emtricitabine, rilpivirine hydrochloride, and tenofovir disoproxil fumarate
Dosage Form: tablet, film coated
FULL PRESCRIBING INFORMATION
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Complera, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].
Complera is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Complera have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD, which are components of Complera. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Complera. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)].
Indications and Usage for Complera
Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) is indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naive adults.
This indication is based on Week 48 safety and efficacy analyses from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naive subjects comparing rilpivirine to efavirenz [See Clinical Studies (14)].
The following points should be considered when initiating therapy with Complera:
- More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy [See Clinical Studies (14)].
- The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz [See Microbiology (12.4)].
- More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz [See Microbiology (12.4)].
Complera is not recommended for patients less than 18 years of age [See Use in Specific Populations (8.4)].
Complera Dosage and Administration
Adults: The recommended dose of Complera is one tablet taken orally once daily with a meal [See Clinical Pharmacology (12.3)].
Renal Impairment: Because Complera is a fixed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute).
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.
Contraindications
Complera should not be coadministered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs [See Drug Interactions (7) and Clinical Pharmacology (12.3)]:
- the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
- the antimycobacterials rifabutin, rifampin, rifapentine
- proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
- the glucocorticoid systemic dexamethasone (more than a single dose)
- St. John's wort (Hypericum perforatum)
Warnings and Precautions
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 [See Adverse Reactions (6.2)].
It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with Complera. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA.
Complera should be avoided with concurrent or recent use of a nephrotoxic agent.
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 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 [See Contraindications (4), Drug Interactions (7), and Clinical Pharmacology (12.3)].
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 [See Drug Interactions (7) and Clinical Pharmacology (12.2)]. 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), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N=686) or efavirenz (N=682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 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. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz 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.
Decreases in Bone Mineral Density
Bone mineral density (BMD) monitoring should be considered for HIV-1 infected 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.
Tenofovir Disoproxil Fumarate: In a 144 week study of HIV-1 infected treatment-naive adult subjects treated with tenofovir DF (Study 903), decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir DF group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF-treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir DF group and 6 subjects in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.
The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the VIREAD prescribing information.
Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].
Coadministration with Other Products
Complera should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir DF (EMTRIVA, EDURANT, VIREAD, TRUVADA, ATRIPLA), with medicinal products containing lamivudine (EPIVIR, EPIVIR-HBV, EPZICOM, COMBIVIR, TRIZIVIR), or with adefovir dipivoxil (HEPSERA).
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.
Adverse Reactions
The following adverse drug reactions are discussed in other sections of the labeling:
- Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].
- Severe Acute Exacerbations of Hepatitis B [See Boxed Warning, Warnings and Precautions (5.2)].
- New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)].
- Depressive Disorders [See Warnings and Precautions (5.5)].
- Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].
- Immune Reconstitution Syndrome [See Warnings and Precautions (5.9)].
Adverse Reactions from 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.
Studies C209 and C215 – Treatment-Emergent Adverse Drug Reactions: The safety assessment of rilpivirine, used in combination with other antiretroviral drugs, is based on pooled data from 1368 patients in the Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naive HIV-1 infected adult patients. A total of 686 patients 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 56 weeks.
Adverse drug reactions (ADR) observed in patients who received rilpivirine or efavirenz plus emtricitabine + tenofovir DF as background regimen are shown in Table 1. The adverse drug reactions observed in this subset of patients 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: 8 (1.5%) 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%) subjects 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 + FTC/TDF | Efavirenz + FTC/TDF | |
|---|---|---|
| N=550 | N=546 | |
| ||
| Gastrointestinal Disorder | ||
| Nausea | 1% | 2% |
| Nervous System Disorders | ||
| Headache | 2% | 2% |
| Dizziness | 1% | 7% |
| Psychiatric Disorders | ||
| Depressive disorders† | 1% | 2% |
| Insomnia | 2% | 2% |
| Abnormal dreams | 1% | 3% |
| Skin and Subcutaneous Tissue Disorders | ||
| Rash | 1% | 5% |
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 regimen (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 and glomerulonephritis mesangioproliferative.
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 occurred in at least 10% of treatment-naive 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 (Grade 1 to 4), representing worst grade toxicity are presented in Table 2.
| Rilpivirine + FTC/TDF | Efavirenz + FTC/TDF | ||
|---|---|---|---|
| Laboratory Parameter Abnormality, (%) | DAIDS Toxicity Range | N=550 | N=546 |
| N = number of subjects per treatment group | |||
| Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine + tenofovir DF as background regimen. | |||
| |||
| BIOCHEMISTRY | |||
| Increased Creatinine | |||
| Grade 1 | ≥1.1–≤1.3 × ULN* | 5% | <1% |
| Grade 2 | >1.3–≤1.8 × ULN | <1% | 1% |
| Increased AST | |||
| Grade 1 | ≥1.25–≤2.5 × ULN | 13% | 16% |
| Grade 2 | >2.5–≤5.0 × ULN | 3% | 7% |
| Grade 3 | >5.0–≤10.0 × ULN | 2% | 2% |
| Grade 4 | >10.0 × ULN | <1% | 1% |
| Increased ALT | |||
| Grade 1 | ≥1.25–≤2.5 × ULN | 16% | 19% |
| Grade 2 | >2.5–≤5.0 × ULN | 4% | 6% |
| Grade 3 | >5.0–≤10.0 × ULN | 1% | 2% |
| Grade 4 | >10.0 x ULN | 1% | 1% |
| Increased Total Bilirubin | |||
| Grade 1 | ≥1.1–≤1.5 × ULN | 5% | <1% |
| Grade 2 | >1.5–≤2.5 × ULN | 2% | <1% |
| Grade 3 | >2.5–≤5.0 × ULN | <1% | <1% |
| Increased Total Cholesterol (fasted) | |||
| Grade 1 | 5.18–6.19 mmol/L 200–239 mg/dL | 13% | 29% |
| Grade 2 | 6.20–7.77 mmol/L 240–300 mg/dL | 4% | 15% |
| Grade 3 | >7.77 mmol/L >300 mg/dL | <1% | 2% |
| Increased LDL Cholesterol (fasted) | |||
| Grade 1 | 3.37–4.12 mmol/L 130–159 mg/dL | 11% | 25% |
| Grade 2 | 4.13–4.90 mmol/L 160–190 mg/dL | 5% | 11% |
| Grade 3 | >4.91 mmol/L >191 mg/dL | 1% | 2% |
| Increased Triglycerides (fasted) | |||
| Grade 2 | 5.65–8.48 mmol/L 500–750 mg/dL | 1% | 1% |
| Grade 3 | 8.49–13.56 mmol/L 751–1,200 mg/dL | <1% | 1% |
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 × 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) 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 48, the overall mean change from baseline in basal cortisol showed a decrease of -13.1 nmol/L in the rilpivirine group, and an increase of +9.0 nmol/L in the efavirenz group. At Week 48, the mean change from baseline in ACTH-stimulated cortisol levels was lower in the rilpivirine group (+16.5 ± 6.14 nmol/L) than in the efavirenz group (+58.1 ± 6.66 nmol/L). Mean values for both basal and ACTH-stimulated cortisol values at Week 48 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), increases in serum creatinine occurred within the first four weeks of treatment and remained stable through 48 weeks. A mean change of 0.09 mg/dL (range: -0.20 mg/dL to 0.62 mg/dL) was observed after 48 weeks of treatment. 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.
| Pooled Data from the C209 and C215 Trials | ||||||||
|---|---|---|---|---|---|---|---|---|
| Rilpivirine + FTC/TDF N=550 | Efavirenz + FTC/TDF N=546 | |||||||
| N | Baseline | Week 48 | N | Baseline | Week 48 | |||
| N = number of subjects per treatment group | ||||||||
| ||||||||
| Mean | Mean (mg/dL) | Mean (mg/dL) | Mean Change† (mg/dL) | Mean (mg/dL) | Mean (mg/dL) | Mean Change† (mg/dL) | ||
| Total Cholesterol (fasted) | 460 | 162 | 162 | 0 | 438 | 160 | 185 | 25 |
| HDL-cholesterol (fasted) | 459 | 42 | 45 | 3 | 437 | 40 | 49 | 9 |
| LDL-cholesterol (fasted) | 457 | 97 | 95 | -2 | 436 | 95 | 109 | 13 |
| Triglycerides (fasted) | 460 | 122 | 111 | -11 | 438 | 129 | 138 | 8 |
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 emtricitabine or tenofovir DF. 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.
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
Complera is a complete regimen for the treatment of HIV-1 infection; therefore, Complera should not be administered with other antiretroviral medications. Information regarding potential drug-drug interactions with other antiretroviral medications is not provided. Please refer to the EDURANT, VIREAD and EMTRIVA prescribing information as needed.
There were no drug-drug interaction trials conducted with the fixed-dose combination tablet. Drug interaction studies were conducted with emtricitabine, rilpivirine, or tenofovir DF, the components of Complera. This section describes clinically relevant drug interactions with Complera [See Contraindications (4) and Clinical Pharmacology (12.3)].
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, and valganciclovir.
QT Prolonging Drugs
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram [See Clinical Pharmacology (12.2)]. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.
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 [for pharmacokinetic data see Clinical Pharmacology (12.3), Tables 6–7]. The tables include potentially significant interactions, but are not all inclusive.
| Concomitant Drug Class: Drug Name | Effect on Concentration† | Clinical Comment |
|---|---|---|
| ||
| Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate) | ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) | The combination of Complera and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after Complera. |
| Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole | ↑ rilpivirine‡,§ ↓ ketoconazole‡,§ | Concomitant use of Complera with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when Complera is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with Complera. |
| H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine | ↔ rilpivirine‡,§ (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) ↓ rilpivirine‡,§ (famotidine taken 2 hours before rilpivirine) | The combination of Complera and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after Complera. |
| Macrolide Antibiotics: clarithromycin erythromycin troleandomycin | ↑ rilpivirine ↔ clarithromycin ↔ erythromycin ↔ troleandomycin | Concomitant use of Complera with clarithromycin, erythromycin and troleandomycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered. |
| Narcotic Analgesics: methadone | ↓ R(-) methadone‡ ↓ S(+) methadone‡ ↔ rilpivirine‡ ↔ methadone‡ (when used with tenofovir) | No dose adjustments are required when initiating coadministration of methadone with Complera. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
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, ethinylestradiol, norethindrone, sildenafil, or tenofovir DF. No clinically relevant drug-drug interaction is expected when rilpivirine is coadministered with ribavirin.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category B
Emtricitabine: The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120-times higher than human exposures at the recommended daily dose.
Rilpivirine: Studies in animals have shown no evidence of embryonic or fetal toxicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with rilpivirine during pregnancy and lactation, there were no toxicologically significant effects on developmental endpoints. The exposures at the embryo-fetal No Observed Adverse Effects Levels in rats and rabbits were respectively 15 and 70 times higher than the exposure in humans at the recommended dose of 25 mg once daily.
Tenofovir 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.
