Tuesday, December 16, 2008
Johns Hopkins Health Alerts:
The Connection Between Sedatives and
Fractures in Elderly Patients
All drugs have potential side effects. Indeed, at some point you've probably squinted down the laundry list of possible side effects on the package insert of your medications. Common drug-related side effects include blurred vision, drowsiness, dizziness, dry mouth, heart palpitations, erectile dysfunction, memory impairment, and nervousness. Fortunately, many of these drug side effects occur in only small numbers of people.
Now researchers have called into question the connection between sedatives which can cause dizziness and the potential for falls in elderly patients. They point out that well-meant policies discouraging sedative use in older people to prevent falls and fractures may not be necessary.
Starting in 1989, New York State required doctors to fill out prescriptions in triplicate for benzodiazepines, the most widely used class of sedatives. Twenty-one months later, use of these drugs plummeted by more than half. However, the number of hip fractures did not fall accordingly.
Benzodiazepines can make elderly people unsteady on their feet, potentially increasing the risk of falls and hip fractures. Policy makers hoped that restricting access to these drugs might help prevent these fractures. In fact, since January 2006, benzodiazepines have been excluded from coverage under the Medicare drug benefit.
But this study, which was reported in the Annals of Internal Medicine (Volume 146, page 96), did not confirm the alleged link between hip fractures and benzodiazepines. Thus, Medicare beneficiaries may not receive a class of drugs that might, in appropriate situations, benefit them. Commonly prescribed benzodiazepines include Xanax (alprazolam), Librium (chlordiazepoxide), Valium (diazepam), and Ativan (lorazepam).
Monday, December 15, 2008
Isotretinoin in India: A tragedy in the offing
Wednesday, March 28, 2007 08:00 IST
Isotretinoin is the drug of choice for severe calcitrant cystic acne vulgaris, which often causes scarring and depression from disfigurement. Isotretinoin has been called "the greatest medical advance of the 1980's." A majority of patients with acne are permanently cleared after a four to five months course of treatment. It has also been used off-label for a variety of oncology uses including: cervical cancer, head and neck cancer, squamous cell cancer of the skin, juvenile chronic myelogenous leukemia (CML), and neuroblastoma. However, the drug is a proved teratogen and carries a significant risk of birth defects, if it taken during pregnancy. Birth defects, which have been documented following isotretinoin exposure include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, and thymus and parathyroid glands. There is an increased risk of spontaneous abortion and premature births have been reported. Hence, women who are pregnant or who might become pregnant are strictly advised against its use.
The drug was initially made available under a risk management programme -System to Manage Accutane Related Teratogenicity (SMART) - by Roche Pharmaceuticals, which marketed Accutane, the innovator isotretinoin product. Under SMART, stickers were provided by isotretinoin manufacturers to physicians who registered to become authorised prescribers of the drug and valid prescriptions for isotretinoin must bear a yellow sticker signifying that the woman presenting the prescription has twice tested negative for pregnancy before initiating therapy. To meet its goals, SMART relied on unauthorised physicians to refrain from prescribing isotretinoin and pharmacists to refuse to fill prescriptions unless they bear the sticker. Another key element was that authorised physicians must not affix the sticker to a woman's prescription unless a properly timed negative pregnancy test result was obtained.
Strengthened distribution programme for isotretinoin
The generic versions of the drug entered into the market in late 2002, with each manufacturer providing the drug through separate risk management programmes modelled after SMART. Recently, the United States Food and Drug Administration (US FDA) announced approval of a strengthened distribution programme for isotretinoin, called iPLEDGE, aimed at preventing use of the drug during pregnancy. The iPLEDGE programme is a computer-based risk management programme, designed to further the public health goal to eliminate fetal exposure to isotretinoin through a special restricted distribution programme approved by the US FDA and has been fully implemented on March 1, 2006. The programme strives to ensure that:
No female patient starts isotretinoin therapy if pregnant;
No female patient on isotretinoin therapy becomes pregnant.
Thus, the iPLEDGE programme requires registration of all wholesalers distributing isotretinoin, all healthcare professionals prescribing isotretinoin, all pharmacies dispensing isotretinoin, and all patients prescribed isotretinoin. To obtain the drug, patients must comply with a number of key requirements that include:
(1) Being registered with iPLEDGE,
(2) Completing an informed consent form,
(3) Obtaining counselling about the risks and requirements for safe use of the drug,
(4) And, for women of childbearing age, complying with necessary pregnancy testing. A female of childbearing potential selects and commits to use two forms of effective contraception simultaneously for one month before, during, and for one month after isotretinoin therapy. She must have two negative urine or blood (serum) pregnancy tests with a sensitivity of at least 25 mIU/ml before receiving the initial isotretinoin prescription.
Each month, the prescriber must enter the female patient's pregnancy results and the two forms of contraception she has been using in the iPLEDGE system. The iPLEDGE system verifies that all criteria have been met by the prescriber, patient, and pharmacy prior to granting the pharmacy authorization to fill and dispense isotretinoin. The pharmacist must obtain authorization from the iPLEDGE system via the programme website prior to dispensing each isotretinoin prescription for all the patients. The FDA approved this programme under its regulations, known as Subpart H, that require restrictions on the distribution of a drug to assure safe use.
After patent expiry of the drug in February 2002, a number of generic versions of isotretinoin were launched in India and the drug was made available for the treatment of acne. But, the fact that isotretinoin is a wonder drug for treatment of acne and that its formulation is so easily accessible in India without even a prescription, raises concern. Implementation of a web-based programme on the lines of iPLEDGE is neither feasible nor practical in India. Though isotretinoin manufacturers have taken care to warn the patients regarding teratogenic potential of the drug by including the details in package insert and with the help of appropriate warning on labels, this simply does not suffice the purpose. It is the moral responsibility of all the formulation manufacturers in India to forward the information regarding risk potential of isotretinoin to dermatologist as well as patients. Both the manufacturing concerns as well as dermatologists should make sure that the important information should be passed on to the patient especially woman of childbearing age. Thus, before the patient receives his/her isotretinoin prescription, the prescriber must counsel the patient about the risks of isotretinoin. The drug authorities will have to gear up all the isotretinoin manufacturing concerns to come together and to make sure that the drug is used safely and with all precautionary measures being taken especially for patients of childbearing age. If adequate measures are not taken early and the drug is continued to be freely available in our country, we may be heading for a thalidomide-like tragedy of 1960s. Hence, this delicate issue must not be ignored any further and the availability of this valuable, effective medication should be regularised through a restrictive distribution programme.
Douglas Pharmaceuticals Ltd. Oratane data sheet 24 May 2001. http://www.medsafe.govt.nz/Profs/Datasheet/o/oratanecap.htm
Roche Products (New Zealand) Ltd. Roaccutane data sheet 24 May 2001. http://www.medsafe.govt.nz/Profs/Datasheet/r/Roaccutanecap.htm
Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am Acad Dermatol 1992;26(4):599-606.
(The author is an assistant professor,GVM College of Pharmacy,Murthal Road, Sonipat)
- Dr Ramanand Nadig
President Operations and
Clinical Research Education and Management Academy (CREMA)
Genes are segments of DNA present in the chromosomes in the nucleus of every cell. Genes carry instructions for making proteins, which are then copied by special enzymes into many copies of messenger RNA (mRNA). The mRNA then comes out of the nucleus, into the body of the cell; where it goes on to create the proteins needed for everyday life. Faulty or mutated genes lead to malfunctioning proteins that cause disease. Gene expression can be blocked by restricting the ability of chromosomal DNA to be copied into RNA and made into proteins. This research has given the lead wherein the ways to correct genetic disease by changing mutant gene sequences to its normal has been made possible.
Cancer patients will be the prime beneficiaries of gene silencing. Dr Rohit Joshi, Medical Oncology, Assistant Professor, Department of Medicine, Christian Medical College, Ludhiana, says, "The process of gene silencing is important for the differentiation of many different types of cells. Gene silencing or Ribonucleic Acid Interference (RNAi) has been described as one of the major science breakthroughs. It is a revolutionary technology, but it has many limitations. The exaggerated hope is that it will cure everything. Most of the research in this field has been in botany, with major potential seen in human research. Every few months a newer and better way to do something is revealed, but it is every few years that something of real worth is discovered or invented. Gene silencing is meant to fit into the latter category." He adds, "The prospects for this technology in developing therapeutic applications for diseases including cancers, autoimmune dysfunctions and viral infections are enormous. Additionally, it can be used as a tool for determining gene function. If you can selectively switch off a gene, you can then observe its biological function."
Safety and quality issues have always dogged the vaccine sector, and when the National Regulatory Authority was recently de-recognised by the World Health Organisation, it took down the reputation of domestic vaccine players with it. Aashruti Kak reviews past and present vaccine controversies
Since the inception of vaccination in the late 18th century, there have always been concerns over the morality, ethics, effectiveness, or safety of vaccination. However, the general medical belief has been that the benefits of preventing various diseases, and therefore, death from infectious diseases offset the risks of adverse effects following immunisation. This reasoning is justified, as prevention is always better than cure. Vaccines have proved to be a much more cost-effective strategy to promote and protect health compared to treatments of acute and chronic diseases. In fact, vaccines have saved more lives than all the 'wonder drugs' put together.
It is only in the 1990s that vaccines started to attract controversies because of certain rumours about various side-effects, that they may cause, including auto immune disorders, autism and so on. Safety will always be a primary concern, but it is normally understood that all vaccines may cause side-effects. One such controversy that has managed to stay alive till date is the presence of thiomersal (International Nonproprietary Names—INN), commonly known as thimerosal, in vaccines. This is a mercury containing antifungal widely used as a preservative to prevent life threatening microbial contamination. Although US Food and Drug Administration (USFDA) has found no evidence of harm from the use of thimerosal as a vaccine preservative, other than local hypersensitivity reactions, there is a theoretical possibility of thimerosal being neurotoxic. However, with frequent modifications in manufacturing technology, the need to add preservatives during manufacturing has gone down.
There are still many companies that use the preservatives in their drugs and biologicals. Dr Suresh Jadhav, Executive Director, Serum Institute of India Limited (SIIL), says, "Some of our vaccines and those of other companies available in the market do still contain thimerosal as a preservative. There is a clear Position Paper of WHO, and now even the Centre for Disease Control and Prevention (CDC) of USA, that acknowledges the fact that thimerosal has not been found to be responsible for any of the adverse events or neurotoxicity, which has been caused following the use of vaccines containing the organomercurial." He adds, "There is a clear guidance as per WHO that a vaccine that is distributed in multi-dose containers must contain preservatives. However, some vaccines which are available in mono dose/single dose containers are preferred without preservatives." SIIL is currently working on meningococcal A conjugate vaccine, measles aerosol vaccine, rotavirus vaccine and seasonal pandemic influenza vaccine.
In today’s safety conscious world, it becomes imperative for companies and governments to be extra cautious to earn the trust of the population they are serving, otherwise incidents like the measles vaccine deaths in Tamil Nadu (April 2008) and Aurangabad (September 2008) cannot be controlled or curbed. It becomes even more important during an outbreak of a disease, where one of the most vital steps in ensuring protection is to monitor vaccine safety, because during an emergency, more vaccines are given, which could lead to more adverse events; more rare and serious adverse events may occur because people of all ages and health conditions would be vaccinated; and most importantly, the usual testing of a vaccine before its widespread use may be shortened to speed up its availability.
"In case of an epidemic/outbreak, to the best of my knowledge the Indian Government has a system in place. They have various laboratories under their control such as National Institute of Communicable Diseases (NICD), National Institute of Virology (NIV), National Aids Research Institute (NARI), and several laboratories working under Indian Council of Medical Research (ICMR)," says Jadhav. He continues to say that with respect to the benefits of vaccination, if a vaccine is already available against the outbreak/disease, then it can be used in the population in and around the centre of outbreak. "There is no question of using a vaccine, which is 'hurriedly' tested. All the vaccines need to be fully tested by the manufacturing laboratories, and then, are also to be tested/released by the National Control Laboratory; only then the product can be actually distributed and used. In view of this, the question of causing more adverse events using hurriedly tested vaccine does not arise," he adds.
In the US, it has the the Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance programme co-sponsored by the FDA and the Centers for Disease Control and Prevention (CDC), that detects and analyses possible adverse events that occur after the administration of US licensed vaccines so scientists can find out if it is the vaccine that is causing health problems.
Regulatory compliance issues in India
As of today, there are five Indian vaccine manufacturers who are pre-qualified by WHO for supplies to UN agencies, says Jadhav. These manufacturers, in addition to catering to the Indian requirements, both in the private market as well as government programmes, also meet 65 to 70 percent requirement of UN agencies for Bacillus Calmette-Guérin (BCG), tetanus toxoid (TT), diphtheria and tetanus toxoid (DT), diphtheria, tetanus and pertussis (DTP), measles, rubella, measles and rubella (MR), measles, mumps and rubella (MMR), polio, rabies, hepatitis-B and haemophilus influenza type-B vaccines. "In fact, one of the UN Millennium Development Goals was to reduce mortality due to measles by 50 percent in Africa by 2010 as against what was in 1997. In reality, this has been achieved much earlier ie before November 2007, and that too not only 50 percent.
Mesenchymal stem cells might be the answer to spinal cord injury
In India, 20,000 new cases of spinal cord injury are added to the list every year, as compared to 11,000 in US and 700 in UK. Stempeutics Research has done a pilot study on the application of mesenchymal stem cells in spinal cord injury. Patients with fresh injuries have responded well to this therapy. Although many cell types contribute to organ repair in spinal cord injury, bone marrow mesenchymal stem cells have the greatest potential for repairing the spinal cord injury. Stempeutics has collaborated with Manipal Hospital for these pilot studies.
GSK adds CHF boxed warning on Avandia label
Friday, August 17, 2007 10:00 IST
GlaxoSmithKline announced that the US Food and Drug Administration (FDA) has approved updated US prescribing information for the thiazolidinediones (TZD) class of medicines used in the treatment of type 2 diabetes. This approval allows GSK to implement changes in the label for Avandia (rosiglitazone maleate) as previously committed.
The label will contain a boxed warning, which increases the prominence of an already existing warning for all medicines in the TZD class on the risk of congestive heart failure (CHF), a well known and well characterized risk in this class of medicine. The boxed warning also will note that TZDs are not recommended in patients with symptomatic heart failure, and that initiation of TZDs in patients with established NYHA class III or IV heart failure is contraindicated.
The contraindications have also been updated regarding initiation of Avandia in patients with Nyha class III or IV heart failure.
Information about CHF has been included in the prescribing information for Avandia since 1999, when the medicine was first approved by the US Food and Drug Administration. Since 2001, US prescribing information for Avandia has included a warning for "Cardiac Failure and Other Cardiac Effects" with a recommendation that use of Avandia be discontinued in patients if their cardiac status worsened.
The changes related to CHF are being implemented on the labels of all rosiglitazone-containing products: Avandia, Avandamet (rosiglitazone maleate and metformin hydrochloride) and Avandaryl (rosiglitazone maleate and glimepiride).