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依曲韦林片|INTELENCE(etravirine)

2012-04-05 23:58:04 作者：新特药房来源：中国新特药网天津分站浏览次数：577 文字大小：【大】【中】【小】

简介： 英文药名；INTELENCE(etravirine) 中文药名；依曲韦林片（以前名TMC125）品牌药生产商；Tibotec Pharmaceuticals Ltd. 药品介绍：近日；FDA已经快速批准了其抗HIV药物——首个非核苷类逆转录酶抑 ...

关键字：依曲韦林片|INTELENCE(etravirine)

英文药名；INTELENCE(etravirine)

中文药名；依曲韦林片（以前名TMC125）

品牌药生产商；Tibotec Pharmaceuticals Ltd.

药品介绍：

近日；FDA已经快速批准了其抗HIV药物——首个非核苷类逆转录酶抑制剂etravirine片(Intelence)。本品对于那些对NNRTI和其他抗逆转录病毒试剂抵抗的HIV成人患者仍有抗病毒活性。

本品的批准是基于长达24周的对HIV病毒载量和CD4+细胞计数进行的2项随机双盲安慰剂对照研究的会聚分析结果。这2项研究的受试者均为严重的、有三级抗逆转录病毒(NNRTI, N[t]RTI, PI)治疗历史的成人患者。

本品与其他抗逆转录病毒试剂联用，可用于治疗有抗逆转录病毒治疗历史的成人HIV-1感染患者，这些患者的病毒复制和HIV-1菌株对NNRTI和其他ARV试剂有抵抗力。

本品别名TMC125，由Tibotec Pharmaceuticals公司开发，在美国将由Ortho Biotech Products公司的Tibotec Therapeutics部门推广上市。

Intelence (依曲韦林etravirine)片 - 以前名TMC125

批准日期:, 2008年1月18日；公司：Tibotec Pharmaceuticals Ltd.

一般描述：
INTELENCE(etravirine)是人类免疫缺陷病毒类型-1(HIV-1)的非核苷逆转录酶抑制剂(NNRTI)。
Etravirine的化学名是4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]- 3,5dimethylbenzonitrile。其Its分子式是C20H15BrN6O和相对分子量435.28。Etravirine有以下结构式：

适应证：INTELENCE?是人类免疫缺陷病毒类型-1(HIV-1)特异性，非核苷逆转录酶抑制剂(NNRTI)适用于：

在经受治疗成年有病毒复制和HIV-1 株对NNRTI和其它抗病毒药物耐药证据患者中与其它抗病毒药物联用治疗HIV-1感染。对含NNRTI方案经受病毒学失效的患者，不要只用INTELENCE?与N[t]RTIs联用。
尚未确定INTELENCE?在儿童患者或未治疗过成年患者中的安全性和有效性。

剂量和用法：200 mg (2片100 mg)每天餐后服用2次。

禁忌证：无。

不良反应：最常见不良反应为中度至严重强度(≥ 2%)发生率高于安慰剂是皮疹和周围神经病变。

药物相互作用：

INTELENCE不应与下列抗病毒药物合用：

替拉那韦(Tipranavir)/利托那韦(利托那韦)，膦沙那韦(fosamprenavir)/利托那韦, 阿扎那韦(atazanavir)/利托那韦
给予蛋白酶抑制剂无利托那韦 NNRTIs
INTELENCE与抑制或诱导CYP3A、CYP2C9、和/或CYP2C19药物合用，可能使etravirine的治疗作用或不良反应图形改变。
INTELENCE与CYP3A、CYP2C9、和/或CYP2C19酶底物或通过P糖蛋白转运的药物合用，可能使合用药物的治疗作用或不良反应图形改变。

在特殊人群中的使用

1. 妊娠：妊娠类别B—只有潜在获益大于潜在风险时才在妊娠期间使用。可得到抗病毒药物妊娠注册。

2. 哺乳母亲：由于潜在的HIV传播母亲不应哺乳。

Intelence
Generic Name: etravirine

Dosage Form: tablet
FULL PRESCRIBING INFORMATION
Indications and Usage for Intelence
Intelence®1, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

This indication is based on Week 48 analyses from 2 randomized, double-blind, placebo-controlled trials of Intelence®. Both studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, N[t]RTI, PI) treatment-experienced adults.

The following points should be considered when initiating therapy with Intelence®:

Treatment history and, when available, resistance testing, should guide the use of Intelence®.
The use of other active antiretroviral agents with Intelence® is associated with an increased likelihood of treatment response.
In patients who have experienced virologic failure on an NNRTI-containing regimen, do not use Intelence® in combination with only N[t]RTIs [see Clinical Studies (14)].
The risks and benefits of Intelence® have not been established in pediatric patients or in treatment-naïve adult patients.

Registered trademark of Tibotec Pharmaceuticals

Intelence Dosage and Administration
The recommended oral dose of Intelence® tablets is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal [see Clinical Pharmacology (12.3)]. The type of food does not affect the exposure to etravirine. Patients who are unable to swallow Intelence® tablet(s) whole may disperse the tablet(s) in a glass of water. Once dispersed, patients should stir the dispersion well and drink it immediately. The glass should be rinsed with water several times and each rinse completely swallowed to ensure the entire dose is consumed.

Dosage Forms and Strengths

Intelence® 100 mg Tablets

Intelence® 100 mg tablets are supplied as white to off-white oval tablets debossed with "TMC125" on one side and "100" on the other side.

Intelence® 200 mg Tablets

Intelence® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets debossed with "T200" on one side.

Contraindications

None

Warnings and Precautions

Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving Intelence® compared to 0.2% of placebo subjects. A total of 2.2% of HIV-1-infected subjects receiving Intelence® discontinued from Phase 3 trials due to rash [see Adverse Reactions (6)]. Rash occurred most commonly during the first 6 weeks of therapy.

Discontinue Intelence® immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping Intelence® treatment after the onset of severe rash may result in a life-threatening reaction.

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.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Intelence®. 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 complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.

Adverse Reactions

The following adverse reactions are described in greater detail in other sections:

Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1)].

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 is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received Intelence® (200 mg b.i.d.). In these pooled trials, the median exposure for subjects in the Intelence® arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the Intelence® arm and 2.6% in the placebo arm.

The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in < 0.1% of subjects during clinical development with Intelence® [see Warnings and Precautions (5.1)]. A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving Intelence® discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1–2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the Intelence® arm in the Phase 3 trials. Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of Intelence®-related rash compared to patients without a history of NNRTI-related rash.

Common Adverse Reactions

Clinical ADRs of moderate intensity or greater (≥ Grade 2) and reported in ≥ 2% of subjects treated with Intelence® and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 1. Laboratory abnormalities considered ADRs are included in Table 2.

Table 1: Treatment-Emergent Adverse Reactions* of at least Moderate Intensity† (Grades 2–4) in ≥ 2% of Adult Subjects in the Intelence® Treatment Groups and at a higher rate compared to placebo (excess of 1%)
System Organ Class, Preferred Term, %	Pooled TMC125-C206 and TMC125-C216 Trials
System Organ Class, Preferred Term, %	Intelence® + BR N=599	Placebo + BR N=604
N=total number of subjects per treatment group, BR=background regimen
Includes adverse reactions at least possibly, probably, or very likely related to the drug. Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity).
Nervous System Disorders
Peripheral neuropathy	4%	2%
Skin and Subcutaneous Tissue Disorders
Rash	10%	3%

Less Common Adverse Reactions

Treatment-emergent ADRs occurring in less than 2% of subjects (n=599) receiving Intelence® and of at least moderate intensity (≥ Grade 2) are listed below by body system:

Cardiac Disorders: myocardial infarction, angina pectoris, atrial fibrillation

Ear and Labyrinth Disorders: vertigo

Eye Disorders: blurred vision

Gastrointestinal Disorders: gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis

General Disorders and Administration Site Conditions: sluggishness

Hematologic Disorders: hemolytic anemia

Hepatobiliary Disorders: hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis

Immune System Disorders: drug hypersensitivity, immune reconstitution syndrome

Metabolism and Nutrition Disorders: diabetes mellitus, anorexia, dyslipidemia

Nervous System Disorders: paraesthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor

Psychiatric Disorders: anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness, nightmares

Renal and Urinary Disorders: acute renal failure

Reproductive System and Breast Disorders: gynecomastia

Respiratory,Thoracic and Mediastinal Disorders: exertional dyspnea, bronchospasm

Skin and Subcutaneous Tissue Disorders: night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face

Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and haemorrhagic stroke, each reported in no more than 0.5% of subjects.

Laboratory Abnormalities in Treatment-Experienced Patients

Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with Intelence® are presented in Table 2.

Table 2: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects
		Pooled TMC125-C206 and TMC125-C216 Trials
Laboratory Parameter Preferred Term, %	DAIDS Toxicity Range	Intelence® + BR N=599	Placebo + BR N=604
ULN=Upper Limit of Normal, BR=background regimen
GENERAL BIOCHEMISTRY
Pancreatic amylase
Grade 2	> 1.5–2 × ULN	7%	8%
Grade 3	> 2–5 × ULN	7%	8%
Grade 4	> 5 × ULN	2%	1%
Lipase
Grade 2	> 1.5–3 × ULN	4%	6%
Grade 3	> 3–5 × ULN	2%	2%
Grade 4	> 5×ULN	1%	< 1%
Creatinine
Grade 2	> 1.4–1.8 × ULN	6%	5%
Grade 3	> 1.9–3.4 × ULN	2%	1%
Grade 4	> 3.4 × ULN	0%	< 1%
HEMATOLOGY
Decreased hemoglobin
Grade 2	90–99 g/L	2%	4%
Grade 3	70–89 g/L	< 1%	< 1%
Grade 4	< 70 g/L	< 1%	< 1%
White blood cell count
Grade 2	1,500–1,999/mm3	2%	3%
Grade 3	1,000–1,499/mm3	1%	4%
Grade 4	< 1,000/mm3	1%	< 1%
Neutrophils
Grade 2	750–999/mm3	5%	6%
Grade 3	500–749/mm3	4%	4%
Grade 4	< 500/mm3	2%	3%
Platelet count
Grade 2	50,000–99,999/mm3	3%	5%
Grade 3	25,000–49,999/mm3	1%	1%
Grade 4	< 25,000/mm3	< 1%	< 1%
LIPIDS AND GLUCOSE
Total cholesterol
Grade 2	> 6.20–7.77 mmol/L 240–300 mg/dL	20%	17%
Grade 3	> 7.77 mmol/L > 300 mg/dL	8%	5%
Low density lipoprotein
Grade 2	4.13–4.9 mmol/L 160–190 mg/dL	13%	12%
Grade 3	> 4.9 mmol/L > 190 mg/dL	7%	7%
Triglycerides
Grade 2	5.65–8.48 mmol/L 500 –750 mg/dL	9%	7%
Grade 3	8.49–13.56 mmol/L 751 – 1200 mg/dL	6%	4%
Grade 4	> 13.56 mmol/L > 1200 mg/dL	4%	2%
Elevated glucose levels
Grade 2	6.95–13.88 mmol/L 161–250 mg/dL	15%	13%
Grade 3	13.89–27.75 mmol/L 251 – 500 mg/dL	4%	2%
Grade 4	> 27.75 mmol/L > 500 mg/dL	0%	< 1%
HEPATIC PARAMETERS
Alanine amino transferase
Grade 2	2.6–5 × ULN	6%	5%
Grade 3	5.1–10 × ULN	3%	2%
Grade 4	> 10 × ULN	1%	< 1%
Aspartate amino transferase
Grade 2	2.6–5 × ULN	6%	8%
Grade 3	5.1–10 × ULN	3%	2%
Grade 4	> 10 × ULN	< 1%	< 1%

Patients co-infected with hepatitis B and/or hepatitis C virus

In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of Intelence®-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected Intelence®-treated subjects. In general, adverse events reported by Intelence®-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to Intelence®-treated subjects without hepatitis B and/or hepatitis C virus co-infection.

Postmarketing Experience

The following events have been identified during postmarketing use of Intelence®. Because these events are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune System Disorders: Severe hypersensitivity reactions including cases of hepatic failure have been reported [see Warnings and Precautions (5.1)].

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Skin and Subcutaneous Tissue Disorders: Fatal cases of toxic epidermal necrolysis have been reported [see Warnings and Precautions (5.1)].

Drug Interactions

Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of Intelence® with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of Intelence® (see Table 3). [See also Clinical Pharmacology (12.3).]

Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein. Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-glycoprotein with Intelence® may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 3). [See also Clinical Pharmacology (12.3).]

Table 3 shows the established and other potentially significant drug interactions based on which, alterations in dose or regimen of Intelence® and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Intelence® are also included in Table 3.

Table 3: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [See Clinical Pharmacology (12.3)]

Concomitant Drug Class:
Drug Name Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment

↑ = increase, ↓ = decrease, ↔ = no change

The interaction between Intelence® and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.

The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir

HIV-Antiviral Agents: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

efavirenz*
nevirapine* ↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of Intelence® with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of Intelence®. Intelence® and other NNRTIs should not be co-administered.

delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. Intelence® and delavirdine should not be co-administered.

HIV-Antiviral Agents: Protease Inhibitors (PIs)

atazanavir*
(without ritonavir) ↓ atazanavir Concomitant use of Intelence® with atazanavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of atazanavir. Intelence® should not be co-administered with atazanavir without low-dose ritonavir.

atazanavir/ritonavir* ↓ atazanavir
↑ etravirine Concomitant use of Intelence® with atazanavir/ritonavir may cause a significant decrease in atazanavir Cmin and loss of therapeutic effect of atazanavir. In addition, the mean systemic exposure (AUC) of etravirine after co-administration of Intelence® with atazanavir/ritonavir is anticipated to be higher than the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of Intelence® and darunavir/ritonavir (as part of the background regimen). Intelence® and atazanavir/ritonavir should not be co-administered.

darunavir/ritonavir* ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when Intelence® was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and etravirine exposures from these trials were determined to be safe and effective, Intelence® and darunavir/ritonavir can be co-administered without dose adjustments.

fosamprenavir
(without ritonavir) ↑ amprenavir Concomitant use of Intelence® with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Intelence® should not be co-administered with fosamprenavir without low-dose ritonavir.

fosamprenavir/ritonavir* ↑ amprenavir Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of Intelence® and fosamprenavir/ritonavir have not been established. Intelence® and fosamprenavir/ritonavir should not be co-administered.

indinavir*
(without ritonavir) ↓ indinavir Concomitant use of Intelence® with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Intelence® should not be co-administered with indinavir without low-dose ritonavir.

lopinavir/ritonavir* ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced after co-administration of Intelence® with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, Intelence® and lopinavir/ritonavir can be co-administered without dose adjustments.

nelfinavir
(without ritonavir) ↑ nelfinavir Concomitant use of Intelence® with nelfinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Intelence® should not be co-administered with nelfinavir without low-dose ritonavir.

ritonavir* ↓ etravirine Concomitant use of Intelence® with ritonavir 600 mg b.i.d. may cause a significant decrease in the plasma concentration of etravirine and loss of therapeutic effect of Intelence®. Intelence® and ritonavir 600 mg b.i.d. should not be co-administered.

saquinavir/ritonavir* ↓ etravirine The mean systemic exposure (AUC) of etravirine was reduced when Intelence® was co-administered with saquinavir/ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, Intelence® and saquinavir/ritonavir can be co-administered without dose adjustments.

tipranavir/ritonavir* ↓ etravirine Concomitant use of Intelence® with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of Intelence®. Intelence® and tipranavir/ritonavir should not be co-administered.

CCR5 Antagonists

maraviroc* ↔ etravirine
↓ maraviroc When Intelence® is co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg b.i.d. No dose adjustment of Intelence® is needed.

maraviroc/darunavir/ritonavir*† ↔ etravirine
↑ maraviroc When Intelence® is co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 150 mg b.i.d. No dose adjustment of Intelence® is needed.

Other Agents

Antiarrhythmics:
digoxin* ↔ etravirine
↑ digoxin For patients who are initiating a combination of Intelence® and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating Intelence®, no dose adjustment of either Intelence® or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect.

amiodarone,
bepridil,
disopyramide,
flecainide,
lidocaine (systemic),
mexiletine,
propafenone,
quinidine ↓ antiarrhythmics Concentrations of these antiarrhythmics may be decreased when co-administered with Intelence®. Intelence® and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available.

Anticoagulants:
warfarin ↑ anticoagulants Warfarin concentrations may be increased when co-administered with Intelence®. The international normalized ratio (INR) should be monitored when warfarin is combined with Intelence®.

Anticonvulsants:
carbamazepine,
phenobarbital,
phenytoin ↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. Intelence® should not be used in combination with carbamazepine, phenobarbital, or phenytoin as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of Intelence®.

Antifungals:
fluconazole*,
voriconazole* ↑ etravirine
↔ fluconazole
↑ voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of Intelence® or fluconazole is needed.

Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of Intelence® or voriconazole is needed.

Antifungals:
itraconazole,
ketoconazole,
posaconazole ↑ etravirine
↓ itraconazole
↓ ketoconazole
↔ posaconazole Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and Intelence® may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by Intelence®. Dose adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co-administered drugs.

Antiinfectives:
clarithromycin* ↑ etravirine
↓ clarithromycin
↑ 14-OH-clarithromycin Clarithromycin exposure was decreased by Intelence®; however, concentrations of the active metabolite, 14-hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.

Antimycobacterials:
rifampin,
rifapentine ↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. Intelence® should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of Intelence®.

Antimycobacterials:
rifabutin* ↓ etravirine
↓ rifabutin
↓ 25-O-desacetylrifabutin If Intelence® is NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg q.d. is recommended.
If Intelence® is co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure.

Benzodiazepines:
diazepam ↑ diazepam Concomitant use of Intelence® with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed.

Corticosteroids:
dexamethasone (systemic) ↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of Intelence®. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use.

Herbal Products:
St. John's wort (Hypericum perforatum) ↓ etravirine Concomitant use of Intelence® with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of Intelence®. Intelence® and products containing St. John's wort should not be co-administered.

HMG-CoA
Reductase Inhibitors:
atorvastatin*

fluvastatin,
lovastatin,
pravastatin,
rosuvastatin,
simvastatin ↔ etravirine
↓ atorvastatin
↑ 2-OH-atorvastatin

↔ etravirine
↑ fluvastatin,
↓ lovastatin,
↔ pravastatin,
↔ rosuvastatin,
↓ simvastatin The combination of Intelence® and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response.

No interaction between pravastatin, rosuvastatin and Intelence® is expected.

Lovastatin and simvastatin are CYP3A substrates and co-administration with Intelence® may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin is metabolized by CYP2C9 and co-administration with Intelence® may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary.

Immunosuppressants:
cyclosporine,
sirolimus,
tacrolimus ↓ immunosuppressant Intelence® and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected.

Narcotic Analgesics/Treatment of Opioid Dependence:
buprenorphine, buprenorphine/naloxone*,
methadone* ↔ etravirine
↓ buprenorphine
↔ norbuprenorphine
↔ methadone Intelence® and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients.

Intelence® and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Phosphodiesterase Type 5
(PDE-5) Inhibitors:
sildenafil*,
tadalafil,
vardenafil ↓ sildenafil
↓ N-desmethyl-sildenafil Intelence® and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect.

Platelet Aggregation Inhibitors:
clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co-administered with Intelence®. Alternatives to clopidogrel should be considered.

In addition to the drugs included in Table 3, the interaction between Intelence® and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3)]: didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category B

No adequate and well-controlled studies of Intelence® use in pregnant women have been conducted. In addition, no pharmacokinetic studies have been conducted in pregnant patients. Animal reproduction studies in rats and rabbits at systemic exposures equivalent to those at the recommended human dose of 400 mg/day revealed no evidence of fetal harm. Intelence® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry

To monitor maternal-fetal outcomes of pregnant women exposed to Intelence®, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

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. It is not known whether etravirine is secreted in human milk. Because of both the potential for HIV transmission and the potential for adverse reactions in nursing infants, mothers should be instructed not to breastfeed if they are receiving Intelence®.

Pediatric use

Safety and effectiveness in pediatric patients have not been established.

Geriatric use

Clinical studies of Intelence® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Hepatic Impairment

No dose adjustment of Intelence® is required in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The pharmacokinetics of Intelence® have not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C).

Renal Impairment

Since the renal clearance of etravirine is negligible (< 1.2%), a decrease in total body clearance is not expected in patients with renal impairment. No dose adjustments are required in patients with renal impairment. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Overdosage

There is no specific antidote for overdose with Intelence®. Human experience of overdose with Intelence® is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with Intelence® consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. If indicated, elimination of unabsorbed active substance is to be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed active substance. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

Intelence Description

Intelence® (etravirine) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1).

The chemical name for etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O and its molecular weight is 435.28. Etravirine has the following structural formula:

Etravirine is a white to slightly yellowish brown powder. Etravirine is practically insoluble in water over a wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran).

Intelence® 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients hypromellose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate and lactose monohydrate.

Intelence® 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients hypromellose, silicified microcrystalline cellulose, microcrystalline cellulose, colloidal silicon dioxide, croscarmellose sodium and magnesium stearate.

Intelence - Clinical Pharmacology

Mechanism of Action

Etravirine is an antiviral drug [see Clinical Pharmacology (12.4)].

Pharmacodynamics

Effects on Electrocardiogram

In a randomized, double-blind, active, and placebo-controlled crossover study, 41 healthy subjects were administered Intelence® 200 mg b.i.d., Intelence® 400 mg q.d., placebo, and moxifloxacin 400 mg. After 8 days of dosing, etravirine did not prolong the QT interval. The maximum mean (upper 1-sided 95% CI) baseline and placebo-adjusted QTcF were 0.6 ms (3.3 ms) for 200 mg b.i.d. and -1.0 ms (2.5 ms) for 400 mg q.d. dosing regimens.

Pharmacokinetics

Pharmacokinetics in Adults

The pharmacokinetic properties of Intelence® were determined in healthy adult subjects and in treatment-experienced HIV-1-infected adult subjects. The systemic exposures (AUC) to etravirine were lower in HIV-1-infected subjects than in healthy subjects.

Table 4: Population Pharmacokinetic Estimates of Etravirine 200 mg b.i.d. in HIV-1-Infected Subjects (Integrated Data from Phase 3 Trials at Week 48)*
Parameter	Etravirine 200 mg b.i.d. N = 575
* All HIV-1-infected subjects enrolled in Phase 3 clinical trials received darunavir/ritonavir 600/100 mg b.i.d. as part of their background regimen. Therefore, the pharmacokinetic parameter estimates shown in Table 4 account for reductions in the pharmacokinetic parameters of etravirine due to co-administration of Intelence® with darunavir/ritonavir.
AUC12h (ng∙h/mL)
Geometric Mean ± Standard Deviation	4522 ± 4710
Median (Range)	4380 (458 – 59084)
C0h (ng/mL)
Geometric Mean ± Standard Deviation	297 ± 391
Median (Range)	298 (2 – 4852)

Note: The median protein binding adjusted EC50 for MT4 cells infected with HIV-1/IIIB in vitro = 4 ng/mL.

Absorption and Bioavailability

Following oral administration, etravirine was absorbed with a Tmax of about 2.5 to 4 hours. The absolute oral bioavailability of Intelence® is unknown.

In healthy subjects, the absorption of etravirine is not affected by co-administration of oral ranitidine or omeprazole, drugs that increase gastric pH.

Effects of Food on Oral Absorption

The systemic exposure (AUC) to etravirine was decreased by about 50% when Intelence® was administered under fasting conditions, as compared to when Intelence® was administered following a meal. Therefore, Intelence® should always be taken following a meal. Within the range of meals studied, the systemic exposures to etravirine were similar. The total caloric content of the various meals evaluated ranged from 345 kilocalories (17 grams fat) to 1160 kilocalories (70 grams fat). [see Dosage and Administration (2)].

Distribution

Etravirine is about 99.9% bound to plasma proteins, primarily to albumin (99.6%) and alpha 1-acid glycoprotein (97.66%–99.02%) in vitro. The distribution of etravirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.

Metabolism

In vitro experiments with human liver microsomes (HLMs) indicate that etravirine primarily undergoes metabolism by CYP3A, CYP2C9, and CYP2C19 enzymes. The major metabolites, formed by methyl hydroxylation of the dimethylbenzonitrile moiety, were at least 90% less active than etravirine against wild-type HIV in cell culture.

Elimination

After single dose oral administration of 800 mg 14C-etravirine, 93.7% and 1.2% of the administered dose of 14C-etravirine was recovered in the feces and urine, respectively. Unchanged etravirine accounted for 81.2% to 86.4% of the administered dose in feces. Unchanged etravirine was not detected in urine. The mean (± standard deviation) terminal elimination half-life of etravirine was about 41 (± 20) hours.

Special Populations

Hepatic Impairment

Etravirine is primarily metabolized by the liver. The steady state pharmacokinetic parameters of etravirine were similar after multiple dose administration of Intelence® to subjects with normal hepatic function (n = 16), mild hepatic impairment (Child-Pugh Class A, n = 8), and moderate hepatic impairment (Child-Pugh Class B, n = 8). The effect of severe hepatic impairment on the pharmacokinetics of etravirine has not been evaluated.

Hepatitis B and/or Hepatitis C Virus Co-infection

Population pharmacokinetic analysis of the TMC125-C206 and TMC125-C216 trials showed reduced clearance for etravirine in HIV-1-infected subjects with hepatitis B and/or C virus co-infection. Based upon the safety profile of Intelence® [see Adverse Reactions (6)], no dose adjustment is necessary in patients co-infected with hepatitis B and/or C virus.

Renal Impairment

The pharmacokinetics of etravirine have not been studied in patients with renal impairment. The results from a mass balance study with 14C-etravirine showed that <1.2% of the administered dose of etravirine is excreted in the urine as metabolites. No unchanged drug was detected in the urine. As etravirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis.

Gender

No significant pharmacokinetic differences have been observed between men and women. A limited number of women were included in clinical studies.

Race

Population pharmacokinetic analysis of etravirine in HIV-infected subjects did not show an effect of race on exposure to etravirine.

Geriatric Patients

Population pharmacokinetic analysis in HIV-infected subjects showed that etravirine pharmacokinetics are not considerably different within the age range (18 to 77 years) evaluated [see Use in Specific Populations (8.5)].

Pediatric Patients

The pharmacokinetics of etravirine in pediatric patients have not been evaluated. Dosing recommendations for pediatric patients cannot be made due to insufficient data.

Drug Interactions

[See also Drug Interactions (7).]

Drug interaction studies were performed with Intelence® and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of other drugs on the AUC, Cmax, and Cmin values of etravirine are summarized in Table 5 (effect of other drugs on Intelence®). The effect of co-administration of Intelence® on the AUC, Cmax, and Cmin values of other drugs are summarized in Table 6 (effect of Intelence® on other drugs). For information regarding clinical recommendations, see Drug Interactions (7).

Table 5: Drug Interactions: Pharmacokinetic Parameters for Etravirine in the Presence of Co-administered Drugs
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	Exposure	Mean Ratio of Etravirine Pharmacokinetic Parameters 90% CI; No Effect = 1.00
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	Exposure	Cmax	AUC	Cmin
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily; b.i.d. = twice daily; q.a.m. = once daily in the morning
The expected increase in systemic exposure of etravirine when co-administered with atazanavir/ritonavir (~100%) as outlined in Table 3 is theoretical and based on comparing exposures of etravirine in a drug-drug interaction study with exposure in the pivotal Phase 3 trials (in which darunavir/ritonavir was part of the background regimen). The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir.
Co-Administration With Protease Inhibitors (PIs)
Atazanavir	400 mg q.d.	14	↑	1.47 (1.36–1.59)	1.50 (1.41–1.59)	1.58 (1.46–1.70)
Atazanavir/ ritonavir*	300/100 mg q.d.	14	↑	1.30 (1.17–1.44)	1.30 (1.18–1.44)	1.26 (1.12–1.42)
Darunavir/ ritonavir	600/100 mg b.i.d.	14	↓	0.68 (0.57–0.82)	0.63 (0.54–0.73)	0.51 (0.44–0.61)
Lopinavir/ ritonavir (tablet)	400/100 mg b.i.d.	16	↓	0.70 (0.64–0.78)	0.65 (0.59–0.71)	0.55 (0.49–0.62)
Ritonavir	600 mg b.i.d.	11	↓	0.68 (0.55–0.85)	0.54 (0.41–0.73)	N.A.
Saquinavir/ ritonavir	1000/100 mg b.i.d.	14	↓	0.63 (0.53–0.75)	0.67 (0.56–0.80)	0.71 (0.58–0.87)
Tipranavir/ ritonavir	500/200 mg b.i.d.	19	↓	0.29 (0.22–0.40)	0.24 (0.18–0.33)	0.18 (0.13–0.25)
Co-Administration With Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Didanosine	400 mg q.d.	15	↔	1.16 (1.02–1.32)	1.11 (0.99–1.25)	1.05 (0.93–1.18)
Tenofovir disoproxil fumarate	300 mg q.d.	23	↓	0.81 (0.75–0.88)	0.81 (0.75–0.88)	0.82 (0.73–0.91)
Co-Administration With CCR5 Antagonists
Maraviroc	300 mg b.i.d.	14	↔	1.05 (0.95–1.17)	1.06 (0.99–1.14)	1.08 (0.98–1.19)
Maraviroc (when co-administered with darunavir/ritonavir)†	150/600/100 mg b.i.d.	10	↔	1.08 (0.98–1.20)	1.00 (0.86–1.15)	0.81 (0.65–1.01)
Co-Administration With Integrase Strand Transfer Inhibitors
Raltegravir	400 mg b.i.d.	19	↔	1.04 (0.97–1.12)	1.10 (1.03–1.16)	1.17 (1.10–1.26)
Co-Administration With Other Drugs
Atorvastatin	40 mg q.d.	16	↔	0.97 (0.93–1.02)	1.02 (0.97–1.07)	1.10 (1.02–1.19)
Clarithromycin	500 mg b.i.d.	15	↑	1.46 (1.38–1.56)	1.42 (1.34–1.50)	1.46 (1.36–1.58)
Fluconazole	200 mg q.a.m.	16	↑	1.75 (1.60–1.91)	1.86 (1.73–2.00)	2.09 (1.90–2.31)
Omeprazole	40 mg q.d.	18	↑	1.17 (0.96–1.43)	1.41 (1.22–1.62)	N.A.
Paroxetine	20 mg q.d.	16	↔	1.05 (0.96–1.15)	1.01 (0.93–1.10)	1.07 (0.98–1.17)
Ranitidine	150 mg b.i.d.	18	↓	0.94 (0.75–1.17)	0.86 (0.76–0.97)	N.A.
Rifabutin	300 mg q.d.	12	↓	0.63 (0.53–0.74)	0.63 (0.54–0.74)	0.65 (0.56–0.74)
Voriconazole	200 mg b.i.d.	16	↑	1.26 (1.16–1.38)	1.36 (1.25–1.47)	1.52 (1.41–1.64)

Table 6: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Intelence®
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	Exposure	Mean Ratio of Co-administered Drug Pharmacokinetic Parameters 90% CI; No effect = 1.00
Co-administered Drug	Dose/Schedule of Co-administered Drug	N	Exposure	Cmax	AUC	Cmin
CI = Confidence Interval; N = number of subjects with data; N.A. = not available; ↑ = increase; ↓ = decrease; ↔ = no change; q.d. = once daily ; b.i.d. = twice daily; q.a.m. = once daily in the morning
* compared to maraviroc 150 mg b.i.d.
Co-Administration With Protease Inhibitors (PIs)
Atazanavir	400 mg q.d.	14	↓	0.97 (0.73–1.29)	0.83 (0.63–1.09)	0.53 (0.38–0.73)
Atazanavir/ ritonavir	300/100 mg q.d.	13	↓	0.97 (0.89–1.05)	0.86 (0.79–0.93)	0.62 (0.55–0.71)
Darunavir/ ritonavir	600/100 mg b.i.d.	15	↔	1.11 (1.01–1.22)	1.15 (1.05–1.26)	1.02 (0.90–1.17)
Fosamprenavir/ ritonavir	700/100 mg b.i.d.	8	↑	1.62 (1.47–1.79)	1.69 (1.53–1.86)	1.77 (1.39–2.25)
Lopinavir/ ritonavir (tablet)	400/100 mg b.i.d.	16	↔	0.89 (0.82–0.96)	0.87 (0.83–0.92)	0.80 (0.73–0.88)
Saquinavir/ ritonavir	1000/100 mg b.i.d.	15	↔	1.00 (0.70–1.42)	0.95 (0.64–1.42)	0.80 (0.46–1.38)
Tipranavir/ ritonavir	500/200 mg b.i.d.	19	↑	1.14 (1.02–1.27)	1.18 (1.03–1.36)	1.24 (0.96–1.59)
Co-Administration With Nucleoside Reverse Transcriptase Inhibitors (NRTIs)
Didanosine	400 mg q.d.	14	↔	0.91 (0.58–1.42)	0.99 (0.79–1.25)	N.A.
Tenofovir disoproxil fumarate	300 mg q.d.	19	↔	1.15 (1.04–1.27)	1.15 (1.09–1.21)	1.19 (1.13–1.26)
Co-Administration With CCR5 Antagonists
Maraviroc	300 mg b.i.d.	14	↓	0.40 (0.28–0.57)	0.47 (0.38–0.58)	0.61 (0.53–0.71)
Maraviroc (when co-administered with darunavir/ritonavir)*	150/600/100 mg b.i.d.	10	↑	1.77 (1.20–2.60)	3.10 (2.57–3.74)	5.27 (4.51–6.15)
Co-Administration With Integrase Strand Transfer Inhibitors
Raltegravir	400 mg b.i.d.	19	↓	0.89 (0.68–1.15)	0.90 (0.68–1.18)	0.66 (0.34–1.26)
Co-Administration With Other Drugs
Atorvastatin	40 mg q.d.	16	↓	1.04 (0.84–1.30)	0.63 (0.58–0.68)	N.A.

2-hydroxy-atorvastatin		16	↑	1.76 (1.60–1.94)	1.27 (1.19–1.36)	N.A.
Buprenorphine	Individual dose regimen ranging from 4/1 mg to 16/4 mg q.d.	16	↓	0.89 (0.76–1.05)	0.75 (0.66–0.84)	0.60 (0.52–0.68)

Norbuprenorphine		16	↔	1.08 (0.95–1.23)	0.88 (0.81–0.96)	0.76 (0.67–0.87)
Clarithromycin	500 mg b.i.d.	15	↓	0.66 (0.57–0.77)	0.61 (0.53–0.69)	0.47 (0.38–0.57)

14-hydroxy-clarithromycin		15	↑	1.33 (1.13–1.56)	1.21 (1.05–1.39)	1.05 (0.90–1.22)
Digoxin	0.5 mg single dose	16	↑	1.19 (0.96–1.49)	1.18 (0.90–1.56)	N.A.
Ethinylestradiol	0.035 mg q.d.	16	↑	1.33 (1.21–1.46)	1.22 (1.13–1.31)	1.09 (1.01–1.18)

Norethindrone	1 mg q.d.	16	↔	1.05 (0.98–1.12)	0.95 (0.90–0.99)	0.78 (0.68–0.90)
Fluconazole	200 mg q.a.m.	15	↔	0.92 (0.85–1.00)	0.94 (0.88–1.01)	0.91 (0.84–0.98)
R(-) Methadone	Individual dose regimen ranging from 60 to 130 mg/day	16	↔	1.02 (0.96–1.09)	1.06 (0.99–1.13)	1.10 (1.02–1.19)

S(+) Methadone		16	↔	0.89 (0.83–0.97)	0.89 (0.82–0.96)	0.89 (0.81–0.98)
Paroxetine	20 mg q.d.	16	↔	1.06 (0.95–1.20)	1.03 (0.90–1.18)	0.87 (0.75–1.02)
Rifabutin	300 mg q.d.	12	↓	0.90 (0.78–1.03)	0.83 (0.75–0.94)	0.76 (0.66–0.87)

25-O-desacetylrifabutin	300 mg q.d.	12	↓	0.85 (0.72–1.00)	0.83 (0.74–0.92)	0.78 (0.70–0.87)
Sildenafil	50 mg single dose	15	↓	0.55 (0.40–0.75)	0.43 (0.36–0.51)	N.A.

N-desmethyl-sildenafil		15	↓	0.75 (0.59–0.96)	0.59 (0.52–0.68)	N.A.
Voriconazole	200 mg b.i.d.	14	↑	0.95 (0.75–1.21)	1.14 (0.88–1.47)	1.23 (0.87–1.75)

Microbiology

Mechanism of Action

Etravirine is an NNRTI of human immunodeficiency virus type 1 (HIV-1). Etravirine binds directly to reverse transcriptase (RT) and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by causing a disruption of the enzyme's catalytic site. Etravirine does not inhibit the human DNA polymerases α, β, and γ.

Antiviral Activity in Cell Culture

Etravirine exhibited activity against laboratory strains and clinical isolates of wild-type HIV-1 in acutely infected T-cell lines, human peripheral blood mononuclear cells, and human monocytes/macrophages with median EC50 values ranging from 0.9 to 5.5 nM (i.e., 0.4 to 2.4 ng/mL). Etravirine demonstrated antiviral activity in cell culture against a broad panel of HIV-1 group M isolates (subtype A, B, C, D, E, F, G) with EC50 values ranging from 0.29 to 1.65 nM and EC50 values ranging from 11.5 to 21.7 nM against group O primary isolates. Etravirine did not show antagonism when studied in combination with the following antiretroviral drugs—the NNRTIs delavirdine, efavirenz, and nevirapine; the N(t)RTIs abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine; the PIs amprenavir, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, and tipranavir; the fusion inhibitor enfuvirtide; the integrase strand transfer inhibitor raltegravir and the CCR5 co-receptor antagonist maraviroc.

Resistance

In Cell Culture

Etravirine-resistant strains were selected in cell culture originating from wild-type HIV-1 of different origins and subtypes, as well as NNRTI resistant HIV-1. Development of reduced susceptibility to etravirine typically required more than one substitution in reverse transcriptase of which the following were observed most frequently: L100I, E138K, E138G, V179I, Y181C, and M230I.

In Treatment-Experienced Subjects

In the Phase 3 trials TMC125-C206 and TMC125-C216, substitutions that developed most commonly in subjects with virologic failure at Week 48 to the Intelence®-containing regimen were V179F, V179I, and Y181C which usually emerged in a background of multiple other NNRTI resistance-associated substitutions. In all the trials conducted with Intelence® in HIV-1 infected subjects, the following substitutions emerged most commonly: L100I, E138G, V179F, V179I, Y181C and H221Y. Other NNRTI-resistance associated substitutions which emerged on etravirine treatment in < 10% of the virologic failure isolates included K101E/H/P, K103N/R, V106I/M, V108I, Y181I, Y188L, V189I, G190S/C, N348I and R356K. The emergence of NNRTI substitutions on etravirine treatment contributed to decreased susceptibility to etravirine with a median fold-change in etravirine susceptibility of 40-fold from reference and a median fold-change of 6-fold from baseline.

Cross-Resistance

Site-Directed NNRTI Mutant Virus

Etravirine showed antiviral activity against 55 of 65 HIV-1 strains (85%) with single amino acid substitutions at RT positions associated with NNRTI resistance, including the most commonly found K103N. The single amino acid substitutions associated with an etravirine reduction in susceptibility > 3-fold were K101A, K101P, K101Q, E138G, E138Q, Y181C, Y181I, Y181T, Y181V, and M230L, and of these, the greatest reductions were Y181I (13-fold change in EC50 value) and Y181V (17-fold change in EC50 value). Mutant strains containing a single NNRTI resistance associated substitution (K101P, K101Q, E138Q, or M230L) had cross-resistance between etravirine and efavirenz. The majority (39 of 61; 64%) of the NNRTI mutant viruses with 2 or 3 amino acid substitutions associated with NNRTI resistance had decreased susceptibility to etravirine (fold-change > 3). The highest levels of resistance to etravirine were observed for HIV-1 harboring a combination of substitutions V179F + Y181C (187 fold-change), V179F + Y181I (123 fold-change), or V179F + Y181C + F227C (888 fold-change).

Clinical Isolates

Etravirine retained a fold-change ≤ 3 against 60% of 6171 NNRTI-resistant clinical isolates. In the same panel, the proportion of clinical isolates resistant to delavirdine, efavirenz and/or nevirapine (defined as a fold-change above their respective biological cutoff values in the assay) was 79%, 87%, and 95%, respectively. In TMC125-C206 and TMC125-C216, 34% of the baseline isolates had decreased susceptibility to etravirine (fold-change > 3) and 60%, 69%, and 78% of all baseline isolates were resistant to delavirdine, efavirenz, and nevirapine, respectively. Of subjects who received etravirine and were virologic failures in TMC125-C206 and TMC125-C216, 90%, 84%, and 96% of viral isolates obtained at the time of treatment failure were resistant to delavirdine, efavirenz, and nevirapine, respectively. Therefore, cross-resistance to delavirdine, efavirenz, and/or nevirapine is expected after virologic failure with an etravirine-containing regimen for the virologic failure isolates.

Baseline Genotype/Phenotype and Virologic Outcome Analyses

In TMC125-C206 and TMC125-C216, the presence at baseline of the substitutions L100I, E138A, I167V, V179D, V179F, Y181I, Y181V, or G190S was associated with a decreased virologic response to etravirine. Additional substitutions associated with a decreased virologic response to etravirine when in the presence of 3 or more additional 2008 IAS-USA defined NNRTI substitutions include A98G, K101H, K103R, V106I, V179T, and Y181C. The presence of K103N, which was the most prevalent NNRTI substitution in TMC125-C206 and TMC125-C216 at baseline, did not affect the response in the Intelence® arm. Overall, response rates to etravirine decreased as the number of baseline NNRTI substitutions increased (shown as the proportion of subjects achieving viral load < 50 plasma HIV RNA copies/mL at Week 48) (Table 7).

Table 7: Proportion of Subjects with < 50 HIV-1 RNA copies/mL at Week 48 by Baseline Number of IAS-USA-Defined NNRTI Substitutions in the Non-VF Excluded Population of the Pooled TMC125-C206 and TMC125-C216 Trials
IAS-USA-Defined NNRTI substitutions	Etravirine Arms N = 561
	Re-Used/Not Used Enfuvirtide	De Novo Enfuvirtide
2008 IAS-USA defined substitutions = V90I, A98G, L100I, K101E/H/P, K103N, V106A/I/M, V108I, E138A, V179D/F/T, Y181C/I/V, Y188C/H/L, G190A/S, P225H, M230L
All ranges	61% (254/418)	76% (109/143)
0	68% (52/76)	95% (20/21)
1	67% (72/107)	77% (24/31)
2	64% (75/118)	86% (38/44)
3	55% (36/65)	62% (16/26)
≥ 4	37% (19/52)	52% (11/21)
	Placebo Arms N = 592
All ranges	34% (147/435)	59% (93/157)

Response rates assessed by baseline etravirine phenotype are shown in Table 8. These baseline phenotype groups are based on the select subject populations in TMC125-C206 and TMC125-C216 and are not meant to represent definitive clinical susceptibility breakpoints for Intelence®. The data are provided to give clinicians information on the likelihood of virologic success based on pre-treatment susceptibility to etravirine in treatment-experienced patients.

Table 8: Proportion of Subjects with < 50 HIV-1 RNA copies/mL at Week 48 by Baseline Phenotype and Enfuvirtide Use in the Pooled TMC125-C206 and TMC125-C216 Trials*
Etravirine Fold Change	Etravirine Arms N = 559
	Re-Used/Not Used Enfuvirtide	De Novo Enfuvirtide	Clinical Response Range
* Non-VF excluded analysis
All ranges	61% (253/416)	76% (109/143)	Overall Response
0 – 3	69% (188/274)	83% (75/90)	Higher than Overall Response
> 3 – 13	50% (39/78)	66% (25/38)	Lower than Overall Response
> 13	41% (26/64)	60% (9/15)	Lower than Overall Response
	Placebo Arms N = 583
All ranges	34% (145/429)	60% (92/154)

The proportion of virologic responders (viral load < 50 HIV-1 RNA copies/mL) by the phenotypic susceptibility score (PSS) of the background therapy, including enfuvirtide, is shown in Table 9.

Table 9: Virologic Response (Viral Load < 50 HIV-1 RNA copies/mL) at Week 48 by Phenotypic Susceptibility Score in the Non-VF Excluded Population of TMC125-C206 and TMC125-C216 Trials (Pooled Analysis)
	Intelence® + BR N=559	Placebo + BR N=586
The phenotypic susceptibility score (PSS) was defined as the total number of active antiretroviral drugs in the background therapy to which a subject's baseline viral isolate showed sensitivity in phenotypic resistance tests. Each drug in the background therapy was scored as a '1' or '0' based on whether the viral isolate was considered susceptible or resistant to that drug, respectively. In the calculation of the PSS, darunavir was counted as a sensitive antiretroviral if the FC ≤ 10; enfuvirtide was counted as a sensitive antiretroviral if it had not been used previously. Intelence® was not included in this calculation.
PSS*
0	43% (40/93)	5% (5/95)
1	61% (125/206)	28% (64/226)
2	77% (114/149)	59% (97/165)
≥ 3	75% (83/111)	72% (72/100)

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis and Mutagenesis

Etravirine was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to approximately 104 weeks. Daily doses of 50, 200 and 400 mg/kg were administered to mice and doses of 70, 200 and 600 mg/kg were administered to rats in the initial period of approximately 41–52 weeks. The high and middle doses were subsequently adjusted due to tolerability and reduced by 50% in mice and by 50–66% in rats to allow for completion of the studies. In the mouse study, statistically significant increases in the incidences of hepatocellular carcinoma and incidences of hepatocellular adenomas or carcinomas combined were observed in treated females. In the rat study, no statistically significant increases in tumor findings were observed in either sex. The relevance of these liver tumor findings in mice to humans is not known. Because of tolerability of the formulation in these rodent studies, maximum systemic drug exposures achieved at the doses tested were lower than those in humans at the clinical dose (400 mg/day), with animal vs. human AUC ratios being 0.6-fold (mice) and 0.2–0.7-fold (rats).

Etravirine tested negative in the in vitro Ames reverse mutation assay, in vitro chromosomal aberration assay in human lymphocyte, and in vitro clastogenicity mouse lymphoma assay, tested in the absence and presence of a metabolic activation system. Etravirine did not induce chromosomal damage in the in vivo micronucleus test in mice. [See Nonclinical Toxicology (13.2).]

Impairment of Fertility

No effects on fertility and early embryonic development were observed when etravirine was tested in rats at maternal doses up to 500 mg/kg/day, resulting in systemic drug exposure up to the recommended human dose (400 mg/day).

Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Developmental toxicity studies were performed in rabbits (at oral doses up to 375 mg/kg/day) and rats (at oral doses up to 1000 mg/kg/day). In both species, no treatment-related embryo-fetal effects including malformations were observed. In addition, no treatment-related effects were observed in a separate pre- and postnatal study performed in rats at oral doses up to 500 mg/kg/day. The systemic drug exposures achieved in these animal studies were equivalent to those at the recommended human dose (400 mg/day).

Clinical Studies

Treatment-Experienced Subjects

The clinical efficacy of Intelence® is derived from the analyses of 48-week data from 2 ongoing, randomized, double-blinded, placebo-controlled, Phase 3 trials, TMC125-C206 and TMC125-C216 (DUET-1 and DUET-2). These trials are identical in design and the results below are pooled data from the two trials.

TMC125-C206 and TMC125-C216 are Phase 3 studies designed to evaluate the safety and antiretroviral activity of Intelence® in combination with a background regimen (BR) as compared to placebo in combination with a BR. Eligible subjects were treatment-experienced HIV-1-infected patients with plasma HIV-1 RNA > 5000 copies/mL while on a stable antiretroviral regimen for at least 8 weeks. In addition, subjects had 1 or more NNRTI resistance-associated mutations at screening or from prior genotypic analysis, and 3 or more of the following primary PI mutations at screening: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, V82A/F/L/S/T, I84V, N88S, or L90M. Randomization was stratified by the intended use of enfuvirtide (ENF) in the BR, previous use of darunavir/ritonavir (DRV/rtv), and screening viral load. Virologic response was defined as undetectable viral load (< 50 HIV-1 RNA copies/mL) at 48 weeks.

All study subjects received DRV/rtv as part of their BR, and at least 2 other investigator-selected antiretroviral drugs (N[t]RTIs with or without ENF). Of Intelence®-treated subjects, 25.5% used ENF for the first time (de novo) and 20.0% re-used ENF. Of placebo-treated subjects, 26.5% used de novo ENF and 20.4% re-used ENF.

In the pooled analysis for TMC125-C206 and TMC125-C216, demographics and baseline characteristics were balanced between the Intelence® arm and the placebo arm. Table 10 displays selected demographic and baseline disease characteristics of the subjects in the Intelence® and placebo arms.

Table 10: Demographic and Baseline Disease Characteristics of Subjects in the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis)
	Pooled TMC125-C206 and TMC125-C216 Trials
	Intelence® + BR N=599	Placebo + BR N=604
RAMs = Resistance-Associated Mutations, BR=background regimen FC = fold change in EC50
IAS-USA primary PI mutations [August/September 2007]: D30N, V32I, L33F, M46I/L, I47A/V, G48V, I50L/V, I54L/M, L76V, V82A/F/L/S/T, I84V, N88S, L90M Tibotec NNRTI RAMs [June 2008]: A98G, V90I, L100I, K101E/H/P/Q, K103H/N/S/T, V106A/M/I, V108I, E138A/G/K/Q, V179D/E/F/G/I/T, Y181C/I/V, Y188C/H/L, V189I, G190A/C/E/Q/S, H221Y, P255H, F227C/L, M230I/L, P236L, K238N/T, Y318F The PSS was calculated for the background therapy (as determined on Day 7). Percentages are based on the number of subjects with available phenotype data. For fusion inhibitors (enfuvirtide), subjects were considered resistant if the drug was used in previous therapy up to baseline. Intelence® is not included in this calculation.
Demographic Characteristics
Median Age, years (range)	46 (18–77)	45 (18–72)
Sex
Male	90.0%	88.6%
Female	10.0%	11.4%
Race
White	70.1%	69.8%
Black	13.2%	13.0%
Hispanic	11.3%	12.2%
Asian	1.3%	0.6%
Other	4.1%	4.5%
Baseline Disease Characteristics
Median Baseline Plasma HIV-1 RNA (range), log10 copies/mL	4.8 (2.7–6.8)	4.8 (2.2–6.5)
Percentage of Subjects with Baseline Viral Load:
< 30,000 copies/mL	27.5%	28.8%
≥ 30,000 copies/mL and
< 100,000 copies/mL	34.4%	35.3%
≥ 100,000 copies/mL	38.1%	35.9%
Median Baseline CD4+ Cell Count (range), cells/mm3	99 (1–789)	109 (0–912)
Percentage of Subjects with Baseline CD4+ Cell Count:
< 50 cells/mm3	35.6%	34.7%
≥ 50 cells/mm3 and < 200 cells/mm3	34.8%	34.5%
≥ 200 cells/mm3	29.6%	30.8%
Median (range) Number of Primary PI Mutations*	4 (0–7)	4 (0–8)
Percentage of Subjects with Previous Use of NNRTIs:
0	8.2%	7.9%
1	46.9%	46.7%
>1	44.9%	45.4%
Percentage of Subjects with Previous Use of the following NNRTIs:
Efavirenz	70.3%	72.5%
Nevirapine	57.1%	58.6%
Delavirdine	13.7%	12.6%
Median (range) Number of NNRTI RAMs†	2 (0–8)	2 (0–7)
Median Fold Change of the Virus for the Following NNRTIs:
Delavirdine	27.3	26.1
Efavirenz	63.9	45.4
Etravirine	1.6	1.5
Nevirapine	74.3	74.0
Percentage of Subjects with Previous Use of a Fusion Inhibitor	39.6%	42.2%
Percentage of Subjects with a Phenotypic Sensitivity Score (PSS) for the background therapy ‡ of:
0	17.0%	16.2%
1	36.5%	38.7%
2	26.9%	27.8%
≥ 3	19.7%	17.3%

Efficacy at Week 48 for subjects in the Intelence® and placebo arms for the pooled TMC125-C206 and TMC125-C216 study populations are shown in Table 11.

Table 11: Outcomes of Treatment at Week 48 of the TMC125-C206 and TMC125-C216 Trials (Pooled Analysis)
	Pooled TMC125-C206 and TMC125-C216 Trials
	Intelence® + BR N=599	Placebo + BR N=604
BR=background regimen
Virologic Responders at Week 48 Viral Load < 50 HIV-1 RNA copies/mL	359 (60%)	232 (38%)

Virologic Failures (VF) at Week 48 Viral Load ≥ 50 HIV-1 RNA copies/mL	123 (21%)	201 (33%)

Death	11 (2%)	19 (3%)

Discontinuations before Week 48:
due to VF	58 (10%)	110 (18%)
due to Adverse Events	31 (5%)	14 (2%)
due to other reasons	17 (3%)	28 (5%)

At Week 48, 70.8% of Intelence®-treated subjects achieved HIV-1 RNA < 400 copies/mL as compared to 46.4% of placebo-treated subjects. The mean decrease in plasma HIV-1 RNA from baseline to Week 48 was –2.23 log10 copies/mL for Intelence®-treated subjects and –1.46 log10 copies/mL for placebo-treated subjects. The mean CD4+ cell count increase from baseline for Intelence®-treated subjects was 96 cells/mm3 and 68 cells/mm3 for placebo-treated subjects.

Of the study population who either re-used or did not use ENF, 57.4% of Intelence®-treated subjects and 31.7% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL. Of the study population using ENF de novo, 67.3% of Intelence®-treated subjects and 57.2% of placebo-treated subjects achieved HIV-1 RNA < 50 copies/mL.

Treatment-emergent CDC category C events occurred in 4% of Intelence®-treated subjects and 8.4% of placebo-treated subjects.

Study TMC125-C227 was a randomized, exploratory, active-controlled, open-label, Phase 2b trial. Eligible subjects were treatment-experienced, PI-naïve HIV-1-infected patients with genotypic evidence of NNRTI resistance at screening or from prior genotypic analysis. The virologic response was evaluated in 116 subjects who were randomized to Intelence® (n=59) or an investigator-selected PI (n=57), each given with 2 investigator-selected N(t)RTIs. Intelence®-treated subjects had lower antiviral responses associated with reduced susceptibility to the N(t)RTIs and to Intelence® as compared to the control PI-treated subjects.

How Supplied/Storage and Handling

Intelence® 100 mg tablets are supplied as white to off-white, oval tablets containing 100 mg of etravirine. Each tablet is debossed with "TMC125" on one side and "100" on the other side.

Intelence® 200 mg tablets are supplied as white to off-white, biconvex, oblong tablets containing 200 mg of etravirine. Each tablet is debossed with "T200" on one side.

Intelence® tablets are packaged in bottles in the following configuration:

100 mg tablets—bottles of 120 (NDC 59676-570-01). Each bottle contains 3 desiccant pouches.
200 mg tablets—bottles of 60 (NDC 59676-571-01). Each bottle contains 3 desiccant pouches.

Store Intelence® tablets at 25°C (77°F); with excursions permitted to 15°–30°C (59°–86°F) [see USP controlled room temperature]. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches.