On December 9, 2020, the Fukui Prefectural government carried out an on-site investigation at Kobayashi Kako over the issue of contamination of oral antifungal drug “itraconazole” it manufactures and markets with a sleep inducer, for possible violation of the Pharmaceuticals and Medical Devices Act. The inspection was carried out after the company and Meiji Seika Pharma, which jointly sells the products, completed identification of the patients who were prescribed the medicine and necessary communication including discontinuation of use of the drug. As of 17:00, December 10, 128 cases of health problems including serious ones had been reported and the number is thought to be the highest number of reports of pharmaceutical-related health problems caused by improper manufacturing control. Depending on the results of the investigation, the company may be subject to administrative penalties.
The drug was contaminated with 5 mg of rilmazafone hydrochloride hydrate, a sleep-inducing ingredient, per tablet. If the drug ｈas taken 4 times a day, the dosage would be 20 mg; this means that the drug was contaminated with the ingredient as much as 10 to 20 times the usual daily dosage.
The products were delivered to more than 220 medical institutions and the number of cases of the health problems with the patients which are thought to be linked to the mixed rilmazafone exceeded 100 cases totaling 128. It caused dizziness, lightheadedness, loss of consciousness, and strong drowsiness, and there have been reports of automobile accidents, emergency transport, hospitalization and falls due to psychiatric and neurological symptoms as severe damages. The number is likely to increase in the future.
The Fukui prefectural government has been instructing the company to prioritize prevention of spread of health problems among patients. Since all 364 patients who received the prescriptions had been completed and necessary communication to the patients such as discontinuation of medication has been completed, it conducted an on-site investigation at the company’s factory to check the work records and manufacturing sites in accordance with Article 69 of the Pharmaceutical and Medical Devices Act. It will continue investigations as necessary, and consider giving administrative penalties depending on the results of the investigations.
Regarding recall of itraconazole, after December 1, pharmacies in Gifu, Osaka, and Saga reported several cases of adverse reactions after the patient took the drug. When the company checked the manufacturing records, it discovered that the antifungal had been mistakenly contaminated with a sleep inducer and informed the MHLW of that on December 4. In the evening of the same day, the company announced a Class I voluntary recall of the applicable one lot. The company has admitted that the problem was caused by “human error in operations” and that there was a problem with the checking system.
On the 7th, the company launched a Class II recall of all itraconazole preparations other than those subject to the previous recall because it was found that a manufacturing process which was not specified in the approval document had been carried out.
This incident is likely to have a major impact on the pharmaceutical industry. The Japan Pharmaceutical Association called for a halt to the use of the product and for cooperation with the voluntary recall. It also issued a notice to its members stating, “This issue fundamentally shakes the trust in pharmaceuticals. We will make a request to the marketing authorization holder to take appropriate actions.”
Mr. Mitsuo Sawai, Chairman of the Japan Generic Medicines Association issued a statement at a meeting of the Special Committee on Drug Prices, Central Social Insurance Medical Council on December 11, saying, “We deeply apologize to patients, medical institutions, health insurance pharmacies, distributors, and government officials.” He also said, “We take this matter seriously as it concerns the entire industry, and we will have our members to ensure compliance and make efforts to regain trust.
Mr. Isao Teshirogi, Chairman of the Federation of Pharmaceutical Manufacturers’ Associations of JAPAN said, “This is not a case of a single generic pharmaceutical manufacturer, but an opportunity for the industry as a whole to ensure thorough manufacturing and quality control”.
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