Phase III Studies Showed Isentress in Combination Therapy Provided Significant Viral Load Reductions Through 96 Weeks in Treatment-Experienced Patients with Triple-Class Resistant HIV

Merck's Integrase Inhibitor, ISENTRESS, in Combination with Other HIV Medicines Shown as Effective as Efavirenz in Suppressing Viral Load and Increasing CD4 Cell Counts in Treatment-Naïve HIV-infected Patients with High Levels of Virus, Across Various Populations, in Investigational Study

MONTREAL--(BUSINESS WIRE)--Feb 9, 2009 - In new subgroup analyses of a Phase III study (STARTMRK) that compared <!-- cpurl -->Merck & Co<!-- /cpurl -->., Inc.'s integrase inhibitor <!-- ppurl -->ISENTRESS<!-- /ppurl -->® (raltegravir) to efavirenz [one of the leading antiretrovirals prescribed for previously untreated (treatment-naïve) HIV-infected patients], ISENTRESS was found to be as effective as efavirenz at suppressing viral load and provided improvements in immune system function across a broad spectrum of patient subpopulations through 48 weeks. The use of ISENTRESS in previously untreated HIV-infected patients is an investigational use of the drug. Both medicines were taken in combination with tenofovir/emtricitabine (Poster 573).

In other Phase III studies, BENCHMRK-1 and -2, ISENTRESS in combination with optimized background therapy (OBT) demonstrated greater reductions in viral load compared to placebo plus OBT through 96 weeks of therapy in treatment-experienced patients with triple-class resistant HIV who were failing antiretroviral therapy (Poster 571b).

These results as well as data from three additional studies were presented today at the 16th Conference on Retroviruses and Opportunistic Infections (CROI) in Montreal, Canada.

"As physicians continue to use ISENTRESS in treatment-experienced patients, newly presented longer-term data from BENCHMRK-1 and -2 continue to inspire confidence among clinicians when treating patients that are more advanced in their treatment course.

Furthermore, the STARTMRK studies in treatment-naïve patients showed that ISENTRESS may become an important new option for a broader spectrum of patients beginning treatment for HIV infection, if the drug is approved for this use,” said Daniel S. Berger, M.D., clinical associate professor, College of Medicine, University of Illinois at Chicago and medical director of NorthStar Medical Center.

ISENTRESS is the first integrase inhibitor approved for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents. This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, three-class antiretroviral [nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs)] treatment-experienced adults. In these studies the use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response. The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult or pediatric patients.

As with all HIV treatment regimens, ISENTRESS should be used with other active antiviral agents.

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others.

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 evaluation and treatment.

ISENTRESS demonstrated consistent efficacy in reduction of viral load across various patient groups in STARTMRK study

Results from the STARTMRK subgroup analyses showed that at Week 48 ISENTRESS in combination therapy reduced viral load to undetectable levels (less than 50 copies/mL) in 96 percent of women (47 out of 49) compared with 93 percent of women (42 out of 45) receiving efavirenz in combination therapy.

ISENTRESS was also as effective as efavirenz at reducing viral load in patients whose racial background was either black [89 percent for the regimen with ISENTRESS (24 out of 27) compared with 91 percent for the regimen with efavirenz (20 out of 22)], Asian [91 percent (31 out of 34) vs. 87 percent (26 out of 30)], Hispanic [93 percent (54 out of 58) vs. 86 percent (53 out of 62)] or multiracial [91 percent (31 out of 34) vs. 83 percent (30 out of 36)].

The mean increase in CD4 cell counts at 48 weeks was 170 cells/mm3 for women receiving the ISENTRESS-based treatment compared with 168 cells/mm3 for women receiving the regimen with efavirenz. The mean increase from baseline in CD4 cell counts were consistent in patients with diverse racial background and are as follows for patients receiving the regimen with ISENTRESS compared to patients receiving efavirenz-based therapy, respectively: blacks (163 cells/mm3; n=26 vs. 125 cells/mm3; n=21), Asians (185 cells/mm3; n=32 vs. 152 cells/mm3; n=28), Hispanics (196 cells/mm3; n=58 vs. 150 cells/mm3; n=62) and multiracials (182 cells/mm3; n=34 vs. 168 cells/mm3; n=36).

Of those patients with high baseline viral loads (greater than 100,000 copies/mL), 91 percent of patients receiving the regimen with ISENTRESS reduced viral load to undetectable levels versus 89 percent of patients receiving efavirenz-based therapy. The mean increase in CD4 cell counts for patients with high baseline viral loads (greater than 100,000 copies/mL) was 196 cells/mm3 for patients receiving the regimen with ISENTRESS compared with 192 cells/mm3 for patients receiving the regimen with efavirenz.

In this study, 563 treatment-naïve, HIV-infected patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz dosed orally once daily in combination with the same agents. The primary endpoints were reductions in HIV viral load to less than 50 copies/mL at Week 48 and an evaluation of safety and tolerability. Secondary endpoints included antiretroviral activity as measured by reductions in HIV viral load to less than 400 copies/mL and the change from baseline in CD4 cell counts at Week 48.

Durability and persistent tolerability of ISENTRESS demonstrated through 96 weeks in treatment-experienced patients (BENCHMRK-1 and -2)

Ninety-six week results from two Phase III studies, BENCHMRK-1 and -2 were also presented today. Results from these studies showed that at Week 96, 57 percent of patients (262 out of 460) receiving ISENTRESS plus OBT achieved undetectable viral load (less than 50 copies/mL) versus 26 percent of patients (62 out of 237) receiving placebo plus OBT; p<0.001. Additionally, patients receiving the regimen with ISENTRESS experienced significantly greater increases in CD4 cell counts (123 cells/mm3) compared to patients receiving placebo plus OBT (49 cells/mm3) at Week 96; p<0.001.

In the BENCHMRK studies, patients received either 400 mg ISENTRESS administered orally twice daily in combination with OBT (n=462) or 400 mg placebo dosed orally twice daily in combination with OBT (n=237). Data demonstrated that ISENTRESS plus OBT provided potent and greater antiretroviral and immunological efficacy compared to placebo plus OBT. Reductions in viral load and immunological efficacy were sustained through Week 96: 57 percent of patients receiving ISENTRESS plus OBT maintained viral suppression to less than 50 copies/mL; up to 79 percent of patients receiving enfuvirtide and darunavir in OBT with ISENTRESS maintained viral suppression to less than 50 copies/mL. There were few discontinuations due to adverse experiences, four percent for ISENTRESS plus OBT versus five percent for placebo plus OBT, respectively. The risk of developing malignancy was comparable between ISENTRESS and the control group.

Exposure-adjusted rates (per 100 patient-years) of the most commonly drug-related clinical adverse events (greater than or equal to 2.0 percent, and of any intensity) in patients receiving ISENTRESS plus OBT compared to those receiving placebo plus OBT were headache (2.7 per 100 patient-years vs. 4.5 per 100 patient-years), nausea (2.3 per 100 patient-years vs. 4.1 per 100 patient-years), diarrhea (1.8 per 100 patient-years vs. 4.5 per 100 patient years), fatigue (1.8 per 100 patient-years vs. 0.7 per 100 patient-years), abdominal distension (1.2 per 100 patient-years vs. 1.5 per 100 patient-years), vomiting (0.8 per 100 patient-years vs. 1.9 per 100 patient-years) and pyrexia (0.5 per 100 patient-years vs. 2.2 per 100 patient-years), respectively.

The rate of cancer in patients receiving ISENTRESS plus OBT in both BENCHMRK-1 and -2 was 3.0 per 100 patient-years, compared with 2.6 per 100 patient-years in those patients receiving placebo plus OBT, resulting in a relative risk of 1.1 (0.5, 3.1). The rate of new or recurrent AIDS-defining conditions was 2.2 per 100 patient-years for the group receiving ISENTRESS versus 4.1 per 100 patient-years for the placebo group, respectively, resulting in a relative risk of 0.5 (0.2, 1.3).

Based on 48-week data from BENCHMRK-1 and -2, the U.S. Food and Drug Administration granted ISENTRESS traditional approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication with HIV-1 strains resistant to multiple antiretroviral agents in January 2009.

Additional important safety information about ISENTRESS

Due to rifampin's potent induction of uridine diphosphate glucoronosyltransferase (UGT) 1A1, the recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. Caution should be used when coadministering ISENTRESS with other strong inducers of UGT1A1 due to reduced plasma concentrations of ISENTRESS.

The most common adverse reactions of moderate to severe intensity (less than or equal to two percent) which occurred at a higher exposure adjusted rate compared to placebo are headache, nausea, asthenia and fatigue.

Creatine kinase elevations were observed in subjects who received ISENTRESS. Myopathy and rhabdomyolysis have been reported; however, the relationship of ISENTRESS to these events is not known. ISENTRESS should be used with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medication known to cause these conditions.

Additional posters on ISENTRESS presented at CROI

In addition to the STARTMRK study comparing ISENTRESS with efavirenz and the BENCHMRK-1 and -2 studies in treatment-experienced patients with triple-class resistant HIV, two other posters were also presented today further evaluating the safety and efficacy of ISENTRESS. These posters include:

 

  • A review of cancer incidence in ISENTRESS clinical trials in treatment-naïve and treatment-experienced patients, which found to date no difference in the risk of cancer in HIV-infected patients receiving ISENTRESS versus other antiretroviral therapy (Poster 859) and
  • A review of preliminary data from an ongoing prospective, open-label, non-randomized, dose finding study of ISENTRESS plus OBT in treatment-experienced children aged 6 to 18 (IMPAACT P1066). These results will be presented by the National Institutes of Health

Review of cancer incidence in ISENTRESS clinical trials

The occurrence of cancer, a known complication of HIV infection, was reviewed in five randomized, double-blind clinical trials of ISENTRESS in treatment-naïve and treatment-experienced patients, as well as an open-label expanded access program. A pooled data analysis of two Phase II (Protocols 004 and 005) and three Phase III trials (BENCHMRK-1,

BENCHMRK-2 and STARTMRK) with follow-up of at least 48 to 120 weeks (over 1,700 patient-years exposure to ISENTRESS), found that during the double-blind phase cancer rates were slightly lower for those patients receiving the regimen with ISENTRESS (rate of 1.7 per 100 patient-year, broad cancer case definition, including recurrences, non-melanoma skin cancers and carcinoma in situ) but not significantly different from patients receiving comparator antiretroviral treatments (rate of 2.2 per 100 patient-year, broad cancer definition). This resulted in a relative risk of 0.75 with a confidence interval of 0.40 to 1.46.

With approximately 600 patient-years additional exposure to ISENTRESS during open-label phases, cancer rates remained similar (rate of 2.1 per 100 patient-years) to those observed during the double-blind phase. In an expanded access setting, with median follow-up of 24 weeks for over 5,400 patients (over 2,200 patient-years exposure to ISENTRESS), cancer rates were similar to those observed in clinical trials with ISENTRESS.

In Protocol 004, ISENTRESS was dosed at 100 to 600 mg twice daily up to 48 weeks and then at 400 mg thereafter. In Protocol 005, ISENTRESS was dosed at 200 to 600 mg twice daily until at least 24 weeks in the double-blind portion of the study, and then all were dosed at 400 mg in the open-label portion of the study. The analysis of the Phase II and Phase III trials combined included 1,039 patients who received ISENTRESS and 605 patients who were assigned to a comparator treatment, 173 of whom crossed over from the comparator treatment to ISENTRESS in the open-label phase(s). In all cases, ISENTRESS was used in combination regimens. Data were available through at least 48 weeks in the Phase III STARTMRK trial, 96 weeks in BENCHMRK-1 and BENCHMRK-2 trials and at least 120 weeks in the Phase II trials (Protocols 004 and 005). Double-blind and open-label data were included.

About ISENTRESS

ISENTRESS is the first medicine to be approved in a class of antiretroviral drugs called integrase inhibitors. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme. Inhibiting integrase from performing this essential function limits the ability of the virus to replicate and infect new cells. There are drugs in use that inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only drug approved that inhibits the integrase enzyme.

In October 2007, the U.S. Food and Drug Administration granted ISENTRESS accelerated approval for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients with evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents. ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. During coadministration with rifampin, the recommended dosage of ISENTRESS is 800 mg twice daily with or without food. ISENTRESS does not require boosting with ritonavir.

Merck HIV Research

Merck is committed to developing innovative therapies that offer advances in the treatment of infectious diseases – including HIV. Merck's efforts to develop investigational treatments for HIV and AIDS have been under way for more than 20 years and continue today. Merck began its HIV integrase inhibitor research in 1993 and was the first to demonstrate inhibition of HIV integrase in vitro and in vivo.

Prevalence of HIV and AIDS

In 2006, more than one million Americans were living with HIV and AIDS, and it is estimated that approximately more than 56,000 new cases of HIV and AIDS are diagnosed each year in the United States.

Worldwide, an estimated 33 million people are infected with HIV and AIDS, and more than two million new infections occurred in 2007.

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first. Established in 1891, Merck currently discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs. The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them. Merck also publishes unbiased health information as a not-for-profit service. For more information, visit www.merck.com.

Forward-looking statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995. These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements. The forward-looking statements may include statements regarding product development, product potential or financial performance. No forward-looking statement can be guaranteed and actual results may differ materially from those projected. Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events, or otherwise. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2007, and in any risk factors or cautionary statements contained in the Company's periodic reports on Form 10-Q or current reports on Form 8-K, which the Company incorporates by reference.

Prescribing information and patient prescribing information for ISENTRESS® is attached.

 

HIGHLIGHTS OF PRESCRIBING INFORMATION

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

RECENT MAJOR CHANGES

Indications And Usage (1) 01/2009

Dosage And Administration (2) 01/2009

Warnings And Precautions (5) 01/2009

INDICATIONS AND USAGE

ISENTRESS® is a human immunodeficiency virus integrase strand transfer inhibitor (HIV-1 INSTI) indicated:

 

  • In combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents (1).

The safety and efficacy of ISENTRESS have not been established in treatment-naïve adult patients or pediatric patients (1).

DOSAGE AND ADMINISTRATION

 

  • 400 mg administered orally, twice daily with or without food (2).
  • During coadministration with rifampin, 800 mg twice daily (2).

DOSAGE FORMS AND STRENGTHS

Tablets: 400 mg (3).

CONTRAINDICATIONS

None

WARNINGS AND PRECAUTIONS

Monitor for Immune Reconstitution Syndrome (5.1).

ADVERSE REACTIONS

 

  • The most common adverse reactions of moderate to severe intensity ((>=)2%) which occurred at a higher exposure adjusted rate compared to placebo are headache, nausea, asthenia and fatigue (6.1).
  • Creatine kinase elevations were observed in subjects who received ISENTRESS. 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 (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Merck & Co., Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy:

 

  • ISENTRESS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Physicians are encouraged to register pregnant women exposed to ISENTRESS by calling 1-800-258-4263 so that Merck can monitor maternal and fetal outcomes (8.1).

Nursing Mothers:

 

  • Breast-feeding is not recommended while taking ISENTRESS (8.3).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 01/2009

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Immune Reconstitution Syndrome

5.2 Drug Interactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents

7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Use in Patients with Hepatic Impairment

8.7 Use in Patients with Renal Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

12.4 Microbiology

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the Full Prescribing Information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ISENTRESS1 in combination with other antiretroviral agents is indicated for the treatment of HIV-1 infection in treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in two controlled studies of ISENTRESS. These studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced 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 treatment-naïve adult patients or pediatric patients.

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 Immune Reconstitution Syndrome

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 evaluation and treatment.

5.2 Drug Interactions

Due to rifampin's potent induction of uridine diphosphate glucuronosyltransferase (UGT) 1A1, the recommended dosage of ISENTRESS is 800 mg twice daily during coadministration with rifampin. Caution should be used when coadministering ISENTRESS with other strong inducers of UGT1A1 due to reduced plasma concentrations of raltegravir [see Drug Interactions (7)].

6 ADVERSE REACTIONS

6.1 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.

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 adverse drug reactions (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 1.

Table 1: 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
ISENTRESS 400 mg Twice Daily + OBT

(n = 462)¡

 

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
*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).

¡n=total number of subjects per treatment group.

 

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

Adverse Events

Regardless of Drug Relationship

Cancers were reported in treatment-experienced subjects who initiated ISENTRESS with OBT; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ cell counts below 50 cells/mm3 and most had prior AIDS diagnoses). The cancers included Kaposi's sarcoma, lymphoma, squamous cell carcinoma, hepatocellular carcinoma and anal cancer. Most subjects had other risk factors for cancer including tobacco use, papillomavirus and active hepatitis B virus infection. It is unknown if these cancer diagnoses were related to ISENTRESS use.

Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS (see Table 3). 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.

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 2.

Table 2: 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)

 

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%
ULN = Upper limit of normal range
Patients with Co-existing Conditions

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

In the clinical studies, P018 and P019, subjects with chronic (but not acute) active hepatitis B and/or hepatitis C virus co-infection (N = 114/699 or 16%) were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). The rates of AST and ALT abnormalities were higher in the subgroup of subjects with hepatitis B and/or hepatitis C virus co-infection for both treatment groups. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to subjects without hepatitis B and/or hepatitis C virus co-infection. 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.

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.

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

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

7 DRUG INTERACTIONS

7.1 Effect of Raltegravir on the Pharmacokinetics of Other Agents

Raltegravir does not inhibit (IC50>100 µM) CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A in vitro. Moreover, in vitro, raltegravir did not induce 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 (IC50>50 µM) of the UDP-glucuronosyltransferases (UGT) tested (UGT1A1, UGT2B7), and raltegravir does not inhibit P-glycoprotein-mediated transport. Based on these data, ISENTRESS is not expected to affect the pharmacokinetics of drugs that are substrates of these enzymes or P-glycoprotein (e.g., protease inhibitors, NNRTIs, methadone, opioid analgesics, statins, azole antifungals, proton pump inhibitors and anti-erectile dysfunction agents).

In drug interaction studies, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: hormonal contraceptives, lamivudine, tenofovir, etravirine.

7.2 Effect of Other Agents on the Pharmacokinetics of Raltegravir

Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway.

Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS. Therefore, the dose of ISENTRESS should be increased during coadministration with rifampin [

Posted: February 2009

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