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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.
COMPLERA (NDA-202123)
(EMTRICITABINE; RILPIVIRINE HYDROCHLORIDE; TENOFOVIR DISOPROXIL FUMARATE)
Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)
11/27/2019 (SUPPL-31)
5 Warnings and Precautions
5.9 Immune Reconstitution Syndrome(additions 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.
10/31/2018 (SUPPL-29)
4 Contraindications
4 CONTRAINDICATIONSCOMPLERA is contraindicated when coadministered with the following drugs; coadministration may result in loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs:
theAnticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin
Antimycobacterials: rifampin, rifapentine
Glucocorticoid (systemic): 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 all patients with HIV-1 for the presence of chronic 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 HBV and HIV-1 and have discontinued products containing FTC and/or TDF, two of the components of COMPLERA. Patients coinfected with HIV-1 and HBV who discontinue COMPLERA should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with COMPLERA. If appropriate, initiation of
anti-hepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.
(Additions and/or revisions are underlined)
Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) with RPV-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, treatment-related rashes with at least Grade 2 severity were reported in 1% of subjects receiving RPV plus FTC/TDF. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy.
Discontinue COMPLERA immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.
(Additions and/or revisions are underlined)
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 ordevelopment of liver-associated test elevations with use of COMPLERA. A few cases of hepatic toxicity have been reported in adult patients receiving an RPV-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors.…
(Additions and/or revisions are underlined)
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with RPV. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to COMPLERA, and if so, to determine whether the risks of continued therapy outweigh the benefits.
During the Phase 3 trials in adults (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among RPV (n=686) or efavirenz (EFV, n=682) was 9% and 8%, respectively. Most events were mild or moderate in severity. The incidence of Grades 3 and 4 depressive disorders (regardless of causality) was 1% for both RPV and EFV. The incidence of discontinuation due to depressive disorders among RPV or EFV was 1% in each arm. Suicidal ideation was reported in 4 subjects in each arm while suicide attempt was reported in 2 subjects in the RPV arm.
During the Phase 2 trial in pediatric subjects 12 to less than 18 years of age (N=36) receiving RPV through 48 weeks, the incidence of depressive disorders (regardless of causality, severity) was 19.4% (7/36). Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 5.6% (2/36). None of the subjects discontinued due to depressive disorders. Suicidal ideation and suicide attempt were reported in 1 subject.
(Additions and/or revisions are 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 TDF.
Prior to initiation of COMPLERA, and during treatment with COMPLERA, 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.
COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple nonsteroidal anti-inflammatory drugs [NSAIDs]). Cases of acute renal failure after initiation of high-dose or multipleNSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.
Emtricitabine and TDF are principally eliminated by the kidney; however, RPV is not. Since COMPLERA is a combination product and the dose of the individual components cannot be altered, COMPLERA is not recommended in patients with estimated creatinine clearance below 50 mL per minute.
(Subsection title has been revised; additions and/or revisions are underlined)
Bone Mineral Density
In clinical trials in HIV-1-infected adults, TDF, a component of COMPLERA, was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving TDF.
Clinical trials evaluating TDF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1-infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the TDF-treated HIV-1-infected pediatric subjects as compared to the control groups.
trends were observed in chronic hepatitis B-infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected.
The effects of TDF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and Vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
Mineralization Defects
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of TDF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy.
Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing TDF.
(Newly added subsection)
The concomitant use of COMPLERA and other drugs may result in potentially significant drug interactions, some of which may lead to:
- Loss of therapeutic effect of COMPLERA and possible development of resistance due to reduced exposure to RPV.
- Possible clinically significant adverse reaction from greater exposures of components of COMPLERA.
In healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in COMPLERA) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to COMPLERA when coadministered with a drug that is known to have a risk of Torsade de Pointes.
See Table 4 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 COMPLERA therapy and review concomitant medications during COMPLERA therapy.
(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 TDF and FTC, components of COMPLERA, alone or in combination with other antiretrovirals. Treatment with COMPLERA 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).
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 in Patients Coinfected with HIV-1
and HBV.
Skin and Hypersensitivity Reactions
Hepatotoxicity.
Depressive Disorders.
New Onset or Worsening Renal Impairment.
Bone Loss and Mineralization Defects .
Lactic Acidosis/Severe Hepatomegaly with Steatosis.
Immune Reconstitution Syndrome.
(Additions and/or revisions are underlined)
…
Studies C209 and C215
The safety assessment of RPV, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 subjects in the Phase 3 trials
TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1-infected adult subjects. A total of 686 subjects received RPV in combination with other antiretroviral drugs as background regimen; most (N=550) received FTC/TDF as background regimen. The number of subjects randomized to the control arm EFV was 682, of which 546 received FTC/TDF as background regimen. The median duration of exposure for subjects in either treatment arm was 104 weeks.
Adverse reactions observed at Week 96 in subjects who received RPV or +EFV + FTC/TDF as background regimen are shown in Table 1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant).
The proportion of subjects who discontinued treatment with RPV or EFV + FTC/TDF due to adverse reactions, regardless of severity, was 2% and 5%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the RPV + FTC/TDF arm and 12 (2.2%) subjects in the EFV + FTC/TDF arm. Rash led to discontinuation in 1 (0.2%) subject in the RPV + FTC/TDF arm and 10 (1.8%) subjects in the EFV + FTC/TDF arm.
Common Adverse Reactions: Clinical adverse reactions to RPV or EFV of at least moderate intensity (greater than or equal to Grade 2) reported in at least 2% of adult subjects are shown in Table 1.
(Table 1 has been revised; please refer to label)
…
Rilpivirine: Adverse reactions of at least moderate intensity (?Grade 2) that occurred in less than 2% of subjects treated with RPV plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.
In Virologically Suppressed HIV-1-Infected Adult Subjects
No new adverse reactions to COMPLERA were identified in stable, virologically suppressed subjects switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however, the frequency of adverse reactions increased by 20% (Study 106) after switching to COMPLERA.
Emtricitabine and Tenofovir DF: The most common adverse reactions that occurred in at least 10% of HIV-1-infected treatment-naïve adult subjects in a Phase 3 clinical trial of FTC and TDF in combination with another antiretroviral agent were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.
Adverse reactions that occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving FTC or TDF with other antiretroviral agents in clinical trials included abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.
Skin discoloration has been reported with higher frequency among FTC-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
Laboratory Abnormalities in Adult Subjects
The percentage of subjects treated with RPV + FTC/TDF or EFV + FTC/TDF in studies C209 and C215 with selected laboratory abnormalities (Grades 1–4), representing worst-grade toxicity, is presented in Table 2.
(Table 2 has been revised; please refer to label)
Emtricitabine or Tenofovir DF: The following Grade 3 or 4 laboratory abnormalities have been previously reported in subjects treated with FTC or TDF with other antiretroviral agents in other clinical trials: increased pancreatic amylase (>2.0 ´ ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 ´ ULN), increased alkaline phosphatase (>550 U/L), increased or decreased serum glucose (<40 or >250 mg/dL), increased glycosuria (greater than or equal to 3+), increased creatine kinase (M: >990 U/L; F: >845 U/L), decreased neutrophils (<750/mm3), and increased hematuria (>75 RBC/HPF).
Adrenal Function: In the pooled Phase 3 trials of C209 and C215, in subjects treated with RPV plus any of the allowed background regimens (N=686), at Week 96 there was an overall mean change from baseline in basal cortisol of –0.69 (?1.12, 0.27) micrograms/dL in the RPV group, and of ?0.02 (?0.48, 0.44) micrograms/dL in the EFV group.
In the RPV group, 43/588 (7.3%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3.2%) in the EFV group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the RPV group and 9 subjects in the EFV group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the RPV group is not known.
Serum Creatinine: In the pooled Phase 3 trials of C209 and C215 in subjects treated with RPV plus any of the allowed background regimens (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with RPV. Most of this increase occurred within the first 4 weeks of treatment, with a mean change of 0.1 mg/dL (range –0.3 to 0.6 mg/dL) observed through Week 96. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not considered to be clinically relevant, and no subject discontinued treatment due to increases in serum creatinine. Creatinine increases were comparable by background N(t)RTIs.
Serum Lipids: Changes from baseline in total cholesterol, LDL-cholesterol, and triglycerides are presented in Table 3.
(Table 3 has been revised; please refer to label)
Adult Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In adult subjects coinfected with hepatitis B or C virus receiving RPV in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving RPV who were not coinfected. The same increase was also observed in the EFV arm. The pharmacokinetic exposure of RPV in coinfected subjects was comparable to that in subjects without coinfection.
Adverse Reactions from Clinical Trials Experience in Pediatric Subjects
Emtricitabine: In addition to the adverse reactions reported in adults, anemia and hyperpigmentation were observed in 7% and 32%, respectively, of pediatric subjects (3 months to less than 18 years of age) who received treatment with FTC in the larger of two open-label, uncontrolled pediatric trials (N=116). For additional information, please consult the EMTRIVA prescribing information.
Rilpivirine: The safety assessment is based on the Week 48 analysis of the single-arm, open-label Phase 2 trial, TMC278-C213, in which 36 antiretroviral treatment-naïve
HIV-1-infected subjects 12 to less than 18 years of age and weighing at least 32 kg received RPV (25 mg once daily) in combination with other antiretroviral agents. The median duration of exposure for subjects was 63.5 weeks. No subjects discontinued treatment due to adverse reactions. No new adverse reactions were identified compared to those seen in adults.
Adverse reactions were reported in 19 pediatric subjects (52.8%). Most adverse reactions were Grade 1 or 2. The most common adverse reactions reported in at least 2 subjects (regardless of severity) include headache (19.4%), depression (19.4%), somnolence (13.9%), nausea (11.1%), dizziness (8.3%), abdominal pain (8.3%), vomiting (5.6%), and rash (5.6%).
Observed laboratory abnormalities were comparable to those in adults. For additional information, please consult the Edurant prescribing information.
Adrenal Function
In trial TMC278-C213, at Week 48, the overall mean change from baseline in basal cortisol showed an increase of 1.59 (0.24, 2.93) micrograms/dL.
Six of 30 (20%) subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial. Three of these subjects had an abnormal 250 micrograms ACTH stimulation test at Week 48. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the abnormal 250 micrograms ACTH stimulation tests is not known.
Tenofovir DF: In a pediatric clinical trial conducted in subjects 12 to less than 18 years of age, the adverse reactions observed in pediatric subjects who received treatment with TDF were consistent with those observed in clinical trials of TDF in adults. For additional information, including information on bone mineral density changes, please consult the VIREAD prescribing information.
(Additions and/or revisions are underlined)
The following adverse reactions have been identified during postmarketing experience in patients receiving RPV- or TDF-containing regimens. Because postmarketing 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.
…
7 Drug Interactions
7.1 Not Recommended with Other Antiretroviral Medications(Additions and/or revisions are underlined)
Because COMPLERA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not Information recommended. Comprehensive information regarding potential drug-drug interactions with other antiretroviral medications is not provided.
This section describes clinically relevant drug interactions with COMPLERA. Drug interaction studies were conducted with the components of COMPLERA (FTC, RPV, and TDF as single agents) or with COMPLERA as a combination product.
(Additions and/or revisions are underlined)
Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus 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. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.
(Additions and/or revisions are underlined)
Coadministration of RPV with drugs that increase gastric pH may decrease plasma concentrations of RPV and 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.
(Additions and/or revisions are underlined)
Because FTC and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of COMPLERA withdrugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of FTC, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
(Additions and/or revisions are underlined)
There is limited information available on the potential for a pharmacodynamic interaction between RPV and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, 75 mg once daily and 300 mg once daily doses of RPV (3 times and 12 times the dose in COMPLERA) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to COMPLERA when coadministered with a drug with a known risk of Torsade de Pointes.
(Additions and/or revisions are underlined)
Important drug interaction information for COMPLERA is summarized in Table 4. The drug interactions described are based on studies conducted with FTC, RPV, or TDF as individual medications or with COMPLERA as a combination product, or are potential drug interactions. For list of contraindicated drugs, [see Contraindications(4)].
(Table 4 has been revised; please refer to label)
(Additions and/or revisions are underlined)
No clinically significant drug interactions have been observed between FTC and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF.
No clinically significant drug interactions have been observed between TDF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, sofosbuvir, or tacrolimus in studies conducted in healthy subjects.
No clinically significant drug interactions have been observed between RPV and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, or TDF. RPV did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.
8 Use in Specific Populations
8.1 Pregnancy(Extensive changes; PLLR conversion; please refer to label)
(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, FTC and tenofovir have been shown to be present in human milk. There are no data on the presence of RPV in human milk. RPV has been shown to be present in rat milk.
It is not known if the components of COMPLERA affect milk production or have effects on the breastfed child. 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 COMPLERA.
Data
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).
(Additions and/or revisions are underlined)
The safety and effectiveness of COMPLERA as a complete regimen for the treatment of HIV-1 infection was established in pediatric subjects 12 years of age and older with body weight greater than or equal to 35 kg. Use of COMPLERA in this age group weighing at least 35 kg is supported by adequate and well-controlled studies of RPV+FTC+TDF in adults with HIV-1 infection as well as data from pediatric studies of the individual components of COMPLERA (RPV, FTC, and TDF).
COMPLERA should only be administered to pediatric patients with a body weight greater than or equal to 35 kg. Because COMPLERA is a fixed-dose combination tablet, the dose of COMPLERA cannot be adjusted for patients of lower weight. Safety and effectiveness for COMPLERA have not been established in pediatric patients weighing less than 35 kg.
(Additions and/or revisions are underlined)
Clinical studies of FTC, RPV, or TDF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for elderly patients should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
(Additions and/or revisions are underlined)
Because COMPLERA is a fixed-dose combination, and cannot be dose adjusted, it is not recommended in patients with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Posttreatment Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV
Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and who have discontinued products containing FTC or TDF. Advise patients to not discontinue COMPLERA without first informing their healthcare provider.
Severe Skin Reactions and Hypersensitivity
Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking COMPLERA and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as DRESS severe hypersensitivity: fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), severe allergic reaction causing swelling of the face, eyes, lips, mouth, tongue, or throat which may lead to difficulty swallowing or breathing, and any signs and symptoms of liver problems, as they may be a sign of a more serious reaction. Patients should understand that if severe rash occurs, they will be closely monitored, laboratory tests will be performed and appropriate therapy will be initiated.
Inform patients that hepatotoxicity has been reported with COMPLERA and that monitoring for hepatotoxicity is recommended
Depressive Disorders
Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with COMPLERA. Advise patients to seek immediate medical evaluation if they experience depressive symptoms.
New Onset or Worsening Renal Impairment
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF. COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs).
Bone Loss and Mineralization Defects
Inform patients that decreases in bone mineral density have been observed with the use of TDF. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
Drug Interactions
COMPLERA may interact with many drugs and is not recommended to be coadministered with numerous drugs. Advise patients to report to their healthcare provider the use of any other prescription or nonprescription medication or herbal products, including St. John's wort.
For patients receiving rifabutin, an additional 25 mg tablet of RPV (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.
Lactic Acidosis and Severe Hepatomegaly
Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with COMPLERA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
Immune Reconstitution Syndrome
Inform patients to inform their healthcare provider immediately of any signs and symptoms of inflammation from previous infections, which may occur soon after anti-HIV treatment is started.
Dosing Instructions
Advise patients that it is important to take COMPLERA on a regular dosing schedule with food and to avoid missing doses. A protein drink is not a substitute for food. If the healthcare provider decides to stop COMPLERA and the patient is switched to new medicines to treat HIV that include RPV tablets, the RPV tablets should be taken only with a meal.
Pregnancy Registry
Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes in those exposed to COMPLERA 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(Extensive changes; please refer to the label)
04/07/2017 (SUPPL-27)
5 Warnings and Precautions
5.4 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 tenofovir DF and emtricitabine, components of COMPLERA, alone or in combination with other antiretrovirals…
(Additions and/or revisions are underlined)
COMPLERA is a fixed-dose combination of rilpivirine, emtricitabine, and tenofovir DF. Do not coadminister COMPLERA with other drugs containing emtricitabine, tenofovir DF, or tenofovir alafenamide, including ATRIPLA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD; or with medicinal products containing lamivudine (Epivir, Epivir-HBV, Epzicom, Combivir, Triumeq, Trizivir);…
6 Adverse Reactions
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The following adverse reactions are discussed in other sections of the labeling:
- Drug Interactions
7 Drug Interactions
7.5 Established and Other Potentially Significant Drug InteractionsTable 4 Established and Other Potentially Significant (superscript a) Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
(Table has been revised; please refer to label)
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No clinically significant drug interactions have been observed between emtricitabine and the following medications: famciclovir, ledipasvir/sofosbuvir, sofosbuvir/velpatasvir, or tenofovir DF…
No clinically significant drug interactions have been observed between rilpivirine and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, telaprevir, or tenofovir DF…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
17 PATIENT COUNSELING INFORMATION(Additions and/or revisions are underlined)
Information for Patients
Drug Interactions
…COMPLERA should not be coadministered with ATRIPLA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD; or with drugs containing lamivudine, including Combivir, Epivir or Epivir-HBV, Epzicom, Triumeq, or Trizivir; or with HEPSERA…
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What are the possible side effects of COMPLERA?
COMPLERA can 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.
02/23/2016 (SUPPL-24)
02/09/2016 (SUPPL-23)
7 Drug Interactions
Drugs with No Observed or Predicted Interactions with COMPLERA- No clinically significant drug interactions have been observed between rilpivirine and the following medications: ledipasvir/sofosbuvir, simeprevir, sofosbuvir
ledipasvir/sofosbuvir
- Patients receiving COMPLERA concomitantly with HARVONI (ledipasvir/sofosbuvir) should be monitored for adverse reactions associated with tenofovir disoproxil fumarate.