PRAC November 2022 – Measures for Janus kinase inhibitors, modified product information of mRNA COVID-19 vaccines Comirnaty and Spikevax, and addition of warning to the product information for ustekinumab (Stelara)

date: 16/11/2022

During its November 2022 meeting, the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency recommended measures to minimise risk of serious side effects with Janus kinase inhibitors for chronic inflammatory disorders. Furthermore, the PRAC recommended to add heavy menstrual bleeding to the product information as a side effect of the mRNA COVID-19 vaccines Comirnaty and Spikevax, and to add a warning to the product information for ustekinumab (Stelara).

Janus kinase (JAK) inhibitors: measures to minimise the risk of serious side effects 
The Pharmacovigilance Risk Assessment Committee (PRAC) recommends measures to minimise the risk of serious side effects associated with Janus kinase (JAK) inhibitors used to treat several chronic inflammatory disorders. These side effects include cardiovascular conditions, blood clots, cancer and serious infections.

The PRAC recommends that these medicines should be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer.

The PRAC also recommends using JAK inhibitors with caution in patients with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism, VTE) other than those listed above. Further, the doses should be reduced in some patient groups who may be at risk of VTE, cancer or major cardiovascular problems. 

The recommendations follow a review of available data, including the final results from a clinical trial of the JAK inhibitor Xeljanz (tofacitinib) and preliminary findings from an observational study involving Olumiant (baricitinib), another JAK inhibitor. During the review, the PRAC sought advice from an expert group of rheumatologists, dermatologists, gastroenterologists and patient representatives.

The review confirmed Xeljanz increases the risk of major cardiovascular problems, cancer, VTE, serious infections and death due to any cause when compared with TNF-alpha inhibitors. The PRAC has now concluded that these safety findings apply to all approved uses of JAK inhibitors in chronic inflammatory disorders (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata). 

The product information for JAK inhibitors used to treat chronic inflammatory disorders will be updated with the new recommendations and warnings. In addition, the educational material for patients and healthcare professionals will be revised accordingly. Patients who have questions about their treatment or their risk of serious side effects should contact their doctor.

The following immunomodulatory medicinal products, belonging to the pharmacological class of protein kinase inhibitors of the Janus kinase (JAK) family, are authorised and marketed in Belgium:

  • Olumiant (with active substance baricitinib),
  • Jyseleca (with active substance filgotinib),
  • Xeljanz (with active substance tofacitinib),
  • Rinvoq (with active substance upadacitinib).

More information is available on the European Medicines Agency (EMA) website.

Comirnaty and Spikevax : heavy menstrual bleeding added as a side effect
The PRAC recommends that heavy menstrual bleeding should be added to the product information as a side effect of unknown frequency of the mRNA COVID-19 vaccines Comirnaty and Spikevax. 

Heavy menstrual bleeding (heavy periods) may be defined as bleeding characterised by an increased volume and/or duration which interferes with the person’s physical, social, emotional and material quality of life. Cases of heavy menstrual bleeding have been reported after the first, second and booster doses of Comirnaty and Spikevax.

The PRAC finalised the assessment of this safety signal after reviewing the available data, including cases reported during clinical trials, cases spontaneously reported in Eudravigilance and findings from the medical literature. 

After reviewing the data, the Committee concluded that there is at least a reasonable possibility that the occurrence of heavy menstrual bleeding is causally associated with these vaccines and therefore recommended the update of the product information. 

The available data reviewed involved mostly cases which appeared to be non-serious and temporary in nature.

Menstrual disorders in general are quite common and they can occur for a wide range of reasons. This includes some underlying medical conditions. Any person who experiences postmenopausal bleeding or is concerned about a change in menstruation should consult their doctor. 

There is no evidence to suggest the menstrual disorders experienced by some people have any impact on reproduction and fertility. Available data provides reassurance about the use of mRNA COVID-19 vaccines before and during pregnancy. A review carried out by EMA’s Emergency Task Force showed that mRNA COVID-19 vaccines do not cause pregnancy complications for expectant mothers and their babies, and they are as effective at reducing the risk of hospitalisation and deaths in pregnant people as they are in non-pregnant people.

The Committee reiterates that the totality of data available confirms that the benefits of these vaccines greatly outweigh the risks.

Healthcare professionals and patients are encouraged to continue to report cases of heavy menstrual bleeding to their national authorities.

The PRAC will continue to monitor for cases of this condition and will communicate further if new recommendations are warranted. 

Comirnaty and Spikevax vaccines are authorised and available in Belgium.

More information is available on the EMA website.

Ustekinumab (Stelara) : warning on use of live vaccines in infants whose mothers received ustekinumab during pregnancy
The PRAC recommendes adding a warning to the product information for ustekinumab (Stelara) on the use of live vaccines in infants whose mothers received ustekinumab during their pregnancy.

Ustekinumab is authorised in the European Union to treat severe plaque psoriasis, psoriatic arthritis, Crohn’s disease and ulcerative colitis.

The product information already advises that it is preferable to avoid use of ustekinumab during pregnancy. People of childbearing potential are advised to avoid becoming pregnant and must use adequate contraception while using Stelara and for at least 15 weeks after the last Stelara treatment. 

The PRAC reviewed the available evidence regarding use of ustekinumab during pregnancy, including observational studies from the EU, United States and Canada, as well as a cumulative review requested from the marketing authorisation holder. 

Ustekinumab can cross the placenta. It has been detected in the serum (the fluid component of the blood) of infants who were exposed to ustekinumab in utero (infants whose mothers were treated with the medicine during pregnancy).

Although the data on ustekinumab are limited, the risk of infection may be increased after birth in infants who were exposed to ustekinumab in utero.

Therefore, the PRAC recommends that, in infants who were exposed to ustekinumab in utero, the administration of live vaccines (vaccines made from a virus or bacterium that has been weakened) is not recommended for six months following birth or until the infant’s serum levels of ustekinumab are undetectable. In case of a clear clinical benefit for the individual infant, administration of a live vaccine might be considered earlier, if the infant’s serum levels of ustekinumab are undetectable.

The PRAC’s recommendation will be forwarded to EMA’s human medicines committee (CHMP) for adoption.

The medicinal product Stelara is authorised and marketed in Belgium.
More information is available on the EMA website.

Last updated on 16/11/2022