Health Products Regulatory Authority (HPRA) Safety Information
Contents
January 2026: Oral retinoids (acitretin and isotretinoin): Psychiatric disorders and pregnancy prevention programme reminder
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Key Messages Psychiatric disorders: • Psychiatric disorders have been reported in patients treated with oral retinoids. • Healthcare professionals are reminded that all patients should be monitored for signs of depression and referred for appropriate treatment if necessary. Particular care should be taken in patients with a history of depression. Pregnancy prevention programme: • Oral retinoids are highly teratogenic and associated with a high frequency of severe and life-threatening birth defects, as well as increased incidence of spontaneous abortion. • Healthcare professionals are reminded that use of oral retinoids is strictly contraindicated in pregnancy and in women of childbearing potential unless the conditions of the pregnancy prevention programme (PPP) are met. • Recent studies conducted in several other European countries suggested variability in adherence to key PPP conditions; pregnancies continue to occur in women treated with oral retinoids. |
Oral retinoids, including acitretin and isotretinoin*, are authorised in Ireland to treat various dermatological conditions, including severe forms of acne, psoriasis, congenital ichthyosis, keratosis follicularis and lichen planus.
This article highlights key points from regulatory recommendations concerning the use of these products. A reminder of existing warnings related to psychiatric disorders as well as findings from studies evaluating the effectiveness of pregnancy prevention programmes** implemented for oral retinoids are included. For full details, please refer to the product information for the specific medicine, including the Summary of Product Characteristics.*
Psychiatric disorders
Product information for oral retinoids includes a warning on psychiatric disorders.
The warning followed EU-wide reviews of this safety concern in 2003 and again in 2018. The 2018 review acknowledged the limitations of the available data, including that the body of evidence did not allow for a clear establishment of whether reports of psychiatric disorders were due to the use of oral retinoids. However, given the intended patient population and considering that patients with severe skin conditions may be more vulnerable to psychiatric disorders due to the nature of the disease, the product information for oral retinoids includes a warning about this possible risk and provides advice to healthcare professionals and patients.
A further routine review of national and EU-level pharmacovigilance data from recent years indicates that psychiatric adverse reactions associated with oral retinoids continue to be reported. This includes cases of completed suicide associated with isotretinoin. Therefore, the HPRA is highlighting the existing warning to reinforce awareness amongst healthcare professionals of the importance of discussing potential psychiatric risks with patients before, during and in the case of isotretinoin, after treatment.
Information for Healthcare professionals
- Cases of depression, depression aggravated, anxiety, mood alterations and psychotic symptoms have been reported in patients taking systemic retinoids.
- Additionally, aggressive tendencies, suicidal ideation, suicide attempts, and suicide have been reported in patients treated with isotretinoin.
- All patients should be monitored for signs of depression and referred for appropriate treatment if necessary.
- Particular care is advised in patients with a history of depression.
- Awareness by family or friends may be useful in detecting mental health deterioration.
- For patients treated with isotretinoin, discontinuation of treatment may be insufficient to alleviate symptoms, and further psychiatric or psychological evaluation may be necessary.
- Refer patients to the package leaflet that comes with the medicine pack or is accessible online when prescribing these medicines and discuss any questions or concerns that they may have.
Pregnancy prevention programme
A pregnancy prevention program is in place for oral retinoids approved for use in Ireland, which incorporates strengthened measures recommended following a 2018 EU-wide review. To evaluate the strengthened measures, companies marketing these medicines had to conduct a drug utilisation study (DUS) along with a survey of healthcare professionals and patients or caregivers.
Studies on the effectiveness of strengthened measures
Results of the survey, conducted in seven European countries (France, Germany, Greece, Norway, Poland, the UK and Spain), indicate that both healthcare professionals and patients/caregivers are aware of the teratogenic risks of oral retinoids and the conditions of the pregnancy prevention programme.
However, the survey findings, together with the DUS (conducted in France, Germany, Sweden and Spain), suggest that these medicines may not always be prescribed and used in full alignment with the conditions of the pregnancy prevention programme, particularly with respect to medically supervised pregnancy testing and contraceptive use. Furthermore, pregnancies continued to occur in women treated with oral retinoids.
These results must be interpreted in the context of the studies' limitations, including the possibility of incomplete information on markers of adherence in the data sources used, leading to an underestimation of actual compliance within the DUS and response biases, which may impact the generalisability of the survey findings.
In Ireland, a separate survey1 evaluating the awareness, knowledge, and practice of specialists, GPs, and community pharmacists following the implementation of the strengthened pregnancy prevention measures for isotretinoin was conducted in 2019. Amongst survey respondents, the results of the survey were as follows:
- High awareness amongst all healthcare professional groups that isotretinoin is contraindicated in women of childbearing potential unless the conditions of the pregnancy prevention program are fulfilled.
- Lower awareness among GPs and community pharmacists that exposure during pregnancy can cause spontaneous abortions, as well as severe foetal malformations.
- Limited provision and utilisation of the patient reminder card to support patient counselling for women of childbearing potential.
Key conditions of the pregnancy prevention programme
Oral retinoids are powerful human teratogens that can induce a high frequency of severe and life-threatening birth defects. They are also associated with an increased incidence of spontaneous abortion.
Oral retinoids are strictly contraindicated in pregnant women and in women of childbearing potential unless the conditions of the pregnancy prevention programme are met. If pregnancy does occur during or after treatment (after one month for isotretinoin/after three years for acitretin), there is a great risk of very severe and serious malformations of the foetus. Oral retinoids are also contraindicated in women who are breastfeeding due to the potential for side effects in the exposed child.
If pregnancy occurs in a woman treated with oral retinoids, treatment must be stopped, and the patient should be referred to a physician specialised or experienced in teratology for evaluation and advice.
To minimise these risks, the pregnancy prevention programme includes an assessment of the potential for pregnancy in females of childbearing potential. Prescribers must discuss the following information with females of childbearing potential:
- Teratogenicity: Prescribers must ensure that women of childbearing potential understand the teratogenic risk and the need to follow the conditions of the pregnancy prevention programme while taking oral retinoids. Patients should understand the need to rapidly consult their doctor if there is a risk of pregnancy.
- Contraception: Prescribers must ensure women of childbearing potential understand the importance of consistent and correct use of effective contraception. Effective contraception should be used before, during and after treatment, unless the prescriber considers there are compelling reasons to indicate there is no risk of pregnancy.
- Follow-up visits, pregnancy testing and monthly prescriptions: Prescribers must ensure women of childbearing potential understand the need for regular follow-up visits and negative pregnancy test results before, during and after the end of treatment (for 1 month after isotretinoin, and periodically for 3 years after acitretin). To support this, prescriptions should ideally be limited to 30 days.
Contraception
Female patients must be provided with comprehensive information on pregnancy prevention and if they are not using effective contraception, they should be provided/referred for contraceptive advice.
Individual circumstances should be evaluated in each case when choosing the contraception method, involving the patient in the discussion, to guarantee her engagement and compliance with the chosen measures.
As a minimum requirement, female patients of childbearing potential must be in agreement to use at least one highly effective method of contraception (e.g. a user-independent form such as an intra-uterine device or implant), or two complementary user-dependent forms of contraception (e.g. an oral hormonal contraceptive and barrier method). Contraception should be used for at least 1 month prior to starting treatment, throughout treatment and continue for at least 1 month after stopping treatment with isotretinoin, and for at least 3 years after stopping treatment with acitretin, due to the persisting risk.
These conditions apply to all females of childbearing potential, including those with amenorrhea or who are not currently sexually active, unless the prescriber considers there are compelling reasons to indicate there is no risk of pregnancy, as provided for in product information.*
Prescription duration and dispensing
To support regular follow-up, including pregnancy testing and monitoring, the prescription duration for women of childbearing potential should be limited to 30 days. Ideally, pregnancy testing, issuing a prescription, and dispensing should occur on the same day. Dispensing of isotretinoin and acitretin should occur within a maximum of 7 days of the prescription.
Male patients
Healthcare professionals should remind male patients that they must not share their medication with anyone, particularly not females. Available data suggest the levels of oral retinoid in the semen of men taking isotretinoin or acitretin are too low to be associated with teratogenic effects.
Other precautions
Healthcare professionals should remind patients never to share their oral retinoids with another person, and to return any unused medicine to their pharmacist at the end of treatment.
Patients should not donate blood during therapy and for 1 month following discontinuation of isotretinoin and 3 years following discontinuation of acitretin, due to the potential risk to the foetus if given to a pregnant transfusion recipient.
Educational materials to support implementation
To support prescribers and pharmacists in implementing the pregnancy prevention programme, educational materials are available. These materials aim to reinforce warnings about teratogenicity, provide guidance on contraception, and outline requirements for pregnancy testing. These materials include:
- Physician checklist/acknowledgement form: This form must be completed by the physician and patient at initial and follow-up visits for all female patients prescribed acitretin or isotretinoin to confirm that appropriate advice to prevent oral retinoid exposure during pregnancy has been provided and understood.
- Pharmacist checklist: This form is used to provide guidance on the appropriate dispensing of isotretinoin and acitretin to both male and female patients.
- Patient reminder card: The prescriber and pharmacist should ensure all patients (male and female) are provided with the patient reminder card each time acitretin or isotretinoin is prescribed or dispensed, and check for patient understanding. The card is now included as part of the medicine pack. If broken bulk dispensing cannot be avoided, the patient should be provided with a copy of the package leaflet and the patient reminder card.
Educational materials for acitretin and isotretinoin medicines are available on the HPRA website. To access them, search using the 'Find a Medicine' and select the medicine or the educational material ('EdM') symbol.
References:
1. Hughes JE, Buckley N, Looney Y, Kirwan G, Mullooly M, Bennett KE. Evaluating awareness, knowledge and practice of healthcare professionals following implementation of a revised pregnancy prevention programme for isotretinoin in Ireland: A multi-stakeholder cross-sectional study. Pharmacoepidemiol Drug Saf. 2023 Feb;32(2):137-147
* Further details, including the approved product information and educational materials, of currently authorised oral retinoid products, containing isotretinoin or acitretin, are available from www.hpra.ie.
** A Direct Healthcare Professional Communication (DHPC) has been issued to remind healthcare professionals of the necessary precautions and measures in place.
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Key messages:
• Suicidal ideation: following an EU review of available data, suicidal ideation is considered an adverse reaction of oral finasteride containing medicines, mainly reported in patients treated for androgenic alopecia (AGA), and new advice to manage this risk has been recommended.
• New recommendations for patients treated for androgenetic alopecia (AGA): - Advise patients treated with oral finasteride for AGA to stop treatment and seek medical advice if they experience depressed mood, depression or suicidal ideation. - Sexual dysfunction that may contribute to mood alterations, including suicidal ideation has been reported in some patients treated for AGA. Inform patients to seek medical advice if they experience sexual dysfunction and consider discontinuation of treatment. - To further highlight this risk for patients treated for AGA, a patient card will be available in the package of finasteride 1 mg to highlight the risks of depressed mood, depression, suicidal ideation and sexual dysfunction reported with finasteride. • Dutasteride authorised for benign prostatic hyperplasia (BPH) indications: - Despite the insufficient evidence to establish a direct association of suicidal ideation with dutasteride, and based on the common mechanism of action for medicinal products of the class of 5-alpha reductase inhibitors, patients treated with dutasteride should be recommended to seek prompt medical advice if symptoms of mood alterations occur. |
Background
Finasteride and dutasteride are 5-alpha reductase inhibitors that reduce dihydrotestosterone (DHT) levels by inhibiting the enzyme 5-alpha reductase. Finasteride is an inhibitor of the enzyme 5-alpha-reductase types 1 and 2 with a greater affinity for type 2. Dutasteride targets both isoforms of this enzyme. DHT is involved in the pathophysiology of androgenic alopecia (AGA) and benign prostatic hyperplasia (BPH).
In Ireland, finasteride 1 mg tablets are authorised for the treatment of early-stage AGA in men aged 18 to 41 years1. Additionally, finasteride 5 mg tablets and medicines containing dutasteride 0.5 mg are authorised for the treatment of symptoms of BPH.
For finasteride- and dutasteride-containing medicinal products, some psychiatric disorders are known risks and are already reflected in the product information. An EU review commenced to examine concerns regarding a risk of suicidal ideation, as outlined in Edition 117 of the HPRA Drug Safety Newsletter. The scientific review, undertaken by the EMA’s Pharmacovigilance Risk Assessment Committee (PRAC), has concluded, and the PRAC have issued new recommendations and advice, which are outlined below.
Further regulatory steps will be completed by the Co-ordination Group for Mutual Recognition and Decentralised Procedures for human medicines (CMDh) and the European Commission, for a legally binding decision to complete the regulatory process.
PRAC recommendations
As part of the scientific review, the EMA’s PRAC reviewed the available data, including data from clinical trials, case reports, the scientific literature and information received during the review from the public. The existing warnings and advice available for these products concerning mood disorders were considered.
The PRAC assessed 325 relevant case reports of suicidal ideation identified in EudraVigilance, the EU database of suspected adverse reaction reports. This included 313 cases were reported for finasteride and 13 for dutasteride (1 case reported for both). Most cases involved patients treated for AGA, while a 10 times lower number of cases were reported for patients treated for BPH. These numbers should be considered in the context of an estimated exposure of approximately 270 million patient years for finasteride and 82 million patient years for dutasteride.
Overall, the PRAC concluded that regarding suicidal ideation and behaviours reported with 5-alpha reductase inhibitors, the level of evidence for these events differs according to the respective indications, active substances and formulations, and has made recommendations accordingly, as set out below.
Finasteride 1 mg (androgenetic alopecia)
Suicidal ideation is an adverse reaction of oral finasteride products with a frequency not known, meaning that it cannot be estimated from the available data.
• The product information already includes warnings on mood alterations, including suicidal ideation, together with a recommendation to stop treatment and seek prompt medical advice if these symptoms occur.
• In addition, the review identified cases of suicidal ideation in which sexual dysfunction contributed to the development of mood alterations, including suicidal ideation.
• Sexual dysfunction is a known adverse reaction of finasteride, with persistence of sexual dysfunction (including decreased libido, erectile dysfunction and ejaculation disorders) reported in post-marketing use, including after discontinuation of treatment.
• Warnings and precautions for use will be updated to advise patients to consult their doctor if they experience sexual dysfunction, and discontinuation of the treatment should be considered.
• A new patient card will be included in the package for finasteride 1 mg to inform about the risks of mood alterations, including suicidal ideation, and sexual dysfunction, as well as to advise on the appropriate actions to be taken.
Finasteride 5 mg (BPH), including combination products
• The review also confirmed that suicidal ideation is an adverse reaction with the frequency not known (cannot be estimated from the available data).
• The current product information of these formulations already contains a warning on mood alterations, including suicidal ideation, together with the recommendation to seek prompt medical advice if these symptoms occur.
• The review included combination products of finasteride with tadalafil or tamsulosin, but there are no authorised combination products with these active ingredients in Ireland.
Dutasteride 0.5 mg (BPH), including combinations with tamsulosin
• There is insufficient evidence to establish a risk of suicidal ideation with dutasteride.
• However, as a precautionary measure, and based on the evidence for another oral 5-alpha reductase inhibitors, warnings and precautions for use will be updated to inform about the potential risk of suicidal ideation, with a recommendation that patients should seek prompt medical advice if symptoms of mood alterations occur.
Following completion of the regulatory steps, it is planned to implement the above recommendations for authorised medicines in Ireland.
February/March 2025: Fluconazole: Update on pregnancy outcomes following use and new advice for women of childbearing potential
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Key Messages
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Fluconazole is a member of the class of triazole antifungal agents and a potent and specific inhibitor of fungal sterol synthesis. Fluconazole containing medicines are indicated in the treatment and prophylaxis of a wide range of fungal infections, including cryptococcosis, systemic candidiasis, mucosal candidiasis, genital candidiasis, prevention of fungal infections in patients with malignancy, and deep endemic mycoses in immunocompetent patients*.
Following a review by the European Medicines Agency's (EMA) Pharmacovigilance Risk Assessment Committee (PRAC), updates to product information** for fluconazole containing medicines were recommended to reflect available data on abnormal pregnancy outcomes, as follows:
Risk of spontaneous abortion
Observational studies suggest an increased risk of spontaneous abortion in women treated with fluconazole during the first and/or second trimester compared to women who were either not treated with fluconazole or received topical azoles during the same period1.
Risk of cardiac malformations
Available epidemiological studies on cardiac malformations with the use of fluconazole during pregnancy provide inconsistent results. However, a meta-analysis of five observational studies including several thousand pregnant women exposed to fluconazole during the first trimester found a 1.8-to-2-fold increased risk of cardiac malformations when compared to no fluconazole use and/or topical azoles use2.
Other birth defects
Case reports describe a pattern of birth defects among infants whose mothers received high-dose (400 to 800 mg/day) fluconazole during pregnancy for three months or more in the treatment of coccidioidomycosis. The birth defects seen in these infants include brachycephaly, ear dysplasia, giant anterior fontanelles, femoral bowing and radio-humeral synostosis. A causal relationship between fluconazole use and these birth defects is uncertain.
Advice for healthcare professionals
Based on the review of available data on adverse pregnancy outcomes, the EMA’s PRAC has recommended new advice on use of fluconazole in women of childbearing potential:
- Before starting treatment in women of childbearing potential, healthcare professionals should inform patients of the potential risks to the foetus.
- After a single dose treatment, a washout period of one week is recommended before becoming pregnant.
- For longer courses of treatment, contraception may be considered, as appropriate, in women of childbearing potential throughout the treatment period and for one week after the final dose.
- Healthcare professionals are reminded of existing advice that fluconazole should not be used during pregnancy in standard doses or for short-term treatments unless absolutely necessary. Additionally, high doses or prolonged use of fluconazole should only be considered during pregnancy for treating potentially life-threatening infections.
* Further details on fluconazole products are available at www.hpra.ie.
** The approved product information is made up of the Summary of Product Characteristics (SmPC) and Package Leaflet (PL) and is available at www.hpra.ie.
References:
- Mølgaard-Nielsen D, Svanström H, Melbye M, Hviid A, Pasternak B. Association between use of oral fluconazole during pregnancy and risk of spontaneous abortion and stillbirth. JAMA. 2016 Jan 5;315(1):58-67.
- Budani MC, Fensore S, Di Marzio M, Tiboni GM. Maternal use of fluconazole and congenital malformations in the progeny: A meta-analysis of the literature. Reprod Toxicol. 2021;100:42-51.
This information is supplied by the Health Products Regulatory Authority (HPRA) for use in the IMF. However, the HPRA is independent and impartial to any other information contained in this formulary.
September 2024: Updated Recommendations on the Use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) During Pregnancy
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Key Messages
The EMAs Pharmacovigilance Risk Assessment Committee (PRAC) has issued updated recommendations following a review of recently available data that indicates
that from the 20th week of pregnancy onward, prolonged use of systemic NSAIDs may lead to oligohydramnios due to foetal renal dysfunction. Additionally, there have
been reports of ductus arteriosus constriction following NSAID treatment during the second trimester, with most cases resolving after treatment cessation.
Systemic NSAIDs
Topical NSAIDs
Acetylsalicylic acid
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Background information
The EMA’s PRAC has recommended that the approved product information* for systemic (i.e. oral and injectable) NSAID-containing medicinal products, including fixed-dose combinations, should be updated with regard to the use of these products during pregnancy. The updates follow the review of available data which concluded that the use from the 20th week of pregnancy onward may cause oligohydramnios resulting from foetal renal dysfunction. It was observed that this may occur shortly after treatment initiation and was usually reversible upon treatment discontinuation. Additionally, there have been reports of ductus arteriosus constriction following treatment in the second trimester, most of which resolved after treatment cessation.
The PRAC recommendations for systemic NSAIDs during pregnancy
During the first and second pregnancy trimesters, systemic NSAIDs should not be given unless deemed clearly necessary. If the NSAID is deemed necessary, the dose should be kept as low and the duration of treatment as short as possible. This recommendation also applies to a woman attempting to conceive.
Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to NSAIDs for several days from gestational week 20 onward. The NSAID should be discontinued if oligohydramnios or ductus arteriosus constriction are found.
While the product information for NSAIDs will be amended to include updated advice for use during pregnancy, when stricter advice on use in pregnancy already exists, the stricter advice will remain.
These new recommendations primarily concern the first and second pregnancy trimesters; currently, the use of systemic NSAIDs is contraindicated in the last trimester of pregnancy as they may induce foetal cardiopulmonary and renal toxicity, inhibit uterine contraction, leading to delayed or prolonged labour and possibly extend the bleeding time for mothers and neonates due to anti-aggregating effects that may occur even at very low doses.
New recommendations for topical NSAIDs in pregnancy
Following several routine reviews of available data concerning medicines within the same therapeutic class, the PRAC concluded that although systemic exposure with the use of topical NSAIDs (including oromucosal formulations and transdermal patches) is typically lower compared to oral administration, it could not definitively exclude the potential risk of oligohydramnios and ductus arteriosus to the embryo/foetus.
Consequently, to date the PRAC recommended updating the product information for several topical NSAIDs, including naproxen, ketoprofen, ibuprofen and flurbiprofen products. It is recommended to avoid the use of topical NSAID products during the first and second pregnancy trimesters unless deemed clearly necessary. If deemed necessary, the dosage should be kept as low and the treatment duration as short as possible. As is the case for systemic NSAIDs, use of topical NSAIDs is contraindicated during the last trimester of pregnancy.
Healthcare professionals are advised to check relevant product information when considering the use of topical NSAIDs during pregnancy, as it is already recommended to avoid certain topical NSAIDs, like ibuprofen, during pregnancy.
Implication for Acetylsalicylic Acid-containing Products
Due to the different clinical applications and dosages of acetylsalicylic acid-containing products, and the need to evaluate the available data and the implications of the NSAID recommendations, acetylsalicylic acid-containing products are currently excluded from the implementation of PRAC recommendations to date.
This information is supplied by the Health Products Regulatory Authority (HPRA) for use in the IMF. However, the HPRA is independent and impartial to any other information contained in this formulary.
Page Revised: 17 December 2025