*Updates the story with EMA comments
According to media investigations, the off-label use of a gastrointestinal drug to induce labour has led to severe health implications and even deaths. The European Medicines Agency (EMA) told EURACTIV the drug’s safety information was updated already in 2009, but admitted this has had a limited impact on the off-label use.
The approved indication for Cytotec (active ingredient misoprostol) is for the treatment of gastric ulcers. However, Misoprostol has been used off-label, meaning for indications other than those prescribed, in the areas of gynaecology and obstetrics to weaken the uterus and induce contractions for the induction of labour.
Off-label use of medicines is not prohibited and may turn out to be helpful, particularly to address several rare diseases.
However, an investigation of German media in February showed that the off-label use of Misoprostol to induce labour has had numerous health implications for pregnant women and babies. German media warned of deaths and other personal harm caused by such a use of the medicine.
EURACTIV asked EMA whether it had conducted or been informed of a risk-assessment when it comes to the off-label use of Misoprostol by pregnant women, in light of the German media reports.
EMA said that as part of the risk assessment, it has been closely monitoring the off-label use of misoprostol medicines (such as Cytotec), in particular for labour induction, pregnancy termination and any other misuse.
“Although Cytotec is a nationally authorised medicine, EMA’s safety committee (PRAC) conducts Periodic Safety Update Single Assessments (PSUSAs) on the gastrointestinal indication and the off-label use in gynaecological indications. Following a review in 2009, which highlighted a high rate of off-label use with adverse events associated, the safety information in the summary of product characteristics (SmPC) was updated with warnings and harmonised across Europe,” it said.
“However, after discussing the increased off-label use of Cytotec in 2009, the PRAC concluded that the updates in the SmPC and package leaflet had a limited impact on the prevention of intentional off-label use,” EMA added.
The topic has taken centre stage in two biggest EU member states, Germany and France.
EMA added that Cytotec is not authorised in Germany. “In March 2020, the Federal Institute for Drugs and Medical Devices (BfArM) issued a direct healthcare professional communication (DHPC) in accordance with the warnings included in the SmPC and recommended that off-label use of Cytotec be avoided.”
In 2018, Cytotec producer Pfizer notified France’s National Agency for the Safety of Medicines and Health Products (ANSM) that it would stop the commercialisation of the medicine while ANSM stressed that this off-label use “can lead to serious undesirable effects for the mother and the child, such as the occurrence of uterine rupture (tearing of the uterine muscle), haemorrhage or abnormal fetal heart rate”.
Considering that the issue has not been widespread across Europe, critics suggest that there may be numerous unreported incidents in other member states as well.
Pfizer told EURACTIV it opposes any off-label use of Cytotec.
“Cytotec is a treatment option for NSAID-induced gastric ulcers in certain at high-risk patients if used according to the approved label. Like all other prescription medicines, Cytotec must only be used for the approved indication under the supervision by a trained physician,” Pfizer said in an emailed response.
“The prescribing information includes strong warnings against use in women who are pregnant. Pfizer does not support any off-label use of Cytotec or any Pfizer medicine,” the pharma company added.
The low cost
Dr Peter Husslein, director of the University Clinic for Gynecology in Vienna, said there are enough options and alternatives of registered drugs – namely prostaglandin E2 derivatives – which are slightly less efficient but carry fewer risks.
“I have always wondered why the German authorities have not simply forbidden the use of Cytotec – there is a justified risk leading to sometimes catastrophic complications affecting young families considering that a brain-damaged child is affecting the whole family for life,” he told EURACTIV.
He said the only reason why German obstetricians use Cytotec is its great efficiency, making it possible to achieve a vaginal delivery even in difficult cases, potentially resulting in a lower cesarean section rate and very low costs.
“In my opinion, this is not justifiable because it comes at a price of a relatively high complication rate,” he warned.
Dr Husslein also wondered why no action has been taken so far at the EU level to regulate this potentially devastating misuse.
The European Commission’s role
In 2017, the European Commission commissioned a study which cited misoprostol risks.
“The representative of Irish Premature Babies (interviewee patient organisation) expressed her concern with regard to the off-label use of misoprostol as, according to her, it has led to unnecessary harm to mothers to be and their infants,” the study reads.
Asked by EURACTIV since when the EU executive has been informed about the case, EU sources did not provide a clear answer. The answer about the actions the executive has taken so far to address the issue has also been vague.
Sources pointed out that in regard to the scientific assessment of medicinal products, the Commission relies on the expertise of EMA.
“The European Commission has full trust in the assessment of EMA experts to make an adequate recommendation concerning the appropriate use of medicines, special warnings or contraindications,” the sources said, adding that before prescribing a medicine such as Cytotec, a physician must always consider whether the proposed therapy is adequate in view of the benefits and risks it involves and in view of the specific patient the doctor is treating.
The debate over the EU’s role in protecting European citizens’ public health is expected to heat up especially after the COVID-10 pandemic. In an op-ed recently published on EURACTIV, former EU health commissioner Vytenis Andriukaitis wondered if we are “doing enough to protect the health of our citizens”.
“It is abundantly clear that during the COVID-19 crisis, our citizens are asking the European Union to do more, but the hands of the EU institutions are tied. The Union can only operate on the basis of powers allocated by the Treaties,” he said, adding that the role of health policy in the European Treaties should be reconsidered.
[Edited by Zoran Radosavljevic]