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Guide
Drug Safety-related Labeling Changes (SrLC) Database
| ANDA | Abbreviated New Drug Application |
| BLA | Biologics License Application |
| CDER | Center for Drug Evaluation and Research |
| MG | Medication Guide |
| NDA | New Drug Application |
| PCI | Patient Counseling Information |
| PI | Patient Information |
| PLR | Physician Labeling Rule |
| PLLR | Pregnancy and Lactation Labeling Rule |
| Italics | For the most part, italics indicate an FDA comment such as:
Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section. |
| Underlines | Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text. |
Sections
| BW | Box Warning |
| WP | Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format) |
| AR | Adverse Reactions (in pre-PLR format, this may be a subheading under precautions). |
| DI | Drug Interactions (in pre-PLR format, this may be a subheading under precautions). |
| USP | Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format. |
| PCI/PI/MG | Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events. |
Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.
Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.
ODEFSEY (NDA-208351)
(EMTRICITABINE; RILPIVIRINE HYDROCHLORIDE; TENOFOVIR ALAFENAMIDE FUMARATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
02/19/2025 (SUPPL-15)
5 Warnings and Precautions
5.5 New Onset or Worsening Renal ImpairmentAdditions and revisions underlined:
Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients.
6 Adverse Reactions
6.1 Clinical Trials ExperienceExtensive changes; please refer to label
8 Use in Specific Populations
8.2 LactationAdditions and revisions underlined:
Risk Summary
Data from the published literature report the presence of FTC, TAF, and TFV (tenofovir) in human milk; it is unknown if RPV is present in human milk. RPV is present in rat milk (see Data). Data from the published literature have not reported adverse effects of FTC or TAF on a breastfed child; it is not known if RPV has effects on the breastfed child. It is not known if the components of ODEFSEY affect milk production.
Potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV-1, and (3) adverse reactions in a breastfed infant similar to those seen in adults.
Additions and revisions underlined:
The efficacy and safety of ODEFSEY as a complete regimen for the treatment of HIV-1 was established in pediatric patients 6 years of age and older with body weight greater than or equal to 25 kg [see Dosage and Administration (2.2)]. No pediatric clinical trials were conducted with ODEFSEY. Use of ODEFSEY in this age group is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection, adequate and well-controlled studies of FTC+TAF with EVG+COBI in adults with HIV-1, and by the following pediatric studies conducted using the components of ODEFSEY [see Clinical Studies (14)]:
48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 32 kg (N=36) and aged 6 to less than 12 years weighing at least 17 kg (N=18) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in antiretroviral treatment-naïve adults with HIV-1 on this regimen [see Adverse Reactions (6.1) and Clinical Studies (14)].
48-week open-label trial of 26 virologically-suppressed pediatric participants with HIV- 1 aged less than 12 years old and weighing at least 16 kg (N=26) treated with RPV and other antiretrovirals. The safety and efficacy of RPV administered with other antiretrovirals were similar to that in virologically-suppressed adults with HIV-1 on this regimen [see Adverse Reactions (6.1)]
48-week open-label trials of antiretroviral treatment-naïve pediatric participants with HIV-1 aged 12 to less than 18 years and weighing at least 35 kg (N=50) and virologically-suppressed pediatric participants between the ages of 6 to less than 12 years weighing at least 25 kg (N=52) treated with FTC+TAF with EVG+COBI. The safety and efficacy of FTC+TAF with EVG+COBI were similar to that in adults with HIV-1 on this regimen, with the exception of a decrease from baseline in CD4+ cell counts in participants 6 to less than 12 years of age weighing at least 25 kg [see Adverse Reactions (6.1) and Clinical Studies (14)].
Because it is a fixed-dose combination tablet, the dose of ODEFSEY cannot be adjusted for patients of lower age and weight. The safety and efficacy of ODEFSEY have not been established in pediatric patients weighing less than 25 kg [see Clinical Pharmacology (12.3) and Clinical Studies (14)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Counseling InformationAdditions and revisions underlined:
Lactation
Instruct patients with HIV-1 that the potential risks of breastfeeding include: (1) HIV-1 transmission to infants without HIV-1, (2) developing viral resistance in infants with HIV- 1, and (3) adverse reactions in a breastfed infant similar to those seen in adults [see Use in Specific Populations (8.2)].
Additions and revisions underlined:
ODEFSEY is a prescription medicine that is used to treat human immunodeficiency virus-1 (HIV-1) infection in adults and children who weigh at least 55 pounds (25 kg):
who have not received HIV-1 medicines in the past and who have an amount of HIV-1 in their blood (this is called “viral load”) that is no more than 100,000 copies/mL, or
to replace their current HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.
HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).
ODEFSEY contains the prescription medicines emtricitabine, rilpivirine and tenofovir alafenamide.
. . .
Two of the medicines in ODEFSEY can pass to your baby in your breast milk. It is not known if the other medicine in ODEFSEY can pass into your breast milk.
Talk to your healthcare provider about the following risks of breastfeeding during treatment with ODEFSEY:
The HIV-1 virus may pass to your baby if your baby does not have HIV-1.
The HIV-1 virus may become harder to treat if your baby has HIV-1.
Your baby may get side effects from ODEFSEY.
09/10/2021 (SUPPL-13)
8 Use in Specific Populations
8.1 Pregnancy
(Additions and/or revisions are underlined)
Risk Summary
Available data from the APR show no statistically significant difference in the overall risk of major birth defects for emtricitabine (FTC), rilpivirine (RPV) or tenofovir alafenamide (TAF) compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15 - 20%.
Data
Human Data
Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of ODEFSEY are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.
Emtricitabine (FTC):
Based on prospective reports to the APR of over 5,400 exposures to FTC-containing regimens during pregnancy resulting in live births (including over 3,900 exposed in the first trimester and over 1,500 exposed in the second/third trimester), the prevalence of birth defects in live births was 2.6% (95% CI: 2.2% to 3.2%) and 2.7% (95% CI: 1.9% to 3.7%) following first and second/third trimester exposure, respectively, to FTC-containing regimens.
Rilpivirine (RPV):
Based on prospective reports to the APR of over 750 exposures to RPV-containing regimens during pregnancy resulting in live births (including over 550 exposed in the first trimester and over 200 exposed in the second/third trimester), the prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to RPV-containing regimens.
Tenofovir Alafenamide (TAF):
Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2% (95% CI: 2.6% to 6.3%) and 3.0% (95% CI: 0.8% to 7.5%) following first and second/third trimester exposure, respectively, to TAF-containing regimens.
03/04/2021 (SUPPL-11)
5 Warnings and Precautions
5.5 New Onset or Worsening Renal ImpairmentAddition and/or revisions underlined
Postmarketing case of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir-related adverse events [see Adverse Reactions (6.1, 6.2)].
…
6 Adverse Reactions
6.1 Clinical Trials Experience
Additions underlined
…
Renal Laboratory Tests
…
In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24. FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects.
…
6.2 Postmarketing Experience
Additions underlined
…
Renal and Urinary Disorders
Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATIONAdditions underlined
…
New Onset or Worsening Renal Impairment
Advise patients to avoid taking ODEFSEY with concurrent or recent use of nephrotoxic agents. Postmarketing cases of renal impairment, including acute renal failure, have been reported [see Warnings and Precautions (5.5)].
…
Additions underlined
…
What is the most important information I should know about ODEFSEY? ODEFSEY can cause serious side effects, including:
Worsening of hepatitis B virus (HBV) infection. Your healthcare provider will test you for HBV infection before or when you start treatment with ODEFSEY. If you have HBV infection and take ODEFSEY, your HBV may get worse (flare-up) if you stop taking ODEFSEY. A “flare-up” is when your HBV infection suddenly returns in a worse way than before.
…
If you stop taking ODEFSEY, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your liver, and may give you a medicine to treat hepatitis B. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking ODEFSEY.
…
12/03/2019 (SUPPL-10)
5 Warnings and Precautions
5.5 New Onset or Worsening Renal Impairment(additions underlined)
… ODEFSEY is not
recommended in patients with estimated creatinine clearance of 15 to below
30 mL per minute, or in patients with estimated creatinine clearance
below 15 mL per minute who are not receiving chronic
hemodialysis.
…
(addition underlined)
…
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.
6 Adverse Reactions
6.2 Postmarketing Experience
(additions underlined)
The following adverse reactions have been identified during postmarketing experience in patients receiving RPV or TAF-containing regimens. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Rilpivirine:
Metabolism and Nutrition Disorders : Weight increased
Skin and Subcutaneous Tissue Disorders:
Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)
Renal and Urinary Disorders :Nephrotic syndrome
Tenofovir alafenamide:
Skin and Subcutaneous Tissue Disorders: Angioedema, urticaria, and rash
8 Use in Specific Populations
8.6 Renal Impairment(additions and/or revisions underlined)
No dosage adjustment of ODEFSEY is recommended in patients with estimated creatinine clearance greater than or equal to 30 mL per minute. ODEFSEY should be used with caution in adults patients with ESRD (estimated creatinine clearance below 15mL per minute) who are receiving chronic hemodialysis and increased monitoring is recommended for RPV-related adverse effects in patients with ESRD, as RPV concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. On days of hemodialysis, administer the daily dose of ODEFSEY after completion of hemodialysis treatment.
ODEFSEY is not recommended in patients with severe renal impairment (estimated creatinine clearance of 15 to below 30 mL per minute), or in patients with ESRD who are not receiving chronic hemodialysis, as the safety of ODEFSEY has not been established in these populations.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT INFORMATION(additions underlined)
…
How should I take ODEFSEY?
…
If you are on dialysis, take your daily dose of ODEFSEY following dialysis.
…
10/31/2018 (SUPPL-6)
4 Contraindications
(Additions and/or revisions are underlined)ODEFSEY is contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to ODEFSEY or to the class of NNRTIs:
Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Antimycobacterials: rifampin, rifapentine
Glucocorticoid (thesystemic): dexamethasone (more than a single-dose)
Herbal Products: St. John’s wort (Hypericum perforatum)
Proton Pump Inhibitors: e.g., dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
5 Warnings and Precautions
5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV(Additions and/or revisions are underlined)
Test patients with HIV-1 for the presence of hepatitis B virus (HBV) before or when initiating antiretroviral therapy.
Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HIV-1 and HBV and have discontinued products containing FTC and/or TDF, and may occur with discontinuation of ODEFSEY. Patients coinfected with HIV-1 and HBV who discontinue ODEFSEY should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with ODEFSEY. If appropriate, initiation of anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since post treatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
(Newly added subsection)
Hepatic adverse events have been reported in patients receiving an RPV-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in liver-associated tests prior to treatment, may be at increased risk for worsening or development of liver-associated test elevations with use of ODEFSEY. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-containing regimen who had no preexisting hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with ODEFSEY is recommended in patients with underlying hepatic disease such as hepatitis B or C, or in patients with marked elevations in liver-associated tests prior to treatment initiation. Liver-associated test monitoring should also be considered for patients without preexisting hepatic dysfunction or other risk factors.
(Additions and/or revisions are underlined)
…
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions. Prior to or when initiating ODEFSEY, and during treatment with ODEFSEY, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
(Additions and/or revisions are underlined)
The concomitant use of ODEFSEY and other drugs may result in potentially significant drug interactions, some of which may lead to :
Loss of therapeutic effect of ODEFSEY and possible development of resistance due to reduced exposure of RPV.
In healthy subjects, higher than recommended doses of RPV (75 mg once daily and 300 mg once daily –3 and 12 times the recommended dosages in ODEFSEY, respectively) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to ODEFSEY when coadministered with a drug that is known to have a risk of Torsade de Pointes.
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 ODEFSEY therapy and review concomitant medications during ODEFSEY therapy.
6 Adverse Reactions
6 ADVERSE REACTIONS(Additions and/or revisions are underlined)
The following adverse reactions are discussed in other sections of the labeling:
Severe Acute Exacerbations of Hepatitis B
Skin and Hypersensitivity Reactions
Hepatotoxicity
Depressive Disorders
New Onset or Worsening Renal Impairment
Lactic Acidosis/Severe Hepatomegaly with Steatosis
Immune Reconstitution Syndrome
7 Drug Interactions
7.1 Not Recommended with Other Antireteroviral Medications(Subsection title has been revised; additions and/or revisions are underlined)
Because ODEFSEY is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.
(Subsection title has been revised)
7.3 Drugs Inducing or Inhibiting P-glycoprotein
(Subsection title has been revised)
7.4 Drugs Increasing Gastric pH
(Subsection title has been revised)
7.6 Drugs Affecting Renal Function
(Subsection title has been revised)
7.7 Significant Drug Interactions
(Subsection title has been revised; additions and/or revisions are underlined)
Table 3 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.
(Table 3 has been revised; please refer to label)
7.8 Drugs Without Clinically Significant Interactions with ODEFSEY
(Additions and/or revisions are underlined)
Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been observed when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, metformin, midazolam, norethindrone, norgestimate, sildenafil, simeprevir, sofosbuvir, velpatasvir, and voxilaprevir.
8 Use in Specific Populations
8.1 Pregnancy(Additions and/or revisions are underlined)
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to ODEFSEY during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.
Risk Summary
Available data from the APR show no increase in the risk of overall major birth defects with first trimester exposure for emticitabine (FTC) or rilpivirine (RPV) compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP (see Data). There are insufficient tenofovir alafenamide (TAF) data from the APR to adequately assess the risk of major birth defects. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period. The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%.
Based on the experience of HIV-1-infected pregnant individuals who completed a clinical trial through the postpartum period with an RPV-based regimen, no dose adjustments are required for pregnant patients who are already on a stable RPV-containing regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). Lower exposures of RPV were observed during pregnancy, therefore viral load should be monitored closely.
In animal studies, no adverse developmental effects were observed when the components of ODEFSEY were administered separately during the period of organogenesis at exposures up to 60 and 108 times (mice and rabbits, respectively; FTC), 15 and 70 times (rats and rabbits, respectively; RPV) and equal to and 53 times (rats and rabbits, respectively; TAF) the exposure at the recommended daily dose of these components in ODEFSEY. Likewise, no adverse developmental effects were seen when FTC was administered to mice and RPV was administered to rats through lactation at exposures up to approximately 60 and 63 times, respectively, the exposure at the recommended daily dose of these components in ODEFSEY. No adverse effects were observed in the offspring when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of ODEFSEY.
Data
Human Data
Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of ODEFSEY are compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease.
Emtricitabine: Based on prospective reports to the APR of exposures to FTC-containing regimens during pregnancy resulting in live births (including over 2,750 exposed in the first trimester and over 1,200 exposed in the second/third trimester), there was no increase in overall birth defects with FTC compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.4% (95% CI: 1.9% to 3.1%) with first trimester exposure to FTC-containing regimens and 2.3% (95% CI: 1.5% to 3.3%) with second/third trimester exposure to FTC-containing regimens.
Rilpivirine: RPV in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant subjects during the second and third trimesters and postpartum. Each of the subjects were on an RPV-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6-12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C0h and AUC) of total RPV was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 12 weeks). The protein binding of RPV was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following fetal death at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6-12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant subjects, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. RPV was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of RPV in HIV–1-infected adults.
Based on prospective reports to the APR of over 450 exposures to RPV-containing regimens during pregnancy (including over 290 exposed in the first trimester and over 160 exposed in the second/third trimester), there was no significant increase in overall risk of major birth defects with RPV compared with the background rate of 2.7% for major birth defects in the U.S. reference population of the MACDP. The prevalence of major birth defects in live births was 1.0% (95% CI: 0.2% to 2.9%) with first trimester exposure to RPV- containing regimens and 1.2% (95% CI: 0.2% to 4.4%) with second/third trimester exposure to RPV-containing regimens.
Tenofovir Alafenamide: Based on prospective reports to the APR of 85 exposures to TAF- containing regimens during pregnancy (including 56 exposed in the first trimester and 29 exposed in the second/third trimester), there have been 3 birth defects with first trimester exposure to TAF-containing regimens.
…
8.2 Lactation
(Additions and/or revisions are underlined)
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.
Based on published data, emtricitabine has been shown to be present in human milk; it is unknown if rilpivirine (RPV) and tenofovir alafenamide (TAF) are present in human milk. RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF (see Data). It is unknown if TAF is present in animal milk.
It is not known if the components of ODEFSEY affect milk production or have effects on the breastfed infant. Because of the potential for (1) HIV transmission (in HIV-negative infants),
(2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving ODEFSEY.
Rilpivirine: In animals, no studies have been conducted to assess the excretion of RPV directly; however, RPV was measured in rat pups which were exposed through the milk of treated dams (dosed up to 400 mg/kg/day).
Tenofovir Alafenamide: Studies in rats and monkeys have demonstrated that tenofovir is excreted in milk. Tenofovir was excreted into the milk of lactating rats following oral administration of TDF (up to 600 mg/kg/day) at up to approximately 24% of the median plasma concentration in the highest dosed animals at lactation day 11 .Tenofovir was excreted into the milk of lactating monkeys, following a single subcutaneous (30 mg/kg) dose of tenofovir, at concentrations up to approximately 4% of plasma concentration resulting in exposure (AUC) of approximately 20% of plasma exposure.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
…
Pregnancy Registry
Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to ODEFSEY during pregnancy.
Lactation
Instruct patients with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk
…
Other
Patient Information(Additions and/or revisions are underlined)
…
What is ODEFSEY?
…
HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). ODEFSEY does not cure HIV-1 or AIDS.
…
What is ODEFSEY?
…
HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). ODEFSEY does not cure HIV-1 or AIDS.
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08/21/2017 (SUPPL-2)
5 Warnings and Precautions
5.8 New Onset or Worsening Renal Impairment(additions underlined)
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF with EVG+COBI, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment- naïve subjects and in virologically-suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virologically- suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute. ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.
is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose and urine protein be assessed before initiating ODEFSEY therapy and during therapy in all patients as clinically appropriate. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.
Adverse Reactions in Clinical Trials of ODEFSEY in Virologically-Suppressed Adult Subjects with HIV-1 Infection
The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult subjects who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively. A total of 754 subjects received one tablet of ODEFSEY daily.
The most common adverse reactions (all Grades) reported in at least 2% of subjects in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1). Over 98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity. The proportion of subjects who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF.
Table 1 Adverse Reactionsa (All Grades) Reported in ?1% of HIV-1 Infected Virologically-Suppressed Adults in Trial 1160 or Trial 1216 (Week 48 analysis)
(please refer to label to view Table 1)
Renal Laboratory Tests
In Trial 1216, the median baseline eGFR was104 mL per minute for subjects who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48.
In Trial 1160, the median baseline eGFR was 110 mL per minute for subjects who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48.
Bone Mineral Density Effects
Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160.
In Trial 1216, mean bone mineral density (BMD) increased in subjects who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in subjects who remained on FTC/RPV/TDF (0.08% lumbar spine,?0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY subjects and 3.0% of FTC/RPV/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY subjects and 1.2% of FTC/RPV/TDF subjects.
In Trial 1160, mean BMD increased in subjects who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in subjects who remained on EFV/FTC/TDF (?0.05% lumbar spine, ?0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY subjects and 4.9% of EFV/FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY subjects and 3.3% of EFV/FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.
Serum Lipids
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2.
Table 2 Lipid Values, Mean Change from Baseline Reported in Subjects Receiving ODEFSEY, FTC/RPV/TDF and EFV/FTC/TDF in Trials 1216 and 1160 at 48 Weeks
(please refer to label to view Table 2)
Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Treatment-Naïve Adult Subjects with HIV-1 Infection
In pooled 96-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2?4) were headache, depressive disorders, and insomnia. The proportion of subjects who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).
Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult Subjects with HIV-1 Infection
In pooled 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse event [see Clinical Studies (14)]. Antiretroviral treatment-naïve adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.
Renal Laboratory Tests
two 48-week trials in antiretroviral treatment-naïve HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24.
…
7 Drug Interactions
7.1 Potential for Other Drugs to Affect One or More Components of ODEFSEY(additions underlined)
Drugs that Induce or Inhibit CYP3A Enzymes
RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of RPV. 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.
These drugs are contraindicated and include:
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampin and rifapentine
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St. John’s wort (Hypericum perforatum)
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 and BCRP activity may lead to changes in TAF absorption (see Table 3). 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 and BCRP may increase the absorption and plasma concentration of TAF.
Drugs that Increase Gastric pH
Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration.
(addition underlined)
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, sofosbuvir, and velpatasvir.
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
…
Risk Summary
There are insufficient human data on the use of ODEFSEY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) use in women during pregnancy have not been evaluated; however, emtricitabine (FTC) and rilpivirine (RPV) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the risk of overall major birth defects for FTC and RPV compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.
…
Data
Human Data
Emtricitabine: Based on prospective reports to the APR of 3406 exposures to FTC-containing regimens during pregnancy (including 2326 exposed in the first trimester and 1080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with second/third trimester exposure to FTC-containing regimens.
Rilpivirine: Based on prospective reports to the APR of 326 live births following exposures to RPV-containing regimens during pregnancy (including 202 exposed in the first trimester and 124 exposed in the second/third trimester), there was no difference in the rate of overall birth defects for RPV compared with the background rate of 2.7% for major birth defects in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 0.5% (95% CI: 0.0% to 2.7%) with first trimester exposure to RPV-containing regimens and 0.8% (95% CI: 0.0% to 4.4%) with second/third trimester exposure to RPV- containing regimens.
…
(additions underlined)
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.
Based on published data, FTC has been shown to be present in human breast milk; it is unknown if RPV and TAF are present in human breast milk. RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF [see Data]. It is unknown if TAF is present in animal milk.
…
No dosage adjustment of ODEFSEY is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. ODEFSEY has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(additions underlined)
…
What is ODEFSEY?
ODEFSEY is a prescription medicine that is used to treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and older:
• who have not received anti-HIV-1 medicines in the past and who have an amount of HIV-1 in their blood (this is called “viral load”) that is no more than 100,000 copies/mL, or
• to replace their current anti-HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.
HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
ODEFSEY contains the prescription medicines emtricitabine, rilpivirine and tenofovir alafenamide.
It is not known if ODEFSEY is safe and effective in children under 12 years of age or who weigh less than 77 lb (35 kg).
…
08/21/2017 (SUPPL-3)
5 Warnings and Precautions
5.8 New Onset or Worsening Renal Impairment(additions underlined)
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs in both animal toxicology studies and human trials. In clinical trials of FTC+TAF with EVG+COBI, there have been no cases of Fanconi syndrome or proximal renal tubulopathy (PRT). In clinical trials of FTC+TAF with EVG+COBI in treatment- naïve subjects and in virologically-suppressed subjects switched to FTC+TAF with EVG+COBI with eGFRs greater than 50 mL per minute, renal serious adverse events or discontinuations due to renal adverse reactions were encountered in less than 1% of participants treated with FTC+TAF with EVG+COBI. In a study of virologically- suppressed subjects with baseline eGFRs between 30 and 69 mL per minute treated with FTC+TAF with EVG+COBI for a median duration of 43 weeks, FTC+TAF with EVG+COBI was permanently discontinued due to worsening renal function in two of 80 (3%) subjects with a baseline eGFR between 30 and 50 mL per minute. ODEFSEY is not recommended in patients with estimated creatinine clearance below 30 mL per minute because data in this population are insufficient.
Patients taking tenofovir prodrugs who have impaired renal function and those taking nephrotoxic agents, including nonsteroidal anti-inflammatory drugs are at increased risk of developing renal-related adverse reactions.
is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose and urine protein be assessed before initiating ODEFSEY therapy and during therapy in all patients as clinically appropriate. Discontinue ODEFSEY in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
6 Adverse Reactions
6.1 Clinical Trials Experience(additions underlined)
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug (or a drug given in various combinations with other concomitant therapy) cannot be directly compared to rates in the clinical trials of another drug (or drug given in the same or different combination therapy) and may not reflect the rates observed in practice.
Adverse Reactions in Clinical Trials of ODEFSEY in Virologically-Suppressed Adult Subjects with HIV-1 Infection
The safety of ODEFSEY in virologically-suppressed adults is based on Week 48 data from two randomized, double-blinded, active-controlled clinical trials, 1160 and 1216, that enrolled 1505 adult subjects who were virologically-suppressed for at least 6 months. Both trials were designed to compare switching to ODEFSEY to maintaining efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) or emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF) in Trials 1160 and 1216, respectively. A total of 754 subjects received one tablet of ODEFSEY daily.
The most common adverse reactions (all Grades) reported in at least 2% of subjects in the ODEFSEY group across Trials 1216 and 1160 were headache and sleep disturbances (Table 1). Over 98% of the adverse reactions in the ODEFSEY group were of mild to moderate intensity. The proportion of subjects who discontinued treatment with ODEFSEY due to adverse events, regardless of severity, was 2% compared to 1% for FTC/RPV/TDF and 2% for EFV/FTC/TDF.
Table 1 Adverse Reactionsa (All Grades) Reported in ?1% of HIV-1 Infected Virologically-Suppressed Adults in Trial 1160 or Trial 1216 (Week 48 analysis)
(please refer to label to view Table 1)
Renal Laboratory Tests
In Trial 1216, the median baseline eGFR was104 mL per minute for subjects who switched to ODEFSEY from FTC/RPV/TDF (N=316) and the mean serum creatinine decreased by 0.02 mg per dL from baseline to Week 48.
In Trial 1160, the median baseline eGFR was 110 mL per minute for subjects who switched to ODEFSEY from EFV/FTC/TDF (N=438), and the mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48.
Bone Mineral Density Effects
Changes in BMD from baseline to Week 48 were assessed by dual-energy X-ray absorptiometry (DXA) in Trials 1216 and 1160.
In Trial 1216, mean bone mineral density (BMD) increased in subjects who switched to ODEFSEY (1.61% lumbar spine, 1.04% total hip) and remained stable or decreased in subjects who remained on FTC/RPV/TDF (0.08% lumbar spine,?0.25% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 1.7% of ODEFSEY subjects and 3.0% of FTC/RPV/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 0% of ODEFSEY subjects and 1.2% of FTC/RPV/TDF subjects.
In Trial 1160, mean BMD increased in subjects who switched to ODEFSEY (1.65% lumbar spine, 1.28% total hip) and decreased slightly in subjects who remained on EFV/FTC/TDF (?0.05% lumbar spine, ?0.13% total hip). BMD declines of 5% or greater at the lumbar spine were experienced by 2.3% of ODEFSEY subjects and 4.9% of EFV/FTC/TDF subjects. BMD declines of 7% or greater at the femoral neck were experienced by 1.4% of ODEFSEY subjects and 3.3% of EFV/FTC/TDF subjects. The long-term clinical significance of these BMD changes is not known.
Serum Lipids
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and total cholesterol to HDL ratio for Trials 1216 and 1160 are presented in Table 2.
Table 2 Lipid Values, Mean Change from Baseline Reported in Subjects Receiving ODEFSEY, FTC/RPV/TDF and EFV/FTC/TDF in Trials 1216 and 1160 at 48 Weeks
(please refer to label to view Table 2)
Adverse Reactions in Clinical Trials of RPV-Containing Regimens in Treatment-Naïve Adult Subjects with HIV-1 Infection
In pooled 96-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reactions in subjects treated with RPV+FTC/TDF (N=550) (incidence greater than or equal to 2%, Grades 2?4) were headache, depressive disorders, and insomnia. The proportion of subjects who discontinued treatment with RPV+FTC/TDF due to adverse reactions, regardless of severity, was 2%. The most common adverse reactions that led to discontinuation in this treatment group were psychiatric disorders (1.6%) and rash (0.2%). Although the safety profile was similar in virologically-suppressed adults with HIV-1 infection who were switched to RPV and other antiretroviral drugs, the frequency of adverse events increased by 20% (N=317).
Adverse Reactions in Clinical Trials of FTC+TAF with EVG+COBI in Treatment-Naïve Adult Subjects with HIV-1 Infection
In pooled 48-week trials of antiretroviral treatment-naïve HIV-1 infected adult subjects, the most common adverse reaction in subjects treated with FTC+TAF with EVG+COBI (N=866) (incidence greater than or equal to 10%, all grades) was nausea (10%). In this treatment group, 0.9% of subjects discontinued FTC+TAF with EVG+COBI due to adverse event [see Clinical Studies (14)]. Antiretroviral treatment-naïve adult subjects treated with FTC+TAF with EVG+COBI experienced mean increases of 30 mg/dL of total cholesterol, 15 mg/dL of LDL cholesterol, 7 mg/dL of HDL cholesterol and 29 mg/dL of triglycerides after 48 weeks of use.
Renal Laboratory Tests
two 48-week trials in antiretroviral treatment-naïve HIV-1 infected adults treated with FTC+TAF with EVG+COBI (N=866) with a median baseline eGFR of 115 mL per minute, mean serum creatinine increased by 0.1 mg per dL from baseline to Week 48. In a 24-week trial in adults with renal impairment (baseline eGFR 30 to 69 mL per minute) who received FTC+TAF with EVG+COBI (N=248), mean serum creatinine was 1.5 mg per dL at both baseline and Week 24.
…
7 Drug Interactions
7.1 Potential for Other Drugs to Affect One or More Components of ODEFSEY(additions underlined)
Drugs that Induce or Inhibit CYP3A Enzymes
RPV is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of RPV. 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.
These drugs are contraindicated and include:
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifampin and rifapentine
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St. John’s wort (Hypericum perforatum)
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 and BCRP activity may lead to changes in TAF absorption (see Table 3). 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 and BCRP may increase the absorption and plasma concentration of TAF.
Drugs that Increase Gastric pH
Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and lead to loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Use of RPV with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration.
(addition underlined)
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, sofosbuvir, and velpatasvir.
8 Use in Specific Populations
8.1 Pregnancy(additions underlined)
…
Risk Summary
There are insufficient human data on the use of ODEFSEY during pregnancy to inform a drug-associated risk of birth defects and miscarriage. Tenofovir alafenamide (TAF) use in women during pregnancy have not been evaluated; however, emtricitabine (FTC) and rilpivirine (RPV) use during pregnancy has been evaluated in a limited number of women reported to the APR. Available data from the APR show no difference in the risk of overall major birth defects for FTC and RPV compared with the background rate for major birth defects of 2.7% in a US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in the clinically recognized pregnancies in the U.S. general population is 15-20%. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.
…
Data
Human Data
Emtricitabine: Based on prospective reports to the APR of 3406 exposures to FTC-containing regimens during pregnancy (including 2326 exposed in the first trimester and 1080 exposed in the second/third trimester), there was no difference between FTC and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 2.3% (95% CI: 1.7% to 3.0%) with first trimester exposure to FTC-containing regimens and 2.0% (95% CI: 1.3% to 3.1%) with second/third trimester exposure to FTC-containing regimens.
Rilpivirine: Based on prospective reports to the APR of 326 live births following exposures to RPV-containing regimens during pregnancy (including 202 exposed in the first trimester and 124 exposed in the second/third trimester), there was no difference in the rate of overall birth defects for RPV compared with the background rate of 2.7% for major birth defects in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 0.5% (95% CI: 0.0% to 2.7%) with first trimester exposure to RPV-containing regimens and 0.8% (95% CI: 0.0% to 4.4%) with second/third trimester exposure to RPV- containing regimens.
…
(additions underlined)
Risk Summary
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV.
Based on published data, FTC has been shown to be present in human breast milk; it is unknown if RPV and TAF are present in human breast milk. RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF [see Data]. It is unknown if TAF is present in animal milk.
…
No dosage adjustment of ODEFSEY is recommended in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. ODEFSEY has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
Patient Information(additions underlined)
…
What is ODEFSEY?
ODEFSEY is a prescription medicine that is used to treat Human Immunodeficiency Virus-1 (HIV-1) in people 12 years of age and older:
• who have not received anti-HIV-1 medicines in the past and who have an amount of HIV-1 in their blood (this is called “viral load”) that is no more than 100,000 copies/mL, or
• to replace their current anti-HIV-1 medicines for people whose healthcare provider determines that they meet certain requirements.
HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
ODEFSEY contains the prescription medicines emtricitabine, rilpivirine and tenofovir alafenamide.
It is not known if ODEFSEY is safe and effective in children under 12 years of age or who weigh less than 77 lb (35 kg).
…
04/07/2017 (SUPPL-1)
5 Warnings and Precautions
5.9 Lactic Acidosis/Severe Hepatomegaly with Steatosis(Additions and/or revisions are underlined)
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine, a component of ODEFSEY, and tenofovir DF, another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with ODEFSEY should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Lactic Acidosis and Severe Hepatomegaly
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported…
(Additions and/or revisions are underlined)
What are the possible side effects of ODEFSEY?
ODEFSEY may cause serious side effects, including:
- Too much lactic acid in your blood (lactic acidosis). Too much lactic acid is a serious but rare medical emergency that can lead to death. Tell your healthcare provider right away if you get these symptoms: weakness or being more tired than usual, unusual muscle pain, being short of breath or fast breathing, stomach pain with nausea and vomiting, cold or blue hands and feet, feel dizzy or lightheaded, or a fast or abnormal heartbeat.
- Severe liver problems. In rare cases, severe liver problems can happen that can lead to death. Tell your healthcare provider right away if you get these symptoms: skin or the white part of your eyes turns yellow, dark “tea-colored” urine, light-colored stools, loss of appetite for several days or longer, nausea, or stomach-area pain.