"The U.S. Food and Drug Administration today approved Tivicay (dolutegravir), a new drug to treat HIV-1 infection.
Tivicay is an integrase strand transfer inhibitor that interferes with one of the enzymes necessary for HIV to multiply. "...
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].
- Severe Acute Exacerbations of Hepatitis B [See BOXED WARNING, WARNINGS AND PRECAUTIONS].
- New Onset or Worsening Renal Impairment [See WARNINGS AND PRECAUTIONS].
- Depressive Disorders [See WARNINGS AND PRECAUTIONS].
- Hepatotoxicity [See WARNINGS AND PRECAUTIONS].
- Bone Effects of Tenofovir DF [See WARNINGS AND PRECAUTIONS].
- Immune Reconstitution Syndrome [See WARNINGS AND PRECAUTIONS].
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.
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-na´ve 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]. 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.
Table 1 : Selected Treatment-Emergent Adverse Drug
Reactionsa (Grades 2-4) Reported in ≥ 2% of Subjects Receiving
Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in
Studies C209 and C215(Week 96 analysis)
|Rilpivirine + FTC/TDF
|Efavirenz + FTC/TDF
|Nervous System Disorders|
|Skin and Subcutaneous Tissue Disorders|
|a Frequencies of adverse reactions are based
on all Grades 2-4 treatment-emergent adverse events assessed to be related to
b Includes adverse drug reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation.
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, virologicallysuppressed subjects switching to COMPLERA from a regimen containing a ritonavirboosted 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-na´ve 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-na´ve 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.
Table 2 : Selected Laboratory Abnormalities (Grades
1-4) Reported in Subjects WhoReceived Rilpivirine or Efavirenz in Combination
with Emtricitabine/Tenofovir DF in Studies C209 and C215 (Week 96 Analysis)
|Laboratory Parameter Abnormality, (%)||DAIDS Toxicity Range||Rilpivirine + FTC/TDF
|Efavirenz + FTC/TDF
|Grade 1||1.1-1.3 x ULNa||6%||1%|
|Grade 2||> 1.3-1.8 x ULN||1%||1%|
|Grade 3||> 1.8-3.4 x ULN||< 1%||0|
|Grade 4||> 3.4 x ULN||0||< 1%|
|Grade 1||1.25-2.5 x ULN||16%||19%|
|Grade 2||> 2.5-5.0 x ULN||4%||7%|
|Grade 3||> 5.0-10.0 x ULN||2%||3%|
|Grade 4||> 10.0 x ULN||1%||1%|
|Grade 1||1.25-2.5 x ULN||19%||22%|
|Grade 2||> 2.5-5.0 x ULN||5%||7%|
|Grade 3||> 5.0-10.0 x ULN||1%||2%|
|Grade 4||> 10.0 x ULN||1%||1%|
|Increased Total Bilirubin|
|Grade 1||1.1-1.5 x ULN||6%||< 1%|
|Grade 2||> 1.5-2.5 x ULN||3%||1%|
|Grade 3||> 2.5-5.0 x 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||751-1,200 mg/dL||1%||2%|
|Grade 4||> 1,200 mg/dL||0||1%|
|N = number of subjects per
a ULN = Upper limit of normal value.
Note: Percentages were calculated versus the number of subjects in ITT population with emtricitabine + tenofovir DF as background regimen.
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.
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.
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.
Table 3 : Lipid Values Reported in Subjects Receiving
Rilpivirine or Efavirenz in Combination with Emtricitabine/Tenofovir DF in
Studies C209 and C215a
|Mean||Pooled Data from the Week 96 Analysis of C209 and C215 Trials|
|Rilpivirine + FTC/TDF
|Efavirenz + FTC/TDF
|N||Baseline||Week 96||N||Baseline||Week 96|
|Mean (mg/dL)||Mean (mg/dL)||Mean Changeb (mg/dL)||Mean (mg/dL)||Mean (mg/dL)||Mean Changeb (mg/dL)|
|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|
|N = number of subjects per
a Excludes subjects who received lipid lowering agents during the treatment period.
b The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.
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.
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.
Renal and Urinary Disorders nephrotic syndrome
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
Respiratory, Thoracic, and Mediastinal Disorders
pancreatitis, increased amylase, abdominal pain
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders
Musculoskeletal and Connective Tissue Disorders
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
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.
Read the Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate tablets) Side Effects Center for a complete guide to possible side effects
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 DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and CLINICAL PHARMACOLOGY].
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, CONTRAINDICATIONS]. 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 [See WARNINGS AND PRECAUTIONS].
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]. 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, Tables 6-7]. The tables include potentially significant interactions, but are not all inclusive.
Table 4 : Established and Other Potentially Significanta
Drug Interactions: Alterationin Dose or Regimen May Be Recommended Based on
Drug Interaction Studies or Predicted Interaction
|Concomitant Drug Class: Drug Name||Effect on Concentrationb||Clinical Comment|
|Antacids: antacids (e.g., aluminium, magnesium hydroxide, or calcium carbonate)||↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine)
↓ rilpivirine (concomitant intake)
|The combination of COMPLERA and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after COMPLERA.|
|Antimycobacterials: rifabutin||↓rilpivirine0||Concomitant use of COMPLERA with rifabutin may cause significant decreases in rilpivirine plasma concentrations (induction of CYP3A enzymes). If COMPLERA is coadministered with rifabutin, an additional 25 mg tablet of rilpivirine (Edurant) once per day is recommended to be taken concomitantly with COMPLERA and with a meal for the duration of rifabutin coadministration.|
|Azole Antifungal Agents:
|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.|
|↔ rilpivirinec,d (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine)
↓ rilpivirinec,d (famotidine taken 2 hours before rilpivirine)
|The combination of COMPLERA and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after COMPLERA.|
|Macrolide or Ketolide Antibiotics: clarithromycin
|Concomitant use of COMPLERA with clarithromycin, erythromycin or telithromycin may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). Where possible, alternatives such as azithromycin should be considered.|
|Narcotic Analgesics: methadone||↓R(-) methadonec
↔methadonec (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.|
|a This table is not all inclusive.
b Increase = ↑; Decrease = ↓; No Effect = ↔
c The interaction was evaluated in a clinical study. All other drug-drug interactions shown are predicted.
d This interaction study has been performed with a dose higher than the recommended dose for rilpivirine. The dosing recommendation is applicable to the recommended dose of rilpivirine 25 mg once daily.
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.
Read the Complera Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 11/17/2014
This monograph has been modified to include the generic and brand name in many instances.
Additional Complera Information
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