Buclizine Hydrochloride, an antihistamine known mainly for its antiemetic action was recently introduced in Goa two months ago as an appetite stimulant by UCB India Pvt Ltd. This product has been marketed for the same indication in most of the cities in India for some years now.
The carton of the 200 ml Buclizine Syrup pack mentions the indication ‘‘For increase in appetite and weight gain’’ below its registered trade name of the product, Longifene. The formulation contains six mg of buclizine hydrocholoride BP for every 5 ml of the flavoured syrup.
The company’s literature to doctors includes, among others, a comparison of longifene with cyproheptadine, delineating the superiority of the former over the latter as an appetite stimulant on various counts, citing three references.
According to experts, in the absence of readily available information, there are two ways at looking into this issue. One is the regulatory approval for this indication from the DCGI, and the other is evidence-based scientific data for the said indication.
This correspondent tried in vain to elicit information about the appetite stimulation indication, both from the DCGI office and the company. No confirmation was forthcoming from the DCGI office readily with the Dy Drug Controller saying, ‘‘May be the company could have taken approval previously when they applied for antihistamine...’’ adding that it is not possible to get the old records easily and instead requested us to get information from the company.
The medical head of the company also said that he would have to check records and asked for time citing that it was a pre-1993 product when UCB was promoting longifene jointly with another Indian company. He, however, added that the promotion was ‘‘Ethical and does not go against the law of the land.’’
Among the various anti-neurotic drugs evaluated by the National Academy of Sciences in the US in 1966-68 period, the US FDA ordered many drugs to be withdrawn from 1968 to 1974 based on reports of experts reasoning that the clinical trials were underpowered controlled trials often with heterogenous population. Buclizine was one of the drugs withdrawn, but it was mentioned that it may be effective for nausea. This is cited by Brian P A and Stern L H in The drug efficacy study 1962-1970 FDA Papers, vol 4, pgs 14-17, 1970.
The article ‘‘Buclizine- an orexigenic and eutrophic agent’’ by Rajadhyaksha et al in Indian Medical Gazette, November 1998, mentions that ‘‘The exact mechanism of action of buclizine in promoting weight gain is not elucidated, but mild hypoglycaemia is caused...’’ This is incorrect as all classical antihistamines as a group modulate serotonergic, noradrenergic and acetyl choline receptors in CNS and their responses do involve appetite control.
Buclizine, by its chemical structure, is a highly lipophilic compound. If taken over longer periods for appetite stimulation, it’s entry into brain/CNS can create increased drowsiness. A UCB-R&D clinical research dept report cited in the journal says that the only side effect noted was a transient drowsiness. Perhaps, a ‘log P factor’ study for buclizine as per the Norinder Haeberline Rules needs to be carried out and studied by the R&D team. Pharmacokinetic data on absorbtion, distribution and elimination in humans is apparently not known.
The same paper while talking of buclizine as causing a condition of anoxia, resulting in increased peripheral utilisation of glucose leading to increased appetite and weight gain, forgets to mention about the highly dangerous lactic acidosis phenomenon. Tissue anoxia leading to increased anaerobic glycolysis is the exact mechanism by which phenformin causes lactic acidosis. This drug was therefore banned. Question is, are there any buclizine studies recording an increase in blood lactate levels even in small study population?
Again, Dhoble and Phadke’s paper in ‘The Indian Practitioner’, March 1981, also cited in Rajadhyaksha’s paper, studying buclizine’s weight gain in children ( 37 completed the trial ) has a ‘mean’ increase in weight of just about 1.0 kg difference between the study and placebo groups. There is a wide variation in weight gain from 1.0 to 5.0 kg in the study group and from 0.5 to 4.0 kg in the placebo group. Researchers do not consider such results on a small study group as statistically significant.
Even as it may be laudable to promote an economical drug at 70 paise per tablet for such indications, can the claims based on such small groups stand scrutiny for approvals by the regulators? Study in large numbers — usually 3000 to 5000 patient study — is necessary. The drug industry knows that a large number of drugs have fallen off after such studies.
As there are concerns as cited above for buclizine and the past history of cyproheptadine being well known, drug regulatory authorities in India need to take a decision whether the current practice of promoting antihistamines for appetite stimulant indication is evidence based.
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