The drug scene

FDA warns against taking antidepressants, migraine drugs together 

The Food and Drug Administration (FDA) has important new safety information about taking triptans (drugs used to treat migraine headaches) together with certain types of antidepressants. The antidepressant medicines of concern are selective serotonin reuptake inhibitors (SSRIs) and selective serotonin/norepinephrine reuptake inhibitors (SNRIs); brand names are provided below. A life-threatening condition called serotonin syndrome may occur when triptans are used together with an SSRI or an SNRI.

Serotonin syndrome occurs when the body has too much serotonin, a chemical found in the nervous system. Symptoms may include restlessness, hallucinations, loss of coordination, fast heartbeat, rapid changes in blood pressure, increased body temperature, overactive reflexes, nausea, vomiting, and diarrhea. Serotonin syndrome may be more likely to occur when starting or increasing the dose of a triptan, SSRI, or SNRI.

The FDA has determined that serotonin syndrome occurs with combined use of triptans and an SSRI or SNRI through patient reports. Each of these types of medicine increases serotonin levels on its own, as well. Patients who are taking a triptan along with an SSRI or SNRI should talk to their doctor before stopping their medications.

Physicians prescribing a triptan, SSRI, or SNRI should:

Drug Names

	SSRIs and a Combination Drug Containing an SSRI	SNRIs	Triptans
	Celexa (citalopram)	Cymbalta (duloxetine)	Amerge (naratriptan)
	Fluvoxamine	Effexor (venlafaxine)	Axert (almotriptan)
	Lexapro (escitalopram)		Frova (frovatriptan)
	Paxil (paroxetine)		Imitrex (sumatriptan)
	Prozac (fluoxetine)		Maxalt and Maxalt-MLT (rizatriptan)
	Symbyax (olanzapine/fluoxetine)		Relpax (eletriptan)
	Zoloft (sertraline)		Zomig and Zomig ZMT (zolmitriptan)

Patients should know which medicines they take and tell all their health-care providers (physicians, nurses, and pharmacists) what these medicines are. In short, triptans treat migraine headaches, and SSRIs and SNRIs treat depression and other mood disorders.

The FDA has requested that all manufacturers of triptans, SSRIs, and SNRIs update their prescribing information to warn of the possibility of serotonin syndrome when triptans and SSRIs or SNRIs are taken together.

New HIV treatment approved for patients who don't respond to existing drugs 

The FDA has approved Prezista (darunavir), a new drug for adults whose infection with the human immunodeficiency virus (HIV) has not responded to treatment with other antiretroviral drugs. Prezista, a new protease inhibitor, is approved to be coadministered with a low dose of ritonavir and other active anti-HIV agents. Ritonavir, a protease inhibitor approved in 1996, slows the breakdown of Prezista in the body, thereby increasing its concentration in the patient's system.

The most common side effects reported by patients on the Prezista-ritonavir regimen included diarrhea, nausea, and headache. About 7% of patients on this combination therapy experienced skin rashes ranging from mild to serious. The risks and benefits of Prezista have not been established for adults who have not been previously treated for HIV or for children.

As a condition of the accelerated approval, the manufacturer is required to conduct postmarketing trials to verify and describe the clinical benefits of Prezista. Other postmarketing studies that the manufacturer has committed to conduct include studies in pediatric populations, studies to better define certain drug interactions, and studies to evaluate the drug in patients with varying degrees of liver impairment to identify appropriate dosing for this patient population.

Patients are advised to take the combination with food and not to use the combination therapy together with St. John's wort or various other drugs, including certain anticonvulsants, antihistamines, sedatives, and a few protease inhibitors.

FDA approves new treatment for Parkinson disease 

The FDA cleared Azilect (rasagiline), a new molecular entity, for the treatment of Parkinson disease. The drug is a monoamine oxidase type B (MAO-B) inhibitor that blocks the breakdown of dopamine, a chemical that sends information to the parts of the brain that control movement and coordination.

Parkinson disease is a chronic, progressive neurodegenerative condition caused by the destruction of the brain cells that produce dopamine. As the level of this chemical declines, messages from the brain telling the body how and when to move are delivered more slowly, leaving a person incapable of initiating and controlling movements in a normal way.

Azilect, manufactured by Teva, was approved for use as an initial single-drug therapy in early Parkinson disease and as an addition to levodopa in more advanced patients. The safety and effectiveness of Azilect was demonstrated in three 18- to 26-week controlled clinical trials.

Azilect may be associated with hypertensive crisis if patients also consume tyramine-rich foods and beverages (such as cheese and red wine) or dietary supplements or amines contained in many cough/cold medications. Therefore, patients will need to avoid these sources of tyramine and amines when taking the drug. As with most other medications for Parkinson, Azilect has the potential to cause involuntary movements (dyskinesias), hallucinations, and lowered blood pressure. These side effects are described in the product labeling.

FDA rapidly approves new treatment for rare leukemia 

The FDA granted accelerated approval for Sprycel (dasatinib), a new oral treatment for patients with chronic myeloid leukemia (CML), a rare cancer characterized by the uncontrolled growth of white blood cells. In the United States, CML affects about 4600 people annually. In addition, the FDA gave regular approval to Sprycel for use in adults who have Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), a more serious form of leukemia.

Manufactured by Bristol-Myers Squibb, Sprycel is intended for patients with CML who are no longer responding to or can no longer tolerate therapy with Gleevec (imatinib), a drug approved in 2001 for this life-threatening disease. This new option works by reducing the activity of one or more proteins responsible for the uncontrolled growth of the leukemia cells. Sprycel treatment has been shown to reduce, and in some cases eliminate, detectable leukemia cells in the blood and bone marrow of patients with CML. As provided for under FDA-accelerated approval regulations, studies are underway to demonstrate that these improved white blood cell counts also result in clinical benefit, such as improved survival or improvement in related symptoms.

The approval of Sprycel is based on evidence from four single-arm studies in more than 400 patients who were no longer responsive to or tolerant of treatment with Gleevec. Efficacy was determined by the response rate, defined as the percentage of patients in whom treatment resulted in the elimination of or significant reduction in leukemia cells. Responses were measured primarily in the bone marrow for those patients with the earliest stage of disease and in the blood for patients with later stage disease. Forty-five percent of patients with the earliest stage of CML (chronic phase) responded to the drug. Response rates for patients with advanced phases and Ph+ ALL ranged from 31% to 59%.

Side effects reported in clinical trials included fluid retention, bleeding, diarrhea, skin rash, infections, headache, fatigue, and nausea. Sprycel also frequently causes low red blood cell counts (anemia), low white blood cell counts (neutropenia) and low platelet counts (thrombocytopenia).

First treatment for dementia of Parkinson disease gets FDA nod 

The FDA has approved Exelon (rivastigmine tartrate) for the treatment of mild to moderate dementia (chronic loss or impairment of intellectual capacity) associated with Parkinson disease, a disorder of the central nervous system. Exelon, manufactured by Novartis, was previously approved for the treatment of mild to moderate dementia of Alzheimer type.

“It's been recognized for almost a decade that the dementia of patients with Parkinson's disease differs from the dementia of patients with Alzheimer,” said Dr. Steven Galson, Director of FDA's Center for Drug Evaluation and Research, “but until now, there has been no treatment that has been shown to be effective specifically for the dementia associated with Parkinson disease. Approval of Exelon helps to fill this medical need.”

An estimated 0.2% to 0.5% of people over 65 are affected by Parkinson dementia and experience symptoms such as impairments in executive function, memory, and attention. The approval of Exelon for this dementia is given on the basis of results of a randomized, placebo-controlled clinical study with 541 patients who showed symptoms of mild to moderate dementia 2 years or more after their diagnosis. At the end of the 24-week trial, the condition of the Exelon-treated patients, as shown on a scale that measures mental processes, was significantly better than the condition of the patients on placebo.

The use of this drug, however, has been associated with significant gastrointestinal adverse reactions. In clinical trials, 47% of the patients developed nausea, and 26% of women and 18% of men on high doses experienced significant weight loss. Other common adverse events reported include vomiting, anorexia, dyspepsia, and asthenia (loss of strength). In some patients with Parkinson disease, treatment with Exelon was associated with worsening tremor.

FDA greenlights first drug for late-stage cervical cancer 

The FDA has approved a combination of Hycamtin (topotecan hydrochloride) and cisplatin as the first drug treatment for women with late-stage (IVB, incurable) cancer of the cervix when a physician determines that surgery or radiation therapy is unlikely to be effective. The approval includes a new indication for GlaxoSmithKline's Hycamtin, which was approved in 1996 for ovarian cancer and in 1998 for small cell lung cancer.

In the United States there are an estimated 10,000 new cases of cervical cancer and about 3700 related deaths each year.

In clinical trials, 293 patients were randomized to Hycamtin plus cisplatin or to cisplatin alone. Most of the participants had received prior radiation therapy as the standard treatment; some had undergone prior surgery. The combination therapy significantly improved survival compared with the use of cisplatin alone. Patients on combined therapy survived an average of 9.4 months, about 3 months longer than patients on cisplatin alone (6.5 months).

Hycamtin is associated with a significant risk of neutropenia (a drop in white blood cell count), a condition that makes it more difficult for the body to fight infections. Serious side effects also include thrombocytopenia, a decrease in blood platelets that can lead to excessive bleeding and anemia. Less serious side effects include nausea and vomiting. The incidences of neutropenia, anemia, and thrombocytopenia were significantly increased among patients receiving the combination treatment compared with those receiving cisplatin alone, as were nausea and vomiting, mucositis, rash, and liver toxicity.

Campaign seeks to reduce mistakes caused by unclear medical abbreviations 

Earlier this year, the FDA and the Institute for Safe Medication Practices (ISMP) launched a nationwide health professional education campaign aimed at reducing the number of common but preventable sources of medication mix-ups and mistakes caused by the use of unclear medical abbreviations.

According to the Institute of Medicine, more than 7000 deaths a year occur as a result of medication errors. Mistakes can occur anywhere in the medication-use system, from prescribing to administering a drug in a variety of settings (eg, hospitals, outpatient clinics, nursing homes, home care).

The educational campaign focuses on eliminating the use of potentially confusing abbreviations by health care professionals, medical students, medical writers, the pharmaceutical industry, and FDA staff. The campaign will address mistake-prone abbreviations in all forms of medical communication, including written medication orders, computer-generated labels, medication administration records, pharmacy or prescriber computer order-entry screens, and commercial medication labeling, packaging, and advertising.

The ISMP has a list of abbreviations, symbols, and dose designations (www.ismp.org/PDF/ErrorProne.pdf) that are most often associated with medication errors, and it should be considered whenever medical information is communicated. This list includes abbreviations that have been associated with medication errors reported to the USP (United States Pharmacopeia)-ISMP Medication Errors Reporting Program.

Examples of common error-prone notations that the campaign will seek to eliminate include:

All of these materials are available at www.fda.gov/cder/drug/MedErrors and www.ismp.org/tools/abbreviations.

FDA licenses new vaccine for cervical cancer, other diseases in women 

The FDA approved Gardasil, the first vaccine developed to prevent cervical cancer, precancerous genital lesions, and genital warts resulting from human papillomavirus (HPV) types 6, 11, 16, and 18. The vaccine is approved for use in females 9 to 26 years old. The vaccine was evaluated and approved in 6 months under priority review, a process for products with potential to provide significant health benefits.

Human papillomavirus is the most common sexually transmitted infection. The Centers for Disease Control and Prevention estimates that about 6.2 million Americans become infected with genital HPV each year and that more than half of all sexually active men and women become infected at some time in their lives. On average, there are 9710 new cases of cervical cancer and 3700 deaths attributed to HPV in the United States each year. Worldwide, cervical cancer is the second most common cancer in women and is estimated to cause over 470,000 new cases and 233,000 deaths each year.

For most women, the body's own defense system will clear the virus and not develop related health problems. However, some HPV types can cause abnormal cells on the cervix lining that can turn into cancer years later. Other HPV types can cause genital warts. The vaccine is effective against HPV types 16 and 18, which cause approximately 70% of cervical cancers, and types 6 and 11, which cause approximately 90% of genital warts.

Gardasil is a recombinant vaccine (contains no live virus) that is given in three injections over a 6-month period. Immunization is expected to prevent most cases of cervical cancer resulting from HPV types included in the vaccine. However, women who have been infected with that (those) HPV type(s) before vaccination are not protected, indicating the importance of immunization before potential exposure. Also, the vaccine does not protect against less common HPV types not included in it; thus, routine and regular pap screening remain critically important to detect precancerous changes in the cervix to allow treatment before cancer develops.

Gardasil is manufactured by Merck. For other details, go to www.fda.gov/bbs/topics/NEWS/2006/NEW01385.html.

Marketing of Tysabri resumes under special distribution program 

The FDA approved an application for resumed marketing of Tysabri (natalizumab) subject to a special restricted-distribution program. Tysabri is a monoclonal antibody used to treat patients with relapsing forms of multiple sclerosis (MS) to reduce the frequency of exacerbations. Tysabri is indicated for use as a monotherapy, meaning it should not be used in combination with other immune system–modifying drugs, and is for patients who have not responded adequately to or cannot tolerate other treatments for MS.

Initially approved by the FDA in November 2004, the drug was withdrawn by the manufacturer, Biogen Idec, in February 2005 after three patients in clinical trials developed progressive multifocal leukoencephalopathy (PML), a serious and rare viral infection of the brain. Two cases were fatal. On the basis of this information, the FDA put clinical trials of the drug on hold. After a re-examination of the patients who had participated in the previous trials that confirmed there were no additional cases of PML, the FDA allowed a clinical trial to resume in February 2006.

To reduce the possibility of patients developing PML in the future while also making Tysabri available to appropriate MS patients, the FDA consulted in March 2006 with its Peripheral and Central Nervous Systems Drugs Advisory Committee. The Advisory Committee recommended a risk-minimization program with mandatory patient registration and periodic follow-up to identify as early as possible any cases of PML that may occur and to try to determine the reason the infection occurs. In response, Biogen Idec submitted to the FDA a risk-management plan, called the TOUCH Prescribing Program, to help ensure safe use of the product.

The FDA determined that Tysabri can be made available under TOUCH with the following main features:

More information, including a detailed product history, is available at www.fda.gov/cder/drug/infopage/natalizumab/default.htm. Additional information on the TOUCH Program is available at 800-456-2255.

FDA licenses new vaccine to reduce elders' risk of shingles 

The FDA has licensed Zostavax, a new vaccine, to reduce the risk of shingles (herpes zoster) for use in people age 60 and older. Shingles is caused by the varicella-zoster virus, the same virus that causes chickenpox. After an attack of chickenpox, the virus lies dormant in certain nerve tissue. As people age, it is possible for the virus to reappear in the form of shingles, which is estimated to affect 2 in every 10 people in their lifetime. Shingles is characterized by clusters of blisters that develop on one side of the body and can cause severe pain that may last for weeks, months, or years after the virus reappears.

Zostavax, a live virus vaccine manufactured by Merck, was shown to boost immunity against varicella-zoster virus. This is thought to be the mechanism by which the vaccine protects against zoster and its complications. The vaccine is given as a single injection under the skin, preferably in the upper arm.

Zostavax was studied in approximately 38,000 individuals throughout the United States who were age 60 and older. Half received the drug, and half received a placebo. All study participants were then followed for an average of 3 years to see if they developed shingles and, if they did, how long the pain lasted. Researchers found that, overall in those age 60 and above, the vaccine reduced the occurrence of shingles by about 50%. For individuals ages 60 to 69, it reduced occurrence by 64%.

The most common side effects were redness, pain and tenderness, swelling at the site of injection, itching, and headache. The percentage of significant adverse events observed in the study was not different between persons who received the vaccine versus placebo.

Remicade OK'd for children with Crohn disease 

The FDA gave its approval to Remicade (infliximab) to treat children with active Crohn disease, a chronic, inflammatory condition of the bowel that can be severely debilitating. Initially approved in 1998 to treat Crohn disease in adults, Remicade is a genetically engineered monoclonal antibody that reduces inflammation (swelling/redness) by blocking the action of tumor necrosis factor–alpha (TNF-·).

Dr. Steven Galson, director of the FDA?s Center for Drug Evaluation and Research, noted that there have been no satisfactory treatments for children who have moderate to severe disease activity, despite traditional or conventional therapies. Crohn disease can cause diarrhea, cramping, abdominal pain, gastrointestinal bleeding, and in some cases creates abnormal connections (fistulas) leading from the intestine to the skin.

“Remicade is not a cure, but it provides a much-needed option for reducing the symptoms and inducing and maintaining disease remission in children who have no other safe and effective therapy,” Galson said. “We believe that the potential benefits of this product outweigh the risks that are known and have been carefully evaluated.”

For more information, go to www.fda.gov/bbs/topics/NEWS/2006/NEW01376.html.

FDA approves first treatment for Pompe disease 

The FDA approved a biologics license application for Myozyme (alglucosidase alfa, rhGAA), the first treatment for patients with Pompe disease, a rare but severely debilitating disease. Pompe disease, which affects one in 40,000 to 300,000 individuals, drastically reduces a person's muscle and respiratory function. Myozyme, manufactured by Genzyme, had been granted orphan drug designation and was approved under a priority review.

Pompe disease is an inherited disease caused by the deficiency or lack of the enzyme acid alpha-glucosidase, which is essential for normal muscle development and function. The disease usually results in death from respiratory failure and is rapidly fatal in newborns.

The FDA approved Myozyme for administration by intravenous infusion. Its safety and efficacy were assessed in two separate clinical trials in 39 infantile-onset patients ranging in age from 1 month to 3.5 years at the time of the first infusion.

Patient survival without needing invasive ventilatory support was substantially greater in the Myozyme-treated infants than would be expected compared with the known high mortality rate of untreated patients of similar age and disease severity.

The drug's safety and effectiveness in other forms of Pompe disease have not been adequately studied.

The most serious adverse reactions were heart and lung failure and allergic shock. Most common reactions included pneumonia, respiratory failure and distress, infections, and fever. A boxed warning is included in the label to warn about the possibility of life-threatening allergic reactions.

FDA approves the first drug for seasonal depression 

The FDA has approved Wellbutrin XL for prevention of major depressive episodes in patients with a history of seasonal affective disorder (SAD). This is the first drug approved for SAD. Wellbutrin XL (bupropion HCL extended-release tablets) previously was approved for major depressive disorder.

SAD is characterized by recurrent major depressive episodes that usually coincide with the seasonal decrease of daylight during autumn and winter. The depressive episodes can last up to 6 months. Although patients with SAD may have depressive episodes during other times of the year, the formal diagnosis requires that the number of seasonal episodes substantially outnumber the nonseasonal episodes during the individual's lifetime.

A major depressive episode is defined as the presence of five or more of the nine core symptoms of major depression for at least 2 weeks. The symptoms include depressed mood, loss of interest, weight loss (or other weight or appetite changes), insomnia or hypersomnia, agitation or psychomotor retardation, fatigue, feelings of worthlessness or guilt, impaired concentration, and suicidal thinking or behavior. One of the five symptoms must be either depressed mood or loss of interest in activities. Another essential feature of major depression is the presence of significant distress or impairment in social, occupational, or other important areas of functioning. A seasonal major depressive episode is defined by identical features.

Wellbutrin XL's labeling includes a black-box warning concerning the increased risk of suicidal thoughts and behavior in pediatric patients treated with antidepressant medications. As with all antidepressants, Wellbutrin XL has a Medication Guide (MedGuide, or patient labeling) advising that pediatric patients on antidepressants should be watched closely for these serious symptoms. Important side effects, especially shortly after the initiation of the treatment, include agitation, anxiety, and insomnia.