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 tramadol, PSUSA/00003002/20230, drew the following conclusions.
In view of the available data on the risk of drug dependence/abuse from the literature and spontaneous reports, and in view of the existing warnings in other instructions for medical use of medicinal products containing opioids, the PRAC considers that updating the sections “Dosage and administration”, “Special precautions for use”, and “Adverse reactions” of the instructions for medical use is justified in order to strengthen the warning on the risk of drug dependence/abuse by adding the negative consequences of opioid use disorders and the risk factors identified in accordance with the wording already implemented for other opioids.
In view of the data available in the literature on the interaction between opioids and gabapentinoids (gabapentin and pregabalin), as well as the warnings already present in other instructions for medical use of medicinal products containing opioids, the PRAC considers that updating the section “Interaction with other medicinal products and other forms of interaction” of the instructions for medical use is justified in order to reflect the interaction with gabapentinoids.
The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the scientific conclusions drawn by PRAC.
Based on the scientific conclusions on tramadol, the CMDh considers that the benefit/risk balance of medicinal products containing tramadol is unchanged, provided that the proposed changes are made to the instructions for medical use.
Changes to be made to the relevant sections of the package insert (new text underlined and in bold, deleted text struck through).
- Update to strengthen warnings about the risk of drug dependence/abuse.
Section "Posology and method of administration"
Method of administration
…
Treatment goals and discontinuation of treatment
Before starting treatment with [name of the medicinal product], a treatment strategy, including the duration and goals of treatment, should be agreed with the patient in accordance with the pain management protocol. During therapy, the physician should maintain frequent contact with the patient in order to assess the need to continue treatment, consider discontinuation of treatment and, if necessary, adjust the doses. When the patient no longer requires tramadol therapy, a gradual dose reduction may be recommended to prevent the occurrence of withdrawal symptoms. In the absence of adequate pain control, the possibility of hyperalgesia, development of tolerance and progression of the underlying disease should be considered (see section “Special warnings and precautions for use”).
“Special precautions for use” section
The existing warning should be changed as follows (the existing wording of the relevant warning should be replaced with the following paragraph, if necessary):
Tolerance and disorders associated with opioid use (abuse and dependence)
Tolerance, physical and psychological dependence, and opioid use disorders (OUD) may develop after repeated use of opioids, such as [name of the medicinal product]. Repeated use of [name of the medicinal product] may lead to opioid use disorders (OUD). A higher dose and longer duration of opioid treatment may increase the risk of developing OUD. Abuse or intentional misuse of [name of the medicinal product] may lead to overdose and/or death. The risk of developing OUD is increased in patients with a personal or family history (parents or siblings) of substance use disorders (including alcohol use disorders), in those who currently use tobacco products, or in patients with other existing mental disorders (for example, major depression, anxiety, and personality disorders).
Before and during treatment with [name of the medicinal product], the treatment goals and the treatment discontinuation plan should be discussed with the patient (see section “Method of administration and dosage”). Before and during treatment, the patient should also be informed about the risks and signs of OUD. Patients should be advised to contact their doctor if such signs appear.
Patients should be monitored for signs of drug-seeking behavior (for example, requests for an additional dose that are too early). This includes checking for concomitant use of opioids and psychoactive medicinal products (for example, benzodiazepines). For patients with signs and symptoms of OUD, consider consulting an addiction specialist.
“Adverse reactions” section
The following paragraph should be added below the table summarizing adverse reactions:
Drug dependence
Repeated use of [name of the medicinal product] may lead to drug dependence, even at therapeutic doses. The risk of developing drug dependence may vary depending on the patient's individual risk factors, the dose and the duration of opioid treatment (see section “Special warnings and precautions for use”).
- Update to add an interaction with gabapentinoids.
Section "Interaction with other medicinal products and other forms of interaction"
The interaction should be added as follows. If identical wording is already included in the section “Interaction with other medicinal products and other forms of interaction” of the instructions for medical use: “Concomitant use of <medicinal product> with [...] may result in respiratory depression, hypotension, profound sedation, coma, or death.”, the newly proposed text (i.e., “gabapentinoids (gabapentin and pregabalin)”) may be added to the existing sentence. If wording identical to that in the previous sentence is not yet included in the section “Interaction with other medicinal products and other forms of interaction” of the instructions for medical use, the newly proposed sentence may be added directly after any existing wording on interaction with other centrally acting medicinal products that may lead to potentiation of CNS effects (for example, directly after “When <medicinal product> is used concomitantly with other centrally acting medicinal products, including alcohol, potentiation of CNS effects should be taken into account (see section “Adverse reactions”).”).
Concomitant use of <medicinal product> with other central nervous system depressants […] and gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma, or death.
Changes to the safety information of medicinal products containing tramadol (tramadol) following the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of 05 – 08 February 2024
The European Medicines Agency (EMA) published the minutes of the meeting of the Pharmacovigilance Risk Assessment Committee (PRAC) of February 05 – 08, 2024. Based on the results of the meeting, a decision was made on the need to introduce safety-related changes to the registration materials/instructions for medical use of medicinal products containing tramadol.
Tramadol – PSUSA/00003002/20230
Tramadol is an opioid analgesic indicated for the treatment of moderate to severe pain.
Based on the evaluation of Periodic Safety Update Reports (PSURs), the PRAC reviewed the benefit/risk balance of medicinal products containing tramadol and provided the following recommendations.
Summary of recommendations and conclusions
- Based on the analysis of safety and efficacy data, the benefit/risk balance of the use of medicinal products containing tramadol (tramadol), for the approved indications remains unchanged.
- Nevertheless, in view of the data available in the literature on drug dependence and abuse (opioid use disorders), as well as recent evaluations of PSUSA procedures for other opioids, the existing warning on drug dependence and potential abuse should be strengthened by adding the negative consequences of opioid use disorders and risk factors, identified in line with the wording already implemented for other opioids. The instructions for medical use should also be updated to reflect the interaction between tramadol and gabapentinoids. Thus, the existing provisions of the instructions for medical use must be amended1.
- In the next PSUR, registration certificate holders must provide a cumulative review of cases of restless legs syndrome (RLS) and tinnitus, as well as a review of cases of opioid-induced hyperalgesia and allodynia, and discuss the need to update the instructions for the medicinal product, if justified.
1 Update of the sections “Posology and method of administration”, “Special warnings and precautions for use”, “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions” of the instructions for medical use. The risk assessment report and PRAC recommendations are forwarded to the CMDh for a decision.
List of medicinal products containing tramadol and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 16.04.2024).
To analyze the published information, the applicant must use the original text available at the link:
