Denosumab – Risk of severe hypocalcemia
United States warning.
The US Food and Drug Administration (FDA) has concluded that the osteoporosis medicine denosumab (Prolia®) increases the risk of severe hypocalcemia, very low blood calcium levels, in patients with advanced chronic kidney disease (CKD), particularly patients on dialysis. Severe hypocalcemia appears to be more common in patients with CKD who also have a condition known as mineral and bone disorder (CKD-MBD). In patients with advanced CKD taking denosumab, severe hypocalcemia resulted in serious harm, including hospitalization, lifethreatening events, and death.
Denosumab is a monoclonal antibody initially developed for the treatment of osteoporosis in postmenopausal women at increased risk of fracture or who are refractory to or cannot tolerate other therapies. Denosumab was later approved to increase bone mass in men with osteoporosis; to treat men with high risk for fracture receiving androgen deprivation therapy for prostate cancer; to treat women at high risk for fracture receiving aromatase inhibitor therapy for breast cancer; and, to treat men and women with glucocorticoid-induced osteoporosis. FDA is adding a Boxed Warning to the denosumab prescribing information about the significant risk of developing severe hypocalcemia in patients with advanced CKD. This warning and new labelling contains information to help reduce this risk, including appropriate patient selection for denosumab treatment, increased monitoring of blood calcium levels, and other strategies. The FDA is adding this updated information to the patient Medication Guide and the denosumab Risk Evaluation and Mitigation Strategy (REMS).
Reference: Drug safety communication, US FDA, 19 January 2024 (link to the source within www.fda.gov) (See also WHO Pharmaceuticals Newsletter No.1, 2023: Denosumab and potential risk of severe hypocalcemia in patients on dialysis)
Canada warning.
Health Canada has alerted health-care professionals that the Indications, Warnings and Precautions, Adverse Reactions (Post-Market Adverse Reactions), Clinical Pharmacology (Pharmacokinetics, Special Populations and Conditions), and Patient Medication Information sections of the Canadian product monograph for denosumab (Prolia®) have been updated with additional information on the risk of severe symptomatic hypocalcemia and safety in paediatric patients.
In the post-market setting, severe symptomatic hypocalcemia (resulting in hospitalization, life threatening events and fatal cases) have been reported. This is particularly observed in patients with severe renal impairment, receiving dialysis or treatment with other calcium-lowering drugs. While most cases occurred in the first weeks of initiating therapy, it can also occur later. Examples of the clinical manifestations of severe symptomatic hypocalcemia have included QT interval prolongation, tetany, convulsions and altered mental status.
Based on the data submitted and reviewed by Health Canada, the safety and efficacy of denosumab (Prolia®) in paediatric patients has not been established; therefore, Health Canada has not authorized an indication for paediatric use. In clinical trials, hypercalcemia has been reported in paediatric patients with osteogenesis imperfecta treated with denosumab. Some cases required hospitalization and were complicated by acute renal injury.
Reference : Health Product InfoWatch, Health Canada, 25 January 2024 (link to the source within www.hc-sc.gc.ca)
WHO pharmaceuticals newsletter No. 3, 2024, p 4
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Paracetamol – Risk of hepatotoxicity
Ireland warning.
The HPRA has reminded health-care professionals that hepatotoxicity in association with paracetamol may occur even at doses within the normal therapeutic range in patients who are at increased risk. It is important to maintain awareness of any emerging or changing risk factors during treatment with paracetamol.
Paracetamol is recommended for the short-term treatment of the mild to moderate pain such as headache, toothache, musculoskeletal disorders and menstrual pain and for fever associated with cold and flu.
Patients at an increased risk of hepatotoxicity include those who are underweight, of low body mass index, malnourished, dehydrated, chronic alcoholism or with coexisting renal or hepatic impairment. Those with conditions that may predispose to glutathione deficiency or depletion and those concomitantly taking hepatotoxic drugs are also considered at risk.
Health-care professionals should take into consideration any emerging or changing risk factors (e.g. malnourishment, weight loss, dehydration) and maintain awareness over the course of treatment to any dose adjustment that may be warranted when prescribing or administering paracetamol.
For some patients considered to be at higher risk of hepatotoxicity, a lower starting dose, a reduction in dose and/or a reduced frequency of dosing may be appropriate.
Reference: HPRA drug safety newsletter, HPRA, 21 December 2023 (link to the source within www.hpra.ie) (See also WHO Pharmaceuticals Newsletter No.5, 2019: Paracetamol and dangerous when not used correctly)
WHO pharmaceuticals newsletter No. 3, 2024, p 11 ; Geneva: World Health Organization; 2024.
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Oral anticoagulants – Risk of acute kidney injury
Japan warning.
The Ministry of Health, Labour and Welfare (MHLW) and the Pharmaceuticals and Medical Devices Agency (PMDA) have issued a notification instructing the addition of “acute kidney injury” to the Clinically Significant Adverse Reactions section in the PRECAUTIONS of oral anticoagulants. The notification was in response to the cases reported in Japan for which a causal relationship between oral anticoagulants and acute kidney injury including anticoagulant-related nephropathy was reasonably possible.
Oral anticoagulants include apixaban, edoxaban tosilate hydrate, dabigatran etexilate methanesulfonate, rivaroxaban, and warfarin potassium. They are indicated for the prevention and treatment of thromboembolic conditions.
Health-care professionals are requested to pay sufficient attention to the onset of acute kidney injury related to the administration of oral anticoagulants as well as to take appropriate measures considering the possibility of anticoagulant-related nephropathy when acute kidney injury is noted in patients treated with oral anticoagulants.
Reference: Pharmaceuticals and Medical Devices Safety Information , MHLW/PMDA, 19 December 2023 (link to the source within www.pmda.go.jp/english/) (See also WHO Pharmaceuticals Newsletter No.4, 2023: Oral anticoagulants and potential risk of anticoagulant-related nephropathy (ARN))
WHO pharmaceuticals newsletter No. 3, 2024, p 6 ; Geneva: World Health Organization; 2024.
