis
• Myocardial ischemia

• Coronary artery disease
• Infection
• Orthostatic hypotension

The most common adverse effects (incidence >8%) reported in antiretroviral-experienced adults that occurred at a higher frequency compared with placebo are upper respiratory tract infections, cough, pyrexia, rash, and dizziness.

The most common adverse effects (incidence >8%) reported in treatment-naive adults that occurred at a higher frequency than the comparator(s) are upper respiratory tract infections, bronchitis, flatulence, bloating and distention, upper respiratory tract signs and symptoms, and GI atonic and hypomotility disorders.

The most common adverse effects (incidence >=3%) reported in treatment-experienced pediatric patients are vomiting, abdominal pain, diarrhea, nausea, and dizziness. In the study in neonates birth to 6 weeks of age, the most common adverse effect reported with maraviroc was decreased hemoglobin. No additional adverse reactions were observed in these neonates compared with those seen in adults.

More Frequent

• Avascular necrosis of bone
• Upper respiratory infection

Less Frequent

• Bronchospastic pulmonary disease
• Dysesthesia
• Edema
• Hyperbilirubinemia
• Increased alanine transaminase
• Increased aspartate transaminase
• Infection
• Paresthesia
• Peripheral neuropathy
• Respiration changes
• Stomatitis

Rare or Very Rare

• Abnormal hepatic function tests
• Acute decompensated heart failure
• Acute myocardial infarction
• Anemia
• Bone marrow depression
• Bronchitis
• Cerebrovascular accident
• Clostridioides difficile infection
• Coronary artery disease
• DRESS syndrome
• Endocarditis
• Eosinophilia
• Graves' disease
• Guillain-barre syndrome
• Hepatic cirrhosis
• Hepatic failure
• Hepatitis
• Hypertension
• Hypoplastic anemia
• Leukopenia
• Malignancy
• Myelodysplastic syndrome
• Myocardial ischemia
• Neoplasm
• Obstructive hyperbilirubinemia
• Pancytopenia
• Polymyositis
• Rhabdomyolysis
• Seizure disorder
• Stevens-johnson syndrome
• Thromboembolic disorder
• Toxic epidermal necrolysis
• Unstable angina pectoris

More Frequent

• Cough
• Diarrhea
• Dizziness
• Fever
• Headache disorder
• Nausea
• Skin rash

Less Frequent

• Acute abdominal pain
• Appetite changes
• Arthralgia
• Condylomata acuminata
• Conjunctivitis
• Constipation
• Depression
• Dyspepsia
• Folliculitis
• Herpes simplex infection
• Lipodystrophy
• Myalgia
• Myositis
• Pain
• Pruritus of skin
• Sinusitis
• Skin inflammation
• Sleep disorder
• Syncope

Rare or Very Rare

• Altered consciousness
• Basal cell carcinoma of skin
• Dysphagia
• Erythema
• Facial palsy
• Hyperlipidemia
• Lymphadenopathy
• Nasal congestion
• Orthostatic hypotension
• Otitis
• Symptoms of anxiety
• Tremor
• Visual field defect

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The safety and efficacy of maraviroc have been established in pediatric patients from birth to <18 years of age. The use of maraviroc in pediatric patients was supported by pharmacokinetic and safety data in pediatric patients and by previous demonstration of efficacy in adult patients.

A multicenter clinical trial evaluated the safety, antiviral activity, and pharmacokinetics of maraviroc in treatment-experienced, CCR5-tropic, HIV-1-infected pediatric patients 2 to <18 years of age weighing >=10 kg. The pharmacokinetics of maraviroc in those receiving potent CYP3A inhibitors (with or without a potent CYP3A inducer) were similar to those observed in adults. There are limited clinical pharmacokinetic data in pediatric patients 2 to <18 years of age receiving noninteracting concomitant drugs. Based on population pharmacokinetic modeling and simulation, the recommended dosing regimen of maraviroc for this population is predicted to result in similar maraviroc exposures as seen in adults receiving maraviroc 300 mg twice daily with noninteracting concomitant drugs.

No clinical trials or pharmacokinetic data are available in children 6 weeks to <2 years of age. Maraviroc dosing recommendations in these patients when they are concomitantly receiving noninteracting drugs are solely based on population pharmacokinetic modeling and simulation.

A clinical trial evaluated the safety and pharmacokinetics of maraviroc in HIV-1-exposed neonates (born to HIV-1 infected mothers) who weighed >=2 kg at birth; ages ranged from birth to 6 weeks. Pharmacokinetic parameters were similar to those in adults. Exposure to maternal efavirenz in utero (for >=2 weeks immediately prior to delivery) did not have a meaningful impact on maraviroc pharmacokinetics.

There are insufficient data to make dosage recommendations for the use of maraviroc in pediatric patients weighing <10 kg and concomitantly receiving drugs that are CYP3A inhibitors, or in any pediatric patient receiving a potent CYP3A inducer (efavirenz, etravirine, rifampin, carbamazepine, phenobarbital, or phenytoin) without a potent CYP3A inhibitor.

Maraviroc is not recommended in pre-term neonates or in pediatric patients weighing <2 kg.

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to maraviroc during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.apregistry.com/.

There are limited data on the use of maraviroc in pregnant women. In animal studies, no evidence of adverse developmental outcomes was observed in rats or rabbits with maraviroc systemic exposures that were approximately 20 or 5 times higher, respectively, than systemic exposures in humans at recommended dosages.

In a study in 18 pregnant women receiving maraviroc (150 or 300 mg twice daily) in conjunction with other antiretrovirals, overall maraviroc exposures were 28-30% lower during the third trimester of pregnancy compared with postpartum exposures. Limited amounts of maraviroc were distributed across the placenta (median cord blood to maternal blood concentration ratio was 0.33).

In the clinical trial evaluating maraviroc pharmacokinetics in HIV-1-exposed neonates (born to HIV-1 infected mothers) from birth to 6 weeks of age, exposure to maternal efavirenz in utero (for >=2 weeks immediately prior to delivery) did not have a meaningful impact on maraviroc pharmacokinetics.

Maraviroc is distributed into milk in rats. It is not known whether maraviroc is distributed into human milk, affects human milk production, or affects the breast-fed infant.

In the clinical trial evaluating maraviroc pharmacokinetics in HIV-1-exposed neonates (born to HIV-1 infected mothers) from birth to 6 weeks of age, exposure to maternal efavirenz during breast-feeding did not have a meaningful impact on maraviroc pharmacokinetics.

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.

The manufacturer makes no specific dosage recommendations for maraviroc in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Experience in patients >=65 years of age is insufficient to determine whether they respond differently than younger adults.

Use maraviroc with caution in geriatric patients because of age-related decreases in hepatic and renal function and potential for concomitant disease and drug therapy.

Maraviroc pharmacokinetics have not been fully assessed in patients >=65 years of age.