Transdermal Patches: An Innovative Drug Delivery System That Has Raised Serious Safety ConcernsMar 6, 2006 | Newsinferno News Staff Until recently, drugs were administered in three basic ways; orally, intravenously, and by injection. At home, patients were limited to oral medications except for those who were trained to inject themselves with insulin.
As drugs have become more sophisticated in terms of their applications and extended-release capabilities, it has become necessary to devise methods by which patients can administer these new medications.
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 can be found at: http://www.marketresearch.com/map/prod/891760.html
There are oral delivery systems including:
- Oral Controlled-Release
- Chewable Tablets
- Rapid Disintegration
- 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
- Peritoneal Dialysis
- Enteral Feeding Products
- Dosage Formulations
- Metered Dose Inhalers
- Dry Powder Inhalers
- Nasal Spray Dispensers
- Transdermal Drug Delivery Systems
- Implantable Drug Delivery Systems
- Pulse Generators
- Drug Inserts
- Drug-Eluting Stents
- Respiratory Agents
- Central Nervous System Agents
- Cardiovascular Agents
- Digestive & Genito-Urinary Agents
- Hormones & Related Agents
- Anti-Cancer Agents
- Anti-Infective Agents
- Vitamins & Related Preparations
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.
One particular delivery system, transdermal patches, has raised concern since several medications utilizing this method of administration have been linked to a number of serious adverse reactions.
The reasons for the problems being encountered are diverse. Absorption levels and rates, patient abuse, environmental factors, and other variables have made transdermal patches the subject of any number of scientific articles, FDA investigations, lawsuits, and even a bizarre criminal prosecution (discussed below).
The following is an up-to-date collection of the newsworthy stories involving a number of the more controversial transdermal patches and the medications that are currently associated with them.
ORTHO EVRA BIRTH-CONTROL PATCH
The FDA has acknowledged the finding of a new study that indicates women using the Ortho Evra birth-control patch have an elevated risk of developing blood clots.
Notwithstanding the fact that this is far from the first evidence linking this potentially fatal side-effect to the “patch,” the FDA has taken the position that the results are only preliminary and do not require immediate action other than to advise women to discuss this risk with their doctors.
According to Dr. Daniel Shames, who is director of the division of reproductive and urological drug products at the FDA, preliminary findings from a study by i3 Drug Safety found women using the patch had twice the risk of developing blood clots compared to women taking birth-control pills.
In November 2005, after years of debate over the safety of the Ortho Evra birth-control patch, the drug’s manufacturer Ortho-McNeil (a subsidiary of Johnson & Johnson the world’s 4th largest drugmaker) finally acknowledged the fact that women who use the product are at a significantly greater risk of blood clots, stroke, and death than woman who use other forms of oral contraceptives.
Ortho-McNeil has now admitted that women who use the patch can be exposed to up to 60% more estrogen than they would be exposed to if they were taking a birth control pill instead.
Critics of both the ‘patch’ and the FDA’s approval and monitoring practices, however, see the warning as simply another example of economics being placed above public safety. There has been a constant chorus of warnings about the extremely serious side-effects associated with the patch from a number of experts as well as the consumer watchdog group, Public Citizen (www.worstpills.org) and the Associated Press.
Several lawsuits have already been commenced around the U.S. alleging that serious injuries and deaths have been caused by the Patch.
CBS News also presented a significant story from Austin, Texas, concerning documents produced in the course of a pending lawsuit involving a young mother who was paralyzed by a stroke only 12 days after she began using the patch. She is now a total invalid.
According to that story, Ortho-McNeil’s own records show the company received some 500 reports of serious health problems associated with the patch between April 2002 and December 2004. During that time only 61 such reports were received with respect to all types of existing oral contraceptives.
In addition, there were four times as many strokes in women using the patch as in women using oral contraceptives even though three times as many women were taking those other forms of birth control.
Finally, the evidence indicated, that in medically confirmed cases, the risk of blood clots is 14 times as high with the patch.
An investigative report published by the Associated Press on July 18, 2005 linked the birth control patch, which contains a combination of norelgestromin and ethinyl estradiol, to an increased risk of blood clots and deaths (compared to older contraceptives) in some young healthy women.
Ortho Evra, like the other hormonal contraceptives, has a black box warning about an increased risk of cardiovascular adverse reactions in older women who smoke. This type of warning is the strongest that the FDA can request.
The Associated Press follow-up story is even more damning, however. In that article, the AP stated: “Documents released to attorneys as a result of that litigation show Ortho McNeil have been analyzing the FDA's death and injury reports, creating its own charts that document a higher rate of blood clots and deaths in association with the patch than with the pill.
In addition, an internal Ortho McNeil memo shows that the company refused, in 2003, to fund a study comparing its Ortho Evra patch to its Ortho-Cyclen pill because of concerns there was ‘too high a chance that study may not produce a positive result for Evra’ and there was a ‘risk that Ortho Evra may be the same or worse than Ortho-Cyclen.’”
The patch, like many oral contraceptives, contains two hormones, a progestin and an estrogen. The progestin in Ortho Evra is a new drug (2001) known as norelgestromin, and the estrogen is an existing one known as ethinyl estradiol.
Ortho Evra was approved by the Food and Drug Administration (FDA) in November 2001 and is the first contraceptive product to be approved as a skin patch. It was launched and marketed in a series of “glitzy” television ads featuring “sexy models.” (CBS 11/2/05).
In 2004, the drug accounted for more than 9.9 million prescriptions with sales topping $411 million.
Contraceptives are often referred to as second- or third-generation based on their progestin component. Since some experts classify norelgestromin as a third-generation progestin, Ortho Evra is considered third-generation contraceptive.
Public citizen first listed some third-generation oral contraceptives as “DO NOT USE” drugs in 1998 and 1999 because of an increased risk of blood clots compared to the older, second-generation birth control pills. Thus, elevated blood levels of progestin as well as estrogen are possible with the Patch.
The Associated Press used the Freedom of Information Act (FOIA) to obtain adverse drug reaction reports for Ortho Evra from the FDA and reportedly found that of the 23 cases in which death was the outcome, doctors reviewing the cases found 17 that appeared to be blood-clot-related, including 12 from 2004.
Since the FDA estimates that it receives reports of only between 1% and 10% of the serious adverse drug reactions that actually occur, the death rate for Ortho Evra may be significantly higher.
The Associated Press also analyzed the reviews of clinical trial results done by FDA physicians and scientists prior to the drug’s approval. Those results were submitted for review by Ortho-McNeil in support of Ortho-Evra and are available on the FDA’s Web site at: http://www.fda.gov/cder/foi/nda/2001/021-180_ORTHO.htm.
Significantly, Ortho-McNeil and the FDA medical officer reviewing Ortho Evra strongly disagreed about whether two cases of blood clots in the lungs (pulmonary embolus) in young women participating in the pre-approval clinical trials were caused by the drug. The FDA medical officer wrote:
“THE REVIEWER DOES NOT AGREE WITH THE SPONSOR’S [Ortho-McNeil] ABOVE CONCLUSIONS. The two cases of pulmonary embolus, a serious and potentially fatal condition, must be counted as two cases in the group” [emphasis in the original].
The FDA medical officer also included the following statement in his comments:
The professional product labeling and information written specifically for women using Ortho-Evra “should reflect the possible increased risk of venous thromboembolism (VTE) [blood clots] associated with this new transdermal combination hormonal contraceptive containing the new molecular entity progestin norelgestromin (17d-norgestimate).”
In addition, the medical officer expressed concern that 211 out of 3,088 women (6.8%) in the pre-approval clinical trials gained 10 or more pounds in the trials and noted that the contraceptive effectiveness of Ortho-Evra was reduced in women weighing more than 198 pounds (90 kilograms).
The professional product label warns that Ortho-Evra should not be used in the following circumstances:
- A history of heart attack or stroke
- Blood clots in the legs (thrombophlebitis), lungs (pulmonary embolism), or eyes
A history of blood clots in the deep veins of your legs
- Chest pain (angina pectoris)
- Known or suspected breast cancer or cancer of the lining of the uterus, cervix or vagina Unexplained vaginal bleeding (until your doctor reaches a diagnosis)
- Hepatitis or yellowing of the whites of your eyes or of the skin (jaundice) during pregnancy or during previous use of hormonal
- Contraceptives such as ORTHO EVRA, NORPLANT [levonorgestrel], or the birth control pill
- Liver tumor (benign or cancerous)
- Known or suspected pregnancy
- Severe high blood pressure
- Diabetes with complications of the kidneys, eyes, nerves, or blood vessels
- Headaches with neurological symptoms
- Use of oral contraceptives (birth control pills)
- Disease of heart valves with complications
- Need for a prolonged period of bed rest following major surgery
- An allergic reaction to any of the components of Ortho Evra
- Women who may be using Ortho Evra should contact their physician if any of the following warning signals develop:
- Sharp chest pain, coughing of blood, or sudden shortness of breath (indicating a possible clot in the lung)
- Pain in the calf (indicating a possible clot in the leg)
- Crushing chest pain or tightness in the chest (indicating a possible heart attack)
- Sudden severe headache or vomiting, dizziness or fainting, disturbances of vision or speech, weakness, or numbness in an arm or leg (indicating a possible stroke)
- Sudden partial or complete loss of vision (indicating a possible clot in the eye)
- Breast lumps (indicating possible breast cancer or fibrocystic disease of the breast; ask your doctor or health care professional to show you how to examine your breasts)
- Severe pain or tenderness in the stomach area (indicating a possibly ruptured liver tumor) Severe problems with sleeping, weakness, lack of energy, fatigue, or change in mood (possibly indicating severe depression)
- Jaundice or a yellowing of the skin or eyeballs accompanied frequently by fever, fatigue, loss of appetite, dark colored urine, or light colored bowel movements (indicating possible liver problems)
Blood clots in the lungs were seen in two women given Ortho Evra in clinical trials conducted before the drug was even approved (in addition to several similar cases after the drug was marketed).
There is also no evidence that the patch is a superior contraceptive compared to older second-generation birth control pills. As stated in the September 2005 issue of Worst Pills Best Pills (published by Public Citizen); “Rarely do randomized pre-approval studies, the scientific ‘gold standard’ for proving safety or efficacy, present such strong evidence of a serious problem.”
As a result of what it considers strong evidence of the increased risk of blood clots and death, Public Citizen states: “There is no medical reason for women to use the more dangerous Ortho Evra rather than one of the older, better understood, and equally effective oral contraceptives.”
When reading the November 2005 Ortho-McNeil’s Press Release, the first thing that becomes obvious is that the company made a concerted effort to present the information in a way that was difficult (if not impossible) for anyone but an expert to understand.
For example, the acronym AUC is used without definition thereby making the references to estrogen concentrations difficult to extrapolate. AUC, however, is a measure of how much of a drug reaches the bloodstream in a set period of time, usually 24 hours. AUC is calculated by plotting drug blood concentration at various times during a 24-hour or longer period and then measuring the area under the curve between 0 and 24 hours.
When the implications of AUC are considered with respect to the amount of estrogen that can be released in a given period of time, the result is shocking since that amount can easily exceed 50 mg which is well beyond the level already determined to be unsafe.
A previous study conducted with respect to another contraceptive product (the “vaginal ring”) documented these excessively high levels of estrogen associated with the patch almost a year ago in the journal Contraception.
In addition to the risks already discussed cigarette smoking increases the risk of serious cardiovascular side effects from hormonal contraceptive use. This risk increases with age and with heavy smoking (15 or more cigarettes per day) and is quite marked in women over 35 years of age. As a result, women who use hormonal contraceptives, including Ortho Evra, should not smoke.
Finally, litigation involving Ortho Evra has been gaining momentum in recent months and especially in light of the Associated Press investigation. The litigation focuses on the claim that Ortho-McNeil knew of the blood clot risk and even disagreed with the FDA medical officer who suspected the two incidents that occurred during the clinical trial were related to the drug.
A lawsuit was filed in July 2005 against Ortho-McNeil on behalf of a 30-year-old woman who suffered fatal blood clots thought to be linked to the Ortho Evra risk. The woman was admitted into the intensive care unit shortly before her death suffering from severe headache, visual problems, vomiting, and nausea.
The other deaths reported in connection with Ortho Evra risk factors were the result of heart attacks and strokes. One of the most recent deaths linked to Ortho Evra was suffered by a 25-year- old woman who suffered fatal headaches thought to be linked to a surge of hormone release from the birth control patch.
The youngest woman to die, as reported in a recent study, had been an 18-year-old college student who collapsed in the New York subway. Ten other women ranging in age from 18 to 27 have also sued Ortho-McNeil.
In mid-November, however, another high-profile wrongful death case was commenced against Ortho-McNeil and Johnson & Johnson. It involves Alycia Brown, an eighth-grader in La Crosse, Wisconsin, who died of blood clots in her lower pelvis on May 7, 2004. She had been using the Ortho Evra birth control patch for about eight weeks.
The federal law suit filed in Madison by her parents claims the patch was the cause of their daughter’s tragic death. The La Crosse County medical examiner has found that Ortho Evra was a likely contributing factor in Alycia’s death.
Although many lawsuits have already been commenced against Ortho-McNeil and its parent company, Johnson & Johnson, for injuries and deaths allegedly caused by the patch, the 14-year-old is now the youngest known victim.
In September 2005, Parker & Waichman, a major New York based plaintiffs’ personal injury law firm that is heavily involved in pharmaceutical litigation announced that it had filed suit against Ortho-McNeil Pharmaceutical, Inc., a division of Johnson and Johnson Inc., on behalf of a 37-year-old woman who suffered a pulmonary embolism after using the Ortho Evra contraceptive patch for seven months. The suit was filed U.S. District Court for the District of New Jersey.
According to the complaint in that lawsuit, from April 2002 through September 2003, the U.S. Food and Drug Administration logged 9,116 reports of adverse events because of the patch.
This is significant since there were only 1,237 adverse reports by women taking the leading oral contraceptive, Ortho Tri-Cyclen, over a six-year period even though that drug was used by almost six times as many women as Ortho Evra in 2003.
Ortho-McNeil has routinely denied the allegations that these deaths and injuries were the result of Ortho Evra risk factors. It claimed that the “unsolicited reports” it received were not reliable evidence of a problem with the drug.
The company also claimed its own investigation had not found any causal factor linking these deaths to Ortho Evra and relied on the absence of any reports of fatal adverse side-effects during the clinical trials as proof of the drug’s safety.
Ortho-McNeil’s reluctance to accept even the possibility that the patch could be at fault has lead to the drug being kept on the market without adequate warnings. Even the company’s press release and FDA advisory regarding new labeling requirements do not satisfy the patch’s many critics.
In the eyes of those critics, the fact that Ortho-McNeil notified the FDA that it has undertaken a “much larger study” with respect to the potential problem of blood clots, strokes, and death associated with the patch merely prolongs the time in which millions of women are exposed to an unacceptable risk of catastrophic injuries and death.
In addition to the rather cryptic press release issued by Ortho-McNeil in November 2005 concerning the serious risks associated with its Ortho Evra birth control patch, the FDA published its own information for consumers wishing to learn more about those potentially fatal side-effects (http://www.fda.gov/bbs/topics/news/2005/NEW01262.html) as well as a series of questions and answers.
Some of the more telling remarks in the FDA material follow:
“FDA is announcing a revision to the label for the drug Ortho Evra. This change includes a new bolded warning about higher exposure to estrogen. Higher levels of estrogen may put some women at increased risk for getting blood clots.”
“A woman on Ortho Evra may be exposed to approximately 60% more estrogen than if she were taking a typical 35 microgram estrogen birth control pill. Estrogen use is linked to blood clots in the legs and lungs and other clotting problems such as strokes and heart attacks.”
“In general, a woman may be at higher risk for getting side effects if she takes higher doses of estrogen. Women should discuss with their health care professional whether the Ortho Evra patch is a good method of contraception for them.”
Following the November 2005 Ortho-McNeil Press Release and FDA Advisory, there have been several reports of doctors and other healthcare providers curtailing or even suspending the prescribing of the patch.
The Wall Street Journal (WSJ) reported that: “Many doctors have stopped writing prescriptions for a popular form of birth control after the Food and Drug Administration warned earlier this month of increased hormone exposure to women who use it.”
According to the WSJ: “[A] number of individual practitioners and major health-care providers say they don't want to take any chances. In Memphis, Tenn., obstetrician and gynecologist Henry Sullivant says he has stopped writing new patch prescriptions and suggests that his roughly two dozen patch users try other forms of prescription contraceptives, such as the pill or a monthly vaginal ring. Pennsylvania State University, which provides health services for 42,000 students, is no longer issuing prescriptions and says it is considering whether to contact all students who have been given prescriptions for Ortho Evra, even if they are no longer at the university.”
In a effort to exercise caution, similar actions are being taken by many other university health officials including those at the University of Texas at Austin, Stanford University, the University of California, Berkeley, and Connecticut College in New London, Connecticut where one patch user experienced a blood clot in her lung last spring.
In addition “Lee Shulman, incoming board chairman of the Association of Reproductive Health Professionals, says he expects that ‘there will be a decrease in use’ of Ortho Evra, at least over the next several months. He adds that he has been inundated with doctor and patient phone calls asking whether the patch is safe to use.”
A number of litigation attorneys we spoke with, who are familiar with pharmaceutical litigation, agreed that it is becoming more difficult for doctors and major healthcare providers like colleges and universities to ignore the mounting evidence and warnings and simply write thousands of prescriptions for the patch. The percentages indicate that when that many prescriptions are written some of the women will suffer serious or fatal adverse reactions.
There are also many well-publicized law suits alleging deaths and catastrophic injuries from the very side-effects contained in the November 2005 warning. Thus, any doctor writing a prescription for the patch from that point on is doing so at his or her peril. Given the potentially fatal side-effects of the drug, writing a prescription now could be considered irresponsible in terms of good and accepted medical practice especially if an otherwise healthy woman is paralyzed or dies from a stroke caused by blood clots after using the patch.
Thus, it is not surprising that so many healthcare providers are rethinking their policies and recommending alternative medications to their patients. The patch, like many oral contraceptives, contains two hormones, a progestin and an estrogen. The progestin in Ortho Evra is a new drug (2001) known as norelgestromin, and the estrogen is an existing one known as ethinyl estradiol.
Ortho Evra was approved by the Food and Drug Administration (FDA) in November 2001 and is the first contraceptive product to be approved as a skin patch. It was launched and marketed in a series of “glitzy” television ads featuring “sexy models.” (CBS 11/2/05).
As Lorie Brown, Alycia’s grieving mother, told reporters: "I'm out to let people know: get off (Ortho Evra). That's my biggest goal here. I didn't save her life, but maybe I can save somebody else's." It seems that many responsible doctors and major healthcare providers are trying to do the very thing.
Many experts, consumer watchdog groups, and critics of the FDA drug approval process in general, and Ortho Evra in particular, believe the dangers presented by the patch should have been obvious to the FDA before the drugs approval. They are also concerned by the FDA’s position that it intends to do nothing at present because it considers the information regarding the risks posed by Ortho Evra merely “preliminary.”
NICOTINE REPLACEMENT THERAPY
One of the most popular NRTs (nicotine replacement therapies) is the nicotine transdermal patch. The patch was first marketed in the U.S. by prescription only in 1992. By 1996 it could be purchased OTC (over-the-counter). Available brands include Habitrol, NicoDerm CQ, and Nicotrol.
The patch comes in several different strengths and is applied once a day in the morning. It is supposed to be removed just before going to bed. Wearing the nicotine patch to bed can disrupt sleep and cause vivid dreams.
A patient should not change brands without consulting a doctor and should not attempt to adjust dosages by cutting a patch in pieces. If the patch does not work in 4 to 10 weeks, it is unlikely that the patch will be successful.
Patients are cautioned to never use 2 patches at once. Patches should not be removed from their wrappers until ready for use and should never be stored at temperatures higher than 86 degrees Fahrenheit.
Side effects cannot be anticipated with respect to this patch. Thus, users are cautioned to monitor their reactions and to consult a doctor immediately if any occur or change in degree.
Common side-effects include; dizziness, high blood pressure, itching and burning at the application site, nausea, redness of the skin. Less common, but more serious side-effects may include; abnormal dreaming, allergic reactions, back pain, chest pain, constipation, cough, diarrhea, drowsiness, dry mouth, headache, impaired concentration, indigestion, inflammation of sinuses, menstrual irregularities, numbness, pain, pins and needles sensation, rash, sleeplessness, sore throat, stomach pain, sweating, taste changes, tingling, vomiting, and weakness.
NRT patches should not be used by people who are sensitive to or have ever had an allergic reaction to nicotine. Also, users are cautioned to monitor their condition if they have ever had a bad reaction to a different brand of nicotine patch or to adhesive tape or other adhesive material.
Patch users are warned not to smoke, chew, or sniff any form of tobacco while wearing a patch since doing so can produce a nicotine overdose. Moreover, for several hours after a patch is removed, nicotine is still in a user’s skin and passing into the bloodstream. Thus, users should not smoke even when the patch is removed.
Users are also warned that nicotine patches may aggravate certain medical conditions. Before you use any brand of nicotine patch, make sure your doctor knows if you have, or have ever had, any of the following conditions:
- Allergies to drugs, adhesive tape, or bandages
- Chest pain from a heart condition (angina)
- Diabetes requiring insulin injections
- Heart attack or heart disease
- High blood pressure (severe)
- Irregular heartbeat (heart arrhythmia)
- Kidney disease
- Liver disease
- Overactive thyroid
- Skin disease
- Stomach ulcer
Since the safety and effectiveness of nicotine patches have not been tested in children. OTC Nicotrol is not for use by children under age 18. Moreover, because a used nicotine patch still contains enough nicotine to poison a child or a pet, used patches must be disposed of with special care. There is a risk that if nicotine patches are used with certain other drugs, the effects of either could be increased, decreased, or altered. Thus, users are warned that it is especially important to check with a doctor before combining nicotine patches with any of the following:
- Acetaminophen-containing drugs such as Tylenol
- Caffeine-containing drugs such as No Doz
- Certain airway-opening drugs such as Isuprel, Dristan, and Neo-Synephrine
- Certain blood pressure medicines such as Minipress, Trandate, and Normodyne
- Cimetidine (Tagamet)
- Haloperidol (Haldol)
- Imipramine (Tofranil)
- Lithium (Eskalith, Lithobid)
- Non-nicotine quit-smoking drugs such as Zyban
- Pentazocine (Talwin)
- Propranolol (Inderal)
- Theophylline (Theo-Dur)
Although the patch is used to stop smoking, it is a source of significant amount of nicotine and, thus, may also be harmful to an unborn baby.
Since nicotine passes easily into breast milk, the patch should not be used during breastfeeding. Smoking while wearing a patch gives the user a "double dose" of nicotine; if the user is pregnant or breastfeeding, the baby will also get a "double dose" of nicotine.
EMSAM (SELEGILINE) TRANSDERMAL PATCH FOR DEPRESSION
Only last week, the Food and Drug Administration (FDA) 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 8th 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.”
DURAGESIC (FENTANYL) PAIN PATCHES
One of the most problematic transdermal patches has been the one containing the powerful painkiller fentanyl. In fact, in July 2005, the FDA announced that it was investigating claims that the patch was responsible for some 120 deaths up to that point.
The Duragesic patch (Johnson & Johnson) was designed to provide up to 72 hours of relief from severe chronic pain associated with such conditions as bone cancer. Fentanyl, however, is a dangerous drug and an overdose of the narcotic (100 times more potent than morphine) can induce a coma and shut down breathing. Thus, improper administration of the drug or problems with the patch itself can have fatal consequences if either cause too rapid a release of the medication into the bloodstream.
Healthcare professionals and patients should be aware of the signs of fentanyl overdose, which include; troubled or shallow breathing, tiredness, extreme sleepiness, inability to think, talk or walk normally, and feeling faint, dizzy or confused. Patients experiencing these symptoms should get medical attention immediately.
Because of the extremely serious risks associated with this patch, Duragesic and its generic equivalent already carry a "black box" warning from the FDA. The FDA advised doctors to prescribe the lowest effective dose of the medication and not use fentanyl patches to treat short-term pain, or pain after an operation.
Patients were also warned not to use any patches that are damaged or broken and to not drink alcoholic beverages or bask in the sun while taking the drug because alcohol and a rise in body temperature can accentuate its effects.
In a strange story from October 2005, a West Virginia woman, who had been working as a nursing home aide, pleaded guilty to “neglect of a vulnerable adult” after admitting she removed a patient’s time-release pain patch in order to suck out the medication.
The former aide, 21-year-old Megan Oglesbee, was sentenced to 18 months in jail (suspended) and three years supervised probation. She must, however, complete substance abuse treatment and has been barred from caring for “vulnerable adults” in the future. A fine of $1,000 was also suspended by the judge.
The Attorney General’s office claimed that on October 15, 2004, while Oglesbee was a nursing assistant at Moran Manor Nursing Home in Westernport, West Virginia, a patient in her care had been prescribed a 72-hour transdermal pain patch.
The day after the patch had been applied; Oglesbee removed it, stuck a pin in the patch, and sucked out the medication. She then asked another nursing assistant to help her reapply the patch to the patient. When the second assistant became suspicious, Oglesbee admitted what she had done.
METHYLPHENIDATE TRANSDERMAL SYSTEM FOR ADHD
Late last year, FDA reviewers have concluded that an experimental skin patch designed to treat ADHD in children is 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 rejected the patch because induced high rates of anorexia, insomnia and weight loss in children when used for 12 hours.
The drug makers, Britain’s Shire Pharmaceuticals Group Plc, and U.S. Noven Pharmaceuticals Inc., have since conducted further tests, hoping to prove that MTS was safe and effective when used for 9 hours. The companies plan to market the patch as Daytrana, for use in children 6-12 years old.
But 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.
According to the FDA staff: "The safety and tolerability profile of MTS treatment in these two new studies does not appear to be significantly more acceptable than that in the previous MTS submission."
The companies claim that the problems cited are no worse than ones that arise from pill versions of the medication. Experts say that while some of these side-effects do occur with the pills, the problems were more prevalent with the patch.
One serious drawback to this patch is that up to 22% of those who used the patch became so sensitive to it that they could never take the drug methylphenidate again, in any form.
FDA scientists also fear that abuse of the drug will occur with the patch, as it does with the tablet version. Studies show that Ritalin and other ADD and ADHD drugs are currently some of the most abused pills among youth and teens.
The biggest threat, experts say, would be children sharing the patch. But since the patch takes two to three hours to take effect, drug abusers would not get the same rush or high as they would get from taking a tablet.
All of the documents can be accessed online at http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4195B-index -with-disclaimer.htm/.
Thus, despite the manufacturer’s claims that the ADHD patch is no more dangerous than existing pill versions of the medication, it would seem that the FDA cautious approach is fully justified. While the advisory committee recommended approval, it did so only in the case of children who could not swallow pills.
FDA TO INVESTIGATE THE TRANSDERMAL PATCH ISSUE
Since the safety of medications delivered by way of transdermal patches seem to present common problems, the FDA has decided to investigate the matter.
The agency will look at a number of factors that may affect absorption rates including the introduction of heat to the products themselves. Many experts claim that increasing the temperature of any transdermal patch will increase the absorption rate of the drug involved.
Several studies have shown that heat has a marked effect on absorption. For example, a1986 study found that 20 minutes of bicycling with a nitroglycerin heart medication patch increased concentration of the drug 200% to 300%. Similar results were found after half an hour in a sauna.
There is also the fact that the concerns associated with some of the more inherently dangerous drugs, or drugs that may become dangerous when taken in higher than recommended dosages, may not apply to medications where an increase in the absorption rate is less problematic.
Clearly, transdermal patches are convenient, ensure compliance with a drug regimen in people with problems remembering their medication schedule, and are particularly useful with drugs that require only lose dosages.
Before transdermal patches can be regarded as an acceptable and safe “delivery system,” however, much more research appears to be necessary. It may very well turn out that “patches” simply cannot be used for certain drugs that pose unacceptable risks when absorption rates may vary to the point of causing a dangerous overdose or other adverse reaction.
(Sources: Public Citizen – Worst Pills Best Pills; CBS News; Associated Press; Food and Drug Administration Web Site; Los Angeles Times; San Francisco Inquirer; Wall Street Journal; Newsinferno.com Archives)