This is one of the three articles in our special report, published 18 August 2023: “Japan’s approval in 2023 of abortion pills”
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PHOTO SOURCE : Open Access Government, 24 April 2023
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by Kumi Tsukahara
In Japan, Linepharma KK’s Mefeego Pack (the brand name of the combi-pack of abortion pills mifepristone and misoprostol) was finally approved on 28 April 2023, but labelled as “deleterious”, 35 years later than their approval in France. As for their components, both the formulation and the active ingredient of mifepristone and the formulation of misoprostol were classified as “deleterious”, meaning “causing harm or damage”.
Moreover, in July 2023, the Japanese Ministry of Health, Labour and Welfare (MHLW) abruptly designated the active ingredient of misoprostol in the Mefeego Pack as a “poison”. They apparently decided to adopt Cytotec’s description of the active ingredient of misoprostol, which according to the EMC website (the company that sells Cytotec) is based on the use of Cytotec for treatment of gastric ulcers. And they have already had Linepharma rewrite their documents accordingly.
Japanese pharmacists tend to regard such classifications of medicines as not a major concern. However, given that this drug is a World Health Organization (WHO) approved essential medicine that could and should be made as widely available as possible, the designation of misoprostol as a deleterious drug and the accompanying restrictions are surely serving as barriers to access. Mefeego Pack’s conditions of approval also include strict control of who can be a provider and who can prescribe and monitor use – that is, a “designated” obstetrician/gynaecologist under the Maternal Protection Act. They also include forced hospitalisation of the woman or her remaining in a medical institution until the expulsion of the fetal sac, as well as with multiple requirements for distribution and medication controls.
In these conditions, patients are deprived of the best aspects of medical abortion, including privacy and self-management, and are even deprived of freedom of movement. Spousal consent is still required, as with all abortions, and the fee is said to be around 100,000 yen (about US$700), equivalent to the cost of a surgical abortion, which is not covered by health insurance. Confined to the island nation of Japan, one tends to lose sight of such injustices.
The combination of mifepristone and misoprostol for medical abortion has been recognised around the world as safe and effective for many years. Yet, before it was approved, the MHLW spread the image of the (illegally imported) abortion pills as being dangerous. Designating the pills as “deleterious drugs”, let alone as “poison”, could deepen people’s misconceptions.
I have spent the past 20 years researching the problems surrounding abortion in Japan from multiple perspectives. I have also met many foreign experts and seen firsthand how hopelessly different Japan’s abortion care is from the rest of the world. The problems include more than just abortion as well. For example, the birth control pill was finally approved in Japan only in 1999, some 40 years later than the rest of the world, and even now the utilisation rate is only 2-3%. I am increasingly concerned that the same fate may befall the abortion pills.
Surely, the use of “deleterious” and “poisonous” as labels should be understood as creating a false and fear-based reason to force medical abortions up to 12 weeks, which could safely take place at home, and those after 12 weeks that could take place as day cases managed by a trained nurse or midwife, to take place in in-patient hospital beds and ensure that the fees paid for abortion care are as high as those for D&C.
Recently I also realised that Japanese women will not be able to use additional misoprostol to complete their abortions, if needed, after using the pills in the Mefeego Pack. Yet it has been learned in other countries and is on the way to becoming standard practice, that if additional misoprostol is needed and available, almost all abortions would be completed without requiring a surgical procedure. Cytotec, the only misoprostol product in Japan apart from what is in the combi-pack, is “contraindicated for pregnant women,” and doctors are reluctant to prescribe it off-label. Even though the purpose would be to complete the termination of the pregnancy.
According to Dr Sam Rowlands, Visiting Professor at Bournemouth University in the United Kingdom, there are few countries that approve misoprostol alone for abortion. It is basically a treatment for gastric ulcers, and no company dared to submit for the approval of an additional indication that might involve them in potential abortion controversies. Instead, they count on doctors using it off-label to earn the company some extra money.
Yet the Japanese Association of Obstetricians and Gynecologists (an association of many of the “abortion designated” doctors) explicitly prohibits off-label use as follows:
“Off-label use is strictly prohibited because if you use the drug in the same way as other drugs (prescribing for additional dosing, comorbid abortion, or emergency contraception), it will cause inconvenience to fill out the Mefeego Pack Application Report that must be submitted monthly to your medical association, and you can expect to receive guidance from your medical association.”
In this prohibition, the convenience of document processing that must be followed due to “strict control” appears to take precedence over women’s health and good clinical practice.
While examining the detailed product description of Cytotec, also labelled a “deleterious drug,” to see if there was any possibility of using it as an add-on to the Mefeego Pack, I was puzzled to find that its active ingredient, misoprostol, has been designated as a “poison”. This designation seems to be due to the results of a safety test carried out on animals in 1985, called the Reproductive and Developmental Toxicity Study. In fact, this paper was the same one that MHLW officials had previously cited as the basis for labelling the pills in the Mefeego Pack as deleterious drugs. The toxicity study results identified the risk of birth defects and of induced miscarriage in the fetuses of rabbits exposed to misoprostol. However, an incredibly large dose of misoprostol had been used in these toxicology tests. Specifically, the study reported that “oral administration of 990 µg/kg of Cytotec to rabbits” resulted in post-implantation death or increased organogenesis abnormalities in the rabbit fetuses.
Cytotec taken as a treatment for gastric ulcers is usually at a dose of 200 µg four times a day, for a total daily dose of 800 µg. In contrast, the dose administered in the rabbit experiment, when converted to a human being weighing 50 kg, was 49,500 µg, or about 62 times the normal dose, which is equivalent to taking nearly 250 misoprostol tablets at one time for the human being. Everyone knows that even mere salt will kill you if taken in comparably large quantities. I am not a pharmacologist, but it seems insane to me that misoprostol was designated as “deleterious” and/or “poisonous” based on the results of giving rabbits such an extraordinarily large dose.
“There are human data now, after decades of experience; it seems odd to go back to animal studies,” Professor Rowlands said when I asked about the relationship between abortion drugs and malformation. He referred me to a letter published in the Lancet in 1998, which found that the prostaglandin gemeprost had been associated with a few isolated reports of fetal malformation when, in rare cases, the woman had taken the pills following the failure of the medication and later decided to continue the pregnancy. However, the letter also clearly stated:
“There were no reported cases of malformation associated with use of misoprostol when used with mifepristone.”
Gemeprost is the ingredient of the first abortion medication, Preglandin Vaginal Suppository 1 mg, which was developed in the 1970s and approved in 1984 in Japan. Gemeprost has been used exclusively for mid-term abortions in Japan for the past four decades, and it too is strictly controlled as a deleterious drug. The Japanese designated abortion doctors have demanded that the Mefeego Pack be managed as strictly as Preglandin.
The drug information for Preglandin notes that it “should not be used to induce labour in the delivery of a live baby” because “clinical trials of the drug were conducted only in patients in the second trimester of pregnancy who required therapeutic abortion, and its effects on the fetus were not studied at all”. While Mefeego Pack medications are listed as “deleterious drugs” because of possible adverse effects on “a fetus that survives a failed abortion”, Preglandin has never been considered for its effects on a fetus that survives a failed abortion. In fact, according to newspaper reports at the time of the approval, Preglandin was placed under strict control as a “deleterious drug” because of the intense opposition from conservative representatives and designated doctors themselves objecting to the idea of “abortion by medication alone”.
In fact, Preglandin had been trialled for early abortions in the 1970s and attracted national and international attention with its high success rate. However, Japanese abortion-designated doctors, who were accustomed to performing early abortions by curettage, hid the data on early abortions and pressed the pharmaceutical company to apply for approval of the drug exclusively for mid-term abortions. Only 63 patients used Preglandin in the clinical trial at the time. In the 1990s, several cases of uterine rupture and cervical lacerations were reported with the use of preglandin, and in 1996, the then Ministry of Health and Welfare further tightened the handling rules and issued a warning.
During this whole period of time, most Japanese doctors were unaware of the increasing use of abortion pills around the world. In a survey I did as part of my research on designated abortion doctors in 2010, the majority of doctors answered that RU486 (mifepristone) was “dangerous”, about 70% said it was “ineffective”, about 60% said it was “difficult to introduce”, and about 50% “opposed its introduction”. Thus, many designated doctors were not aware, even then, that the WHO had positioned abortion pills as a safe and reliable method of pregnancy termination.
Japan had long had the Internet, yet was isolated from the situation overseas. Abortion in Japan must change, and for that we should discuss it across borders.
Experts around the world, including WHO and FIGO, have recognised that the combination of mifepristone and misoprostol at the recommended regimens are very safe for abortions in both the first and second trimester. To designate them as deleterious or poisonous drugs today, based on outdated literature from 1985, only serves to delegitimise the medical professionals and others who know it is safe to use these abortion medications, and also violates the rights of women and girls seeking an abortion.
About the author:
Kumi Tsukahara is a self-employed researcher on Japanese abortion issues. She is the author of three books on abortion issues in Japanese, and also a Japanese translator of Tiana Norgren’s “Abortion before Control”, Heren Hardacre’s “Marketing the Menacing Fetus in Japan” and Robin Stevenson’s “My Body My Choice.”