23 Dec 2009: Suspension of sales of dextropropoxyphene-containing products
HSA would like to inform healthcare professionals that the sales of dextropropoxyphene-containing products (Dolpoxene® and Dolpocetmol®) have been suspended effective from 9 November 2009. Based on the assessment of the data available to-date, HSA and its Pharmacovigilance Advisory Committee (PVAC) have concluded that the risk of dextropropoxyphene causing fatal overdose outweighs its benefits in the treatment of mild to moderate pain. Healthcare professionals are advised not to start new patients on dextropropoxyphene and to consider alternative treatment options for patients currently taking dextropropoxyphene products for pain relief.
HSA would like to highlight the recent findings of significant drug interactions which healthcare professionals need to be aware of.
A) The interaction between clopidogrel and proton pump inhibitors (PPI)
Some reports suggest that use of certain PPI may make clopidogrel less effective by inhibiting the enzyme that converts clopidogrel to the active form of the drug while others do not suggest this effect. The results of a recently published JAMA article supports the findings from prior platelet studies demonstrating that PPI reduce the anti-platelet effects of clopidogrel, possibly by sharing common metabolic pathways mediated by cytochrome P450 isoenzymes (i.e. CYP2C19). It is recommended that the concomitant use of PPI with clopidogrel be avoided unless absolutely necessary.
B) The interaction between colchicine, P-glycoprotein (P-gp) and strong CYP3A4 inhibitors.
There is a risk of colchicine toxicity through the modulation of P-gp and CYP3A4 activity, which is supported by the presence of fatal and non-fatal cases of colchicine toxicity reported in literature with concomitant use of other CYP3A4 and P-gp inhibitors such as cyclosporine, erythromycin and calcium channel blockers eg, verapamil and diltiazem. In view of this, the US FDA has recommended that P-gp or strong CYP3A4 inhibitors not be used in patients with renal or hepatic impairment who are currently taking colchicine and that healthcare professionals consider a dose reduction or interruption of colchicine in patients with normal renal and hepatic function if treatment with a P-gp or strong CYP3A4 inhibitor is required. Healthcare professionals are advised to take into consideration the above safety information when prescribing colchicine with a P-gp or strong CYP3A4 inhibitor.
On 7 September 2009, a ‘Compliance Communication' letter was issued to healthcare professionals who purchase Revlimid® by the Compliance Branch of HSA to inform them of the safety monitoring protocols that have been imposed on the prescribing and dispensing of lenalidomide (Revlimid®), a potentially teratogenic drug marketed by Celgene Pte Ltd. The letter also to sought the co-operation of healthcare professionals to comply to the safety monitoring protocols when prescribing lenalidomide to their patients.
HSA would like to bring to the attention of healthcare professionals, the results of the clinical study, Innohep® in Renal Insufficiency Study (IRIS), suggesting that tinzaparin (Innohep®, LEO Pharma) may increase the risk for death, compared to unfractionated heparin (UFH) when used to treat elderly patients with renal insufficiency. An interim finding of the IRIS study, showed an increase in all-cause mortality in patients receiving Innohep®. HSA is working with the company to strengthen the local package insert for Innohep® to caution on the use of Innohep® in patients with renal impairment and to monitor patients for anti-factor Xa activity.
23 Dec 2009: Local experience with oseltamivir (Tamiflu®) HSA would like to update healthcare professionals on the local ADR reports associated with oseltamivir (Tamiflu®, Roche) since the issuance of the Dear Healthcare Professional Letter on 31 July 2009 on the same subject. Since the start of the Influenza A/H1N1 (2009) pandemic, there has been a sharp increase in the usage of oseltamivir. As of 1 October 2009, HSA's Vigilance Branch received a total of 42 ADR reports suspected to be associated with Tamiflu® (36 were received after 1 July 2009). Out of the 42 reports, 23 were CNS related. Majority of these patients were young patients (74%) (17 patients were <17 years and six were >18 years). 15 (65%) were males and eight (35%) were females. HSA will continue to closely monitor this emerging safety concern and update our healthcare professionals.
12 Aug 2009: Serious skin reactions associated with allopurinol HSA would like to alert healthcare professionals on the four local fatal cases of adverse drug reactions linked to allopurinol reported to HSA over the first five months of 2009. Of these reports, three of the patients developed toxic epidermal necrolysis (TEN) while the fourth patient developed hypersensitivity syndrome to allopurinol. All of them were elderly patients with co-morbidities such as ischaemic heart disease, chronic renal failure, diabetes and hypertension. Prior to these four cases, HSA has received 19 reports of fatality between 1997 to 2008 of which 16 cases were associated with Stevens-Johnson syndrome (SJS), TEN or Allopurinol Hypersensitivity Syndrome (AHS). Healthcare professionals are reminded to exercise caution in using allopurinol for the treatment and prophylaxis of hyperuricaemia and to advise their patients on the recognition of rash and skin reactions which may be early signs of SJS and AHS.
12 Aug 2009: Update on drotrecogin alfa (Xigris ®) and increased risk of bleeding HSA would like to bring to the attention of healthcare professionals a recent retrospective study that revealed an increase risk of death and serious bleeding events in patients with baseline bleeding tendencies treated with drotrecogin alfa (Xigris®, Eli Lilly) The study revealed that serious bleeding events occurred in seven of twenty patients (35%) who were predisposed to bleeding tendencies vs. only two of 53 (3.8%) patients without any bleeding tendencies. However, there were no clear trends by type of baseline bleeding risk factors and type or incidence of serious bleeding event. More patients with bleeding risk factors died (13 out of 20; 65%) compared with patients without any risk factors for bleeding (13 out of 53; 24.5%). In light of the new data from the recent retrospective study, healthcare professionals are encouraged to carefully weigh the benefits versus risk of using Xigris® in patients predisposed to bleeding. Healthcare professionals are also encouraged to report suspected adverse drug reactions associated with drotrecogin alfa to the Pharmacovigilance Branch of HSA.
12 Aug 2009: Traditional Medicines Adulterated with Steriods In recent months, the Pharmacovigilance Branch of HSA has received four reports of adverse drug reactions from our healthcare professionals, leading to the detection of the following adulterated traditional medicines- “Bao Ling Capsule” (保灵丸), “Air Ikan Haruan Extract”, “Delima Raja Urat” and “Cao Gen Bai Lin Wan” (草根百龄丸). These traditional medicines were found to contain western medicines at therapeutic doses. The adulterants include betamethasone,dexamethasone, hydrochlorothiazide, chlorpheniramine and sibutramine. HSA would like to remind healthcare professional to consider the possible contribution of adulterated complementary health products when a patient presents with unexplained adverse symptoms without a plausible medical cause. A careful taking of patient's medical history is encouraged as it may elicit important and useful information relevant to the diagnosis of the patient's condition.
12 Aug 2009: Oral sodium phosphates (OSP) and renal toxicity HSA would like to update healthcare professionals on recent overseas reports of serious adverse events of acute kidney injury associated with the use of oral sodium phosphates (OSP) at higher doses. The US FDA and Health Canada have received reports of kidney injury such as acute phosphate nephropathy associated with OSP. Most of the patients amongst the cases from US were taking concomitant medicines such as ACE inhibitors, diuretics and NSAIDs. The risk of renal toxicity from OSP also appeared to be associated with the higher doses used for bowel cleansing. To date, HSA has not received any local reports of acute phosphate nephropathy associated with OSP. Healthcare professionals are advised to use OSP with caution in patients who are risk of developing acute phosphate nephropathy.
12 Aug 2009: Reports of warfarin- glucosamine interaction
HSA would like to highlight to healthcare professionals of a potential drug interaction between warfarin and glucosamine. International regulatory agencies, the Australian Therapeutic Drugs Administration (TGA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA) have received reports suggesting possible interactions between glucosamine and warfarin. Patients who were previously stabilised on their respective doses of warfarin doses and taking glucosamine were found to have changes (mostly elevations) in their International Normalised Ratio (INR). A report from the World Health Organisation (WHO) Collaborating Centre for International Drug Monitoring identified 22 spontaneous cases of suspected warfarin-glucosamine interaction originating from Australia, Canada, Denmark, Sweden, United Kingdom and the United States. Healthcare professionals are advised to monitor the INR of their patients who are consuming or commencing glucosamine or other complementary and herbal medicines closely and titrate warfarin doses accordingly
4 May 2009: Voluntary recall of Hydroxycut® products in Singapore
The Health Sciences Authority (HSA) is warning consumers to stop using Hydroxycut® products, manufactured by Iovate HealthSciences USA. These are being recalled in the USA due to 23 reports of serious adverse reactions affecting the liver including one death due to liver failure occurring there. Hydroxycut® products are marketed for weight-loss and are distributed by Global Active Limited in Singapore through GNC outlets and other retail outlets, including pharmacies. They are also sold over the Internet. To-date, no local reports of adverse reactions have been received in relation to the consumption of Hydroxycut® products. HSA advises consumers who have been taking Hydroxycut® products to stop taking them immediately and to discard them. If they experience any adverse reactions or feel unwell, they should seek medical advice from their doctors.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse skin reactions, with mortality rates of up to 5% and 40% respectively. Recently, carbamazepine (CBZ)-induced SJS and TEN have been found to be associated with the HLA-B*1502 allele among Han Chinese and Thais. Also, the allele HLA-B*1502 was not observed in patients with other forms of CBZ-induced cutaneous reactions such as hypersensitivity syndrome or maculopapular eruptions, suggesting that the genetic association is phenotype-specific.The US FDA has concluded based on the above findings, that the risk of SJS/TEN from CBZ is significantly increased in Asian patients positive for the HLA-B*1502 allele and recommended screening for HLA-B*1502 for most patients of Asian ancestry. In the meantime, HSA is embarking on a pharmacogenetics-based pharmacovigilance programme with other researchers to further study the local impact and significance of the genetic association between HLA-B*1502 allele and CBZ-induced serious skin reactions.
Bayer Schering Pharma has received 24 reports (20 females, four males) of meningiomas suspected to be associated with its product cyproterone acetate (Androcur®) either used singly or in combination with estrogens since 1972. In nine of the 24 patients, multiple meningiomas were present at the time of the first meningioma diagnosis. All the cases were associated with high doses of cyproterone acetate and after long treatment periods of four to 24 years. Froelich et al also reported nine case studies of female patients, aged between 33 to 62 years old, who presented with multiple meningiomas after receiving daily cyproterone acetate treatments for durations of between ten to 20 years. Healthcare professionals are advised to take into consideration the above safety information when prescribing high dosages of cyproterone acetate to their patients. HSA will be working with the drug companies to update the prescribing information in the package inserts.
HSA would like to bring the attention of healthcare professionals to a very rare, but serious risk of toxicity in breastfed babies posed by codeine use in nursing mothers who are ultra-rapid metabolisers of codeine. Limited evidence suggests that individuals with a specific CYP2D6 genotype or otherwise known as ultra-rapid metabolisers, may convert codeine to morphine more rapidly and completely than other people. In nursing mothers, this metabolism can result in a higher than expected levels of morphine in serum and breast milk, putting nursing infants at increased risk for morphine overdose. When prescribing codeine to a nursing mother, physicians are advised to choose the lowest effective dose for the shortest period of time.
In February 2008, Bayer HealthCare issued a Dear Healthcare Professional Letter (DHCPL) in Europe to inform healthcare professionals of very rare liver injuries and serious skin reactions associated with moxifloxacin. Bayer reported eight cases of fatal hepatic injuries considered as possibly related to moxifloxacin therapy, 35 cases of Stevens-Johnson syndrome (SJS), of which three had fatal outcomes and seven were considered life threatening. TEN was reported in several cases where a causal relationship was considered possible. In view of the increased risk of adverse hepatic reactions associated with moxifloxacin, the European Medicines Agency (EMEA) restricted oral moxifloxacin-containing medicines to second-line therapy. To date, HSA has received 22 local spontaneous adverse drug reaction reports associated with oral moxifloxacin. HAS will update the package inserts for moxifloxacin with the above safety information. Healthcare professionals are advised to be vigilant for early signs and symptoms of severe liver injury and bullous skin reactions (eg. SJS, TEN) in patients taking moxifloxacin.
27 Feb 2009: Sales of efalizumab (Raptiva®) suspendedThe Health Sciences Authority (HSA) has requested for Merck Pte Ltd to suspend the sales of its product, Raptiva® in Singapore. HSA and its Pharmacovigilance advisory committee has reviewed the risk-benefit profile of Raptiva® and concluded that the benefits of Raptiva® in the treatment of plague psoriasis no longer outweigh its risks due to safety concerns including the occurrence of Progressive Multifocal Leukoencephalopathy (PML). Both EMEA and Health Canada have also recommended the suspension of the marketing authorization for Raptiva®. Patients who are taking Raptiva® should not stop treatment abruptly but consult their doctors as soon as possible to assess the most appropriate replacement treatment. Prescribers are advised not to issue any new prescriptions for Raptiva® and should review the treatment of patients currently taking the drug.
