On the Market, Possibly Risky

Accutane

Potent acne drug tied

to severe birth defects

Accutane is a highly effective drug for clearing up severe acne that is resistant to other forms of treatment. Derived from vitamin A, it essentially stops the production of oil in the sebaceous glands of the skin, shrinking those glands to the size of a baby’s.

The drug causes dry lips in most patients, dry eyes (which can lead to conjunctivitis) in 40% of patients, and back pain in 30% of patients. Less common side effects included joint pain, headaches, itching and sensitivity to the sun.

Far overwhelming those, however, is the risk of birth defects if the drug is given to pregnant women. When the drug was first prescribed in the 1970s in France, physicians found more than 800 severely deformed babies among 1,000 births in women taking the drug.

Over the intervening years, physicians have been warned about prescribing it to women who might be pregnant, but a pre-treatment pregnancy test only recently became mandatory rather than voluntary.

Data presented to the Food and Drug Administration in 2000 showed that there were 1,995 pregnancies exposed to Accutane treatment from 1982 to 2000. The known outcomes of those pregnancies included 1,214 elective abortions and 383 live births. Among those live births, 162 had birth defects.

The Centers for Disease Control and Prevention estimated in 1989 that there were about 4,000 U.S. women of child-bearing age with acne sufficiently severe to require the drug; experts say there are probably about 6,000 now. Nonetheless, 156,800 women received the drug in 2002 and 2003.

Bextra

Litany of adverse effects

in trials of pain reliever

Bextra is meant to relieve pain without causing the stomach damage and bleeding associated with aspirin and other nonsteroidal anti-inflammatory drugs.

It is approved to treat painful menstrual symptoms, osteoarthritis and rheumatoid arthritis. There is an injectable form of the drug called parecoxib.

Bextra is a sulfonamide drug and can cause anaphylactic shock in people who are allergic to sulfa drugs. The labeling did not initially indicate that Bextra was a sulfa drug and many allergic reactions, some of them life-threatening, occurred before the labeling was changed.

The drug is in the same class as Vioxx, which Merck & Co. took off the market in September after a study showed the drug nearly doubled the risk of heart attacks and strokes among people taking it for at least 18 months. Both drugs are known as Cox-2 inhibitors.

G. D. Searle & Co., which was bought by Pfizer Inc., initially applied for permission to market the drug to treat acute pain, but that indication was not approved by the FDA. Although the agency did not initially release the clinical trials that led to the rejection, they were eventually published and showed an excess number of adverse effects, including heart attacks and strokes, associated with the drug.

Last week, Dr. Garrett A. Fitzgerald of the University of Pennsylvania reported at a New Orleans meeting of the American Heart Assn. on a study of 59,000 patients showing that those who received Bextra were 2.19 times as likely to have a heart attack or stroke than those taking a placebo. Some previous studies showed no unusual risk.

Crestor

Cholesterol drug can lay

waste to muscle tissue

Crestor is the newest member of a family of drugs called statins that reduces cholesterol levels in the blood by blocking the synthesis of cholesterol by the body. In general, the drugs have been shown to be very effective in reducing the risk of heart attack and stroke, even in patients who do not have unusually high levels of cholesterol.

The most common severe side effect of statins is rhabdomyolysis, a potentially life-threatening deterioration of muscle tissue. One statin drug, Baycol, has been removed from the market because it is much more likely to produce muscle damage than the other statins.

Critics charge that Crestor is more similar to Baycol than to the other statins in its potential for damaging muscles. They also say that there have been at least 29 cases of severe kidney damage associated with use of the drug.

AstraZeneca halted clinical trials of the drug in 2001 following reports of kidney damage and early stages of rhabdomyolysis among subjects receiving an 80-milligram dose. The drug is now sold in doses of 5 to 40 milligrams, although there are restrictions on use of the 40-milligram formulation.

Meridia

Diet pill, antidepressants

form a dangerous mix

Meridia increases the concentration in the brain of three neurotransmitters -- norepinephrine, serotonin and dopamine -- to decrease appetite.

A review published in May showed that the average weight loss among Meridia users was 9.8 pounds after a year of use, and much of that lost weight eventually returned after drug use was halted.

Meridia causes dry mouth, headache, insomnia and other problems. It also increases blood pressure in direct proportion to the dosage and has been associated with some heart abnormalities. There have been reports of serious cardiovascular events requiring hospitalization and some deaths associated with Meridia use.

It is also potentially subject to abuse because it can be addictive.

The most dangerous side effect occurs when it is used at the same time as other drugs that raise serotonin levels in the brain, particularly antidepressants, but also Parkinson’s drugs, migraine drugs and illegal drugs, such as cocaine and Ecstasy.

These drugs can combine to produce a potentially life-threatening condition called serotonin syndrome. Symptoms can include confusion, agitation, lethargy, spasms, tremors and a condition called autonomic instability that includes elevated temperature, rapid heart rate, sweating, nausea, diarrhea and dilated pupils.

An FDA advisory panel initially recommended against approval of the drug, but was overruled when manufacturer Abbott Laboratories filed suit against the agency.

The drug is banned in Italy and is under investigation in France and the United Kingdom, where there have been more than 100 serious adverse reactions and two deaths.

Serevent

Asthma treatment can

prompt serious episodes

Salmeterol is the primary ingredient in Serevent and in Advair, which are typically used twice a day to provide long-lasting protection against allergies and asthmas. They are not rescue inhalers, which are used to combat short periods of intense asthmatic activity.

The drug is probably the least problematic of those cited in the congressional testimony. The primary concern is that it can increase the risk of life-threatening asthma episodes and asthma deaths in some patients.

That concern arises from a large clinical trial of the drug begun by GlaxoSmithKline in 1996. The study was terminated prematurely in January 2003 because of initial indications of increased risk of death.

Although the data form the study have not been published, the product warning label required by FDA says that there were 13 deaths out of 13,174 patients treated for 28 weeks, compared to four deaths among 13,179 patients receiving a placebo. The risk was higher in blacks than in whites, but data were not presented.

The drug has also been weakly linked to bone pain, an increased risk of bronchitis and infections, sleep disorders and gall bladder problems, among others.

Thomas H. Maugh II

*

(BEGIN TEXT OF INFOBOX)

Accutane

The capsules are manufactured by Roche Holding. The patent expires in 2005.

What it does: Treats a type of severe acne (nodular acne)

Active ingredient: Isotretinoin

Possible side effects: Birth defects, mental disorders, pain in the abdomen, bones, muscles and joints

FDA approval date: May 7, 1982

Total sales: $300 million*

Total prescriptions: 374,023**

*12 months ending September 2003

**12 months ending October 2004

**

Bextra

Sources: FDA, NDCHealth

G.D. Searle & Co, makes this tablet, which is patented through 2015.

What it does: Relieves pain from arthritis and menstrual cycles

Active ingredient: Valdecoxib

Possible side effects: Bleeding stomach ulcers, liver damage, indigestion, nausea, stomach pain, upper respiratory tract infection, diarrhea, headache, increases the risk of death from heart attack and stroke

FDA approval date: Nov. 16, 2001

Total sales: $900 million*

Total prescriptions: 12.2 million**

Pfizer Inc. makes this tablet, which is patented through 2015.

*12 months ending September 2003

**12 months ending October 2004

**

Crestor

This tablet is made by AstraZeneca Pharmaceuticals. Patents expire in 2012, 2019 and 2020.

What it does: Lowers “bad” cholesterol and triglycerides and raises “good” cholesterol in the blood

Active ingredient: Rosuvastatin

Possible side effects: Muscle damage, liver damage, muscle pain, constipation, weakness, abdominal pain, nausea

FDA approval date: Aug. 14, 2003

Total sales: N/A

Total prescriptions: 5.7 million*

*12 months ending October 2004

**

Meridia

Abbott Laboratoriesmarkets this drug in capsule form and holds patents through 2007, 2012 and 2013.

What it does: Helps with weight loss and weight control

Active ingredient: Sibutramine hydrochloride monohydrate

Possible side effects: Dry mouth, constipation, insomnia, increased blood pressure and heart rate

FDA approval date: Nov. 22, 1997

Total sales: N/A

Total prescriptions: 696,740*

*12 months ending October 2004

**

Serevent

This drug is sold as powder or aerosol by GlaxoSmithKline.Its patent expires in 2008.

What it does: Asthma treatment

Active ingredient: Salmeterol Xinafoate

Possible side effects: Allergic reaction, increased difficulty breathing, increased risk of death from severe asthma attacks

FDA approval date: Feb. 4, 1994 (aerosol); Sept. 19, 1997 (powder)

Total sales: $200 million*

Total prescriptions: 2.4 million (Diskus), 22,910 (Serevent)**

*12 months ending September 2003

**12 months ending October 2004

Sources: FDA,NDCHealth