新型复方抗艾病新药Evotaz(ATAZANAVIR SULFATE; COBICISTAT)获FDA批准
近日，百时美施贵宝艾滋病新药Evotaz获FDA批准， Evotaz是atazanavir、cobicistat和其它抗病毒药的固定剂量复方制剂，用于治疗成人艾滋病。
​​Evotaz为片剂，用法是每日一次，由300mg的 atazanavir（一种蛋白酶抑制剂，以商品名Reyataz 单独销售）、150mg的cobicistat（据称是一种“增强药代动力学”的药物，目前由吉利德以商品名Tybost销售）组成。​​Evotaz获批对HIV感染者而言是一个好消息。
据悉：每年约有50000人感染HIV而导致获得性免疫缺陷综合征（AIDS）。目前美国的HIV感染者约为110万人，而大多数患者对治疗有耐药性，因此需要新的治疗方法来抑制病毒。​​
FDA批准Evotaz是基于称为114号研究的3期临床试验的阳性结果。
该双盲试验比较了300mg Reyataz+150mg cobicistat(即Evotaz)和300mg Reyataz+100mg  ritonavir的效果。48周治疗后，服用Evotaz的病人中85%的HIV-1 RNA水平低于50个拷贝/ml，与对照组Reyataz/ritonavir的87%消退率相比是不分伯仲。此外，Evotaz作为蛋白酶抑制剂单独使用时抗病毒的失效率低于6%，与cobicistat联用后，失效率就降到最低。​​
最重要的是，临床试验结果表明48周后病人的耐药性为零，单独用tenofovir无耐药性，而当用Evotaz 后病人表现出对 emtricitabine有耐药性。但是总体而言，3期临床结果表明了Evotaz的有效性和安全性。​​百时美施贵宝的全球市场总管Murdo Gordon表示， 百时美很高兴能为全球AIDS患者提供新的治疗方法，atazanavir与cobicistat 联用能维持48周以上安全、有效的治疗。​​此番Evotaz获批标志着一个开创性的治疗方式。
然而，Evotaz和Reyataz并不代表能完全治愈HIV-1感染造成的AIDS。并且那些接受 Evotaz 治疗的患者此前也接受过其他的抗病毒治疗，一定程度上已经获得了蛋白酶抑制剂治疗的耐药性“基线”水平。此外对Evotaz任意一种成分过敏的患者也不能用药。​​Evotaz获批是百时美施贵宝努力了20年的结果，这次也表明百时美对HIV药物的研发水平已经上了一个新台阶。​​

INDICATIONS for Evotaz (atazanavir and cobicistat) and Reyataz (R) (atazanavir)
Evotaz is a fixed dose combination of atazanavir and cobicistat, and is indicated for use with other antiretroviral agents for the treatment of HIV-1 infection in adults.
Reyataz is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults, and for patients 3 months and older weighing at least 10 kg.
LIMITATIONS OF USE
•Use of Evotaz or Reyataz/ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions
•Reyataz is not recommended for use in patients less than 3 months due to the risk of kernicterus
IMPORTANT SAFETY INFORMATION for EVOTAZ and REYATAZ
CONTRAINDICATIONS
EVOTAZ and REYATAZ are contraindicated:
•In patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the product components
•When coadministered with drugs highly dependent on CYP3A or UGT1A1 for clearance and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events. The following are contraindicated with EVOTAZ and REYATAZ: alfuzosin, rifampin, irinotecan, triazolam, orally administered midazolam, dihydroergotamine, ergotamine, methylergonovine, cisapride, St. John’s wort (Hypericum perforatum), lovastatin, simvastatin, pimozide, sildenafil when used for pulmonary arterial hypertension, indinavir, nevirapine. Additionally, EVOTAZ is contraindicated with: dronedarone, ranolazine, lurasidone, colchicine in patients with renal and/or hepatic impairment. Additionally, REYATAZ is contraindicated with ergonovine
•When coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ and REYATAZ
WARNINGS AND PRECAUTIONS
The following Warnings & Precautions are associated with EVOTAZ (atazanavir and cobicistat) and REYATAZ (atazanavir):
•Cardiac Conduction Abnormalities: PR interval prolongation may occur in some patients. Atrioventricular (AV) conduction abnormalities were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities. There is limited clinical experience in patients with preexisting conduction system disease such as marked first degree AV block or second or third degree AV block. Consider ECG monitoring in these patients
•Rash: Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir. Discontinue if severe rash develops. Mild-to-moderate maculopapular skin eruptions have also been reported, and generally did not require discontinuation of treatment
•Nephrolithiasis and cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving atazanavir. Some patients required hospitalization and some had complications. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, consider temporary interruption or discontinuation of therapy
•Hepatotoxicity: Patients with hepatitis B or C viral infections or marked elevations in transaminases are at risk of further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be performed before and during therapy
•EVOTAZ is not recommended in patients with hepatic impairment
•REYATAZ/ritonavir is not recommended in patients with hepatic impairment
•REYATAZ is not recommended for patients with severe hepatic impairment
•Hyperbilirubinemia: Reversible, asymptomatic elevations in indirect (unconjugated) bilirubin occurred in most patients treated with atazanavir. There are no long-term safety data for patients with persistent elevations in total bilirubin >5 times upper limit of normal. Alternative antiretroviral therapy may be considered if jaundice or scleral icterus present cosmetic concerns
•Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barre 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
•Diabetes mellitus/hyperglycemia: New onset of diabetes, exacerbation of preexisting diabetes, and hyperglycemia have been reported in postmarketing surveillance in HIV-infected patients treated with protease inhibitor therapy. A causal relationship has not been established
•Fat Redistribution or accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance” have been seen in patients receiving antiretroviral therapy. A causal relationship has not been established
•Hemophilia: Increased bleeding has been reported in patients with hemophilia type A and B treated with protease inhibitors. A causal relationship has not been established
EVOTAZ (atazanavir and cobicistat): ADDITIONAL WARNINGS AND PRECAUTIONS
•Effects on Serum Creatinine: Cobicistat decreases estimated creatinine clearance (CrCl) by inhibiting the tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated CrCl in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated CrCl. Prior to initiating therapy with EVOTAZ, assess estimated CrCl. Dosage recommendations are not available for drugs that require dosage adjustment in cobicistat-treated patients with renal impairment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety
•New onset or worsening renal impairment when used with tenofovir disoproxil fumarate: Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used with tenofovir disoproxil fumarate (tenofovir DF).
•Coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min
•When EVOTAZ is used with tenofovir DF, evaluate baseline and perform routine monitoring of estimated CrCl, urine glucose, and urine protein. Measure serum phosphorus in patients at risk for renal impairment
•Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended
•Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: Coadministration of EVOTAZ with medications that are metabolized by CYP3A may lead to increased exposures of these medications, which may increase the risk of clinically significant adverse reactions (including life-threatening or fatal reactions). Coadministration of EVOTAZ with CYP3A inducers may lead to lower exposure of atazanavir and cobicistat and loss of efficacy of atazanavir and possible resistance. The potential for drug interactions prior to and during EVOTAZ therapy should be considered, review concomitant medications and monitor patients for adverse reactions
•Antiretrovirals that are Not Recommended: EVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g. other HIV protease inhibitors or elvitegravir) because dosing for such combinations has not been established; coadministration may lead to loss of therapeutic effect and development of resistance
EVOTAZ is not recommended in combination with products containing the individual components of EVOTAZ (atazanavir or cobicistat) or in combination with ritonavir containing products
REYATAZ: ADDITIONAL WARNING AND PRECAUTION
•Patients with Phenylketonuria: Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). REYATAZ capsules do not contain phenylalanine
•Resistance/cross resistance in various degrees have been observed among protease inhibitors
MOST COMMON MODERATE OR SEVERE ADVERSE REACTIONS
EVOTAZ (atazanavir and cobicistat), regardless of causality:
•In treatment-naive adults (>=2%): nausea (2%), ocular icterus (3%), jaundice (5%), rash (5%)
REYATAZ (atazanavir), regardless of causality:
•In treatment-naive adults (>=2%): nausea (4-14%), jaundice/scleral icterus (5-7%), rash (3-7%), headache (1-6%), abdominal pain (4%), vomiting (3-4%), peripheral neurologic symptoms (<1-4%), diarrhea (1-3%), insomnia (<1-3%), and dizziness (<1-2%)
•In treatment-experienced adults (>=2%): jaundice/scleral icterus (9%), myalgia (4%), diarrhea (3%), depression (2%), and fever (2%)
•In pediatric patients taking the capsule formulation (>=5%): cough (21%), fever (18%), jaundice/sclera icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%)
•In pediatric patients taking the oral powder formulation: the adverse reactions were generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking the capsule formulation
DRUG INTERACTIONS
EVOTAZ: Coadministration of EVOTAZ and the following drugs is not recommended
•efavirenz, etravirine, ritonavir, boceprevir, telaprevir, simeprevir, apixaban, rivaroxaban, dabigatran etexilate (in specific renal impairment groups), voriconazole, salmeterol, avanafil, inhaled or nasal corticosteroids that are metabolized by CYP3A
•when EVOTAZ is coadministered with tenofovir DF and an H2-receptor antagonist in treatment-experienced patients
•proton pump inhibitors in treatment-experienced patients
REYATAZ: Coadministration of REYATAZ and the following drugs is not recommended
•salmeterol
•when REYATAZ is coadministered with ritonavir: boceprevir, other HIV protease inhibitors, voriconazole
•when REYATAZ is coadministered without ritonavir: carbamazepine, phenytoin, phenobarbital, bosentan, buprenorphine
•in treatment-experienced patients: proton pump inhibitors or efavirenz
•in patients with renal or hepatic impairment: cholchicine
See Table 5 of the EVOTAZ Full Prescribing Information, and Table 16 of the REYATAZ Full Prescribing Information for additional established and potentially significant Drug Interactions, and related dose modification recommendations.
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