Isentress (raltegravir), from Merck, was as Effective as Efavirenz at Suppressing HIV Viral Load and Increasing CD4 Cell Counts in Treatment-Naïve Patients up to 144 Weeks When Used in Combination Therapy

CAPE TOWN, South Africa--(BUSINESS WIRE)--Jul 20, 2009 - ISENTRESS® (raltegravir) tablets, an integrase inhibitor from Merck & Co., Inc., Whitehouse Station, N.J., U.S.A., was as effective as efavirenz at maintaining viral load suppression to undetectable levels (less than 50 copies/mL) and at improving CD4 counts in previously untreated (treatment-naïve) patients through 144 weeks in a Phase II study still underway. Both medicines were administered in combination with two other anti-HIV medicines, tenofovir and lamivudine. These results were presented today at the 5th International AIDS Society's (IAS) Conference on HIV Pathogenesis, Treatment & Prevention in Cape Town, South Africa.

“We are encouraged that these data demonstrate the efficacy and tolerability profile of ISENTRESS, with less effect on lipid levels, for up to 144 weeks,” said Martin Markowitz, M.D., study investigator and clinical director of the Aaron Diamond AIDS Research Center in New York. "It is important for patients at any stage of HIV to have treatment options like ISENTRESS that are effective and have a demonstrated tolerability profile in order to help them manage their disease."

On July 8, ISENTRESS was approved by the U.S. Food and Drug Administration (FDA) for use in treatment-naïve adult patients in combination with other antiretroviral (ARV) medicines for the treatment of HIV-1 infection. In markets outside the United States, where ISENTRESS is approved for treatment-experienced patients, the use of ISENTRESS in treatment-naïve patients is investigational. The expanded indication in the United States for ISENTRESS was based on analyses of plasma HIV-1 RNA levels through 48 weeks in three double-blind controlled studies. Two of these studies were conducted in clinically advanced, three-class antiretroviral (NNRT, 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. The safety and efficacy of ISENTRESS have not been established in pediatric patients.

In addition, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMEA) is expected to issue an opinion soon regarding an expanded marketing authorization of ISENTRESS in the European Union for patients starting HIV therapy for the first time, as well as all treatment-experienced patients, when used in combination with other antiretroviral medicines for the treatment of HIV-1 infection in adult patients.

ISENTRESS studied for 144 weeks in nearly 200 previously untreated adult patients

These 144-week findings are from an ongoing multi-center, dose-ranging, double-blind, randomized trial of previously untreated HIV-infected adult patients. In this study, 198 treatment-naïve, HIV-infected patients received either ISENTRESS administered orally twice daily in combination with tenofovir and lamivudine or 600 mg efavirenz dosed orally once daily in combination with the same agents. During the first 48 weeks of the study, patients were randomized to one of four dose regimens (100, 200, 400 and 600 mg twice daily). After 48 weeks, all groups receiving ISENTRESS received 400 mg dosed twice daily. The primary endpoints were reductions in HIV RNA to below 400 copies/mL and the evaluation of safety at 144 weeks. The evaluation of total cholesterol, LDL cholesterol and triglycerides were exploratory endpoints.

Viral load reductions and increase in CD4 cell counts maintained through 144 weeks

After 144 weeks of therapy, 78 percent of the 160 patients on the regimen containing ISENTRESS maintained HIV viral load suppression to below 50 copies/mL. Results were comparable for patients taking the efavirenz-based regimen, with 76 percent of the 38 patients maintaining suppression to below 50 copies/mL (95 percent CI). Eighty percent of patients receiving the regimen containing ISENTRESS maintained suppression in viral load to less than 400 copies/mL compared to 76 percent of patients taking the regimen containing efavirenz (95 percent CI). Patients on both treatment regimens experienced increases in CD4 cell counts. At 144 weeks of treatment, the mean increase in CD4 cell counts from baseline was 252 cells/mm3 for patients receiving the regimen containing ISENTRESS and 233 cells/mm3 for patients receiving the regimen containing efavirenz.

Tolerability profile and effect on lipid levels

At 144 weeks, cumulative rates of drug-related clinical adverse experiences (AEs) were less frequent in the regimen containing ISENTRESS versus the regimen containing efavirenz (54 percent vs. 76 percent, respectively). ISENTRESS had less effect on total or LDL cholesterol, or triglycerides:

Lipid Level Mean Changes from Baseline at Week 144

 

    ISENTRESS   Efavirenz   P Value
    Baseline mean

 

  Mean change

 

  Baseline mean

 

  Mean change

 

   
Total Cholesterol   166.2   +6.8   171.7   +33.5   P<0.001
LDL-Cholesterol   103.8   -1.9   110.4   +10.5   P=0.015
HDL-Cholesterol   38.0   +6.6   37.9   +11.7   P=0.007
Triglycerides   135.4   +1.1   131.2   +55.8   P=0.118
Total: HDL Ratio   4.6   -0.5   4.6   -0.4   P=0.451

In the study, the most commonly reported AEs in the regimens containing ISENTRESS and efavirenz, respectively, were diarrhea (6.9 vs. 10.5 percent), nausea (12.5 vs. 10.5 percent), dizziness (8.8 vs. 26.3 percent), headache (8.8 vs. 23.7 percent), abnormal dreams (6.3 vs. 18.4 percent), insomnia (8.1 vs. 10.5 percent) and nightmares (0.0 vs. 10.5 percent).

About ISENTRESS

ISENTRESS is a first-in-class integrase inhibitor. ISENTRESS works by inhibiting the insertion of HIV-1 DNA into human DNA by the integrase enzyme and has demonstrated rapid antiviral activity. 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.

ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. ISENTRESS does not require boosting with ritonavir.

ISENTRESS is now approved in more than 80 countries worldwide for treatment-experienced adult patients. Merck is continuing to move forward with filings in additional countries around the world for use of ISENTRESS in both treatment-experienced and treatment-naïve patients.

Important safety information about ISENTRESS

ISENTRESS does not cure HIV or AIDS and does not prevent passing HIV to others. Healthcare providers should know that immune reconstitution syndrome has been reported in patients treated with antiretroviral therapy, which may necessitate further evaluation and treatment.

The most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical adverse experience (AE) of moderate or severe intensity in treatment-naïve patients receiving ISENTRESS and at a higher incidence compared to efavirenz was insomnia (4 percent vs. 3 percent). The most commonly (greater than or equal to 2 percent in either treatment group) reported drug-related clinical AEs of moderate or severe intensity in treatment-experienced patients receiving ISENTRESS and at a higher rate compared to placebo were headache (rate of 3 vs. 1, per 100 patient years), nausea (rate of 2 vs. 1, per 100 patient years), asthenia/weakness (rate of 2 vs. 1, per 100 patient years) and fatigue (rate of 2 vs. 1, per 100 patient years).

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 rhabdomyolysuis, such as patients receiving concomitant medication known to cause these conditions.

Drug interactions

Based on the results of drug interaction studies and the clinical trials data, no dose adjustment of ISENTRESS is required when coadministered with other ARV agents. Also, preclinical studies show that ISENTRESS is not metabolized by cytochrome P450 enzymes. The dose of ISENTRESS should be increased during coadministration with rifampin, a strong uridine diphosphate glucuronosyltransferase (UGT) 1A1, due to reduced plasma concentrations of ISENTRESS.

Merck's commitment to providing access to treatment

For more than 20 years, Merck has been at the forefront of the global response to the HIV and AIDS pandemic through a three-pronged approach that includes working to discover, develop, and deliver breakthrough medicines; improving access to our antiretroviral medicines; and participating in partnerships that help build infrastructure and address health and development challenges, particularly in the developing world.

Since 2001, Merck has implemented a differential pricing policy that provides our ARVs at the lowest possible price at which Merck makes no profit in public sectors in the poorest countries and those hardest hit by the HIV and AIDS pandemic. Merck also provides its ARVs at significantly reduced prices in middle income countries.

About HIV and AIDS

According to the Centers for Disease Control and Prevention (CDC), in 2006 there were more than one million Americans living with HIV and AIDS. In the same year, an estimated 56,000 new cases were diagnosed in the United States.

In South Africa, there are an estimated 5.7 million adults and children living with HIV and AIDS. Furthermore, an estimated 350,000 South African adults and children died of AIDS in 2007.

An estimated 33 million people are living with HIV and AIDS worldwide, and about 2.7 million new infections occurred worldwide in 2007. AIDS is one of the top causes of infectious disease-related mortality worldwide, responsible for approximately two million deaths in 2007 alone.

About Merck & Co., Inc., Whitehouse Station, NJ, USA

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, 2008, 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.

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

ISENTRESS® is a registered trademark of Merck & Co., Inc. Whitehouse Station, NJ USA.

Patient Information ISENTRESS® (eye sen tris) (raltegravir) Tablets

Read the patient information that comes with ISENTRESS1 before you start taking it and each time you get a refill. There may be new information. This leaflet is a summary of the information for patients. Your doctor or pharmacist can give you additional information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.

What is ISENTRESS?

 

  • ISENTRESS is an anti-HIV (antiretroviral) medicine used for the treatment of HIV. The term HIV stands for Human Immunodeficiency Virus. It is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). ISENTRESS is used along with other anti-HIV medicines. ISENTRESS will NOT cure HIV infection.  
  • People taking ISENTRESS may still develop infections, including opportunistic infections or other conditions that happen with HIV infection.  
  • Stay under the care of your doctor during treatment with ISENTRESS.  
  • The safety and effectiveness of ISENTRESS in children has not been studied.  

ISENTRESS must be used with other anti-HIV medicines.

How does ISENTRESS work?

 

  • ISENTRESS blocks an enzyme which the virus (HIV) needs in order to make more virus. The enzyme that ISENTRESS blocks is called HIV integrase.  
  • When used with other anti-HIV medicines, ISENTRESS may do two things:  

1. Reduce the amount of HIV in your blood. This is called your "viral load".

2. Increase the number of white blood cells called CD4 (T) cells.

 

  • ISENTRESS may not have these effects in all patients.  

Does ISENTRESS lower the chance of passing HIV to other people?

No. ISENTRESS does not reduce the chance of passing HIV to others through sexual contact, sharing needles, or being exposed to your blood.

 

  • Continue to practice safer sex.  
  • Use latex or polyurethane condoms or other barrier methods to lower the chance of sexual contact with any body fluids. This includes semen from a man, vaginal secretions from a woman, or blood.  
  • Never re-use or share needles.  

Ask your doctor if you have any questions about safer sex or how to prevent passing HIV to other people.

What should I tell my doctor before and during treatment with ISENTRESS?

Tell your doctor about all of your medical conditions. Include any of the following that applies to you:

 

  • You have any allergies.  
  • You are pregnant or plan to become pregnant.  

- ISENTRESS is not recommended for use during pregnancy. ISENTRESS has not been studied in pregnant women. If you take ISENTRESS while you are pregnant, talk to your doctor about how you can be included in the Antiretroviral Pregnancy Registry.

 

  • You are breast-feeding or plan to breast-feed.  

- It is recommended that HIV-infected women should not breast-feed their infants. This is because their babies could be infected with HIV through their breast milk.

- Talk with your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take. Include the following:

 

  • prescription medicines, including rifampin (a medicine used to treat some infections such as tuberculosis)  
  • non-prescription medicines  
  • vitamins  
  • herbal supplements  

Know the medicines you take.

 

  • Keep a list of your medicines. Show the list to your doctor and pharmacist when you get a new medicine.  

How should I take ISENTRESS?

Take ISENTRESS exactly as your doctor has prescribed. The recommended dose is as follows:

 

  • Take only one 400-mg tablet at a time.  
  • Take it twice a day.  
  • Take it by mouth.  
  • Take it with or without food.  

Do not change your dose or stop taking ISENTRESS or your other anti-HIV medicines without first talking with your doctor.

IMPORTANT: Take ISENTRESS exactly as your doctor prescribed and at the right times of day because if you don't:

 

  • The amount of virus (HIV) in your blood may increase if the medicine is stopped for even a short period of time.  
  • The virus may develop resistance to ISENTRESS and become harder to treat.  
  • Your medicines may stop working to fight HIV.  
  • The activity of ISENTRESS may be reduced (due to resistance).  

If you fail to take ISENTRESS the way you should, here's what to do:

 

  • If you miss a dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do NOT take two tablets of ISENTRESS at the same time. In other words, do NOT take a double dose.  
  • If you take too much ISENTRESS, call your doctor or local Poison Control Center.  

Be sure to keep a supply of your anti-HIV medicines.

 

  • When your ISENTRESS supply starts to run low, get more from your doctor or pharmacy.  
  • Do not wait until your medicine runs out to get more.  

What are the possible side effects of ISENTRESS?

When ISENTRESS has been given with other anti-HIV drugs, the most common side effects included:

 

  • nausea  
  • headache  
  • tiredness  
  • weakness  
  • trouble sleeping  

Other side effects include rash, severe skin reactions, feeling anxious, depression, suicidal thoughts and actions, paranoia.

A condition called Immune Reconstitution Syndrome can happen in some patients with advanced HIV infection (AIDS) when combination antiretroviral treatment is started. Signs and symptoms of inflammation from opportunistic infections that a person has or had may occur as the medicines work to treat the HIV infection and help to strengthen the immune system. Call your doctor right away if you notice any signs or symptoms of an infection after starting ISENTRESS with other anti-HIV medicines.

Contact your doctor promptly if you experience unexplained muscle pain, tenderness, or weakness while taking ISENTRESS. This is because on rare occasions, muscle problems can be serious and can lead to kidney damage.

Tell your doctor if you have any side effects that bother you.

These are not all the side effects of ISENTRESS. For more information, ask your doctor or pharmacist.

How should I store ISENTRESS?

 

  • Store ISENTRESS at room temperature (68 to 77°F).  
  • Keep ISENTRESS and all medicines out of the reach of children.  

General information about the use of ISENTRESS

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets.

 

  • Do not use ISENTRESS for a condition for which it was not prescribed.  
  • Do not give ISENTRESS to other people, even if they have the same symptoms you have. It may harm them.  

This leaflet gives you the most important information about ISENTRESS.

 

  • If you would like to know more, talk with your doctor.  
  • You can ask your doctor or pharmacist for additional information about ISENTRESS that is written for health professionals.  
  • For more information go to www.ISENTRESS.com or call 1-800-622-4477.  

What are the ingredients in ISENTRESS?

Active ingredient: Each film-coated tablet contains 400 mg of raltegravir.

Inactive ingredients: Microcrystalline cellulose, lactose monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 (contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide.

Manufactured and Distributed by:

MERCK & CO., Inc.

Whitehouse Station, NJ 08889, USA

Revised July 2009

9795104

U.S. Patent Nos. US 7,169,780

1 Registered trademark of MERCK & CO., Inc. COPYRIGHT © 2007, 2009 MERCK & CO., Inc. All rights reserved

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)   07/2009
Dosage And Administration (2)   01/2009
Warnings And Precautions (5.2) - removal   07/2009

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 adult patients (1).  

The safety and efficacy of ISENTRESS have not been established in 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 (4)

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 rate than the comparator are insomnia, 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.

DRUG INTERACTIONS

 

  • Coadministration of ISENTRESS with drugs that are strong inducers of UGT1A1 may result in reduced plasma concentrations of raltegravir (7.2).  

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: 07/2009

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
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 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.

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.

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-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.

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
  ISENTRESS 400 mg Twice Daily +

Emtricitabine (+) Tenofovir

(n = 281)¡

%

 

  Efavirenz 600 mg At Bedtime +

Emtricitabine (+) Tenofovir

(n = 282)¡

%

 

Psychiatric Disorders
Insomnia   4   3
*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).

¡n = total number of subjects per treatment group

 

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.

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)

 

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

Posted: July 2009

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