Safety updates: Valproate – Tirzepatide - Glyceryl Trinitrate - Kisqali – Thiocolchicoside – Chlorhexidine containing products

??????????????????: ???????????? ???? ?????? ?????????????????????? ???? ???????????????? ?????? ???????????????????? ?????????????????? ?????? ?????? ?????? ???????? ???????????????? ?????????????? ???????????? ?????????????????? - ????????

????????????????:

Valproate is an antiseizure medication used for epilepsy and bipolar disorder. It is available in various formulations, including sodium valproate, valproic acid, and valproate semisodium. While effective, valproate is associated with significant reproductive risks, particularly when used during pregnancy.

????????????:

A review by two specialists was required for initiating valproate in patients under 55 years old. However, this requirement does not apply now to men already taking valproate.

????????????????:

• Valproate exposure during pregnancy is linked to major congenital malformations (1 in 9 babies exposed) and neurodevelopmental disorders (3-4 in 10 babies exposed).
• Emerging studies indicate a lower but still present risk of neurodevelopmental disorders (around 5 in 100 babies) when fathers take valproate three months before conception.
• Additional male reproductive risks include infertility and testicular toxicity in animal studies.

????????????????????:

Valproate remains an important treatment for epilepsy and bipolar disorder but must be prescribed with caution, particularly in individuals of reproductive age. The updated guidelines reinforce the necessity of specialist review before initiation, except for men already on the medication. Healthcare professionals should ensure appropriate patient counseling and adhere to safety measures to minimize reproductive risks.

?????????? ???????????????????????? ???????? ???????? ???????????????? ???????? ?????????????????? & ???????????????????? ?????????????? ???????????????????? ???????????? (????????) ???? ?????????????? ???? ?????????? ?????????????????? ?????? ???????????????????? ???????????? ?????? ???? ????????????????:

For further reading

???????????????? ?????????????? ???????????????? ???????????????????? ???????? ?????? ???????????????????????????? ???? ?????????????????????? - ??????

????????????????:

Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist. It is indicated as an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes mellitus. Tirzepatide has demonstrated superior glucose control and weight loss compared to selective GLP-1 receptor agonists in both preclinical and clinical trials.

????????????:

A potential safety signal has been identified regarding impaired gastric emptying (gastroparesis) associated with the administration of tirzepatide. This signal emerged following the review of a serious domestic case and further analysis of post-marketing data.

????????????????:

• A domestic case of a male patient hospitalized due to gastroparesis following tirzepatide administration was reported in December 2024. The condition improved after discontinuation of the medication as per the physician’s recommendation.
• A case series analysis of 389 cases retrieved from VigiBase/VigiLyze was conducted. In 279 cases (71.7%), tirzepatide was the single suspect drug.
• 26 cases (6.7%) were medically confirmed by physicians.
• In 25.7% of cases, gastroparesis or delayed gastric emptying was also associated with co-reported drugs (semaglutide and dulaglutide).
• The mechanism of action aligns with the known effect of GLP-1 receptor agonists in delaying gastric emptying.

????????????????????:

The weighted available evidence from case series analysis and literature review suggests a potential risk of impaired gastric emptying with tirzepatide use. Given the plausibility of this mechanism and its occurrence in post-marketing settings, PVGA has agreed to consider it as a potential safety risk.

For further reading

?????????? ???????? ???????????? ???????????????? ???????????????????? ???? ???????????????????????? ??????????????????????: ?? ???????? ???? ?????????? ?????????????? ???? ?????????? ???????????????? ?????????? ???? ?????????????????????????? ?????????????? ???????? -??????

????????????????:

Glyceryl trinitrate is an organic nitrate (vasodilator) used in cardiac diseases to reduce vascular smooth muscle tone. It decreases systemic vascular resistance, pulmonary vascular pressure, and arterial pressure, ultimately reducing both preload and afterload, thereby decreasing the workload on the heart. It improves oxygen supply by redistributing blood flow from epicardial to endocardial regions.

????????????:

A case report from the Egyptian Pharmaceutical Vigilance Centre highlighted a rapid and severe decline in blood pressure following the inappropriate administration of glyceryl trinitrate in a hypertensive emergency.

????????????????:

• Case Details: A 75-year-old male patient with a history of peptic ulcer, ischemic heart disease, hypertension, chronic kidney disease, and previous coronary artery bypass graft surgery was admitted to the ICU with a hypertensive emergency and pulmonary edema. He was administered glyceryl trinitrate at an inappropriate initial dose (20 mcg/minute), leading to a rapid decline in blood pressure (90/60 mmHg), shock, and bradycardia, necessitating vasopressors.
• Background on Hypertensive Emergency: Defined as severely elevated blood pressure (systolic ≥180 mmHg and/or diastolic ≥120 mmHg) with acute target-organ damage. Treatment aims to gradually lower blood pressure to prevent organ damage.
• Labeled Information (SmPC): Glyceryl trinitrate should not be given by bolus injection and must be diluted before infusion. Initial recommended dose: 5 mcg/min, increasing in increments of 5 mcg/min every 3 to 5 minutes up to 20 mcg/min. If unresponsive, further increases up to 200 mcg/min may be considered. Rapid blood pressure reduction and severe hypotension/bradycardia may occur, especially in cases of volume depletion, myocardial infarction, or valvular heart disease.

????????????????????:

This case highlights the importance of adhering to the recommended dosing guidelines for glyceryl trinitrate in hypertensive emergencies. Healthcare professionals should initiate treatment at the lowest recommended dose and gradually titrate upward to avoid complications such as severe hypotension and shock. Strict hemodynamic monitoring is essential to ensure patient safety.

For further reading

???????????? ???????????????????? ???????????????????????? ?????????????????????????? (????????)

?????????????? - (????????) – ??????

Drug:

Kisqali (ribociclib)

Overview:

Kisqali (ribociclib) is used for treating hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant. It is also used in combination with an aromatase inhibitor for the adjuvant treatment of patients with HR-positive, HER2-negative early breast cancer at high risk of recurrence.

Update:

• Kisqali must now be stored in a refrigerator (2°C to 8°C) for up to 10 months until dispensed to patients.
• After dispensing, Kisqali can be stored at up to 25°C for up to 2 months in the original blister packs.
• The total shelf life of Kisqali is now limited to 12 months.
• The product information, labeling, and package leaflet have been updated to reflect these changes.

Findings:

The changes in storage conditions and shelf-life are aimed at maintaining the quality of Kisqali throughout its lifecycle, especially with its expanded indication for early breast cancer. These updates are applicable across all indications of the drug. Novartis has implemented a transition plan to manage existing stock and ensure a smooth shift to the revised storage guidelines.

Conclusion:

Healthcare professionals, including pharmacists and medical oncologists, should adhere to the new storage conditions to ensure the effectiveness and safety of Kisqali. The updated information has been approved by regulatory authorities and will be implemented at the national level in EU member states. Patients should be informed of the revised storage instructions upon dispensing to ensure proper handling of the medication.

For further reading

???????????????????????????????? ???????????????????? ?????????????????? ?????? ???????????????? ??????: - ?????????????????? ?????????????????????? ???? ???????????????????????? ???????????????????? ???????? ?????? ???????? ???? ???????????????????????? - ???????? – ??????

?????? ??????????????????????????????????:

• Men who do not wish to use effective contraception during and for 3 months after treatment.
• Women of childbearing age who are not using effective contraception during and for 1 month after treatment.

???????????????? ??????????????????????????????????:

• Women of childbearing age not using contraception.
• Pregnant and breastfeeding women.
• Updated information is now included in medicinal product leaflets.

???????????? ??????????????:

• Preclinical studies show that a metabolite of thiocolchicoside is genotoxic at exposure levels close to those observed in humans.

?????????????????? ?????????? ??????????????:

·???????? Teratogenicity, fetal toxicity, spontaneous abortion, reduced male fertility, and tumor development.

• Risk increases with long-term use and high doses.
• EMA guidelines recommend contraception after stopping drugs with known genotoxic risks.

???????????????? ??????????????????????????????:

• Thiocolchicoside is restricted to short-term (maximum 7 days oral, 5 days intramuscular) adjuvant treatment of painful muscle contractures in acute spinal disorders in adults and adolescents (16+ years).
• Healthcare professionals must ensure adherence to updated contraceptive precautions.

For further reading

??????????????????????????-???????????????????? ????????????????: ?????????? ???? ???????????????????? ?????????????? ???????????? ?????? ?????????????????????? ???????????? ???????????????????? - ???????? – ??????

????????????????????:

• Chlorhexidine is an antimicrobial agent used for skin disinfection before medical procedures.
• Intended for cutaneous use only, with minimal systemic absorption.
• Ocular exposure can cause severe and irreversible corneal damage, even when protective measures are taken. In some cases, this may necessitate a corneal transplant.

???????????? ??????????????:

• A causal link has been established between chlorhexidine-containing products and persistent corneal injury and significant visual impairment.
• New warnings highlight risks of: Corneal erosion, epithelium defects, and permanent visual impairment due to accidental ocular exposure.
• Accidental exposure may occur during head and neck surgical site preparation when the solution migrates beyond the intended area.

?????????????????????????????? ?????? ????????:

• Ensure strict application control to avoid migration to unintended areas.
• Educate surgical teams on the risks and necessary precautions.
• Be vigilant with anesthetized patients to prevent unnoticed exposure.
• Act immediately if exposure occurs to minimize the risk of permanent damage.

For further reading