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Revision as of 16:11, 26 August 2014
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];
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Overview
Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate is an anti- HIV agent that is FDA approved for the treatment of HIV infection. Common adverse reactions include depressive disorders, insomnia, and headache, diarrhea, nausea, fatigue, dizziness, abnormal dreams, and rash.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- 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 adult patients with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy, and in certain virologically-suppressed (HIV-1 RNA <50 copies/mL) adult patients on a stable antiretroviral regimen at start of therapy in order to replace their current antiretroviral treatment regimen (see below).
- The following points should be considered when initiating therapy with COMPLERA in adult patients with no antiretroviral treatment history:
- More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine-treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL.
- Regardless of HIV-1 RNA level at the start of therapy, more rilpivirine-treated subjects with CD4+ cell count less than 200 cells/mm3 experienced virologic failure compared to rilpivirine-treated subjects with CD4+ cell count greater than or equal to 200 cells/mm3.
- The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
- More subjects treated with rilpivirine developed tenofovir and lamivudine/emtricitabine associated resistance compared to efavirenz.
- The efficacy of COMPLERA was established in patients who were virologically-suppressed (HIV-1 RNA <50 copies/mL) on stable ritonavir-boosted protease inhibitor-containing regimen. The following points should be met when considering replacing the current regimen with COMPLERA in virologically-suppressed adults:
- Patients should have no history of virologic failure.
- Patients should have been stably suppressed (HIV-1 RNA <50 copies/mL) for at least 6 months prior to switching therapy.
- Patients should currently be on their first or second antiretroviral regimen prior to switching therapy.
- Patients should have no current or past history of resistance to any of the three components of COMPLERA.
Additional monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.
COMPLERA is not recommended for patients less than 18 years of age.
DOSAGE AND ADMINISTRATION
- Adults: The recommended dose of COMPLERA is one tablet taken orally once daily with food.
- Renal Impairment: Because COMPLERA is a fixed-dose combination, it should not be prescribed for patients requiring dose reduction such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute).
- Rifabutin Coadministration: If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant®) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration.
DOSAGE FORMS AND STRENGTHS
- COMPLERA is available as tablets. Each tablet contains 200 mg of emtricitabine (FTC), 27.5 mg of rilpivirine hydrochloride (equivalent to 25 mg of rilpivirine) and 300 mg of tenofovir disoproxil fumarate (tenofovir DF or 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.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in pediatric patients.
Contraindications
Coadministration of COMPLERA is contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance.
Warnings
Lactic 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 tenofovir DF, a component of COMPLERA, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. 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).
Patients Coinfected with HIV-1 and HBV
It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy. COMPLERA is not approved for the treatment of chronic HBV infection and the safety and efficacy of COMPLERA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued emtricitabine or tenofovir DF, two of the components of COMPLERA. In some patients infected with HBV and treated with EMTRIVA®, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Patients who are coinfected with HIV-1 and HBV 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.
New 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 tenofovir DF.
It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with COMPLERA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA®, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of COMPLERA, and periodically during COMPLERA therapy.
COMPLERA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)). 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 tenofovir DF. 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 tenofovir are principally eliminated by the kidney; however, rilpivirine is not. Since COMPLERA is a combination product and the dose of the individual components cannot be altered, patients with estimated creatinine clearance below 50 mL per minute should not receive COMPLERA.
Drug Interactions
Caution should be given to prescribing COMPLERA with drugs that may reduce the exposure of rilpivirine.
In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.
Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N=686) or efavirenz (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 rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz 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 rilpivirine arm. 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.
Hepatotoxicity
Hepatic adverse events have been reported in patients receiving a rilpivirine containing regimen. Patients with underlying hepatitis B or C, 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 patients receiving a rilpivirine 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.
Bone Effects of Tenofovir DF
Bone Mineral Density:
In clinical trials in HIV-1-infected adults, tenofovir DF 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 tenofovir DF. For more information, please consult the VIREAD prescribing information.
The effects of tenofovir DF-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 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 tenofovir DF. 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 tenofovir DF.
Coadministration with Other Products
COMPLERA should not be administered concurrently with other medicinal products containing the active components emtricitabine or tenofovir DF (ATRIPLA®, EMTRIVA, STRIBILD®, TRUVADA®, VIREAD), with medicinal products containing lamivudine (Epivir®, Epivir-HBV®, Epzicom®, Combivir®, Trizivir®), or with adefovir dipivoxil (HEPSERA). COMPLERA should not be administered with rilpivirine (Edurant) unless needed for dose adjustment (e.g., with rifabutin).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established.
Immune 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, and Guillain-Barré syndrome) 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.
Adverse Reactions
Clinical 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.
In HIV-1-Infected Subjects With No Antiretroviral Treatment History
Studies C209 and C215 – Treatment-Emergent Adverse Drug Reactions: The safety assessment of rilpivirine, used in combination with other antiretroviral drugs, is based on the Week 96 pooled data from 1368 subjects in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naive HIV-1-infected adult subjects. A total of 686 subjects received rilpivirine in combination with other antiretroviral drugs as background regimen; most (N=550) received emtricitabine/tenofovir DF as background regimen. The number of subjects randomized to the control arm efavirenz was 682, of which 546 received emtricitabine/tenofovir DF as background regimen [See Clinical Studies (14)]. The median duration of exposure for subjects in either treatment arm was 104 weeks.
Adverse drug reactions (ADR) observed at Week 96 in subjects who received rilpivirine or efavirenz plus emtricitabine/tenofovir DF as background regimen are shown in Table 1. No new types of adverse reactions were identified between Week 48 and Week 96. The adverse drug reactions observed in this subset of subjects were generally consistent with those seen for the overall patient population participating in these studies (refer to the prescribing information for Edurant).
The proportion of subjects who discontinued treatment with rilpivirine or efavirenz + emtricitabine/tenofovir DF due to ADR, regardless of severity, was 2% and 5%, respectively. The most common ADRs leading to discontinuation were psychiatric disorders: 9 (1.6%) subjects in the rilpivirine + emtricitabine/tenofovir DF arm and 12 (2.2%) subjects in the efavirenz + emtricitabine/tenofovir DF arm. Rash led to discontinuation in 1 (0.2%) subject in the rilpivirine + emtricitabine/tenofovir DF arm and 10 (1.8%) subjects in the efavirenz + emtricitabine/tenofovir DF arm.
Common Adverse Drug Reactions
Clinical ADRs to rilpivirine or efavirenz of at least moderate intensity (≥ Grade 2) reported in at least 2% of adult subjects are shown in Table 1.
Rilpivirine: Treatment-emergent adverse drug reactions of at least moderate intensity (≥ Grade 2) that occurred in less than 2% of subjects treated with rilpivirine plus any of the allowed background regimens (N=686) in clinical studies C209 and C215 include (grouped by Body System): vomiting, diarrhea, abdominal discomfort, abdominal pain, fatigue, cholecystitis, cholelithiasis, decreased appetite, somnolence, sleep disorders, anxiety, glomerulonephritis membranous, glomerulonephritis mesangioproliferative, and nephrolithiasis.
In Virologically-Suppressed HIV-1-Infected Subjects
No new adverse reactions to COMPLERA were identified in stable, virologically-suppressed subjects switching to COMPLERA from a regimen containing a ritonavir-boosted protease inhibitor; however the frequency of adverse reactions increased by 20% (Study 106) after switching to COMPLERA.
Emtricitabine and Tenofovir Disoproxil Fumarate: The following adverse reactions were observed in clinical trials of emtricitabine or tenofovir DF in combination with other antiretroviral agents:
The most common adverse drug reactions occurring in at least 10% of HIV-1-infected treatment-naive adult subjects in a Phase 3 clinical trial of emtricitabine and tenofovir DF in combination with another antiretroviral agent are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash. In addition, adverse drug reactions that occurred in at least 5% of treatment-experienced or treatment-naive subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in clinical trials include abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.
Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
Laboratory Abnormalities: The percentage of subjects treated with rilpivirine + emtricitabine/tenofovir DF or efavirenz + emtricitabine/tenofovir DF in studies C209 and C215 with selected treatment-emergent laboratory abnormalities (Grades 1 to 4), representing worst grade toxicity, are presented in Table 2.
Emtricitabine or Tenofovir Disoproxil Fumarate: The following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of increased pancreatic amylase (>2.0 x ULN), increased serum amylase (>175 U/L), increased lipase (>3.0 x 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) occurred.
Adrenal Function
In the pooled Phase 3 trials of C209 and C215, in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), at Week 96, there was an overall mean change from baseline in basal cortisol of -19.1 (95% CI: -30.9; -7.4) nmol/L in the rilpivirine group, and of -0.6 (95% CI: -13.3; 12.2) nmol/L in the efavirenz group. At Week 96, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine group (+18.4 ± 8.36 nmol/L) than in the efavirenz group (+54.1 ± 7.24 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 96 were within the normal range. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. Effects on adrenal function were comparable by background N(t)RTIs.
Serum Creatinine
In the pooled Phase 3 trials of C209 and C215 trials in subjects treated with rilpivirine plus any of the allowed background regimen (N=686), there was a small increase in serum creatinine over 96 weeks of treatment with rilpivirine. Most of this increase occurred within the first four weeks of treatment with a mean change of 0.1 mg/dL (range: -0.3 mg/dL 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.
Subjects Coinfected with Hepatitis B and/or Hepatitis C Virus
In patients coinfected with hepatitis B or C virus receiving rilpivirine in studies C209 and C215, the incidence of hepatic enzyme elevation was higher than in subjects receiving rilpivirine who were not coinfected. The same increase was also observed in the efavirenz arm. The pharmacokinetic exposure of rilpivirine in coinfected subjects was comparable to that in subjects without coinfection.
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of rilpivirine- or tenofovir DF-containing regimens . Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Rilpivirine:
- Renal and Urinary Disorders
- nephrotic syndrome
Emtricitabine:
No postmarketing adverse reactions have been identified for inclusion in this section.
Tenofovir Disoproxil Fumarate:
- Immune System Disorders
- allergic reaction, including angioedema
- Metabolism and Nutrition Disorders
- lactic acidosis, hypokalemia, hypophosphatemia
- Respiratory, Thoracic, and Mediastinal Disorders
- dyspnea
- Gastrointestinal Disorders
- pancreatitis, increased amylase, abdominal pain
- Hepatobiliary Disorders
- hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
- Skin and Subcutaneous Tissue Disorders
- rash
- Musculoskeletal and Connective Tissue Disorders
- rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
- Renal and Urinary Disorders
- acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
- General Disorders and Administration Site Conditions
- asthenia
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
Drug Interactions
Drugs Inducing or Inhibiting CYP3A Enzymes
Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine [See Clinical Pharmacology (12.3), Contraindications (4)]. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
Rilpivirine at a dose of 25 mg once daily is not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes.
Drugs Increasing Gastric pH
Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs [See Table 4].
Drugs Affecting Renal Function
Because emtricitabine and tenofovir are primarily eliminated by the kidneys through a combination of glomerular filtration and active tubular secretion, coadministration of COMPLERA with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.
QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. COMPLERA should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.
Established and Other Potentially Significant Drug Interactions
Important drug interaction information for COMPLERA is summarized in Table 4. The drug interactions described are based on studies conducted with emtricitabine, rilpivirine, or tenofovir DF as individual medications that may occur with COMPLERA or are potential drug interactions; no drug interaction studies have been conducted using COMPLERA, [Tables 6–7]. The tables include potentially significant interactions, but are not all inclusive.
Drugs with No Observed or Predicted Interactions with COMPLERA
No clinically significant drug interactions have been observed between emtricitabine and the following medications: famciclovir or tenofovir DF. Similarly, no clinically significant drug interactions have been observed between tenofovir DF and the following medications: entecavir, methadone, oral contraceptives, ribavirin, or tacrolimus in studies conducted in healthy subjects.
No clinically significant drug interactions have been observed between rilpivirine and the following medications: acetaminophen, atorvastatin, chlorzoxazone, ethinyl estradiol, norethindrone, sildenafil, telaprevir, or tenofovir DF. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. No clinically relevant drug-drug interaction is expected when rilpivirine is coadministered with ribavirin.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA): B Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose.
Rilpivirine: Studies in animals have shown no evidence of embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
Tenofovir Disoproxil Fumarate: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, COMPLERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to COMPLERA, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate during labor and delivery.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV.
Emtricitabine: Samples of breast milk obtained from five HIV-1-infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Rilpivirine: Studies in lactating rats and their offspring indicate that rilpivirine was present in rat milk. It is not known whether rilpivirine is secreted in human milk.
Tenofovir Disoproxil Fumarate: Samples of breast milk obtained from five HIV-1-infected mothers in the first post-partum week show that tenofovir is excreted in human milk. The impact of this exposure in breastfed infants is unknown.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving COMPLERA.
Pediatric Use
COMPLERA is not recommended for patients less than 18 years of age because not all the individual components of COMPLERA have safety, efficacy and dosing recommendations available for all pediatric age groups.
Geriatic Use
Clinical studies of emtricitabine, rilpivirine, or tenofovir DF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for the 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.
Gender
There is no FDA guidance on the use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate with respect to specific racial populations.
Renal Impairment
Because COMPLERA is a fixed-dose combination, it should not be prescribed for patients requiring dosage adjustment such as those with moderate, severe or end stage renal impairment (estimated creatinine clearance below 50 mL per minute) or that require dialysis.
Hepatic Impairment
No dose adjustment of COMPLERA is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. COMPLERA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C).
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate in patients who are immunocompromised.
Administration and Monitoring
Administration
Adults: The recommended dose of COMPLERA is one tablet taken orally once daily with food [See Clinical Pharmacology (12.3)].
Renal Impairment: Because COMPLERA is a fixed-dose combination, it should not be prescribed for patients requiring dose reduction such as those with moderate or severe renal impairment (estimated creatinine clearance below 50 mL per minute).
Rifabutin Coadministration: If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant®) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of the rifabutin coadministration.
Monitoring
The efficacy of COMPLERA was established in patients who were virologically-suppressed (HIV-1 RNA <50 copies/mL) on stable ritonavir-boosted protease inhibitor-containing regimen.
Monitoring of HIV-1 RNA and regimen tolerability is recommended after replacing therapy to assess for potential virologic failure or rebound.
IV Compatibility
There is limited information regarding the compatibility of Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate and IV administrations.
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: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study, single doses of emtricitabine 1200 mg were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Rilpivirine: There is no specific antidote for overdose with rilpivirine. Human experience of overdose with rilpivirine is limited. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of rilpivirine.
Administration of activated charcoal may be used to aid in removal of unabsorbed active substance.
Tenofovir Disoproxil Fumarate: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir DF was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
Pharmacology
Mechanism of Action
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Mechanism of Action in the drug label.
Structure
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Structure in the drug label.
Pharmacodynamics
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Clinical Studies in the drug label.
How Supplied
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate How Supplied in the drug label.
Storage
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Storage in the drug label.
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Patient Counseling Information
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Emtricitabine, Rilpivirine Hydrochloride, And Tenofovir Disoproxil Fumarate Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.