The Malaysian Health Authority-National Pharmaceutical Regulatory Agency (NPRA), Ministry of Health Malaysia released the following new drug safety alerts for bringing awareness to health care professionals for a better patient safety.
Drug Safety Alert 1: Risk of cutaneous amyloidosis with Insulin
Drug Safety Alert 2: Risk of uveitis with Topiramate
Drug Safety Alert 1: Risk of cutaneous amyloidosis with Insulin
Cutaneous amyloidosis is a disorder which involves abnormal accumulation of amyloid proteins in the skin tissue (between dermis and epidermis) forming amyloid lumps.
Potential Misdiagnosis:
There is a possibility of misdiagnosis for cutaneous amyloidosis condition as lipohypertrophy (abnormal accumulation of additional fat at the subcutaneous injection site region of Insulin forming a lump under the skin), as both (cutaneous amyloidosis and lipohypertrophy) are local site injection site reactions associated with the use of Insulin. These adverse reactions are considered as the “class-effects” of Insulin products. The misdiagnosis could lead to ‘underreporting’ of cases with Insulin associated cutaneous amyloidosis.
Consequences of cutaneous amyloidosis:
Lack of drug efficacy: The insulin absorption into the bloodstream may be reduced or delayed after insulin injection at the subcutaneous site with amyloid lump. This could lead to poor glycemic control.
Severe hyperglycemia: With the inadequate knowledge on the presence of amyloid lump at the Insulin injection site, higher doses of insulin might be administered to compensate for the hyperglycemia (high glucose levels in the blood). There are case reports with severe hypoglycemia developed by patients when there is a sudden change in the injection site from affected area (with amyloid lumps) to an unaffected area.
European Medicines Agency (EMA) and Pharmaceuticals and Medical devices agency (PMDA) have requested the product registration holders of Insulin to update their product’s prescribing information documents with the risk of cutaneous amyloidosis based on the available evidence in drug safety databases and from medical literature.
Case Reports at NPRA:
Malaysian health authority, NPRA has received safety information pertaining to case reports of cutaneous amyloidosis associated with Insulin use. However, there were no cases reported from Malaysia nation regarding cutaneous amyloidosis or skin hypertrophy/ lipohypertrophy adverse conditions with Insulin.
Other case reports: A total 1,477 case reports were received by NPRA with insulin as suspected product. These case reports comprising of 3,053 adverse events attributed (considered related) to insulin. Out of these reports, 37 cases were pertaining to swelling at the injection site.
Advice for Healthcare Professionals:
- Inform and educate patients to routinely check for lumps or any other dermatologic changes
- Continuously rotate the injection site of Insulin to reduce or to prevent the development of amyloid lumps.
- Counsel patients to avoid injecting into the affected area (having lumps).
- In order to minimize the risk of hypoglycemia, monitor the patient’s blood glucose levels particularly after there is a change in the injection site, and to consider adjusting the dose accordingly.
Drug Safety Alert 2: Risk of uveitis with Topiramate
Topiramate is an anticonvulsant medication used in the treatment of epilepsy (seizures), and also used in the prevention of migraine headaches.
Topiramate acts by following ways:
- Blocking voltage-dependent sodium ion channels (thereby disrupting the abnormal and unregulated electrical discharges occurring in the brain)
- Stimulates gamma-aminobutyrate (GABA) receptors (thereby promoting inhibitory neurotransmission effect)
- Inhibiting the glutamate receptors like AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) and kainate receptors (Thereby reducing the excitatory neurotransmission/glutamate activity).
Hence by increasing inhibitory GABA activity and inhibiting excitatory glutamate activity, topiramate blocks neuronal excitability, preventing seizures and migraines.
Uveitis is the eye disorder which involves the inflammation of middle layer of the eyeball (uvea) appearing as red and swollen. Uvea has many blood vessels to nourish the eye. Uveitis may result in permanent vision loss by causing damage to vital eye tissues.
Causal link between uveitis and topiramate use:
EMA has received few case reports with complaints of bilateral uveitis as safety concerns associated with the use of topiramate use. The case reports has revealed the following significant information for the establishment of causal relationship for bilateral uveitis topiramate.
Temporal relationship: The time required for the onset of symptoms for bilateral uveitis is short after the administration of topiramate product.
Dechallenge: Bilateral uveitis resolved within short period of time after the withdrawal of topiramate (a positive dechallenge scenario).
Alternative causalities: There were no confounding factors (underlying medical conditions or concomitant medications) reported for the patients in the case reports for safety review by EMA.
Based on the available safety evidence, EMA concluded the causal relationship for bilateral uveitis topiramate. NPRA received this safety information/update from the EMA in July 2019 for updating topiramate product information documents (package inserts) by including the risk of uveitis.
NPRA case Reports:
Malaysian health authority has not received any case reports pertaining to uveitis association with topiramate. There are other case reports (35) with 61 adverse drug events suspected to be related to topiramate product.
Advice for Healthcare Professionals:
- Be aware and cautious on the risk of uveitis associated with the use of topiramate.
- Provide awareness to patients on the signs and symptoms of uveitis, such as eye redness, pain and blurring of vision and to inform their respective physician immediately after the symptoms identification.
Health care professionals and consumers are advised to report any suspected adverse reactions or experienced with the use of Insulin or Insulin-containing products and Topiramate to the Malaysian health authority by online voluntary reporting facility through ADR web form. This will facilitate in accumulation of the more evident safety data which could help in taking early regulatory actions by NPRA.