NPC Archive Item: October Drug Safety Update from MHRA/CHM

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15 October 2009

The MHRA and CHM have published the October edition of Drug Safety Update. There is a first-year safety review of the human papillomavirus immunisation programme, based on Yellow Card reports, which reports that the balance of risks and benefits remains positive. Important new drug safety advice for ceftriaxone and high-dose cyproterone acetate is included, and some potentially clinically important interactions between medicines and smoking status are considered. There is also a review of two recent studies of aspirin, which do not give support to its use for primary prevention of vascular events (currently an unlicensed indication). A ‘Stop Press’ summarises the results of a recent cohort study that found no clear evidence of an increased risk of fatal or non-fatal self-harm with the use of varenicline.

Drug Safety Update (DSU) is an essential read for everyone whose professional practice involves medicines. It is published every month in electronic format only. In light of recent media attention, the section on the adverse event picture seen with HPV vaccine is of particular note.

First-year safety review of the human papillomavirus (HPV) immunisation programme
At least 1.4 million doses of Cervarix▼ HPV vaccine have now been administered across the UK. As at the end of July 2009, the MHRA had received 2,195 Yellow Cards, reporting 4,830 suspected adverse reactions, in association with the vaccine. According to the MHRA, the total number and nature of suspected side effects reported was much as expected. Most reports related to the signs and symptoms of recognised side effects, which are generally not serious. The most commonly reported suspected adverse reactions were dizziness, headache and nausea.

A quarter of the reported suspected reactions were classified as “psychogenic reactions”. These include vasovagal syncope, faints, panic attacks, and associated symptoms. These can occur with any injection procedure, not only vaccination, and can be common in adolescents. Such events can be associated with a wide range of temporary signs and symptoms, including: loss of consciousness; vision disturbance; injury; limb jerking (often misinterpreted as a seizure or convulsion); limb numbness or tingling; and difficulty in breathing or hyperventilation. These are due to fear or anticipation of the needle injection and are not side effects of HPV vaccine as such.

No new risks were identified, and the balance of risks and benefits remains positive. The MHRA and CHM encourage health professionals and members of the public to report all suspected adverse reactions to HPV vaccine, via the Yellow Card system. As with all vaccines, the MHRA and CHM will continue to monitor closely the safety of Cervarixq during continued use in the UK.

Updated safety advice: Ceftriaxone (Rocephin®) — interaction with calcium containing solutions
Ceftriaxone should not be given simultaneously with calcium-containing solutions (other than total parenteral nutrition solutions given via a different infusion line at a different site) for intravenous administration because of a risk of calcium precipitation. Ceftriaxone is contraindicated in newborns up to age 28days who need intravenous treatment with any calcium-containing solution. Calcium and ceftriaxone may be infused sequentially in patients aged 28days or older provided that either a) the infusion line is rinsed or flushed between solutions, or b) the infusions are given via different infusion lines at different sites.

Updated safety advice: High-dose cyproterone acetate — potential risk of (multiple) meningiomas
Patients with existing meningioma or a history of meningioma must not be prescribed high-dose (greater than or equal to 25mg per day) cyproterone acetate (i.e. Cyprostat-50®, Cyprostat-100®, or Androcur-50®). This advice does not apply to low-dose cyproterone acetate products such as co-cyprindiol (Dianette®).

Smoking and smoking cessation: clinically significant interactions with commonly used medicines
Smoking induces the drug-metabolising enzyme CYP1A2 and thus in patients who smoke, or who are cutting down or stopping smoking (with or without the aid of drug treatment), the doses of any concomitant medication metabolised by CYP1A2 may need to be adjusted accordingly. The most important medicines to consider in those who smoke, or who are trying to quit, include theophylline, olanzapine, clozapine, caffeine, and warfarin.

In addition to this pharmacokinetic interaction, it is important to consider pharmacodynamic interactions. The most clinically significant interacting drugs include: hormonal contraceptives (increased risk of cardiovascular disease); inhaled corticosteroids (efficacy may be reduced in smokers with asthma); and betablockers (nicotine activation of sympathetic nervous system may counteract effect).

Although clear guidelines for clinical practice are not available, it is suggested that the following general approach should be taken:

On starting CYP1A2 substrates:

    –       Obtain smoking status
    –       Determine clinical significance of any potential interaction
    –       Monitor efficacy and side effects

–       Adjust dose if necessary

–       Monitor smoking status and advise patients to seek advice from doctor if smoking status is to changeDuring smoking cessation:

    –       Find out what medicines the patient is taking
    –       Determine clinical significance of any potential interaction
    –       Monitor for side effects

–       Adjust dose if necessaryAspirin: not licensed for primary prevention of thrombotic vascular disease
A recent randomised controlled trial (AAA, available as a congress report only) and a meta-analysis (ATT) have looked at the use of low-dose aspirin in the prevention of heart attacks and strokes in people without a history of vascular disease — i.e. primary prevention. Both studies found that the risk of having a major bleed outweighed any vascular benefit. In the UK, low-dose aspirin is licensed for prevention of thrombotic cerebrovascular or cardiovascular disease only in those who already have vascular disease — i.e. secondary prevention. Although aspirin is used in primary prevention, this is not a licensed indication. This issue is discussed further in a MeReC Rapid Review Blog of the ATT meta-analysis.

Varenicline▼ and suicidal behaviour — cohort study provides some reassurance
A Stop Press reports the results of a recently published observational study of 80,660 people, which did not identify a statistically significant increased risk of fatal or non-fatal self-harm for varenicline▼ compared with nicotine replacement therapy (NRT) or bupropion. However, a two-fold increased risk cannot be ruled out on the basis of the upper 95% confidence interval (CI). Compared with NRT, the hazard ratio for self-harm in people prescribed varenicline▼ was 1·12 (95%CI 0·67 to 1·88), and was 1·17 (95%CI 0·59 to 2·32) for those prescribed bupropion.

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