Other safety alerts
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| The United Kingdom: Aminoglycosides (gentamicin, amikacin, tobramycin, and neomycin): increased risk of deafness in patients with mitochondrial mutations |
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Medicines and Healthcare products Regulatory Agency (MHRA) announces that evidence suggests an increased risk of aminoglycoside-associated ototoxicity in patients with mitochondrial mutations, including cases in which the patient’s aminoglycoside serum levels were within the recommended range.
In 2020, MHRA conducted a safety review following concerns received about the impact of mitochondrial mutations on the risk of ototoxicity with aminoglycosides. MHRA identified several published epidemiological studies showing an increased risk of deafness in patients with the m.1555A>G mutation who were given aminoglycosides. There have also been reported cases of deafness in m.1555A>G patients with aminoglycoside use within the recommended serum levels. Some cases were associated with a maternal history of deafness or mitochondrial mutations or both. Although no cases were identified with neomycin or topical preparations of gentamicin, amikacin, or tobramycin, based on a shared mechanism of action there is the potential for a similar effect with neomycin and other aminoglycosides that are administered at the site of toxicity (the ear).
The m.1555A>G mutation is the most common mitochondrial DNA (mtDNA) mutation, with an estimated prevalence of 0.2% in the general population. The mutation is associated with sensorineural deafness and occurs in families with maternally transmitted deafness. Clinicians should follow local guidelines on mitochondrial mutation screening in patients with a maternal history of deafness or mitochondrial mutations or both and who require aminoglycoside therapy. Genetic screening may be especially appropriate in patients requiring recurrent or long-term aminoglycoside therapy where the risk of ototoxicity is increased.
MHRA’s review focused on four key epidemiological studies that reported an association between having mitochondrial mutations and an increased risk of deafness with aminoglycoside use. In addition, 10 case reports were identified from the medical literature indicating this toxicity. This evidence is further supported by a plausible biological mechanism where mutated mitochondrial ribosome more closely resembles the bacterial ribosome and may provide a binding site for aminoglycosides; this effect has been shown in biochemical tests.
While many of the epidemiological studies had weak statistical power due to the rarity of the mitochondrial mutations, the evidence is considered sufficient to update the product information for aminoglycoside products with systemic absorption or that are administered at the site of toxicity (the ear). The product information will be updated to include warnings of a potentially increased risk of ototoxicity in patients with known mitochondrial mutations. The patient information leaflet will ask patients to talk to their doctor or pharmacist before taking this medicine if they know (or think they have) a mitochondrial disease.
These mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown. For patients known to have susceptible mutations, it is important to consider the need for aminoglycoside treatment and the alternative treatment options available when making prescribing decisions.
Advice for healthcare professionals:
- Aminoglycoside use can result in rare cases of ototoxicity; some evidence suggests an association between mitochondrial mutations (particularly the m.1555A>G mutation) with an increased risk of this ototoxicity.
- Some cases reported ototoxicity in patients with mitochondrial mutations who had aminoglycoside serum levels within the recommended ranges.
- These mitochondrial mutations are rare, and the penetrance of the observed increased ototoxic effect is unknown.
- Consider the need for genetic testing especially in patients, particularly in those requiring recurrent or long-term treatment with aminoglycosides, but do not delay urgent treatment in order to test.
- When making prescribing decisions in patients with susceptible mutations, consider the need for aminoglycoside treatment versus alternative options available.
- To minimise the risks of adverse events, including ototoxicity, continuous monitoring (before, during and after treatment) of renal function (serum creatinine, creatinine clearance) and auditory function, as well as hepatic and laboratory parameters, is recommended for all patients.
- Patients with known mitochondrial mutations or a family history of ototoxicity are advised to inform their doctor or pharmacist before they take an aminoglycoside.
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/aminoglycosides-gentamicin-amikacin-tobramycin-and-neomycin-increased-risk-of-deafness-in-patients-with-mitochondrial-mutations
In Hong Kong, there are registered pharmaceutical products for systemic and otic (the ear) administration in human containing gentamicin (13 products), amikacin (12 products), tobramycin (2 products) and neomycin (9 products). All products are prescription-only medicines.
So far, the Department of Health (DH) has received adverse drug reaction related to gentamicin (2 cases) and amikacin (5 cases), but these cases are not related to deafness. The DH has not received any case of adverse drug reaction related to tobramycin and neomycin.
The risk of ototoxicity associated with the use of aminoglycosides, including an increased susceptibility in patients with a mitochondrial DNA A1555G point mutation, is documented in overseas reputable drug references such as the “Martindale: The Complete Drug Reference”. The DH will remain vigilant on safety update of the drugs issued by other overseas drug regulatory authorities for consideration of any action deemed necessary.
Ends/Friday, Jan 8, 2021
Issued at HKT 18:00
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