Cabenuva (cabotegravir/rilpivirine)

No dosing information is available for this tab.

Cabotegravir/rilpivirine is commercially available as cabotegravir extended-release injectable suspension in a single-dose vial and rilpivirine extended-release injectable suspension in a single-dose vial copackaged for coadministration by IM administration. The injections must be administered by a healthcare provider by gluteal IM injection only; administer the IM injections at separate gluteal sites (on opposite sides or at least 2 cm apart) during the same visit. The ventrogluteal site is recommended, but a dorsogluteal approach (upper outer quadrant) is acceptable, if preferred by the healthcare professional. Do not administer by any other route or anatomical site. Consider the body mass index (BMI) of the patient to ensure that the needle length is sufficient to reach the gluteus muscle. Longer needle lengths (not included in the dosing kit) may be required for patients with higher BMI (e.g., >30 kg/m2) to ensure that injections are administered intramuscularly as opposed to subcutaneously. The administration order of cabotegravir and rilpivirine extended-release injections is not important.

Cabotegravir and rilpivirine combination therapy may be initiated with oral forms of the drugs (oral lead-in daily dose is cabotegravir 30 mg and rilpivirine 25 mg with a meal for approximately 1 month (at least 28 days)) prior to beginning the IM injections to assess tolerability or the combination therapy may be initiated directly with the injectable forms without an oral lead-in. Cabotegravir and rilpivirine extended-release suspensions can be injected monthly or every 2 months. Discuss these 2 dosing options with the patient prior to starting treatment to determine which dosing frequency is more appropriate.

Store the co-packaged cabotegravir/rilpivirine extended-release suspensions at 2-8degrees C in their original carton; do not freeze.

No dosing information is available for this tab.

No dosing information is available for this tab.

Rilpivirine is primarily metabolized by cytochrome P-450 (CYP) 3A and cabotegravir is primarily metabolized by uridine diphosphate-glucuronosyltransferases (UGT) 1A1 with some contribution from UGT1A9.

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)

Cabotegravir-Rilpivirine/Strong Cyp3a4 & Ugt1a1 Inducers

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: Apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may induce the metabolism of cabotegravir-rilpivirine by CYP3A4 and uridine diphosphate (UDP)-glucuronosyl transferase 1A1 (UGT1A1).(1)

CLINICAL EFFECTS: Concurrent or recent use of apalutamide, barbiturates, carbamazepine, dexamethasone, efavirenz, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, ritonavir, or St. John's wort may result in decreased levels and effectiveness of cabotegravir-rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of cabotegravir-rilpivirine states that concurrent use of CYP3A4 inducers and/or UGT1A1 inducers is contraindicated.(1) It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)

DISCUSSION: In a study in 16 subjects, rifampin (600 mg daily) decreased the concentration maximum (Cmax), area-under-curve (AUC), and concentration minimum (Cmin) of rilpivirine (150 mg daily) by 69%, 80%, and 89%, respectively. There were no significant effects on the Cmax or AUC of rifampin or 25-desacetylrifampin.(1) In a study in 15 subjects, rifampin (600 mg daily) decreased the Cmax, AUC, and Cmin of cabotegravir by 6%, 59%, and 50%, respectively.(1) Strong CYP3A4 inducers linked include: apalutamide, barbiturates, carbamazepine, dexamethasone, encorafenib, enzalutamide, eslicarbazepine, fosphenytoin, ivosidenib, lumacaftor, mitotane, natisedine, oxcarbazepine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, or St. John's wort.(1,2) UGT1A1 inducers linked include: carbamazepine, efavirenz, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone, rifapentine, rifampin, and ritonavir.(1,2)

Nnrtis/Cobicistat-Elvitegravir

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: Cobicistat inhibits CYP2D6, CYP3A4, BCRP, OATP1B1 and OATP1B3. Elvitegravir induces CYP2C9. Efavirenz may induce the metabolism of cobicistat via CYP3A4.(1)

CLINICAL EFFECTS: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors (NNRTIs) may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The combination product containing cobicistat-elvitegravir-emtricitabine-tenofovir should not be used with non-nucleoside reverse transcriptase inhibitors.(1)

DISCUSSION: Concurrent use of cobicistat-elvitegravir with non-nucleoside reverse transcriptase inhibitors may result in altered and/or suboptimal pharmacokinetics of cobicistat, elvitegravir, and/or the NNRTI.(1)

Oat3 Inhibitors/Ketorolac

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: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal clearance of ketorolac.

CLINICAL EFFECTS: Enhanced ketorolac toxicity including gastrointestinal and renal toxicity as well as increased risk of bleeding.

PREDISPOSING FACTORS: The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Concomitant administration of ketorolac and organic anion transporter 3 (OAT3) inhibitors are contraindicated by the manufacturer. If concurrent therapy is deemed medically necessary, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling.

DISCUSSION: Probenecid has been reported to increase serum concentrations and toxicity of nonsteroidal anti-inflammatory drugs (e.g., indomethacin, ketoprofen, naproxen).(1-3) Based upon material from the manufacturer of ketorolac, concurrent administration of probenecid and ketorolac also increases serum concentrations of the NSAID ketorolac and produces a 2-fold increase in the half-life of ketorolac and a 3-fold increase in the area under the plasma concentration-time curve.(4) Ketorolac is a potent NSAID analgesic and increasing the serum concentrations may increase the risk of occurrence of serious renal, GI and hematologic side effects. OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(5)

Oat3 Inhibitors/Sodium Phenylbutyrate-Taurursodiol

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: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of conjugated sodium phenylbutyrate and sodium phenylbutyrate metabolites.(1,2)

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of sodium phenylbutyrate.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium phenylbutyrate-taurursodiol (sodium phenylbutyrate-ursodoxicoltaurine) states that concurrent use with organic anion transporter 3 (OAT3) inhibitors should be avoided.(1) The Canadian manufacturer of sodium phenylbutyrate-taurursodiol states that OAT3 inhibitors should not be used with sodium phenylbutyrate-taurursodiol.(2)

DISCUSSION: Probenecid may inhibit the renal elimination of conjugated sodium phenylbutyrate and sodium phenylbutyrate metabolites.(1,2) OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(3)

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)

Oat1 And Oat3 Inhibitors/Selected Carbapenem Antibiotics

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

MECHANISM OF ACTION: Inhibitors of organic anion transporter 1 (OAT1) and organic anion transporter 3 (OAT3) may inhibit the renal excretion of doripenem(1), meropenem(2), and tebipenem(3) by competing with them for active tubular secretion.

CLINICAL EFFECTS: Concurrent use of OAT1 and OAT3 inhibitors may result in elevated levels of and toxicity from doripenem(1), meropenem(2) or tebipenem.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of doripenem states that concurrent use of OAT1 and OAT3 inhibitors is not recommended.(1) The US manufacturer of meropenem states that concurrent use of OAT1 and OAT3 inhibitors is not recommended.(2) The US manufacturer of tebipenem states concurrent use of tebipenem and OAT1 and OAT3 inhibitors is generally not recommended. If concurrent use with tebipenem is necessary, monitor more frequently for adverse reactions associated with tebipenem, such as diarrhea and headache.(3)

DISCUSSION: Probenecid has been shown to increase doripenem half-life (T1/2) and area-under-curve (AUC) by 53% and 75%, respectively.(1) In a study in six subjects, concurrent probenecid increased meropenem T1/2 by 33%.(4) Other studies have shown probenecid to increase the T1/2 of meropenem by 38% and the extent of meropenem systemic exposure by 58%.(2) In a study, coadministration of a single oral dose of 250 mg of tebipenem pivoxil with probenecid (OAT1 and OAT3 inhibitor) increased tebipenem maximum concentration (Cmax) by approximately 1.5-fold and plasma area-under-curve (AUC) by approximately 2.9-fold.(3) OAT1 inhibitors linked to this monograph include: cabotegravir and probenecid. OAT3 inhibitors linked to this monograph include: cabotegravir, leflunomide, nitisinone, probenecid, teriflunomide, and vadadustat.(5)

Oat3 Inhibitors/Baricitinib

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

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of baricitinib.(1,2)

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of baricitinib.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If concurrent therapy with a strong organic anion transporter 3 (OAT3) inhibitor is warranted, and the recommended dosage is 4 mg once daily, reduce to 2 mg once daily. If the recommended dosage is 2 mg once daily, reduce dose to 1 mg once daily. If the recommended dosage is 1 mg once daily, consider discontinuing probenecid.(2) OAT3 inhibitors with less inhibitor potency are not expected to cause a clinically significant change in baricitinib levels.(1,2)

DISCUSSION: In a clinical pharmacology study, dosing of probenecid (an OAT3 inhibitor with strong inhibition potential) resulted in approximately a 2-fold increase in area-under-curve (AUC) with no change in time maximum (Tmax) or concentration maximum (Cmax) of baricitinib.(1,2) OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid and vadadustat.(1-3)

Oat3 Inhibitors/Methotrexate(ONCOLOGY-INJ)

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

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of methotrexate.

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: If coadministration cannot be avoided, monitor closely for methotrexate adverse reactions.

DISCUSSION: Concomitant administration of methotrexate and probenecid has been shown to increase methotrexate plasma levels two to four times higher than when methotrexate is administered alone.(2-5) OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid and vadadustat.(7)

Oat3 Inhibitors/Pemetrexed

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

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of pemetrexed.

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of pemetrexed, including myelosuppression, neutropenia, renal toxicity, and gastrointestinal toxicity.

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with mild to moderate renal function insufficiency (creatinine clearance (CrCl) of 45 ml/min to 79 ml/min).

PATIENT MANAGEMENT: Avoid concomitant administration of OAT3 inhibitors before and after administration of pemetrexed when possible. If concomitant administration cannot be avoided, monitor patients more frequently for myelosuppression, renal, and gastrointestinal toxicity.

DISCUSSION: In patients with normal renal function, ibuprofen (400 mg 4 times daily) decreased the clearance of pemetrexed by 20% and increased its area-under-curve (AUC) by 20%.(1) In two randomized, controlled cross-over trials, 27 cancer patients with a creatinine clearance (CrCl) less than or equal to 60 ml/min received pemetrexed (500 mg/m2) infusion on Day 1 of a 21-day cycle and either aspirin 325 mg or ibuprofen 400 mg orally every 6 hours starting 2 days before pemetrexed administration. Ibuprofen decreased the clearance of pemetrexed by 16%, increased its maximum concentration (Cmax) by 15%, and increased the AUC by 20%.(2) OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid, and vadadustat.(3)

Selected Protease Inhibitors And Nnrtis/Garlic

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

MECHANISM OF ACTION: The exact mechanism is unknown. Garlic may induce the metabolism of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs) by CYP3A4. P-glycoproteins may also be involved.(1,2)

CLINICAL EFFECTS: Concurrent use of garlic and a protease inhibitor or NNRTI may result in decreased levels and effectiveness of the protease inhibitor or NNRTI therapy.(2-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking a protease inhibitor or NNRTI should avoid taking garlic supplements. Garlic from food sources is not likely to cause a problem, although there may be some concern if patients are ingesting a large quantity of garlic on a regular basis.

DISCUSSION: A study in nine HIV-negative subjects examined the effects of the concurrent use of a garlic supplement (taken twice daily) on saquinavir (1200 mg twice daily). Concurrent use resulted in a decrease in saquinavir area-under-curve (AUC), maximum concentration (Cmax), and trough concentration (Cmin) by 51%, 49%, and 54%, respectively, when compared to the administration of saquinavir alone. Following a garlic washout period, saquinavir levels only returned to 60-70% of baseline.(2) In a study in 10 healthy subjects, the administration of garlic (10 mg twice daily) for four days had no significant effects on a single dose of ritonavir (400 mg). Ritonavir AUC and Cmax decreased by 17% and by 25%, respectively. However, the authors cautioned that their results should not be extrapolated to steady-state conditions.(4)

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

Oat3 Inhibitors/Methotrexate (LOW STRENGTH INJ, ORAL)

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

MECHANISM OF ACTION: Inhibitors of organic anion transporter 3 (OAT3) may inhibit the renal elimination of methotrexate.

CLINICAL EFFECTS: Concurrent use of organic anion transporter 3 (OAT3) inhibitors may result in an increase in both the therapeutic and toxic effects of methotrexate, leading to increased risk of severe neurotoxicity, stomatitis, and myelosuppression, including neutropenia.

PREDISPOSING FACTORS: Risk factors for methotrexate toxicity include: - High-dose oncology regimens - Impaired renal function, ascites, or pleural effusions

PATIENT MANAGEMENT: If concurrent use cannot be avoided, monitor methotrexate blood levels closely and adjust the dose accordingly.

DISCUSSION: Concomitant administration of methotrexate and probenecid has been shown to increase methotrexate plasma levels two to four times higher than when methotrexate is administered alone. OAT3 inhibitors linked to this monograph include: cabotegravir, nitisinone, probenecid and vadadustat.(7)

Rilpivirine/Ombitasvir-Paritaprevir-Ritonavir

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

MECHANISM OF ACTION: Ombitasvir-paritaprevir-ritonavir may inhibit the CYP3A4 mediated metabolism of rilpivirine leading to increased systemic exposure (area-under-curve, AUC).(1)

CLINICAL EFFECTS: Increased exposure to rilpivirine may result in toxicity, including potentially life-threatening cardiac arrhythmias, such as torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, advanced age or when receiving concomitant treatment with additional inhibitors of CYP3A4.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose, or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The concurrent use of rilpivirine with ombitasvir-paritaprevir-ritonavir is not recommended due to the potential risk for QT prolongation.(1) Rilpivirine does not prolong the QT interval at the recommended dose of 25 mg daily. In interaction studies the combination of ombitasvir-paritaprevir-ritonavir and dasabuvir with rilpivirine (25 mg daily) increased rilpivirine exposure (AUC) approximately 3-fold (range: 2.80-3.77), similar to the exposure associated with a rilpivirine dose of 75 mg daily.(3) In rilpivirine QT studies, a 75 mg daily dose increased the QTc interval by 10.7 msec, just above the 10 msec threshold for regulatory concern.(3,4) If concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a clinical trial in healthy adults, rilpivirine at recommended dosages (25 mg daily) had no significant effects on the QTc interval. However, supratherapeutic dosages (75 mg daily and 300 mg daily) increased the QTc interval by 10.7 msec and 23.3 msec, respectively. Rilpivirine dosages of 75 mg daily and 300 mg daily resulted in rilpivirine maximum concentration (Cmax) levels of 2.6-fold and 6.7-respectively.(4)

Rilpivirine/Selected Moderate Cyp3a4 Inducers

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

MECHANISM OF ACTION: Moderate CYP3A4 inducers may induce the metabolism of rilpivirine.(1)

CLINICAL EFFECTS: Concurrent or recent use of moderate CYP3A4 inducers may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US DHHS HIV guidelines state that concurrent use of bosentan or mavacamten (moderate CYP3A4 inducers) with oral or intramuscular rilpivirine should be monitored closely. Consider alternative therapies that do not affect CYP3A4 or alternative antiretroviral agents. If concurrent use is necessary, virologic response should be monitored.(2) The US manufacturer of oral rilpivirine states that concurrent use of rifabutin (moderate CYP3A4 inducer) warrants dose adjustment. When administering moderate CYP3A4 inducers with oral rilpivirine, increase the dose of rilpivirine to 50 mg once daily. When rifabutin co-administration is stopped, the rilpivirine dose should be decreased to 25 mg once daily. It may take several weeks after the discontinuation of an enzyme inducer for enzyme activity to return to normal.(1)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily) decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine. (1) Selected moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, elagolix, eslicarbazepine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine and tovorafenib.(3)

Rilpivirine/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 rilpivirine by CYP3A4.(1-4)

CLINICAL EFFECTS: Concurrent or recent use of tecovirimat may result in decreased levels and effectiveness of rilpivirine, as well as the development of resistance.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Coadministration of rilpivirine with tecovirimat should be approached with caution. Consider increasing rilpivirine to 50 mg daily during treatment with tecovirimat and for approximately 2 weeks after the end of treatment.(1-4)

DISCUSSION: In a study in 18 subjects, rifabutin (300 mg daily), a moderate CYP3A4 inducer, decreased the maximum concentration (Cmax), area-under-curve (AUC), and minimum concentration (Cmin) of rilpivirine (25 mg orally daily) by 31%, 42%, and 48%, respectively.(1) A study in 18 subjects compared rilpivirine administered alone (25 mg orally daily) to coadministration with rifabutin (300 mg daily) and rilpivirine (50 mg orally daily). A significant difference was not found with the Cmax (1.43), AUC (1.16), or Cmin (0.93) of rilpivirine.(1) In a pharmacokinetic study, tecovirimat decreased the Cmax and AUC of midazolam by 39% and 32%, respectively.(2-3)

*Previous hypersensitivity reaction to cabotegravir or rilpivirine.

*Coadministration with drugs for which significant decreases in cabotegravir plasma concentrations may occur due to uridine diphosphate glucuronosyl transferase (UGT)1A1 enzyme induction and/or cytochrome P-450 (CYP) 3A enzyme induction, which may result in loss of virologic response (e.g., anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antimycobacterials (rifampin, rifabutin, rifapentine), systemic glucocorticoids (dexamethasone; more than a single dose treatment), and herbal products (St John's wort)).

There are no contraindication contraindications for this drug.

• Depression
• Disease of liver
• Suicidal ideation

• Chronic kidney disease stage 4 (severe) GFR 15-29 ml/min
• Chronic kidney disease stage 5 (failure) GFr<15 ml/min
• Disease of liver
• Viral hepatitis

The most common adverse reactions observed in >=2% of subjects receiving cabotegravir/rilpivirine were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

Rare or Very Rare

• Abnormal hepatic function tests
• Abnormal hepatic function tests
• Angioedema
• Angioedema
• Autoimmune hepatitis
• Biliary calculus
• Blistering skin
• Bronchospastic pulmonary disease
• Cholecystitis
• Conjunctivitis
• DRESS syndrome
• DRESS syndrome
• Dyspnea
• Eosinophilia
• Facial edema
• Glomerulonephritis
• Graves' disease
• Guillain-barre syndrome
• Hypersensitivity drug reaction
• Hypersensitivity drug reaction
• Increased alanine transaminase
• Increased aspartate transaminase
• Kidney stone
• Nephrotic syndrome
• Nephrotic syndrome
• Polymyositis
• Stevens-johnson syndrome
• Stomatitis
• Suicidal
• Suicidal
• Suicidal ideation
• Suicidal ideation
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Back pain
• Diarrhea
• Dizziness
• Dream disorder
• Drowsy
• Fatigue
• Headache disorder
• Headache disorder
• Injection site sequelae
• Injection site sequelae
• Insomnia
• Insomnia
• Musculoskeletal pain
• Musculoskeletal pain
• Nausea
• Skin rash
• Skin rash
• Sleep disorder
• Symptoms of anxiety
• Upper respiratory infection

Less Frequent

• Anorexia
• Diarrhea
• Dizziness
• Dream disorder
• Fatigue
• Fever
• Fever
• Flatulence
• Nausea
• Pruritus of skin
• Vomiting
• Vomiting

Rare or Very Rare

• Acute abdominal pain
• Agitation
• Allergic conjunctivitis
• Anorexia
• Depression
• Depression
• Drowsy
• Drug fever
• Eosinophilia
• General weakness
• Hypercholesterolemia
• Hypertriglyceridemia
• Mood changes
• Myalgia
• Oral hypoesthesia
• Sleep disorder
• Stomatitis
• Symptoms of anxiety
• Urticaria
• Urticaria
• Weight gain
• Weight gain

No enhanced messaging available.

Safety and effectiveness of cabotegravir/rilpivirine have been established in pediatric patients 12 to younger than 18 years of age and weighing at least 35 kg.

Efficacy and safety of cabotegravir/rilpivirine in HIV-1-infected patients as a complete regimen including oral lead-in therapy were established in 3 adult clinical studies (FLAIR, ATLAS, ATLAS-2M) and an adolescent clinical study (MOCHA).

Safety, tolerability, and pharmacokinetics of oral and injectable cabotegravir and oral and injectable rilpivirine in adolescent patients are being assessed in an ongoing Phase 1/2, open-label, non-comparative study (MOCHA). The primary objective of this study at week 16 was to confirm the use of the adult dose, through the evaluation of safety and pharmacokinetics, for oral and injectable cabotegravir and injectable rilpivirine in 23 HIV-1-infected virologically suppressed patients 12 to younger than 18 years of age and weighing at least 35 kg. Patients were assigned to 1 of 2 cohorts, 1C or 1R, based on their background antiretroviral regimen. In cohort 1C, 8 patients received cabotegravir 30 mg daily for 1 month, followed by monthly cabotegravir injections (Month 1: 600 mg injection, Months 2 and 3: 400 mg injection) for an additional 3 months, while continuing background antiretroviral therapy. In cohort 1R, 15 patients received rilpivirine 25 mg daily for 1 month, followed by monthly rilpivirine injections (Month 1: 900 mg injection, Months 2 and 3: 600 mg injection) for an additional 3 months, while continuing background antiretroviral therapy. The safety of cabotegravir and rilpivirine injections in patients 12 to younger than 18 years of age and weighing at least 35 kg is expected to be similar to adults, as there was no clinically significant difference in drug exposure for the components of cabotegravir and rilpivirine extended-release injection. The efficacy of cabotegravir and rilpivirine injections in patients 12 to younger than 18 years of age and weighing at least 35 kg is extrapolated from adults with support from pharmacokinetic analyses showing similar drug exposure.

The safety, efficacy, and pharmacokinetics of the combined regimen of cabotegravir and rilpivirine extended-release injection have not been established in pediatric patients <12 years of age or weighing <35 kg.

Antiretroviral Pregnancy Registry at 800-258-4263 or https://www.apregistry.com.

The manufacturer states that data are insufficient on the use of cabotegravir/rilpivirine during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. Healthcare professionals should discuss the risks and benefits of using cabotegravir and rilpivirine extended-release injection with individuals of childbearing potential or during pregnancy.

The Health and Human Services Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that data are not available regarding use of cabotegravir for the treatment of HIV-1 infection during pregnancy and, therefore it is not recommended as a complete treatment regimen in pregnant females or females of reproductive potential trying to conceive. The Panel recommends that pregnant individuals who present to care on this regimen should be switched to an appropriate 3-drug antiretroviral regimen recommended for use in pregnancy.

Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on cabotegravir and rilpivirine extended-release injection during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to >=12 months after discontinuing injections of cabotegravir and rilpivirine injection; therefore, consideration should be given to the potential for fetal exposure during pregnancy.

Rilpivirine is present in human milk. There are no data on the presence of cabotegravir in human milk; however, cabotegravir is present in animal milk. When a drug is present in animal milk, it is likely present in human milk. If cabotegravir and/or rilpivirine are present in human milk, residual exposures may remain for >=12 months after the last injections have been administered. It is unknown if cabotegravir and rilpivirine affect milk production or have effects on the breastfed infant.

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.

Use caution when administering cabotegravir/rilpivirine in elderly patients.

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

Cabotegravir/rilpivirine should be used with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.