European medicines agency has released a new Issue (135-June-2020) for medicine updates.

The drug safety updates from this issue were discussed below in brief.

Fatal Drug Interactions between fluoropyrimidines and brivudine

Risk of breast cancer with hormone replacement therapy

Potential medication errors with Leuprorelin depot medicines

 

Fatal Drug Interactions between fluoropyrimidines and brivudine

European Medicines Agency (EMA) published a direct health care professional communication (DHPC) to its national competent authorities to disseminate the significant information on this safety concern.

Brivudine is an antiviral medication and a uridine derivative used in the treatment of herpes zoster. This drug acts by blocking the action of DNA polymerases of virus, thereby inhibiting the viral replication. Fluoropyrimidines are anti-metabolites class of drugs (anti-cancer) which included flucytosine, capecitabine. carmofur, doxifluridine, fluorouracil and tegafur.

Dihydropyrimidine dehydrogenase (DPD) is the key enzyme involved in the metabolism of these anti-metabolite drugs (drugs containing pyrimidine nucleus in their molecular structure).

Inhibition of Dihydropyrimidine dehydrogenase (DPD)

The main metabolite of Brivudine –Bromo vinyl uracil (BVU) (a pyrimidine moiety and inactive form of brivudine) is inhibiting the key metabolizing enzyme of pyrimidine-based drugs, Dihydropyrimidine dehydrogenase (DPD). Because of this DPD inhibition, metabolizing process of fluoropyrimidines is decreased which results in increased levels of fluoropyrimidine drug moieties leading to fluoropyrimidine toxicity with potentially fatal outcome.

Brivudine is contraindicated in the following conditions due to potential drug interaction:

1. Cancer chemotherapy: Patients with medicines containing fluorouracil including its topical preparations, its prodrugs (e.g. capecitabine, tegafur) and combination products containing these active substances or other fluoropyrimidines- who recently received or are currently receiving or patients who are planned to receive these fluoropyrimidine medication within 4 weeks.
2. Anti fungal therapy: Patients who recently received or are currently receiving flucytosine (a small amount of it is metabolized to fluorouracil).
3. Immunosuppressive therapy: Immunocompromised patients or patients with concurrent cancer chemotherapy.

Key information for Health care professionals:

• All health care professionals should be aware of this new potential drug interaction of brivudine metabolite with fluoropyrimidine drugs to prevent/minimize the risk potentially fatal toxicity
• Should inquire the patient’s past drug history, concurrent medication use before prescribing or dispensing brivudine.
• A checklist is suggested by EMA for prescribers to check the suitability of the patient to receive brivudine treatment.

 

Risk of breast cancer with hormone replacement therapy

Hormone replacement therapy (HRT) is a treatment used in relieving symptoms of the menopause. It replaces hormones that are at a lower level as the patient approach menopause. HRT is also useful in preventing osteoporosis (weakening of the bones) which is more common after the menopause.

The review of safety committee of EMA-Pharmacovigilance Risk Assessment Committee (PRAC) has identified a new information on the breast cancer (known risk) with HRT and recommended update of the product information document with the updated information. The new information has confirmed the known higher risk of breast cancer in women using HRT. This safety evidence is based on the results of a large study published in Aug-2019.

The results showed that the breast cancer risk may continue to be increased for ten years or more after permanent discontinuation of HRT, if it has been used for more than five years.

Key information from Safety review committee:

• Low dose and exposure time: Women should only take HRT for the treatment of symptoms of menopause at the lowest dose and for the shortest possible time that works for them.
• Regular check-ups: Women should also have regular check-ups, including breast screening, in line with current recommendations, and seek medical attention if they notice any changes in their breasts.

 

Potential medication errors with Leuprorelin depot medicines

Leuprorelin Depot formulations are used in the treatment of prostate cancer, breast cancer and certain conditions that affect the female reproductive system and early puberty. Several formulations of this medicine require some complex steps to prepare the injection. They are given by injection under the skin or into a muscle and they release the active substance gradually over 1 to 6 months. They include implants as well as powders and solvents for the preparation of injections. Leuprorelin medicines have been authorised and marketed in many EU countries with several brand names which included Eligard, Eliprogel, Enantone, Ginecrin, Lupron, Lutrate, Politrate and Procren.

Leuprolide acetate (Eligard) is a type of hormonal therapy used in the treatment of advanced prostate cancer. It is a “luteinizing hormone-releasing hormone” (LHRH) agonist which lowers testosterone hormone levels. This medicine is available in injectable suspension (prescription drug) given by injection to patients with advanced prostate cancer. Lutrate Depot (leuprolide acetate for depot suspension) is a gonadotropin-releasing hormone (GnRH) agonist used in the palliative treatment of advanced prostatic cancer

The review of safety committee of EMA-Pharmacovigilance Risk Assessment Committee (PRAC) identified handling errors for leuprorelin depot medicines during time of preparation and administration to patients which results in receiving of insufficient amounts of their leuprorelin to the affected patients.

The possible medication errors identified by safety review team (PRAC) are listed below-

1. Incorrect use of the needle or syringe (which causes the medicine to leak from the syringe)
2. Failure to inject leuprorelin properly or Incorrect Injection (Insufficient amount would be administered)
3. Inadequate reconstitution

Hence, safety committee recommended that “only healthcare professionals familiar with the preparation steps for leuprorelin depot medicines should prepare and administer the medicines to patients. Patients should not prepare or inject these medicines themselves.” This measure to would minimize/avoid the possible handling errors during preparation and administration of leuprorelin depot medicines (medication error).

As per EMA’s safety committee recommendation, the product information document for Eligard and Lutrate Depot is to be updated with warnings to strictly follow the instructions for preparation and administration and to monitor patients if a handling error occurs.

In addition to above risk minimizing measure, EMA requested Eligard manufacturer to replace the current device used to administer the medicine with a new medical device which is easier to handle (with a deadline for device replacement-October 2021).  And also, to change the packaging to facilitate easy access to these instructions.

Key Information for patients

• Patients should not prepare or inject these medicines by own, as the handling errors while administering leuprorelin depot medicines might make treatment less effective (which are designed to work over a long period)
• These medicines should only be prepared and given by a physician or other health care professional with experience in using these depot formulations.
• Consult your respective physician or pharmacist for any concerns or queries.

Key Information for healthcare professionals

• Patients should not inject the Leuprorelin depot medicines themselves and should only be prepared and given by healthcare professionals who are familiar with the administration procedures.
• Potential for Lack of Efficacy & Under-dosing: Handling errors with depot formulations of leuprorelin medicines which could result in under dosing and lack of drug efficacy.
• Handling errors are related to the complexity of the reconstitution process, which involves multiple steps for some leuprorelin depot formulations.
• Refer Product Information documents (summary of product characteristics)- which included warnings to inform healthcare professionals about cases of handling errors and to remind them to strictly follow the instructions for preparation and administration of the medicine.
• Patients should be monitored appropriately, in case of suspected or known handling error with the medicine.
• Leuprorelin medicines are also available as daily injections but this formulation is not included in this update by the safety review committee as there have been no reports of handling errors with the daily-use injections.