Twice Daily Doses Re-evaluated
Compiled by Badpuppy's GayToday
From Merck & Co. Reports
Merck & Co., Inc. announced Friday that it has discontinued the evaluation of twice- daily dosing regimens of its HIV protease inhibitor, Crixivan(R) (indinavir sulfate), in combination with reverse transcriptase inhibitors (RTIs).
Merck recommends that patients in the twice-daily dosing arms in these studies be changed to a regimen with the approved dosing (800 mg every eight hours) of Crixivan to ensure that they receive optimal therapy. Merck will continue to study twice-daily dosing of Crixivan in combination trials with other protease inhibitors.
The Company had initiated two studies to compare the antiviral efficacy and tolerability of the approved 800 mg three-times daily dosing with twice- daily dosing (1,200 mg every 12 hours) of Crixivan. The first study compared Crixivan twice-daily versus Crixivan three-times daily, each in combination with the RTIs AZT(a) and 3TC(b), in patients starting antiretroviral therapy. The second, a transition study, evaluated the two dosing regimens (Crixivan twice-daily with RTIs and three-times daily with RTIs) among patients who had already achieved levels of virus below detection after six months on therapy with the approved three-times daily dosing of Crixivan with RTIs.
The decision is based on data from an interim analysis of the initial therapy study at week 24 that showed that the three-times daily regimen was more effective than the twice-daily regimen in reducing levels of viral RNA to below detection (less than 400 copies/mL) in patients initiating therapy. At week 24, 91 percent of patients on the approved dosing regimen had achieved viral levels below 400 copies/mL, compared to 64 percent of patients on the twice-daily regimen. "Although the initial therapy study provided us with additional evidence of the potent antiviral effect of Crixivan dosed every eight hours in combination with AZT and 3TC," explained Bach-Yen Nguyen, M.D., director, Clinical Research, Merck Research Laboratories, "the difference in efficacy between the two treatment arms over time indicates that the approved dosing regimen and the twice-daily dosing regimen are unlikely to reach equivalence."
Crixivan in combination with other antiretroviral agents is indicated for the treatment of HIV infection. Crixivan can help reduce the chance of illnesses and death associated with HIV as demonstrated in clinical trials of approximately one year. Patients currently on treatment with Crixivan should continue to take their medication as prescribed by their physicians. Physicians treating patients with Crixivan should consult the prescribing information.
Other Studies with Twice-Daily Crixivan Continue
Other studies now under way by Merck to evaluate the antiviral activity of twice-daily dosing of Crixivan combined with other protease inhibitors dosed twice-daily, such as nelfinavir and ritonavir, are continuing.
Potent Antiviral Effect Seen with Approved Dosing of Crixivan
The Merck studies were part of the Company's commitment to evaluate further the twice-daily dosing regimen in larger numbers of patients in an attempt to confirm encouraging antiviral results seen in a twice-daily dosing pilot study. Like the earlier pilot study, the larger twice-daily initial therapy study evaluated patients who had not received prior treatment with a protease inhibitor or 3TC. This study enrolled 635 patients. The transition study with 283 patients was designed to evaluate the two dosing regimens among patients who had achieved viral levels below the level of detection (<400 copies/mL) after six months on triple therapy with approved dosing (800 mg every eight hours) of Crixivan.
Analysis -- Initial Therapy Study
Efficacy results from the preliminary intent-to-treat analysis of the initial therapy study were based on a total of 287 patients. At week 16, 78 percent of patients on the approved dosing regimen compared to 72 percent on the twice-daily regimen had viral load levels below 400 copies/mL. Among the 87 patients who had been followed in the study through 24 weeks, 91 percent of the group on the approved dosing regimen had viral load levels below 400 copies/mL, compared to 64 percent of the patients on the twice-daily arm.
Patients enrolling in the study had CD4 counts greater than 100 cells/mm3 and viral RNA levels greater than 10,000 copies/mL. The study started in November 1997 and was being conducted at 49 sites around the world.
Discontinuation rates were low and similar for both groups in the initial treatment study, although there was a trend toward more discontinuations due to nausea and vomiting in the twice-daily group compared to the approved- dosing group.
Important Cautionary Information About Crixivan
There are some common and AIDS-related medications that should not be taken with Crixivan. Crixivan should not be administered concurrently with terfenadine, cisapride, astemiozole, triazolam, midazolam or ergot derivatives.
Crixivan can be taken with a light meal or on an empty stomach. Crixivan is generally well-tolerated. There are side effects associated with protease inhibitors in general and Crixivan in particular. Some patients treated with Crixivan may develop kidney stones. For some, this can lead to more severe kidney problems including kidney failure. Drinking at least six glasses of water (1.5 L) each day may help reduce the chance of forming a kidney stone.
Other side effects reported include rapid breakdown of red blood cells and liver problems. As with other protease inhibitors, increased bleeding in some patients with hemophilia and increased blood sugar levels or diabetes have been reported.
More than 170,000 people with HIV/AIDS around the world are on treatment with Crixivan today, and it is now approved in more than 80 countries. Crixivan is the most widely prescribed protease inhibitor in the world.
Information about Crixivan is available on Merck's website, www.crixivan.com.
Merck & Co., Inc., is a global research-driven pharmaceutical company that discovers, develops, manufactures and markets a broad range of human and animal health products, directly and through its joint ventures, and provides pharmaceutical benefit services through Merck-Medco Managed Care.
The patient prescribing information for Crixivan is attached. Full prescribing information is available by calling 1-800-753-0352, ext. 706.
Crixivan(R) is the Merck registered trademark for indinavir sulfate.
(a) Zidovudine (Retrovir(R) or AZT), Glaxo Wellcome
(b) Lamivudine (Epivir(R) or 3TC), Glaxo Wellcome
CRIXIVAN(R)* (indinavir sulfate) Capsules
Patient Information about
for HIV (Human Immunodeficiency Virus) Infection
Generic name: indinavir (in-DIH-nuh-veer) sulfate
Please read this information before you start taking CRIXIVAN. Also, read the leaflet each time you renew your prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss CRIXIVAN when you start taking your medication and at regular checkups. You should remain under a doctor's care when using CRIXIVAN and should not change or stop treatment without first talking with your doctor.
What is CRIXIVAN?
CRIXIVAN is an oral capsule used for the treatment of HIV (Human Immunodeficiency Virus). HIV is the virus that causes AIDS (acquired immune deficiency syndrome). CRIXIVAN is a type of HIV drug called a protease (PRO-tee-ase) inhibitor.
How does CRIXIVAN work?
CRIXIVAN is a protease inhibitor that fights HIV. CRIXIVAN can help reduce your chances of getting illnesses associated with HIV. CRIXIVAN can also help lower the amount of HIV in your body (called "viral load") and raise your CD4 (T) cell count. CRIXIVAN may not have these effects in all patients.
CRIXIVAN is usually prescribed with other anti-HIV drugs such as ZDV (also called AZT), 3TC, ddI, ddC, or d4T. CRIXIVAN works differently from these other anti-HIV drugs. Talk with your doctor about how you should take CRIXIVAN.
CRIXIVAN has been studied in adults. The safety and effectiveness of CRIXIVAN in children and adolescents have not been established.
How should I take CRIXIVAN?
There are six important things you must do to help you benefit from CRIXIVAN:
Examples of light meals include:
Dry toast with jelly, juice, and coffee (with skim or non-fat milk and sugar if you want) cornflakes with skim or non-fat milk and sugar
Do not take CRIXIVAN at the same time as any meals that are high in calories, fat, and protein (for example -- a bacon and egg breakfast). When taken at the same time as CRIXIVAN, these foods can interfere with CRIXIVAN being absorbed into your bloodstream and may lessen its effect.
6. It is critical that you drink at least six 8-ounce glasses of liquids (preferably water) throughout the day, every day. CRIXIVAN can cause kidney stones. Having enough fluids in your body should help reduce the chances of forming a kidney stone. Call your doctor or other health care provider if you develop kidney pains (middle to lower stomach or back pain) or blood in the urine.
Does CRIXIVAN cure HIV or AIDS?
CRIXIVAN is not a cure for HIV or AIDS. People taking CRIXIVAN may still develop infections or other conditions associated with HIV. Because of this, it is very important for you to remain under the care of a doctor. Although CRIXIVAN is not a cure for HIV or AIDS, CRIXIVAN can help reduce your chances of getting illnesses, including death, associated with HIV. CRIXIVAN may not have these effects in all patients.
Does CRIXIVAN reduce the risk of passing HIV to others?
CRIXIVAN has not been shown to reduce the risk of passing HIV to others through sexual contact or blood contamination.
Who should not take CRIXIVAN?
Do not take CRIXIVAN if you have had a serious allergic reaction to CRIXIVAN or any of its components.
What other medical problems or conditions should I discuss with my doctor?
Talk to your doctor if:
Also talk to your doctor if you have:
Tell your doctor about any medicines you are taking or plan to take, including non-prescription medicines.
Can CRIXIVAN be taken with other medications?
Drugs you should not take with CRIXIVAN: **
Ergot medications (e.g., Wigraine(R) and Cafergot(R)
Taking CRIXIVAN with the above medications could result in serious or life-threatening problems (such as irregular heartbeat or excessive sleepiness).
In addition, you should not take CRIXIVAN with rifampin, known as RIFADIN(R), RIFAMATE(R), RIFATER(R), or RIMACTANE(R).
Drugs you can take with CRIXIVAN include:
RETROVIR(R) EPIVIR(TM) (zidovudine, ZDV (lamivudine, 3TC) also called AZT)
ZERIT(R) isoniazid (stavudine, d4T) (INH)
ORTHO-NOVUM 1/35(R) (oral contraceptive)
VIDEX(R) (didanosine, ddI) -- If you take CRIXIVAN with VIDEX(R), take them at least one hour apart.
MYCOBUTIN(R) (rifabutin) -- If you take CRIXIVAN with MYCOBUTIN(R), your doctor may adjust both the dose of MYCOBUTIN and the dose of CRIXIVAN.
NIZORAL(R) (ketoconazole) -- If you take CRIXIVAN with NIZORAL(R), your doctor may adjust the dose of CRIXIVAN.
Talk to your doctor about any medications you are taking.
What are the possible side effects of CRIXIVAN?
Like all prescription drugs, CRIXIVAN can cause side effects. The following is not a complete list of side effects reported with CRIXIVAN when taken either alone or with other anti-HIV drugs. Do not rely on this leaflet alone for information about side effects. Your doctor can discuss with you a more complete list of side effects.
Some patients treated with CRIXIVAN developed kidney stones. In some of these patients this led to more severe kidney problems, including kidney failure or inflammation of the kidneys. Drinking at least six 8-ounce glasses of liquid (preferably water) each day should help reduce the chances of forming a kidney stone. Call your doctor or other health care provider if you develop kidney pains (middle to lower stomach or back pain) or blood in the urine.
Some patients treated with CRIXIVAN have had rapid breakdown of red blood cells (hemolytic anemia) which in some cases was severe or resulted in death.
Some patients treated with CRIXIVAN have had liver problems including liver failure and death. Some patients had other illnesses or were taking other drugs. It is uncertain if CRIXIVAN caused these liver problems.
Diabetes and high blood sugar (hyperglycemia) have occurred in patients taking protease inhibitors. In some of these patients, this led to ketoacidosis, a serious condition caused by poorly controlled blood sugar. Some patients had diabetes before starting protease inhibitors, others did not. Some patients required adjustments to their diabetes medication. Others needed new diabetes medication.
In some patients with hemophilia, increased bleeding has been reported.
Increases in bilirubin (one laboratory test of liver function) have been reported in approximately 10% of patients. Usually, this finding has not been associated with liver problems. However, on rare occasions, a person may develop yellowing of the skin and/or eyes.
Side effects occurring in 2% or more of patients included: abdominal pain, fatigue or weakness, flank pain, feeling unwell, nausea, diarrhea, vomiting, acid regurgitation, loss of appetite, dry mouth, back pain, headache, trouble sleeping, dizziness, taste changes, rash, upper respiratory infection, dry skin, and sore throat.
Swollen kidneys due to blocked urine flow occurred rarely.
Other side effects reported since CRIXIVAN has been marketed include: abdominal swelling; inflammation of the kidneys; increased fat appearing in areas such as the neck, abdomen, and back; change in skin color; severe skin reactions; hair loss; crystals in the urine; and allergic reactions.
Tell your doctor promptly about these or any other unusual symptoms. If the condition persists or worsens, seek medical attention.
How should I store CRIXIVAN capsules?
This medication was prescribed for your particular condition. Do not use it for any other condition or give it to anybody else. Keep CRIXIVAN and all medicines out of the reach of children. If you suspect that more than the prescribed dose of this medicine has been taken, contact your local poison control center or emergency room immediately.
This leaflet provides a summary of information about CRIXIVAN. If you have any questions or concerns about either CRIXIVAN or HIV, talk to your doctor.
** The brands listed are the registered trademarks of their respective owners and are not trademarks of Merck & Co., Inc.