Report on the meeting of the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) held on 19-20 July 2022

Nonsteroidal anti-inflammatory drugs (NSAIDs) for systemic use and their use during pregnancy

In July 2022, PRAC gave a recommendation to a Member State regarding a type II variation for an ibuprofen-containing medicinal product for systemic use, in order to update the instructions for medical use regarding use during pregnancy.

It was decided that the package leaflet should be updated by adding the following text:

Section “Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility”

Starting from week 20 of pregnancy, the use of <x> may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after the start of treatment and is usually reversible after treatment is discontinued. In addition, there are reports of constriction of the ductus arteriosus following treatment in the second trimester of pregnancy, most of which resolved after treatment was discontinued. Therefore during the first and second trimesters of pregnancy <x> should not be prescribed unless clearly necessary. If <x> is used by a woman who is trying to become pregnant, or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Antenatal monitoring for oligohydramnios and constriction of the ductus arteriosus should be considered after exposure to <х> for several days, starting from gestational week 20. The use of <х> should be discontinued if oligohydramnios or constriction of the ductus arteriosus is detected.

During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may cause the following risks:

Risks to the fetus:

• cardiopulmonary toxicity (with premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
• renal dysfunction (see above);

Risks for the mother late in pregnancy and for the newborn:

• possible prolongation of bleeding time, an antiplatelet effect that may occur even at very low doses;
• suppression of uterine contractions, leading to delayed or prolonged labor.

Therefore, <x> is contraindicated during the third trimester of pregnancy (see section “Contraindications”).

It was further decided that the changes to the instructions for medical use, as shown above, will be applied to other medicinal products containing ibuprofen for systemic use (including fixed-dose combinations) ⃰ and to all other systemic NSAIDs.

It should be noted that if the instructions for medical use already contain stricter recommendations for use during pregnancy, those recommendations remain in force and must be retained. Medicinal products containing acetylsalicylic acid are currently excluded from the implementation request. Further recommendations for these medicinal products will be provided after the agreement on the shared use of the originator variation is concluded. It should be noted that the above recommendations apply only to medicinal products for systemic use.

Registration certificate holders of topical NSAIDs are asked to address this topic in future periodic safety update reports (PSURs) for their medicinal products.

⃰Except for medicinal products for the treatment of hemodynamically significant patent ductus arteriosus in children

Regarding amendments to the instructions for medical use of medicinal products for systemic use containing

• dexketoprofen (dexketoprofen)
• diclofenac (diclofenac)

The Pharmacovigilance Risk Assessment Committee (PRAC), based on the assessment of the analysis of Periodic Safety Update Reports (PSURs) for medicinal products containing dexketoprofen and diclofenac for systemic use, reached the following conclusions.

The use of dexketoprofen and diclofenac for systemic use after 20 weeks of pregnancy causes fetal renal dysfunction, oligohydramnios, and neonatal renal failure.

Given the available data from the literature and spontaneous reports on the use of non-steroidal anti-inflammatory medicinal products after week 20 of pregnancy, including cases with a close temporal relationship, a case with a positive rechallenge and de-challenge, and given the plausible mechanism of action, the PRAC considers that a causal relationship between the use of dexketoprofen and diclofenac for systemic use after week 20 of pregnancy and the risk of renal dysfunction, oligohydramnios and neonatal renal failure is at least a reasonable possibility. The PRAC concluded that the package leaflets of medicinal products containing dexketoprofen and diclofenac for systemic use should be amended accordingly, if similar information on use during pregnancy is not already included.

The Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) agrees with the scientific conclusions drawn by the PRAC.

Based on the scientific conclusions, the CMDh considers that the benefit/risk balance of medicinal products containing dexketoprofen, diclofenac for systemic use remains unchanged, subject to the appropriate changes being made to the instructions for medical use.

Changes to be included in the relevant sections of the instructions for medical use (new text underlined in bold, deleted text struck through).

Section “Use during pregnancy or breastfeeding. Pregnancy. Breastfeeding. Fertility”

From week 20 of pregnancy, use of <x> may cause oligohydramnios due to fetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible after treatment discontinuation. During the first and second trimesters of pregnancy, <x> should not be prescribed unless strictly necessary. If <x> is used by women trying to become pregnant, or during the first and second trimesters of pregnancy, the dose should be as low as possible and the duration of treatment as short as possible. Antenatal monitoring for oligohydramnios should be considered after exposure to <x> for several days, starting from week 20 of pregnancy. <x> should be discontinued if oligohydramnios is found.

During the third trimester, all prostaglandin synthesis inhibitors cause:

Risks to the fetus:

• cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension);
• impaired renal function (see above);

Risks for the woman late in pregnancy and for the newborn:

• possible prolongation of bleeding time, an antiplatelet effect that may occur even at very low doses;
• suppression of uterine contractions, leading to delayed or prolonged labor.

Therefore, <x> is contraindicated during the third trimester of pregnancy (see sections “Contraindications”).

Medicinal products containing diclofenac for intramuscular administration

Section “Special warnings and precautions for use”

The instructions for intramuscular administration must be strictly followed to avoid injection site adverse reactions that can lead to muscle weakness, muscle paralysis, hypoesthesia, medicinal embolism (Nicolau syndrome) and necrosis at the injection site.

Warnings should be added or amended as follows:

Injection site reactions

Injection site reactions have been reported following intramuscular administration of diclofenac, including injection site necrosis and medication embolism, also known as Nicolau syndrome (especially after inadvertent subcutaneous administration). When administering diclofenac intramuscularly, appropriate needle selection and injection technique should be observed (see section “Method of administration and doses”).

“Adverse reactions” section

The adverse reaction should be added to the section “General disorders and administration site conditions” with frequency “unknown”:

Medication-induced embolism (Nicolau syndrome)

For the analysis of published information, the applicant must use the original text available at the link: