The ISP orders new warnings about DRESS syndrome in amitriptyline leaflets

The Public Health Institute of Chile has ordered the sanitary registration holders of medications containing amitriptyline to incorporate warnings regarding serious cutaneous adverse reactions, including DRESS syndrome, into their professional and patient information leaflets. The instruction is formalized in exempt resolution No. E 5.216, published in Section I of the Official Gazette of the Republic of Chile, number 44,596, on Wednesday, November 11, 2026 (CVE 2897435). Affected laboratories have 90 business days to submit the corrected texts.

The regulation is issued under Article 63 of Supreme Decree No. 3 of 2010 of the Ministry of Health, which allows for the modification of sanitary registration mentions of a pharmaceutical specialty through a reasoned resolution, and under Article 64, which empowers the Institute to demand changes when international scientific evidence establishes a safety risk. This authority is further supported by exempt resolution No. E140, dated January 9, 2026, regarding regulatory reliance mechanisms applicable to the Pharmacovigilance Sub-department of the National Medicines Agency Department.

What the leaflets must state

The first resolution establishes the minimum text that both leaflets must contain, in any presentation of the drug, whether alone or in combination with other active ingredients:

• Warning that serious cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), which are potentially fatal, have been reported.
• Specification that most of these cases occurred within a period of 2 to 6 weeks.
• Obligation to warn the patient at the time of prescription and to closely monitor for the appearance of skin reactions.
• Instruction to discontinue amitriptyline immediately upon compatible signs or symptoms, to never resume treatment in that patient, and to consider a therapeutic alternative.
• Inclusion of DRESS in the adverse reactions section as an effect of unknown frequency.
• In the patient leaflet, the instruction to stop the medication and seek immediate medical attention in the event of a generalized rash, elevated body temperature, and enlargement of the lymph nodes.

Deadline, scope, and new registrations

Holders whose leaflets do not comply with the instructions must submit the modification of the professional and patient information leaflets for approval by the Public Health Institute within a period not exceeding 90 business days, counted from the publication of the resolution. The third resolution extends this requirement to all sanitary registrations of products containing amitriptyline that are granted or requested after the instrument enters into force.

The resolution was signed by Fresia Catterina Ferreccio Readi, director of the Institute of Public Health of Chile, on October 19, 2026, and provides for its publication on the institutional website and its full text in the Official Gazette.

International background and local registry

The Chilean pronouncement aligns with decisions adopted in Europe, Spain, and Australia. The third recital cites the European Medicines Agency (EMA) document on the periodic safety update PSUSA/00010374/202401, dated October 28, 2024, in which the Pharmacovigilance Risk Assessment Committee (PRAC) concluded that there was at least a reasonable possibility of a causal relationship between DRESS and amitriptyline, with subsequent approval by the CMDh.

Added to this are the September 2024 Bulletin on the Safety of Medicinal Products for Human Use, disseminated by the Spanish Agency of Medicines and Medical Devices (AEMPS) on November 8, 2024, and the “Product Information safety updates - March 2025” communication from the Therapeutic Goods Administration of Australia (TGA), dated March 31, 2025. On the local level, the Technical Safety Report No. 25-179, dated September 8, 2026, prepared by the Medicines and Cosmetics Information and Safety Section, concluded that not all available leaflets include the safety information and recommended the alignment.

The file further records that the database of the ISP’s National Pharmacovigilance Center registered, between January 2013 and September 21, 2026, 526 notifications of suspected adverse reactions associated with amitriptyline, none of which were described as DRESS.

The measure applies to patients using the drug for depression and chronic pain, who will receive a written warning to discontinue treatment in the event of severe skin symptoms, and obliges laboratories to update their texts within a peremptory period under penalty of failing to comply with internationally aligned safety information.

Source: Official Gazette of the Republic of Chile, no. 44,596, November 11, 2026, Section I, page 1 (official reference: CVE 2897435).