These highlights do not include all the information needed to use ISENTRESS safely and effectively. See full prescribing information for ISENTRESS. ISENTRESS (raltegravir) Tablets Initial U.S. Approval: 2007

ISENTRESS is indicated in combination with other anti-retroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in three double-blind controlled studies of ISENTRESS. Two of these studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults and one was conducted in treatment-naïve adults.

The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response [see Clinical Studies (14)].

The safety and efficacy of ISENTRESS have not been established in pediatric patients.

For the treatment of patients with HIV-1 infection, the dosage of ISENTRESS is 400 mg administered orally, twice daily with or without food. During coadministration with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily with or without food.

400 mg pink, oval shaped, film-coated tablets with "227" on one side.

None

During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, Mycobacterium tuberculosis, or reactivation of varicella zoster virus), which may necessitate further eva luation and treatment.

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.

Treatment-Naïve Studies

The following safety assessment of ISENTRESS in treatment-naïve subjects is based on the randomized double-blind active controlled study of treatment-naïve subjects, STARTMRK (Protocol 021) with ISENTRESS 400 mg twice daily in combination with a fixed dose of emtricitabine 200 mg (+) tenofovir 300 mg, (N=281) versus efavirenz (EFV) 600 mg at bedtime in combination with emtricitabine (+) tenofovir, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir was 247 patient-years and 241 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir.

In Protocol 021, the rate of discontinuation of therapy due to adverse reactions was 3% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir and 6% in subjects receiving efavirenz + emtricitabine (+) tenofovir.

The clinical adverse drug reactions (ADRs) listed below were considered by investigators to be causally related to ISENTRESS + emtricitabine (+) tenofovir or efavirenz + emtricitabine (+) tenofovir. Clinical ADRs of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS and occurring at a higher rate than efavirenz are presented in Table 1.

Less Common Adverse Reactions

The following ADRs occurred in <2% of subjects receiving ISENTRESS + emtricitabine (+) tenofovir. These events have been included because of their seriousness, increased frequency on ISENTRESS compared with efavirenz or investigator's assessment of potential causal relationship.

General Disorders and Administration Site Conditions: fatigue

Psychiatric Disorders: abnormal dreams

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or efavirenz in Protocol 021 with selected Grades 2 to 4 laboratory abnormalities that represent a worsening from baseline are presented in Table 2.

Lipids, Change from Baseline

Changes from baseline in fasting lipids are shown in Table 3.

Treatment-Experienced Studies

The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 (Protocols 018 and 019) in antiretroviral treatment-experienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 48 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 387 patient-years versus 156 patient-years on placebo. The rates of discontinuation due to adverse events were 2% in subjects receiving ISENTRESS and 3% in subjects receiving placebo.

Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS and occurring at a higher exposure adjusted rate compared to placebo are presented in Table 4.

Less Common Adverse Reactions

The following ADRs occurred in <2% of subjects receiving ISENTRESS + OBT. These events have been included because of either their seriousness, increased frequency on ISENTRESS compared with placebo or investigator's assessment of potential causal relationship.

Gastrointestinal Disorders: abdominal pain, gastritis

Hepatobiliary Disorders: hepatitis

Immune System Disorders: hypersensitivity

Infections and Infestations: genital herpes, herpes zoster

Nervous System Disorders: dizziness

Renal and Urinary Disorders: renal failure

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Protocols 018 and 019 with selected Grade 2 to 4 laboratory abnormalities representing a worsening from baseline are presented in Table 5.

Selected Adverse Events

Regardless of Drug Relationship

Cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 5). Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions.

Patients with Co-existing Conditions

Patients Co-infected with Hepatitis B and/or Hepatitis C Virus

In the randomized, double-blind, placebo-controlled trials, treatment-experienced subjects (N = 114/699 or 16%) and treatment-naïve subjects (N = 34/563 or 6%) with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus co-infection for all treatment groups. In treatment-experienced subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 25%, 31% and 12%, respectively, of co-infected subjects treated with ISENTRESS as compared to 8%, 7% and 8% of all other subjects treated with ISENTRESS. In treatment-naïve subjects, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 17%, 22% and 11%, respectively, of co-infected subjects treated with ISENTRESS as compared to 4%, 4% and 3% of all other subjects treated with ISENTRESS.

Table 1: Adverse Reactions of Moderate to Severe Intensity Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Efavirenz (48 Week Analysis)
System Organ Class, Preferred Term	Randomized Study Protocol 021
System Organ Class, Preferred Term	ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir (n = 281)n = total number of subjects per treatment group %	Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (n = 282) %
Psychiatric Disorders
Insomnia	4	3

Table 2: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects (48 Week Analysis)
		Randomized Study Protocol 021
Laboratory Parameter Preferred Term (Unit)	Limit	ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir (N = 281)	Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir (N = 282)
ULN = Upper limit of normal range
Hematology
Absolute neutrophil count (10³/μL)
Grade 2	0.75 - 0.999	3%	3%
Grade 3	0.50 - 0.749	1%	<1%
Grade 4	<0.50	<1%	0%
Hemoglobin (gm/dL)
Grade 2	7.5 - 8.4	<1%	<1%
Grade 3	6.5 - 7.4	<1%	<1%
Grade 4	<6.5	0%	0%
Platelet count (10³/μL)
Grade 2	50 - 99.999	2%	0%
Grade 3	25 - 49.999	0%	<1%
Grade 4	<25	0%	0%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)
Grade 2	126 - 250	2%	3%
Grade 3	251 - 500	<1%	0%
Grade 4	>500	0%	0%
Total serum bilirubin
Grade 2	1.6 - 2.5 x ULN	4%	0%
Grade 3	2.6 - 5.0 x ULN	<1%	0%
Grade 4	>5.0 x ULN	0%	0%
Serum aspartate aminotransferase
Grade 2	2.6 - 5.0 x ULN	3%	4%
Grade 3	5.1 - 10.0 x ULN	1%	1%
Grade 4	>10.0 x ULN	<1%	<1%
Serum alanine aminotransferase
Grade 2	2.6 - 5.0 x ULN	4%	6%
Grade 3	5.1 - 10.0 x ULN	<1%	2%
Grade 4	>10.0 x ULN	<1%	<1%
Serum alkaline phosphatase
Grade 2	2.6 - 5.0 x ULN	<1%	2%
Grade 3	5.1 - 10.0 x ULN	0%	<1%
Grade 4	>10.0 x ULN	0%	0%

Table 3: Lipid Values, Mean Change from Baseline, Protocol 021
Laboratory Parameter Preferred Term	ISENTRESS 400 mg Twice Daily + Emtricitabine (+) Tenofovir N = 281			Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir N = 282
			Change from Baseline at Week 48			Change from Baseline at Week 48
	Baseline Mean(mg/dL)	Week 48 Mean(mg/dL)	Mean Change (mg/dL)	Baseline Mean(mg/dL)	Week 48 Mean(mg/dL)	Mean Change (mg/dL)
Notes:
N = Number of subjects in the treatment group. The analysis is based on all available data.
If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving ISENTRESS and 3% in the efavirenz group. Through Week 48, serum lipid-reducing agents were used in 6% of subjects in the group receiving ISENTRESS and 6% in the efavirenz group.
LDL-CholesterolFasting (non-random) laboratory tests.	97	103	6	92	108	16
HDL-Cholesterol	38	42	4	38	48	10
Total Cholesterol	159	169	10	156	188	33
Triglyceride	125	122	-3	136	174	37

Table 4: Adverse Drug Reactions of Moderate to Severe Intensity Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Exposure Adjusted Rate Compared to Placebo (48 Week Analysis, Exposure Adjusted Incidence Rates)
System Organ Class, Adverse Reactions	Randomized Studies Protocol 018 and 019
System Organ Class, Adverse Reactions	ISENTRESS 400 mg Twice Daily + OBT (n = 462)n=total number of subjects per treatment group.	Placebo + OBT (n = 237)
	Rate per 100 Patient-Years	Rate per 100 Patient-Years
Nervous System Disorders
Headache	3	1
Gastrointestinal Disorders
Nausea	2	1
General Disorders and Administration Site Conditions
Asthenia	2	1
Fatigue	2	1

Table 5: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (48 Week Analysis)
		Randomized Studies Protocol 018 and 019
Laboratory Parameter Preferred Term (Unit)	Limit	ISENTRESS 400 mg Twice Daily + OBT (N = 462)	Placebo + OBT (N = 237)
ULN = Upper limit of normal range
Hematology
Absolute neutrophil count (10³/μL)
Grade 2	0.75 - 0.999	3%	5%
Grade 3	0.50 - 0.749	3%	3%
Grade 4	<0.50	1%	<1%
Hemoglobin (gm/dL)
Grade 2	7.5 - 8.4	1%	3%
Grade 3	6.5 - 7.4	1%	<1%
Grade 4	<6.5	<1%	0%
Platelet count (10³/μL)
Grade 2	50 - 99.999	3%	5%
Grade 3	25 - 49.999	1%	<1%
Grade 4	<25	1%	<1%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)
Grade 2	126 - 250	8%	5%
Grade 3	251 - 500	2%	1%
Grade 4	>500	0%	0%
Total serum bilirubin
Grade 2	1.6 - 2.5 x ULN	5%	3%
Grade 3	2.6 - 5.0 x ULN	2%	2%
Grade 4	>5.0 x ULN	1%	0%
Serum aspartate aminotransferase
Grade 2	2.6 - 5.0 x ULN	8%	6%
Grade 3	5.1 - 10.0 x ULN	3%	3%
Grade 4	>10.0 x ULN	<1%	1%
Serum alanine aminotransferase
Grade 2	2.6 - 5.0 x ULN	7%	8%
Grade 3	5.1 - 10.0 x ULN	3%	2%
Grade 4	>10.0 x ULN	1%	2%
Serum alkaline phosphatase
Grade 2	2.6 - 5.0 x ULN	2%	<1%
Grade 3	5.1 - 10.0 x ULN	<1%	1%
Grade 4	>10.0 x ULN	1%	<1%
Serum pancreatic amylase test
Grade 2	1.6 - 2.0 x ULN	2%	1%
Grade 3	2.1 - 5.0 x ULN	3%	3%
Grade 4	>5.0 x ULN	<1%	0%
Serum lipase test
Grade 2	1.6 - 3.0 x ULN	4%	3%
Grade 3	3.1 - 5.0 x ULN	1%	<1%
Grade 4	>5.0 x ULN	0%	0%
Serum creatine kinase
Grade 2	6.0 - 9.9 x ULN	2%	2%
Grade 3	10.0 - 19.9 x ULN	3%	3%
Grade 4	≥20.0 x ULN	2%	1%

The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these 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.

Blood and Lymphatic System Disorders: thrombocytopenia

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Psychiatric Disorders: anxiety, depression (particularly in patients with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors, paranoia

Skin and Subcutaneous Tissue Disorders: rash, Stevens-Johnson syndrome

Raltegravir does not inhibit (IC>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce CYP1A2, CYP2B6 or CYP3A4. A midazolam drug interaction study confirmed the low propensity of raltegravir to alter the pharmacokinetics of agents metabolized by CYP3A4 in vivo by demonstrating a lack of effect of raltegravir on the pharmacokinetics of midazolam, a sensitive CYP3A4 substrate. Similarly, raltegravir is not an inhibitor (IC>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegr