Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Tenofovir disoproxil fumarate (tenofovir DF), an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor that is active against HIV and hepatitis B virus (HBV).
Emtricitabine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).
Efavirenz, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).
Tenofovir disoproxil fumarate (tenofovir DF), a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) nucleotide reverse transcriptase inhibitor. Tenofovir DF is a prodrug and is inactive until it undergoes diester hydrolysis in vivo to tenofovir and is subsequently metabolized to the active metabolite, tenofovir diphosphate. After conversion to the pharmacologically active metabolite, tenofovir inhibits replication of retroviruses, including HIV type 1 (HIV-1), by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).
In vitro and in vivo studies indicate that tenofovir is active against HIV-1 and hepatitis B virus (HBV); the drug also has some activity against HIV-2.
Like HIV nucleoside reverse transcriptase inhibitors (NRTIs), the antiviral activity of tenofovir depends on intracellular conversion to an active metabolite; however, tenofovir is a nucleotide containing a phosphonate group and the steps and enzymes involved in enzymatic conversion to the active metabolite differ from those involved in the conversion of NRTIs. Tenofovir is phosphorylated by cellular nucleotide kinases to tenofovir diphosphate; tenofovir diphosphate is a structural analog of deoxyadenosine-5'-triphosphate, the usual substrate for viral RNA-directed DNA polymerase. Although other mechanisms may be involved in the antiretroviral activities of the drug, tenofovir diphosphate appears to compete with deoxyadenosine-5'-triphosphate for viral RNA-directed DNA polymerase and for incorporation into viral DNA.
Following incorporation of tenofovir diphosphate into the viral DNA chain, DNA synthesis is prematurely terminated because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages.
Tenofovir diphosphate is a weak inhibitor of mammalian DNA alpha- and beta-polymerases and mitochondrial DNA gamma-polymerase. In vitro studies using human hepatoblastoma cells, skeletal muscle cells, or renal proximal tubule epithelial cells indicate that tenofovir has only a low potential to induce mitochondrial toxicity.
HIV-1 strains with reduced susceptibility to tenofovir DF can be produced in vitro and strains with reduced susceptibility to tenofovir have emerged during therapy with the drug. Resistant strains have contained a K65R substitution in reverse transcriptase. HIV-1 with a K70E substitution that results in low-level reduced susceptibility to tenofovir also have been selected in vitro and identified in clinical isolates.
Cross-resistance occurs between tenofovir and some NRTIs. The K65R and K70E substitutions selected by tenofovir also are selected in some patients treated with abacavir or didanosine; isolates with such substitutions may show reduced susceptibility to emtricitabine and lamivudine. Therefore, presence of the K65R or K70E substitution may result in cross-resistance between tenofovir and NRTIs.
In vitro studies indicate that HIV isolates with multiple substitutions associated with zidovudine resistance have reduced susceptibility to tenofovir. Cross-resistance between tenofovir and HIV protease inhibitors (PIs) or HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs) is unlikely.
Tenofovir inhibits HBV replication through competitive inhibition of viral reverse transcriptase. Although treatment-emergent amino acid substitutions have been reported in patients with HBV infection who received at least 24 weeks of tenofovir DF monotherapy and remained viremic, no specific substitutions occurred at a sufficient frequency to be associated with tenofovir resistance (genotypic and phenotypic analysis). Tenofovir may be active against some HBV strains that are resistant to adefovir and/or lamivudine.
However, cross-resistance occurs among the HBV nucleoside/nucleotide reverse transcriptase inhibitors and some adefovir-, entecavir-, lamivudine-, or telbivudine-resistant HBV may have reduced susceptibility to tenofovir.
When a 300-mg tenofovir DF tablet is administered with a high-fat meal, plasma tenofovir concentrations and AUC are increased; pharmacokinetics are not appreciably affected by administration with a light meal.
The pharmacokinetics of tenofovir DF in healthy individuals is similar to that in individuals with HIV-1 infection. Following oral administration of tenofovir DF in fasting HIV-infected individuals, oral bioavailability of tenofovir is approximately 25% and peak plasma concentrations are attained in about 1 hour. Pharmacokinetics are dose proportional over a tenofovir DF dosage range of 75-600 mg and are not affected by repeated dosing.
In a single-dose study in nonfasting individuals, mean peak plasma concentrations of tenofovir were 26% lower when tenofovir DF was administered as an oral powder compared with administration as tablets; however, the mean AUC of tenofovir was similar with both preparations. Food delays the time to peak plasma concentrations by approximately 1 hour. Administration of 300 mg of tenofovir DF (as tablets) following a high-fat meal (approximately 700-1000 kcal containing 40-50% fat) increases oral bioavailability resulting in a 14% increase in peak plasma concentrations and 40% increase in AUC.
Administration of tenofovir DF with a light meal does not have a clinically important effect on the pharmacokinetics of tenofovir compared to administration in the fasting state.
In vitro, tenofovir is less than 0.7 or 7.2% bound to plasma or serum proteins, respectively, over the concentration range of 0.01-25 mcg/mL. Following oral administration of tenofovir DF, there is some evidence that tenofovir is distributed into semen and vaginal tissue and cervicovaginal fluid in low concentrations. Very low concentrations may be distributed into saliva.
Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate. Tenofovir and its prodrug are not substrates of cytochrome P-450 (CYP) isoenzymes. Tenofovir is eliminated principally by the kidneys via glomerular filtration and active tubular secretion.
Following multiple oral doses, approximately 32% of a dose is eliminated in urine over 24 hours. Tenofovir is removed by hemodialysis; following a 300-mg dose of tenofovir DF, a 4-hour hemodialysis session removes approximately 10% of the dose. Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Clinical studies did not include sufficient numbers from racial and ethnic groups other than white patients to adequately determine potential pharmacokinetic differences among these populations. Pharmacokinetics of tenofovir DF are similar in male and female patients.
Emtricitabine, a synthetic antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI). Emtricitabine is inactive until converted intracellularly to an active 5'-triphosphate metabolite. Following conversion to the pharmacologically active metabolite, the drug inhibits replication of human retroviruses by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).
The pharmacokinetics of emtricitabine in healthy individuals are similar to that in individuals with human immunodeficiency virus type 1 (HIV-1) infection. Following oral administration, emtricitabine is rapidly and extensively absorbed; peak plasma concentrations of the drug are attained within 1-2 hours. The mean absolute oral bioavailability of emtricitabine capsules is 93%.
The mean absolute oral bioavailability of emtricitabine oral solution is 75%. Food does not appear to have a clinically important effect on emtricitabine absorption. Administration of emtricitabine capsules with food (approximately 1000 kcal high-fat meal) did not affect the area under the concentration-time curve (AUC) of emtricitabine, but resulted in a 29% decrease in peak plasma concentrations of the drug.
Administration of emtricitabine oral solution with a high-fat or low-fat meal did not affect the AUC or peak plasma concentrations of emtricitabine. Pharmacokinetics in pediatric patients 3 months to 17 years of age receiving recommended emtricitabine dosage (6 mg/kg daily (up to 240 mg daily) as the oral solution or 200-mg capsule once daily) is similar to that reported in adults receiving 200 mg daily. The AUC reported in neonates receiving emtricitabine 3 mg/kg daily for 4 days is similar to that reported in children 3 months to 17 years of age receiving the recommended dosage.
Emtricitabine is less than 4% bound to plasma proteins; binding is independent of drug concentrations over the range of 0.01-200 mcg/mL. Emtricitabine is distributed into human milk in low concentrations. Emtricitabine undergoes oxidation and conjugation with glucuronic acid.
Intracellularly, emtricitabine is phosphorylated and converted by cellular enzymes to the active metabolite, emtricitabine 5'-triphosphate. Emtricitabine is eliminated in urine (86%) and feces (14%). The drug is eliminated in urine by glomerular filtration and active tubular secretion; 13% of a dose is recovered in urine as 3 metabolites.
Emtricitabine is removed by hemodialysis; it is not known whether the drug is removed by peritoneal dialysis. The plasma elimination half-life of emtricitabine is approximately 10 hours. Peak plasma concentrations and AUC of emtricitabine are increased in adults with renal impairment (creatinine clearance less than 50 mL/minute or end-stage renal disease requiring dialysis) due to reduced renal clearance of the drug.
Dosage adjustments are needed. The pharmacokinetics of emtricitabine are not affected by race or gender.
Emtricitabine is active against HIV type 1 (HIV-1) and also has some in vitro activity against HIV type 2 (HIV-2). HIV-1 strains with reduced susceptibility to emtricitabine can be produced in vitro and strains with reduced susceptibility to the drug have emerged during emtricitabine therapy. These strains have contained a M184V/I mutation.
HIV-1 strains with the M184V/I mutation have been resistant to lamivudine but retained susceptibility to didanosine, tenofovir, zidovudine, delavirdine, efavirenz, and nevirapine.
Although the complete mechanism(s) of antiviral activity of efavirenz has not been fully elucidated, the drug inhibits human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Efavirenz binds directly to HIV-1 reverse transcriptase and exerts a virustatic effect by acting as a specific, noncompetitive HIV-1 reverse transcriptase inhibitor.
Efavirenz is a highly specific inhibitor of HIV-1 reverse transcriptase and does not appear to interfere with the activity of cellular DNA polymerases, including human alpha-, beta-, gamma-, or delta-polymerases.
The pharmacokinetics of efavirenz have been studied in healthy individuals, adults with human immunodeficiency virus (HIV) infection, and HIV-infected children 3-16 years of age. The pharmacokinetics of efavirenz capsules (or capsule contents mixed with soft food or infant formula) in pediatric patients were predicted using a population pharmacokinetic model.
Following oral administration of efavirenz 200, 400, or 600 mg once daily in HIV-infected adults, mean peak plasma concentration, mean trough plasma concentration, and AUC of the drug at steady-state were dose proportional. In HIV-infected adults receiving efavirenz 200, 400, or 600 mg once daily, peak plasma concentrations of the drug generally occur in 3-5 hours and steady-state plasma concentrations are achieved in 6-10 days. Efavirenz has been shown to induce CYP enzymes, resulting in the induction of its own metabolism.
Following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance of the drug. In one study in individuals receiving efavirenz 200-400 mg once daily for 10 days, plasma concentrations of the drug were 22-42% lower than those predicted from single-dose studies. Oral bioavailability of efavirenz may be affected by administration with food.
Administration of a single 600-mg dose of efavirenz as capsules with a high-fat, high-calorie meal (894 kcal, 54 g fat, 54% of calories from fat) or a reduced-fat, normal-calorie meal (440 kcal, 2 g fat, 4% of calories from fat) increases peak plasma concentrations of the drug by 39 or 51%, respectively, and AUC by 22 or 17%, respectively, compared with administration in the fasting state. Administration of a single 600-mg dose of efavirenz as tablets with a high-fat, high-calorie meal (approximately 1000 kcal, 500-600 kcal from fat) increases peak plasma concentrations and AUC of the drug by 79 and 28%, respectively, compared with administration in the fasting state. Therefore, the manufacturer states that efavirenz should be administered on an empty stomach.
In healthy adults who received a 600-mg efavirenz dose administered by opening 200-mg capsules and mixing the contents of 3 capsules with 2 teaspoonfuls of soft food (e.g., applesauce, grape jelly, yogurt) or infant formula, the AUC of efavirenz met bioequivalency criteria compared with intact capsules administered in the fasted state.
Efavirenz is about 99.5-99.75% bound to plasma proteins, principally albumin. Efavirenz appears to induce its own metabolism. The terminal elimination half-life of efavirenz reported in single-dose studies is longer than that reported in multiple-dose studies and has averaged 52-76 hours after a single oral dose and 40-55 hours following administration of 200-400 mg daily for 10 days.
In addition, following continued administration of efavirenz, plasma concentrations are lower than expected from single-dose studies, presumably because of increased clearance. The metabolic fate of efavirenz has not been fully determined, but the drug is metabolized in the liver. Efavirenz is principally metabolized by the cytochrome P-450 (CYP) isoenzymes 3A and 2B6 to several hydroxylated metabolites, which undergo subsequent glucuronidation.
Efavirenz is excreted principally in the feces. Following oral administration of 400 mg of radiolabeled efavirenz on day 8, 14-34% of the dose was excreted in urine (nearly all in the form of metabolites), and 16-61% was excreted in feces (predominantly as unchanged drug). Because efavirenz is highly protein bound, it is unlikely that substantial amounts of the drug would be removed from the body by dialysis.
Pharmacokinetic studies have not revealed gender- or race-related differences in the pharmacokinetics of efavirenz. Pharmacokinetics of efavirenz are not affected by mild hepatic impairment (Child-Pugh class A); data are insufficient to determine whether moderate or severe hepatic impairment (Child-Pugh class B or C) affects pharmacokinetics of the drug. The pharmacokinetics of efavirenz have not been specifically studied in patients with renal impairment.
USES: This product contains 3 different medications: efavirenz, emtricitabine, and tenofovir. It is used alone or with other HIV medications to help control HIV infection. It helps to decrease the amount of HIV in your body so your immune system can work better.
This lowers your chance of getting HIV complications (such as new infections, cancer) and improves your quality of life. Efavirenz belongs to a class of drugs known as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Emtricitabine and tenofovir belong to a class of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs).
Efavirenz/emtricitabine/tenofovir is not a cure for HIV infection. To decrease your risk of spreading HIV disease to others, continue to take all HIV medications exactly as prescribed by your doctor. Use an effective barrier method (latex or polyurethane condoms/dental dams) during sexual activity as directed by your doctor.
Do not share personal items (such as needles/syringes, toothbrushes, and razors) that may have contacted blood or other body fluids. Consult your doctor or pharmacist for more details.
Generic name: efavirenz/emtricitabine/tenofovir disoproxil fumarate
Pronunciation: (eh-FAV-er-enz/em-tri-SITE-ah-bean/te-NOE-fo-veer)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Atripla
Indications
The following indications are listed for Atripla:
- Hiv Infection
Also known as: Human Immunodeficiency Virus Disease, Human Immunodeficiency Virus Infection.
Dosing
Although tenofovir DF is a prodrug that requires metabolism for activation, dosage of the drug is expressed in terms of the prodrug diester (i.e., tenofovir DF).
Dosage of tenofovir DF oral powder containing 40 mg/g is expressed as the number of scoops of powder.
Emtricitabine capsules and oral solution are not bioequivalent. Bioavailability of the oral solution is 80% relative to that of the capsule.
If efavirenz is used for treatment of HIV-1 infection in patients receiving rifampin, those weighing >=50 kg should receive an increased efavirenz dosage of 800 mg daily.
If efavirenz is used for treatment of HIV-1 infection in patients receiving voriconazole, the voriconazole dosage should be increased to 400 mg every 12 hours and the efavirenz dosage should be reduced to 300 mg daily using the capsule formulation.
Reduce dosage in patients with renal impairment; emtricitabine is principally eliminated by the kidney.
Single-entity tenofovir DF is commercially available as tablets or oral powder.
Tenofovir DF tablet is administered orally once daily without regard to meals.
Tenofovir DF oral powder is administered once daily. Measure the appropriate dosage of the oral powder using only the scoop provided by the manufacturer. One level scoop delivers 1 g of powder, which contains 40 mg of tenofovir DF. Mix the required number of scoops of the powder with 2-4 ounces of soft food that can be swallowed without chewing (e.g., applesauce, baby food, yogurt), and ingest the entire mixture immediately to avoid a bitter taste. Do not administer the oral powder in a liquid since the powder may float to the top of the liquid, even after stirring.
Store tenofovir DF oral power and tablets at 25oC (excursions permitted to 15-30oC). Dispense in the original container, and keep the container tightly closed.
Emtricitabine is administered orally once daily without regard to meals.
Single-entity emtricitabine is commercially available as 200-mg capsules or an oral solution containing 10 mg/mL.
Emtricitabine is also commercially available in the following fixed-combination tablets for oral use: emtricitabine/tenofovir DF (Truvada(R)), efavirenz/emtricitabine/tenofovir DF (Atripla(R)), emtricitabine/rilpivirine/tenofovir DF (Complera(R)), elvitegravir/cobicistat/emtricitabine/tenofovir DF (Stribild(R)), elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (Genvoya(R)), emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey(R)), emtricitabine/tenofovir alafenamide (Descovy(R)), and bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy(R)). See the full prescribing information for administration of each of these combination products.
Emtricitabine is used in conjunction with other antiretrovirals. Single-entity emtricitabine should not be used concomitantly with any other emtricitabine-containing preparations.
Store capsules at 25degreesC (excursions permitted to 15-30degreesC).
Store oral solution at 2-8degreesC. For patient use, store at 25degreesC (excursions permitted to 15-30degreesC); use within 3 months.
Single-entity efavirenz is commercially available as capsules or tablets.
Efavirenz capsules and tablets are administered orally once daily on an empty stomach, preferably at bedtime.
Because administration with food increases plasma efavirenz concentrations and may increase the incidence of adverse effects, the drug should be taken on an empty stomach. Administration of efavirenz at bedtime may make adverse CNS effects (e.g., dizziness, insomnia, impaired concentration, somnolence, abnormal dreams) more tolerable.
Efavirenz is used in conjunction with other antiretrovirals. Single-entity efavirenz should not be used concomitantly with efavirenz/emtricitabine/tenofovir disoproxil fumarate (tenofovir DF; e.g., Atripla(R)), unless needed for adjustment of efavirenz dosage (e.g., when the fixed combination is used concomitantly with rifampin).
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Tenofovir disoproxil fumarate (tenofovir DF) is a substrate of the P-glycoprotein (P-gp) transport system and breast cancer resistance protein (BCRP). Tenofovir and its prodrug (tenofovir DF) are not substrates of cytochrome P-450 (CYP) isoenzymes; in vitro studies indicate tenofovir does not inhibit CYP isoenzymes 3A4, 2D6, 2C9, or 2E1, but may have a slight inhibitory effect on CYP1A.
The following drug interactions are based on studies using tenofovir DF; refer to the full prescribing information for further details. Additional drug interactions may exist for fixed-combinations containing emtricitabine and tenofovir DF (Truvada(R)); doravirine, lamivudine, and tenofovir DF (Delstrigo(R)); efavirenz, emtricitabine, and tenofovir DF (Atripla(R)); emtricitabine, rilpivirine, and tenofovir DF (Complera(R)); elvitegravir, cobicistat, emtricitabine, and tenofovir DF (Stribild(R)); and efavirenz, lamivudine, and tenofovir (Symfi(R) and Symfi Lo(R)). When a fixed combination is used, interactions associated with each drug in the fixed combination should be considered. See the full prescribing information for drug interactions of each combination product.
In vitro studies indicate that emtricitabine does not inhibit cytochrome P-450 (CYP) isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, or 3A4. Emtricitabine does not inhibit uridine-5'-disphosphoglucuronyl transferase. The following drug interactions are based on studies using emtricitabine. When a fixed combination containing emtricitabine is used, interactions associated with each drug in the fixed combination should be considered.
Plasma concentrations of efavirenz may be altered if used concomitantly with drugs that are substrates, inhibitors, or inducers of cytochrome P-450 (CYP) 3A.
Efavirenz induces CYP3A and 2B6 and may alter plasma concentrations of drugs metabolized by these enzymes.
Efavirenz is a substrate of cytochrome P-450 (CYP) 3A and CYP2B6. Efavirenz has been shown to induce CYP3A and 2B6 in vivo; in vitro studies have shown that efavirenz is also an inhibitor of CYP2C9 and 2C19. Efavirenz did not inhibit CYP2E1 in vitro, and did not inhibit CYP2D6 or 1A2 at clinically relevant concentrations.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
*None.
*Known hypersensitivity to the drug or any ingredient in the formulation.
*Clinically important hypersensitivity reaction (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic skin eruption) to efavirenz or any other ingredient in the formulation.
*Concomitant use with elbasvir and grazoprevir.
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
The most common adverse effects (incidence >=10%; grades 2-4) in HIV-infected patients receiving tenofovir DF are rash, diarrhea, headache, pain, depression, asthenia, and nausea.
The most common adverse effect (all grades) in HBV-infected patients with compensated liver disease was nausea (9%).
The most common adverse effects (incidence >=10%; all grades) in HBV-infected patients with decompensated liver disease were abdominal pain, nausea, vomiting, pruritus, insomnia, dizziness, and pyrexia.
Adverse reactions in pediatric patients were consistent with those observed in adults.
The most common adverse reactions experienced in at least 10% of adult patients with HIV-1 treated with emtricitabine include headache, GI effects (diarrhea, nausea), fatigue, dizziness, depression, insomnia, abnormal dreams, rash, abdominal pain, asthenia, increased cough, and rhinitis. Adverse effects reported in pediatric patients 3 months of age or older receiving emtricitabine in clinical studies have been similar to those in adults, with the exception of a higher frequency of hyperpigmentation.
Moderate to severe adverse effects occurring in >5% of patients receiving efavirenz include impaired concentration, abnormal dreams, rash, dizziness, nausea, headache, fatigue, insomnia, and vomiting.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
No enhanced messaging available.
Safety and efficacy of tenofovir DF for treatment of HIV-1 infection in pediatric patients 2 to <18 years of age are supported by data from 2 randomized controlled trials. Peak plasma concentrations and AUC of tenofovir in HIV-1-infected pediatric patients 2 to <18 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as oral powder or receiving 300 mg once daily as tablets were similar to peak plasma concentrations and AUC reported in adults receiving 300 mg once daily. Safety and efficacy of tenofovir DF for treatment of HIV-1 infection have not been established in children <2 years of age weighing <10 kg.
In HBV-infected pediatric patients 12 to <18 years of age receiving tenofovir DF 300 mg once daily as tablets, and pediatric patients 2 to <12 years of age receiving 8 mg/kg of tenofovir DF (up to 300 mg) once daily as tablets or oral powder, tenofovir exposures were similar to those reported in HIV-1-infected adults receiving identical doses.
Safety and efficacy of tenofovir DF for treatment of chronic HBV infection have not been established in children <2 years of age weighing <10 kg.
Safety and efficacy of emtricitabine have been established for treatment of HIV-1 infection in children 3 months of age and older.
The pharmacokinetics and safety of emtricitabine were evaluated in a dose-finding study in 20 neonates born to HIV-infected mothers. These neonates received zidovudine prophylaxis for 6 weeks. In addition, these neonates received 2 short courses of emtricitabine (3 mg/kg daily for 4 days per course) during the first 12 weeks of life. This dosage was not associated with any safety issues. Systemic exposure (AUC) in infants 0-3 months of age receiving emtricitabine 3 mg/kg daily was similar to that reported in children 3 months to 17 years of age receiving emtricitabine 6 mg/kg daily. All neonates were HIV-1 negative at the end of the study (6 months postpartum); the efficacy of emtricitabine for the prevention or treatment of HIV was not determined.
Safety and efficacy of single-entity efavirenz have not been established in neonates and infants <3 months of age or in those weighing <3.5 kg, and the drug should not be used in these pediatric patients.
Adverse effects reported in pediatric patients 3 months to 21 years of age receiving efavirenz are similar to those reported in adults receiving the drug. Rash has been reported more frequently in children than adults, and the incidence of grade 3 or 4 rash has been greater in children than adults. Because of the high incidence of dermatologic reactions in children, antihistamines should be considered for the prevention of rash when initiating efavirenz in children.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to tenofovir DF during pregnancy. Clinicians are encouraged to register patients in the APR by calling 1-800-258-4263 or visiting https://www.apregistry.com/.
Based on prospective data from the APR, the prevalence of birth defects in live births was 2.3% and 2.1% following first and second/third trimester exposure, respectively, to tenofovir DF-containing regimens. The overall risk of birth defects with first-trimester exposure for tenofovir DF was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Limitations of using an external comparator (the MACDP) include differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage is not reported in the APR. Tenofovir crosses the human placenta.
In published studies that included HBV-infected pregnant women treated with tenofovir DF, an increased risk of adverse pregnancy-related outcomes was not observed with use of tenofovir DF during the third trimester. Two stillbirths were identified, and there was 1 major birth defect (talipes) and 1 occurrence of multiple congenital abnormalities (not further specified) in infants exposed to tenofovir DF. No clinically relevant drug-related safety findings were found in infants exposed to tenofovir DF during late gestation.
Animal reproduction studies did not find any adverse developmental effects when tenofovir DF was administered at doses >=14 (tenofovir DF) and exposures 2.7 (tenofovir) times the recommended daily dose of tenofovir DF in humans.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to emtricitabine during pregnancy. Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting https://www.APRegistry.com.
Based on prospective reports to the APR, the overall risk of birth defects among live births with first-trimester exposure to emtricitabine was 2.4%, and 2.3% with second/third trimester exposure, compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Limitations of using an external comparator (i.e., MACDP) include differences in populations and methodology, and confounding due to the underlying disease. The rate of miscarriage for individual drugs is not reported in the APR.
Additional observational data have not shown an increase in major malformations with emtricitabine exposure in pregnancy.
Efavirenz may cause fetal harm if administered during the first trimester of pregnancy. There are retrospective case reports of neural tube defects in infants born to mothers who were exposed to efavirenz during the first trimester of pregnancy. Although prospective data in humans are inadequate to assess risks and a causal relationship between efavirenz exposure in the first trimester and neural tube defects has not been established, similar malformations have been observed in animal studies. The manufacturer states that efavirenz should not be used during the first trimester of pregnancy.
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to antiretroviral agents, including efavirenz, during pregnancy. Clinicians are encouraged to contact the registry at 800-258-4263 or https://www.apregistry.com to report cases of prenatal exposure to antiretroviral agents.
Based on prospective reports from the APR of approximately 1000 live births following exposure to efavirenz (including more than 800 live births following first-trimester exposures), there was no difference between overall birth defects with efavirenz compared with the background birth defect rate (2.7% in the US reference population of the Metropolitan Atlanta Congenital Defects Program). An interim report issued in December 2014 that used data from the registry indicated that the prevalence of birth defects was 2.3% following first-trimester exposures to efavirenz. Defects reported prospectively in first-trimester exposures included 1 case of neural tube defect and 1 case of anophthalmia with severe oblique facial clefts and amniotic banding.
Females of reproductive potential should be advised about the teratogenic potential of efavirenz. Such patients should undergo pregnancy testing before initiation of therapy. If efavirenz is used during the first trimester, or if pregnancy occurs during therapy, the patient should be apprised of the potential risk to the fetus.
Tenofovir is distributed into human milk in low concentrations. In a study of breast-feeding women (not infected with HIV) who were on a tenofovir-containing regimen started between 1-24 weeks postpartum, tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. No serious adverse events were reported in mothers or infants.
It is not known whether tenofovir DF affects human milk production or has effects on the breast-fed infant.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
If using tenofovir DF for the treatment of HBV infection, consider the developmental and health benefits of breast-feeding and the importance of tenofovir DF to the mother along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.
Based on published data, emtricitabine is distributed into human milk. It is not known whether emtricitabine affects milk production or has effects on the breast-fed infant.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding. The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding. During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant. Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk. Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.
The manufacturer makes no specific dosage recommendations for geriatric patients. Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.
The manufacturer makes no specific dosage recommendations for geriatric patients, but recommends cautious dosage selection due to the greater frequency of decreased hepatic, renal, and/or cardiac function, and of concomitant disease and drug therapy.
The manufacturer makes no specific dosage recommendations for geriatric patients, but recommends cautious dosage selection because of possible age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.
Clinical studies did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently to tenofovir DF than younger adults. Select dosage in geriatric patients with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy. Pharmacokinetic studies have not been conducted in patients >=65 years of age.
Experience in those 65 years of age or older is insufficient to determine whether they respond differently to emtricitabine than younger adults. Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.
Clinical studies of efavirenz have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric individuals respond differently to the drug than younger adults. Dosage selection in elderly patients should be cautious, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function and the potential for concomitant disease and drug therapy.
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Last reviewed · Source: First Databank (FDB) drug data
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