ISP requires modification of tramadol leaflets due to dependence and interactions

The Institute of Public Health (ISP) has ordered the sanitary registration holders of all pharmaceutical products containing tramadol —alone or in combination, in any presentation— to modify the information leaflets for professionals and patients. The measure was established through exempt resolution E 5.187, signed on October 16, 2026, by the director of the agency, Fresia Catterina Ferreccio Readi, and published in the Official Gazette No. 44,585 on Wednesday, October 28, 2026, in section I of General Regulations (official reference: CVE 2891244).

The regulatory framework of the decision

The resolution is based on articles 63, 64, and 71 of Supreme Decree No. 3 of 2010, from the Ministry of Health, which empower the Institute to require, through a reasoned resolution, the necessary modifications to guarantee the quality, safety, and efficacy of a pharmaceutical specialty. It also invokes exempt resolution No. E140, dated January 9, 2026, which enables the regulatory trust mechanism in the Pharmacovigilance Sub-department of the National Medicines Agency Department.

The cited international precedents are:

• The European Medicines Agency (EMA) document on tramadol/paracetamol, dated May 6, 2024 (PSUSA/00002310/202308).
• The March 2024 Safety Bulletin for Medicines for Human Use from the Spanish Agency for Medicines and Health Products (AEMPS), published on May 20, 2024.
• Technical Safety Report No. 24-098, dated January 12, 2026, prepared by the Medicines and Cosmetics Information and Safety Section.
• The Health Canada communication “Summary Safety Review - Tramadol - Assessing the Potential Risk of Prolonged, Persistent or Recurrent Hiccups”, dated May 20, 2026, referring to the risk of prolonged, persistent, or recurrent hiccups.

Pharmacovigilance figures

The text states that the suspected adverse drug reaction database of the ISP’s National Pharmacovigilance Center recorded, between January 2013 and September 26, 2026, 2,401 notifications describing tramadol as the suspected drug. Of that total:

• 288 notifications correspond to concomitant use with gabapentinoids: 275 with pregabalin and 12 with gabapentin.
• 36 cases report hypotension, 5 of them with simultaneous use of pregabalin.
• 22 cases describe respiratory depression, 4 of them with pregabalin.
• 1 case of neonatal respiratory depression, in concomitant use with gabapentin.
• 1 case of coma, described as intentional poisoning and also associated with pregabalin.

What each leaflet must incorporate

The professional information leaflet must include content in four sections: dosage and administration (therapeutic strategy, duration, objectives, and discontinuation plan); warnings and precautions (tolerance, physical and psychological dependence, and opioid use disorder, along with their risk factors); interactions (concomitant use with pregabalin or gabapentin may cause respiratory depression, hypotension, deep sedation, coma, or death), and adverse reactions (drug dependence, even at therapeutic doses).

The patient leaflet is required to warn that tramadol is an opioid medication, that repeated use can lead to tolerance, dependence, abuse, and addiction, and that it must not be abruptly discontinued without medical indication. Warning signs are also listed—the need to take it for longer or in higher doses, use for purposes other than those prescribed, failed attempts to stop, and discomfort upon discontinuation—and it warns of the increased risk of adverse effects in those taking gabapentin or pregabalin.

Deadlines and scope of the requirement

Holders whose leaflets do not comply with the instructions must submit the corresponding modification for the Institute’s approval within a period not exceeding 90 business days from the publication of the resolution. Every sanitary registration for tramadol granted or requested thereafter must comply with these requirements. The text orders it to be noted, communicated, and published on the institutional website www.ispch.cl.

The resolution directly affects patients using tramadol, prescribers who must plan and monitor the treatment, and laboratories that must process the modifications before the ISP in less than four and a half months. The articles, however, concentrate the requirements on dependence and interaction with gabapentinoids, while the background regarding persistent hiccups appears among the documents considered in the recitals.

Source: Official Gazette of the Republic of Chile, No. 44,585, Wednesday, October 28, 2026, Section I (General Norms), pp. 1-5 (official reference: CVE 2891244).