Leaves

Report on the impact side from PDF to report suspected adverse effects.

The use of valproate is prohibited in pregnant women due to an increased risk of congenital abnormalities (including neural tube defects) and neurodevelopmental disorders. In girls and women of childbearing age, valproic acid should only be used if strict precautions are taken as part of a pregnancy prevention program. [zie Folia juni 2018 en het symbool  t.h.v. de specialiteiten]. Following the 2018 EMA risk mitigation measures on the use of valproate in women, manufacturers of valproate-based medicines were asked to investigate the risks of valproate exposure in men who wanted to have children. The results of that study suggest that there may be an increased risk of neurodevelopmental disorders in children whose fathers were treated with valproate 3 months before they were born.1. The study was not large enough and had several limitations, which means that a causal relationship cannot be determined between the use of valproate in pregnant men and the development of neurological disorders in their children.
Following these study data, the European Medicines Committee PRAC evaluated the risks of valproate exposure in men of childbearing potential and formulated risk mitigation measures.

A little about the study

This is a retrospective study based on 3 Scandinavian registries. This research has not yet been published.
The aim of the study was to investigate neurodevelopmental disorders in children of fathers treated with valproate around conception, compared to the risk in children of fathers who received lamotrigine or levetiracetam (all in monotherapy).
The hazard ratio for neurodevelopmental disorders in children whose fathers were treated with valproate compared to children whose fathers were treated with lamotrigine or levetiracetam was 1.5 (95% CI: 1.09-2.07).
The risk of developing neurodevelopmental disorders was between 4.0% and 5.6% in the valproate group and between 2.3% and 3.2% in the lamotrigine/levetiracetam group.

Key findings of PRAC

The PRAC1 concluded that there may be an increased risk of neurodevelopmental disorders (5% versus 3%) in children (aged 0 to 11 years) born to fathers treated with valproate monotherapy 3 months before they were born compared to men treated with lamotrigine or levetiracetam was treatment. However, the limitations of the study are also emphasized, such as the variation in indications for valproate use and the limited size of the population studied.

Risk reduction measures for pregnant men

For exposure to valproate in pregnant men, the following risk reduction measures are now in place1:

• Special instructions are recommended when starting treatment with valproate in men.

• Inform patients about the potential risk of neurodevelopmental disorders and the need for effective contraception, including for the female partner, for the duration of treatment and up to 3 months after after stopping it.

• Regular review of treatment to determine whether valproate is still the most appropriate treatment for the patient.

• Men who want to have children should consult a specialist. Valproate treatment should be reassessed and other treatment options considered.

• Inform patients that they should not donate sperm during treatment and for at least 3 months after stopping.

• Male patients will be given educational material about the teratogenic risk [nog niet beschikbaar op 05/03/2024].

Some thoughts

• Valproate has indications in the SPC for the treatment of certain types of epilepsy as well as the treatment of manic episodes in bipolar disorder when lithium is contraindicated or not tolerated. Valproate is also used off-label in the prophylactic treatment of migraine.

• Lecrat says that, based on the data currently available and pending additional information about this study, it is not reasonable to change or stop valproate treatment in a man who wants to have children.2.

• Lareb places a critical note on the interpretation of the retrospective study on which the PRAC advice is based. In this study there was uncertainty about what type of epilepsy the men had (with the risk of passing through with a symptom) and the study was generally not large enough to determine which developmental problems the risk was higher. Lareb also emphasizes the fact that the potential risk of the father using valproate in this study (5%) is much lower than the risk shown for non- developmental prescriptions (30-40%) in children whose mothers took valproate during pregnancy3.

• Another study (Thomson et al.4) found that the prevalence of autism and intellectual disability was slightly higher in children of fathers who used valproate than in children of fathers who did not use antiepileptic drugs. The increased risk was not statistically significant in this study.

• La Revue Préscire says that these results give reason to reconsider the use of valproic acid in men who want to have children. Especially when other options, such as lamotrigine, levetiracetam, propranolol, amitriptyline and lithium, can be considered in the treatment of epilepsy, migraine and mood disorders such as bipolar disorder respectively.5.

Special names:

Valproate: Depakine®, Valproate (see Repertoire)

Sources

1 EMA. https://www.ema.europa.eu/en/news/potential-risk-neurodevelopmental-disorders-children-born-men-treated-valproate-medicines-prac-recommends-precautionary-measures. DHPC was sent to the health care providers: via https://geneeemiddelsdatabank.be/human-use > search term: valproate > download the DHPC for each specialty via “DHPC”
2 CRAT https://www.lecrat.fr/1778/ to arrive on 03/05/2023
3 lareb. Use of valproic acid by men who wish to have children. Available on 03/05/2024. Lareb website
4 Tomson T, Muraca G, Razaz N. Paternal exposure to antiepileptic drugs and offspring outcomes: a national population-based cohort study in Sweden. J Neurol Neurosurg Psychiatry. 2020; 91(9):907-13. PMID:32651245
5 Paternal exposure to valproic acid before birth: neuropsychological developmental disorders in offspring? Rev. Ordinance 2024; 44 (485): 190-192

Report on the impact side from PDF to report suspected adverse effects.

Review Order reminiscent of the narrow therapeutic-toxic margin of colchicine. An overdose can have serious side effects. The dose had to be strictly respected, taking into account renal or hepatic insufficiency and the many interactions.

The indications of Colchicine in the SKP are the treatment of acute gout attacks and the prevention of gout attacks at the beginning of uric acid lowering treatment. They are also known as symptoms: Mediterranean family fever and scleroderma. Low-dose colchicine has been studied in recent years for various heart problems (see Folia March 2016) and is currently being studied in patients with coronary artery disease after percutaneous coronary intervention (PCI, KCE website).

In two recent articles1,2remembering Journal of Education on

• that colchicine a therapeutically toxic edge yes, and

• there is that overdose there is a risk of rhabdomyolysis, neuropathy, bone marrow depression, kidney damage and liver damage. Gastrointestinal complaints (diarrhea, nausea, vomiting) can be the first symptoms of alcohol.

Journal of Education reports that there is still one a large number of overdoses have been reported in Francedespite the risk mitigation measures taken, such as the distribution of DHPC to French health professionals in 2016. In fact, French toxicological surveillance and pharmacovigilance data (period 2016-2020) show that

• medication errors (eg errors in dosage) are still a frequent cause of overdose;

• he is therapeutic scheme often complicated for the patient;

• issues with fatal outcome reported, including at conversation colchicine with a macrolide or statin;

• there are reports about this too deliberate overdosein the context of a suicide attempt.

NB In Belgium he got Antigifcentrum In the’ period 2018-2022 approximately 90 reports of colchicine exposure, of which 29 were accidental overdoses and 19 were intentional overdoses.

To limit the risk of overdose with colchicine, the following elements are important:

• Respect the dosage, taking into account the presence of renal or hepatic insufficiency (note in the elderly).

  • YesAs dosage for acute gout attack as stated therein Directory > 9.3.1. Colchicine (edition 2024) as follows (sources: SKP, Pharmacotherapeutic compass, Normal Arthritis NHG (2017)):

    • Start colchicine as soon as possible. Start with 1 mg in the first 12 hours, then 0.5 mg an hour later, and continue with 0.5 mg 2 to 3 times a day for the next few days.

    • In the elderly and in the case of kidney disease, a dose of 0.5 mg is recommended as the first intake.

    • In the case of moderate renal impairment, a dose of 0.5 mg every two days is recommended. The treatment period should be as short as possible. In patients with severe renal impairment, colchicine is contraindicated.

    • Treatment should be stopped or reduced when pain resolves or when adverse gastrointestinal effects occur.

    • Use up to 6 mg in total during the course of treatment. If a new attack occurs after completing a course of treatment, wait at least 72 hours before starting a new course of treatment.

  • Some additional information about use in acute gout attacks from other sources:

    • Treatment for up to 5 days. Stop treatment as soon as there are signs of intoxication (diarrhea, nausea, vomiting), or if the symptoms have not improved after 5 days, or if the pain has disappeared existence (NHG Status “Arthritis” (2017)).

    • According to the Normal Arthritis NHG (2017) During short-term treatment with the low dose (0.5 mg 2-3 times / day), no dose adjustment is required for patients with renal impairment (moderate or moderately severe).

• Be aware of the many interactions:

  • YesRisk of alcohol When colchicine is associated CYP3A4 inhibitors (in addition to macrolidene clarithromycine and erythromycine; of azolderivaten itraconazol, ketoconazol, posaconazol and voriconazol; pompelmoessap) and from P-gp (including amiodarone; cyclosporine; clarithromycin; the azole derivatives itraconazole and ketoconazole; verapamil): see Table Ic. In Inl.6.3. in Register ID. in Inl.6.3. Contraindications according to the SKP:

    • used together with a strong inhibitor of CYP3A4 or P-gp in patients with renal or hepatic insufficiency;

    • used together with a macrolide in all patients.

  • Increased risk muscle toxicity when you connect to statins of fibrates.

• Avoid antidiarrheals during treatment because they can hide the first signs of an overdose.

  In France there is a strong association of colchcine powder + opium. The opium powder can mask the symptoms of diarrhea. This no doubt explains why several overdoses are reported in France with this link.

Special names:

– Colchicine: Colchicine Opocalcium® (see Repertoire)

Special sources

1 Colchicine and gout attacks. The dose in the RCPs was further reduced due to the risks of overdose. Prescrire Review 2023; 43:347
2 Colchicine: more overdoses and deaths. Prescrire Review 2023; 43:512-515
3 Report of the ANSM Permanent Research and Drug Investigations Committee, meeting on 9/27/2021, via Event – Interface committee with the toxic surveillance network – ANSM (sante.fr)