EDURANT (Page 3 of 9)

6.2 Postmarketing Experience

Adverse reactions have been identified during postmarketing experience in patients receiving a rilpivirine containing regimen. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Renal and Genitourinary Disorders: nephrotic syndrome

Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

7 DRUG INTERACTIONS

[see Dosage and Administration (2), Contraindications (4) and Clinical Pharmacology (12.3).]

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of EDURANT and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.

EDURANT at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.

Table 5 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of EDURANT and/or coadministered drug may be recommended. Drugs that are not recommended for coadministration with EDURANT are also included in Table 5.

Table 5: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see Clinical Pharmacology (12.3)]
Concomitant Drug Class: Drug Name Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
*
The interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted.
This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of EDURANT 25 mg once daily.
Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) The combination of EDURANT and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after EDURANT.
↓ rilpivirine (concomitant intake)
Anticonvulsants: carbamazepineoxcarbazepinephenobarbitalphenytoin ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4)].
Antimycobacterials: rifampinrifapentine ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4)].
Antimycobacterials: rifabutin * ↓ rilpivirine Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout coadministration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily.
Azole Antifungal Agents: fluconazoleitraconazoleketoconazole *posaconazolevoriconazole ↑ rilpivirine↓ ketoconazole Concomitant use of EDURANT with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when EDURANT is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with EDURANT.
Glucocorticoid (systemic): dexamethasone(more than a single-dose treatment) ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4)].
H2-Receptor Antagonists: cimetidinefamotidine *nizatidineranitidine ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) The combination of EDURANT and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT.
↓ rilpivirine (famotidine taken 2 hours before rilpivirine)
Herbal Products: St John’s wort (Hypericum perforatum) ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4)].
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI (delavirdine) ↑ rilpivirine↔ delavirdine It is not recommended to coadminister EDURANT with delavirdine and other NNRTIs.
Other NNRTIs(efavirenz, etravirine, nevirapine) ↓ rilpivirine↔ other NNRTIs
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine * ↔ rilpivirine↔ didanosine No dose adjustment is required when EDURANT is coadministered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT (which should be administered with a meal).
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with coadministration of low-dose ritonavir) or Unboosted (i.e., without coadministration of low-dose ritonavir)
darunavir/ritonavir * ↑ rilpivirine↔ boosted darunavir Concomitant use of EDURANT with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is coadministered with darunavir/ritonavir.
lopinavir/ritonavir * ↑ rilpivirine↔ boosted lopinavir Concomitant use of EDURANT with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT is coadministered with lopinavir/ritonavir.
other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) ↑ rilpivirine↔ boosted PI Concomitant use of EDURANT with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of coadministered PIs.
unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) ↑ rilpivirine↔ unboosted PI Concomitant use of EDURANT with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT is not expected to affect the plasma concentrations of coadministered PIs.
Macrolide or ketolide antibiotics: azithromycinclarithromycinerythromycin ↑ rilpivirine↔ azithromycin↔ clarithromycin↔ erythromycin Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [Warnings and Precautions (5.4)]. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides.
Narcotic Analgesics: methadone * ↓ R(-) methadone↓ S(+) methadone No dose adjustments are required when initiating coadministration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
Proton Pump Inhibitors: e.g., esomeprazolelansoprazoleomeprazolepantoprazolerabeprazole ↓Rilpivirine Coadministration is contraindicated with EDURANT [see Contraindications (4)].

In addition to the drugs included in Table 5, the interaction between EDURANT and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3)]: acetaminophen, atorvastatin, chlorzoxazone, cabotegravir, ethinylestradiol, norethindrone, raltegravir, sildenafil, simeprevir and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when EDURANT is coadministered with maraviroc, ribavirin or the NRTIs abacavir, emtricitabine, lamivudine, stavudine and zidovudine.

QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, 75 mg once daily and 300 mg once daily (3 times and 12 times the dose in EDURANT) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology (12.2)]. Consider alternatives to EDURANT when coadministered with a drug with a known risk of torsade de pointes.

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