FOSTEMSAVIR TROMETHAMINE Drug Interactions: What You Need to Know

INTERACTIONS

• See full prescribing information for complete list of significant drug interactions. ( 4 , 7 )
• Doses of oral contraceptives should not contain more than 30 mcg of ethinyl estradiol per day. ( 7.3 )

7.1 Potential for RUKOBIA to Affect Other Drugs Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> . When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol ( Table 3 ) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )]</span> .

7.2 Potential for Other Drugs to Affect RUKOBIA Coadministration of RUKOBIA with rifampin, a strong CYP3A4 inducer, significantly decreases temsavir plasma concentrations. The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can significantly decrease temsavir plasma concentrations which may lead to loss of virologic response <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )]</span> .

7.3 Established and Other Potentially Significant Drug Interactions Information regarding potential drug interactions with RUKOBIA is provided in Table 3 . These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )]</span> .

Table

3. Established and Other Potentially Significant Drug Interactions a ↑ = Increase; ↓ = Decrease; HCV = Hepatitis C virus. a This table is not all inclusive. b See Clinical Pharmacology ( 12.3 ) for magnitude of interaction.

Concomitant Drug

Class: Drug Name Effect on Concentration of Temsavir and/or Concomitant Drug Clinical Comment Androgen receptor inhibitor: Enzalutamide ↓Temsavir Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA [see Contraindications ( 4 )] . Anticonvulsants: Carbamazepine Phenytoin ↓Temsavir Antimycobacterial: Rifampin b ↓Temsavir Antineoplastic: Mitotane ↓Temsavir Herbal product: St John’s wort ( Hypericum perforatum ) ↓Temsavir Hepatitis C virus direct-acting antivirals: Grazoprevir Voxilaprevir ↑Grazoprevir ↑Voxilaprevir Coadministration may increase exposures of grazoprevir or voxilaprevir; however, the magnitude of increase in exposure is unknown. Increased exposures of grazoprevir may increase the risk of ALT elevations. Use an alternative HCV regimen if possible. Oral contraceptive: Ethinyl estradiol b ↑Ethinyl estradiol Ethinyl estradiol daily dose should not exceed 30 mcg . Caution is advised particularly in patients with additional risk factors for thromboembolic events. Statins: Rosuvastatin b Atorvastatin Fluvastatin Pitavastatin Simvastatin ↑Rosuvastatin ↑Atorvastatin ↑Fluvastatin ↑Pitavastatin ↑Simvastatin Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.

7.4 Drugs that Prolong QT Interval Coadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 ), Clinical Pharmacology ( 12.2 )]</span> . Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes.

7.5 Drugs without Clinically Significant Interactions with RUKOBIA Based on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine, famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

RUKOBIA is contraindicated in patients:

• with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA.
• coadministered strong cytochrome P450 (CYP)3A inducers, as significant decreases in temsavir (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to [see Drug Interactions ( 7 ), Clinical Pharmacology ( 12.3 )] : o Androgen receptor inhibitor: Enzalutamide o Anticonvulsants: Carbamazepine, phenytoin o Antimycobacterial: Rifampin o Antineoplastic: Mitotane o Herbal product: St John’s wort ( Hypericum perforatum )
• Hypersensitivity to fostemsavir or any of the components of the formulation. ( 4 )
• Coadministration with strong cytochrome P450 (CYP)3A inducers as significant decreases in temsavir plasma concentrations may occur, which may result in loss of virologic response. ( 4 )

AND PRECAUTIONS

• Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapies. ( 5.1 )
• QTc prolongation: Use RUKOBIA with caution in patients with a history of QTc prolongation or with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. ( 5.2 )
• Elevations in hepatic transaminases in patients with hepatitis B (HBV) or C (HCV) virus co-infection: Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. ( 5.3 )

5.1 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

5.2 QTc Prolongation with Higher than Recommended Dosages RUKOBIA at 2,400 mg twice daily, 4 times the recommended daily dose, has been shown to significantly prolong the QTc interval of the electrocardiogram <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 ), Clinical Pharmacology ( 12.2 )]</span> . RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

5.3 Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-Infection Monitoring of liver chemistries is recommended in patients with hepatitis B (HBV) and/or C (HCV) virus co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B.

5.4 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions The concomitant use of RUKOBIA and certain other drugs may result in known or potentially significant drug interactions, some of which may lead to <span class="opacity-50 text-xs">[see Contraindications ( 4 ), Warnings and Precautions ( 5.2 ), Drug Interactions ( 7.3 ), Clinical Pharmacology ( 12.3 )]</span> :

• Loss of therapeutic effect of RUKOBIA and possible development of resistance due to reduced exposure of temsavir.
• Possible prolongation of QTc interval from increased exposure to temsavir [see Drug Interactions ( 7.4 )] .

See Table

3 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with RUKOBIA, review concomitant medications during therapy with RUKOBIA, and monitor for the adverse reactions associated with the concomitant drugs.