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)