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每日1次复方片剂的治疗HIV新组方药丸Stribild(elvitegravir, cobicistat, emtricitabine, tenofovirdisoproxil fumarate)获美国FDA批准上市
2012年8月 27日美国食品药品监督管理局(FDA)批准Stribild (elvitegravir，cobicistat，恩曲他滨[emtricitabine]，富马酸替诺福韦酯[tenofovir disoproxil fumarate])，一种新一天次组合丸治疗从来未被治疗的HIV感染成年中HIV-1感染。
Stribild含两种以前批准的HIV药加两种新药，elvitegravir和cobicistat。Elvitegravir是一种HIV整合酶链转移抑制剂，干扰HIV繁殖需要的酶之一。Cobicistat， 药代动力学增强剂，一种抑制代谢某些HIV药的酶和被用于延长elvitegravir 效应。2004年批准恩曲他滨和富马酸替诺福韦酯的组合，和以商品名Truvada上市，阻断在人机体中HIV复制需要的另一种酶作用。这些药物在一起提供对HIV感染一个完整治疗方案。
FDA的药物评价和研究中心抗微生物产品室主任Edward Cox，M.D.，M.P.H. 说：“通过不断的研究和药物发展，对HIV感染者治疗以从单丸治疗演变为多丸治疗,”“新组合HIV药像 Stribild有助于简化治疗方案。”
Stribild 的批准是今年FDA采取的最后的HIV/AIDS-相关行动。其他行动包括批准第一个非处方家用迅速HIV检验；批准第一个药物为暴露前预防在联用与更安全性实践在高危成年中减低性获得性HIV感染和纪念那些在受HIV病毒/HIV流行影响最严重的国家中完全或暂定批准超过150个抗逆转录病毒产品对总统的总统的对HIV救济紧急计划(PEPFAR)治疗。
在两项双盲临床试验中在1,408例以前未治疗过HIV成年患者评价Stribild的安全性和有效性。患者被随机赋予接受Stribild或 Atripla，一个HIV 药物含Truvada和依非韦伦[efavirenz]，每天1次 in the first trial;和Stribild或Truvada 加阿扎那韦[阿扎那韦]和利托那韦 每天1次 in the second trial.
研究被设计测量其在48周时血液中有不可检测到的HIV量患者的百分率。结果显示88%和90%间用Stribild治疗患者其血液中有不可检测到的HIV量，与之比较用Atripla治疗84%和用Truvada(恩曲他滨/富马酸替诺福韦酯)加阿扎那韦和利托那韦[ritonavir]治疗87%。
与用于治疗HIV许多其他药物的使用说明书一样，Stribild的使用说明书中带有黑框警告警惕患者和医疗保健专业人员药物可能导致血液乳酸升高和严重肝脏问题，二者均可致命。黑框警告还陈述Stribild没有被批准治疗慢性异型肝炎病毒感染。
在临床试验中观察到常见副作用包括恶心和腹泻。严重副作用包括新或变坏肾问题，骨矿物质密度减低，脂肪再分布和免疫系统内变化(免疫重建综合征). Stribild的使用说明书对卫生保健提供者建议监视患者肾或骨副作用。
要求Gilead Sciences，Stribild的制造商，进行另外研究有助于进行描述药物在妇女和儿童中安全性特征，对Stribild发生耐药如何。和Stribild和其他药物间相互作用的可能性。
批准日期：2012年8月 27日；公司：Gilead Sciences，Inc
STRIBILD™ (elvitegravir，cobicistat，恩曲他滨[emtricitabine]，富马酸替诺福韦酯[tenofovir disoproxil fumarate])片，为口服使用
美国初次批准：2012
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use STRIBILD safely and effectively. See full prescribing information for STRIBILD.
STRIBILD ® (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) tablets, for oral use
Initial U.S. Approval: 2012
WARNING: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS BSee full prescribing information for complete boxed warning.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate (DF), a component of STRIBILD. (5.1)
STRIBILD is not approved for the treatment of chronic hepatitis B virus (HBV) infection. Severe acute exacerbations of hepatitis B have been reported in patients coinfected with HIV-1 and HBV who have discontinued EMTRIVA or VIREAD, two of the components of STRIBILD. Hepatic function should be monitored closely in these patients. If appropriate, initiation of anti-hepatitis B therapy may be warranted. (5.2)
RECENT MAJOR CHANGES
Dosage and Administration (2.1, 2.2, 2.3, 2.4) 10/2013
Warnings and Precautions
New Onset or Worsening Renal Impairment (5.3) 10/2013
Bone Effects of Tenofovir DF (5.5) 10/2013
INDICATIONS AND USAGE
STRIBILD is a four-drug combination of elvitegravir, an HIV integrase strand transfer inhibitor (HIV-1 INSTI), cobicistat, a CYP3A inhibitor, and emtricitabine and tenofovir DF, both HIV nucleoside analog reverse transcriptase inhibitors (HIV NRTI) and is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve. (1)
DOSAGE AND ADMINISTRATION
Recommended dosage: One tablet taken once daily with food. (2.1)
Dosage in renal impairment: Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Discontinue in patients with estimated creatinine clearance below 50 mL per minute. (2.2)
DOSAGE FORMS AND STRENGTHS
Tablets: 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate. (3)
CONTRAINDICATIONS
Coadministration of STRIBILD is contraindicated with drugs that:
Are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious adverse events. (4)
Strongly induce CYP3A which may lead to lower exposure of one or more components and loss of efficacy of STRIBILD and possible resistance. (4)
WARNINGS AND PRECAUTIONS
New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CLcr), urine glucose and urine protein before initiating treatment with STRIBILD. Monitor CLcr, urine glucose, and urine protein in all patients. Monitor serum phosphorus in patients at risk for renal impairment. Avoid administering STRIBILD with concurrent or recent use of nephrotoxic drugs. (5.3)
Avoid coadministration with other anti-retroviral products: Do not use with drugs containing emtricitabine or tenofovir disoproxil fumarate including ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine; or with drugs or regimens containing ritonavir. Do not administer in combination with HEPSERA. (5.4)
Decreases in bone mineral density (BMD): Consider monitoring BMD in patients with a history of pathologic fracture or other risk factors of osteoporosis or bone loss. (5.5)
Redistribution/accumulation of body fat: Observed in patients receiving antiretroviral therapy. (5.6)
Immune reconstitution syndrome: May necessitate further evaluation and treatment. (5.7)
ADVERSE REACTIONS
Most common adverse drug reactions to STRIBILD (incidence greater than or equal to 10%, all grades) are nausea and diarrhea. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. (5.4, 7.1)
STRIBILD can alter the concentration of drugs metabolized by CYP3A or CYP2D6. Drugs that induce CYP3A can alter the concentrations of one or more components of STRIBILD. Consult the full prescribing information prior to and during treatment for potential drug-drug interactions. (4, 7.2, 7.3, 12.3)
USE IN SPECIFIC POPULATIONS
Pregnancy: Use during pregnancy only if the potential benefit justifies the potential risk. (8.1)
Nursing mothers: Women infected with HIV should be instructed not to breastfeed due to the potential for HIV transmission. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
STRIBILD® is indicated as a complete regimen for the treatment of HIV-1 infection in adults who are antiretroviral treatment-naïve.
DOSAGE & ADMINISTRATION
2.1 Dosage Information
The recommended dosage of STRIBILD is one tablet taken orally once daily with food [see Clinical Pharmacology (12.3)].
2.2 Dosage Adjustment in Patients with Renal Impairment
Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with STRIBILD as dose interval adjustment required for emtricitabine and tenofovir disoproxil fumarate (DF) cannot be achieved [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Use in Specific Populations (8.6), Clinical Pharmacology (12.3), and Clinical Studies (14)].
2.3 Dosage in Patients with Hepatic Impairment
No dosage adjustment of STRIBILD is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
2.4 Testing Prior to Initiation of STRIBILD
Prior to initiation of STRIBILD, patients should be tested for hepatitis B infection [see Warnings and Precautions (5.2)] and estimated creatinine clearance, urine glucose and urine protein should be documented in all patients [see Warnings and Precautions (5.3)].
3 DOSAGE FORMS AND STRENGTHS
Each STRIBILD tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate (tenofovir DF, equivalent to 245 mg of tenofovir disoproxil).
The tablets are green, capsule-shaped, film-coated, debossed with "GSI" on one side and the number "1" surrounded by a square box ( ) on the other side of the tablet.
4 CONTRAINDICATIONS
Coadministration of STRIBILD is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These drugs and other contraindicated drugs (which may lead to reduced efficacy of STRIBILD and possible resistance) are listed in Table 1 [see Drug Interactions (7.5), Clinical Pharmacology (12.3)].
Table 1 Drugs that are Contraindicated with STRIBILD
See Drug Interactions (7), Table 6 for sildenafil when dosed as VIAGRA for erectile dysfunction.
See Drug Interactions (7), Table 6 for parenterally administered midazolam.
WARNINGS AND PRECAUTIONS
5.1 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, a component of STRIBILD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with STRIBILD 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).
5.2 Patients Coinfected with HIV-1 and HBV
It is recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. STRIBILD is not approved for the treatment of chronic HBV infection and the safety and efficacy of STRIBILD 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 STRIBILD. In some patients infected with HBV and treated with EMTRIVA, 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 STRIBILD. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
5.3 New Onset or Worsening Renal Impairment
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, a component of STRIBILD, and with the use of STRIBILD [see Adverse Reactions (6.2)].
In the clinical trials of STRIBILD over 96 weeks, 10 (1.4%) subjects in the STRIBILD group (N=701) and 2 (0.3%) subjects in the combined comparator groups (N = 707) discontinued study drug due to a renal adverse reaction. Of these discontinuations, 8 in the STRIBILD group and 1 in the combined comparator groups occurred during the first 48 week. Four (0.6%) of the subjects who received STRIBILD developed laboratory findings consistent with proximal renal tubular dysfunction leading to discontinuation of STRIBILD compared to none in the comparator groups. Two of these four subjects had renal impairment (i.e. estimated creatinine clearance less than 70 mL per minute) at baseline. The laboratory findings in these 4 subjects with evidence of proximal tubulopathy improved but did not completely resolve in all subjects upon discontinuation of STRIBILD. Renal replacement therapy was not required for these subjects.
Estimated creatinine clearance, urine glucose and urine protein should be documented in all patients prior to initiating therapy. Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per minute is not recommended.
STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs (NSAIDs)) [see Drug Interactions (7.4)]. 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.
Routine monitoring of estimated creatinine clearance, urine glucose, and urine protein should be performed during STRIBILD therapy in all patients. Additionally, serum phosphorus should be measured in patients at risk for renal impairment. Although cobicistat (a component of STRIBILD) may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function [see Adverse Reactions (6.1)], patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg per dL from baseline should be closely monitored for renal safety.
The emtricitabine and tenofovir DF components of STRIBILD are primarily excreted by the kidney. STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per minute as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved with the fixed-dose combination tablet.
5.4 Avoid Use with Other Antiretroviral Products
STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and coadministration with other antiretroviral products is not recommended.
STRIBILD is not recommended for coadministration with the following:
emtricitabine or tenofovir DF (ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, VIREAD);
products containing lamivudine (COMBIVIR, EPIVIR, EPIVIR-HBV, EPZICOM, TRIZIVIR) or adefovir dipivoxil (HEPSERA);
ritonavir (NORVIR, KALETRA).
5.5 Bone Effects of Tenofovir DF
Bone Mineral Density:
In clinical trials in HIV-1 infected adults, tenofovir DF (a component of STRIBILD) 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. For additional information, see Adverse Reactions (6.1) and 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 HIV-1 infected 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 in 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 [see Adverse Reactions (6.2)]. 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 [see Warnings and Precautions (5.3)].
5.6 Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
5.7 Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including STRIBILD. 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.
6 ADVERSE REACTIONS
The following adverse drug reactions are discussed in other sections of the labeling:
Lactic Acidosis/Severe Hepatomegaly with Steatosis [see Boxed Warning, Warnings and Precautions (5.1)].
Severe Acute Exacerbations of Hepatitis B [see Boxed Warning, Warnings and Precautions (5.2)].
New Onset or Worsening Renal Impairment [see Warnings and Precautions (5.3)].
Bone Effects of Tenofovir DF [see Warnings and Precautions (5.5)].
Immune Reconstitution Syndrome [see Warnings and Precautions (5.7)].
6.1 Adverse Reactions from Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety assessment of STRIBILD is based on the Week 96 pooled data from 1408 subjects in two randomized, double-blind, active-controlled clinical trials, Study 102 and Study 103, in antiretroviral treatment-naïve HIV-1 infected adult subjects [see Clinical Studies (14)]. A total of 701 subjects received STRIBILD once daily for at least 96 weeks.
The proportion of subjects who discontinued treatment with STRIBILD (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir DF 300 mg); ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg); or atazanavir (ATV) + ritonavir (RTV) + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) due to adverse events, regardless of severity, was 4.6%, 6.8% and 5.9%, respectively. Table 2 displays the frequency of adverse drug reactions greater than or equal to 5% of subjects in any treatment arm.
Table 2 Adverse Drug Reactions* (all grades) Reported in ≥ 5% of Subjects in Any Treatment Arm in Studies 102 and 103 (Week 96 analysis).
Frequencies of adverse reactions are based on all treatment-emergent adverse events, attributed to study drugs.
Rash event includes dermatitis, drug eruption, eczema, pruritus, pruritus generalized, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash morbilliform, rash papular, rash pruritic, and urticaria.
See Warnings and Precautions (5.3), for a discussion of renal adverse reactions from clinical trials experience with STRIBILD.
Adverse Reactions from Clinical Trials of the Components of STRIBILD
Emtricitabine and Tenofovir Disoproxil Fumarate: In addition to the adverse reactions observed with STRIBILD, the following adverse reactions occurred in at least 5% of treatment-experienced or treatment-naïve subjects receiving emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: depression, abdominal pain, dyspepsia, vomiting, fever, pain, nasopharyngitis, pneumonia, sinusitis, upper respiratory tract infection, arthralgia, back pain, myalgia, paresthesia, peripheral neuropathy (including peripheral neuritis and neuropathy), anxiety, increased cough, and rhinitis.
Skin discoloration has been reported with higher frequency among emtricitabine-treated subjects; it was manifested by hyperpigmentation on the palms and/or soles and was generally mild and asymptomatic. The mechanism and clinical significance are unknown.
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3–4) occurring in at least 2% of subjects receiving STRIBILD in Studies 102 and 103 are presented in Table 3.
Table 3 Laboratory Abnormalities (Grades 3–4) Reported in ≥ 2% of Subjects Receiving STRIBILD in Studies 102 and 103 (Week 96 analysis)
Frequencies are based on treatment-emergent laboratory abnormalities.
For subjects with serum amylase > 1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3–4) occurring in STRIBILD (N=61), ATRIPLA (N=36), and ATV +RTV + TRUVADA (N=36) was 15%, 17%, and 25%, respectively.
In Study 103, BMD was assessed by DEXA in a non-random subset of 120 subjects. Mean percentage decreases in BMD from baseline to Week 96 in the STRIBILD group (N = 47) were comparable to the ATV + RTV + TRUVADA group (N = 53) at the lumbar spine (-2.0% versus -3.5%, respectively) and at the hip (-3.2% versus -4.2%, respectively). In Studies 102 and 103, bone fractures occurred in 14 subjects (2.0%) in the STRIBILD group, 8 subjects (2.3%) in the ATRIPLA group, and 14 subjects (3.9%) in the ATV + RTV + TRUVADA group. These findings were consistent with data from an earlier 144-week trial of treatment-naïve subjects receiving tenofovir DF + lamivudine + efavirenz.
Proteinuria (all grades) occurred in 46% of subjects receiving STRIBILD, 38% of subjects receiving ATRIPLA, and 37% of subjects receiving ATV + RTV + TRUVADA.
The cobicistat component of STRIBILD has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. In Studies 102 and 103, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with STRIBILD, after which they stabilized. Table 4 displays the mean changes in serum creatinine and eGFR levels at Week 96 and the percentage of subjects with elevations in serum creatinine (All Grades).
Table 4 Change from Baseline in Serum Creatinine and eGFR and Incidence of Elevated Serum Creatinine (All Grades) at Week 96
Mean change ±SD
Emtricitabine or Tenofovir DF: In addition to the laboratory abnormalities observed with STRIBILD, the following laboratory abnormalities have been previously reported in subjects treated with emtricitabine or tenofovir DF with other antiretroviral agents in other clinical trials: Grade 3 or 4 laboratory abnormalities of ALT (M: greater than 215 U per L; F: greater than 170 U per L), alkaline phosphatase (greater than 550 U per L), bilirubin (greater than 2.5 × ULN), serum glucose (less than 40 or greater than 250 mg per dL), glycosuria (greater than or equal to 3+), neutrophils (less than 750 per mm3), fasting cholesterol (greater than 240 mg per dL), and fasting triglycerides (greater than 750 mg per dL).
Serum Lipids: In the clinical trials of STRIBILD, a similar percentage of subjects receiving STRIBILD, ATRIPLA, and ATV + RTV + TRUVADA were on lipid lowering agents at baseline (11%, 11%, and 12%, respectively). While receiving study drug through Week 96, an additional 8% of STRIBILD subjects were started on lipid lowering agents, compared to 9% of ATRIPLA and 8% of ATV + RTV + TRUVADA subjects.
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5.
Table 5 Lipid Values, Mean Change from Baseline, Reported in Subjects Receiving STRIBILD or Comparator in Studies 102 and 103
The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 96 values.
6.2 Postmarketing Experience
Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of tenofovir DF. No additional postmarketing adverse reactions specific for emtricitabine have been identified.
Immune System Disorders
allergic reaction, including angioedema
Metabolism and Nutrition Disorders
lactic acidosis, hypokalemia, hypophosphatemia
Respiratory, Thoracic, and Mediastinal Disorders
dyspnea
Gastrointestinal Disorders
pancreatitis, increased amylase, abdominal pain
Hepatobiliary Disorders
hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT)
Skin and Subcutaneous Tissue Disorders
rash
Musculoskeletal and Connective Tissue Disorders
rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy
Renal and Urinary Disorders
acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria
General Disorders and Administration Site Conditions
asthenia
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
7 DRUG INTERACTIONS
See also Contraindications (4) and Clinical Pharmacology (12.3).
7.1 Other Antiretroviral Medications
STRIBILD is a complete regimen for the treatment of HIV-1 infection; therefore, STRIBILD should not be administered with other antiretroviral medications for treatment of HIV-1 infection. Complete information regarding potential drug-drug interactions with other antiretroviral medications is not provided.
7.2 Potential for STRIBILD to Affect Other Drugs
Cobicistat, a component of STRIBILD, is an inhibitor of CYP3A and CYP2D6 and an inhibitor of the following transporters: p-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Thus, coadministration of STRIBILD with drugs that are primarily metabolized by CYP3A or CYP2D6, or are substrates of P-gp, BCRP, OATP1B1 or OATP1B3 may result in increased plasma concentrations of such drugs. Elvitegravir is a modest inducer of CYP2C9 and may decrease the plasma concentrations of CYP2C9 substrates.
7.3 Potential for Other Drugs to Affect One or More Components of STRIBILD
Elvitegravir and cobicistat, components of STRIBILD, are metabolized by CYP3A. Cobicistat is also metabolized, to a minor extent, by CYP2D6.
Drugs that induce CYP3A activity are expected to increase the clearance of elvitegravir and cobicistat, resulting in decreased plasma concentration of cobicistat and elvitegravir, which may lead to loss of therapeutic effect of STRIBILD and development of resistance (see Table 6).
Coadministration of STRIBILD with other drugs that inhibit CYP3A may decrease the clearance and increase the plasma concentration of cobicistat (see Table 6).
7.4 Drugs Affecting Renal Function
Because emtricitabine and tenofovir, components of STRIBILD are primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of STRIBILD with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of emtricitabine, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions. Some examples of drugs that are eliminated by active tubular secretion include, but are not limited to acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g. gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.3)].
7.5 Established and Other Potentially Significant Interactions
Table 6 provides a listing of established or potentially clinically significant drug interactions. The drug interactions described are based on studies conducted with either STRIBILD, the components of STRIBILD, (elvitegravir, cobicistat, emtricitabine, and tenofovir DF) as individual agents and/or in combination, or are predicted drug interactions that may occur with STRIBILD [for magnitude of interaction, see Clinical Pharmacology (12.3)]. The table includes potentially significant interactions but is not all inclusive.
Table 6 Established and Other Potentially Significant* Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction
This table is not all inclusive.
↑ = Increase, ↓ = Decrease, ⇔ = No Effect
Indicates that a drug-drug interaction trial was conducted.
7.6 Drugs without Clinically Significant Interactions with STRIBILD
Based on drug interaction studies conducted with the components of STRIBILD, no clinically significant drug interactions have been either observed or are expected when STRIBILD is combined with the following drugs: entecavir, famciclovir, H2 receptor antagonists, methadone, proton pump inhibitors and ribavirin.
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, STRIBILD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Antiretroviral Pregnancy Registry: To monitor fetal outcomes of pregnant women exposed to STRIBILD, an Antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1-800-258-4263.
Animal Data
Elvitegravir: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with elvitegravir during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal No Observed Adverse Effects Levels (NOAELs) in rats and rabbits were respectively 23 and 0.2 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Cobicistat: Studies in animals have shown no evidence of teratogenicity or an effect on reproductive function. In offspring from rat and rabbit dams treated with cobicistat during pregnancy, there were no toxicologically significant effects on developmental endpoints. The exposures (AUC) at the embryo-fetal NOAELs in rats and rabbits were respectively 1.8 and 4.3 times higher than the exposure in humans at the recommended daily dose of 150 mg.
Emtricitabine: The incidence of fetal variations and malformations was not increased in embryo-fetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60 times higher and in rabbits at approximately 120 times higher than human exposures at the recommended daily dose.
Tenofovir DF: Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.
8.3 Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV. Studies in rats have demonstrated that elvitegravir, cobicistat, and tenofovir are secreted in milk. It is not known whether elvitegravir or cobicistat is excreted in human milk.
In humans, 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.
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.
Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving STRIBILD.
8.4 Pediatric Use
Safety and effectiveness of STRIBILD in pediatric patients less than 18 years of age have not been established [see Clinical Pharmacology (12.3)].
8.5 Geriatric Use
Clinical studies of STRIBILD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of STRIBILD in elderly patients, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3)].
8.6 Renal Impairment
Initiation of STRIBILD in patients with estimated creatinine clearance below 70 mL per min is not recommended. Because STRIBILD is a fixed-dose combination tablet, STRIBILD should be discontinued if estimated creatinine clearance declines below 50 mL per min during treatment with STRIBILD as dose interval adjustment required for emtricitabine and tenofovir DF cannot be achieved [see Warnings and Precautions (5.3), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].
8.7 Hepatic Impairment
No dose adjustment of STRIBILD is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No pharmacokinetic or safety data are available regarding the use of STRIBILD in patients with severe hepatic impairment (Child-Pugh Class C). Therefore, STRIBILD is not recommended for use in patients with severe hepatic impairment [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
10 OVERDOSAGE
No data are available on overdose of STRIBILD in patients. If overdose occurs the patient must be monitored for evidence of toxicity. Treatment of overdose with STRIBILD consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.
Elvitegravir: Limited clinical experience is available at doses higher than the therapeutic dose of elvitegravir. In one study, boosted elvitegravir equivalent to 2 times the therapeutic dose of 150 mg once daily for 10 days was administered to 42 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As elvitegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Cobicistat: Limited clinical experience is available at doses higher than the therapeutic dose of cobicistat. In two studies, a single dose of cobicistat 400 mg (2.7 times the dose in STRIBILD) was administered to a total of 60 healthy subjects. No severe adverse reactions were reported. The effects of higher doses are not known. As cobicistat is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.
Emtricitabine: Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study, single doses of emtricitabine 1200 mg (6 times the dose in STRIBILD) were administered to 11 subjects. No severe adverse reactions were reported. The effects of higher doses are not known.
Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3 hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL per minute and a dialysate flow rate of 600 mL per minute). It is not known whether emtricitabine can be removed by peritoneal dialysis.
Tenofovir DF: Limited clinical experience at doses higher than the therapeutic dose of VIREAD 300 mg is available. In one study, 600 mg tenofovir DF (2 times the dosage in STRIBILD) was administered to 8 subjects orally for 28 days, and no severe adverse reactions were reported. The effects of higher doses are not known. Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of VIREAD, a 4-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.
11 DESCRIPTION
STRIBILD is a fixed-dose combination tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir DF for oral administration.
Elvitegravir is an HIV-1 integrase strand transfer inhibitor.
Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family.
Emtricitabine is a synthetic nucleoside analog of cytidine. EMTRIVA is the brand name for emtricitabine.
Tenofovir DF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5'-monophosphate. VIREAD is the brand name for tenofovir DF.
Each tablet contains 150 mg of elvitegravir, 150 mg of cobicistat, 200 mg of emtricitabine, and 300 mg of tenofovir DF (equivalent to 245 mg of tenofovir disoproxil). The tablets include the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, silicon dioxide, croscarmellose sodium, hydroxypropyl cellulose, sodium lauryl sulfate, and magnesium stearate. The tablets are film-coated with a coating material containing indigo carmine (FD&C Blue #2) aluminum lake, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and yellow iron oxide.
Elvitegravir: The chemical name of elvitegravir is 6-(3-Chloro-2-fluorobenzyl)-1-[(2S)-1-hydroxy-3-methylbutan-2-yl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
It has a molecular formula of C23H23ClFNO5 and a molecular weight of 447.9. It has the following structural formula:
Elvitegravir is a white to pale yellow powder with a solubility of less than 0.3 micrograms per mL in water at 20 °C.
Cobicistat: The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate.
It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. It has the following structural formula:
Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg per mL in water at 20 °C.
Emtricitabine: The chemical name of emtricitabine is 5-fluoro-1-[(2R,5S)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-)enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.
It has a molecular formula of C8H10FN3O3S and a molecular weight of 247.25. It has the following structural formula:
Emtricitabine is a white to off-white crystalline powder with a solubility of approximately 112 mg per mL in water at 25 °C.
Tenofovir Disoproxil Fumarate: Tenofovir DF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)-2-[[bis[[(isopropoxycarbonyl)oxy]-methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C19H30N5O10P C4H4O4 and a molecular weight of 635.51. It has the following structural formula:
Tenofovir DF is a white to off-white crystalline powder with a solubility of 13.4 mg per mL in water at 25 °C. All dosages are expressed in terms of tenofovir DF except where otherwise noted.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
STRIBILD is a fixed-dose combination of antiviral drugs elvitegravir (boosted by the CYP3A inhibitor cobicistat), emtricitabine, and tenofovir DF [see Microbiology (12.4)].
12.2 Pharmacodynamics
Effects on Electrocardiogram
Thorough QT studies have been conducted for elvitegravir and cobicistat. The effect of the other two components, tenofovir and emtricitabine, or the combination regimen STRIBILD on the QT interval is not known.
The effect of multiple doses of elvitegravir 125 and 250 mg (0.83 and 1.67 times the dose in STRIBILD) (coadministered with 100 mg RTV to boost the blood levels of elvitegravir) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) parallel group thorough QT study in 126 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia's correction method (QTcF) was below 10 msec. In this study, there was no clinically relevant prolongation of the QTc interval.
The effect of a single dose of cobicistat 250 mg and 400 mg (1.67 and 2.67 times the dose in STRIBILD) on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 48 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTc) was below 10 msec, the threshold for regulatory concern. Prolongation of the PR interval was noted in subjects receiving cobicistat in the same study. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline-correction was 9.5 (12.1) msec for 250 mg dose and 20.2 (22.8) for 400 mg dose cobicistat. Because the 150 mg cobicistat dose used in the STRIBILD fixed-dose combination tablet is lower than the lowest dose studied in the thorough QT study, it is unlikely that treatment with STRIBILD will result in clinically relevant PR prolongation.
12.3 Pharmacokinetics
Absorption and Bioavailability
STRIBILD : Following oral administration of STRIBILD with food in HIV-1 infected subjects, peak plasma concentrations were observed 4 hours post-dose for elvitegravir, 3 hours post-dose for cobicistat, 3 hours post-dose for emtricitabine, and 2 hours for tenofovir following the conversion of tenofovir DF (see Table 7 for additional pharmacokinetic parameters).
Table 7 Pharmacokinetic Parameters of Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir Exposure Following Oral Administration of STRIBILD in HIV-Infected Subjects
SD = Standard Deviation
* From Population Pharmacokinetic analysis, N=419.
From Intensive Pharmacokinetic analysis, N=61–62, except cobicistat C trough N=53.
Effect of Food on Oral Absorption
Relative to fasting conditions, the administration of single dose STRIBILD with a light meal (~373 kcal, 20% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 34% and 24%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.
Relative to fasting conditions, the administration of single dose STRIBILD with a high fat meal (~ 800 kcal, 50% fat) increased the mean systemic exposure of elvitegravir and tenofovir by 87% and 23%, respectively. The alterations in mean systemic exposures of cobicistat and emtricitabine were not clinically significant.
STRIBILD should be taken with food.
Distribution
Elvitegravir: Elvitegravir is 98–99% bound to human plasma proteins and binding is independent of drug concentration over the range of 1 ng per mL to 1.6 micrograms per mL. The mean blood-to-plasma ratio was 0.73.
Cobicistat: Cobicistat is 97–98% bound to human plasma proteins and the mean blood-to-plasma ratio was approximately 0.5.
Emtricitabine: In vitro binding of emtricitabine to human plasma proteins is less than 4% and is independent of drug concentration over the range of 0.02–200 micrograms per mL.
Tenofovir Disoproxil Fumarate: In vitro binding of tenofovir to human plasma proteins is less than 0.7% and is independent of concentration over the range of 0.01–25 micrograms per mL.
Metabolism
Elvitegravir: The majority of elvitegravir metabolism is mediated by CYP3A enzymes. Elvitegravir also undergoes glucuronidation via UGT1A1/3 enzymes.
Cobicistat: Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation.
Emtricitabine and tenofovir are not significantly metabolized.
Elimination
Elvitegravir: The median terminal plasma half-life of elvitegravir following administration of STRIBILD is approximately 12.9 hours. After single dose administration of [ 14C] elvitegravir (coadministered with 100 mg RTV), 94.8% and 6.7% of the administered dose was excreted in feces and urine, respectively.
Cobicistat: The median terminal plasma half-life of cobicistat following administration of STRIBILD is approximately 3.5 hours. With single dose administration of [ 14C] cobicistat after multiple dosing of cobicistat for six days, 86.2% and 8.2% of the administered dose was excreted in feces and urine, respectively.
Emtricitabine and tenofovir are primarily excreted in the urine by a combination of glomerular filtration and active tubular secretion.
Special Populations
Patients with Renal Impairment
Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with severe renal impairment (estimated creatinine clearance less than 30 mL per min). No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between healthy subjects and subjects with severe renal impairment.
Emtricitabine and Tenofovir Disoproxil Fumarate: The pharmacokinetics of emtricitabine and tenofovir are altered in subjects with estimated creatinine clearance below 50 mL per min or with end stage renal disease requiring dialysis [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
Elvitegravir and cobicistat: A study of the pharmacokinetics of cobicistat-boosted elvitegravir was performed in healthy subjects and subjects with moderate hepatic impairment. No clinically relevant differences in elvitegravir or cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects. No dosage adjustment of elvitegravir or cobicistat is necessary for patients with mild to moderate hepatic impairment. The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of elvitegravir or cobicistat has not been studied [see Use in Specific Populations (8.7)].
Emtricitabine: The pharmacokinetics of emtricitabine has not been studied in subjects with hepatic impairment; however, emtricitabine is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.
Tenofovir Disoproxil Fumarate: The pharmacokinetics of tenofovir following a 300 mg dose of VIREAD has been studied in healthy subjects with moderate to severe hepatic impairment. No clinically relevant differences in tenofovir pharmacokinetics were observed between subjects with hepatic impairment and healthy subjects.
Hepatitis B and/or Hepatitis C Virus Co-infection
Elvitegravir: Limited data from population pharmacokinetic analysis (N=24) indicated that hepatitis B and/or C virus infection had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.
Cobicistat: There were insufficient pharmacokinetic data in the clinical trials to determine the effect of hepatitis B and/or C virus infection on the pharmacokinetics of cobicistat.
Emtricitabine and Tenofovir: Pharmacokinetics of emtricitabine and tenofovir DF have not been fully evaluated in subjects coinfected with hepatitis B and/or C virus.
Race
Elvitegravir: Population pharmacokinetic analysis of elvitegravir in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of cobicistat-boosted elvitegravir.
Cobicistat: Population pharmacokinetics analysis of cobicistat in HIV-1 infected subjects indicated that race had no clinically relevant effect on the exposure of COBI.
Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of EMTRIVA.
Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of VIREAD.
Gender
No clinically relevant pharmacokinetic differences have been observed between men and women for cobicistat-boosted elvitegravir, emtricitabine and tenofovir DF.
Pediatric Patients
Emtricitabine has been studied in pediatric subjects from 3 months to 17 years of age. Tenofovir DF has been studied in pediatric subjects from 2 years to less than 18 years of age. The pharmacokinetics of elvitegravir or cobicistat in pediatric subjects have not been established [see Use in Specific Populations (8.4)].
Geriatric Patients
Pharmacokinetics of elvitegravir, cobicistat, emtricitabine and tenofovir have not been fully evaluated in elderly (65 years of age and older) patients [see Use in Specific Populations (8.5)].
Assessment of Drug Interactions
[see also Contraindications (4) and Drug Interactions (7)]
The drug-drug interaction studies described in Tables 8 and 9 were conducted with STRIBILD, elvitegravir (coadministered with cobicistat or RTV), or cobicistat administered alone.
As STRIBILD is indicated for use as a complete regimen for the treatment of HIV-1 infection and should not be administered with other antiretroviral medications, information regarding drug-drug interactions with other antiretrovirals agents is not provided [see Warnings and Precautions (5.4)].
The effects of coadministered drugs on the exposure of elvitegravir are shown in Table 8. The effects of elvitegravir or cobicistat on the exposure of coadministered drugs are shown in Table 9. For information regarding clinical recommendations, see Drug Interactions (7).
Table 8 Drug Interactions: Changes in Pharmacokinetic Parameters for Elvitegravir in the Presence of the Coadministered Drug*
* All interaction studies conducted in healthy volunteers.
Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Elvitegravir plus Cobicistat, Cobicistat, or STRIBILD*
All interaction studies conducted in healthy volunteers.
N/A = Not Applicable
NC = Not Calculated
Study conducted with STRIBILD.
Comparison based on rifabutin 300 mg once daily.
12.4 Microbiology
Mechanism of Action
Elvitegravir: Elvitegravir inhibits the strand transfer activity of HIV-1 integrase (integrase strand transfer inhibitor; INSTI), an HIV-1 encoded enzyme that is required for viral replication. Inhibition of integrase prevents the integration of HIV-1 DNA into host genomic DNA, blocking the formation of the HIV-1 provirus and propagation of the viral infection. Elvitegravir does not inhibit human topoisomerases I or II.
Cobicistat: Cobicistat is a selective, mechanism-based inhibitor of cytochromes P450 of the CYP3A subfamily. Inhibition of CYP3A-mediated metabolism by cobicistat enhances the systemic exposure of CYP3A substrates, such as elvitegravir, where bioavailability is limited and half-life is shortened by CYP3A-dependent metabolism.
Emtricitabine: Emtricitabine, a synthetic nucleoside analog of cytidine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 RT by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerases α, β, ε, and mitochondrial DNA polymerase γ.
Tenofovir DF: Tenofovir DF is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir DF requires initial diester hydrolysis for conversion to tenofovir and subsequent phosphorylations by cellular enzymes to form tenofovir diphosphate. Tenofovir diphosphate inhibits the activity of HIV-1 RT by competing with the natural substrate deoxyadenosine 5'-triphosphate and, after incorporation into DNA, by DNA chain termination. Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases α, β, and mitochondrial DNA polymerase γ.
Antiviral Activity in Cell Culture
Elvitegravir, Cobicistat, Emtricitabine, and Tenofovir DF: The triple combination of elvitegravir, emtricitabine, and tenofovir was not antagonistic in cell culture combination antiviral activity assays and was not affected by the addition of cobicistat.
Elvitegravir: The antiviral activity of elvitegravir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, monocyte/macrophage cells, and primary peripheral blood lymphocytes. The 50% effective concentrations (EC 50) ranged from 0.02 to 1.7 nM. Elvitegravir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC 50 values ranged from 0.1 to 1.3 nM) and activity against HIV-2 (EC 50 value of 0.53 nM). Elvitegravir did not show inhibition of replication of HBV or HCV in cell culture.
Cobicistat: Cobicistat has no detectable antiviral activity in cell culture against HIV-1, HBV, or HCV and does not antagonize the antiviral activity of elvitegravir, emtricitabine, or tenofovir.
Emtricitabine: The antiviral activity of emtricitabine against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, the MAGI-CCR5 cell line, and primary peripheral blood mononuclear cells. The EC 50 values for emtricitabine were in the range of 0.0013–0.64 micromolar. Emtricitabine displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, and G (EC 50 values ranged from 0.007–0.075 micromolar) and showed strain specific activity against HIV-2 (EC 50 values ranged from 0.007–1.5 micromolar).
Tenofovir DF: The antiviral activity of tenofovir against laboratory and clinical isolates of HIV-1 was assessed in T lymphoblastoid cell lines, primary monocyte/macrophage cells and peripheral blood lymphocytes. The EC 50 values for tenofovir were in the range of 0.04–8.5 micromolar. Tenofovir displayed antiviral activity in cell culture against HIV-1 clades A, B, C, D, E, F, G, and O (EC 50 values ranged from 0.5–2.2 micromolar) and showed strain specific activity against HIV-2 (EC 50 values ranged from 1.6–5.5 micromolar).
Resistance
In Cell Culture:
Elvitegravir: HIV-1 isolates with reduced susceptibility to elvitegravir have been selected in cell culture. Reduced susceptibility to elvitegravir was associated with the primary integrase substitutions T66A/I, E92G/Q, S147G, and Q148R. Additional integrase substitutions observed in cell culture selection included D10E, S17N, H51Y, F121Y, S153F/Y, E157Q, D232N, R263K, and V281M.
Emtricitabine and Tenofovir DF: HIV-1 isolates with reduced susceptibility to emtricitabine or tenofovir have been selected in cell culture. Reduced susceptibility to emtricitabine was associated with M184V/I substitutions in HIV-1 RT. HIV-1 isolates selected by tenofovir expressed a K65R substitution in HIV-1 RT and showed a 2–4 fold reduction in susceptibility to tenofovir.
In Clinical Studies:
In Treatment-Naïve HIV-1-Infected Adult Subjects: In Studies 102 and 103 [see Clinical Studies (14)], the development of one or more primary substitutions associated with resistance to elvitegravir (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), emtricitabine, and/or tenofovir was observed in 53% (16/30) of the STRIBILD-treatment failure subjects with evaluable genotypic resistance data who received at least 8 weeks of STRIBILD and had HIV-1 RNA greater than 400 copies per mL at Week 96 or at the time of early study drug discontinuation. The most common substitutions that emerged were M184V/I (N=15) in HIV-1 RT and the primary elvitegravir resistance-associated substitutions, E92Q (N=9), N155H (N=5), Q148R (N=3), and T66I (N=2) in integrase; K65R in RT was also detected (N=5). In virus isolates harboring the observed primary elvitegravir resistance substitutions, additional substitutions in integrase were detected including H51Y, L68I/V, G70R, I73V, G140C, S153A and E157Q. All subjects with evaluable data for RT and IN and who developed integrase substitutions associated with elvitegravir resistance (N=13) also developed the M184I/V RT substitutions, conferring reduced susceptibility to both elvitegravir and emtricitabine. In phenotypic analyses, HIV-1 isolates expressing M184V/I RT substitutions showed reduced susceptibility to emtricitabine (42- to greater than 152-fold); those expressing the primary elvitegravir resistance-associated integrase substitutions showed reduced susceptibility to elvitegravir (6- to greater than 198-fold); and those expressing the K65R RT substitution showed reduced susceptibility to tenofovir (0.8- to 1.6-fold), compared to wild-type reference HIV-1.
Cross Resistance
STRIBILD-treatment failure subject isolates exhibited varying degrees of cross resistance within the INSTI and NRTI drug classes depending on the specific substitutions observed. These isolates remained susceptible to all NNRTIs and protease inhibitors.
Elvitegravir: Cross-resistance has been observed among INSTIs. Elvitegravir-resistant viruses showed varying degrees of cross-resistance in cell culture to raltegravir depending on the type and number of substitutions in HIV-1 integrase. Of the primary elvitegravir resistance-associated substitutions tested (T66A/I/K, E92G/Q, T97A, S147G, Q148H/K/R, and N155H), all but three (T66I, E92G, and S147G) conferred greater than 1.5-fold reduced susceptibility to raltegravir (above the biological cutoff for raltegravir) when introduced individually into a wild-type virus by site-directed mutagenesis. Of the primary raltegravir resistance-associated substitutions (Y143C/H/R, Q148H/K/R, and N155H), all but Y143C/H conferred greater than 2.5-fold reductions in susceptibility to elvitegravir (above the biological cutoff for elvitegravir).
Emtricitabine: Cross-resistance has been observed among NRTIs. Emtricitabine-resistant isolates harboring an M184V/I substitution in HIV-1 RT were cross-resistant to lamivudine. HIV-1 isolates containing the K65R RT substitution, selected in vivo by abacavir, didanosine, and tenofovir, demonstrated reduced susceptibility to inhibition by emtricitabine.
Tenofovir DF: Cross-resistance has been observed among NRTIs. The K65R substitution in HIV-1 RT selected by tenofovir is also selected in some HIV-1-infected patients treated with abacavir or didanosine. HIV-1 isolates with the K65R substitution also showed reduced susceptibility to emtricitabine and lamivudine. Therefore, cross-resistance among these NRTIs may occur in patients whose virus harbors the K65R substitution. HIV-1 isolates from patients (N=20) whose HIV-1 expressed a mean of 3 zidovudine-associated RT amino acid substitutions (M41L, D67N, K70R, L210W, T215Y/F, or K219Q/E/N) showed a 3.1-fold decrease in the susceptibility to tenofovir. Subjects whose virus expressed an L74V RT substitution without zidovudine resistance-associated substitutions (N=8) had reduced response to VIREAD. Limited data are available for patients whose virus expressed a Y115F substitution (N=3), Q151M substitution (N=2), or T69 insertion (N=4) in HIV-1 RT, all of whom had a reduced response in clinical trials.
Close
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Elvitegravir: Long-term carcinogenicity studies of elvitegravir were carried out in mice (104 weeks) and in rats for up to 88 weeks (males) and 90 weeks (females). No drug-related increases in tumor incidence were found in mice at doses up to 2000 mg per kg per day alone or in combination with 25 mg per kg per day RTV at exposures 3- and 14-fold, respectively, the human systemic exposure at the recommended daily dose of 150 mg. No drug-related increases in tumor incidence were found in rats at doses up to 2000 mg per kg per day at exposures 12- to 27-fold, respectively in male and female, the human systemic exposure.
Elvitegravir was not genotoxic in the reverse mutation bacterial test (Ames test) and the rat micronucleus assay. In an in vitro chromosomal aberration test, elvitegravir was negative with metabolic activation; however, an equivocal response was observed without activation.
Elvitegravir did not affect fertility in male and female rats at approximately 16- and 30-fold higher exposures (AUC), respectively, than in humans at the therapeutic 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 18-fold higher than human exposures at the recommended 150 mg daily dose.
Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose.
Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays.
Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 4-fold higher than human exposures at the recommended 150 mg daily dose.
Fertility was normal in the offspring of rats exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 1.2-fold higher than human exposures at the recommended 150 mg daily dose.
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 per kg per day (23 times the human systemic exposure at the therapeutic dose of 200 mg per day) or in rats at doses up to 600 mg per kg per day (28 times the human systemic exposure at the therapeutic dose).
Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), 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 Disoproxil Fumarate: Long-term oral carcinogenicity studies of tenofovir DF in mice and rats were carried out at exposures up to approximately 10 times (mice) and 4 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 10 times of that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 4 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 seven of gestation. There was, however, an alteration of the estrous cycle in female rats.
14 CLINICAL STUDIES
The efficacy of STRIBILD is based on the analyses of 96-week data from two randomized, double-blind, active-controlled trials, Study 102 and Study 103, in treatment-naïve, HIV-1 infected subjects (N=1408, randomized and dosed) with baseline estimated creatinine clearance above 70 mL per min.
In Study 102, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=348) once daily or ATRIPLA (efavirenz 600 mg/emtricitabine 200 mg/tenofovir DF 300 mg; N=352) once daily. The mean age was 38 years (range 18–67), 89% were male, 63% were White, 28% were Black, and 2% were Asian. Twenty-four percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 2.6–6.5). The mean baseline CD4+ cell count was 386 cells per mm3 (range 3–1348) and 13% had CD4+ cell counts less than 200 cells per mm3. Thirty-three percent of subjects had baseline viral loads greater than 100,000 copies per mL.
In Study 103, subjects were randomized in a 1:1 ratio to receive either STRIBILD (N=353) once daily or ATV 300 mg + RTV 100 mg + TRUVADA (emtricitabine 200 mg/tenofovir DF 300 mg) (N=355) once daily. The mean age was 38 years (range 19–72), 90% were male, 74% were White, 17% were Black, and 5% were Asian. Sixteen percent of subjects identified as Hispanic/Latino. The mean baseline plasma HIV-1 RNA was 4.8 log10 copies per mL (range 1.7–6.6). The mean baseline CD4+ cell count was 370 cells per mm3 (range 5–1132) and 13% had CD4+ cell count less than 200 cells per mm3. Forty-one percent of subjects had baseline viral loads greater than 100,000 copies per mL.
In both studies, subjects were stratified by baseline HIV-1 RNA (less than or equal to 100,000 copies per mL or greater than 100,000 copies per mL).
Treatment outcomes of Study 102 and Study 103 through 96 weeks are presented in Table 10.
Table 10 Virologic Outcome of Randomized Treatment of Study 102 and Study 103 at Week 96*
Week 96 window is between Day 631 and 714 (inclusive).
Includes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL.
Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc.
In Study 102, the mean increase from baseline in CD4+ cell count at Week 96 was 278 cells per mm3 in the STRIBILD-treated subjects and 247 cells per mm3 in the ATRIPLA -treated subjects. In Study 103, the mean increase from baseline in CD4+ cell count at Week 96 was 242 cells per mm3 in the STRIBILD-treated subjects and 240 cells per mm3 in the ATV + RTV + TRUVADA-treated subjects.
16 HOW SUPPLIED/STORAGE AND HANDLING
STRIBILD tablets are green, capsule-shaped, film-coated, debossed with "GSI" on one side and the number "1" surrounded by a square box ( ) on the other side.
They are supplied by State of Florida DOH Central Pharmacy as follows:
Store at 25 °C (77 °F), excursions permitted to 15–30 °C (59–86 °F) (see USP Controlled Room Temperature).
17 PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling (Patient Information)
A statement to patients and healthcare providers is included on the product's bottle label: ALERT: Find out about medicines that should NOT be taken with STRIBILD.
Patients should be advised that:
STRIBILD may interact with many drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products including St. John's wort.
Patients should remain under the care of a healthcare provider when using STRIBILD.
Patients should be informed that STRIBILD is not a cure for HIV-1 infection. Patients should stay on continuous HIV therapy to control HIV-1 infection and decrease HIV-related illnesses. Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death.
Patients should avoid doing things that can spread HIV-1 infection 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 safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
Do not breastfeed. At least two of the drugs contained in STRIBILD can be passed to the baby in breast milk. It is not known whether this could harm the baby. Also, mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in breast milk.
It is important to take STRIBILD on a regular dosing schedule with food and to avoid missing doses.
Do not miss a dose of STRIBILD. If a patient misses a dose of STRIBILD, the patient should take the missed dose as soon as they remember. If it is almost time for the next dose of STRIBILD, the patient should not take the missed dose, but resume the usual dosing schedule. Inform the patient that he or she should not take more or less than the prescribed dose of STRIBILD at any one time.
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Advise patients that treatment with STRIBILD should be suspended if they develop clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [see Warnings and Precautions (5.1)].
Instruct the patient that hepatitis B testing is recommended prior to initiating antiretroviral therapy. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA or VIREAD [see Warnings and Precautions (5.2)]. STRIBILD should not be discontinued without first informing their healthcare provider.
Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of STRIBILD. STRIBILD should be avoided with concurrent or recent use of a nephrotoxic agent (e.g., high dose or multiple NSAIDs) [see Warnings and Precautions (5.3)].
STRIBILD should not be coadministered with other antiretroviral products because it provides a complete treatment regimen and because of potential drug interactions [see Warnings and Precautions (5.4) and Drug Interactions (7)].
STRIBILD should not be administered in combination with ATRIPLA, COMPLERA, EMTRIVA, TRUVADA, or VIREAD; with drugs containing lamivudine, including COMBIVIR, EPIVIR or EPIVIR-HBV, EPZICOM, or TRIZIVIR; with drugs containing RTV or regimens containing RTV; or with HEPSERA [see Warnings and Precautions (5.4)].
Decreases in bone mineral density have been observed with the use of STRIBILD. Assessment of bone mineral density (BMD) should be considered in patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss [see Warnings and Precautions (5.5)].
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 [see Warnings and Precautions (5.6)].
In some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body's immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Patients should be advised to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.7)].
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=144067b2-0532-476a-996e-e4a0a9d09b05#footnote-reference-8
附：欧洲上市药品说明资料：（https://www.medicines.org.uk/emc/medicine/27810）
Stribild 150 mg/150 mg/200 mg/245 mg film-coated tablets
2013年5月30日，吉利德科学（Gilead Sciences）研发的四合一型抗HIV新药Stribild（elvitegravir 150mg/cobicistat 150mg/emtricitabine 200mg/tenofovir disoproxil(as fumarate) 245mg)上市许可申请（MAA）获得了欧盟委员会（EC）的批准，该批准适用于欧盟所有27个成员国。
Stribild为日服一次的单一片剂，由2种在售艾滋病毒药物emtricitabine (恩曲他滨)和tenofovir(泰诺福韦)及2种新型艾滋病毒药物elvitegravir(埃替拉韦)和cobicistat组成。emtricitabine和tenofovir是吉利德公司组合型药物Truvada(特鲁瓦达)的2种成分，同时也是3合1型药物Atripla 的有效成分，特鲁瓦在2004年获批上市。
Stribild是由Gilead开发并在欧洲上市的第3种单一片剂HIV药物。首个单一片剂抗HIV药物为Atripla，该药于2007年获欧盟批准，由Gilead、百时美施贵宝（BMS）及默沙东（Merck & Co）联合推广。第二种单一片剂抗HIV药物为Eviplera，于2011年获欧盟批准，由Gilead和强生旗下杨森（Jassen）联合推广。
目前，Stribild已获美国、加拿大、澳大利亚、韩国、日本、土耳其等国批准上市。
Stribild在欧洲的获批，是基于2项为期48周的关键性III期临床试验的数据：Study 102和Study 103。在这2项试验中，Stribild分别达到了相对于Atripla(依非韦伦600 mg/恩曲他滨200 mg/富马酸替诺福韦酯300 mg)和一种包含利托那韦强化的阿扎那韦加Truvada(恩曲他滨/富马酸替诺福韦酯)治疗方案的非劣性（non-inferiority）主要终点。这些研究旨在评估治疗48周后血液中检测不出HIV水平的患者百分率，结果显示，Stribild、Atripla和Truvada+阿扎那韦+利托那韦治疗组，血液中检测不出HIV水平的患者分别占88%~90%、84%和87%。
在所有关于Stribild的研究中，多数不良事件为轻至中度。临床试验中观察到的常见不良反应包括恶心和腹泻。严重不良反应包括新发肾功能受损或肾功能受损加重、骨密度降低、脂肪再分配和免疫重建综合征。 |
