ISENTRESS

ISENTRESS- raltegravir potassium tablet, film coated
H.J. Harkins Company Inc.

Adult Patients:

ISENTRESS® and ISENTRESS® HD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients.

Pediatric Patients:

ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients 4 weeks of age and older.

ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg.

Dosage and Administration

2.1 General Dosing Recommendations

Because the formulations have different pharmacokinetic profiles, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet or the ISENTRESS HD 600 mg film-coated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension.
Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided [see CLINICAL PHARMACOLOGY (12.3)].
ISENTRESS film-coated tablets must be swallowed whole.
ISENTRESS chewable tablets may be chewed or swallowed whole. Maximum daily dose is 300 mg taken by mouth twice daily.
ISENTRESS for oral suspension:

Pour packet contents of ISENTRESS for oral suspension into 5 mL of water and mix. Each single-use packet for oral suspension contains 100 mg of raltegravir which is suspended in 5 mL of water giving a final concentration of 20 mg per mL. Maximum daily dose is 100 mg taken by mouth twice daily.
Once mixed, measure the recommended volume (dose) of suspension with a syringe and administer the dose orally. The dose of suspension should be administered orally within 30 minutes of mixing.
Discard any remaining suspension.
For more details on preparation and administration of the suspension, see INSTRUCTIONS FOR USE.

2.2 Adults

The recommended adult dosage of ISENTRESS film-coated tablets is displayed in Table 1. ISENTRESS and ISENTRESS HD should be taken by mouth and may be taken with or without food [see CLINICAL PHARMACOLOGY (12.3)].

Table 1: Dosing Recommendations for ISENTRESS and ISENTRESS HD in Adult Patients
Population Recommended Dose
Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily 1200 mg (2 × 600mg) once daily or 400 mg twice daily
Treatment-experienced 400 mg twice daily
Treatment-naïve or treatment-experienced when coadministered with rifampin [see DRUG INTERACTIONS (7.1)] 800 mg (2 × 400 mg) twice daily

2.3 Pediatrics

The recommended pediatric dosage of ISENTRESS is displayed in Table 2. ISENTRESS film-coated tablets, chewable tablets and for oral suspension should be taken by mouth and may be taken with or without food [see CLINICAL PHARMACOLOGY (12.3)].

Table 2: Dosing Recommendations for ISENTRESS and ISENTRESS HD in Pediatric Patients
Recommended Pediatric Dosage and Formulation
Population/Weight Film-Coated Tablets 400 mg Film-Coated Tablets 600 mg Chewable Tablets 100 mg and 25 mg For Oral Suspension 100 mg

*
If able to swallow a tablet

If at least 40 kg and either

treatment-naïve or
virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily

400 mg twice daily 1200 mg (2 × 600mg) once daily 300 mg twice daily (see TABLE 3) NA
If at least 25 kg 400 mg twice daily* NA Weight-based dosing twice daily (see TABLE 3) NA
If at least 4 weeks of age and weighing 3 kg to less than 25 kg NA NA Weight-based dosing twice daily (see TABLE 4) Weight-based dosing twice daily up to 20 kg (see TABLE 4)

Table 3: Alternative Dosage* with ISENTRESS Chewable Tablets for Pediatric Patients Weighing at Least 25 kg
Body Weight
(kg) Dose Number of Chewable Tablets

*
The weight-based dosing recommendation for the chewable tablet is based on approximately 6 mg/kg/dose twice daily [see CLINICAL PHARMACOLOGY (12.3)].
†
The 100 mg chewable tablet can be divided into equal halves.

25 to less than 28 150 mg twice daily 1.5 × 100 mg† twice daily
28 to less than 40 200 mg twice daily 2 × 100 mg twice daily
At least 40 300 mg twice daily 3 × 100 mg twice daily

Table 4: Recommended Dosage* for ISENTRESS For Oral Suspension and Chewable Tablets in Pediatric Patients at Least 4 weeks of Age and Weighing Less than 25 kg
Body Weight
(kg) Volume (Dose) of Suspension to be Administered Number of Chewable Tablets
Note: The chewable tablets are available as 25 mg and 100 mg tablets.
Patients can remain on ISENTRESS for oral suspension formulation as long as their weight is below 20 kg.

*
The weight-based dosing recommendation for the chewable tablet and for oral suspension is based on approximately 6 mg/kg/dose twice daily [see CLINICAL PHARMACOLOGY (12.3)].
†
For weight between 11 and 20 kg either formulation can be used.
‡
The 100 mg chewable tablet can be divided into equal halves.

3 to less than 4 1 mL (20 mg) twice daily
4 to less than 6 1.5 mL (30 mg) twice daily
6 to less than 8 2 mL (40 mg) twice daily
8 to less than 11 3 mL (60 mg) twice daily
11 to less than 14† 4 mL (80 mg) twice daily 3 × 25 mg twice daily
14 to less than 20† 5 mL (100 mg) twice daily 1 × 100 mg twice daily
20 to less than 25 1.5 × 100 mg‡ twice daily

Dosage & Forms

Film-coated Tablets

400 mg pink, oval-shaped, film-coated tablets with “227” on one side (ISENTRESS).
600 mg yellow, oval-shaped, film-coated tablets with Merck logo and “242” on one side and plain on the other side (ISENTRESS HD).

Chewable Tablets

100 mg pale orange, oval-shaped, orange-banana flavored, chewable tablets scored on both sides and imprinted on one face with the Merck logo and “477” on opposite sides of the score.
25 mg pale yellow, round, orange-banana flavored, chewable tablets with the Merck logo on one side and “473” on the other side.

For Oral Suspension

100 mg white to off-white, banana flavored, granular powder that may contain yellow or beige to tan particles in a child resistant single-use foil packet.

Contraindications

none

Warnings and Precautions

5.1 Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS or ISENTRESS HD and other suspect agents 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 aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS or ISENTRESS HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction.

5.2 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, 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.

5.3 Phenylketonurics

ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria.

Adverse reactions

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.

6.1 Clinical Trials Experience

Treatment-Naïve Adults

The safety of ISENTRESS was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies: STARTMRK evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 × 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. Safety data from these two studies are presented side-by-side in Tables 5 and 6 to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up and study design.

STARTMRK (ISENTRESS 400 mg twice daily)

In STARTMRK, subjects received ISENTRESS 400 mg twice daily (N=281) or efavirenz (EFV) 600 mg at bedtime (N=282) both in combination with emtricitabine (+) tenofovir disoproxil fumarate, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate.

In STARTMRK, the rate of discontinuation of therapy due to adverse events through Week 240 was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate.

ONCEMRK (ISENTRESS HD 1200 mg [2 × 600 mg] once daily)

In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (n=531) or ISENTRESS 400 mg twice daily (n=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 516 patient-years and for ISENTRESS 400 mg twice daily was 258 patient-years.

In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 48 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 × 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily.

Clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 48 are presented in Table 5.

In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 48 also include abdominal pain, diarrhea, vomiting, and decreased appetite.

Table 5: Adverse Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and ISENTRESS HD
System Organ Class, Preferred Term STARTMRK
Week 240 ONCEMRK
Week 48
ISENTRESS 400 mg Twice Daily
(N= 281) Efavirenz 600 mg At Bedtime
(N= 282) ISENTRESS HD 1200 mg Once Daily
(N=531) ISENTRESS 400 mg Twice Daily
(N=266)
Note: ISENTRESS BID, ISENTRESS HD and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate
N= total number of subjects per treatment group

*
Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely 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).

Headache 4% 5% 1% <1%
Insomnia 4% 4% <1% <1%
Nausea 3% 4% 1% 0%
Dizziness 2% 6% <1% 0%
Fatigue 2% 3% 0% 0%

Laboratory Abnormalities

The percentages of adult subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade from baseline) who were treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK are presented in Table 6.

Table 6: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects
STARTMRK
Week 240 ONCEMRK
Week 48
Laboratory Parameter Preferred Term
(Unit) Limit ISENTRESS
400 mg Twice Daily
(N = 281) Efavirenz
600 mg At Bedtime
(N = 282) ISENTRESS HD
1200 mg Once Daily
(N=531) ISENTRESS
400 mg Twice Daily
(N=266)
ULN = Upper limit of normal range
Notes: ISENTRESS BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate

*
Test not done in ONCEMRK
†
Test not done in STARTMRK

Hematology
Absolute neutrophil count (103/µL)
Grade 2 0.75 — 0.999 3% 5% 1% 1%
Grade 3 0.50 — 0.749 3% 1% 1% 1%
Grade 4 <0.50 1% 1% 0% 0%
Hemoglobin (gm/dL)
Grade 2 7.5 — 8.4 1% 1% 0% 0%
Grade 3 6.5 — 7.4 1% 1% 0% 0%
Grade 4 <6.5 <1% 0% 0% 0%
Platelet count (103/µL)
Grade 2 50 — 99.999 1% 0% 1% <1%
Grade 3 25 — 49.999 <1% <1% 0% 0%
Grade 4 <25 0% 0% 0% <1%
Blood chemistry
Fasting (non-random) serum glucose test (mg/dL)*
Grade 2 126 — 250 7% 6% — –
Grade 3 251 — 500 2% 1% — –
Grade 4 >500 0% 0% — –
Total serum bilirubin
Grade 2 1.6 — 2.5 × ULN 5% <1% 1% 1%
Grade 3 2.6 — 5.0 × ULN 1% 0% 1% 0%
Grade 4 >5.0 × ULN <1% 0% <1% 0%
Creatinine
Grade 2 1.4-1.8 × ULN 1% 1% 0% <1%
Grade 3 1.9-3.4 × ULN 0% <1% 0% 0%
Grade 4 ≥3.5 × ULN 0% 0% 0% 0%
Serum aspartate aminotransferase
Grade 2 2.6 — 5.0 × ULN 8% 10% 3% 2%
Grade 3 5.1 — 10.0 × ULN 5% 3% 1% <1%
Grade 4 >10.0 × ULN 1% <1% <1% 0%
Serum alanine aminotransferase
Grade 2 2.6 — 5.0 × ULN 11% 12% 3% 1%
Grade 3 5.1 — 10.0 × ULN 2% 2% 1% <1%
Grade 4 >10.0 × ULN 2% 1% <1% 0%
Serum alkaline phosphatase
Grade 2 2.6 — 5.0 × ULN 1% 3% 1% 0%
Grade 3 5.1 — 10.0 × ULN 0% 1% 0% 0%
Grade 4 >10.0 × ULN <1% <1% 0% 0%
Lipase†
Grade 2 1.6-3.0 x ULN — – 5% 5%
Grade 3 3.1-5.0 × ULN — – 2% <1%
Grade 4 >5.0 × ULN — – 1% 0%
Creatine kinase†
Grade 2 6.0-9.9 × ULN — – 3% 2%
Grade 3 10.0-19.9 × ULN — – 1% 3%
Grade 4 ≥20.0 × ULN — – 2% 2%

Lipids, Change from Baseline

Changes from baseline in fasting lipids are shown in Table 7.

Table 7: Lipid Values, Mean Change from Baseline, STARTMRK Study
Laboratory Parameter Preferred Term ISENTRESS 400 mg
Twice Daily + Emtricitabine (+) Tenofovir Disoproxil Fumarate
N = 207 Efavirenz 600 mg
At Bedtime + Emtricitabine (+) Tenofovir Disoproxil Fumarate
N = 187
Change from Baseline at
Week 240 Change from Baseline at
Week 240
Baseline
Mean Week 240
Mean Mean Change Baseline
Mean Week 240
Mean Mean Change
(mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL) (mg/dL)
Notes:
N = total number of subjects per treatment group with at least one lipid test result available. 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 240, serum lipid-reducing agents were used in 9% of subjects in the group receiving ISENTRESS and 15% in the efavirenz group.

*
Fasting (non-random) laboratory tests at Week 240.

LDL-Cholesterol* 96 106 10 93 118 25
HDL-Cholesterol* 38 44 6 38 51 13
Total Cholesterol* 159 175 16 157 201 44
Triglyceride* 128 130 2 141 178 37

Treatment-Experienced Adults

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 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 96 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving ISENTRESS and 5% 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 rate compared to placebo are presented in Table 8.

Table 8: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Placebo (96 Week Analysis)
System Organ Class, Adverse Reactions Randomized Studies BENCHMRK 1 and BENCHMRK 2
ISENTRESS 400 mg Twice Daily + OBT
(n = 462) Placebo + OBT
(n = 237)
Nervous System Disorders
n=total number of subjects per treatment group.

*
Includes adverse reactions at least possibly, probably, or definitely 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).

Headache 2% <1%

Laboratory Abnormalities

The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Studies BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 9.

Table 9: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis)
Randomized Studies BENCHMRK 1 and BENCHMRK 2
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 4% 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 10% 7%
Grade 3 251 — 500 3% 1%
Grade 4 >500 0% 0%
Total serum bilirubin
Grade 2 1.6 — 2.5 × ULN 6% 3%
Grade 3 2.6 — 5.0 × ULN 3% 3%
Grade 4 >5.0 × ULN 1% 0%
Serum aspartate aminotransferase
Grade 2 2.6 — 5.0 × ULN 9% 7%
Grade 3 5.1 — 10.0 × ULN 4% 3%
Grade 4 >10.0 × ULN 1% 1%
Serum alanine aminotransferase
Grade 2 2.6 — 5.0 × ULN 9% 9%
Grade 3 5.1 — 10.0 × ULN 4% 2%
Grade 4 >10.0 × ULN 1% 2%
Serum alkaline phosphatase
Grade 2 2.6 — 5.0 × ULN 2% <1%
Grade 3 5.1 — 10.0 × ULN <1% 1%
Grade 4 >10.0 × ULN 1% <1%
Serum pancreatic amylase test
Grade 2 1.6 — 2.0 × ULN 2% 1%
Grade 3 2.1 — 5.0 × ULN 4% 3%
Grade 4 >5.0 × ULN <1% <1%
Serum lipase test
Grade 2 1.6 — 3.0 × ULN 5% 4%
Grade 3 3.1 — 5.0 × ULN 2% 1%
Grade 4 >5.0 × ULN 0% 0%
Serum creatine kinase
Grade 2 6.0 — 9.9 × ULN 2% 2%
Grade 3 10.0 — 19.9 × ULN 4% 3%
Grade 4 ≥20.0 × ULN 3% 1%

Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies

The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving ISENTRESS or ISENTRESS HD in a combination regimen. These events have been included because of their seriousness, increased frequency compared with efavirenz or placebo, or investigator’s assessment of potential causal relationship.

Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting

General Disorders and Administration Site Conditions: asthenia

Hepatobiliary Disorders: hepatitis

Immune System Disorders: hypersensitivity

Infections and Infestations: genital herpes, herpes zoster

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

Renal and Urinary Disorders: nephrolithiasis, renal failure

Selected Adverse Events — Adults

In studies of ISENTRESS 400 mg twice daily, 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 disoproxil fumarate; 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/mm3 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 and ISENTRESS HD (see TABLES 6 and 8). Myopathy and rhabdomyolysis have been reported with ISENTRESS. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash.

Patients with Co-existing Conditions — Adults

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

In Phase III studies of ISENTRESS, patients 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 the treatment-experienced studies, BENCHMRK 1 and BENCHMRK 2, 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK and ONCEMRK, 6% (34/563) and 3% (23/797), respectively, were co-infected. 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.

At 96 weeks, in treatment-experienced subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-naïve subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS.

At 48 weeks, in treatment-naïve subjects receiving ISENTRESS HD 1200 mg (2 × 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 13%, 33% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 4%, 3% and 2% of all other subjects treated with ISENTRESS HD 1200 mg once daily.

Pediatrics

2 to 18 Years of Age

ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see USE IN SPECIFIC POPULATIONS (8.4) and CLINICAL STUDIES (14.3)]. Of the 126 patients, 96 received the recommended dose of ISENTRESS.

In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults.

One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash.

One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious.

4 Weeks to less than 2 Years of Age

ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066 [see USE IN SPECIFIC POPULATIONS (8.4) and CLINICAL STUDIES (14.3)].

In these 26 infants and toddlers, the frequency, type and severity of drug-related adverse reactions through Week 48 were comparable to those observed in adults.

One patient experienced a Grade 3 serious drug-related allergic rash that resulted in treatment discontinuation.

6.2 Postmarketing Experience

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

Gastrointestinal Disorders: diarrhea

Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Nervous System Disorders: cerebellar ataxia

Psychiatric Disorders: anxiety, paranoia

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