Our group is very keen to improve the reporting ADRs by primary care physicians. To this end we set up an experiment to try an increase the number of Yellow Cards in the West Midlands area of the UK. You can see our poster, currently being presented at at the 12th Annual Meeting of the International Society of Pharmacovigilance, Cancún, Mexico (30th October to 2nd of November 2012) here
Novartis has prematurely halted the AlTITUDE study following an interim safety review. ALTITUDE was a trial of the direct renin inhibitor aliskiren (Rasilez®) in type 2 diabetes and renal impairment patients, with a high risk of cardiovascular and renal events, taking either an angiotensin receptor blocker (ARB) or an angiotension converting enzyme (ACE) inhibitor.
What’s the harm?
The independent Data Monitoring Committee (DMC) found no additional benefit of aliskiren when added to standard therapy. In addition, it was found the aliskiren treatment arm experienced an increased incidence of non-fatal stroke, renal complications, hyperkalemia and hypotension after 18-24 months of treatment.
Prior studies of aliskiren have been of relative short-term treatment, and have focused on falls in blood pressure rather than long-term outcome data. While many those studies have shown little difference in the occurance of serious ADRs between aliskiren and placebo, one study performed in diabetics taking an ACE inhibitor found an increase in the reate of hypokalaemia. Two small observational studies put forward in support of the use of aliskiren at stage 4 of the NICE/BHS hypertension guidelines, when the drug would likely be given with an ARB or an ACE inihibitor can now be discounted. In January 2010 [pdf] tthe Scottish Medicines Consortium failed to reccomend its use with NHS Scotland.
What should you do?
Prescribers should remain aware of the current NICE/BHS and SMC guidance on the treatment of hypertension with aliskiren, and be aware of this additional risk associated with the use of aliskiren when used in combination with ACE inhibitors or ARBs. Prescribers may also wish to review any patients currently co-prescribed aliskiren with ACE inhibitors or ARBs.
As aliskiren (Rasilez®) is a black triangle drug, any suspect adverse drug reactions should be reported on a Yellow Card.
Concerns about a lack of specific antidotes for new anticoagulants has existed for some time, despite the benefits they may bring in other aspects of care. An important piece of correspondence in the New England Journal of Medicine notes the potential for patient harm from a move from warfarin to the newer dabigatran:
Enthusiasm for this agent [dabigatran], however, must be tempered by three notable concerns: there is no readily available means for assessing the degree of anticoagulation with dabigatran, there is no readily available reversal strategy, and life-threatening bleeding complications can occur after an injury in patients taking this drug.
Lack of a readily available method to determine the degree of anticoagulation creates a major challenge to those treating injured patients. Moreover, the irreversible coagulopathy of dabigatran is of great concern to trauma and emergency physicians. Currently, the only reversal option for dabigatran is emergency dialysis (as suggested in a single line in the package insert). The ability to perform rapid dialysis in patients with bleeding whose condition is unstable or in those with large intracranial hemorrhages will present an incredible challenge, even at level 1 trauma centers.
The authors note that they have had several patients attend their hospital with trauma, and “that hemorrhagic complications and death resulting from trauma be included as part of the routine surveillance of all newly approved oral anticoagulants.”
In the UK haemorrhagic complications and death from trauma associated with newer anti-coagulants should be reported via the Yellow Card scheme. Please do so.
UPDATE: 8th December 2011
The FDA has initiated a Safety Review of dabigatran.
A recent study of suicidal behavior and depression in smoking cessation treatments has been published at PLoS ONE. This was widely reported in the media. The authors made the following statement within the paper:
In conclusion, varenicline shows a substantial, statistically significant increased risk of reported depression and suicidal/self-injurious behavior. The excess risk persisted even after adjusting for numbers of patients exposed, for the possibility of different reporting rates, and for concomitant therapy. Bupropion for smoking cessation had increased risks but less so than for varenicline. The findings for varenicline, combined with other problems with its safety profile, render it unsuitable for first-line use in smoking cessation.
It is worth noting that this study relied on US spontaneous reporting data, which cannot definatively show causation. The potential does exist for bias in reporting to show an association, where none exists. This is particularly true in the case of varenicline due to FDA warnings that have been issued, which may have provoked heightened vigilance, and media reporting of high profile cases of neuropsychiatric reactions.
Varenicline remains part of NICE guidance, when prescribed as part of a programme that includes advice from a healthcare professional or other types of support. However, prescribers should also be aware of the following MHRA guidance:
- Patients and their family or caregivers should be made aware of the possibility that trying to stop smoking might cause symptoms of depression
- Patients who are taking varenicline who develop suicidal thoughts or behaviour should stop their treatment and contact their doctor immediately
- Varenicline should be discontinued immediately if agitation, depressed mood, or changes in behaviour are observed that are of concern for the doctor, patient, family, or caregiver
- Patients with serious psychiatric illness did not participate in the premarketing studies of varenicline, and the safety and efficacy of varenicline in such patients has not been established. Care should be taken when prescribing varenicline to patients who have a history of psychiatric illness
Posted in ADRs, FDA, MHRA
The Daily Mail, and other news sources, reported yesterday on the increased cardiovascular risk associated with diclofenac. This is not a new concern, even if the published study in PLoS Medicine [Paper Here] is. The MHRA have issued a press release which contains the following points:
To minimise the risk of side effects, our advice remains that all NSAIDs should be used for the shortest time and at the lowest dose necessary to control symptoms. People should not stop taking their NSAID medicine, but if they have any questions about their treatment they should speak to their doctor or pharmacist.
The MHRA advice on the cardiovascular safety of Cox-2 inhibitors and non-selective NSAIDs still stands. As the National Prescribing Centre said last time a study about this issue was published, this shouldn’t be new news, and the message is sinking in with prescribers.
New Black Triangle drugs under intensive surveillance this month are:
Any adverse reaction, no matter how trivial, should be reported to the Yellow Card scheme.
The MHRA have published a new Drug Safety Update:
Dronedarone: risk of cardiac failure and risk of hepatotoxicity: Use of dronedarone may be associated with:
an elevated risk of worsening, or new-onset, heart failure
Patients should be asked to be vigilant for the symptoms of heart failure or liver toxicity during treatment, and should undergo regular liver-function testing
Daptomycin: risk of eosinophilic pneumonia There have been rare but potentially serious reports of eosinophilic pneumonia associated with daptomycin (Cubicin▼). If eosinophilic pneumonia is suspected, daptomycin should be discontinued immediately and if appropriate the patient treated with corticosteroids.
Lenalidomide: risk of thrombosis and thromboembolismPatients receiving lenalidomide for the management of multiple myeloma should be closely monitored for evidence of arterial and venous thromboembolic events. Modifiable risk factors for thromboembolic events should be managed wherever possible, and appropriate thrombotic prophylactic medication should be considered.
Omalizumab: potential risk of arterial thrombotic events Use of omalizumab may be associated with an increased risk of arterial thrombotic events. Prescribers should be vigilant for possible thrombotic adverse reactions, and should report these events to us promptly via the Yellow Card Scheme
After reviewing all available data relating to the use of Avastin to treat metastatic breast cancer, the FDA has decided the risks of bevacizumab outweigh its benefits in breast cancer. They are recommending the loss of the breast cancer indication:
“After careful review of the clinical data, we are recommending that the breast cancer indication for Avastin be removed based on evidence from four independent studies,” Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “Subsequent studies failed to confirm the benefit observed in the original trial. None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. The limited effects of Avastin combined with the significant risks led us to this difficult decision. The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.”
Full FDA statement.
The European Medicines Agency review is here. They recommend the use of bevacizumab with paclitaxel, but not with other combinations.
For Avastin in combination with paclitaxel, the Committee concluded that the benefits continue to outweigh the risks, because the available data have convincingly shown to prolong progression-free survival of breast cancer patients without a negative effect on the overall survival.
The December issue of the MHRA’s Drug Safety Update is out [HTML] [pdf]. This month includes:
- Saquinavir: update on potential risk of arrhythmia—reduced dose for initial treatment
Reminder about the potential for arrhythmias with Squinavir. particularly in those with risk factors, and advice on reduced dosing for the first week of treatment in anti-retroviral niave patients.
- End-of-year quiz: Test your drug-safety knowledge
A pop quiz about drug safety over the past 12 months! Useful CPD exercise.
- Fibrates: European Medicines Agency concludes first-line treatment is not recommended.
The MHRA’s Drug Safety Update website has been redesigned (or updated if you prefer), and now is fully searchable on-line, both for keywords, therapeutic groups, target audience.
Drug Safety Update.
This month’s edition (November) includes:
- Tamoxifen for breast cancer: drug interactions involving CYP2D6, genetic variants,
Drug safety advice and variability in clinical response
- Memantine pump device (Ebixa): risk of medication errors
- Oral bisphosphonates: oesophageal cancer risk—insufficient evidence of a link
- Tiotropium: safety studies of Spiriva Respimat▼
- Patient Information Leaflet of the month: Spiriva and Spiriva Respimat▼