By Steven DiJoseph

Although This Drug Has Been Deemed Safe by the FDA, Significant Problems with Other ‘Patches’ in Recent Years Require that any Drug using a Transdermal Delivery System Should be Carefully Monitored for Potential Side-Effects – Educational Campaign and Careful Tracking and Follow-up of Adverse Event Reports are Promised

The Food and Drug Administration (FDA) has approved selegiline, which will be the first transdermal (skin) patch for use in the treatment of major depression in adults.

In its press release on the subject, the FDA stated: “Major depressive disorder is a common psychiatric condition in the U.S. population. Symptoms of depression include general emotional dejection, withdrawal and restlessness that interfere with daily functioning, such as loss of interest in usual activities; significant change in weight and/or appetite; insomnia; increased fatigue; feelings of guilt or worthlessness; slowed thinking or impaired concentration; and a suicide attempt or suicidal ideation.”

The new patch, which will be sold under the brand name Emsam, was developed by Somerset Pharmaceuticals, Inc. In December 2004, Bristol-Myers Squibb (BMS) and Somerset entered into an agreement that gives BMS (the world’s 8^th largest drug company) distribution rights to market Emsam in the United States. Selegiline was initially approved in capsule form for use in the treatment of Parkinson’s disease.

The patch is only approved for adults, and will not be used to treat depression in children 17 and younger.

In a statement from BMS, its CEO, Peter R. Dolan stated: “We are pleased to be able to provide this important treatment to people with major depressive disorder. We believe Emsam will help physicians treat their patients living with this illness through a new and unique delivery system.”

Emsam interacts with three neurotransmitters in the brain that are believed to be involved with depression.

According to Dr. Steven Galson, Director of the Center for Drug Evaluation and Research, “Emsam provides a significant advance because at least in its lowest dose patients can use the drug without the usual dietary restrictions associated with these types of drugs known as MAO inhibitors.”

The FDA action comes about two years after the agency first said the patch was “approvable.” The delay was caused by concerns that users of the patch may suffer potential interactions with certain foods.

The main concern is whether patients could have an adverse reaction if they consume foods high in tyramine, like aged cheese, salami and, to a lesser extent, beer and wine, while wearing the patch.

The active ingredient in the patch, selegiline, could interact with tyramine — a substance formed from the breakdown of protein as food ages – causing a sharp and sudden surge in blood pressure.

In general, “MAO inhibitors usually require specific dietary restrictions because when combined with certain foods they can cause a sudden, large increase in blood pressure, or ‘hypertensive crisis.’ A hypertensive crisis can lead to a stroke and death. Symptoms of a hypertensive crisis include sudden onset of severe headache, nausea, stiff neck, a fast heartbeat or a change in the way your heart beats (palpitations), sweating, and confusion. Patients who have these symptoms should get medical care right away.” (FDA Release)

The Emsam patch will be made available in three sizes that deliver 6, 9, or 12 mg of selegiline per 24 hours. “The patch is a matrix containing three layers consisting of a backing, and adhesive drug layer, and a release liner that is placed against the skin.”

Patients using the patch at the lowest dose (6 mg per 24 hours) will not have any special dietary restrictions. Patients using the higher 9-mg and 12-mg patches, however, will be advised to avoid foods high in tyramine.

Last year an FDA panel of independent medical experts said that at the lowest dose, the patch would be safely marketed, without any dietary restrictions, but recommended restrictions be made at the two higher doses.

Other issues mentioned in the FDA press release included the following potential side affects: “The only common side effect of Emsam detected in placebo-controlled trials was a mild skin reaction where the patch is placed. There may be mild redness at the site when a patch is removed. If the redness does not go away within several hours after removing the patch or if irritation or itching continues, patients are advised to contact their doctor.

“Another side effect that was seen less commonly was light-headedness related to a drop in blood pressure.”

Also, the FDA noted that, like all approved antidepressants, the patch will carry a warning of increased suicidality in children and adolescents.

According to the FDA, the “manufacturer and distributor of this new product have planned an educational campaign for patients and prescribers to ensure that advice on dietary modifications for the higher patch strengths is adhered to. They plan to conduct both patient and health care provider surveys to assess the effectiveness of the educational campaign. The manufacturer and distributor will also closely track reports of adverse events, and follow-up on those that might represent hypertensive crises, to further ensure the safe use of this product.”

Although the effects of heat on the patch are not known, the drug labeling advises health care professionals and patients about the possible effects of direct heat applied to the Emsam patch.

“Direct heat may result in an increased amount of the drug absorbed from the patch. Patients should avoid exposing the patch to heating pads, electric blankets, heat lamps, saunas, hot tubs, or prolonged sunlight.”

Such issues are particularly noteworthy since absorption levels and other variables encountered with transdermal delivery systems have proven to be problematic with other patch-type medications in recent years.

The Issue of Delivery System Safety

The fact that the delivery system associated with this medication is a transdermal patch raises an issue some experts believe must be explored more carefully when it comes to finding alternative ways to deliver drugs.

Drug delivery systems are now one of hottest areas of pharmaceutical research and development. It is estimated that U.S. demand for drug delivery systems will grow 9% annually through 2007.

Controlled-release pills are expected to remain as the dominant form while implants, patches, syringes, and inhalers are gaining rapidly. While it is anticipated that respiratory, central nervous system, and cardiovascular agents will stay as the top uses, hormones, anticancer agents, and vaccines are expanding.

The U.S. drug delivery system is now a $54 billion industry. It comprises an ever-growing list of delivery platforms including; controlled-release tablets and capsules, chewable tablets, infusion/IV products, prefilled syringes, hypodermic needles, monoclonal antibodies, liposomes, inhalers, transdermal patches, and implants.

The following summary of delivery systems can be found at Market Research.com at thttp://www.marketresearch.com/map/prod/891760.html .

There are oral delivery systems including:

· Oral Controlled-Release

· Coated-Bead

· Diffusion

· Reservoir

· Chewable Tablets

· Rapid Disintegration

· Buccal

· Effervescent

· Polymer-Based

Parenteral drug delivery systems include

• Infusion devices
• IV Administration Sets
• IV Pumps & Controllers
• IV Catheters
• Premixed IV Solutions
• Hypodermic Products
• Prefilled Syringes
• Hypodermic Syringes
• Hypodermic Needles
• Gene/Protein Delivery Systems
• Hemodialysis
• Peritoneal Dialysis
• Enteral Feeding Products

There are inhalation delivery systems including:

• Dosage Formulations
• Metered Dose Inhalers
• Dry Powder Inhalers
• Nasal Spray Dispensers
• Ventilators
• Nebulizers

Transdermal and implantable systems include:

• Transdermal Drug Delivery Systems
• Implantable Drug Delivery Systems
• Pulse Generators
• Drug Inserts
• Drug-Eluting Stents

End-Use applications include:

• Respiratory Agents
• Central Nervous System Agents
• Cardiovascular Agents
• Digestive & Genito-Urinary Agents
• Hormones & Related Agents
• Anti-Cancer Agents
• Anti-Infective Agents
• Vitamins & Related Preparations
• Biologicals

The evolution of nanotechnology has expanded the drug-delivery-industry even further. Nano-enabled drug delivery systems are expected to be extended to compounds used in treating both infectious disease and cancer.

Six types of drug delivery systems in which nanotechnology is likely to have a significant impact include:

· injectable drugs – nanotechnology promises to create new dosage forms that are easier to administer, more pleasant for the patient, and more competitive in the marketplace.

· implantable delivery systems - often preferable to the use of injectable drugs since injectables often display initial blood concentration that goes up rapidly (then may fall exponentially) thereby causing potential difficulties with toxicity, and diminished efficacy as the drug concentration falls below the targeted range.

· oral drug delivery systems remain preferable (to patients) to implantables or injectables. Thus, development continues with respect to traditional oral delivery systems with nanoengineered improvements.

· (rapid) topical delivery of active compounds. Given their very small size, nanoparticles are able to enter human tissues and cells quickly.

· transdermal systems – Since the number of FDA-approved polymers available for use on skin is increasing rapidly, new opportunities are presented to create new designs with improved ‘on-skin’ properties and diffusion of active molecules compared to current transdermal patches.

· toxin removal. Colloidal dispersions have been demonstrated to remove potentially lethal compounds from the bloodstream, including high concentrations of lipophilic therapeutics, illegal drugs, and chemical and biological agents.

All of these rapidly developing delivery systems have potential down-side risks, however. Their newness and potential unpredictability in any given application has lead some experts to suggest more caution be exercised in approving and monitoring any new delivery system even if it is being used to administer an already approved medication.

If one considers the fact that there have been serious side-effects and dosing problems with the Ortho Evra birth-control patch, the fentanyl (Duragesic) patch, the transdermal nicotine patch, and the methylphenidate ADHD transdermal system, it is not difficult to see why transdermal delivery systems are being questioned by consumer advocates and medical experts.

(Note: In December 2005, FDA reviewers concluded that an experimental skin patch designed to treat ADHD in children was not safe enough to be approved. The patch, known as the methylphenidate transdermal system (MTS) delivers a generic version of Ritalin through the skin. In 2003, FDA officials also rejected the patch because induced high rates of anorexia, insomnia and weight loss in children when used for 12 hours. Britain’s Shire Pharmaceuticals Group Plc, and U.S. Noven Pharmaceuticals Inc., had planned to market the patch as Daytrana; however, FDA officials said that the patch still causes too many dangerous side-effects. In addition to the problems cited on the initial clinical trials, the patch also poses a high risk of skin irritation and muscle tic.

Transdermal patches are also the subject of numerous lawsuits involving extremely serious injuries and deaths.

This entry was posted on Wednesday, March 1st, 2006 at 7:01 am and is filed under Health Concerns, Legal News.