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 previous publication is available on the website of the State Expert Center of the Ministry of Health of Ukraine at the following links:
https://www.dec.gov.ua/materials/zminy-informacziyi-z-bezpeky-likarskyh-zasobiv-shho-mistyat-buklizyn-kodeyin-paraczetamol-buclizine-codeine-paracetamol-aczetylsaliczylovu-kyslotu-kodeyin-paraczetamol-acetylsalicylic-acid-codein-2/?role=applicant
https://www.dec.gov.ua/materials/zminy-informacziyi-z-bezpeky-likarskyh-zasobiv-shho-mistyat-buklizyn-kodeyin-paraczetamol-buclizine-codeine-paracetamol-aczetylsaliczylovu-kyslotu-kodeyin-paraczetamol-acetylsalicylic-acid-codein/?role=doctors
The Pharmacovigilance Risk Assessment Committee (PRAC), based on the evaluation of periodic safety update reports (PSURs) for medicinal products containing buclizine/codeine/paracetamol (buclizine/codeine/paracetamol), acetylsalicylic acid/codeine/paracetamol (acetylsalicylic acid/codeine/paracetamol), caffeine/codeine/paracetamol (caffeine/codeine/paracetamol), PSUSA/00000448/202508, reached the following conclusions.
- In view of the available data on the risk of opioid use disorders (OUD) obtained from the literature and spontaneous reports, as well as the plausible mechanism of action and taking into account the existing warnings in the instructions for medical use of medicinal products containing opioids, it is appropriate to update the sections “Method of administration and doses”, “Special precautions for use” and “Adverse reactions” of the instructions for medical use in order to strengthen the labeling regarding the risk of drug dependence/abuse by adding information on the negative consequences of opioid use disorders and on risk factors, as well as in order to limit the duration of treatment.
- In view of the available data on the risk of hyperalgesia and taking into account the existing warnings in the package inserts of medicinal products containing opioids, it is appropriate to update the section “Special warnings and precautions for use” of the package insert in order to warn about the risk of hyperalgesia with the use of codeine.
- In view of the available data on the risk of central sleep apnea and the potential class effect of opioids, the warning in the section “Special warnings and precautions for use” of the instructions for medical use should be amended in order to describe the risk of central sleep apnea with the use of codeine.
- In view of the available literature data on the interaction of opioids and gabapentinoids (gabapentin and pregabalin), and taking into account the existing warnings in the instructions for medical use of medicinal products containing opioids, it is advisable to update the section “Interaction with other medicinal products and other forms of interaction” of the instructions for medical use in order to reflect information on the interaction with gabapentinoids.
- In view of the available post-marketing and literature data on codeine, a causal relationship between the use of fixed-dose combination medicinal products and the development of pancreatitis/sphincter of Oddi dysfunction is considered at least reasonably possible; therefore, the “Adverse reactions” section of the instructions for medical use should be updated accordingly, and an appropriate warning should be included in the “Special warnings and precautions for use” section.
- In view of the available post-marketing reports of accidental exposure (intoxication in children), the package leaflet should be amended accordingly to emphasize the need to store the medicinal product in a safe place out of reach.
PRAC concluded that the instructions for medical use of medicinal products containing buclizine/codeine/paracetamol, acetylsalicylic acid/codeine/paracetamol, caffeine/codeine/paracetamol 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 regarding medicinal products containing buclizine/codeine/paracetamol, acetylsalicylic acid/codeine/paracetamol, and caffeine/codeine/paracetamol, the CMDh considers that the benefit/risk balance of medicinal products containing buclizine/codeine/paracetamol, acetylsalicylic acid/codeine/paracetamol, and caffeine/codeine/paracetamol remains unchanged, provided that the proposed changes are made to the instructions for medical use.
Changes to be made to the relevant sections of the instruction for medical use (new text underlined and in bold).
Disorders related to opioid use
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 should be agreed with the patient, including the duration and goals of treatment, as well as a treatment completion plan, in accordance with clinical guidelines on pain management. During treatment, regular contact between the physician and the patient should be maintained to assess the need to continue treatment, consider the possibility of discontinuing it, and adjust the dose if necessary. If the patient no longer requires codeine therapy, it is advisable to reduce the dose gradually to prevent the development of withdrawal symptoms. In the absence of adequate pain control, the possibility of developing hyperalgesia, tolerance, and progression of the underlying disease should be considered (see section “Special precautions for use”).
Duration of treatment
The following wording on the duration of treatment should be added. If there is already stricter wording that specifies the maximum duration of treatment, it should be left unchanged.
The duration of treatment should be as short as possible; if effective pain relief is not achieved, patients/caregivers should be advised to consult a doctor.
“Special precautions for use” section
The existing warning should be amended as follows (the existing wording of the relevant warning should be replaced with the paragraph below, except for any additional approved warnings regarding this risk, for example regarding serious clinical consequences, which should be left unchanged):
Tolerance and disorders associated with opioid use (abuse and dependence)
Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop with repeated use of opioids such as [medicinal product name]. Repeated use of [medicinal product name] may lead to OUD. A higher dose and longer duration of opioid treatment may increase the risk of developing OUD. Abuse or intentional misuse of [medicinal product name] may result in 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 disorder), in current tobacco users, and in patients with a history of other mental health disorders (e.g., major depressive disorder, anxiety disorders, and personality disorders).
Before starting treatment with [name of the medicinal product] and during treatment, the treatment goals and a plan for its discontinuation should be agreed with the patient (see section “Method of administration and doses”). Before starting and during treatment, the patient should also be informed about the risks and signs of OUD. If such signs occur, patients should be advised to contact a doctor.
Patients must be monitored for signs of drug-seeking behavior (for example, premature requests for prescription renewal). This includes assessment of concomitant use of opioids and psychoactive medicinal products (such as benzodiazepines). In patients with signs and symptoms of OUD, consultation with an addiction treatment specialist should be considered.
“Adverse reactions” section
Under the table or description summarizing adverse reactions, the following paragraph should be added:
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 depends on the patient’s individual risk factors, the dose, and the duration of opioid treatment (see the section “Special warnings and precautions for use”).
Hyperalgesia
“Special precautions for use” section
If similar wording has not yet been included in the package insert for medical use, it is recommended to make the following changes:
As with other opioids, if pain control is inadequate in response to an increase in the codeine dose, the possibility of opioid-induced hyperalgesia should be considered. Dose reduction or a review of treatment should be considered.
Central sleep apnea
If similar wording has not yet been included in the package insert for medical use, it is recommended to make the following changes:
“Special precautions for use” section
Sleep-related breathing disorders
Opioids can cause sleep-related breathing disorders, including central sleep apnea (CSA) and sleep-related hypoxemia. The use of opioids increases the risk of CSA in a dose-dependent manner. In patients with CSA, consideration should be given to decreasing the total opioid dose.
Interaction with gabapentinoids
Section "Interaction with other medicinal products and other forms of interaction"
Information on the interaction should be added with the following wording:
If the section “Interaction with other medicinal products and other forms of interaction” already contains identical wording: “Concomitant use of <name of the medicinal product> with […] may result in respiratory depression, hypotension, profound sedation, coma or death…”, the new proposed text (i.e., “gabapentinoids (gabapentin and pregabalin)”) can be added to the existing sentence. If this wording is not yet included in the section “Interaction with other medicinal products and other forms of interaction”, the new proposed sentence can be added immediately after any existing wording on interaction with other centrally acting medicinal products that may lead to potentiation of CNS effects.
A reference to the section “Special warnings and precautions for use” should be included only if the interaction leading to an additive effect on the CNS and respiratory depression is also described in the section “Special warnings and precautions for use”. No new wording is proposed for the section “Special warnings and precautions for use”.
Concomitant use of <name of the medicinal product> with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma, or death (see section “Special warnings and precautions for use”).
Sphincter of Oddi dysfunction and hepatobiliary disorders
“Special precautions for use” section
The following warning should be added:
The existing wording of the relevant warning should be replaced with the text below, shown in bold and underlined where appropriate.
Hepatobiliary disorders
Codeine can cause dysfunction and spasm of the sphincter of Oddi, which increases the risk of biliary symptoms and pancreatitis. Therefore, <name of the medicinal product> should be prescribed with caution to patients with pancreatitis and biliary tract diseases.
“Adverse reactions” section
If the adverse reactions “pancreatitis” and “sphincter of Oddi dysfunction” are already included in the “Adverse reactions” section with a different frequency, the existing frequency should be left unchanged.
The following adverse reaction should be added to the System Organ Class (SOC) “Gastrointestinal disorders” with the frequency “not known”:
pancreatitis
or, if pancreatitis is already listed for patients with a history of cholecystectomy:
pancreatitis, including acute pancreatitis, in patients with a history of cholecystectomy
The following adverse reaction should be added to the System Organ Class (SOC) “Hepatobiliary disorders” with the frequency “not known”:
sphincter of Oddi dysfunction
Accidental exposure and storage in a safe place out of reach
Package insert (package leaflet)
Where to store <name of the medicinal product>
[…]
The information below should be added. If recommendations on storage are already included (for example, on storage temperature or storage in a locked place), the new text should be added immediately before or after the existing information, depending on the context.
Keep this medicinal product in a safe and secure place, out of the reach of other persons. It can cause serious harm and lead to death in persons for whom this medicinal product has not been prescribed.
List of medicinal products containing caffeine/codeine/paracetamol (caffeine/codeine/paracetamol) and authorized for medical use in Ukraine (according to the State Register of Medicinal Products as of 19.06.2026). (10 KB) (Downloaded: 29.06.2026 05:46:50)
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:
