PRAC October 2021 – Nomegestrol containing products and chlormadinone containing products and update on COVID-19 vaccines

date: 13/10/2021

During its October 2021 meeting, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) has started a review of meningioma risk with nomegestrol- and chlormadinone-containing medicines. The PRAC also has reviewed data on venous thromboembolism and immune thrombocytopenia with COVID-19 vaccines.

Nomegestrol containing products and chlormadinone containing products
EMA has started a review of medicines containing the active substance nomegestrol or chlormadinone. These medicines can be used, alone or in combination with other active substances, to treat gynaecological disorders such as amenorrhea (absence of menstrual periods) and other menstrual disorders, uterine bleeding, endometriosis (a condition in which tissue similar to the lining of the womb grows elsewhere in the body), breast tenderness, and as hormone replacement therapy or contraceptives (birth control).

The review was requested by the French medicines agency (ANSM) following new data from two epidemiological studies carried out in France in women taking these medicines to investigate the risk of meningioma, a tumour of the membranes covering the brain and spinal cord. This tumour is usually non-malignant and is not considered to be a cancer, but due to their location in and around the brain and spinal cord, meningiomas can in rare cases cause serious problems.

Cases of meningioma have been reported in women taking medicines containing nomegestrol or chlormadinone, and warnings are already included in the prescribing information for some of the medicines. However, the information for prescribers and patients may differ across EU Member States.

Data from the two studies suggest that the risk of meningioma increases with dose and duration of treatment and may be greater in women taking nomegestrol or chlormadinone for several years. The studies also showed that after women had stopped taking nomegestrol or chlormadinone for one year or more, the risk of developing these tumours was reduced and comparable to the risk in people who never used these medicines.

In light of these new data, EMA's safety committee (PRAC) will now examine the available evidence and make recommendations as to whether the marketing authorisations for nomegestrol- and chlormadinone-containing medicines should be amended across the EU.

The following nomegestrol- and chlormadinone-containing medicines are authorised and marketed in Belgium : Lutenyl, Nogest, Nomegestrol Stragen, Zoely, Bellina and Helen

PRAC assessment of rare cases of venous thromboembolism with COVID-19 Vaccine Janssen
The PRAC has concluded that there is a possible link to rare cases of venous thromboembolism (VTE) with COVID-19 Vaccine Janssen.

VTE is a condition in which a blood clot forms in a deep vein, usually in a leg, arm or groin, and may travel to the lungs causing a blockage of the blood supply, with possible life-threatening consequences. This safety issue is distinct from the very rare side effect of thrombosis with thrombocytopenia syndrome (TTS) (i.e. blood clots with low blood platelets). 

VTE was included in the risk management plan for COVID-19 Vaccine Janssen as a safety concern to be investigated, based on a higher proportion of cases of VTE observed within the vaccinated group versus the placebo group in the large clinical study which was used to authorise this vaccine. The issue has been kept under close monitoring.

The PRAC has now reviewed new evidence from the study described above, as well as new evidence from another large clinical study. In this second study, there was no increase in venous thromboembolic events among individuals who received COVID-19 Vaccine Janssen. The PRAC also reviewed evidence from the post marketing setting - that is data gathered while the vaccine is used in the context of vaccination campaigns. When taking all evidence into account, the committee concluded that there is a reasonable possibility that rare cases of VTE are linked to vaccination with COVID-19 Vaccine Janssen.

The committee is therefore recommending listing VTE as a rare side effect of COVID-19 Vaccine Janssen in the product information, together with a warning to raise awareness among healthcare professionals and people taking the vaccine, especially those who may have an increased risk of VTE.

As part of the awareness-raising effort, the PRAC has agreed the content of a direct communication to healthcare professionals that is described further in this document, in the section ’New safety information for healthcare professionals’.

PRAC assessment of cases of immune thrombocytopenia with Vaxzevria and COVID-19 Vaccine Janssen
The PRAC assessed cases of immune thrombocytopenia (ITP) reported following vaccination with Vaxzevria (formerly AstraZeneca COVID-19 Vaccine) as well as COVID-19 Vaccine Janssen.

ITP is a condition in which the immune system mistakenly targets blood cells called platelets that are needed for normal blood clotting. Very low levels of blood platelets can be associated with bleeding, and have serious health consequences.

The committee assessed all the available data and recommended updating the product information of both vaccines to include ITP as an adverse reaction with an unknown frequency.

Furthermore, a warning statement has been agreed to highlight that cases of very low levels of blood platelets have been reported very rarely, usually within the first four weeks following vaccination with COVID-19 Vaccine Janssen or Vaxzevria.

If an individual has a history of ITP, the risk of developing low platelet levels should be considered before vaccination, and platelet monitoring is recommended after vaccination with either of these vaccines.

The PRAC will continue to monitor for new information and will take any further actions as necessary.

As part of the awareness-raising effort, the PRAC has agreed the content of a direct communication to healthcare professionals which is described further in this document, in the section ’New safety information for healthcare professionals’.

New safety information for healthcare professionals
As part of its advice on safety-related aspects, the PRAC agreed on direct healthcare professional communications (DHPCs) containing important safety information for COVID-19 Vaccine Janssen and Vaxzevria.

COVID-19 Vaccine Janssen: risk of immune thrombocytopenia and venous thromboembolism
This DHPC informs healthcare professionals about immune thrombocytopenia (ITP) and venous thromboembolism (VTE).

For ITP, the DHPC highlights that cases of ITP have been reported within the first four weeks after receiving COVID-19 Vaccine Janssen, and that it included serious cases with very low platelet counts.

If an individual has a history of ITP, healthcare professionals should consider the risk of developing low platelet levels prior to administering the vaccine. In individuals with a history of

ITP, it is recommended to monitor platelet levels following vaccination with COVID-19 Vaccine Janssen.
For VTE, it is described that VTE has been observed rarely following vaccination with COVID-19 Vaccine Janssen and that the risk of VTE should be considered for individuals with increased risk factors for thromboembolism (blood clots).

Individuals diagnosed with thrombocytopenia within three weeks after vaccination with COVID-19 Vaccine Janssen should be actively investigated for signs of thrombosis. Similarly, individuals who present with thrombosis within three weeks of vaccination should be evaluated for thrombocytopenia.  This is important, to assess a potential diagnosis of thrombosis with thrombocytopenia syndrome (TTS), which requires specialised clinical management.

Vaxzevria: risk of thrombocytopenia including immune thrombocytopenia
This DHPC informs healthcare professionals of cases of thrombocytopenia (low levels of blood platelets) including immune thrombocytopenia (ITP) that have been reported with Vaxzevria, typically within the first four weeks after vaccination.

Very rarely, these events of thrombocytopenia presented with very low platelet levels and/or were associated with bleeding.

If an individual has a history of a thrombocytopenic disorder, healthcare professionals are advised to consider the risk of developing low platelet levels such as ITP, before administering the vaccine. Additionally, platelet monitoring is recommended after vaccination in an individual who has a history of ITP.

The DHPCs for COVID-19 Vaccine Janssen and Vaxzevria will be forwarded to EMA’s human medicines committee, the CHMP. Following the CHMP agreement, the DHPCs will be disseminated to healthcare professionals by the marketing authorisation holders, according to an agreed communication plan, and published on EMA’s website and in national registers in EU Member States.

Last updated on 13/10/2021