Oxytocin formulations

Faulty prescription

Print edition :

Oxytocin vials being readied for injecting buffaloes for increased supply of milk in Machilipatnam, Andhra Pradesh. Photo: T. Appala Naidu

Citing grave misuse of oxytocin in milch animals, the Centre restricts the manufacture and retail sale of the drug used to prevent postpartum haemorrhage and excessive bleeding after childbirth.

ON June 27, the Union Ministry of Health and Family Welfare issued a notification restricting the manufacture of oxytocin formulations for domestic use. The notification ordained that, beginning July 1, no private firm would be allowed to manufacture the drug and that only Karnataka Antibiotics and Pharmaceuticals Limited (KAPL), a public sector undertaking, would be allowed to produce it. The Ministry had earlier issued a notification banning the import of oxytocin and its formulations. The notification also stated that KAPL would supply oxytocin to registered hospitals and clinics in the public and private sectors directly and that oxytocin would not be allowed to be sold through a retail chemist in any form or name.

The dictionary defines oxytocin as a hormone found in all mammalian species. It is “produced by the hypothalamus and secreted by the pituitary gland. It is also synthetically produced and used for inducing and augmenting labour as well as in arresting postpartum haemorrhage (PPH) in pregnant women. (Blood loss of 500 millilitres or more in the first 24 hours after birth is a known cause of maternal mortality.) It is also called the bonding hormone.”

Its use in milch animals to induce contractions of smooth muscles and increase milk supply has been a subject of debate, more so in the context of India and its bovine politics.

On April 27, the Ministry issued a gazette notification restricting the manufacture of oxytocin citing a Himachal Pradesh High Court order of March 2016 (CWP of 2014), which had observed that there was large-scale clandestine manufacture and sale of oxytocin and “grave misuse” of the drug in animals and humans. The court order had also suggested that the feasibility of restricting the manufacture of the drug to public sector companies and limiting it to those companies to which licences had been given should be considered.

On February 21, the Drugs Technical Advisory Board (DTAB) examined the matter and recommended the regulation, restriction and supply of the formulations to registered hospitals and clinics in the public and private sectors. The objective was to prevent misuse of the drug. The Central government felt that in the light of these suggestions, it was prudent to regulate and restrict the manufacture and sale of the drug in the public interest. Interestingly, the same government has been found wanting in restricting the manufacture and use of many irrational formulations peddled by the pharmaceutical industry. The intriguing question, therefore, was: why oxytocin? While the drug for domestic use would be manufactured only by public sector companies, the government did not place any restriction on the manufacture of oxytocin formulations for export, which would be open to public and private sector companies.

The Centre’s move was initiated a few months before the general elections in 2014. On January 17, 2014, the United Progressive Alliance government issued a gazette notification directing manufacturers of bulk oxytocin drug to supply the active pharmaceutical drug only to manufacturers licensed under the Drugs and Cosmetic Rules, 1945, for the manufacture of formulations of the drug, and stated that the formulations for veterinary use would be sold to veterinary hospitals only.

On October 22, 2014, a little over five months after the formation of the National Democratic Alliance (NDA) government led by the Bharatiya Janata Party (BJP), the Central Drugs Standard Control Organisation (CDSCO) under the Directorate General of Health Services (DGHS), issued a letter to all State Drug Controllers asking them to maintain regulatory control over the manufacture, sale and distribution of oxytocin and suggesting measures to curb its misuse by dairy owners. There was no reference to its use or misuse in human beings.

Gazette notification

Referring to the Government of India’s gazette notification of January 2014, it said, “manufactures of the bulk oxytocin drug would supply the active pharmaceutical drug only to the manufactures licensed under the Drugs and Cosmetic Rules, 1945”, for the manufacture of oxytocin and its formulations and that the formulations meant for veterinary use would be sold to veterinary hospitals only. The CDSCO’s letter also cited Minister for Women and Child Development Maneka Gandhi as having “taken up the matter” with the Secretary, Ministry of Health. She had stated that “the misuse of oxytocin was leading to a substantial loss of livestock in the country”. The Minister had pointed out that not only did the drug make cows barren sooner than normal it also lowered the lifespan of the animal, thus causing economic loss to the cattle owner in the long run. She said oxytocin was being widely used in the dairy industry despite there being a ban on its sale, except by prescription from a registered medical practitioner.

An inter-ministerial committee constituted by the Health Ministry to examine the misuse of oxytocin noted (quoted in the CDSCO letter), that “there was a need to take stringent measures on all cases of misuse of oxytocin by the State Drug Control Authorities in their State/UT and a constant vigil needed to be kept on the illegal movement of oxytocin. The State/UT drug inspectors after picking up the samples from different places should investigate the source of the illegal supply of the oxytocin concoction sold to dairy owners”.

In order to locate the illegal sale of oxytocin, it was suggested that the help of non-governmental organisations in the States/Union Territories could be sought. It was apparent in the CDSCO notification of October 2014 that the authorities were concerned about the drug’s impact on the milch animals. Its use for arresting PPH was not taken into account at all.

Oxytocin is the recommended uterotonic drug (which, according to Wikipedia, is an agent used to induce contraction or tonicity in the uterus), to prevent PPH in caesarean section deliveries.

A 2012 document from the World Health Organisation (WHO) reproductive health library (online), says: “PPH is the primary cause of nearly one-fifth of all maternal deaths globally. Most of these deaths occur during the first 24 hours after birth. The majority could be prevented through the use of prophylactic uterotonics during the third stage of labour, and by timely and appropriate management. It is generally assumed that by preventing and treating PPH, most PPH-associated deaths could be avoided. The prevention and treatment of PPH are, therefore, vital steps towards improving the health care of women during childbirth and the achievement of the Millennium Development Goals [MDGs]. To reach these objectives, health workers in developing countries should be given access to appropriate medications and be trained in procedures relevant to the management of PPH. Countries also need evidence-based guidance to inform their health policies and improve their health outcomes.”

The document refers to the recommendations of a Guideline Development Group (GDG) comprising independent experts who used evidence profiles to assess evidence on the effects of pre-specified outcomes, especially with regard to oxytocin improving maternal outcomes. After looking at the evidence profiles, the GDG recommended oxytocin as the uterotonic drug for the prevention of PPH in caesarean section deliveries and observed that carbotecin, a drug with similar effects as that of oxytocin, made no difference to the reduction of major obstetric haemorrhage and that it was more expensive than oxytocin. It was also under a patent, as per media reports.

Experts’ concern

Mira Shiva, former director of the Voluntary Health Association of India and a known public health practitioner, told Frontline that there was overwhelming evidence to show that oxytocin was “an essential and life-saving drug used for induction of labour in some cases where labour pains do not start even post due date”. It is used for the prevention of PPH by active management in the third stage of labour. Health workers are trained for this.

She pointed out that oxytocin was “very much included in the revised updated National List of Essential Medicines [NLEM] 2011 and was also on the list of NLEM 2015.” Bleeding, she said, was the chief cause of maternal deaths, as mothers were anaemic apart from being malnourished. Decreasing maternal mortality was the most important MDG that was not met. The alternative, misoprostol was not available and health personnel involved in conducting deliveries were not as familiar with its use as they were with oxytocin, she said.

“I have been checking out from across the country among those engaged with maternal health and rational use of drugs and found that they were unaware of the ban. Obviously investment in promoting rational use of drugs or conducting drug utilisation studies to identify misuse and address is grossly inadequate or non-existent with a lot of dependence on pharmaceutical sales representatives for drug-related information. We have been dealing with issues of irrational and hazardous drugs for decades that need banning, including 344 Fixed Dose Combinations [FDCs] banned by the Drugs Controller General of India based on the recommendations of the Kokate Expert Committee on FDCs. It is for the first time in my life that I have witnessed an essential and life-saving drug being banned from sales by chemists and manufacture by all excepting KAPL. Will there be a crisis with increase in maternal deaths due to non-access of an essential drug?” she said.

Mira Shiva wondered whether technical experts in the Ministry were consulted before the ban; whether efforts were made to prepare mothers suffering from anaemia and what the sources of unbiased drug information were. She recalled the closure of leading public sector pharma units and three vaccine-producing PSUs, which compelled the government to procure vaccines at twice the cost from the private sector. As the private sector could not meet the vaccine needs of the country, the pentavalent vaccine—a combination of five vaccines in one vial—entered the scene. Its efficacy has been questioned. “It is pertinent to ask how much of this is being done to address the misuse of oxytocin in dairy to increase milk extraction and how much to create shortage and then fill the vacuum by carbetocin, which is heat stable,” Mira Shiva said.

The public health expert Jashodhara Dasgupta said there was a need to monitor the inappropriate use and administration of oxytocin, referring to a paper co-authored by her on “Unmonitored Intrapartum Oxytocin use in Home Deliveries” on the basis of field studies in Uttar Pradesh, a State with high infant mortality rates and maternal mortality rates (MMRs).

A caesarean operation in progress at the Government Pentland Hospital in Vellore, Tamil Nadu. Oxytocin is used for preventing haemorrhage and thus plays a role in reducing maternal mortality.   -  handout

Public health practitioners and activists and organisations such as the Jan Swasthya Abhiyaan issued a statement urging the government to revoke the restriction on the manufacture and retail sale of oxytocin. It would be a great setback to efforts taken to reduce maternal mortality over the last few decades, the statement said.

It said there was “robust scientific evidence of oxytocin’s role and it was standard practice to use oxytocin as part of Active Management of Third Stage of Labour [AMSTL] in all deliveries”. The government, it said, had been “promoting the practice of AMSTL and put in significant efforts in training health care providers in AMSTL and improving availability of oxytocin at all levels of public health facilities. While there were gaps in the universalisation of AMSTL, the efforts needed to be greatly appreciated”.

In such a situation, confining the production to a single undertaking, was “akin to taking several steps backwards”, as it would affect the availability of the drug in private sector facilities and also in public sector facilities where drug procurement mechanisms were weak. The experts pointed out that alternatives such as misoprostol were proven scientifically to be inferior in the prevention and treatment of PPH.

Misuse of drug

The signatories to the statement concede that there was “evidence of irrational use of oxytocin to augment labour in women” as several studies had documented widespread misuse of oxytocin by front-line health care providers, even in community-level settings. This, they said, had serious consequences for both the woman and the newborn. Also, there was evidence of oxytocin misuse in animals to increase milk production. While acknowledging the need for regulation, “such regulation cannot be done at the cost of denying access to the drug given the serious implications for maternal health and a blanket ban such as that proposed will have immediate negative repercussions”, the statement pointed out. They emphasised that they were “strong supporters of strengthening the public sector production of medicines” and cautioned that the order could be “counterproductive” if alternatives to “ensure a steady and streamlined supply of this essential life-saving drug” were not ensured.

Interestingly, the Himachal Pradesh High Court’s March 2016 order, which the government notification of June 27 referred to, took cognisance of the matter in November 2014 (Court on its own motion vs State of H.P. and others) following a news report in a Hindi daily regarding the use of oxytocin in fruits, vegetables and milch animals. It focussed on the veterinary use of oxytocin more than the obstetric use of the hormone, barring stray examples of it affecting newborns and others when they consume food items such as milk. Members of the DTAB opined that the drug could only be sold on the basis of a prescription by a registered medical practitioner and that a ban was not advisable. Restricting the sale to government hospitals was not a wise decision since people in remote and rural areas cannot access it during obstetric emergencies. Yet, the court observed that it could not be oblivious to the fact that there was large-scale manufacture and sale of drugs in a clandestine manner and misuse by farmers and dairy owners. It said the feasibility of restricting the manufacture of the drug to public sector companies and limiting it to licence holders should be explored.

Interestingly, the National Dairy Research Institute (NDRI), a Government of India body under the Indian Council of Agricultural Research, does not seem to view oxytocin as a major problem. In a newsletter (Vol 21, No 2, July-Sept 2016), A.K. Srivastava, Director of the NDRI, wrote that various studies had shown that there was no adverse effect of oxytocin injections on the quality of milk and its constituents. He suggested that farmers, dairy practitioners and veterinarians be educated about its judicious use.

There has been a 22 per cent reduction in MMRs as per the Sample Registration System (SRS) data released by the Registrar General of India’s office. Yet, at 130 deaths (down from 167) per one lakh live births, the figure was still rather high, higher than the rates in other South Asian countries. PPH has accounted for the bulk of such mortality. The hurry to restrict the availability of oxytocin is intriguing given the government’s emphasis on reducing maternal mortality.

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