Edurant (Rilpivirine Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

DRUG INTERACTIONS

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

Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Co-administration 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. Co-administration of EDURANT and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Co-administration 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 4 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of EDURANT and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with EDURANT are also included in Table 4.

Table 4: 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]

Concomitant Drug Class: Drug Name	Effect on Concentration of Rilpivirine or Concomitant Drug	Clinical Comment
↑ = increase, ↓ = decrease, ↔ = no change
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
didanosine 1 2	↔ rilpivirine ↔ didanosine	No dose adjustment is required when EDURANT is co-administered 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: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
NNRTI (delavirdine)	↑ rilpivirine ↔ delavirdine	It is not recommended to co-administer EDURANT with delavirdine and other NNRTIs.
Other NNRTIs (efavirenz, etravirine, nevirapine)	↓ rilpivirine ↔ other NNRTIs
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with co-administration of low-dose ritonavir) or Unboosted (i.e., without co-administration 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 co-administered 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 co-administered 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 co-administered 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 co-administered PIs.
Other Agents
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 co-administration 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)
Antimycobacterials: rifabutin	↓ rilpivirine	Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout co-administration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin co-administration is stopped, the EDURANT dose should be decreased to 25 mg once daily.
Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole	↑ 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 co-administered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are co-administered with EDURANT.
H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine	↔ 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 co-administration 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)
Macrolide or ketolide antibiotics: clarithromycin erythromycin telithromycin	↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin	Concomitant use of EDURANT with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics: methadone	↓ R(-) methadone ↓ S(+) methadone	No dose adjustments are required when initiating co-administration of methadone with EDURANT. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

In addition to the drugs included in Table 4, 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]: acetaminophen, atorvastatin, chlorzoxazone, ethinylestradiol, norethindrone, raltegravir, sildenafil, telaprevir 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 co-administered 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, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [see Clinical Pharmacology]. EDURANT should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

OVERDOSAGE

There is no specific antidote for overdose with EDURANT. Human experience of overdose with EDURANT is limited. Treatment of overdose with EDURANT consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. Administration of activated charcoal may be used to aid in removal of unabsorbed active substance. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

CONTRAINDICATIONS

EDURANT should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to EDURANT or to the class of NNRTIs [see Drug Interactions (7) and Clinical Pharmacology]:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifampin, rifapentine
• proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
• the glucocorticoid systemic dexamethasone (more than a single dose)
• St John's wort (Hypericum perforatum)