Juluca

JULUCA is contraindicated in patients:

• •with previous hypersensitivity reaction to dolutegravir or rilpivirine
  [see Warnings and Precautions (

  5.1 Skin and Hypersensitivity Reactions

  Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials.

  Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials of rilpivirine, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects. No Grade 4 rash was reported

  [see Adverse Reactions ]

  .

  Discontinue JULUCA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including laboratory parameters with liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with JULUCA after the onset of hypersensitivity may result in a life-threatening reaction

  [see Contraindications ]

  .

  )]
  .
• •receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events
  [see Drug Interactions (

  7 DRUG INTERACTIONS

  • •Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
  • •Refer to the full prescribing information for important drug interactions with JULUCA.
  • •Drugs that induce or inhibit cytochrome P450 (CYP)3A4 or uridine diphosphate glucuronosyltransferase (UGT)1A1 may affect the plasma concentrations of the components of JULUCA.
  • •Drugs that increase gastric pH or containing polyvalent cations may decrease plasma concentrations of the components of JULUCA.
  • •Consider alternatives to prescribing JULUCA with drugs with a known risk of Torsade de Pointes.

  7.1 Concomitant Use with Other Antiretroviral Medicines

  Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended

  [see Indications and Usage ]

  . Information regarding potential drug-drug interactions with other antiretroviral medications is not provided

  [see Contraindications , Warnings and Precautions , Clinical Pharmacology ]

  .

  7.2 Potential for JULUCA to Affect Other Drugs

  Dolutegravir, a component of JULUCA, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1, thus it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin

  [see Contraindications , Drug Interactions ]

  .

  7.3 Potential for Other Drugs to Affect the Components of JULUCA

  Dolutegravir

  Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir

  [see Drug Interactions ]

  . Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.

  Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir

  [see Drug Interactions ]

  .

  Rilpivirine

  Rilpivirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine. Coadministration of JULUCA 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

  [see Contraindications , Drug Interactions ]

  . Coadministration of JULUCA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of JULUCA 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

  [see Contraindications , Drug Interactions , Clinical Pharmacology ]

  .

  QT-Prolonging Drugs:

  In healthy subjects, 75 mg once daily of rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram

  [see Clinical Pharmacology ]

  . Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes.

  7.4 Established and Other Potentially Significant Drug Interactions

  Information regarding potential drug interactions with dolutegravir and rilpivirine are provided in Table 4. These recommendations are based on either drug interaction trials of individual components or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy

  [see Contraindications , Warnings and Precautions , Clinical Pharmacology ]

  .

  Table 4. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions^a

  ↑ = Increase, ↓ = Decrease, ↔ = No change. aThis table is not all inclusive. b See Clinical Pharmacology for magnitude of interaction.
  Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
  Antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)	↓Rilpivirine	Administer JULUCA 4 hours before or 6 hours after taking antacids.
  Antiarrhythmic: Dofetilide	↑Dofetilide	Coadministration is contraindicated with JULUCA [see Contraindications ] .
  Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	↓Dolutegravir ↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  Antidiabetic: Metforminb	↑Metformin	Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of JULUCA and metformin.
  Antimycobacterials: Rifampin Rifapentine	↓Dolutegravir ↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  Antimycobacterial: Rifabutinb	↔Dolutegravir ↔Rifabutin ↓Rilpivirine	An additional rilpivirine 25-mg tablet should be taken with JULUCA once daily with a meal when rifabutin is coadministered.
  Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment)	↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  H2-receptor antagonists: Famotidine Cimetidine Nizatidine Ranitidine	↔Dolutegravir ↓Rilpivirine	JULUCA should only be administered at least 4 hours before or 12 hours after taking H2-receptor antagonists.
  Herbal product: St John’s wort ( Hypericum perforatum )	↓Dolutegravir ↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  Macrolide or ketolide antibiotics: Clarithromycin Erythromycin Telithromycin	↔Dolutegravir ↑Rilpivirine	Where possible, consider alternatives, such as azithromycin.
  Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing productsbor laxatives Sucralfate Buffered medications	↓Dolutegravir	Administer JULUCA 4 hours before or 6 hours after taking products containing polyvalent cations.
  Narcotic analgesic: Methadoneb	↔Dolutegravir ↓Methadone ↔Rilpivirine	No dose adjustments are required when starting coadministration of methadone with JULUCA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
  Oral calcium and iron supplements , including multivitamins containing calcium or ironb(non-antacid)	↓Dolutegravir	Administer JULUCA and supplements containing calcium or iron together with a meal or take JULUCA 4 hours before or 6 hours after taking these supplements.
  Potassium channel blocker: Dalfampridine	↑Dalfampridine	Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with JULUCA should be considered against the risk of seizures in these patients.
  Proton pump inhibitors: e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole	↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .

  )]
  .
• •receiving other coadministered drugs in

  Table 1. Drugs That Are Contraindicated with JULUCA

  Drug Class	Contraindicated Drugs in Class	Clinical Comment
  Antiarrhythmic	Dofetilide	Potential for serious and/or life-threatening events due to the potential for increased dofetilide plasma concentrations.
  Anticonvulsants	Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	Potential for significant decreases in rilpivirine plasma concentrations due to cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response.
  Antimycobacterials	Rifampin Rifapentine
  Glucocorticoid (systemic)	Dexamethasone (more than a single-dose treatment)
  Herbal Products	St John’s wort ( Hypericum perforatum )
  Proton Pump Inhibitors	e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole	Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response.

  that significantly decrease rilpivirine plasma concentrations
  [see Drug Interactions (

  7 DRUG INTERACTIONS

  • •Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
  • •Refer to the full prescribing information for important drug interactions with JULUCA.
  • •Drugs that induce or inhibit cytochrome P450 (CYP)3A4 or uridine diphosphate glucuronosyltransferase (UGT)1A1 may affect the plasma concentrations of the components of JULUCA.
  • •Drugs that increase gastric pH or containing polyvalent cations may decrease plasma concentrations of the components of JULUCA.
  • •Consider alternatives to prescribing JULUCA with drugs with a known risk of Torsade de Pointes.

  7.1 Concomitant Use with Other Antiretroviral Medicines

  Because JULUCA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended

  [see Indications and Usage ]

  . Information regarding potential drug-drug interactions with other antiretroviral medications is not provided

  [see Contraindications , Warnings and Precautions , Clinical Pharmacology ]

  .

  7.2 Potential for JULUCA to Affect Other Drugs

  Dolutegravir, a component of JULUCA, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1, thus it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin

  [see Contraindications , Drug Interactions ]

  .

  7.3 Potential for Other Drugs to Affect the Components of JULUCA

  Dolutegravir

  Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir

  [see Drug Interactions ]

  . Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations.

  Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir

  [see Drug Interactions ]

  .

  Rilpivirine

  Rilpivirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine. Coadministration of JULUCA 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

  [see Contraindications , Drug Interactions ]

  . Coadministration of JULUCA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of JULUCA 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

  [see Contraindications , Drug Interactions , Clinical Pharmacology ]

  .

  QT-Prolonging Drugs:

  In healthy subjects, 75 mg once daily of rilpivirine (3 times the dose in JULUCA) and 300 mg once daily (12 times the dose in JULUCA) have been shown to prolong the QTc interval of the electrocardiogram

  [see Clinical Pharmacology ]

  . Consider alternatives to JULUCA when coadministered with a drug with a known risk of Torsade de Pointes.

  7.4 Established and Other Potentially Significant Drug Interactions

  Information regarding potential drug interactions with dolutegravir and rilpivirine are provided in Table 4. These recommendations are based on either drug interaction trials of individual components or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy

  [see Contraindications , Warnings and Precautions , Clinical Pharmacology ]

  .

  Table 4. Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Trials or Predicted Interactions^a

  ↑ = Increase, ↓ = Decrease, ↔ = No change. aThis table is not all inclusive. b See Clinical Pharmacology for magnitude of interaction.
  Concomitant Drug Class: Drug Name	Effect on Concentration	Clinical Comment
  Antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate)	↓Rilpivirine	Administer JULUCA 4 hours before or 6 hours after taking antacids.
  Antiarrhythmic: Dofetilide	↑Dofetilide	Coadministration is contraindicated with JULUCA [see Contraindications ] .
  Anticonvulsants: Carbamazepine Oxcarbazepine Phenobarbital Phenytoin	↓Dolutegravir ↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  Antidiabetic: Metforminb	↑Metformin	Refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of JULUCA and metformin.
  Antimycobacterials: Rifampin Rifapentine	↓Dolutegravir ↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  Antimycobacterial: Rifabutinb	↔Dolutegravir ↔Rifabutin ↓Rilpivirine	An additional rilpivirine 25-mg tablet should be taken with JULUCA once daily with a meal when rifabutin is coadministered.
  Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment)	↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  H2-receptor antagonists: Famotidine Cimetidine Nizatidine Ranitidine	↔Dolutegravir ↓Rilpivirine	JULUCA should only be administered at least 4 hours before or 12 hours after taking H2-receptor antagonists.
  Herbal product: St John’s wort ( Hypericum perforatum )	↓Dolutegravir ↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .
  Macrolide or ketolide antibiotics: Clarithromycin Erythromycin Telithromycin	↔Dolutegravir ↑Rilpivirine	Where possible, consider alternatives, such as azithromycin.
  Medications containing polyvalent cations (e.g., Mg or Al): Cation-containing productsbor laxatives Sucralfate Buffered medications	↓Dolutegravir	Administer JULUCA 4 hours before or 6 hours after taking products containing polyvalent cations.
  Narcotic analgesic: Methadoneb	↔Dolutegravir ↓Methadone ↔Rilpivirine	No dose adjustments are required when starting coadministration of methadone with JULUCA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.
  Oral calcium and iron supplements , including multivitamins containing calcium or ironb(non-antacid)	↓Dolutegravir	Administer JULUCA and supplements containing calcium or iron together with a meal or take JULUCA 4 hours before or 6 hours after taking these supplements.
  Potassium channel blocker: Dalfampridine	↑Dalfampridine	Elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with JULUCA should be considered against the risk of seizures in these patients.
  Proton pump inhibitors: e.g., Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole	↓Rilpivirine	Coadministration is contraindicated with JULUCA due to decreased rilpivirine concentrations [see Contraindications ] .

  ), Clinical Pharmacology (

  12.3 Pharmacokinetics

  Absorption, Distribution, Metabolism, and Excretion

  The pharmacokinetic (PK) properties of the components of JULUCA are provided in Table 5. The multiple-dose pharmacokinetic parameters are provided in Table 6.

  Table 5. Pharmacokinetic Properties of the Components of JULUCA

  UGT = uridine diphosphate glucuronosyltransferase; CYP = Cytochrome P450.
  aGeometric mean ratio (fed/fasted) in PK parameters and (90% confidence interval). High-calorie/high-fat meal = ~900 kcal, 56% fat. Moderate-fat meal = ~625 kcal, 32% fat. When rilpivirine was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal. bDosing in mass balance studies: single-dose administration of [14C] dolutegravir or [14C] rilpivirine.
  	Dolutegravir	Rilpivirine
  Absorption
  Tmax(h)	3	4
  Effect of moderate-fat meal (relative to fasting)a	AUC Ratio 1.87 (1.54, 2.26)	AUC Ratio 1.57 (1.24, 1.98)
  Effect of high-fat meal (relative to fasting)a	AUC Ratio 1.87 (1.53, 2.29)	AUC Ratio 1.72 (1.36, 2.16)
  Distribution
  % Bound to human plasma proteins	~99	~99
  Source of protein binding data	in vitro	in vitro
  Blood-to-plasma ratio	0.5	0.7
  Metabolism
  Primarily metabolized	UGT1A1 CYP3A (minor)	CYP3A
  Elimination
  Major route of elimination	Metabolism	Metabolism
  t1/2(h)	14	50
  % of dose excreted as total14C (unchanged drug) in urineb	31 (<1)	6.5 (<1)
  % of dose excreted as total14C (unchanged drug) in fecesb	64 (53)	85 (25)

  Table 6. Multiple-Dose Pharmacokinetic Properties of the Components of JULUCA

  aBased on population pharmacokinetic analyses using pooled data from ART treatment-naïve adults receiving 50 mg dolutegravir once daily or 25 mg rilpivirine once daily. bObserved Cmaxin a pharmacokinetic substudy in ART treatment-naïve adults receiving 25 mg rilpivirine once daily.
  Parameter Mean (CV%)	Dolutegravir a	Rilpivirine a
  Cmax(mcg/mL)	3.67 (20)	0.13 (54)b
  AUCtau(mcg/h/mL)	53.6 (27)	2.2 (38)
  Ctrough(mcg/mL)	1.11 (46)	0.08 (44)

  Specific Populations

  Pediatric Patients:

  The pharmacokinetics of dolutegravir plus rilpivirine has not been studied in pediatric subjects

  [see Use in Specific Populations ]

  .

  Geriatric Patients:

  Population pharmacokinetic analyses from studies with the individual components indicated age had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine. Pharmacokinetic data in subjects 65 years of age and older are limited

  [see Use in Specific Populations ]

  .

  Patients with Renal Impairment:

  Population pharmacokinetic analyses indicated that mild and moderate renal impairment had no clinically relevant effect on the exposure of dolutegravir. Dolutegravir AUC, C_max, and C₂₄were lower by 40%, 23%, and 43%, respectively, in subjects (n = 8) with severe renal impairment (creatinine clearance less than 30 mL/min) as compared with matched healthy controls. There is inadequate information to recommend appropriate dosing of dolutegravir in patients requiring dialysis

  [see Use in Specific Populations ]

  .

  Population pharmacokinetic analyses indicated that mild renal impairment had no clinically relevant effect on the exposure of rilpivirine. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment, end-stage renal disease, or patients requiring dialysis.

  Patients with Hepatic Impairment:

  Dolutegravir exposures were similar in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) as compared with matched healthy controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir has not been studied.

  Rilpivirine exposure was 47% higher in subjects (n = 8) with mild hepatic impairment (Child-Pugh Score A) and 5% higher in subjects (n = 8) with moderate hepatic impairment (Child-Pugh Score B) compared with matched controls. The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of rilpivirine has not been studied

  [see Use in Specific Populations ]

  .

  Patients with HBV/HCV Co-infection:

  Population pharmacokinetic analyses indicated that hepatitis C virus co-infection had no clinically relevant effect on the exposure of dolutegravir or rilpivirine. Subjects with hepatitis B co-infection were excluded from studies with dolutegravir plus rilpivirine.

  Gender and Race:

  Population pharmacokinetic analyses from studies with the individual components revealed that gender and race had no clinically relevant effect on the pharmacokinetics of dolutegravir or rilpivirine.

  Pregnancy and Postpartum: Rilpivirine:

  The exposure (C_0hand AUC_24h) to total rilpivirine after taking rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30% to 40% lower during pregnancy (similar for the second and third trimesters) compared with postpartum (see Table 7). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of rilpivirine-containing regimens. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.

  Table 7. Pharmacokinetic Results of Rilpivirine during the 2nd and 3rd Trimesters of Pregnancy and Postpartum Period^a

  aTotal rilpivirine exposure after administration of rilpivirine 25 mg once daily as part of an antiretroviral regimen.
  Pharmacokinetics of Total Rilpivirine (mean ± SD)	Postpartum (6 to 12 Weeks) (n = 11)	2nd Trimester of Pregnancy (n = 15)	3rd Trimester of Pregnancy (n = 13)
  C0h(ng/mL)	111 ± 69.2	65.0 ± 23.9	63.5 ± 26.2
  Cmin(ng/mL)	84.0 ± 58.8	54.3 ± 25.8	52.9 ± 24.4
  Cmax(ng/mL)	167 ± 101	121 ±45.9	123 ± 47.5
  Tmax(h), median (range)	4.00 (2.03-25.08)	4.00 (1.00-9.00)	4.00 (2.00-24.93)
  AUC24h(ng•h/mL)	2,714 ± 1,535	1,792 ± 711	1,762 ± 662

  Drug Interaction Studies

  Drug interaction trials were conducted with dolutegravir or rilpivirine as individual components and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. In vitro, dolutegravir did not inhibit (IC₅₀greater than 50 microM) the following: CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A, UGT1A1, UGT2B7, P‑gp, BCRP, bile salt export pump (BSEP), organic anion transporter polypeptide (OATP)1B1, OATP1B3, OCT1, multidrug resistance protein (MRP)2, or MRP4. In vitro, dolutegravir did not induce CYP1A2, CYP2B6, or CYP3A4.

  In vitro, dolutegravir inhibited the renal OCT2 (IC₅₀= 1.93 microM) and MATE1 (IC₅₀= 6.34 microM). In vivo, dolutegravir inhibits tubular secretion of creatinine by inhibiting OCT2 and potentially MATE1. Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin

  [see Contraindications , Drug Interactions ]

  .

  In vitro, dolutegravir inhibited the basolateral renal transporters, organic anion transporter (OAT)1 (IC₅₀= 2.12 microM) and OAT3 (IC₅₀= 1.97 microM). However, in vivo, dolutegravir did not alter the plasma concentrations of tenofovir or para-amino hippurate, substrates of OAT1 and OAT3.

  Dolutegravir is metabolized by UGT1A1 with some contribution from CYP3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, BCRP, and P-gp in vitro. In vitro, dolutegravir was not a substrate of OATP1B1 or OATP1B3.

  Rilpivirine is primarily metabolized by CYP3A. Rilpivirine 25 mg once daily is not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.

  Dosing recommendations as a result of established and other potentially significant drug-drug interactions with dolutegravir or rilpivirine are provided in Table 4

  [see Drug Interactions ]

  .

  Table 8. Summary of Effect of Dolutegravir on the Pharmacokinetics of Coadministered Drugs

  aThe number of subjects represents the maximum number of subjects that were evaluated.
  Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Geometric Mean Ratio (90% CI) of Pharmacokinetic Parameters of Coadministered Drug with/without Dolutegravir No Effect = 1.00
  			Cmax	AUC	Cτor C24
  Ethinyl estradiol 0.035 mg	50 mg twice daily	15	0.99 (0.91 to 1.08)	1.03 (0.96 to 1.11)	1.02 (0.93 to 1.11)
  Metformin 500 mg twice daily	50 mg once daily	15a	1.66 (1.53 to 1.81)	1.79 (1.65 to 1.93)	_
  Metformin 500 mg twice daily	50 mg twice daily	15a	2.11 (1.91 to 2.33)	2.45 (2.25 to 2.66)	_
  Methadone 16 to 150 mg	50 mg twice daily	11	1.00 (0. 94 to 1.06)	0.98 (0.91 to 1.06)	0.99 (0.91 to 1.07)
  Midazolam 3 mg	25 mg once daily	10	_	0.95 (0.79 to 1.15)	_
  Norelgestromin 0.25 mg	50 mg twice daily	15	0.89 (0.82 to 0.97)	0.98 (0.91 to 1.04)	0.93 (0.85 to 1.03)

  Table 9. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Dolutegravir

  aComparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg twice daily. bComparison is rifampin taken with dolutegravir 50 mg twice daily compared with dolutegravir 50 mg once daily. cThe number of subjects represents the maximum number of subjects that were evaluated.
  Coadministered Drug(s) and Dose(s)	Dose of Dolutegravir	n	Geometric Mean Ratio (90% CI) of Dolutegravir Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
  			Cmax	AUC	Cτor C24
  Antacid (MAALOX) simultaneous administration	50 mg single dose	16	0.28 (0.23 to 0.33)	0.26 (0.22 to 0.32)	0.26 (0.21 to 0.31)
  Antacid (MAALOX) 2 h after dolutegravir	50 mg single dose	16	0.82 (0.69 to 0.98)	0.74 (0.62 to 0.90)	0.70 (0.58 to 0.85)
  Calcium carbonate 1,200 mg simultaneous administration (fasted)	50 mg single dose	12	0.63 (0.50 to 0.81)	0.61 (0.47 to 0.80)	0.61 (0.47 to 0.80)
  Calcium carbonate 1,200 mg simultaneous administration (fed)	50 mg single dose	11	1.07 (0.83 to 1.38)	1.09 (0.84 to 1.43)	1.08 (0.81 to 1.42)
  Calcium carbonate 1,200 mg 2 h after dolutegravir	50 mg single dose	11	1.00 (0.78 to 1.29)	0.94 (0.72 to 1.23)	0.90 (0.68 to 1.19)
  Carbamazepine 300 mg twice daily	50 mg once daily	16c	0.67 (0.61 to 0.73)	0.51 (0.48 to 0.55)	0.27 (0.24 to 0.31)
  Ferrous fumarate 324 mg simultaneous administration (fasted)	50 mg single dose	11	0.43 (0.35 to 0.52)	0.46 (0.38 to 0.56)	0.44 (0.36 to 0.54)
  Ferrous fumarate 324 mg simultaneous administration (fed)	50 mg single dose	11	1.03 (0.84 to 1.26)	0.98 (0.81 to 1.20)	1.00 (0.81 to 1.23)
  Ferrous fumarate 324 mg 2 h after dolutegravir	50 mg single dose	10	0.99 (0.81 to 1.21)	0.95 (0.77 to 1.15)	0.92 (0.74 to 1.13)
  Multivitamin (One-A-Day) simultaneous administration	50 mg single dose	16	0.65 (0.54 to 0.77)	0.67 (0.55 to 0.81)	0.68 (0.56 to 0.82)
  Omeprazole 40 mg once daily	50 mg single dose	12	0.92 (0.75 to 1.11)	0.97 (0.78 to 1.20)	0.95 (0.75 to 1.21)
  Prednisone 60 mg once daily with taper	50 mg once daily	12	1.06 (0.99 to 1.14)	1.11 (1.03 to 1.20)	1.17 (1.06 to 1.28)
  Rifampina 600 mg once daily	50 mg twice daily	11	0.57 (0.49 to 0.65)	0.46 (0.38 to 0.55)	0.28 (0.23 to 0.34)
  Rifampinb 600 mg once daily	50 mg twice daily	11	1.18 (1.03 to 1.37)	1.33 (1.15 to 1.53)	1.22 (1.01 to 1.48)
  Rifabutin 300 mg once daily	50 mg once daily	9	1.16 (0.98 to 1.37)	0.95 (0.82 to 1.10)	0.70 (0.57 to 0.87)

  Table 10. Summary of Effect of Rilpivirine on the Pharmacokinetics of Coadministered Drugs

  n = Maximum number of subjects with data; NA = Not available. aThis interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. bN (maximum number of subjects with data) for AUC(0-∞)= 15. cAUC(0-last).
  Coadministered Drug(s) and Dose(s)	Dose of Rilpivirine	n	Geometric Mean Ratio (90% CI) of Coadministered Drug Pharmacokinetic Parameters with/without EDURANT No Effect = 1.00
  			Cmax	AUC	Cmin
  Acetaminophen 500 mg single dose	150 mg once dailya	16	0.97 (0.86 to 1.10)	0.91 (0.86 to 0.97)	NA
  Atorvastatin 40 mg once daily	150 mg once dailya	16	1.35 (1.08 to 1.68)	1.04 (0.97 to 1.12)	0.85 (0.69 to 1.03)
  2-hydroxy-atorvastatin			1.58 (1.33 to 1.87)	1.39 (1.29 to 1.50)	1.32 (1.10 to 1.58)
  4-hydroxy-atorvastatin			1.28 (1.15 to 1.43)	1.23 (1.13 to 1.33)	NA
  Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine	150 mg once dailya	16	0.98 (0.85 to 1.13)	1.03 (0.95 to 1.13)	NA
  Digoxin 0.5 mg single dose	25 mg once daily	22	1.06 (0.97 to 1.17)	0.98 (0.93 to 1.04)c	NA
  Ethinylestradiol 0.035 mg once daily	25 mg once daily	17	1.17 (1.06 to 1.30)	1.14 (1.10 to 1.19)	1.09 (1.03 to 1.16)
  Norethindrone 1 mg once daily			0.94 (0.83 to 1.06)	0.89 (0.84 to 0.94)	0.99 (0.90 to 1.08)
  Ketoconazole 400 mg once daily	150 mg once dailya	14	0.85 (0.80 to 0.90)	0.76 (0.70 to 0.82)	0.34 (0.25 to 0.46)
  Methadone 60-100 mg once daily, individualized dose	25 mg once daily	13
  R(‑) methadone			0.86 (0.78 to 0.95)	0.84 (0.74 to 0.95)	0.78 (0.67 to 0.91)
  S(+) methadone			0.87 (0.78 to 0.97)	0.84 (0.74 to 0.96)	0.79 (0.67 to 0.92)
  Metformin 850 mg single dose	25 mg once daily	20	1.02 (0.95 to -1.10)	0.97 (0.90 to 1.06)b	NA
  Omeprazole 20 mg once daily	150 mg once dailya	15	0.86 (0.68 to 1.09)	0.86 (0.76 to 0.97)	NA
  Rifampin 600 mg once daily	150 mg once dailya	16	1.02 (0.93 to 1.12)	0.99 (0.92 to 1.07)	NA
  25-desacetylrifampin			1.00 (0.87 to 1.15)	0.91 (0.77 to 1.07)	NA
  Sildenafil 50 mg single dose	75 mg once dailya	16	0.93 (0.80 to 1.08)	0.97 (0.87 to 1.08)	NA
  N -desmethyl-sildenafil			0.90 (0.80 to 1.02)	0.92 (0.85 to 0.99)c	NA
  Simeprevir 150 mg once daily	25 mg once daily	21	1.10 (0.97 to 1.26)	1.06 (0.94 to 1.19)	0.96 (0.83 to 1.11)

  Table 11. Summary of Effect of Coadministered Drugs on the Pharmacokinetics of Rilpivirine

  n = Maximum number of subjects with data; NA = Not available; ↔ = No change. aThis interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the coadministered drug. bComparison based on historic controls.
  Coadministered Drug(s) and Dose(s)	Dose of Rilpivirine	n	Geometric Mean Ratio (90% CI) of Rilpivirine Pharmacokinetic Parameters with/without Coadministered Drugs No Effect = 1.00
  			Cmax	AUC	Cmin
  Acetaminophen 500 mg single dose	150 mg once dailya	16	1.09 (1.01 to 1.18)	1.16 (1.10 to 1.22)	1.26 (1.16 to 1.38)
  Atorvastatin 40 mg once daily	150 mg once dailya	16	0.91 (0.79 to 1.06)	0.90 (0.81 to 0.99)	0.90 (0.84 to 0.96)
  Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine	150 mg once dailya	16	1.17 (1.08 to 1.27)	1.25 (1.16 to 1.35)	1.18 (1.09 to 1.28)
  Ethinylestradiol/ Norethindrone 0.035 mg once daily/ 1 mg once daily	25 mg once daily	15	↔b	↔b	↔b
  Famotidine 40 mg single dose taken 12 hours before rilpivirine	150 mg single dosea	24	0.99 (0.84 to 1.16)	0.91 (0.78 to 1.07)	NA
  Famotidine 40 mg single dose taken 2 hours before rilpivirine	150 mg single dosea	23	0.15 (0.12 to 0.19)	0.24 (0.20 to 0.28)	NA
  Famotidine 40 mg single dose taken 4 hours after rilpivirine	150 mg single dosea	24	1.21 (1.06 to 1.39)	1.13 (1.01 to 1.27)	NA
  Ketoconazole 400 mg once daily	150 mg once dailyb	15	1.30 (1.13 to 1.48)	1.49 (1.31 to 1.70)	1.76 (1.57 to 1.97)
  Methadone 60-100 mg once daily, individualized dose	25 mg once daily	12	↔b	↔b	↔b
  Omeprazole 20 mg once daily	150 mg once dailya	16	0.60 (0.48 to 0.73)	0.60 (0.51 to 0.71)	0.67 (0.58 to 0.78)
  Rifabutin 300 mg once daily	25 mg once daily	18	0.69 (0.62 to 0.76)	0.58 (0.52 to 0.65)	0.52 (0.46 to 0.59)
  Rifabutin 300 mg once daily	50 mg once daily	18	1.43 (1.30 to 1.56)	1.16 (1.06 to 1.26)	0.93 (0.85 to 1.01)
  			(reference arm for comparison was 25-mg-once-daily rilpivirine administered alone)
  Rifampin 600 mg once daily	150 mg once dailya	16	0.31 (0.27 to 0.36)	0.20 (0.18 to 0.23)	0.11 (0.10 to 0.13)
  Sildenafil 50 mg single dose	75 mg once dailya	16	0.92 (0.85 to 0.99)	0.98 (0.92 to 1.05)	1.04 (0.98 to 1.09)
  Simeprevir 150 mg once daily	25 mg once daily	23	1.04 (0.95 to 1.13)	1.12 (1.05 to 1.19)	1.25 (1.16 to 1.35)

  )]
  .