ODEFSEY fixed dose approved

On March 1, 2016 the FDA approved ODEFSEY (emtricitabine, rilpivirine, and tenofovir alafenamide), 200/25/25 mg fixed-dose combination tablet. OFEFSEY is indicated as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies per mL; or to replace a stable antiretroviral regimen in those who are virologically-suppressed (HIV-1 RNA less than 50 copies per mL) for at least six months with no history of treatment failure and no known substitutions associated with resistance to the individual components of ODEFSEY.

The approval is supported by a bioequivalence study demonstrating that Odefsey achieved similar drug levels of emtricitabine and TAF in the blood as Genvoya® (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg or E/C/F/TAF) and similar drug levels of rilpivirine as Edurant® (rilpivirine 25 mg). The safety, efficacy and tolerability of Odefsey is supported by clinical studies of rilpivirine-based therapy (administered as R+F/TDF or R/F/TDF) and F/TAF-based therapy (administered as E/C/F/TAF) in a range of patients with HIV, including treatment-naïve adults and adolescents, virologically suppressed adults who switched from PI-, NNRTI- and INSTI-based regimens and virologically suppressed adults with mild-to-moderate renal impairment.

DOSAGE AND ADMINISTRATION

Testing Prior to Initiation of ODEFSEY

Prior to initiation of ODEFSEY, patients should be tested for hepatitis B virus infection.

Estimated creatinine clearance, urine glucose, and urine protein should be assessed before initiating ODEFSEY therapy and should be monitored during therapy in all patients.

Recommended Dosage

ODEFSEY is a 3-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 25 mg of tenofovir alafenamide (TAF). The recommended dosage of ODEFSEY is one tablet taken orally once daily with a meal in the following patient population: adults and in pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg and a creatinine clearance greater than or equal to 30 mL per minute.

Testing After Initiation of ODEFSEY

In virologically-suppressed patients, additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.  

Not Recommended in Patients with Severe Renal Impairment

ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute.

CONTRAINDICATIONS

ODEFSEY is contraindicated when coadministered with the following drugs, as significant decreases in RPV plasma concentrations may occur due to cytochrome P450 (CYP) 3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to ODEFSEY or to the class of NNRTIs:

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

The WARNINGS AND PRECAUTIONS include

• Lactic Acidosis/Severe Hepatomegaly with Steatosis
• Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
• Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience with RPV-containing regimens, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries.
• Concomitant use of ODEFSEY with other drugs that may reduce the exposure of RPV may lead to loss of therapeutic effect of ODEFSEY and possible development of resistance.
• Concomitant use of ODEFSEY with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes.
• Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders
• Hepatotoxicity: Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Monitor liver-associated tests before and during treatment with ODEFSEY in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors.
•  Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy.
• Immune reconstitution syndrome: May necessitate further evaluation and treatment.
• New onset or worsening renal impairment: Assess creatinine clearance, urine glucose, and urine protein in all patients before initiating ODEFSEY therapy and monitor during therapy. Monitor serum phosphorus in patients with chronic kidney disease.
• Bone loss and mineralization defects: Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss.

Section 6 Adverse Reactions contains data from clinical trials of rilpivirine containing regimens in adults and adverse reactions in clinical trials of emtricitabine/tenofovir alafenamide with elvitegravir cobicistat in adults and pediatric patients. Data regarding renal laboratory tests and bone mineral density effects as described with emtricitabine/tenofovir alafenamide with elvitegravir cobicistat is also included. A summary of the adverse reaction information is as follows:

Rilpivirine: Most common adverse reactions to RPV (incidence greater than or equal to 2%, Grades 2–4) are depressive disorders, insomnia, and headache.

Emtricitabine & Tenofovir Alafenamide: Most common adverse reaction (incidence greater than or equal to 10%, all grades) is nausea.

The following information is contained in section 7 DRUG INTERACTIONS

Potential for Other Drugs to Affect One or More Components of ODEFSEY

Drugs that Induce or Inhibit CYP3A Enzymes

RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV [see Contraindications (4) and Clinical Pharmacology (12.3)]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV and possible adverse events.

Drugs that Induce or Inhibit P-glycoprotein

TAF, a component of ODEFSEY, is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3. Drugs that strongly affect P-gp activity (e.g., cyclosporine) may lead to changes in TAF absorption (see Table 1). Drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of ODEFSEY and development of resistance. Coadministration of ODEFSEY with other drugs that inhibit P-gp may result in increased absorption and plasma concentrations of TAF and possible adverse events.

Drugs that Increase Gastric pH  

Coadministration of RPV with drugs that increase gastric pH (e.g., famotidine) may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs (see Table 1).

QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval. In a study of healthy subjects, higher than recommended doses of RPV, 75 mg once daily and 300 mg once daily (3 times and 12 times recommended daily dose in ODEFSEY) prolonged the QTc interval[see Warnings and Precautions (5.5) and Clinical Pharmacology (12.2)]. Consider alternative medications to ODEFSEY in patients taking a drug with a known risk of Torsade de Pointes.

Drugs that Affect Renal Function

Because FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of ODEFSEY with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.10)].

Established and Other Potentially Significant Drug Interactions

Table 1 provides a listing of established or potentially clinically significant drug interactions with recommended steps to prevent or manage the drug interaction (the table is not all inclusive). The drug interactions described are based on studies conducted with either ODEFSEY, the components of ODEFSEY (FTC, RPV and TAF) as individual agents, or are predicted drug interactions that may occur with ODEFSEY. For pharmacokinetic data, see Tables 5−8 [see Clinical Pharmacology (12.3)].

Table 1 Established and Other Potentially Significant^a Drug Interactions

Concomitant Drug Class: Drug Name	Effect on Concentrationb	Clinical Comment
Antacids:         antacids (e.g., aluminum, magnesium hydroxide, or calcium carbonate)	« RPV (antacids taken at least 2 hours before or at least 4 hours after RPV) ¯ RPV (concomitant intake)	Administer antacids at least 2 hours before or at least 4 hours after ODEFSEY.
Antimycobacterials: rifabutin	¯ RPVc ¯ TAF	Coadministration of ODEFSEY with rifabutin is not recommended.
Azole Antifungal Agents:         fluconazole itraconazole ketoconazole posaconazole voriconazole	RPVc,d ­ TAF ¯ ketoconazolec,d	No dosage adjustment is required when ODEFSEY is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with ODEFSEY.
H2-Receptor Antagonists:         cimetidine           famotidine nizatidine ranitidine	« RPVc,d (famotidine taken 12 hours before RPV or 4 hours after RPV) ¯ RPVc,d (famotidine taken 2 hours before RPV)	Administer H2-receptor antagonists at least 12 hours before or at least 4 hours after ODEFSEY.
Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin	RPV « clarithromycin « erythromycin « telithromycin	Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:         methadone	¯ R(-) methadonec ¯ S(+) methadonec « RPVc « methadonec (when used with tenofovir)	No dosage adjustments are required when initiating coadministration of methadone with ODEFSEY. However, clinical monitoring is recommended, as methadone maintenance therapy may need to be adjusted in some patients.

a. This table is not all inclusive.
b. Increase=­; Decrease=¯; No Effect=«
c. The interaction was evaluated in a clinical study. All other drug interactions shown are predicted.
d. This interaction study has been performed with a dose higher than the recommended dose for RPV. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily.

Drugs Without Clinically Significant Interactions with ODEFSEY

Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been either observed or expected when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, buprenorphine, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, lorazepam, metformin, midazolam, naloxone, norbuprenorphine, norethindrone, norgestimate/ethinyl estradiol, sildenafil, simeprevir and sofosbuvir.

CLINICAL STUDIES

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in adults as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed [see Indications and Usage (1)] was established in trials of:

• RPV+FTC/TDF in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=550) and to replace a first or second stable antiretroviral regimen containing a protease inhibitor and ritonavir in those who were virologically-suppressed with no history of virologic failure or for at least 6 months with no known resistance substitutions (n=317). The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) in these two populations was 77% at Week 96 and 89% at Week 48, respectively. Among treatment-naïve subjects, the virologic response rate at 96 weeks was 83% in subjects with baseline HIV-1 RNA less than or equal to 100,000 copies per mL and 71% in subjects with baseline HIV-1 RNA greater than 100,000 copies per mL. Further, the virologic response rate at 96 weeks among subjects with baseline CD4+ cell counts less than 200 and greater than or equal to 200 cells/mm3 were 68% and 82%, respectively.
• FTC+TAF with EVG+COBI in HIV-1 infected adults as initial therapy in those with no antiretroviral treatment history (n=866) and to replace a stable antiretroviral regimen in those who were virologically-suppressed for at least 6 months with no known resistance substitutions (n=799). At Week 48, 92% and 96% of patients in the two populations, respectively, had HIV-1 RNA less than 50 copies per mL.

The efficacy of RPV, FTC, and TAF in the treatment of HIV-1 infection in pediatric patients aged 12 to less than 18 years old and greater than 32-35 kg as initial therapy in those with no antiretroviral treatment history and to replace a stable antiretroviral regimen in those who are virologically-suppressed [see Indications and Usage (1)] was established in trials of antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years old with:

• RPV in combination with other antiretroviral agents in 36 treatment-naïve HIV-1 infected adolescents weighing at least 32 kg. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had a baseline HIV-1 RNA less than or equal to 100,000 copies per mL. The virologic response rate in these 20 subjects (i.e., HIV-1 RNA less than 50 copies per mL) was 80% (16/20) at 48 weeks.
• FTC+TAF with EVG+COBI in 23 adolescents weighing at least 35 kg. The virologic response rate (i.e., HIV-1 RNA less than 50 copies per mL) was 91% at 24 weeks.

In the clinical trial of 248 HIV-1 infected adult patients with estimated creatinine clearance greater than 30 mL per minute but less than 70 mL per minute, 95% (235/248) of the combined populations of treatment-naïve (N=6) begun on FTC+TAF with EVG +COBI and those previously virologically suppressed on other regimens (N=242) and switched to FTC+TAF with EVG +COBI had HIV-RNA levels less than 50 copies per mL at Week 24.

You will be able to view the complete label at drugs@fda or dailymed.

Richard Klein
Office of Health and Constituent Affairs
Food and Drug Administration

Kimberly Struble
Division of Antiviral Products
Food and Drug Administration

Steve Morin
Office of Health and Constituent Affairs
Food and Drug Administration

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