Complera: HIV Medication Side Effects, Dosage & Warnings

Generic drug: emtricitabine, rilpivirine, tenofovir disoproxil fumarate

Brand name: Complera

What is Complera, and how does it work?

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).

What are the side effects of Complera?

WARNING

LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

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.

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.

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.

What is the dosage for Complera?

Testing Prior To Initiation And During Treatment With Complera

Prior to or when initiating Complera, test patients for hepatitis B virus
infection.
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.

Recommended 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.

Recommended 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.

Not Recommended In Patients With Moderate Or Severe Renal
Impairment

Complera is not recommended in patients with moderate or severe renal
impairment (estimated creatinine clearance below 50 mL per minute).

Recommended 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 .

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What drugs interact with Complera?

Not Recommended With Other Antiretroviral Medications

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.

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 RPV.
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.

Drugs 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.

Drugs 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.

QT 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. Consider alternatives to Complera when coadministered with a drug with a known risk of Torsade de Pointes.

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 prescribing information for list of contraindicated drugs.

Table 4 : Significanta Drug Interactions

Concomitant Drug Class: Drug Name
Effect on Concentrationb
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
↓ RPV^c
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^c,d
↓ ketoconazole^c,d
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^c
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^c,d(famotidine taken 12 hours before RPV or 4 hours after RPV)
↓ RPV^c,d (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(-) methadonec
↔S(+) methadonec ↔RPV^c↑methadone^c(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.

^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 RPV assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended dose of RPV 25 mg once daily.

Drugs 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.

QUESTION

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Is Complera safe to use while pregnant or breastfeeding?

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).
In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period.
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.
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.
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.