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MHRA Updates on Fluoroquinolones, Methotrexate and Valproate

In its end of August round-up, the Medicines and Healthcare products Regulatory Agency (MHRA) reminded healthcare professionals treating patients with fluoroquinolones, methotrexate, and valproate about the risks of irreversible side effects, photosensitivity, and current guidelines.

Be mindful of the risk of "disabling and potentially long-lasting or irreversible side effects" when prescribing fluoroquinolone antibiotics — ciprofloxacin, delafloxacin, levofloxacin, moxifloxacin, ofloxacin — the MHRA counselled. These side effects could potentially affect multiple systems, organ classes, and senses, it said.

The Agency alerted that despite new restrictions and precautions being introduced in 2019 to minimise the risk of these reactions, a new study had shown "no evidence of a change" in fluoroquinolone prescribing patterns in the UK, and the MHRA had continued to receive Yellow Card reports of these side effects.

Fluoroquinolone treatment should be discontinued at the "first signs" of a serious adverse reaction, including tendon pain or inflammation, instructed the MHRA. It advised that patients be told to stop treatment at the first signs of a serious adverse reaction — such as

tendon pain or swelling, joint pain or swelling in shoulders, arms, or legs, abnormal pain or sensations such as persistent pins and needles, tingling, tickling, numbness, or burning, weakness or difficulty walking, changes in vision, taste, smell, or hearing — and to seek medical advice immediately.

The Agency went on to tell healthcare professionals not to prescribe fluoroquinolones for non-severe or self-limiting infections, or for mild to moderate infections — such as in acute exacerbation of chronic bronchitis and chronic obstructive pulmonary disease — unless other antibiotics that were commonly recommended for these infections were considered inappropriate. 

Methotrexate - Take Precautions in the Sun

Photosensitivity reactions are known side effects of methotrexate treatment and can be severe, warned the MHRA. It added that these can occur with both low-dose and high-dose treatment.

Reactions usually manifested as severe sunburn — such as rashes with papules or blistering — and could also cause swelling. 

The MHRA explained that photosensitivity reactions fell into two categories:

  • Phototoxic reactions – occurred when exposure to UV light activated a drug, causing skin damage that could look and feel like sunburn or a rash. These reactions could happen within minutes or after hours of exposure and were usually limited to the skin that had been exposed
  • Photoallergic reactions - occurred when UV rays interacted with the ingredients in medicines or other products applied directly to the skin, resulting in an allergic reaction
However, there was concern that photosensitivity was "not a well-known side effect" and that many patients might not be aware of the additional risks of sun exposure during methotrexate treatment.

Moreover, the MHRA had recently received a coroner's report following a case of a photosensitivity reaction in a patient on methotrexate. The reaction was found to have contributed to death by secondary infection.

"Patients should be advised to take precautions to protect their skin in the sun," the Agency urged, as these reactions can be "severe".

Usual sun protection advice should be adhered to, stressed the Agency. This included:

  • Avoiding exposure to intense sunlight
  • Avoiding the use of sunbeds or tanning equipment
  • Using a sun protection product with a high protection factor when exposed to the sun
  • Wearing a hat and clothes that covered arms and legs when in the sun

Valproate Study Re-analysis Needed

Two studies that were conducted by researchers in 2013 did not find evidence of an increased risk to children with paternal use of epilepsy medicines, but the studies had "limitations", explained the MHRA. As part of the outcome of the 2018 European review of valproate, a new retrospective study was requested from the marketing authorisation holders to examine this risk. 

The findings of this latest study suggested an increased risk of neurodevelopmental disorders in children whose fathers took valproate in the 3 months before conception, compared with those whose fathers took lamotrigine or levetiracetam.

However, the MHRA alerted that "errors" had subsequently been identified in this study, which might "impact on the results". Therefore, a full re-analysis was required before conclusions could be drawn.

"No action is needed from patients," reassured the Agency, which emphasised the importance of patients not stopping taking valproate unless they were advised by their specialist to do so. GPs and pharmacists should continue to provide repeat prescriptions for valproate, it said.

For female patients, the MHRA reminded healthcare professionals to continue to follow the existing strict precautions related to preventing the use of valproate in pregnancy – the Valproate Pregnancy Prevention Programme.

"As soon as the revised study analysis is available, it will be carefully re-assessed, and any further guidance will be communicated to patients and healthcare professionals as soon as possible," emphasised the MHRA.

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