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COMPLERA (emtricitabine 200 mg rilpivirine hydrochloride 25 mg tenofovir disoproxil fumarate 300 mg) Dailymed

  1. Human Prescription
  2. Human Immunodeficiency Virus 1 Non-Nucleoside Analog Reverse Transcriptase Inhibitor
  3. Gilead Sciences, Inc.

Generic: emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate is used for the treatment of HIV Infections Hepatitis B, Chronic Acquired Immunodeficiency Syndrome

COMPLERA tablet, film coated - (emtricitabine 200 mg rilpivirine hydrochloride 25 mg tenofovir disoproxil fumarate 300 mg) image

IMPRINT: GSI     SHAPE: oval
    COLOR: purple

Boxed Warning

Warning: Posttreatment Acute Exacerbation Of Hepatitis B

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA. Closely monitor hepatic function 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. Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients coinfected with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA. Closely monitor hepatic function 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. (5.1)

  1. FDA Adverse Reactions

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Warning: Posttreatment Acute Exacerbation Of Hepatitis B


Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA.

Closely monitor hepatic function 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.

Severe acute exacerbations of hepatitis B virus (HBV) have been reported in patients coinfected with HIV-1 and HBV who have discontinued products containing emtricitabine (FTC) and/or tenofovir disoproxil fumarate (TDF), two of the components of COMPLERA. Closely monitor hepatic function 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. (5.1)

Recent Major Changes Section


Warnings and Precautions
  Immune Reconstitution Syndrome (5.9) 11/2019

1 Indications And Usage


COMPLERA® is indicated as a complete regimen for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg:
  • as initial therapy in those with no antiretroviral treatment history with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy or
  • to replace a stable antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of COMPLERA [see Microbiology (12.4) and Clinical Studies (14)].


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 patients weighing at least 35 kg (1) as initial therapy in those with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, or (2) or to replace a stable antiretroviral regiment in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable antiretroviral regimen for at least 6 months with no treatment failure and no known substitutions associated with resistance to the individual components of COMPLERA. (1, 14)

Limitations of Use:
  • 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. (1, 14)


Limitations of Use:
  • 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)].

2 Dosage And Administration


  • Testing: Prior to or when initiating COMPLERA, test for hepatitis B virus infection. Prior to initiation 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. (2.1)
  • Recommended dosage in adults and pediatric patients weighing at least 35 kg: One tablet taken orally once daily with food. (2.2)
  • For pregnant patients who are already on COMPLERA prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet taken once daily may be continued. Lower exposures of rilpivirine were observed during pregnancy; therefore, viral load should be monitored closely. (2.3)
  • Renal impairment: Not recommended in patients with estimated creatinine clearance below 50 mL per minute. (2.4)
  • Recommended dosage with rifabutin coadministration: an additional 25 mg tablet of rilpivirine (Edurant) once per day taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration. (2.5, 7.6, 12.3)

2.1Testing Prior to Initiation and During Treatment with COMPLERA


Prior to or when initiating COMPLERA, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

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 [see Warnings and Precautions (5.5)].

2.2Recommended Dosage


COMPLERA is a three-drug fixed dose combination product containing 200 mg of emtricitabine (FTC), 25 mg of rilpivirine (RPV), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of COMPLERA in adult and pediatric patients 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)].

2.3Recommended Dosage During Pregnancy


For pregnant patients who are already on COMPLERA prior to pregnancy and are virologically suppressed (HIV-1 RNA less than 50 copies per mL), one tablet of COMPLERA taken once daily may be continued. Lower exposures of rilpivirine, a component of COMPLERA, were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.3)].


COMPLERA is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute) [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].

2.5Recommended Dosage with Rifabutin Coadministration


If COMPLERA is coadministered with rifabutin, take an additional 25 mg tablet of rilpivirine (Edurant®) with COMPLERA once daily with a meal for the duration of the rifabutin coadministration [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths


Each COMPLERA tablet contains 200 mg of emtricitabine (FTC), 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine [RPV]), and 300 mg of tenofovir disoproxil fumarate (TDF, equivalent to 245 mg of tenofovir disoproxil).

The tablets are purplish pink, capsule shaped, film coated, debossed with "GSI" on one side, and plain faced on the other side.


Tablets: 200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir disoproxil fumarate. (3)

4 Contraindications


COMPLERA 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 [see Warnings and Precautions (5.7), Drug Interactions (7), and Clinical Pharmacology (12.3)]:
  • Anticonvulsants: 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


COMPLERA is contraindicated when coadministered with drugs which may result in loss of virologic response and possible resistance to COMPLERA. (4)

5 Warnings And Precautions


  • Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develops and closely monitor clinical status, including hepatic serum biochemistries. (5.2)
  • Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Monitor liver-associated tests before and during treatment with COMPLERA in patients with underlying hepatic disease or marked elevations in liver-associated tests. Also consider monitoring liver-associated tests in patients without risk factors. (5.3)
  • Depressive disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. (5.4)
  • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Avoid administering COMPLERA with concurrent or recent use of nephrotoxic drugs. (5.5)
  • Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.6)
  • Concomitant use of COMPLERA with drugs with a known risk to prolong the QTc interval of the electrocardiogram may increase the risk of Torsade de Pointes. (5.7)
  • Lactic acidosis/severe hepatomegaly with steatosis: Discontinue treatment in patients who develop symptoms or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity. (5.8)
  • Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.9)

5.1Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV


Test all patients with HIV-1 for the presence of chronic hepatitis B virus (HBV) before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)].

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.

5.2Skin and Hypersensitivity Reactions


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 [see Adverse Reactions (6.1 and 6.2)].

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, bulers, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated.

5.3Hepatotoxicity


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 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. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with COMPLERA 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 pre-existing hepatic dysfunction or other risk factors.

5.4Depressive Disorders


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.

5.5New Onset or Worsening Renal Impairment


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 [see Adverse Reactions (6.2)].

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]) [see Drug Interactions (7.4)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs 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 [see Use in Specific Populations (8.6)].

5.6Bone Loss and Mineralization Defects



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. Similar 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 [see Adverse Reactions (6.2)]. 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 [See Warnings and Precautions (5.5)].

5.7Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions


The concomitant use of COMPLERA and other drugs may result in potentially significant drug interactions, some of which may lead to [see Dosage and Administration (2.5), Contraindications (4), and Drug Interactions (7)]:
  • 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 Drug Interactions (7) and Clinical Pharmacology (12.2)].

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.

5.8Lactic Acidosis/Severe Hepatomegaly with Steatosis


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).

5.9Immune Reconstitution Syndrome


Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of COMPLERA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

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


The following adverse reactions are discussed in other sections of the labeling:

  • 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

6.1Clinical Trials Experience


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.


Adverse Reactions from Clinical Trials Experience in Adult Subjects


In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History


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.


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 Selected Laboratory Abnormalities (Grades 1–4) Reported in Adult Subjects Who Received RPV or EFV in Combination with FTC/TDF in Studies C209 and C215 (Week 96 Analysis)
Laboratory Parameter Abnormality DAIDS Toxicity Range RPV + FTC/TDF EFV + FTC/TDF
N=550 N=546
N=number of subjects per treatment groupULN=Upper limit of normal value.Note: Percentages were calculated versus the number of subjects in ITT population with FTC + TDF as background regimen.
BIOCHEMISTRY
Increased Creatinine
  Grade 1 1.1–1.3 × ULN 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 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 (≥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 Lipid Values Reported in Adult Subjects Receiving RPV or EFV in Combination with FTC/TDF 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
RPV + FTC/TDFN=550 EFV + FTC/TDFN=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 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.


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 [see Warnings and Precautions (5.6)]. For additional information, including information on bone mineral density changes, please consult the VIREAD® prescribing information.

6.2Postmarketing Experience


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.


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, uled under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

7 Drug Interactions


  • COMPLERA is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral medications for treatment of HIV-1 infection is not recommended. (7.1)
  • Consult the Full Prescribing Information prior to and during treatment for important drug interactions. (4, 5.7, 7)


Because COMPLERA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not 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 [see Dosage and Administration (2), Contraindications (4), and Clinical Pharmacology (12.3)].

7.2Drugs 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 RPV [see Contraindications (4), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)]. Coadministration of RPV and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV or to the class of NNRTIs. Coadministration of RPV and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV.

7.3Drugs Increasing Gastric pH


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 [see Contraindications (4) and Clinical Pharmacology (12.3)].

7.4Drugs Affecting Renal Function


Because FTC 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 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 [see Warnings and Precautions (5.5)].

7.5QT Prolonging Drugs


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 [see Warnings and Precautions (5.7) and Clinical Pharmacology (12.2)]. Consider alternatives to COMPLERA when coadministered with a drug with a known risk of Torsade de Pointes.

7.6 Significant Drug Interactions


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 [see Clinical Pharmacology (12.3) , Tables 9–14]. For ul of contraindicated drugs, [see Contraindications (4)].
Table 4 SignificantThis table is not all inclusive. Drug Interactions
Concomitant Drug Class: Drug Name Effect on ConcentrationIncrease = ↑; Decrease = ↓; No Effect = ↔ Clinical Comment
Antacids:   antacids  (e.g., aluminum, magnesium hydroxide, or calcium carbonate) ↔ RPV (antacids taken at least 2 hours before or at least 4 hours after RPV)↓ RPV (concomitant intake) Administer antacids at least 2 hours before or at least 4 hours after COMPLERA.
Anticonvulsants:   carbamazepine  oxcarbazepine  phenobarbital   phenytoin ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
Antimycobacterials:   rifampin  rifapentine ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
  rifabutin ↓ RPVThe interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted. If COMPLERA is coadministered with 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.
Azole Antifungal Agents:   fluconazole  itraconazole  ketoconazole  posaconazole  voriconazole ↑ RPV , This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily. ↓ ketoconazole , 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.
Glucocorticoid (systemic):   dexamethasone  (more than a single-dose treatment) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
Hepatitis C Antiviral Agents:   ledipasvir/sofosbuvir  sofosbuvir/velpatasvir  sofosbuvir/velpatasvir/voxilaprevir ↑ tenofovir Patients receiving COMPLERA concomitantly with HARVONI® (ledipasvir/sofosbuvir), EPCLUSA® (sofosbuvir/velpatasvir), or VOSEVI® (sofosbuvir/velpatasvir/voxilaprevir) should be monitored for adverse reactions associated with TDF.
H2-Receptor Antagonists:   cimetidine  famotidine  nizatidine  ranitidine ↔ RPV , (famotidine taken 12 hours before RPV or 4 hours after RPV)↓ RPV , (famotidine taken 2 hours before RPV) Administer H2-receptor antagonists at least 12 hours before or at least 4 hours after COMPLERA.
Herbal Products:   St John's wort   (Hypericum perforatum) ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.
Macrolide or Ketolide Antibiotics:   clarithromycin  erythromycin  telithromycin ↑ RPV↔ clarithromycin↔ erythromycin↔ telithromycin Where possible, alternatives such as azithromycin should be considered.
Narcotic Analgesics:  methadone ↓ R(–) methadone ↓ S(+) methadone ↔ RPV ↔ 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.
Proton Pump Inhibitors:   e.g., dexlansoprazole  esomeprazole  lansoprazole  omeprazole  pantoprazole  rabeprazole ↓ RPV Coadministration is contraindicated due to potential for loss of virologic response and development of resistance.

7.7Drugs with No Observed Interactions with COMPLERA


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


  • Pregnancy: Monitor viral load closely during pregnancy as rilpivirine exposures were generally lower during pregnancy. (2.3, 8.1, 12.3)
  • Lactation: Breastfeeding not recommended due to the potential for HIV-1 transmission. (8.2)
  • Pediatrics: Not recommended for patients weighing less than 35 kg. (8.4)

8.1 Pregnancy


Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to COMPLERA 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 overall risk of major birth defects with first trimester exposure for emtricitabine (FTC), rilpivirine (RPV), or tenofovir (TDF) compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period [see Clinical Pharmacology (12.3)]. The rate of miscarriage for individual drugs is not reported in the APR. The estimated background rate of miscarriage in 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 [see Data and Clinical Pharmacology (12.3)].

In animal studies, no adverse developmental effects were observed when the components of COMPLERA were administered separately during the period of organogenesis at exposures up to 60 and 120 times (mice and rabbits, respectively, FTC) and 15 and 70 times (rats and rabbits, respectively; RPV) the exposure of these components in COMPLERA and at 14 and 19 times (rats and rabbits, respectively) the human dose of TDF based on body surface area comparisons (see Data). 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 COMPLERA. No adverse effects were observed in the offspring of rats when TDF was administered through lactation at tenofovir exposures of approximately 14 times the exposure at the recommended daily dosage of COMPLERA.


Data


Human Data

Prospective reports from the APR of overall major birth defects in pregnancies exposed to drug components of COMPLERA 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.


Animal Data

8.2 Lactation



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 (see Data).

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).

8.4 Pediatric Use


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 [see Dosage and Administration (2.2)]. 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) [see Clinical Pharmacology (12.3), and Clinical Studies (14.2)].

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 [see Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].

8.5 Geriatric Use


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 [see Clinical Pharmacology (12.3)].

8.6Renal Impairment


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 [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)].

8.7Hepatic 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)].

10 Overdosage


If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with COMPLERA consists of general supportive measures, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient.


Emtricitabine: Hemodialysis treatment removes approximately 30% of the FTC dose over a 3-hour dialysis period starting within 1.5 hours of FTC dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether FTC can be removed by peritoneal dialysis.


Rilpivirine: There is no specific antidote for overdose with RPV. Human experience of overdose with RPV is limited. Since RPV is highly bound to plasma protein, dialysis is unlikely to result in significant removal of RPV.


Tenofovir DF: Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 Description


COMPLERA is a fixed-dose combination tablet containing FTC, rilpivirine hydrochloride, and TDF. Emtricitabine (FTC) is a synthetic nucleoside analog of cytidine. Rilpivirine (RPV) is a non-nucleoside reverse transcriptase inhibitor. Tenofovir disoproxil fumarate (TDF) is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate.

COMPLERA tablets are for oral administration. Each tablet contains 200 mg of FTC, 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of RPV), and 300 mg of TDF (equivalent to 245 mg of tenofovir disoproxil) as active ingredients. The tablets include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, povidone, pregelatinized starch. The tablets are film coated with a coating material containing FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, titanium dioxide, triacetin.


Emtricitabine: The chemical name of FTC is 5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.24. It has the following structural formula:



FTC is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25 °C.


Rilpivirine: RPV is available as the hydrochloride salt. The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C22H18N6 ∙ HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula:



Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range.


Tenofovir DF: TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of TDF is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P ∙ C4H4O4 and a molecular weight of 635.52. It has the following structural formula:



TDF is a white to off-white crystalline powder with a solubility of 13.4 mg per mL in water at 25 °C. All dosages are expressed in terms of TDF except where otherwise noted.

12 Clinical Pharmacology


12.1 Mechanism of Action


COMPLERA is a fixed-dose combination of the antiretroviral drugs FTC, RPV, and TDF [see Microbiology (12.4)].

12.2 Pharmacodynamics



Effects on Electrocardiogram

The effect of RPV at the recommended dose of 25 mg once daily on the QTcF interval was evaluated in a randomized, placebo-, and active- (moxifloxacin 400 mg once daily) controlled crossover study in 60 healthy adults, with 13 measurements over 24 hours at steady state. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction was 2.0 (5.0) milliseconds (i.e., below the threshold of clinical concern).

When doses of 75 mg once daily and 300 mg once daily of RPV (3 times and 12 times the dose in COMPLERA) were studied in healthy adults, the maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline correction were 10.7 (15.3) and 23.3 (28.4) milliseconds, respectively. Steady-state administration of RPV 75 mg once daily and 300 mg once daily resulted in a mean steady-state Cmax approximately 2.6-fold and 6.7-fold, respectively, higher than the mean Cmax observed with the recommended 25 mg once daily dose of RPV [see Warnings and Precautions (5.7)].

12.3 Pharmacokinetics



COMPLERA: Under fed conditions (total calorie content of the meal was approximately 400 kcal with approximately 13 grams of fat), RPV, FTC, and tenofovir exposures were similar when comparing COMPLERA to EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg) following single-dose administration to healthy subjects (N=34).

Single-dose administration of COMPLERA tablets to healthy subjects under fasted conditions provided approximately 25% higher exposure of RPV compared to administration of EMTRIVA capsules (200 mg) plus Edurant tablets (25 mg) plus VIREAD tablets (300 mg), while exposures of FTC and tenofovir were comparable (N=15).


Absorption, Distribution, Metabolism, and Excretion

The pharmacokinetic properties of the components of COMPLERA are provided in Table 5. The PK parameters of RPV, FTC, and tenofovir are provided in Table 6.
Table 5 Pharmacokinetic Properties of the Components of COMPLERA
RPV FTC Tenofovir
NC=Not Calculated
Absorption
  Tmax (h) 4–5 1–2 1
  % Fasted oral bioavailabilityMedian NC 93 25Oral bioavailability of tenofovir from VIREAD.
  Effect of a light meal (relative to fasting)Values refer to % change based on calculated geometric mean ratio [fed/fasted] in AUC. COMPLERA light meal = 390 kcal, 12 g fat; COMPLERA standard meal = 540 kcal, 21 g fat. High fat meal not evaluated. Increase = ↑; Decrease = ↓; No Effect= ↔ ↑9% ↔ ↑28%
  Effect of a standard meal (relative to fasting) ↑16% ↔ ↑38%
Distribution
  % Bound to human plasma proteins ~99 <4 <0.7
  Source of protein binding data In vitro In vitro In vitro
Metabolism
  Metabolism CYP3A Not significantly metabolized
Elimination
  Major route of elimination Metabolism Glomerular filtration and active tubular secretion
  CLrenal Mean ± SD (mL/min) NC 213±89 243±33
  t1/2 (h)t1/2 values refer to median terminal plasma half-life. 50 10 17
  % Of dose excreted in urineDosing in mass balance studies: FTC (single dose administration of [14C] FTC after multiple dosing of FTC for 10 days); RPV (single dose administration of [14C] RPV); mass balance study not conducted for tenofovir. 6 86 70−80
  % Of dose excreted in feces 85 ~14 NC
Table 6 Pharmacokinetic Parameters for RPV, FTC, and Tenofovir in HIV-Infected Adults
ParameterMean ± SD RPVPopulation PK estimates of RPV 25 mg once daily in antiretroviral treatment-naïve HIV-1-infected adult subjects (pooled data from Phase 3 trials through Week 96; n=679) FTCMultiple-dose oral administration of FTC 200 mg to HIV-1-infected subjects (n=20) TenofovirSingle 300 mg dose of TDF to HIV-1-infected subjects in the fasted state
NA=Not Applicable; SD=Standard Deviation
Cmax (μg/mL) NA 1.80±0.72Data presented as steady state values 0.30±0.09
AUCtau (μg∙hr/mL) 2.24±0.85 10.0±3.12 2.29±0.69AUC0–24h
C0h (μg/mL) 0.08±0.04 0.09±0.07 NA


Specific Populations


Geriatric Patients

The pharmacokinetics of FTC, RPV, and tenofovir have not been fully evaluated in the elderly (65 years of age and older) [see Use in Specific Populations (8.5)].


Pediatric Patients

Pediatric trials have not been conducted using COMPLERA tablets. Pediatric information is based on trials conducted with the individual components of COMPLERA [see Use in Specific Populations (8.4)].


Gender

No clinically relevant pharmacokinetic differences have been observed based on gender for FTC, RPV, and TDF.


Race


Patients with Renal Impairment


Patients with Hepatic Impairment


Hepatitis B and/or Hepatitis C Virus Coinfection

The pharmacokinetics of FTC and TDF have not been fully evaluated in hepatitis B and/or C virus-coinfected patients. Population pharmacokinetic analysis indicated that hepatitis B and/or C virus coinfection had no clinically relevant effect on the exposure to RPV.


Pregnancy and Postpartum

The exposure (C0h and AUC24h) to total RPV after intake of RPV 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials of RPV-containing regimens. Based on the exposure-response relationship for RPV, this decrease is not considered clinically relevant in patients who are virologically suppressed. The protein binding of RPV was similar (>99%) during the second trimester, third trimester, and postpartum.
Table 8: Pharmacokinetic Results of Total RPV After Administration of RPV 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2nd Trimester of Pregnancy, the 3rd Trimester of Pregnancy and Postpartum
Pharmacokinetics of total RPV(mean ±SD, tmax: median [range]) Postpartum(6–12 Weeks)(n=11) 2nd Trimester of pregnancy(n=15) 3rd Trimester of pregnancy(n=13)
C0h, ng/mL 111 ± 69.2 65.0 ± 23.9 63.5 ± 26.2
Cmin, ng/mL 84.0 ± 58.8 54.3 ± 25.8 52.9 ± 24.4
Cmax, ng/mL 167 ± 101 121 ± 45.9 123 ± 47.5
tmax, h 4.00 (2.03−25.08) 4.00 (1.00−9.00) 4.00 (2.00−24.93)
AUC24h, ng∙h/mL 2,714 ± 1,535 1,792 ± 711 1,762 ± 662


Drug Interaction Studies


Rilpivirine: RPV is primarily metabolized by cytochrome CYP3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of RPV. Coadministration of COMPLERA and drugs that induce CYP3A may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance. Coadministration of COMPLERA and drugs that inhibit CYP3A may result in increased plasma concentrations of RPV. Coadministration of COMPLERA with drugs that increase gastric pH may result in decreased plasma concentrations of RPV and loss of virologic response and possible resistance to RPV and to the class of NNRTIs.

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


Emtricitabine and Tenofovir DF: In vitro and clinical pharmacokinetic drug-drug interaction studies have shown that the potential for CYP-mediated interactions involving FTC and tenofovir with other medicinal products is low.

FTC and tenofovir are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion. No drug-drug interactions due to competition for renal excretion have been observed; however, coadministration of FTC and TDF with drugs that are eliminated by active tubular secretion may increase concentrations of FTC, tenofovir, and/or the coadministered drug [see Drug Interactions (7.4, 7.6)].

Drugs that decrease renal function may increase concentrations of FTC and/or tenofovir.

The drug interaction studies described in Tables 9–14 were conducted with COMPLERA (RPV/FTC/TDF) or the components of COMPLERA (RPV, FTC, or TDF) administered individually.

The effects of coadministration of other drugs on the AUC, Cmax, and Cmin values of RPV, FTC, and TDF are summarized in Tables 9, 10, and 11, respectively. The effect of coadministration of RPV, FTC, and TDF on the AUC, Cmax, and Cmin values of other drugs are summarized in Tables 12, 13, and 14, respectively. For information regarding clinical recommendations, see Drug Interactions (7) .
Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for RPV in the Presence of the Coadministered Drugs
Coadministered Drug Dose of Coadministered Drug (mg) RPV Dose (mg) NN=maximum number of subjects for Cmax, AUC, or Cmin Mean % Change of RPV Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Cmax AUC Cmin
NA=not available
Acetaminophen 500 single dose 150 once dailyThe interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily) assessing the maximal effect on the coadministered drug. 16 ↑9(↑1 to ↑18) ↑16(↑10 to ↑22) ↑26(↑16 to ↑38)
Atorvastatin 40 once daily 150 once daily 16 ↓9(↓21 to ↑6) ↓10(↓19 to ↓1) ↓10(↓16 to ↓4)
Chlorzoxazone 500 single dose taken 2 hours after RPV 150 once daily 16 ↑17(↑8 to ↑27) ↑25(↑16 to ↑35) ↑18(↑9 to ↑28)
Ethinyl Estradiol/Norethindrone 0.035 once daily/1 once daily 25 once daily 16 ↔Study conducted with COMPLERA (RPV/FTC/TDF) coadministered with HARVONI (ledipasvir/sofosbuvir). ↔ ↔
Famotidine 40 single dose taken 12 hours before RPV 150 single dose 24 ↓1(↓16 to ↑16) ↓9(↓22 to ↑7) NA
40 single dose taken 2 hours before RPV 150 single dose 23 ↓85(↓88 to ↓81) ↓76(↓80 to ↓72) NA
40 single dose taken 4 hours after RPV 150 single dose 24 ↑21(↑6 to ↑39) ↑13(↑1 to ↑27) NA
Ketoconazole 400 once daily 150 once daily 15 ↑30(↑13 to ↑48) ↑49(↑31 to ↑70) ↑76(↑57 to ↑97)
Ledipasvir/Sofosbuvir 90/400 once daily 25 once daily 14 ↓3(↓12 to ↑7) ↑2(↓6 to ↑11) ↑12(↑3 to ↑21)
Methadone 60–100 once daily individualized dose 25 once daily 12 ↔Comparison based on historic controls. ↔ ↔
Omeprazole 20 once daily 150 once daily 16 ↓40(↓52 to ↓27) ↓40(↓49 to ↓29) ↓33(↓42 to ↓22)
Rifabutin 300 once daily 25 once daily 18 ↓31(↓38 to ↓24) ↓42(↓48 to ↓35) ↓48(↓54 to ↓41)
300 once daily 50 once daily 18 ↑43(↑30 to ↑56)Reference arm for comparison was 25 mg q.d. RPV administered alone. ↑16(↑6 to ↑26) ↓7(↓15 to↑1)
Rifampin 600 once daily 150 once daily 16 ↓69(↓73 to ↓64) ↓80(↓82 to ↓77) ↓89(↓90 to ↓87)
Simeprevir 25 once daily 150 once daily 23 ↑ 4(↓ 5 to ↑ 13) ↑ 12(↑ 5 to ↑ 19) ↑ 25(↑ 16 to ↑ 35)
Sildenafil 50 single dose 75 once daily 16 ↓8(↓15 to ↓1) ↓2(↓8 to ↑5) ↑4(↓2 to ↑9)
Sofosbuvir/Velpatasvir 400/100 once daily 25 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA (sofosbuvir/velpatasvir). 24 ↓7(↓12 to ↓2) ↓5(↓10 to 0) ↓4(↓10 to ↑3)
Sofosbuvir/Velpatasvir/VoxilaprevirStudy conducted with ODEFSEY® (FTC/RPV/tenofovir alafenamide). 400/100/100 + 100 voxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. once daily 25 once daily 30 ↓21(↓26 to ↓16) ↓20(↓24 to ↓15) ↓18(↓23 to ↓13)
TDF 300 once daily 150 once daily 16 ↓4(↓19 to ↑13) ↑1(↓13 to ↑18) ↓1(↓17 to ↑16)
Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drugs
Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) NN=maximum number of subjects for Cmax, AUC, or Cmin Mean % Change of FTC Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Cmax AUC Cmin
NA=not available
Famciclovir 500 × 1 200 × 1 12 ↔ ↔ NA
Ledipasvir/Sofosbuvir 90/400 once daily 200 once dailyStudy conducted with COMPLERA coadministered with HARVONI. 15 ↑2(↓2 to ↑6) ↑5(↑2 to ↑8) ↑6(↓3 to ↑15)
Sofosbuvir/Velpatasvir 400/100 once daily 200 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA. 24 ↓5(↓10 to 0) ↓1(↓3 to ↑2) ↑5(↓1 to ↑11)
Sofosbuvir/Velpatasvir/Voxilaprevir 400/100/100 + VoxilaprevirStudy conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients. 100 once daily 200 once dailyStudy conducted with ODEFSEY (FTC/RPV/tenofovir alafenamide). 30 ↓12(↓17 to ↓7) ↓7(↓10 to ↓4) ↑7(↑1 to ↑14)
TDF 300 once daily × 7 days 200 once daily × 7 days 17 ↔ ↔ ↑ 20(↑ 12 to ↑ 29)
Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir in the Presence of the Coadministered Drugs
Coadministered Drug Dose of Coadministered Drug (mg) TDF Dose (mg)Subjects received VIREAD 300 mg daily. NN=maximum number of subjects for Cmax, AUC, or Cmin Mean % Change of Tenofovir Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Cmax AUC Cmin
NA=not available
Entecavir 1 once daily × 10 days 300 once daily ↔ ↔ ↔
Emtricitabine 200 once daily × 7 days 300 once daily × 7 days 17 ↔ ↔ ↔
Ledipasvir/Sofosbuvir 90/400 once daily × 10 days 300 once dailyStudy conducted with COMPLERA coadministered with HARVONI. 14 ↑ 32(↑ 25 to ↑ 39 ) ↑ 40(↑ 31 to ↑ 50 ) ↑ 91(↑ 74 to ↑ 110)
Sofosbuvir/Velpatasvir 400/100 once daily 300 once daily 24 ↑ 44(↑ 33 to ↑ 55) ↑ 40(↑ 34 to ↑ 46) ↑ 84(↑ 76 to ↑ 92)
Tacrolimus 0.05 mg/kg twice daily × 7 days 300 once dailyStudy conducted with COMPLERA coadministered with EPCLUSA. 21 ↑ 13(↑ 1 to ↑ 27) ↔ ↔
Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of RPV
Coadministered Drug Dose of Coadministered Drug (mg) RPV Dose (mg) NN=maximum number of subjects for Cmax, AUC, or Cmin Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; Decrease = ↓; No Effect = ↔ (90% CI)
Cmax AUC Cmin
NA = not available
Acetaminophen 500 single dose 150 once dailyThe Interaction study has been performed with a dose higher than the recommended dose for RPV (25 mg once daily). 16 ↓ 3(↓ 14 to ↑ 10) ↓ 8(↓ 15 to ↓ 1) NA
Atorvastatin 40 once daily 150 once daily 16 ↑ 35(↑ 8 to ↑ 68) ↑ 4(↓ 3 to ↑ 12) ↓ 15(↓ 31 to ↑ 3)
2-hydroxy-atorvastatin 16 ↑ 58(↑ 33 to ↑ 87) ↑ 39(↑ 29 to ↑ 50) ↑ 32(↑ 10 to ↑ 58)
4-hydroxy-atorvastatin 16 ↑ 28(↑ 15 to ↑ 43) ↑ 23(↑ 13 to ↑ 33) NA
Chlorzoxazone 500 single dose taken 2 hours after RPV 150 once daily 16 ↓ 2(↓ 15 to ↑ 13) ↑ 3(↓ 5 to ↑ 13) NA
Digoxin 0.5 single dose 25 once daily 22 ↑ 6(↓ 3 to ↑ 17) ↓ 2(↓ 7 to ↑ 4) NA
Ethinyl estradiol 0.035 once daily 25 once daily 17 ↑ 17(↑ 6 to ↑ 30) ↑ 14(↑ 10 to ↑ 19) ↑ 9(↑ 3 to ↑ 16)
Norethindrone 1 mg once daily ↓ 6(↓ 17 to ↑ 6) ↓ 11(↓ 16 to ↓ 6) ↓ 1(↓ 10 to ↑ 8)
Ketoconazole 400 once daily 150 once daily 14 ↓ 15(↓ 20 to ↓ 10) ↓ 24(↓ 30 to ↓ 18) ↓ 66(↓ 75 to ↓ 54)
Ledipasvir 90 once daily 25 once daily 41 ↑ 1(↓ 3 to ↑ 5) ↑ 2(↓ 3 to ↑ 6) ↑ 2(↓ 2 to ↑ 7)
R(-) methadone 60−100 once daily individualized dose 25 once daily 13 ↓ 14(↓ 22 to ↓ 5) ↓ 16(↓ 26 to ↓ 5) ↓ 22(↓ 33 to ↓ 9)
S(+) methadone 13 ↓ 13(↓ 22 to ↓ 3) ↓ 16(↓ 26 to ↓ 4) ↓ 21(↓ 33 to ↓ 8)
Metformin 850 single dose 25 once daily 20 ↑ 2(↓ 5 to ↑ 10) ↓ 3(↓ 10 to ↑ 6) NA
Omeprazole 20 once daily 150 once daily 15 ↓ 14(↓ 32 to ↑ 9) ↓ 14(↓ 24 to ↓ 3) NA
Rifampin 600 once daily 150 once daily 16 ↑ 2(↓ 7 to ↑ 12) ↓ 1(↓ 8 to ↑ 7) NA
25-desacetylrifampin 16 ↔(↓ 13 to ↑ 15) ↓ 9(↓ 23 to ↑ 7) NA
Simeprevir 150 once daily 25 once daily 21 ↑ 10(↓ 3 to ↑ 26) ↑ 6(↓ 6 to ↑ 19) ↓ 4(↓ 17 to ↑ 11)
Sildenafil 50 single dose 75 once daily 16 ↓ 7(↓ 20 to ↑ 8) ↓ 3(↓ 13 to ↑ 8) NA
N-desmethyl-sildenafil ↓ 10(↓ 20 to ↑ 2) ↓ 8(↓ 15 to ↓ 1) NA
Sofosbuvir 400 once daily 25 once daily 24 ↑ 9(↓ 5 to ↑ 25) ↑ 16(↑ 10 to ↑ 24) NA
GS-331007The predominant circulating nucleoside metabolite of sofosbuvir. ↓ 4(↓ 10 to ↑ 1) ↑ 4(0 to ↑ 7) ↑ 12(↑ 7 to ↑ 17)
Velpatasvir 100 once daily 25 once daily 24 ↓ 4(↓ 15 to ↑ 10) ↓ 1(↓ 12 to ↑ 11) ↑ 2(↓ 9 to ↑ 15)
Sofosbuvir 400 once daily 25 once dailyStudy conducted with ODEFSEY. 30 ↓ 5(↓ 14 to ↑ 5) ↑ 1(↓ 3 to ↑ 6) NA
GS-331007 ↑ 2(↓ 2 to ↑ 6) ↑ 4(↑ 1 to ↑ 6) NA
Velpatasvir 100 once daily 25 once daily 30 ↑ 5(↓ 4 to ↑ 16) ↑ 1(↓ 6 to ↑ 7) ↑ 1(↓ 5 to ↑ 9)
Voxilaprevir 100 + 100 once daily 25 once daily 30 ↓ 4(↓ 16 to ↑ 11) ↓ 6(↓ 16 to ↑ 5) ↑ 2(↓ 8 to ↑ 12)
TDF 300 once daily 150 once daily 16 ↑ 19(↑ 6 to ↑ 34) ↑ 23 (↑ 16 to ↑ 31) ↑ 24(↑ 10 to ↑ 38)
Table 13 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of FTC
Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) NAll interaction trials conducted in healthy volunteers Mean % Change of Coadministered Drug Pharmacokinetic ParametersNo Effect = ↔ (90% CI)
Cmax AUC Cmin
NA=not available
Famciclovir 500 × 1 200 × 1 12 ↔ ↔ NA
TDF 300 once daily × 7 days 200 once daily × 7 days 17 ↔ ↔ ↔

No clinically significant drug interactions have been observed between FTC and indinavir, sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, stavudine, and zidovudine.
Table 14 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drugs in the Presence of TDF
Coadministered Drug Dose of Coadministered Drug (mg) TDF Dose (mg) NAll interaction trials conducted in healthy volunteers Mean % Change of Coadministered Drug Pharmacokinetic ParametersIncrease = ↑; No Effect = ↔ (90% CI)
Cmax AUC Cmin
NA=not available
Emtricitabine 200 once daily × 7 days 300 once daily × 7 days 17 ↔ ↔ ↑ 20(↑ 12 to ↑ 29)
Entecavir 1 once daily × 10 days 300 once daily 28 ↔ ↑ 13(↑ 11 to ↑ 15) ↔
Tacrolimus 0.05 mg/kg twice daily × 7 days 300 once daily 21 ↔ ↔ ↔

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with TDF: methadone, oral contraceptives (ethinyl estradiol/norgestimate), or ribavirin.

12.4 Microbiology



Mechanism of Action


Emtricitabine: FTC, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA, which results in chain termination. Emtricitabine 5′-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.


Rilpivirine: RPV is a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 RT. RPV does not inhibit the human cellular DNA polymerases α, β, and mitochondrial DNA polymerase γ.


Tenofovir DF: TDF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. TDF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5′-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.


Antiviral Activity


Emtricitabine, Rilpivirine, and TDF: The triple combination of FTC, RPV, and TDF was not antagonistic in cell culture.


Emtricitabine: The antiviral activity of FTC against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, the MAGI-CCR5 cell line, and peripheral blood mononuclear cells. The 50% effective concentration (EC50) values for FTC were in the range of 0.0013–0.64 µM. FTC displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC50 values ranged from 0.007–0.075 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 0.007–1.5 µM). In drug combination studies of FTC with nucleoside reverse transcriptase inhibitors (abacavir, lamivudine, stavudine, tenofovir, zidovudine), non-nucleoside reverse transcriptase inhibitors (delavirdine, EFV, nevirapine, and RPV), and protease inhibitors (amprenavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.


Rilpivirine: RPV exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM. RPV demonstrated limited activity in cell culture against HIV-2 with a median EC50 value of 5220 nM (range 2510–10,830 nM). RPV demonstrated antiviral activity against a broad panel of HIV-1 group M (subtype A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07–1.01 nM and was less active against group O primary isolates with EC50 values ranging from 2.88–8.45 nM. The antiviral activity of RPV was not antagonistic when combined with the NNRTIs EFV, etravirine, or nevirapine; the N(t)RTIs abacavir, didanosine, FTC, lamivudine, stavudine, tenofovir, or zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, or tipranavir; the gp41 fusion inhibitor enfuvirtide; the CCR5 co-receptor antagonist maraviroc; or the integrase strand transfer inhibitor raltegravir.


Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in lymphoblastoid cell lines, primary monocyte/macrophage cells, and peripheral blood lymphocytes. The EC50 values for tenofovir were in the range of 0.04–8.5 µM. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC50 values ranged from 0.5–2.2 µM) and showed strain specific activity against HIV-2 (EC50 values ranged from 1.6–5.5 µM). In drug combination studies of tenofovir with NRTIs (abacavir, didanosine, FTC, lamivudine, stavudine, and zidovudine), NNRTIs (delavirdine, EFV, nevirapine, and RPV), and PIs (amprenavir, indinavir, nelfinavir, ritonavir, saquinavir), no antagonistic effects were observed.


Resistance


In Cell Culture


In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History

In the Week 96 pooled resistance analysis for adult subjects receiving RPV or EFV in combination with FTC/TDF in the Phase 3 clinical trials C209 and C215, the emergence of resistance was greater among subjects' viruses in the RPV + FTC/TDF arm compared to the EFV + FTC/TDF arm and was dependent on baseline viral load. In the pooled resistance analysis, 61% (47/77) of the subjects who qualified for resistance analysis (resistance analysis subjects) in the RPV + FTC/TDF arm had virus with genotypic and/or phenotypic resistance to RPV compared to 42% (18/43) of the resistance analysis subjects in the EFV + FTC/TDF arm who had genotypic and/or phenotypic resistance to EFV. Moreover, genotypic and/or phenotypic resistance to FTC or tenofovir emerged in viruses from 57% (44/77) of the resistance analysis subjects in the RPV arm compared to 26% (11/43) in the EFV arm.

Emerging NNRTI substitutions in the RPV resistance analysis of subjects' viruses included V90I, K101E/P/T, E138K/A/Q/G, V179I/L, Y181C/I, V189I, H221Y, F227C/L, and M230L, which were associated with an RPV phenotypic fold change range of 2.6–621. The E138K substitution emerged most frequently during RPV treatment, commonly in combination with the M184I substitution. The FTC and lamivudine resistance-associated substitutions M184I or V and NRTI resistance-associated substitutions (K65R/N, A62V, D67N/G, K70E, Y115F, K219E/R) emerged more frequently in the RPV resistance analysis subjects than in EFV resistance analysis subjects (See Table 15).

NNRTI- and NRTI-resistance substitutions emerged less frequently in the resistance analysis of viruses from subjects with baseline viral loads of ≤100,000 copies/mL compared to viruses from subjects with baseline viral loads of >100,000 copies/mL: 23% (10/44) compared to 77% (34/44) of NNRTI-resistance substitutions and 20% (9/44) compared to 80% (35/44) of NRTI-resistance substitutions. This difference was also observed for the individual FTC/lamivudine and tenofovir resistance substitutions: 22% (9/41) compared to 78% (32/41) for M184I/V and 0% (0/8) compared to 100% (8/8) for K65R/N. Additionally, NNRTI and/or NRTI-resistance substitutions emerged less frequently in the resistance analysis of the viruses from subjects with baseline CD4+ cell counts ≥200 cells/mm3 compared to the viruses from subjects with baseline CD4+ cell counts <200 cells/mm3: 32% (14/44) compared to 68% (30/44) of NNRTI-resistance substitutions and 27% (12/44) compared to 73% (32/44) of NRTI-resistance substitutions.
Table 15 Proportion of Frequently Emerging Reverse Transcriptase Substitutions in the HIV-1 Virus of Resistance Analysis Adult SubjectsSubjects who qualified for resistance analysis Who Received RPV or EFV in Combination with FTC/TDF from Pooled Phase 3 TMC278-C209 and TMC278-C215 Trials in the Week 96 Analysis
C209 and C215N=1096
RPV+ FTC/TDF EFV+ FTC/TDF
N=550 N=546
Subjects who Qualified for Resistance Analysis 14% (77/550) 8% (43/546)
Subjects with Evaluable Postbaseline Resistance Data 70 31
Emergent NNRTI SubstitutionsV90, L100, K101, K103, V106, V108, E138, V179, Y181, Y188, V189, G190, H221, P225, F227, and M230
Any 63% (44/70) 55% (17/31)
V90I 14% (10/70) 0
K101E/P/T/Q 19% (13/70) 10% (3/31)
K103N 1% (1/70) 39% (12/31)
E138K/A/Q/G 40% (28/70) 0
  E138K+M184IThis combination of NRTI and NNRTI substitutions is a subset of those with the E138K. 30% (21/70) 0
V179I/D 6% (4/70) 10% (3/31)
Y181C/I/S 13% (9/70) 3% (1/31)
V189I 9% (6/70) 0
H221Y 10% (7/70) 0
Emergent NRTI SubstitutionsA62V, K65R/N, D67N/G, K70E, L74I, Y115F, M184V/I, L210F, K219E/R
Any 63% (44/70) 32% (10/31)
M184I/V 59% (41/70) 26% (8/31)
K65R/N 11% (8/70) 6% (2/31)
A62V, D67N/G, K70E, Y115F, or K219E/RThese substitutions emerged in addition to the primary substitutions M184V/I or K65R; A62V (n=2), D67N/G (n=3), K70E (n=4), Y115F (n=2), K219E/R (n=8) in RPV resistance analysis subjects. 20% (14/70) 3% (1/31)


In Virologically Suppressed HIV-1-Infected Adult Subjects

Study 106: Through Week 48, 4 subjects who switched to COMPLERA (4 of 469 subjects, 0.9%) and 1 subject who maintained their ritonavir-boosted protease inhibitor-based regimen (1 of 159 subjects, 0.6%) developed genotypic and/or phenotypic resistance to a study drug. All 4 of the subjects who had resistance emergence on COMPLERA had evidence of FTC resistance and 3 of the subjects had evidence of RPV resistance.


Cross Resistance


Rilpivirine, Emtricitabine, and Tenofovir DF:


Rilpivirine:

13 Nonclinical Toxicology


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


Emtricitabine: In long-term carcinogenicity studies of FTC, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg per kg per day (26 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (31 times the human systemic exposure at the therapeutic dose).

FTC was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.

FTC did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.


Rilpivirine: RPV was evaluated for carcinogenic potential by oral gavage administration to mice and rats up to 104 weeks. Daily doses of 20, 60, and 160 mg per kg per day were administered to mice and doses of 40, 200, 500, and 1500 mg per kg per day were administered to rats. In rats, there were no drug-related neoplasms. In mice, RPV was positive for hepatocellular neoplasms in both males and females. The observed hepatocellular findings in mice may be rodent-specific. At the lowest tested doses in the carcinogenicity studies, the systemic exposures (based on AUC) to RPV were 21 fold (mice) and 3 fold (rats), relative to those observed in humans at the recommended dose (25 mg once daily).

RPV has tested negative in the absence and presence of a metabolic activation system, in the in vitro Ames reverse mutation assay and in vitro clastogenicity mouse lymphoma assay. RPV did not induce chromosomal damage in the in vivo micronucleus test in mice.

In a study conducted in rats, there were no effects on mating or fertility with RPV up to 400 mg per kg per day, a dose of RPV that showed maternal toxicity. This dose is associated with an exposure that is approximately 40 times higher than the exposure in humans at the recommended dose of 25 mg once daily.


Tenofovir DF: Long-term oral carcinogenicity studies of TDF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.

Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, TDF was negative when administered to male mice.

There were no effects on fertility, mating performance, or early embryonic development when TDF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats.

13.2 Animal Toxicology and/or Pharmacology



Tenofovir DF: Tenofovir and TDF administered in toxicology studies to rats, dogs, and monkeys at exposures (based on AUCs) greater than or equal to 6-fold those observed in humans caused bone toxicity. In monkeys the bone toxicity was diagnosed as osteomalacia. Osteomalacia observed in monkeys appeared to be reversible upon dose reduction or discontinuation of tenofovir. In rats and dogs, the bone toxicity manifested as reduced bone mineral density. The mechanism(s) underlying bone toxicity is unknown.

Evidence of renal toxicity was noted in 4 animal species. Increases in serum creatinine, BUN, glycosuria, proteinuria, phosphaturia, and/or calciuria and decreases in serum phosphate were observed to varying degrees in these animals. These toxicities were noted at exposures (based on AUCs) 2–20 times higher than those observed in humans. The relationship of the renal abnormalities, particularly the phosphaturia, to the bone toxicity is not known.

14 Clinical Studies


14.1Adult Subjects


In HIV-1-Infected Adult Subjects With No Antiretroviral Treatment History

The efficacy of COMPLERA is based on the analyses of 48- and 96-week data from two randomized, double-blind, controlled studies (Study C209 [ECHO] and TRUVADA subset of Study C215 [THRIVE]) in treatment-naïve, HIV-1-infected subjects (N=1368). The studies are identical in design with the exception of the background regimen (BR). Subjects were randomized in a 1:1 ratio to receive either RPV 25 mg (N=686) once daily or EFV 600 mg (N=682) once daily in addition to a BR. In Study C209 (N=690), the BR was FTC/TDF. In Study C215 (N=678), the BR consisted of 2 NRTIs: FTC/TDF (60%, n=406), lamivudine/zidovudine (30%, n=204), or abacavir + lamivudine (10%, n=68).

For subjects who received FTC/TDF (N=1096) in studies C209 and C215, the mean age was 37 years (range 18–78), 78% were male, 62% were White, 24% were Black, and 11% were Asian. The mean baseline CD4+ cell count was 265 cells/mm3 (range 1–888) and 31% had CD4+ cell counts <200 cells/mm3. The median baseline plasma HIV-1 RNA was 5 log10 copies/mL (range 2–7). Subjects were stratified by baseline HIV-1 RNA. Fifty percent of subjects had baseline viral load ≤100,000 copies/mL, 39% of subjects had baseline viral load between 100,000 copies/mL to 500,000 copies/mL, and 11% of subjects had baseline viral load >500,000 copies/mL.

Treatment outcomes through 96 weeks for the subset of subjects receiving FTC/TDF in studies C209 and C215 (Table 16) are generally consistent with treatment outcomes for all participating subjects (presented in the prescribing information for Edurant). The incidence of virologic failure was higher in the RPV arm than the EFV arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment.
Table 16 Pooled Virologic Outcome of Randomized Treatment of Studies C209 and C215 at Week 96 in Adult Subjects With No Antiviral Treatment History in Combination with FTC/TDF) at Week 96Analyses were based on the last observed viral load data within the Week 96 window (Week 90–103).
RPV+ FTC/TDF EFV+ FTC/TDF
N=550 N=546
HIV-1 RNA <50 copies/mLPredicted difference (95% CI) of response rate is 0.5% (–4.5% to 5.5%) at Week 96. 77% 77%
HIV-1 RNA ≥50 copies/mLIncludes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy and at the time of discontinuation had a viral load value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol. 14% 8%
No Virologic Data at Week 96 Window  Reasons
  Discontinued study due to adverse event or deathIncludes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. 4% 9%
  Discontinued study for other reasonsIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. and the last available HIV-1 RNA <50 copies/mL (or missing) 4% 6%
  Missing data during window but on study <1% <1%
HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL)
  ≤100,000 83% 80%
  >100,000 71% 74%
HIV-1 RNA ≥50 copies/mL by Baseline HIV-1 RNA (copies/mL)
  ≤100,000 7% 5%
  >100,000 22% 12%
HIV-1 RNA <50 copies/mL by Baseline CD4+ Cell Count (cells/mm3)
  <200 68% 72%
  ≥200 82% 79%
HIV-1 RNA ≥50 copies/mL by Baseline CD4+ Cell Count (cells/mm3)
  <200 27% 12%
  ≥200 8% 7%

Based on the pooled data from studies C209 and C215, the mean CD4+ cell count increase from baseline at Week 96 was 226 cells/mm3 for RPV + FTC/TDF-treated subjects and 223 cells/mm3 for EFV + FTC/TDF-treated subjects.


In Virologically Suppressed HIV-1-Infected Adult Subjects

The efficacy and safety of switching from a ritonavir-boosted protease inhibitor in combination with two NRTIs to COMPLERA was evaluated in Study 106, a randomized, open-label study in virologically suppressed HIV-1-infected adults. Subjects had to be on either their first or second antiretroviral regimen with no history of virologic failure, have no current or past history of resistance to any of the three components of COMPLERA, and must have been suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to screening. Subjects were randomized in a 2:1 ratio to either switch to COMPLERA at baseline (COMPLERA arm, N=317), or stay on their baseline antiretroviral regimen for 24 weeks (SBR arm, N=159) and then switch to COMPLERA for an additional 24 weeks (N=52). Subjects had a mean age of 42 years (range 19–73), 88% were male, 77% were White, 17% were Black, and 17% were Hispanic/Latino. The mean baseline CD4+ cell count was 584 cells/mm3 (range 42–1484). Randomization was stratified by use of TDF and/or lopinavir/ritonavir in the baseline regimen.

Treatment outcomes are presented in Table 17.
Table 17 Virologic Outcomes of Study GS-US-264-0106 in Virologically Suppressed Subjects
COMPLERA Stayed on Baseline Regimen (SBR)
Week 48Week 48 window is between Day 295 and 378 (inclusive). Week 24For subjects in the SBR arm who maintained their baseline regimen for 24 weeks and then switched to COMPLERA, the Week 24 window is between Day 127 and first dose day on COMPLERA.
N=317 N=159
HIV-1 RNA <50 copies/mLPredicted difference (95% CI) of response rate for switching to COMPLERA at Week 48 compared to staying on baseline regimen at Week 24 (in absence of Week 48 results from the SBR group by study design) is –0.7% (–6.4% to 5.1%). 89% (283/317) 90% (143/159)
HIV-1 RNA ≥50 copies/mLIncludes subjects who had HIV-1 RNA ≥50 copies/mL in the time window, subjects who discontinued early due to lack or loss of efficacy, and subjects who discontinued for reasons other than an adverse event or death and at the time of discontinuation had a viral load value of ≥50 copies/mL. 3% (8/317) 5% (8/159)
No Virologic Data at Week 24 Window
  Discontinued study drug due to AE or deathIncludes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. 2% (7/317) 0%
  Discontinued study drug due to other reasons and last available HIV-1 RNA <50 copies/mLIncludes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. 5% (16/317) 3% (5/159)
  Missing data during window but on study drug 1% (3/317) 2% (3/159)

14.2Pediatric Subjects


The pharmacokinetics, safety, and efficacy of RPV in combination with other antiretroviral agents was evaluated in a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1-infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg (TMC-C213). Thirty-six (36) subjects were enrolled with a median age of 14.5 years (range 12 to 17 years), and were 55.6% female, 88.9% Black, and 11.1% Asian. The majority of subjects (24/36) received RPV in combination with FTC and TDF. Of these 24 subjects, 20 had baseline HIV RNA ≤100,000 copies/mL. The baseline characteristics and efficacy outcomes at Week 48 are further described below for the 20 subjects.

The median baseline plasma HIV-1 RNA and CD4+ cell count were 49,550 (range 2060 to 92,600 copies/mL) and 437.5 cells/mm3 (range 123 to 983 cells/mm3), respectively. At Week 48, 80% (16/20) of the subjects had HIV RNA <50 copies/mL, 15% (3/20) had HIV RNA ≥50 copies/mL, and one subject discontinued therapy prior to Week 48 and before reaching virologic suppression (HIV RNA <50 copies/mL). At Week 48, the mean increase in CD4+ cell count from baseline was 225 cells/mm3.

16 How Supplied/storage And Handling


COMPLERA tablets are purplish pink, capsule shaped, film coated, debossed with "GSI" on one side, and plain faced on the other side. Each bottle contains 30 tablets (NDC 61958-1101-1), a silica gel desiccant, and a polyester fiber coil, and is closed with a child-resistant closure.

STORAGE AND HANDLING SECTION


Store at 25 °C (77 °F), excursions permitted to 15 °C–30 °C (59 °F–86 °F) [See USP Controlled Room Temperature].

Keep container tightly closed.

Dispense only in original container.

17 Patient Counseling Information


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 [see Warnings and Precautions (5.1)]. 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, bulers, 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 [see Warnings and Precautions (5.2)].


Hepatotoxicity

Inform patients that hepatotoxicity has been reported with COMPLERA and that monitoring for hepatotoxicity is recommended [see Warnings and Precautions (5.3)].


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 [see Warnings and Precautions (5.4)].


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) [see Warnings and Precautions (5.5)].


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 [see Warnings and Precautions (5.6)].


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 [see Contraindications (4), Warnings and Precautions (5.7), and Drug Interactions (7)].

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 [see Warnings and Precautions (5.8)].


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 [see Warnings and Precautions (5.9)].


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 [see Use in Specific Populations (8.1)].


Lactation

Instruct patients with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations (8.2)].


Manufactured and distributed by:Gilead Sciences, Inc.Foster City, CA 94404

COMPLERA, EMTRIVA, EPCLUSA, GSI, HARVONI, ODEFSEY, TRUVADA, VIREAD, and VOSEVI are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.

© 2019 Gilead Sciences, Inc. All rights reserved.

202123-GS-013

Spl Patient Package Insert Section

   This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 11/2019   
Patient InformationCOMPLERA® (kom-PLEH-rah) (emtricitabine, rilpivirine, tenofovir disoproxil fumarate)tablets
Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with COMPLERA. For more information, see the section "What should I tell my healthcare provider before taking COMPLERA?"
What is the most important information I should know about COMPLERA?COMPLERA can cause serious side effects, including:Worsening of Hepatitis B virus (HBV) infection. Your healthcare provider will test you for HBV before starting treatment with COMPLERA. If you have HBV infection and take COMPLERA, your HBV may get worse (flare-up) if you stop taking COMPLERA. A "flare-up" is when your HBV infection suddenly returns in a worse way than before.
  • Do not stop taking COMPLERA without first talking to your healthcare provider.
  • Do not run out of COMPLERA. Refill your prescription or talk to your healthcare provider before your COMPLERA is all gone.
  • If you stop taking COMPLERA, your healthcare provider will need to check your health often and do blood tests regularly for several months to check your HBV infection. Tell your healthcare provider about any new or unusual symptoms you may have after you stop taking COMPLERA.
For more information about side effects, see the section " What are the possible side effects of COMPLERA? ".
What is COMPLERA? COMPLERA is a prescription medicine that is used to treat Human Immunodeficiency Virus-1 (HIV-1) in people weighing at least 77 lb (35 kg) who:
  • have never taken HIV-1 medicines before, 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 before they start taking COMPLERA, or
  • in certain people who have a viral load that is less than 50 copies/mL when they start taking COMPLERA, to replace their current HIV-1 medicines.
HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). COMPLERA does not cure HIV-1 or AIDS. COMPLERA contains 3 medicines (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) combined in one tablet. Emtricitabine (EMTRIVA®) and tenofovir disoproxil fumarate (VIREAD®) are HIV-1 nucleoside analog reverse transcriptase inhibitors (NRTIs). Rilpivirine (Edurant®) is an HIV-1 non-nucleoside analog reverse transcriptase inhibitor (NNRTI).It is not known if COMPLERA is safe and effective in children less than 12 years of age or who weigh less than 77 lb (35 kg).
Who should not take COMPLERA?Do not take COMPLERA if you also take:
  • anti-seizure medicines:
    • carbamazepine
    • oxcarbazepine
    • phenobarbital
    • phenytoin
  • anti-tuberculosis (anti-TB) medicines:
    • rifampin
    • rifapentine
  • proton pump inhibitor (PPI) medicine for certain stomach or intestinal problems:
    • dexlansoprazole
    • esomeprazole
    • lansoprazole
    • omeprazole
    • pantoprazole sodium
    • rabeprazole
  • more than 1 dose of the steroid medicine dexamethasone or dexamethasone sodium phosphate
  • St. John's wort (Hypericum perforatum)
What should I tell my healthcare provider before taking COMPLERA?Before taking COMPLERA, tell your healthcare provider about all your medical conditions, including if you:
  • have liver problems, including hepatitis B or C virus infection
  • have kidney problems
  • have a history of depression or suicidal thoughts
  • have bone problems
  • are pregnant or plan to become pregnant. It is not known if COMPLERA can harm your unborn child. Tell your healthcare provider if you become pregnant during treatment with COMPLERA. Pregnancy Registry. There is a pregnancy registry for those who take COMPLERA during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.
  • are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking COMPLERA.
    • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
    • At least two of the medicines contained in COMPLERA can be passed to your baby in your breast milk.
    • Talk with your healthcare provider about the best way to feed your baby during treatment with COMPLERA.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some medicines interact with COMPLERA. Keep a ul of your medicines to show your healthcare provider and pharmacist when you get a new medicine.
  • You can ask your healthcare provider or pharmacist for a ul of medicines that can interact with COMPLERA.
  • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take COMPLERA with other medicines.
How should I take COMPLERA?
  • Take COMPLERA exactly as your healthcare provider tells you to take it.
  • Take COMPLERA with food. Taking COMPLERA with food is important to help get the right amount of medicine in your body. A protein drink does not replace food. If your healthcare provider decides to stop COMPLERA and you are switched to new medicines to treat HIV-1 that include rilpivirine tablets, the rilpivirine tablets should be taken only with a meal.
  • Do not change your dose or stop taking COMPLERA without first talking with your healthcare provider. Stay under the care of your healthcare provider during treatment with COMPLERA.
  • If you miss a dose of COMPLERA within 12 hours of the time you usually take it, take your dose of COMPLERA with food as soon as possible. Then, take your next dose of COMPLERA at the regularly scheduled time. If you miss a dose of COMPLERA by more than 12 hours of the time you usually take it, wait and then take the next dose of COMPLERA at the regularly scheduled time.
  • Do not take more than your prescribed dose to make up for a missed dose.
  • If you take too much COMPLERA, contact your local poison control center or go to the nearest hospital emergency room right away.
  • When your COMPLERA supply starts to run low, get more from your healthcare provider or pharmacy. It is very important not to run out of COMPLERA. The amount of virus in your blood may increase if the medicine is stopped for even a short time.
What are the possible side effects of COMPLERA?COMPLERA can cause serious side effects, including:
  • See "What is the most important information I should know about COMPLERA?"Severe skin rash and allergic reactions. Skin rash is a common side effect of COMPLERA. Rash can be serious. Call your healthcare provider right away if you get a rash. In some cases, rash and allergic reaction may need to be treated in a hospital. If you get a rash with any of the following symptoms, stop taking COMPLERA and call your healthcare provider or get medical help right away:
  • fever
  • skin bulers
  • mouth sores
  • redness or swelling of the eyes (conjunctivitis)
  • swelling of the face, lips, mouth, tongue or throat
  • trouble breathing or swallowing
  • pain on the right side of the stomach (abdominal) area
  • dark or "tea colored" urine
  • 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.
  • Change in liver enzymes. People with a history of hepatitis B or C virus infection or who have certain liver enzyme changes may have an increased risk of developing new or worsening liver problems during treatment with COMPLERA. Liver problems can also happen during treatment with COMPLERA in people without a history of liver disease. Your healthcare provider may need to do tests to check your liver enzymes before and during treatment with COMPLERA.
  • Depression or mood changes. Tell your healthcare provider right away if you have any of the following symptoms:
    • feel sad or hopeless
    • feel anxious or restless
    • have thoughts of hurting yourself (suicide) or have tried to hurt yourself
  • New or worse kidney problems, including kidney failure, can happen in some people who take COMPLERA. Your healthcare provider should do blood tests to check your kidneys before starting treatment with COMPLERA. If you have had kidney problems in the past or need to take another medicine that can cause kidney problems, your healthcare provider may need to do blood tests to check your kidneys during your treatment with COMPLERA.
  • Bone problems can happen in some people who take COMPLERA. Bone problems include bone pain, softening, or thinning (which may lead to fractures). Your healthcare provider may need to do additional tests to check your bones.
  • 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.
  • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine.
The most common side effects of rilpivirine, one of the medicines in COMPLERA, include:
  • depression
  • trouble sleeping
  • headache
The most common side effects of emtricitabine and tenofovir disoproxil fumarate, two of the medicines in COMPLERA, include:
  • diarrhea
  • nausea
  • tiredness
  • headache
  • dizziness
  • depression
  • trouble sleeping
  • abnormal dreams
  • rash
These are not all the possible side effects of COMPLERA.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store COMPLERA?
  • Store COMPLERA at room temperature between 68 °F to 77 °F (20 °C to 25 °C).
  • Keep COMPLERA in its original container and keep the container tightly closed.
  • Do not use COMPLERA if the seal over the bottle opening is broken or missing.
Keep COMPLERA and all other medicines out of reach of children.
General information about safe and effective use of COMPLERA Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use COMPLERA for a condition for which it was not prescribed. Do not give COMPLERA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about COMPLERA that is written for health professionals. For more information, call 1-800-445-3235 or go to www.COMPLERA.com.
What are the ingredients of COMPLERA?Active ingredients: emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate. Inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20 povidone, pregelatinized starch. The tablet film coating contains FD&C Blue #2 aluminum lake, FD&C Yellow #6 aluminum lake, hypromellose, iron oxide red, lactose monohydrate, polyethylene glycol, titanium dioxide, triacetin.Manufactured and distributed by: Gilead Sciences, Inc. Foster City, CA 94404COMPLERA, EMTRIVA, and VIREAD are trademarks of Gilead Sciences, Inc., or its related companies. All other trademarks referenced herein are the property of their respective owners.© 2019 Gilead Sciences, Inc. All rights reserved.202123-GS-013

Package Label.principal Display Panel


PRINCIPAL DISPLAY PANEL - 30 Tablet Bottle Label

NDC 61958-1101-130 tablets

COMPLERA® (emtricitabine, rilpivirine, tenofovir disoproxil fumarate) tablets 200 mg/25 mg/300 mg Rx only

Note to pharmacist:Do not cover ALERT box with pharmacy label.

ALERT: Find out about medicines thatshould NOT be taken with COMPLERA

DISCLAIMER:

"This tool does not provide medical advice, and is for informational and educational purposes only, and is not a substitute for professional medical advice, treatment or diagnosis. Call your doctor to receive medical advice. If you think you may have a medical emergency, please dial 911."

"Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service."

"This product uses publicly available data from the U.S. National Library of Medicine (NLM), National Institutes of Health, Department of Health and Human Services; NLM is not responsible for the product and does not endorse or recommend this or any other product."

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