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

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11th September 2009

New data show that insulin glargine is not associated with an increase in cancer (07/08/12)
Since these materials were published, ORIGIN (2012), a 6-year randomised controlled trial, has been completed. This found that insulin glargine was not associated with a significant increase in the incidence of any cancer, death from cancer, or cancer at specific sites, as had been suggested by some earlier epidemiological data.

The MHRA and CHM have published the September edition of Drug Safety Update. This issue provides information on new warnings and tighter controls relating to over-the-counter (OTC) sales of analgesics containing codeine or dihydrocodeine, gives useful advice relating to concerns about insulin glargine and cancer and a review of measures to reduce illicit use of pseudoephedrine and ephedrine, and clarifies some advice about clopidogrel interactions. It also gives a helpful guide to completing a Yellow Card online.

Drug Safety Update (DSU) is an essential read for everyone whose professional practice involves medicines. It is published every month in electronic format only.

New restrictions on OTC analgesics containing codeine or dihydrocodeine
New warnings and tighter controls on the sales of over the counter (OTC) medicines containing codeine or dihydrocodeine (DHC) are being introduced to minimise the risk of overuse and addiction to these medicines, in line with recent advice from the CHM. The package of measures includes changes to indications, labels and leaflets, pack size, and advertising. Feedback from patient groups has indicated that the existing warnings of the risks of addiction and overuse headache have not proved effective, and pharmacists appear to be selling more packs of 100 effervescent paracetamol and codeine products since the reduction in pack size of the other forms.

  • All packs greater than 32 of codeine- or DHC-containing OTC medicines, including effervescent formulations, will no longer be available as P products
  • All indications related to colds, flu, coughs and sore throats, and references to minor painful conditions will be removed. The remaining list of indications will be for the short term treatment of acute, moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone.
  • The Patient Information Leaflets (PILs) and labels will state that the products are for short term use only, for the treatment of moderate, acute pain, and that the products can cause addiction or overuse headache if used continuously for more than three days. The following warning will appear prominently on the front of the pack: ‘Can cause addiction. For three days use only’. The PILs will also carry information about the warning signs of addiction.

Changes to Marketing Authorisations will be completed by 31 December 2009 and all products with the updated information will be on pharmacy shelves 3–6 months later. Existing packs of greater than 32 effervescent tablets and marked for dispensing purposes should be supplied only in accordance with RPSGB guidance.

The CHM/MHRA asks pharmacists to support the public health measures by:

  • recommending codeine- or DHC-containing products appropriately within the OTC analgesic range
  • giving key safety messages regarding short-term use and avoidance of addiction if taken as recommended
  • noting that packs of more than 32 tablets are for dispensing use only.

Clopidogrel and PPI: interaction—clarification
An article in the July issue of DSU stated that concomitant use of other medicines that inhibit CYP2C19 would also be expected to reduce the efficacy of clopidogrel and should be avoided; cimetidine was listed as a medicine that inhibits CYP2C19. Therefore, the section on ‘alternative gastrointestinal therapies’ should have read: “On the basis of pharmacokinetic data, other medicines for the treatment of gastrointestinal disorders (such as H2 blockers, with the exception of cimetidine, or antacids) would not be expected to interact with clopidogrel. However, there are currently no substantial data from clinical-outcome studies to support this.”

We have recently blogged an analysis of two studies which found that, although PPIs attenuated the in-vitro antiplatelet effects of clopidogrel and prasugrel▼, the combination was not associated with an increased risk of adverse cardiovascular outcomes. These findings were consistent regardless of which PPI was used, or whether an H2 blocker was used. These data provide reassurance for patients for whom the combination of clopidogrel and a PPI is considered necessary. However, until further, higher quality evidence is available, it would still seem sensible to follow MHRA advice and review people on the combination. Healthcare professionals should consider stopping the clopidogrel (if it is being used outside NICE guidance or beyond the recommended period), stopping the PPI, or stopping both, unless considered essential. If the original reason for using clopidogrel was gastrointestinal intolerance to aspirin alone, switching to aspirin plus a PPI would seem a reasonable approach. For patients who need to continue taking clopidogrel and also require gastroprotection, there is currently insufficient evidence to recommend H2 blockers or other therapies as alternatives to PPIs.

Insulin glargine and possible cancer link
Recent observational studies have suggested a possible association between insulin glargine and an increased risk of cancer. The results are not entirely consistent, and can neither confirm nor exclude a relationship between insulin glargine and cancer. Therefore, the European Medicines Agency (EMEA) has advised that no change in recommendations for use is required at present. We discussed the relevant evidence – and the very high cost of insulin glargine – in a previous blog.

Review of restrictions on products containing pseudoephedrine and ephedrine
Pseudoephedrine and ephedrine are medicines used as nasal decongestants. There has been increasing concern that these active substances can be extracted from OTC medicines and used in the illegal manufacture of the Class A controlled drug methylamphetamine (crystal meth).

On April 1 2008, it became illegal to sell or supply:

  • any product that contains more than 720 mg pseudoephedrine or 180 mg ephedrine without a prescription
  • a combination of products that between them add up to more than 720 mg pseudoephedrine or 180 mg ephedrine without a prescription
  • a product that contains pseudoephedrine and a product that contains ephedrine in one transaction.

Furthermore, the RPSGB issued professional guidance, advising that the sale and supply of products that contain pseudoephedrine or ephedrine must be made by a pharmacist or suitably trained pharmacy staff under the supervision of a pharmacist.

In July 2009, the Commission on Human Medicines (CHM) considered a report from its Working Group on pseudoephedrine/ephedrine. The CHM agreed with its Working Group that medicines that contain pseudoephedrine or ephedrine may continue to be sold as pharmacy medicines, provided the measures put in place to contain misuse continue to be effective.

Reporting safety concerns about medicines
The Yellow Card scheme provides an important mechanism by which health professionals and members of the public can report concerns about possible adverse effects of medicines. September’s DSU provides a very useful guide to completing the online version of the Yellow Card, with a worked example. (Note that suspected adverse drug reactions (ADRs) to swine flu antivirals, oseltamivir▼ (Tamiflu) or zanamivir▼ (Relenza) should be reported via the dedicated Swine Flu ADR Portal.

Other articles
Patient Information Leaflet of the month: Hyalgan

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