U.S. Food and Drug Administration
FDA Consumer magazine
January-February 2001
Table of Contents
Glaxo Wellcome of Research Triangle Park, N.C., recently informed the Food and Drug Administration that it will voluntarily withdraw Lotronex (alosetron hydrochloride) tablets from the market. Lotronex is a prescription medication approved to treat irritable bowel syndrome in women. FDA is advising patients taking Lotronex to contact their health-care providers to discuss treatment alternatives.
FDA analyzed postmarketing reports of serious adverse events, which included five reports of death, in patients taking Lotronex. Specifically, FDA has been concerned about reported cases of intestinal damage resulting from reduced blood flow to the intestine (ischemic colitis) and severely obstructed or ruptured bowels (complications of severe constipation).
As of Nov. 10, 2000, FDA had received and reviewed 70 cases of serious postmarketing adverse events, including 49 cases of ischemic colitis and 21 cases of severe constipation. Of the 70 cases, 34 resulted in hospitalization without surgery, 10 resulted in surgical procedures, and three resulted in death. FDA received two additional reports of death, but the association with the use of Lotronex remained uncertain.
Prior to approval of the drug on Feb. 9, 2000, four cases of ischemic colitis were observed in clinical studies and were discussed at a November 1999 meeting of FDA's Gastrointestinal Drugs Advisory Committee. These symptoms were transient, mild-to-moderate in nature, and reversible upon discontinuation of the drug.
Between approval and June 1, 2000, FDA received seven postmarketing reports of serious complications of constipation. This resulted in the hospitalization of six patients, three of whom required surgery. During the same time period, FDA received eight postmarketing reports of ischemic colitis. This resulted in four hospitalizations, four endoscopic procedures, and no surgeries.
Risk management options in response to the serious adverse event reports were discussed at a public advisory committee meeting convened by FDA on June 27, 2000. No deaths were reported up to that date. Following the meeting, FDA updated the health-care professional labeling for Lotronex and required Glaxo Wellcome to distribute a Medication Guide that warned patients directly about risks associated with the drug. At the request of FDA, Glaxo Wellcome also issued letters to health-care professionals and pharmacists about the drug's risks.
FDA continued to receive severe adverse event reports of ischemic colitis and complications of constipation associated with Lotronex. In addition, FDA received reports of death and more serious complications of ischemic colitis requiring a blood transfusion or surgery.
Glaxo Wellcome's action to voluntarily withdraw Lotronex followed a meeting on Nov. 28, 2000, where the company and FDA discussed risk management options that included restricting the distribution of the drug and marketing withdrawal.
The first anti-cancer drug to be proven effective in treating patients with advanced or chronic multiple sclerosis (MS) was approved for this new use by the Food and Drug Administration in October. Novantrone (mitoxantrone hydrochloride), which is administered intravenously by a doctor, reduces the frequency of flare-ups and helps keep mobility in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS. These are all forms of MS in which patients become significantly worse between relapses and over time. The drug is not, however, approved for treating primary progressive MS, one form in which the patient's neurologic condition deteriorates over time without specific relapses.
MS is a highly debilitating autoimmune disease that attacks the nervous system and can cause weakness, impaired vision, loss of balance, and poor muscle coordination. The disease can have different patterns, sometimes leaving patients relatively well after episodes of acute worsening, and other times leading to progressive disability that persists after episodes of worsening. In the worst cases, MS can lead to paralysis. According to the Multiple Sclerosis Foundation, more than 300,000 Americans are diagnosed with MS today.
FDA cautions that some patients treated with Novantrone may develop serious heart problems. The risk of congestive heart failure increases with the cumulative dose, and patients with MS should ordinarily not receive more than eight to 12 doses administered over two to three years. FDA advises having the heart and blood tested regularly to help avoid serious side effects. Less severe side effects include nausea, hair thinning, loss of menstrual periods, bladder infections, and mouth sores.
Novantrone is manufactured for Immunex Corporation, of Seattle, by Lederle Labs.
A new arsenic-based drug may benefit some leukemia patients for whom standard therapy has failed. The Food and Drug Administration approved Trisenox (arsenic trioxide) to treat patients with acute promyelocytic leukemia (APL) who have not responded to, or have relapsed after the use of, trans-retinoic acid and anthracyline-based chemotherapy, which is considered the first-line therapy. Trisenox was approved for marketing only three years after the study of the drug first started in the United States-the fastest development of any cancer therapy.
APL is a cancer in which abnormal white blood cells in bone marrow and blood accumulate quickly, resulting in anemia (a reduction in red blood cells), susceptibility to infections, and bleeding. About 1,500 new cases of APL are diagnosed each year and an estimated 400 of those patients will not respond to or will relapse from first-line therapy.
Trisenox offers a new alternative. Arsenic trioxide changes immature cancerous white blood cells into normal white blood cells. The result can be a sudden increase in the white blood cell count. In a multi-center clinical study of 40 patients who received arsenic trioxide infusions, 28 patients (70 percent) had a remission of their leukemia.
In some cases, the increase in the white blood cell count is accompanied by the "APL differentiation syndrome," a potentially fatal condition characterized by inflammation and fluid accumulation, particularly in the lining of the heart and lungs. The usual treatment is to temporarily stop the leukemia therapy and treat with high-dose steroids. This syndrome appeared in eight of the 40 patients (20 percent), but no cases were severe enough to require interrupting the arsenic trioxide therapy.
Trisenox can also cause changes in the heart's function, revealed by an increase in what is termed the Q-T interval, a part of the measurement on an electrocardiogram. This condition can sometimes lead to irregular heart rhythms that can be fatal. Significant increases of the QT interval appeared in 16 of the 40 patients (40 percent). No serious abnormal rhythm developed in those patients, but the risk of the effect required close monitoring of the patients and their electrocardiograms.
Other adverse effects of Trisenox are abdominal discomfort, nausea, vomiting, headache, fatigue, skin changes, and fluid accumulation. Most of the adverse effects were considered mild and resolved after therapy was completed.
Interest in arsenic-based therapy--used more than 100 years ago in the United States to treat leukemia and infections before being replaced by modern chemotherapy and antibiotics--has resurfaced due to reports of anti-leukemic activity of traditional Chinese preparations containing arsenic trioxide.
Cell Therapeutics, Inc., of Seattle will market the drug.
Serious Product Problem? Report ItHealth professionals can report serious adverse reactions or other product problems to FDA's MedWatch program by:
FDA encourages consumers to report through their doctors, but if they prefer, they may submit the MedWatch form themselves. |
In September, the Food and Drug Administration gave accelerated approval for a new treatment that combines two drugs to fight human immunodeficiency virus (HIV) infection. Called Kaletra, the new therapy relies on the antiviral properties of lopinavir, a drug that inhibits a critical HIV enzyme called protease, combined with a low dose of ritonavir, a drug that slows down the rate at which the body metabolizes lopinavir. This results in blood levels of lopinavir that enhance its effectiveness against HIV.
FDA approved Kaletra for adults and children older than six months. It is used with other anti-HIV drugs and should be taken with food to increase absorption into the blood stream. Kaletra was studied in six controlled clinical trials and one expanded access trial. Side effects include diarrhea, fatigue, headache, and nausea. The drug also increases blood lipid levels (cholesterol and triglycerides), which may require treatment for some patients. People with high levels of triglycerides in the blood can be at risk for pancreatitis. Infrequent cases of pancreatitis have been observed among patients receiving antiretroviral regimens that included Kaletra.
Like other protease inhibitors, Kaletra may be associated with other significant or serious adverse events, including increases in blood glucose, redistribution of body fat, and potentially serious or life-threatening drug interactions. To prevent such drug interactions and potential loss of drug effectiveness, health-care providers and patients should find out about drugs that should not be used with Kaletra and other antiretrovirals.
Abbott Laboratories in North Chicago, Ill., manufactures Kaletra.
A large international study has shown that a drug approved nearly 10 years ago to treat high blood pressure can also reduce the risk of heart attacks, strokes, and even death. Because of the new findings, the Food and Drug Administration gave the manufacturer approval in October to market the drug--ramipril--for these new uses.
The Heart Outcomes Prevention Evaluation (HOPE) study took place in 19 countries in North and South America and Europe. Of the more than 9,000 patients enrolled in the study, approximately 4,600 received ramipril and the rest a placebo.
Patients in the study were 55 years or older and were considered at high risk for cardiovascular events because they had a history of coronary artery disease, stroke, or peripheral vascular disease. In addition, diabetic patients were eligible to participate if they had at least one other risk factor for heart disease, such as hypertension, high total cholesterol, or cigarette smoking.
The study participants treated with ramipril showed a 22 percent reduction, compared with placebo, in the risk of heart attack, stroke, or death from cardiovascular or other causes over a five-year follow-up period. Complications related to diabetes also decreased substantially among the patients who took ramipril. "These results indicate that if ramipril is used widely in appropriate patients, over one million premature deaths, heart attacks and strokes would be prevented each year [worldwide]," says Salim Yusuf, MD, HOPE study chairman and professor of medicine at McMaster University, Hamilton, Ontario. The results of the HOPE study were published in the New England Journal of Medicine, January 20, 2000, and can be found on the journal's Web site at www.nejm.org.
Another arm of the HOPE study, continuing for several more years, is examining the effects of vitamin E versus placebo on heart disease and cancer.
Side effects of ramipril include headaches, dizziness, fatigue and dry cough. As with all angiotensin-converting enzyme (ACE) inhibitors, the drug should not be taken by pregnant women.
Ramipril is manufactured under the brand name Altace by Aventis Pharmaceuticals, Kansas City, Mo., and distributed by Monarch Pharmaceuticals, Bristol, Tenn., a wholly owned subsidiary of King Pharmaceuticals, Inc.
Women now have one more way to prevent pregnancy. In October, the Food and Drug Administration approved Lunelle, a once-a-month injection that combines the hormones progestin and estrogen to inhibit ovulation. The injection contains medoxyprogesterone acetate and estradiol cypionate as its active ingredients.
The intramuscular injections are given by a health-care provider every 28 to 30 days, and no longer than 33 days apart. To ensure that Lunelle is not accidentally given to a pregnant woman, the first injection should be given during the first five days of the menstrual period. The effects of Lunelle are reversible, and women can begin ovulating again two to four months after discontinuing the injections.
Several clinical trials of Lunelle's safety and effectiveness have reported failure rates of less than 1 percent. Most women experience changes in their menstrual cycle. In the U.S. trial, weight gain was the most common adverse event leading to discontinuation of Lunelle. Out of 782 women using Lunelle for up to 15 cycles, nearly 6 percent of participants stopped using the drug because of weight gain.
Doctors and consumers should be aware that there are some groups of women who should not use Lunelle, including women known or suspected to be pregnant, heavy smokers (more than 15 cigarettes per day) who are over the age of 35, and women with severe hypertension.
Pharmacia Corporation in Peapack, N.J., manufactures Lunelle.
"Take 1 tsp. 3 times a day."
A parent reads these familiar dosage directions on her child's prescription medicine. She reaches into her kitchen silverware drawer and selects a small spoon, then carefully pours the liquid and gives the tot the correct dose. Right?
Probably not. Almost three-quarters of caregivers surveyed in a recent study use standard flatware spoons to measure medicines at least some of the time. But typical household teaspoons hold from 2 to 10 milliliters of liquid, so chances are this mom gave something other than the prescribed 5 milliliter dose--the equivalent of one measuring teaspoon.
Even though the American Academy of Pediatrics has been recommending for 25 years that more accurate dosing devices be used, there have been few studies that look at how often or how well these devices--including oral dosing syringes, medicine cups, and calibrated medicine droppers and spoons--are actually used by parents. So physicians Diane J. Madlon-Kay and Frederick S. Mosch of Regions Hospital in St. Paul, Minn., and the University of Minnesota Medical School in Minneapolis designed a study to find out. They surveyed patients at three primary care clinics in St. Paul, Minn., to see what dosing devices caregivers use and how accurately they are measuring their medications.
Seventy-three percent of the 130 patients surveyed reported using a household teaspoon for measuring medicines, but most could also use more accurate devices correctly. The participants were able to measure the proper amount of liquid using an oral dosing syringe more than 90 percent of the time. When interpreting dosing instructions, survey participants usually were correct when instructions called for taking medicine three or four times a day. But in many cases, they misinterpreted instructions calling for a dose every six hours, assuming that medicine should be given in six-hour intervals while awake, resulting in three daily doses, rather than the prescribed four a day.
Based on these survey results, the researchers encourage clinicians to promote the use of accurate dosing implements, especially oral dosing syringes. They also suggest that medication instructions should indicate the dosing interval by number of doses per day, rather than hours between doses. (The Journal of Family Practice, August 2000)
| For more on how to give medicines properly, see "Avoiding Problems: Liquid Medication and Dosing Devices," October 1994 FDA Consumer, and "How to Give Medicine to Children," January-February 1996 FDA Consumer. To request a printed copy of the 1996 article, write to FDA (HFD-210), 5600 Fishers Lane, Rockville, MD 20857. |
A new glue offers another option for reducing blood loss in a rare form of brain surgery. The Food and Drug Administration approved the Trufill n-BCA Liquid Embolic System for use in patients at risk of hemorrhaging and dying from a cerebral arteriovenous malformation (AVM). An AVM consists of abnormally connected arteries and veins that may rupture and cause a stroke. Typically, surgery is performed to remove the AVM and reduce the risk of serious complications. Approximately 4,000 cerebral AVM procedures are performed each year.
Cordis Neurovascular Inc., of Miami Lakes, Fla., makes the glue, which reduces blood flow to the surgical site in the brain before the procedure begins. Surgeons inject the glue into the AVM prior to its removal. The glue is infused into blood vessels through a catheter that is inserted into the leg and threaded up to the brain. Later, the glue is removed during surgery.
The company's multi-center study of 104 patients showed the glue was as effective in blocking blood flow as the standard treatment with polyvinyl alcohol particles. Half the patients in the study were treated with glue and half with polyvinyl alcohol particles. Both groups had about the same rate of complications.
FDA based approval of the product on a review of Cordis' preclinical and clinical studies of safety and effectiveness, and on the recommendation of the Neurological Devices Panel of FDA's Medical Devices Advisory Committee.
There's new hope for patients with a rare neurological disease who lose their hearing after undergoing surgery to remove tumors growing on cranial nerves. A newly approved implanted device restores some of the hearing lost when the auditory nerves that transmit sounds to the brain are severed.
The auditory brain stem implant, approved for marketing in October by the Food and Drug Administration, is the first of its kind. Part of the electronic device is surgically implanted into the brain, where it stimulates the area that normally receives electrical signals from the ear. The patient wears a pocket-sized speech processor that picks up sound and changes it into electrical pulses that are transmitted to the implant.
The implant was approved for use in teenagers and adults who have a rare disease called Neurofibromatosis Type 2 (NF2). People with the disease eventually need surgery to remove tumors on cranial nerves. When this surgery severs the auditory nerve, the patient will have a total loss of hearing that cannot be helped by external hearing aids or cochlear implants (devices that aid hearing by stimulating the cochlea, a structure of the inner ear).
In studies conducted to establish its safety and effectiveness, the device was implanted in about 90 people during surgery for NF2. When patients were evaluated after six months, most were able to perceive at least some sounds. More than 80 percent of the people who were evaluated after receiving the implant could detect certain familiar sounds, such as honking horns and ringing doorbells, and could understand conversation with the aid of lip reading. And 12 percent of those evaluated could hear well enough to use a telephone. However, 18 percent of all patients studied were not able to hear any sound at all, because the implant was either placed incorrectly or it moved after surgery.
The device, called the Nucleus 24 Multichannel Auditory Brainstem Implant, is manufactured by Cochlear Corporation of Englewood, Colo.
The same shock wave treatment that has been used for years to break up kidney stones without surgery is now helping to relieve chronic heel pain. The Food and Drug Administration has approved the OssaTron device to treat chronic proximal plantar fasciitis, a condition that causes severe pain in the heel of the foot, for use on adults who have been unsuccessful with other treatments.
Plantar fasciitis is usually caused by an inflammation of the ligament that runs from the heel to the ball of the foot, and is typically treated with physical therapy, pain relievers, cortisone injections, heel-cushions, and in severe cases, with surgery.
The shock used in the treatment is created by a spark-plug-like device that's enclosed in a soft plastic dome filled with water. During treatment, the dome is placed closely against the heel so that the shock waves pass through the dome to the heel. One theory for the mechanism of action is that the shock wave-induced damage causes new blood vessels to form, in turn healing cells that grow new, healthy tissue. A total of 1,500 shocks are usually delivered, and treatment is performed as an outpatient procedure.
FDA approval was granted based on the results of a multi-center, randomized, placebo-controlled study of about 300 patients. Approximately 60 percent of patients were completely relieved of symptoms following a single OssaTron treatment, and 80 percent experienced significant relief.
The OssaTron's side effects include mild neurological symptoms and tears in the tissue on the bottom of the foot. As a condition of approval in October, FDA is requiring the manufacturer, HealthTronics, Inc., of Marietta, Ga., to conduct another study to evaluate further the problems of neurological symptoms and plantar fascial ruptures.
There may be one more reason to wear that bike helmet now, says epidemiologist Richard Havlik, MD, of the National Institute on Aging in Bethesda, Md. Serious head injury in early adulthood may be linked to developing Alzheimer's disease (AD) and other forms of dementia later in life, according to Havlik and a team of researchers at NIA and Duke University Medical Center in Durham, NC.
The researchers studied the records of more than 7,000 World War II male veterans who were sent to military hospitals with head injuries or unrelated conditions. They then tracked down 1,776 veterans who were eligible for the study--548 of whom had suffered a head injury. The remaining 1,228 without head injuries made up the control group. Telephone interviews with the veterans or a family member were used to determine the current cognitive and functional abilities of the men.
Study results suggested that the more severe the head injury, the greater the risk of developing AD or other forms of dementia. The risk was doubled for individuals with moderate head injury, and men with severe head injuries had a fourfold greater risk. Moderate injury was defined as a skull fracture, or amnesia or loss of consciousness for more than 30 minutes but less than 24 hours. Severe injury was amnesia or loss of consciousness for 24 hours or more. Results for participants who had mild injury--loss of consciousness or amnesia for less than 30 minutes--were inconclusive.
Previous studies have suggested a relationship between head injuries and dementia, but were thought to be influenced by "recall errors" because they relied on patient and family memories of injuries that may have occurred decades earlier. Havlik cautions that the new findings do not show a direct cause-and-effect relationship between head injury and dementia but do show an association that warrants further study. "We now need to hone in on what's behind these findings, especially what may be happening biologically," he says.
Each year, an estimated 1.5 to 2 million individuals in the United States suffer a significant head injury, according to the National Institutes of Health. It is estimated that up to 4 million Americans currently have AD. (Neurology, October 24, 2000)
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For further information on Alzheimer's disease, contact the Alzheimer's Disease Education and Referral (ADEAR) Center, a service of the National Institute on Aging, at PO Box 8250, Silver Spring, MD 20907-8250, toll-free telephone 1-800-438-4380, Web site www.alzheimers.org. |
Call the Food and Drug Administration's toll-free information lines for answers to your questions about FDA-regulated products.
Or call the public affairs specialist in your local FDA field office (check the blue pages of the phone book under "U.S. Government/Food and Drug Administration").
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