Below Safety Updates for medicinal products were released for the month of May-2020 by Ireland Health Authority-Health Products Regulatory Agency (HPRA)

 

A confirmed “Negative Benefit-Risk Profile” for Picato (ingenol mebutate)

Risk of abnormal and aggressive behaviors with Levetiracetam use

Restricted use of Cyproterone acetate due to risk of meningioma

Restricted use of thyroid drugs in pregnant women and in women of childbearing potential

Acute pancreatitis risk associated with carbimazole

Testosterone-containing medicinal products: caution in patients with thrombophilia or risk factors for venous thromboembolism (VTE)

 

A confirmed “Negative Benefit-Risk Profile” for Picato (ingenol mebutate)

In the year 2012 throughout the European Union, Picato was authorized for use as a 150 micrograms/gram gel (for use on the face and scalp) and 500 micrograms/gram gel (for use on the trunk and extremities).

The potential for development of benign skin tumours (keratoacanthoma) in patients treated with ingenol mebutate was identified based on the results from the study NCT01998984 in the year 2017. Post-marketing reports of skin tumours in Picato-treated patients have also been received with the temporal relationship (time taken for onset of symptoms for tumour formation) ranging from weeks to months. Due to this increased number of skin cancer cases (squamous cell carcinoma) associated with ingenol mebutate use, European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) initiated the evaluation the benefit-risk balance of ingenol mebutate by assessing the available data. PRAC review commented in Sep 2019 and during the review period, a direct Healthcare Professional Communication (DHPC) was circulated by the marketing authorisation holder (product’s sponsor) for the suspension of use throughout the entire Europe, as per EMA recommendation. In February 2020, batches of Picato were recalled from pharmacies and marketing authorisation had voluntarily withdrawn the EU marketing authorisation for this product.

PRAC Review highlights:

• Risk minimization measures were not identified for skin tumours risk in the treatment area to an acceptable level and considered evidence that Picato’s effectiveness is not maintained over time.
• Alternative treatment options are available for actinic keratosis.
• PRAC review concluded that the risk of skin malignancy associated with Picato outweighs its potential benefits

• Picato is no longer authorized in the EU and batches of Picato have been recalled from pharmacies.

Advice to Healthcare Professionals

• The risk-benefit balance of Picato (ingenol mebutate) is negative due to the risk of skin malignancy.
• To look for alternative treatment and to stop prescribing Picato
• To advise patients to be vigilant for any symptoms or skin lesions developing within the treatment area and to seek medical advice immediately should any occur.

 

Risk of abnormal and aggressive behaviors with Levetiracetam use

Levetiracetam is a pyrrolidone derivative and an anticonvulsant medication indicated for the treatment of specified forms of epilepsy, either as a monotherapy or as adjunctive treatment in defined circumstances.

Abnormal behavior which means “any behavior that deviates from what is considered normal” which included irritable and aggressive behaviors. These safety concerns are already considered as important identified risks for levetiracetam, and this information is reflected in the Summary of Product Characteristics (SmPC) which is an approved product information and Package Leaflet (PL)), where several adverse reactions relating to this risk, including hostility/ aggression, nervousness/irritability, psychotic disorder, abnormal behavior, anger, affect lability/mood swings and agitation are described, as are depression, anxiety, suicidal ideation/attempt and completed suicide.

A periodic review of the available safety and efficacy data for levetiracetam is completed by PRAC and considered that the warnings in the product information should be updated to include a warning on the risk of abnormal and aggressive behaviors in patients treated with levetiracetam.

Advice to Healthcare Professionals

• Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness.
• Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviors are noticed, treatment adaptation or gradual discontinuation should be considered.
• Healthcare professionals should counsel patients or patient’s care givers for monitoring the side effects which become serious or last longer than a few days: Abnormal thoughts, feeling irritable or reacting more aggressively than usually or if patients or their family/friends notice important changes in mood or behavior.
• If levetiracetam is to be discontinued, gradual withdrawal is recommended. Healthcare professionals should refer to section 4.2 of the Summary of Product Characteristics (SmPC).

 

Restricted use of Cyproterone acetate due to risk of meningioma

Cyproterone acetate is an anti-androgen and progestin medication (a synthetic progesterone derivative with anti-androgenic properties) used for antiandrogen treatment in men with prostate cancer (an inoperable carcinoma) excessive hair growth, for reduction of drive in sexual deviations and for early puberty, lack of menstrual period and acne. This medicine also used as contraception and in hormone replacement therapy.

In the year 2008, the association of meningioma with high dose cyproterone acetate was first described which led to the update of product information documents with an inclusion of a ‘contraindication in patients with meningioma or a history of meningioma’, and a warning added regarding the risk of meningioma associated with long-term use of cyproterone acetate.

The results of an epidemiological cohort study demonstrated that there is a cumulative dose-dependent association between cyproterone acetate and meningioma.

Advice to Healthcare Professionals

• The occurrence of meningiomas (single and multiple) has been reported in association with the use of cyproterone acetate, primarily at doses of 25 mg/day and above.
• The risk of meningioma is dose dependent which is more with increasing cumulative dose.
• Cyproterone acetate is contraindicated in patients with a meningioma or a history of meningioma.
• Patients should be monitored for symptoms of meningiomas in accordance with clinical practice.
• Treatment should be stopped permanently, if there is a diagnosis of meningioma,
• For reduction of drive in sexual deviations in men, cyproterone acetate 100 mg can be used when other interventions are considered inappropriate.
• The use of cyproterone acetate for the treatment of inoperable prostate cancer remains unchanged.
• The product information for cyproterone acetate containing medicines are updated with this current safety knowledge of meningioma risk associated with cyproterone acetate.
• A Direct Healthcare Professional Communication (DHPC) advising healthcare professionals of the outcome of the PRAC review is available from the HPRA website.

 

Restricted use in pregnant women and in women of childbearing potential

For Carbimazole:

Carbimazole (a pro-drug) is a carboethoxy derivative of methimazole used in the treatment of hyperthyroidism and thyrotoxicosis. Carbimazole is metabolized into its active form-thiamazole in the body. Carbimazole has shown some teratogenic effects (effect on foetus development) based on the strength of evidence from the case reports and data from epidemiological studies.

Exposure of carbimazole/thiamazole during pregnancy is associated with an increased risk of congenital malformations, especially when administered in the first trimester of pregnancy and at high doses. Some of the reported congenital malformations associated with Carbimazole exposure include aplasia cutis congenita, craniofacial malformations, defects of the abdominal wall and gastrointestinal tract, and ventricular septal defects.

Advice to healthcare professionals

• Women of childbearing potential should use effective contraception during treatment with carbimazole.
• The use of carbimazole during pregnancy should be reserved for cases where a definitive therapy of the underlying disease (thyroidectomy or radio-iodine treatment) was not suitable prior to pregnancy, or in cases of new occurrence/recurrence during pregnancy.
• Individual benefit/risk ratio- a strict assessment must be conducted when carbimazole must only be used during pregnancy and only at the lowest effective dose without additional administration of thyroid hormones.
• A close maternal, foetal, and neonatal monitoring is recommended for pregnant women exposed to carbimazole.
• A Direct Healthcare Professional Communication (DHPC) to communicate the strengthened advice on contraception was circulated by the Marketing Authorisation Holders for carbimazole-containing products (following approval by the HPRA) to relevant healthcare professionals and is available from the HPRA website.

For Propylthiouracil:

Propylthiouracil is an anti-thyroid drug used for the treatment of hyperthyroidism. The available evidence from epidemiological studies is conflicting regarding the risk of congenital malformations associated with the use of propylthiouracil during pregnancy.

Advice to healthcare professionals

• Individual benefit/risk assessment must be conducted before initiating treatment with propylthiouracil during pregnancy.
• Propylthiouracil should be administered during pregnancy at the lowest effective dose without additional administration of thyroid hormones.
• Close monitoring is recommended for maternal, foetal, and neonatal exposed patients.

 

Acute pancreatitis risk associated with carbimazole

Based on the safety evidence received from the post-marketing case reports suggests a causal link between acute pancreatitis and the use of medicinal products containing carbimazole/thiamazole.

Although the mechanism is not fully understood, decreased time to onset after re-exposure could suggest an immunological mechanism.

Advice to healthcare professionals

• Immediate discontinuation– is required in patients who develop pancreatitis following exposure to carbimazole and treatment should not be restarted.
• Individual benefit/risk assessment- Should be performed and if necessary, an alternative treatment need to considered for patients with pancreatitis.

 

Testosterone-containing medicinal products: caution in patients with thrombophilia or risk factors for venous thromboembolism (VTE)

Testosterone-containing medicinal products are licensed in Ireland as testosterone replacement therapy for male hypogonadism.

PRAC highlighted the need for amendment of product information document for testosterone-containing medicinal products by including- caution in patients with risk factors for venous thromboembolism (VTE) to the existing warning of clotting disorders.

PRAC considered to specify risk factors for VTE in the Package Leaflet (product information document) and additionally to include signs and symptoms of thrombosis in order to highlight these for patients.

Advice to Healthcare Professionals

• Caution– testosterone-containing medicinal products (topical, oral, and injectable formulations) should be used with caution in patients with risk factors for venous thromboembolism (VTE).
• RMM (risk minimization measures) implementation for patients with VTE risk.
• A careful evaluation is needed for patients with thrombophilia having first thrombotic event with continuing testosterone treatment and further measures should be taken to minimize the individual VTE risk.

 

Voluntary Reporting:

Health care professionals and consumers are advised to report any suspected adverse drug reactions and quality concerns to the HPRA by online voluntary reporting facility through various methods available in- Report an Issue. This would facilitate the accumulation of the more evident safety data which could expedite further regulatory actions by Ireland Health Authority.