Merck's ISENTRESS (raltegravir) Tablets Studied in Comparison to Efavirenz in Combination Therapy Through 96 Weeks in HIV-1 Treatment-Naïve Patients
SAN FRANCISCO--(BUSINESS WIRE)--Sep 13, 2009 - ISENTRESS® , an integrase inhibitor from Merck & Co., Inc., was studied in comparison to efavirenz in maintaining viral load suppression to undetectable levels (less than 50 copies/mL) and at improving CD4 cell counts in previously untreated (treatment-naïve) HIV-1-infected patients through 96 weeks in a Phase III study called STARTMRK. In STARTMRK, ISENTRESS patients received either ISENTRESS or efavirenz in combination therapy. The data was presented today at the 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco, CA.
The U.S. Food and Drug Administration (FDA) recently approved an expanded indication for ISENTRESS on July 8, 2009, to include the treatment of adult patients starting HIV-1 therapy for the first time, as well as treatment-experienced adult patients, in combination with other antiretroviral (ARV) medicines. The expanded indication 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 [nonnucleoside reverse transcriptase inhibitor (NNRTI), nucleoside reverse transcriptase inhibitor (NRTI) and protease inhibitor (PI)] treatment-experienced adults. The third study was a 48-week analysis of the STARTMRK trial in treatment-naïve patients.
ISENTRESS is used in combination with other ARV medicines for the treatment of HIV-1 infection in adult patients. The safety and efficacy of ISENTRESS have not been established in pediatric patients. The use of other active agents with ISENTRESS is associated with a greater likelihood of treatment response.
“Results from the 96 week analysis of STARTMRK showed that ISENTRESS in combination therapy was as effective as efavirenz at suppressing HIV viral load and increasing immune system function,” said Edwin de Jesus, M.D., F.A.C.P., medical director of the Orlando Immunology Center in Orlando, Florida. "These results further confirm the findings from the 48 week analysis of this ongoing study.”
ISENTRESS studied through 96 weeks in 563 previously untreated adult patients
In this ongoing, multi-center, double-blind, randomized, active-controlled Phase III STARTMRK trial, 563 treatment-naïve adult patients received either 400 mg ISENTRESS administered orally twice daily in combination with tenofovir/emtricitabine or 600 mg efavirenz administered orally once daily in combination with the same agents. The primary endpoints were reductions in HIV-1 viral load to less than 50 copies/mL and an evaluation of safety and tolerability at Week 48. Secondary endpoints included ARV activity as measured by the proportion of patients achieving HIV viral load to less than 50 copies/mL, less than 400 copies/mL and change from baseline in CD4 count at Week 96, as well as tolerability and safety at Week 96.
Patients who entered the study were required to have HIV viral loads greater than 5,000 copies/mL. At baseline, geometric mean viral load levels for patients on the regimen including ISENTRESS was 103,205 copies/mL (n=281) and for the efavirenz regimen was 106,215 copies/mL (n=282). Mean baseline CD4 cell counts were 218.9 cells/mm3 and 217.4 cells/mm3 for the groups receiving ISENTRESS and efavirenz, respectively.
Viral load reductions and increase in CD4 cell counts maintained through 96 weeks
After 96 weeks of treatment, the ISENTRESS-based regimen suppressed HIV RNA levels below 50 copies/mL at a rate comparable to the regimen containing efavirenz (81 percent versus 79 percent, respectively); the treatment difference was two percent favoring ISENTRESS with an associated 95 percent confidence interval (CI) of (-4.3, 9.0). Results also showed that patients on the regimen containing ISENTRESS in combination therapy experienced a statistically similar yet numerically greater mean increase in CD4 cell count (240 cells/mm3) than those on the regimen containing efavirenz (225 cells/mm3). The treatment difference was 15 with an associated 95 percent CI of (-13, 42).
Impact on lipid levels and tolerability profile of ISENTRESS
At 96 weeks, ISENTRESS in combination therapy had less impact on lipid levels, including total, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels, as well as triglycerides than the regimen containing efavirenz in previously untreated adults:
|
Mean Changes from Baseline in Lipid Levels at Week 96
|
||||||
| ISENTRESS | Efavirenz | P-Value | ||||
| Total Cholesterol | 10 mg/dL | 38 mg/dL | <0.001 | |||
| LDL Cholesterol | 7 mg/dL | 21 mg/dL | <0.001 | |||
| HDL Cholesterol | 3 mg/dL | 10 mg/dL | <0.001 | |||
| Triglycerides | -4 mg/dL | 40 mg/dL | 0.001 | |||
| Total HDL Cholesterol Ratio | -0.18 mg/dL | -0.04 mg/dL | 0.192 | |||
Additionally, 47.0 percent of patients taking the regimen containing ISENTRESS experienced drug-related side effects versus 78.0 percent of patients receiving the efavirenz-based regimen; p-value <0.00.
In the study, the most commonly reported clinical adverse experiences (AEs) in the regimens containing ISENTRESS and efavirenz, respectively, were:
|
Clinical Adverse Experiences Occurring in ‰¥ 10
percent of patients; 95 percent CI
|
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|
ISENTRESS Group (n=281)
|
Efavirenz Group (n=282)
|
Raltegravir vs. Efavirenz Difference from
Efavirenz
|
||||||||||
| n | % | n | % | n | % | |||||||
| Patients with ‰¥ 1 AE | 266 | (94.7) | 275 | (97.5) | -2.86 | (-6.4, 0.4) | ||||||
| Eye Disorders | 13 | (4.6) | 29 | (10.3) | -5.66 | (-10.2, -1.4) | ||||||
| Gastrointestinal Disorders | 140 | (49.8) | 155 | (55.0) | -5.14 | (-13.3, 3.1) | ||||||
| General Disorders and Administration Site Conditions | 76 | (27.0) | 96 | (34.0) | -7.00 | (-14.6, 0.6) | ||||||
| Infections and Infestations | 197 | (70.1) | 204 | (72.3) | -2.23 | (-9.7, 5.3) | ||||||
| Injury, Poisoning and Procedural Complications | 39 | (13.9) | 36 | (12.8) | 1.11 | (-4.6, 6.8) | ||||||
| Metabolism and Nutrition Disorders | 25 | (8.9) | 34 | (12.1) | -3.16 | (-8.4, 2.0) | ||||||
| Musculoskeletal and Connective Tissue Disorders | 70 | (24.9) | 83 | (29.4) | -4.52 | (-11.9, 2.8) | ||||||
| Nervous System Disorders | 106 | (37.7) | 169 | (59.9) | -22.21 | (-30.1, -14.0) | ||||||
| Psychiatric Disorders | 81 | (28.8) | 105 | (37.2) | -8.41 | (-16.1, -0.6) | ||||||
| Reproductive and Breast Disorders | 17 | (6.0) | 29 | (10.3) | -4.23 | (-9.0, 0.3) | ||||||
| Respiratory, Thoracic and Mediastinal Disorders | 83 | (29.5) | 71 | (25.2) | 4.36 | (-3.0, 11.7) | ||||||
| Skin and Subcutaneous Disorders | 81 | (28.8) | 118 | (41.8) | -13.02 | (-20.8, -5.1) | ||||||
Additional posters on ISENTRESS presented at ICAAC
Three additional posters being presented at the ICAAC meeting described studies that evaluated the safety profile and efficacy of ISENTRESS in combination therapy. These posters include:
- Metabolic analysis and body composition changes from the 48-week findings in STARTMRK (Poster 329 )
- A review of the effect of ISENTRESS on the pharmacokinetics of methadone (Poster 1295)
- The lack of a clinically important effect of rifabutin on raltegravir pharmacokinetics (Poster 29)
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.
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.
In STARTMRK, the most commonly (greater than or equal to two percent in either treatment group) reported drug-related clinical AE of moderate or severe intensity in treatment-naïve patients receiving ISENTRESS and at a higher incidence compared to efavirenz was insomnia (four percent versus three percent).
In Phase III clinical trials of ISENTRESS, the most commonly (greater than or equal to two 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 three versus one, per 100- patient years), nausea (rate of two versus one, per 100- patient years), asthenia/weakness (rate of two versus one, per 100 patient years) and fatigue (rate of two versus one, per 100 patient years).
Dosing and administration
ISENTRESS is a single 400 mg tablet taken twice daily without regard to food. The dose of ISENTRESS should be increased during coadmistration with rifampin to 800 mg twice daily.
Drug interactions
Coadmistration with strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may reduce plasma concentrations of ISENTRESS. 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.
About ISENTRESS
ISENTRESS is the first medicine to be approved in a class of ARV drugs called integrase inhibitors. 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. Other HIV-1 drugs in use inhibit two other enzymes critical to the HIV-1 replication process – protease and reverse transcriptase – but ISENTRESS is the only approved drug that inhibits the integrase enzyme.
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.
Patient assistance programs in the U.S.
Merck recently launched a co-pay assistance program in the U.S. for eligible patients on ISENTRESS who are commercially insured and have co-pays or coinsurance above $30 up to a maximum of $400 per month. With this program, eligible patients can receive savings off their out-of-pocket costs for up to one year. Information about the co-pay assistance program can be obtained by calling 866-350-9232 or at www.isentress.com.
In addition, for eligible patients with HIV, Merck provides patient assistance to ensure access to ISENTRESS through a program called SUPPORT™. The SUPPORT Program helps patients who have been prescribed ISENTRESS by providing personalized support and patient advocacy regarding individual reimbursement issues. The Program can also provide patient assistance which may provide ISENTRESS free of charge to eligible patients. Information about the SUPPORT Program can be obtained by calling 1-800-850-3430 or at www.isentress.com.
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.
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
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.
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 |
Posted: September 2009
