In accordance with paragraph 8 of Section IV of the Procedure for Expert Evaluation, the applicant must amend the instructions for medical use of the medicinal product upon receipt of new data, including bringing the instructions for medical use into line with the approved instructions for medical use of the original (reference) medicinal product, and ensure that the information on the medicinal product corresponds to current scientific knowledge.
The Pharmacovigilance Risk Assessment Committee (PRAC), based on the analysis of periodic safety update reports (PSURs) for medicinal products containing isotretinoin (oral formulations), PSUSA/00010488/202505, reached the following conclusions.
In view of the data available in the literature on anal fissures and spontaneous reports that in some cases contain a close temporal relationship and a positive re-challenge, and given the plausible mechanism of action, the PRAC considers that a causal relationship between the use of isotretinoin and the occurrence of anal fissures is at least reasonably possible. The PRAC concluded that the instructions for medical use of medicinal products containing isotretinoin should be amended accordingly.
Given the data available in the literature on acute generalized exanthematous pustulosis (AGEP), spontaneous reports including cases with a close temporal relationship, a positive de-challenge, and also given the plausible mechanism of action, PRAC considers that a causal relationship between the use of isotretinoin and the development of AGEP is at least reasonably possible. PRAC concluded that the instructions for medical use of medicinal products containing isotretinoin should be amended accordingly.
Having considered the PRAC recommendations, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the overall conclusions of the PRAC and the grounds for the recommendations.
Based on the scientific conclusions on isotretinoin for oral use [isotretinoin (oral formulations)], the CMDh considers that the benefit/risk balance of medicinal products containing isotretinoin for oral use [isotretinoin (oral formulations)] remains unchanged, provided that the proposed changes are made to the instruction for medical use.
Changes to be made to the relevant sections of the instruction for medical use (new text underlined and in bold).
“Special precautions for use” section
The precaution should be amended as follows:
Cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP), which can be life-threatening or fatal, have been reported with the use of <name of the medicinal product> (see section "Adverse reactions").
Patients should be informed about the signs and symptoms of severe cutaneous adverse reactions and should seek medical attention from a doctor immediately if any signs or symptoms of these reactions appear.
If signs and symptoms that may indicate these reactions appear, <medicinal product> should be discontinued immediately and alternative treatment options should be considered (if necessary).
If a patient has developed a severe cutaneous adverse reaction such as SJS, TEN, or AGEP while using <medicinal product>, treatment with <medicinal product> must never be resumed in this patient.
“Adverse reactions” section
The following adverse reaction should be added to the System Organ Class (SOC) “Skin and subcutaneous tissue disorders” with a frequency of “not known”:
acute generalized exanthematous pustulosis (AGEP)
The following adverse reaction should be added to the System Organ Class (SOC) "Gastrointestinal disorders" with the frequency "not known":
anal fissure
Changes to the safety information of medicinal products containing isotretinoin for oral use [isotretinoin (oral formulations)] following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 24 – 27 November 2025
The European Medicines Agency (EMA) has published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 24 – 27 November 2025. Following the meeting, a decision was made on the need to make safety-related changes to the registration materials/instructions for medical use of medicinal products containing isotretinoin for oral use [isotretinoin (oral formulations)].
Isotretinoin for oral use [isotretinoin (oral formulations)] – PSUSA/00010488/202505
Isotretinoin for oral use [isotretinoin (oral formulations)] is a retinoid (a vitamin A derivative) indicated for the treatment of severe forms of acne.
Based on the assessment of Periodic Safety Update Reports (PSURs), PRAC reviewed the benefit/risk balance of the use of medicinal products containing isotretinoin and provided relevant recommendations.
Summary of recommendations and conclusions
- Based on the analysis of safety and efficacy data, the benefit/risk balance of medicinal products containing isotretinoin (isotretinoin) for the approved indications remains unchanged.
- At the same time, the instructions for medical use should be updated by adding anal fissure as an adverse reaction with a frequency of “not known”. In addition, the instructions for medical use should be updated to include acute generalized exanthematous pustulosis (AGEP) as a warning and an adverse reaction with a frequency of “not known”. Thus, the existing provisions of the instructions for medical use should be amended1.
- In the next PSUR, registration certificate holders (RCHs) must provide cumulative reviews of cases of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL syndrome – Headache and Neurologic Deficit with cerebrospinal fluid Lymphocytosis), as well as all cases of headache/migraine that may be characterized as HaNDL syndrome, including data from clinical and observational studies and the literature, and discuss the need to update the instructions for medical use. RCHs must also continue monitoring pregnancy cases and submit them as part of the evaluation of identified important risks in the next PSUR.
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1Update of the “Special warnings and precautions for use” and “Adverse reactions” sections of the instructions for medical use. The risk assessment report and the PRAC recommendation are forwarded to CMDh for decision.
List of medicinal products containing isotretinoin and approved for medical use in Ukraine (according to the State Register of Medicinal Products as of 31.03.2026). (14 KB) (Downloaded: 10.04.2026 09:27:53)
TO ANALYZE THE PUBLISHED INFORMATION AND SUBMIT THE RELEVANT APPLICATION FOR AMENDMENTS TO THE REGISTRATION MATERIALS, THE APPLICANT MUST USE THE ORIGINAL TEXT AVAILABLE AT THE FOLLOWING LINKS:
