Kompozisyon:
Tedavide kullanılır:
Kovalenko Svetlana Olegovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 08.04.2022
Dikkat! Sayfadaki bilgiler sadece sağlık profesyonelleri içindir! Bilgi kamu kaynaklarında toplanır ve anlamlı hatalar içerebilir! Dikkatli olun ve bu sayfadaki tüm bilgileri tekrar kontrol edin!
Aynı bileşenlere sahip en iyi 20 ilaç:
ATRIPLA® yetişkinlerde ve en az 40 kg ağırlığındaki pediatrik hastalarda HIV-1 enfeksiyonunun tedavisi için tam bir rejim veya diğer antiretroviral ajanlarla kombinasyon halinde endikedir.
Başlamadan Önce ve ATRIPLA ile Tedavi Sırasında Test Yapılması
ATRIPLA'dan önce veya başlatılırken, hastaları hepatit B virüsü enfeksiyonu açısından test edin.
ATRIPLA'nın başlatılmasından önce ve klinik olarak uygun bir programda, tüm hastalarda serum kreatinin, tahmini kreatinin klerensi, idrar şekeri ve idrar proteinini değerlendirin. Kronik böbrek hastalığı olan hastalarda serum fosforunu da değerlendirin.
ATRIPLA ile tedavi öncesinde ve sırasında hepatik fonksiyonu izleyin
Çocuk doğurma potansiyeli olan ergenlerde ve yetişkinlerde ATRIPLA'nın başlatılmasından önce hamilelik testi yapın.
En Az 40 kg Ağırlığındaki Yetişkinler ve Pediatrik Hastalar İçin Önerilen Dozaj
ATRIPLA, 600 mg efavirenz (EFV), 200 mg emtrisitabin (FTC) ve 300 mg tenofovir disoproksil fumarat (TDF) içeren üç ilaçlı sabit dozlu bir kombinasyon ürünüdür. Yetişkinlerde ve en az 40 kg ağırlığındaki pediatrik hastalarda önerilen ATRIPLA dozu, aç karnına oral yoldan alınan günde bir kez bir tablettir. Yatmadan önce dozlama, sinir sistemi semptomlarının tolere edilebilirliğini artırabilir.
Orta veya Şiddetli Böbrek yetmezliği olan hastalarda önerilmez
ATRIPLA, orta veya şiddetli böbrek yetmezliği olan hastalarda (tahmini kreatinin klerensi 50 mL / dk'nın altında) önerilmez.
Orta ila Şiddetli Karaciğer yetmezliği olan hastalarda önerilmez
ATRIPLA, orta ila şiddetli karaciğer yetmezliği olan hastalarda (Child Pugh B veya C) önerilmez.
Rifampin ile Dozaj Ayarı
ATRIPLA, 50 kg veya daha ağır hastalarda rifampin ile birlikte uygulanırsa, günde bir kez bir tablet ATRIPLA ve ardından günde bir kez 200 mg efavirenz alın.
- ATRIPLA, daha önce klinik olarak anlamlı aşırı duyarlılık gösteren hastalarda kontrendikedir (ör., Stevens-Johnson sendromu, eritema multiforme veya toksik cilt döküntüleri) ATRIPLA'nın bir bileşeni olan efavirenz'e .
- ATRIPLA, vorikonazol veya elbasvir / grazoprevir ile birlikte uygulanacak şekilde kontrendikedir.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Patients Coinfected With HIV-1 And HBV
It is recommended that all patients with HIV-1 be tested for the presence of chronic HBV before initiating antiretroviral therapy. ATRIPLA is not approved for the treatment of chronic HBV infection, and the safety and efficacy of ATRIPLA 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 ATRIPLA. In some patients infected with HBV and treated with emtricitabine, 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 ATRIPLA. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
ATRIPLA should not be administered with HEPSERA® (adefovir dipivoxil).
Drug Interactions
Efavirenz plasma concentrations may be altered by substrates, inhibitors, or inducers of CYP3A. Likewise, efavirenz may alter plasma concentrations of drugs metabolized by CYP3A or CYP2B6. The most prominent effect of efavirenz at steady state is induction of CYP3A and CYP2B6.
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 and emtricitabine, components of ATRIPLA, alone or in combination with other antiretrovirals. Treatment with ATRIPLA 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).
Coadministration With Related Products
ATRIPLA is a fixed-dose combination of efavirenz, emtricitabine, and tenofovir DF. Do not coadminister ATRIPLA with other drugs containing emtricitabine, tenofovir DF, or tenofovir alafenamide, including COMPLERA®, DESCOVY®, EMTRIVA®, GENVOYA® , ODEFSEY®, STRIBILD®, TRUVADA®, VEMLIDY®, or VIREAD®. SUSTIVA® (efavirenz) should not be coadministered with ATRIPLA unless needed for dose-adjustment (e.g., with rifampin). Due to similarities between emtricitabine and lamivudine, ATRIPLA should not be coadministered with drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir, or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).
QTc Prolongation
QTc prolongation has been observed with the use of efavirenz. Consider alternatives to ATRIPLA when coadministered with a drug with a known risk of Torsade de Pointes or when administered to patients at higher risk of Torsade de Pointes.
Psychiatric Symptoms
Serious psychiatric adverse experiences have been reported in patients treated with efavirenz. In controlled trials of 1008 subjects treated with regimens containing efavirenz for a mean of 2.1 years and 635 subjects treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among subjects who received efavirenz or control regimens, respectively, were: severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0%), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from Study AI266006 (006), treatment with efavirenz was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at trial entry; similar associations were observed in both the efavirenz and control treatment groups. In Study 006, onset of new serious psychiatric symptoms occurred throughout the trial for both efavirenz-treated and control-treated subjects. One percent of efavirenz-treated subjects discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms. There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, and catatonia, although a causal relationship to the use of efavirenz cannot be determined from these reports. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of efavirenz, and if so, to determine whether the risks of continued therapy outweigh the benefits.
Nervous System Symptoms
Fifty-three percent (531/1008) of subjects receiving efavirenz in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of subjects receiving control regimens. These symptoms included dizziness (28.1% of the 1008 subjects), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). Other reported symptoms were euphoria, confusion, agitation, amnesia, stupor, abnormal thinking, and depersonalization. The majority of these symptoms were mild to moderate (50.7%); symptoms were severe in 2.0% of subjects. Overall, 2.1% of subjects discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2-4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in subjects treated with regimens containing efavirenz and from 3% to 5% in subjects treated with a control regimen. Patients should be informed that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms. Dosing at bedtime may improve the tolerability of these nervous system symptoms.
Analysis of long-term data from Study 006 (median follow-up 180 weeks, 102 weeks, and 76 weeks for subjects treated with efavirenz + zidovudine + lamivudine, efavirenz + indinavir, and indinavir + zidovudine + lamivudine, respectively) showed that, beyond 24 weeks of therapy, the incidences of new-onset nervous system symptoms among efavirenz-treated subjects were generally similar to those in the indinavir-containing control arm.
Patients receiving ATRIPLA should be alerted to the potential for additive central nervous system effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs.
Patients who experience central nervous system symptoms such as dizziness, impaired concentration, and/or drowsiness should avoid potentially hazardous tasks such as driving or operating machinery.
New Onset Or Worsening Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney; however, efavirenz is not. Since ATRIPLA is a combination product and the dose of the individual components cannot be altered, patients with estimated creatinine clearance below 50 mL/min should not receive ATRIPLA.
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia) has been reported with the use of tenofovir DF.
It is recommended that estimated creatinine clearance be assessed in all patients prior to initiating therapy and as clinically appropriate during therapy with ATRIPLA. In patients at risk of renal dysfunction, including patients who have previously experienced renal events while receiving HEPSERA, it is recommended that estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein be assessed prior to initiation of ATRIPLA and periodically during ATRIPLA therapy.
ATRIPLA should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]). Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on tenofovir DF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.
Persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in at-risk patients.
Reproductive Risk Potential
Pregnancy Category D: Efavirenz may cause fetal harm when administered during the first trimester to a pregnant woman. Pregnancy should be avoided in women receiving ATRIPLA. Barrier contraception must always be used in combination with other methods of contraception (e.g., oral or other hormonal contraceptives). Because of the long half-life of efavirenz, use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA is recommended. Women of childbearing potential should undergo pregnancy testing before initiation of ATRIPLA. If this drug is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.
There are no adequate and well-controlled trials of ATRIPLA in pregnant women. ATRIPLA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus, such as in pregnant women without other therapeutic options.
Rash
In controlled clinical trials, 26% (266/1008) of adult subjects treated with 600 mg efavirenz experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1008) of subjects treated with efavirenz. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with efavirenz in all trials and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with efavirenz (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with efavirenz, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1008). ATRIPLA can be reinitiated in patients interrupting therapy because of rash. ATRIPLA should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction  (e.g., Stevens-Johnson syndrome), alternative therapy should be considered.
Experience with efavirenz in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with efavirenz. Nine of these subjects developed mild-to-moderate rash while receiving therapy with efavirenz, and two of these subjects discontinued because of rash.
Rash was reported in 59 of 182 pediatric subjects (32%) treated with efavirenz. Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3-1642 days). Prophylaxis with appropriate antihistamines before initiating therapy with ATRIPLA in pediatric patients should be considered.
Hepatotoxicity
Monitoring of liver enzymes before and during treatment is recommended for patients with underlying hepatic disease, including hepatitis B or C infection; patients with marked transaminase elevations; and patients treated with other medications associated with liver toxicity. A few of the postmarketing reports of hepatic failure occurred in patients with no pre-existing hepatic disease or other identifiable risk factors. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. In patients with persistent elevations of serum transaminases to greater than five times the upper limit of the normal range, the benefit of continued therapy with ATRIPLA needs to be weighed against the unknown risks of significant liver toxicity.
Bone Effects Of Tenofovir DF
Bone Mineral Density
In clinical trials in HIV-1 infected adults, tenofovir DF was associated with slightly greater decreases in bone mineral density (BMD) and increases in biochemical markers of bone metabolism, suggesting increased bone turnover relative to comparators. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in subjects receiving tenofovir DF.
Clinical trials evaluating tenofovir DF in pediatric and adolescent subjects were conducted. Under normal circumstances, BMD increases rapidly in pediatric patients. In HIV-1 infected subjects aged 2 years to less than 18 years, bone effects were similar to those observed in adult subjects and suggest increased bone turnover. Total body BMD gain was less in the tenofovir DF treated HIV-1 infected pediatric subjects as compared to the control groups. Similar trends were observed in chronic hepatitis-B infected adolescent subjects aged 12 years to less than 18 years. In all pediatric trials, skeletal growth (height) appeared to be unaffected. For more information, consult the VIREAD prescribing information.
The effects of tenofovir DF-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. Assessment of BMD should be considered for adult and pediatric patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected, then appropriate consultation should be obtained.
Mineralization Defects
Cases of osteomalacia associated with proximal renal tubulopathy, manifested as bone pain or pain in extremities and which may contribute to fractures, have been reported in association with the use of tenofovir DF. Arthralgias and muscle pain or weakness have also been reported in cases of proximal renal tubulopathy. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms while receiving products containing tenofovir DF.
Convulsions
Convulsions have been observed in adult and pediatric patients receiving efavirenz, generally in the presence of known medical history of seizures. Caution must be taken in any patient with a history of seizures.
Patients who are receiving concomitant anticonvulsant medications primarily metabolized by the liver, such as phenytoin and phenobarbital, may require periodic monitoring of plasma levels.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of ATRIPLA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.
Autoimmune disorders (such as Graves' disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
Fat Redistribution
Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance,” has been observed in patients receiving antiretroviral therapy, including efavirenz. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
Drug Interactions
A statement to patients and healthcare providers is included on the product's bottle labels: ALERT: Find out about medicines that should NOT be taken with ATRIPLA. ATRIPLA may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription or nonprescription medication, vitamins, or herbal supplements.
General Information For Patients
Inform patients that ATRIPLA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using ATRIPLA.
Advise patients to avoid doing things that can spread HIV-1 to others:
- Do not share needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. Some of the medicines in ATRIPLA can be passed to your baby in your breast milk. We do not know whether it could harm your baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.
Advise patients that:
- The long-term effects of ATRIPLA are unknown.
- Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known.
- ATRIPLA should not be coadministered with COMPLERA, DESCOVY, EMTRIVA, GENVOYA, ODEFSEY, STRIBILD, TRUVADA, VEMLIDY, or VIREAD; or drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir. SUSTIVA should not be coadministered with ATRIPLA unless needed for dose adjustment.
- ATRIPLA should not be administered with HEPSERA.
Patients Coinfected With HIV-1 And HBV
Advise patients that severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA (emtricitabine) or VIREAD (tenofovir DF), which are components of ATRIPLA.
Lactic Acidosis And Severe Hepatomegaly
Inform patients that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with ATRIPLA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity.
New Onset Or Worsening Renal Impairment
Inform patients that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported. Advise patients to avoid using ATRIPLA with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs).
Bone Effects Of Tenofovir DF
Inform patients that decreases in bone mineral density have been observed with the use of tenofovir DF. Advise patients that bone mineral density monitoring may be performed in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss.
Dosing Instructions
Nervous System Symptoms
- Inform patients that central nervous system symptoms (NSS) including dizziness, insomnia, impaired concentration, drowsiness, and abnormal dreams, are commonly reported during the first weeks of therapy with efavirenz. Dosing at bedtime may improve the tolerability of these symptoms, which are likely to improve with continued therapy.
- Alert patients to the potential for additive effects when ATRIPLA is used concomitantly with alcohol or psychoactive drugs.
- Instruct patients that if they experience NSS to avoid potentially hazardous tasks such as driving or operating machinery.
Psychiatric Symptoms
- Inform patients that serious psychiatric symptoms including severe depression, suicide attempts, aggressive behavior, delusions, paranoia, psychosis-like symptoms, and catatonia have been reported in patients receiving efavirenz.
- Advise patients that if they experience severe psychiatric adverse experiences they should seek immediate medical evaluation.
- Advise patients to inform their physician of any history of mental illness or substance abuse.
Rash
Inform patients that a common side effect is rash, and that rashes usually go away without any change in treatment. However, since rash may be serious, advise patients to contact their physician promptly if rash occurs.
Reproductive Risk Potential
- Instruct women receiving ATRIPLA to avoid pregnancy. A reliable form of barrier contraception must always be used in combination with other methods of contraception, including oral or other hormonal contraception. Because of the long half-life of efavirenz, recommend use of adequate contraceptive measures for 12 weeks after discontinuation of ATRIPLA.
- Advise women to notify their physician if they become pregnant or plan to become pregnant while taking ATRIPLA.
- Apprise women of the potential harm to the fetus if ATRIPLA is used during the first trimester of pregnancy, or if the patient becomes pregnant while taking this drug.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Efavirenz: Long-term carcinogenicity studies in mice and rats were carried out with efavirenz. Mice were dosed with 0, 25, 75, 150, or 300 mg/kg/day for 2 years. Incidences of hepatocellular adenomas and carcinomas and pulmonary alveolar/bronchiolar adenomas were increased above background in females. No increases in tumor incidence above background were seen in males. In studies in which rats were administered efavirenz at doses of 0, 25, 50, or 100 mg/kg/day for 2 years, no increases in tumor incidence above background were observed. The systemic exposure (based on AUCs) in mice was approximately 1.7-fold that in humans receiving the 600mg/day dose. The exposure in rats was lower than that in humans. The mechanism of the carcinogenic potential is unknown. However, in genetic toxicology assays, efavirenz showed no evidence of mutagenic or clastogenic activity in a battery of in vitro and in vivo studies. These included bacterial mutation assays in S. typhimurium and E. coli, mammalian mutation assays in Chinese hamster ovary cells, chromosome aberration assays in human peripheral blood lymphocytes or Chinese hamster ovary cells, and an in vivo mouse bone marrow micronucleus assay. Given the lack of genotoxic activity of efavirenz, the relevance to humans of neoplasms in efavirenz-treated mice is not known.
Efavirenz did not impair mating or fertility of male or female rats, and did not affect sperm of treated male rats. The reproductive performance of offspring born to female rats given efavirenz was not affected. As a result of the rapid clearance of efavirenz in rats, systemic drug exposures achieved in these studies were equivalent to or below those achieved in humans given therapeutic doses of efavirenz.
Emtricitabine: In long-term carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/day (31 times the human systemic exposure at the therapeutic dose).
Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), or the mouse lymphoma or mouse micronucleus assays.
Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.
Tenofovir DF: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the high dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose.
Tenofovir DF was mutagenic in the in vitro mouse lymphoma assay and negative in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir DF was negative when administered to male mice.
There were no effects on fertility, mating performance, or early embryonic development when tenofovir DF was administered to male rats at a dose equivalent to 10 times the human dose based on body surface area comparisons for 28 days prior to mating and to female rats for 15 days prior to mating through Day 7 of gestation. There was, however, an alteration of the estrous cycle in female rats.
Use In Specific Populations
Pregnancy
Pregnancy Category D
Antiretroviral Pregnancy Registry
To monitor fetal outcomes of pregnant women, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients who become pregnant by calling (800) 258-4263.
Efavirenz: As of July 2010, the Antiretroviral Pregnancy Registry has received prospective reports of 792 pregnancies exposed to efavirenz-containing regimens, nearly all of which were first-trimester exposures (718 pregnancies). Birth defects occurred in 17 of 604 live births (first-trimester exposure) and 2 of 69 live births (second/third-trimester exposure). One of these prospectively reported defects with first-trimester exposure was a neural tube defect. A single case of anophthalmia with first-trimester exposure to efavirenz has also been prospectively reported; however, this case included severe oblique facial clefts and amniotic banding, a known association with anophthalmia. There have been six retrospective reports of findings consistent with neural tube defects, including meningomyelocele. All mothers were exposed to efavirenz-containing regimens in the first trimester. Although a causal relationship of these events to the use of efavirenz has not been established, similar defects have been observed in preclinical studies of efavirenz.
Animal Data
Effects of efavirenz on embryo-fetal development have been studied in three nonclinical species (cynomolgus monkeys, rats, and rabbits). In monkeys, efavirenz 60 mg/kg/day was administered to pregnant females throughout pregnancy (gestation Days 20 through 150). The maternal systemic drug exposures (AUC) were 1.3 times the exposure in humans at the recommended clinical dose (600 mg/day), with fetal umbilical venous drug concentrations approximately 0.7 times the maternal values. Three fetuses of 20 fetuses/infants had one or more malformations; there were no malformed fetuses or infants from placebo-treated mothers. The malformations that occurred in these three monkey fetuses included anencephaly and unilateral anophthalmia in one fetus, microphthalmia in a second, and cleft palate in the third. There was no NOAEL (no observable adverse effect level) established for this study because only one dosage was evaluated. In rats, efavirenz was administered either during organogenesis (gestation Days 7 to 18) or from gestation Day 7 through lactation Day 21 at 50, 100, or 200 mg/kg/day. Administration of 200 mg/kg/day in rats was associated with an increase in the incidence of early resorptions, and doses 100 mg/kg/day and greater were associated with early neonatal mortality. The AUC at the NOAEL (50 mg/kg/day) in this rat study was 0.1 times that in humans at the recommended clinical dose. Drug concentrations in the milk on lactation Day 10 were approximately 8 times higher than those in maternal plasma. In pregnant rabbits, efavirenz was neither embryo lethal nor teratogenic when administered at doses of 25, 50, and 75 mg/kg/day over the period of organogenesis (gestation Days 6 through 18). The AUC at the NOAEL (75 mg/kg/day) in rabbits was 0.4 times that in humans at the recommended clinical dose.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in humans have shown that efavirenz, tenofovir, and emtricitabine are excreted in human milk. Because the risks of low-level exposure to efavirenz, emtricitabine, and tenofovir to infants are unknown, and because of the potential for HIV-1 transmission, mothers should be instructed not to breastfeed if they are receiving ATRIPLA.
Emtricitabine
Samples of breast milk obtained from five HIV-1 infected mothers show that emtricitabine is secreted in human milk. Breastfeeding infants whose mothers are being treated with emtricitabine may be at risk for developing viral resistance to emtricitabine. Other emtricitabine-associated risks in infants breastfed by mothers being treated with emtricitabine are unknown.
Tenofovir DF
Samples of breast milk obtained from five HIV-1 infected mothers show that tenofovir is secreted in human milk. Tenofovir-associated risks, including the risk of viral resistance to tenofovir, in infants breastfed by mothers being treated with tenofovir disoproxil fumarate are unknown.
Pediatric Use
ATRIPLA should only be administered to pediatric patients 12 years of age and older with a body weight greater than or equal to 40 kg (greater than or equal to 88 lbs). Because ATRIPLA is a fixed-dose combination tablet, the dose adjustments recommended for pediatric patients younger than 12 years of age for each individual component cannot be made with ATRIPLA.
Geriatric Use
Clinical trials of efavirenz, emtricitabine, or tenofovir DF did not include suffic
Aşağıdaki advers reaksiyonlar etiketlemenin diğer bölümlerinde tartışılmaktadır:
- HIV-1 ve HBV ile enfekte hastalarda Hepatit B'nin Şiddetli Akut Alevlenmesi
- Döküntü.
- Hepatotoksisite.
- Psikiyatrik Belirtiler.
- Sinir Sistemi Belirtileri.
- Yeni Onset veya Kötüleştirici Böbrek Bozukluğu.
- Embriyo-Fetal Toksisite.
- Kemik Kaybı ve Mineralizasyon Kusurları.
- Konvülsiyonlar.
- Laktik Asidoz / Steatozlu Şiddetli Hepatomegali.
- Bağışıklık Sulandırma Sendromu.
- Yağ Yeniden Dağıtımı.
Klinik Araştırmalar Deneyimi
Klinik araştırmalar çok çeşitli koşullar altında yapıldığından, bir ilacın klinik çalışmalarında gözlenen advers reaksiyon oranları, başka bir ilacın klinik çalışmalarındaki oranlarla doğrudan karşılaştırılamaz ve uygulamada gözlemlenen oranları yansıtmayabilir.
Yetişkinlerde Klinik Araştırmalar
Çalışma 934, 511 antiretroviral naif deneğin EFV (N = 257) veya zidovudin (AZT) / lamivudin (3TC) ile birlikte uygulanan FTC + TDF aldığı açık etiketli aktif kontrollü bir çalışmadır. N = 254).
Çalışma 934'te meydana gelen en yaygın advers reaksiyonlar (% 10'dan büyük veya buna eşit insidans, herhangi bir şiddet) ishal, bulantı, yorgunluk, baş ağrısı, baş dönmesi, depresyon, uykusuzluk, anormal rüyalar ve döküntüdür. Çalışma 934'te gözlenen advers reaksiyonlar genellikle tek tek bileşenlerin önceki çalışmalarında görülenlerle tutarlıdır (Tablo 1).
Tablo 1 Seçilmiş Olumsuz Reaksiyonlara (2-4. Sınıflar) Çalışma 934'te (0-144 Hafta) Her İki Tedavi Grubunda ≥% 5 olarak bildirilmiştir
FTC + TDF + EFVb | AZT / 3TC + EFV | |
N = 257 | N = 254 | |
Yorgunluk | 9% | 8% |
Depresyon | 9% | 7% |
Bulantı | 9% | 7% |
İshal | 9% | 5% |
Baş dönmesi | 8% | 7% |
Üst solunum yolu enfeksiyonları | 8% | 5% |
Sinüzit | 8% | 4% |
Döküntü Etkinliğic | 7% | 9% |
Baş ağrısı | 6% | 5% |
Uykusuzluk | 5% | 7% |
Anksiyete | 5% | 4% |
Nazofarenjit | 5% | 3% |
Kusma | 2% | 5% |
a Advers reaksiyonların sıklıkları, çalışma ilacı ile olan ilişkisine bakılmaksızın, tedaviye bağlı tüm advers olaylara dayanır. b Araştırmanın 96 ila 144. Haftalarından deneklere EFV ile FTC + TDF yerine EFV ile kombinasyon halinde uygulanan FTC / TDF verildi c Döküntü olayı döküntü, eksfolyatif döküntü, genel döküntü, maküler döküntü, makülopapüler döküntü, kaşıntı döküntüsü ve veziküler döküntü içerir. |
Çalışma 073'te, antiretroviral tedavi üzerinde stabil, virolojik supresyonu olan ve virolojik başarısızlık öyküsü olmayan denekler ATRIPLA almak veya başlangıç rejimlerinde kalmak için randomize edildi. Çalışma 073'te gözlenen advers reaksiyonlar genellikle Çalışma 934'te görülenlerle ve her biri diğer antiretroviral ajanlarla kombinasyon halinde uygulandığında ATRIPLA'nın ayrı bileşenleri ile görülenlerle tutarlıdır.
Efavirenz, Emtrisitabin veya TDF
Çalışma 934 ve Çalışma 073'teki advers reaksiyonlara ek olarak, EFV, FTC veya TDF'nin diğer antiretroviral ajanlarla kombinasyon halinde klinik çalışmalarında aşağıdaki advers reaksiyonlar gözlenmiştir.
Efavirenz
EFV ile tedavi edilen hastalarda gözlenen en önemli advers reaksiyonlar sinir sistemi semptomları, psikiyatrik semptomlar ve döküntüdür.
İki kontrollü klinik çalışmada EFV ile tedavi edilen deneklerin% 2'sinden daha fazla veya buna eşit olarak gözlemlenen orta ila şiddetli advers reaksiyonlar arasında ağrı, konsantrasyon bozukluğu, anormal rüyalar, uyku hali, anoreksiya, dispepsi, karın ağrısı, sinirlilik ve kaşıntı.
EFV ile nedensel bir ilişki kurulmamış olmasına rağmen, pankreatit de bildirilmiştir. EFV 600 mg ile tedavi edilen deneklerde kontrol deneklerine göre serum amilaz düzeylerinde asemptomatik artışlar gözlenmiştir.
FTC ile tedavi edilen denekler arasında daha yüksek sıklıkta cilt renk değişikliği bildirilmiştir; avuç içi ve / veya tabanlar üzerinde hiperpigmentasyon ile kendini gösterdi ve genellikle hafif ve asemptomatikti. Mekanizma ve klinik önemi bilinmemektedir.
Pediatrik Konularda Klinik Çalışmalar
Efavirenz
Olumsuz reaksiyonların değerlendirilmesi, 123 haftalık bir medyan için diğer antiretroviral ajanlarla kombinasyon halinde EFV alan 182 HIV-1 enfekte pediatrik hastada yapılan üç pediatrik klinik çalışmaya dayanmaktadır. Üç çalışmadaki advers reaksiyonların türü ve sıklığı, daha yüksek döküntü insidansı hariç olmak üzere, genellikle yetişkin deneklere benzerdi, % 32 olarak rapor edilmiştir (59/182) pediatrik deneklerin yetişkinlerin% 26'sına kıyasla, ve% 3 oranında daha yüksek Derece 3 veya 4 döküntü sıklığı bildirilmiştir (6/182) pediatrik deneklerin yetişkinlerin% 0.9'una kıyasla.
Emtrisitabin
Yetişkinlerde bildirilen advers reaksiyonlara ek olarak, iki açık etiketli, kontrolsüz pediatrik çalışmanın daha büyüklerinde FTC ile tedavi gören pediatrik deneklerin sırasıyla% 7 ve% 32'sinde anemi ve hiperpigmentasyon gözlenmiştir (N = 116).
Tenofovir DF
12 ila 18 yaş arasındaki deneklerde yapılan bir pediatrik klinik çalışmada, TDF (N = 81) ile tedavi gören pediatrik deneklerde gözlenen advers reaksiyonlar, yetişkinlerde TDF'nin klinik çalışmalarında gözlenenlerle tutarlıdır.
Laboratuvar Anormallikleri
Efavirenz, Emtrisitabin ve Tenofovir DF
Çalışma 934'te gözlenen laboratuvar anormallikleri genellikle önceki çalışmalarda görülenlerle tutarlıdır (Tablo 2).
Tablo 2 Çalışma 934'te (0-144 Hafta) Her İki Tedavi Grubundaki Deneklerin% ≥1'inde Bildirilen Önemli Laboratuvar Anormallikleri
FTC + TDF + EFVa | AZT / 3TC + EFV | |
N = 257 | N = 254 | |
Herhangi bir ≥ Sınıf 3 Laboratuvar Anormalliği | % 30 | % 26 |
Oruç Kolesterol (> 240 mg / dL) | % 22 | % 24 |
Kreatin Kinaz (M:> 990 U / L) (F:> 845 U / L) | 9% | 7% |
Serum Amilaz (> 175 U / L) | 8% | 4% |
Alkalin Fosfataz (> 550 U / L) | 1% | 0% |
AST (M:> 180 U / L) (F:> 170 U / L) | 3% | 3% |
ALT (M:> 215 U / L) (F:> 170 U / L) | 2% | 3% |
Hemoglobin (<8.0 mg / dL) | 0% | 4% |
Hiperglisemi (> 250 mg / dL) | 2% | 1% |
Hematüri (> 75 RBC / HPF) | 3% | 2% |
Glikozüri (≥3 +) | <% 1 | 1% |
Nötrofiller (<750 / mm3) | 3% | 5% |
Oruç Trigliseritler (> 750 mg / dL) | 4% | 2% |
a Araştırmanın 96 ila 144. Haftalarından deneklere EFV ile FTC + TDF yerine EFV ile kombinasyon halinde uygulanan FTC / TDF verildi |
Çalışma 073'te gözlenen laboratuvar anormallikleri genellikle Çalışma 934'tekilerle tutarlıdır.
Karaciğer olayları
Çalışma 934'te EFV, FTC ve TDF ile tedavi edilen 19 denek ve EFV ve sabit doz zidovudin / lamivudin ile tedavi edilen 20 denek hepatit B yüzey antijeni veya hepatit C antikoru pozitifti. Bu enfekte olmuş denekler arasında, EFV, FTC ve TDF kolundaki bir denek (1/19), transaminazlarda ULN'den 144 haftaya kadar beş kattan daha yüksek yükselmelere sahipti. Sabit doz zidovudin / lamivudin kolunda, iki denek (2/20) transaminazlarda 144 hafta boyunca ULN'nin beş katından daha yüksek yüksekliklere sahipti. Hepatobiliyer bozukluklar nedeniyle HBV ve / veya HCV ile enfekte olmuş denek denek kesilmemiştir.
Pazarlama Sonrası Deneyim
EFV, FTC veya TDF'nin onay sonrası kullanımı sırasında aşağıdaki advers reaksiyonlar tanımlanmıştır. Pazarlama sonrası reaksiyonlar belirsiz büyüklükteki bir popülasyondan gönüllü olarak bildirildiğinden, sıklıklarını güvenilir bir şekilde tahmin etmek veya ilaca maruz kalmayla nedensel bir ilişki kurmak her zaman mümkün değildir.
Efavirenz
Kardiyak Bozukluklar
Çarpıntı
Kulak ve Labirent Bozuklukları
Kulak çınlaması, baş dönmesi
Endokrin Bozuklukları
Jinekomasti
Göz bozuklukları
Anormal görme
Gastrointestinal Hastalıklar
Kabızlık, malabsorpsiyon
Genel Bozukluklar ve Uygulama Yeri Koşulları
Asteni
Hepatobiliyer Bozukluklar
Karaciğer enzimi artışı, karaciğer yetmezliği, hepatit
Bağışıklık Sistemi Bozuklukları
Alerjik reaksiyonlar
Metabolizma ve Beslenme Bozuklukları
Vücut yağının yeniden dağılımı / birikimi, hiperkolesterolemi, hipertrigliseridemi
Kas-iskelet sistemi ve Bağ Doku Bozuklukları
Artralji, kas ağrısı, miyopati
Sinir Sistemi Bozuklukları
Anormal koordinasyon, ataksi, serebellar koordinasyon ve denge bozuklukları, konvülsiyonlar, hipoestezi, parestezi, nöropati, titreme
Psikiyatrik Bozukluklar
Agresif reaksiyonlar, ajitasyon, sanrılar, duygusal değişkenlik, mani, nevroz, paranoya, psikoz, intihar, katatoni
Solunum, Göğüs ve Mediastinal Bozukluklar
Dispne
Deri ve Deri Altı Doku Bozuklukları
Kızarma, eritema multiforme, fotoalerjik dermatit, Stevens-Johnson sendromu
Emtrisitabin
Bu bölüme dahil edilmek üzere pazarlama sonrası advers reaksiyonlar tespit edilmemiştir.
Tenofovir DF
Bağışıklık Sistemi Bozuklukları
Anjiyoödem dahil alerjik reaksiyon
Metabolizma ve Beslenme Bozuklukları
Laktik asidoz, hipokalemi, hipofosfatemi
Solunum, Torasik ve Mediastinal Bozukluklar
Dispne
Gastrointestinal Hastalıklar
Pankreatit, artmış amilaz, karın ağrısı
Hepatobiliyer Bozukluklar
Hepatik steatoz, hepatit, artmış karaciğer enzimleri (en yaygın olarak AST, ALT, gama GT)
Deri ve Deri Altı Doku Bozuklukları
Döküntü
Kas-iskelet sistemi ve Bağ Doku Bozuklukları
Rabdomiyoliz, osteomalazi (kemik ağrısı olarak kendini gösterir ve kırıklara katkıda bulunabilir), kas zayıflığı, miyopati
Böbrek ve Üriner Bozukluklar
Akut böbrek yetmezliği, böbrek yetmezliği, akut tübüler nekroz, Fanconi sendromu, proksimal renal tubulopati, interstisyel nefrit (akut vakalar dahil), nefrojenik diyabet insipidus, böbrek yetmezliği, artmış kreatinin, proteinüri, poliüri
Genel Bozukluklar ve Uygulama Yeri Koşulları
Asteni
Yukarıdaki vücut sistemi başlıkları altında listelenen aşağıdaki advers reaksiyonlar, proksimal renal tubulopatinin bir sonucu olarak ortaya çıkabilir: rabdomiyoliz, osteomalazi, hipokalemi, kas zayıflığı, miyopati, hipofosfatemi.
Doz aşımı meydana gelirse, hasta toksisite kanıtı açısından izlenmeli ve gerektiğinde standart destekleyici tedavi uygulanmalıdır. Aktif kömür uygulaması, emilmemiş EFV'nin çıkarılmasına yardımcı olmak için kullanılabilir. Hemodiyaliz hem FTC hem de TDF'yi çıkarabilir (aşağıdaki ayrıntılı bilgilere bakın), ancak EFV'yi kandan önemli ölçüde çıkarması olası değildir.
Efavirenz
Yanlışlıkla günde iki kez 600 mg alan bazı hastalar sinir sistemi semptomlarında artış olduğunu bildirmiştir. Bir hastada istemsiz kas kasılmaları yaşandı.
Emtrisitabin
Hemodiyaliz tedavisi, FTC dozundan 1.5 saat sonra (400 mL / dak kan akış hızı ve 600 mL / dak diyalizat akış hızı) başlayarak 3 saatlik diyaliz süresi boyunca FTC dozunun yaklaşık% 30'unu temizler. FTC'nin periton diyalizi ile çıkarılıp çıkarılamayacağı bilinmemektedir.
Tenofovir DF
Tenofovir, yaklaşık% 54'lük bir ekstraksiyon katsayısı ile hemodiyaliz ile verimli bir şekilde çıkarılır. Tek bir 300 mg TDF dozunun ardından, 4 saatlik bir hemodiyaliz seansı uygulanan tenofovir dozunun yaklaşık% 10'unu çıkardı.
Cardiac Electrophysiology
Efavirenz
The effect of EFV on the QTc interval was evaluated in an open-label, positive and placebo-controlled, fixed single sequence 3-period, 3-treatment crossover QT study in 58 healthy subjects enriched for CYP2B6 polymorphisms. The mean Cmax of EFV in subjects with CYP2B6 *6/*6 genotype following the administration of 600 mg daily dose for 14 days was 2.25-fold the mean Cmax observed in subjects with CYP2B6 *1/*1 genotype. A positive relationship between EFV concentration and QTc prolongation was observed. Based on the concentration-QTc relationship, the mean QTc prolongation and its upper bound 90% confidence interval are 8.7 msec and 11.3 msec in subjects with CYP2B6*6/*6 genotype following the administration of 600 mg daily dose for 14 days.
ATRIPLA
One ATRIPLA tablet is bioequivalent to one Sustiva tablet (600 mg) plus one EMTRIVA® capsule (200 mg) plus one VIREAD® tablet (300 mg) following single-dose administration to fasting healthy subjects (N=45).
Efavirenz
In HIV-1 infected subjects time-to-peak plasma concentrations were approximately 3–5 hours and steady-state plasma concentrations were reached in 6–10 days. In 35 HIV-1 infected subjects receiving EFV 600 mg once daily, steady-state Cmax was 12.9 ± 3.7 μM (mean ± SD), Cmin was 5.6 ± 3.2 μM, and AUC was 184 ± 73 μM·hr. EFV is highly bound (approximately 99.5–99.75%) to human plasma proteins, predominantly albumin. Following administration of 14C-labeled EFV, 14–34% of the dose was recovered in the urine (mostly as metabolites) and 16–61% was recovered in feces (mostly as parent drug). In vitro studies suggest CYP3A and CYP2B6 are the major isozymes responsible for EFV metabolism. EFV has been shown to induce CYP enzymes, resulting in induction of its own metabolism. EFV has a terminal half-life of 52–76 hours after single doses and 40–55 hours after multiple doses.
Emtricitabine
Following oral administration, FTC is rapidly absorbed, with peak plasma concentrations occurring at 1–2 hours postdose. Following multiple dose oral administration of FTC to 20 HIV-1 infected subjects, the steady-state plasma FTC Cmax was 1.8 ± 0.7 μg/mL (mean ± SD) and the AUC over a 24-hour dosing interval was 10.0 ± 3.1 μg•hr/mL. The mean steady-state plasma trough concentration at 24 hours postdose was 0.09 μg/mL. The mean absolute bioavailability of FTC was 93%. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02−200 μg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. FTC is eliminated by a combination of glomerular filtration and active tubular secretion with a renal clearance in adults with normal renal function of 213 ± 89 mL/min (mean ± SD). Following a single oral dose, the plasma FTC half-life is approximately 10 hours.
Tenofovir DF
Following oral administration of a single 300 mg dose of TDF to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax) were achieved in 1.0 ± 0.4 hrs (mean ± SD) and Cmax and AUC values were 296 ± 90 ng/mL and 2287 ± 685 ng•hr/mL, respectively. The oral bioavailability of tenofovir from TDF in fasted subjects is approximately 25%. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01–25 μg/mL. Approximately 70−80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion, with a renal clearance in adults with normal renal function of 243 ± 33 mL/min (mean ± SD). Following a single oral dose, the terminal elimination half-life of tenofovir is approximately 17 hours.
Effects of Food on Oral Absorption
ATRIPLA has not been evaluated in the presence of food. Administration of EFV tablets with a high-fat meal increased the mean AUC and Cmax of EFV by 28% and 79%, respectively, compared to administration in the fasted state. Compared to fasted administration, dosing of TDF and FTC in combination with either a high-fat meal or a light meal increased the mean AUC and Cmax of tenofovir by 35% and 15%, respectively, without affecting FTC exposures.