Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 31 December 2017

Indication(s)

1 INDICATIONS AND USAGE COMPLERA®, a combination of two nucleoside analog HIV-1 reverse transcriptase inhibitors (NRTIs) (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside reverse transcriptase inhibitor (NNRTI) (rilpivirine), is indicated for use as a complete regimen for the treatment of HIV-1 infection in patients 12 years of age and older with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, and in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see below). The following points should be considered when initiating therapy with COMPLERA in patients with no antiretroviral treatment history: More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [See Clinical Studies (14)]. Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count less than 200 cells/mm3 experienced virologic failure compared to rilpivirine-treated subjects with CD4+ cell count greater than or equal to 200 cells/mm3 [See Clinical Studies (14)]. The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz [See Microbiology (12.4)]. More subjects treated with rilpivirine developed tenofovir- and lamivudine/emtricitabine-associated resistance compared to efavirenz [See Microbiology (12.4)]. The efficacy of COMPLERA was established in patients who were virologically-suppressed (HIV-1 RNA <50 copies/mL) on stable ritonavir-boosted protease inhibitor (PI)-containing regimen. The following points should be met when considering replacing the current regimen with COMPLERA in virologically-suppressed patients [See Clinical Studies (14)]: Patients should have no history of virologic failure. Patients should have been stably suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to switching therapy. Patients should currently be on their first or second antiretroviral regimen prior to switching therapy. Patients should have no current or past history of resistance to any of the three components of COMPLERA. Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound. COMPLERA, a combination of two nucleoside analog HIV-1 reverse transcriptase inhibitors (emtricitabine and tenofovir disoproxil fumarate) and one non-nucleoside reverse transcriptase inhibitor (rilpivirine), is indicated for use as a complete regimen for the treatment of HIV-1 infection in (1) patients 12 years of age and older with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, and (2) in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen [see below]. (1, 14) The following points should be considered when initiating therapy with COMPLERA in patients with no antiretroviral treatment history (1, 12.4, 14): More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count less than 200 cells/mm3 at the start of therapy experienced virologic failure compared to subjects with CD4+ cell count greater than or equal to 200 cells/mm3. The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz. More subjects treated with rilpivirine developed tenofovir- and lamivudine/emtricitabine-associated resistance compared to efavirenz. The efficacy of COMPLERA was established in patients who were virologically-suppressed (HIV-1 RNA <50 copies/mL) on stable ritonavir-boosted protease inhibitor-containing regimen. The following points should be met when considering replacing the current regimen with COMPLERA in virologically-suppressed (HIV-1 RNA <50 copies/mL) patients (1,14): Patients should have no history of virologic failure. Patients should have been suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to switching therapy. Patients should currently be on their first or second antiretroviral regimen prior to switching therapy. Patients should have no current or past history of resistance to any of the three components of COMPLERA. Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound. (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS COMPLERA should not be coadministered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to COMPLERA or to the class of NNRTIs [See Drug Interactions (7) and Clinical Pharmacology (12.3)]: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin the antimycobacterials rifampin, rifapentine proton pump inhibitors, such as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole the glucocorticoid systemic dexamethasone (more than a single dose) St. John's wort (Hypericum perforatum) Coadministration of COMPLERA is contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are discussed in other sections of the labeling: Severe Acute Exacerbations of Hepatitis B [See Boxed Warning, Warnings and Precautions (5.1)]. Skin and Hypersensitivity Reactions [See Warnings and Precautions (5.2)]. New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)]. Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Warnings and Precautions (5.4)]. Drug Interactions [See Warnings and Precautions (5.5)]. Depressive Disorders [See Warnings and Precautions (5.6)]. Hepatotoxicity [See Warnings and Precautions (5.7)]. Bone Effects of Tenofovir DF [See Warnings and Precautions (5.8)]. Immune Reconstitution Syndrome [See Warnings and Precautions (5.10)]. Most common adverse reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2–4) are depressive disorders, insomnia, and headache. (6.1) Most common adverse reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater than or equal to 10%) are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Adverse Reactions from Clinical Trials Experience in Adult Subjects Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History Studies C209 and C215 Treatment-Emergent Adverse Drug Reactions: The safety assessment of rilpivirine, 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 rilpivirine in combination with other antiretroviral drugs as background regimen; most (N=550) received emtricitabine/tenofovir DF as background regimen. The number of subjects randomized to the control arm efavirenz was 682, of which 546 received emtricitabine/tenofovir DF as background regimen [See Clinical Studies (14)]. The median duration of exposure for subjects in either treatment arm was 104 weeks. Adverse reactions observed at Week 96 in subjects who received rilpivirine or efavirenz + emtricitabine/tenofovir DF 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 rilpivirine or efavirenz + emtricitabine/tenofovir DF 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 rilpivirine + emtricitabine/tenofovir DF arm and 12 (2.2%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Rash led to discontinuation in 1 (0.2%) subject in the rilpivirine + emtricitabine/tenofovir DF arm and 10 (1.8%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Common Adverse Reactions: Clinical adverse reactions to rilpivirine or efavirenz of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are shown in Table 1. Table 1 Selected Treatment-Emergent Adverse ReactionsFrequencies of adverse reactions are based on all Grades 2–4 treatment-emergent adverse events assessed to be related to study drug. (Grades 2–4) Reported in ≥2% of Adult Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis) System Organ Class Preferred Term Rilpivirine + FTC/TDF Efavirenz + FTC/TDF N=550 N=546 Gastrointestinal Disorders Nausea 1% 2% Nervous System Disorders Headache 2% 2% Dizziness 1% 7% Psychiatric Disorders Depressive disordersIncludes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 2% 2% Insomnia 2% 2% Abnormal dreams 1% 3% Skin and Subcutaneous Tissue Disorders Rash 1% 5% Rilpivirine: Treatment-emergent adverse reactions of at least moderate intensity (≥Grade 2) that occurred in less than 2% of subjects treated with rilpivirine 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 emtricitabine and tenofovir DF 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 emtricitabine or tenofovir DF 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 emtricitabine-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. 6.2 Laboratory Abnormalities in Adult Subjects The percentage of subjects treated with rilpivirine + emtricitabine/tenofovir DF or efavirenz + emtricitabine/tenofovir DF in studies C209 and C215 with selected treatment-emergent laboratory abnormalities (Grades 1–4), representing worst-grade toxicity, is presented in Table 2. Table 2 Selected Laboratory Abnormalities (Grades 1–4) Reported in Adult Subjects Who Received Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis) Laboratory Parameter Abnormality DAIDS Toxicity Range Rilpivirine + FTC/TDF Efavirenz + FTC/TDF N=550 N=546 N=number of subjects per treatment group Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine + tenofovir DF as background regimen. BIOCHEMISTRY Increased Creatinine Grade 1 1.1–1.3 × ULNULN=Upper limit of normal value. 6% 1% Grade 2 >1.3–1.8 × ULN 1% 1% Grade 3 >1.8–3.4 × ULN <1% 0 Grade 4 >3.4 × ULN 0 <1% Increased AST Grade 1 1.25–2.5 × ULN 16% 19% Grade 2 >2.5–5.0 × ULN 4% 7% Grade 3 >5.0–10.0 × ULN 2% 3% Grade 4 >10.0 × ULN 1% 1% Increased ALT Grade 1 1.25–2.5 × ULN 19% 22% Grade 2 >2.5–5.0 × ULN 5% 7% Grade 3 >5.0–10.0 × ULN 1% 2% Grade 4 >10.0 × ULN 1% 1% Increased Total Bilirubin Grade 1 1.1–1.5 × ULN 6% <1% Grade 2 >1.5–2.5 × ULN 3% 1% Grade 3 >2.5–5.0 × ULN 1% <1% Increased Total Cholesterol (fasted) Grade 1 200–239 mg/dL 14% 31% Grade 2 240–300 mg/dL 6% 18% Grade 3 >300 mg/dL <1% 2% Increased LDL Cholesterol (fasted) Grade 1 130–159 mg/dL 13% 28% Grade 2 160–190 mg/dL 5% 13% Grade 3 >190 mg/dL 1% 4% Increased Triglycerides (fasted) Grade 2 500–750 mg/dL 1% 2% Grade 3 751–1200 mg/dL 1% 2% Grade 4 >1200 mg/dL 0 1% Emtricitabine or Tenofovir DF: The following Grade 3 or 4 laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF 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 (≥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 rilpivirine 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 rilpivirine group, and of −0.02 (−0.48, 0.44) micrograms/dL in the efavirenz group. In the rilpivirine 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 efavirenz group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, 14 subjects in the rilpivirine group and 9 subjects in the efavirenz 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 rilpivirine group is not known. Serum Creatinine: In the pooled Phase 3 trials of C209 and C215 in subjects treated with rilpivirine plus any of the allowed background regimens (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with rilpivirine. 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 Lipid Values Reported in Adult Subjects Receiving Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in Studies C209 and C215Excludes subjects who received lipid lowering agents during the treatment period. Pooled Data from the Week 96 Analysis of C209 and C215 Trials Rilpivirine + FTC/TDF N=550 Efavirenz + FTC/TDF N=546 N Baseline Week 96 N Baseline Week 96 Mean Mean (mg/dL) Mean (mg/dL) Mean ChangeThe change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values. (mg/dL) Mean (mg/dL) Mean (mg/dL) Mean Change (mg/dL) N=number of subjects per treatment group Total Cholesterol (fasted) 430 162 164 2 401 160 186 26 HDL-cholesterol (fasted) 429 42 45 4 399 40 50 11 LDL-cholesterol (fasted) 427 97 97 –1 397 96 110 14 Triglycerides (fasted) 430 123 109 –14 401 127 133 6 Adult Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus: In adult subjects coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The same increase was also observed in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection. 6.3 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 EMTRIVA 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 rilpivirine (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 VIREAD were consistent with those observed in clinical trials of VIREAD in adults [See Warnings and Precautions (5.8)]. For additional information, including information on bone mineral density changes, please consult the VIREAD prescribing information. 6.4 Postmarketing Experience The following adverse reactions have been identified during postmarketing experience in patients receiving rilpivirine- or tenofovir DF-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. COMPLERA: 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) Rilpivirine: Renal and Urinary Disorders nephrotic syndrome Emtricitabine: No postmarketing adverse reactions have been identified for inclusion in this section. Tenofovir DF: Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT, gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION The recommended dose of COMPLERA in patients 12 years of age and older and weighing at least 35 kg is one tablet taken orally once daily with food [See Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]. Dose in patients 12 years of age and older: One tablet (containing 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate) taken once daily with food. (2) Dose in renal impairment: Should not be administered in patients with estimated creatinine clearance below 50 mL per minute. (2) With rifabutin coadministration, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration. (2,7.5,12.3) Renal Impairment: Because COMPLERA is a fixed-dose combination, it should not be prescribed for patients requiring dose reduction, such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute) [See Warnings and Precautions (5.3)]. Rifabutin Coadministration: If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant®) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration [See Drug Interactions (7.5) and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1) Nursing mothers: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.3) Pediatrics: Safety and effectiveness have not been established in patients less than 12 years of age. (8.4) 8.1 Pregnancy Pregnancy Category B Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose. Rilpivirine: Studies in animals have shown no evidence of embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily. Tenofovir DF: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, COMPLERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to COMPLERA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263. 8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Emtricitabine: Samples of breast milk obtained from 5 HIV-1-infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown. Rilpivirine: Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Tenofovir DF: Samples of breast milk obtained from 5 HIV-1-infected mothers in the first postpartum week show that tenofovir is excreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMPLERA . 8.4 Pediatric Use Because COMPLERA is a fixed-dose combination tablet, it is not recommended for patients requiring dose adjustments. Safety and efficacy for COMPLERA have not been established in pediatric patients less than 12 years of age or weighing less than 35 kg [See Adverse Reactions (6.3) and Clinical Pharmacology (12.3)]. For additional information, please consult the Edurant, EMTRIVA, and VIREAD prescribing information. 8.5 Geriatric Use Clinical studies of emtricitabine, rilpivirine, or tenofovir DF 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 [See Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Because COMPLERA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment, such as those with moderate, severe, or end-stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis [See Warnings and Precautions (5.3) , Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment No dose adjustment of COMPLERA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. COMPLERA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) [See Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Emtricitabine: Samples of breast milk obtained from 5 HIV-1-infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown. Rilpivirine: Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk. Tenofovir DF: Samples of breast milk obtained from 5 HIV-1-infected mothers in the first postpartum week show that tenofovir is excreted in human milk. The impact of this exposure in breastfed infants is unknown. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMPLERA .

Interactions

7 DRUG INTERACTIONS COMPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, COMPLERA should not be administered with other antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. Please refer to the Edurant, VIREAD, and EMTRIVA prescribing information as needed. This section describes clinically relevant drug interactions with COMPLERA. Drug interaction studies were conducted with the components of COMPLERA (emtricitabine, rilpivirine, and tenofovir DF as single agents) or with COMPLERA as a combination product [See Dosage and Administration (2), Contraindications (4), and Clinical Pharmacology (12.3)]. COMPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, COMPLERA should not be administered with other antiretroviral medications for treatment of HIV-1 infection. CYP3A4 inducers or inhibitors: Drugs that induce or inhibit CYP3A4 may affect the plasma concentrations of rilpivirine. (7.1) Drugs that increase gastric pH: Drugs that increase gastric pH may decrease plasma concentrations of rilpivirine. (7.2) 7.1 Drugs Inducing or Inhibiting CYP3A Enzymes Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine [See Clinical Pharmacology (12.3), Contraindications (4)]. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes. 7.2 Drugs Increasing Gastric pH Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs (See Table 4). 7.3 Drugs Affecting Renal Function Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, 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 [See Warnings and Precautions (5.3)]. 7.4 QT Prolonging Drugs There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [See Clinical Pharmacology (12.2)]. COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes. 7.5 Established and Other Potentially Significant Drug Interactions Important drug interaction information for COMPLERA is summarized in Table 4. The drug interactions described are based on studies conducted with emtricitabine, rilpivirine, or tenofovir DF as individual medications or with COMPLERA as a combination product, or are potential drug interactions [for pharmacokinetic data see Clinical Pharmacology (12.3) , Tables 7 –8]. Table 4 includes potentially significant interactions, but is not all inclusive. Table 4 Established and Other Potentially SignificantThis table is not all inclusive. Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction Concomitant Drug Class: Drug Name Effect on ConcentrationIncrease=↑; Decrease=↓; No Effect=↔ Clinical Comment Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA. Antimycobacterials: rifabutin ↓ rilpivirineThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration. Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ rilpivirine , This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily. ↓ ketoconazole , Concomitant use of COMPLERA with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with COMPLERA. Hepatitis C Antiviral Agents: ledipasvir/sofosbuvir sofosbuvir/velpatasvir ↑ tenofovir Patients receiving COMPLERA concomitantly with HARVONI® (ledipasvir/sofosbuvir) or EPCLUSA® (sofosbuvir/velpatasvir) should be monitored for adverse reactions associated with tenofovir DF. H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine ↔ rilpivirine , (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine , (famotidine taken 2 hours before rilpivirine) The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA. Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ telithromycin Concomitant use of COMPLERA with clarithromycin, erythromycin, or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. Narcotic Analgesics: methadone ↓ R(–) methadone ↓ S(+) methadone ↔ rilpivirine ↔ methadone (when used with tenofovir) No dose adjustments are required when initiating coadministration of methadone with COMPLERA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. 7.6 Drugs with No Observed or Predicted Interactions with COMPLERA 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 tenofovir DF 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 rilpivirine and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, ledipasvir/sofosbuvir, norethindrone, sildenafil, simeprevir, sofosbuvir, sofosbuvir/velpatasvir, telaprevir, or tenofovir DF. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when rilpivirine is coadministered with ribavirin.

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Category Value
Authorisation number NDA202123
Agency product number OTT9J7900I
Orphan designation No
Product NDC 50090-1248
Date Last Revised 16-11-2017
Type HUMAN PRESCRIPTION DRUG
RXCUI 1147337
Marketing authorisation holder A-S Medication Solutions
Warnings WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD, which are components of COMPLERA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue COMPLERA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.1)]. WARNING: POSTTREATMENT ACUTE EXACERBATION OF HEPATITIS B See full prescribing information for complete boxed warning. COMPLERA is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of COMPLERA. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.1)