Adverse Drug Reaction

n e w s
Published by the Centre for Drug Administration, HSA and the Pharmacovigilance Advisory Committee

Advisory on the use of cough and cold medicines in children

n view of concerns raised on the recent recall in the United States of over-the-counter cough and cold products marketed for infants and toddlers, and the ensuing recommendations from the public advisory committee meeting convened by the US Food & Drug Administration (FDA) on the safe use of these medicines in young children, HSA has provided an interim advisory to healthcare professionals on the appropriate use of these products while we continue to review the scientific data. These recommendations were included in the Dear Healthcare Professional Letter issued on 30 October 2007 and posted at the MOH Health Professional portal at http://www.hpp.moh.gov.sg.
Table 1: Interim recommendations on use of cough and cold medicines in various age groups of children

Category / Drug

Under 6 months

6 months to 2 years

2 years & above

Background
The recent recall in the US in October 2007 involved 14 brands of cough and cold preparations (containing antihistamines and decongestants) targeted for infants and very young children. They were voluntarily recalled by drug companies due to the danger of overdosage and misuse in this group of patients. Examples of such products are Concentrated Infants' Tylenol Drops Plus Cold & Cough, Dimetapp Decongestant Plus Cough Infant Drops, and Decongestant Infant Drops. HSA confirms that these products are not licensed for sale or use in Singapore. The US FDA also convened an expert advisory committee in October to deliberate on the efficacy and safety of cough and cold products when used in children under six years of age. In view of the lack of efficacy data in young children balanced against the occurrences of rare but serious adverse drug reactions (ADRs) associated with the use of these products, the expert panel recommended stronger cautionary labels on these products and not to use them in children under six years old. FDA will deliberate on the panels recommendations before coming to a conclusion on this issue.
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Promethazine

Contraindicated

Not recommended

Use with caution

Antihistamines1

Not recommended

Use only when benefits have been assessed to outweigh risks Use only when benefits have been assessed to outweigh risks Use only when benefits have been assessed to outweigh risks

Use with caution

Cough suppressants 2

Not recommended

Use with caution

Cold and flu products 3

Not recommended

Use with caution

Active ingredients discussed during the meeting between US FDA and its expert panel for which adverse event reports were analysed: 1 Brompheniramine,chlorpheniramine,diphenhydramine 2 Codeine, dextromethorphan, diphenhydramine 3 Ephedrine, guaifenesin, phenylephrine, pseudoephedrine

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ISSN: 0219 2152 December 2007 Vol.9 No.3

Advisory on the use of cough and cold medicines in children Association of salbutamol and myocardial ischaemia in premature labour Gadolinium-based contrast agents Important safety information Risk of torsade de pointes and QT prolongation with haloperidol

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Reports of adverse reactions to Beauty Express Miracle Pigmentation Scar Cream Summary of advisories issued by HSA and companies Package insert amendments reflecting safety issues Package insert amendments reflecting safety issues Voluntary withdrawal of clobutinol (Silomat) cough syrup Voluntary suspension of sales of aprotinin (Trasylol)

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CONTENTS

Association of salbutamol and myocardial ischaemia in premature labour

identified for the development of ischaemic events besides preterm labour. In four of the cases, it was specifically stated that the patients had no known risk factors. One patient had a paternal history of cardiovascular disease while another had a possible pre-existing coronary vascular occlusion. laxoSmithKline (GSK) has issued a Dear Healthcare Professional Letter to alert our healthcare professionals on reports of myocardial ischaemia associated with the use of salbutamol (Ventolin) as a tocolytic agent. GSK also advised healthcare professionals to exercise caution when using salbutamol for premature labour, to carefully monitor patients cardiovascular function including ECG, and to discontinue the drug if signs of myocardial ischaemia develop. Background Salbutamol, a selective beta2-adrenoreceptor agonist, is available in several dosage forms with varied uses. Parenteral preparations of salbutamol are registered for the management of uncomplicated premature labour in the last trimester of pregnancy though it is known that salbutamol tablets may sometimes be used for this purpose. The advice by GSK follows a company-initiated review of the available data from published literature, clinical trials and spontaneous reports of myocardial ischaemia in association with salbutamol. The review found eight spontaneously reported cases in the company database and nine reports in published literature, suggestive of a causal association with myocardial ischaemia when salbutamol was given for the treatment of premature labour. Summary of spontaneous reports and literature The reported events included myocardial ischaemia, myocardial infarction, chest pain and ECG abnormalities indicative of myocardial ischaemia. All the events were reported with the use of intravenous salbutamol except one which was reported with the use of salbutamol tablets. Five cases required hospitalisation and one was considered life-threatening. The time to onset ranged between 1.5 hours to 4 days with most of the cases occurring within the same day as treatment initiation. No significant pre-disposing factors could be
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About half of the cases reported a positive dechallenge on salbutamol discontinuation. One case documented ST depression on the re-introduction of salbutamol one year after the first incident of myocardial ischaemia. However, most of the cases did not provide information on rechallenge. Where specified in the reports, actions taken after the occurrence of the adverse event include the discontinuation of salbutamol and treatment with nifedipine, heparin, aspirin, nitroglycerin and verapamil. Conclusions and recommendations Although the effects of sympathomimetics may be exaggerated in preterm labour due to high background sympathetic drive, hyperventilation, dehydration and haemodilution through the use of intravenous fluids, the association between myocardial ischaemia with salbutamol use in preterm labour cannot be ruled out as the reported cases were well-documented and contained no significant pre-disposing factors for the development of ischaemic events other than preterm labour. To date, HSA has not received any spontaneous local ADR report of myocardial ischaemia associated with the use of salbutamol in preterm labour. Nevertheless, healthcare professionals are advised to be cautious when using salbutamol for this purpose, and to report any serious adverse reactions suspected to be due to its use in pregnancy to the Pharmacovigilance Unit of HSA. The local package inserts of parenteral and oral Ventolin products has been updated to include this new safety information.
References 1. Aust N Z J Obstet Gynaecol 1981; 21:1-4. 2. Eur J Obstet Gynecol Reprod Biol 2001; 98:177-185. 3. Singapore J Obstet Gynaecol 1986; 17:54-58. 4. Arch Mal Coeur 1997; 90:1651-1654. 5. Acta Obstet Gynecol Scand 1987; 66:417-420. 6. Am J Obstet Gynecol 1989; 161:318-321. 7. Circulation 2006; 113: 1564-1571.

Review of data by US FDA

A review of the adverse reports from the US FDA associated with the antihistamines (diphenhydramine, brompheniramine and chlorpheniramine), and the decongestants (pseudoephedrine, phenylephrine, and ephedrine) over 19692006 revealed that most of the ADRs occurred in children under two years old and overdosage and drug toxicities were the common causes. A further analysis of the adverse events associated with pseudoephedrine, chlorpheniramine, diphenhydramine and dextromethorphan from 20022007 showed that serious events and deaths related to the nervous system (e.g. seizures), cardiac and respiratory system were associated with both overdoses as well as labeled doses of cough and cold medicines. There is also a potential risk of overdose when using multiple cough and cold products.
Adverse Drug Reaction News December 2007 Vol.9 No.3

Local situtation
HSA has not received any local reports of fatal adverse drug reactions associated with cough and cold medicines. However, taking into consideration the findings by US FDA and the lack of efficacy data of cough and cold medicines used in children, HSA has provided healthcare professionals with an interim advisory on the use of cough and cold medicines in young children. This advisory takes into consideration guidelines developed by other regulatory agencies, and the previous review conducted by HSA and its Pharmacovigilance Advisory Committee in 2005 on the use of promethazine in children under two years of age.

Gadolinium-based contrast agents Important safety information

Omniscan and Magnevist contraindicated in patients with severe renal failure
rising from the emerging concerns associated with gadolinium-based contrast agents (GBCAs) and the protential increased risk of nephrogenic fibrosing dermopathy (NFD) and nephrogenic systemic fibrosis (NSF), the Health Sciences Authority (HSA) and its Pharmacovigilance Advisory Committee have reviewed the safety profile and use of these products, particularly in patients with renal dysfunction. Brief overview Gadolinium-based contrast agents (GBCAs) are approved by HSA for use in magnetic resonance imaging (MRI). Seven GBCAs are registered in Singapore: gadodiamide (Omniscan, GE Healthcare), gadopentetate dimeglumine (Magnevist, Bayer Schering Phama), gadoterate meglumine (Dotarem, Guerbet), gadobutrol (Gadovist, Bayer Schering Phama), gadobenate dimeglumine (Multihance, IDS Pharmaceutical Division), gadoversetamide (Optimark, Tyco Healthcare) and gadoxetic acid (Primovist, Bayer Schering Phama). HSA has been closely monitoring the association of NFD/NSF with these contrast agents since May 2006, following the first alert by GE Healthcare on NFD/NSF reported with the use of Omniscan in patients with severe renal impairment. An article was published in July 2006 issue of the Adverse Drug Reaction News Bulletin to alert healthcare professionals of these adverse reactions. The other GBCAs should be used in patients with severe Following the first alert on Omniscan, more global reports of NFD/NSF were subsequently received for Omniscan (more than 150 cases), as well as Magnevist (78 cases) and Optimark (11 cases). More recently, isolated cases associated with other GBCAs were also reported. All these reports occurred only in patients with renal dysfunction and is associated with swelling and tightening of the skin in the extremities which may develop over a period of days to several weeks. The mechanism by which a GBCA can cause NFD/NSF has not been elucidated but the current understanding is that GBCAs are associated with different levels of NFD/NSF risk based on their physicochemical and pharmacokinetic properties. HSA has issued a Dear Healthcare Professional Letter (DHCPL) in December 2007 to all registered physicians to alert them to the above safety information, as well as advise on appropriate use of these drugs. For details of the DHCPL, please log on to the MOH Health Professionals Portal at http://www.hpp.moh.gov.sg. renal impairment (GFR < 30mL/min) only when absolutely necessary where the benefits outweigh their risks. Any possible alternative imaging tests that do not require GBCA, the clinical need for GBCA use, the relative risk for the patient, the type of agent to be used and any history of prior GBCA exposure should be considered when using the other GBCAs in severe renal impaired patients. There is no robust evidence to show that haemodialysis can prevent or treat the development of NFD/NSF, but haemodialysis shortly after GBCAs administration in patients currently receiving haemodialysis may be useful in removing the agent from the body, and there is some preliminary evidence that suggests NFD/NSF is less likely to develop in patients receiving early and adequate haemodialysis. If it is to be performed, the US and European authorities have recommended that at least two episodes of haemodialysis, the first commencing within 24 hours of administration of GBCA, performed in patients at risk who receive any of the GBCAs. The risk for the development of NFD/NSF in patients with moderate renal impairment is unknown, therefore Omniscan and Magnevist should be used with caution in patients with moderate renal impairment (GFR 3059mL/min/1.73m2), especially if any gadoliniumbased contrast media have been previously administered. Omniscan and Magnevist should be used in neonates and infants only if the benefits outweigh the risks as these patients have immature kidney functions. Summary of recommendations Use of Omniscan or Magnevist is contraindicated in patients with severe renal failure (GFR < 30mL/min/1.72m2).

Adverse Drug Reaction News December 2007 Vol.9 No.3

Risk of torsade de pointes and QT prolongation with haloperidol

aloperidol is a butyrophenone antipsychotic agent and its indications include the management of psychoses, schizophrenia and manic states and management of aggressive and agitated behavior. Haloperidol injection has been registered in Singapore since 1994 and is licensed only for intramuscular administration.

a search of their Benefit Risk Management worldwide safety database. The results revealed 73 cases of TdP, of which 11 of these cases led to fatalities. Eight of these fatalities involved the IV administration of haloperidol. The second study involved a post-marketing investigation that examined reports of cardiac events that involved haloperidol received by the company as of 30 July 2005. Thirteen of these haloperidol related cardiac events reported involved the occurrence of TdP , QT prolongation, ventricular arrhythmia and/or sudden death. Label amendments in the US Based on these recent findings, the labelling of Haldol products in the US were revised to include the following warnings: Higher doses and IV administration of haloperidol appear to be associated with a higher risk of QT prolongation and TdP . Although cases of sudden death, TdP and QT prolongation have been reported even in the absence of predisposing factors, particular caution is advised in treating patients using any formulation of haloperidol who: have other QT prolonging conditions, including electrolyte imbalance (particularly hypokalaemia and hypomagnesemia), have underlying cardiac abnormalities, hypothyroidism, or familial long QT syndrome, or are taking drugs known to prolong the QT interval. Because of this risk of TdP and QT prolongation, ECG monitoring is recommended if haloperidol is given intravenously. Additionally, Johnson & Johnsons recent amendments to Haldols labelling now include that Haldol is not approved for intravenous administration. Conclusion

Recent safety alert issued by the US FDA The US Food and Drug Administration (FDA) has recently issued a safety alert which highlights the potential increased risk of QT prolongation and torsade de pointes (TdP) with the use of intravenous (IV) administration of haloperidol. Although injectable haloperidol is approved by the FDA only to be used as an intramuscular injection, there is considerable evidence from the medical literature that IV haloperidol is a relatively common off-label clinical practice, primarily to treat cases of severe agitation in intensive care units. There are at least 28 case reports of QT prolongation and TdP in the medical literature, some with fatal outcome in the context of off-label IV administration of haloperidol. Additionally, case control studies performed have demonstrated a dose-response relationship between intravenous haloperidol dosing and subsequent TdP . Johnson & Johnson (sponsor of the proprietary brand of haloperidol, Haldol in the US) recently conducted two post-marketing studies analysing QT prolongation and TdP with the administration of haloperidol (both oral and injectable). In the first study, Johnson & Johnson performed
Adverse Drug Reaction News December 2007 Vol.9 No.3

HSA has not received any local reports of prolonged QTc or TdP involving the use of haloperidol, and will continue to monitor the situation. The FDA, in its safety update, stated that based on case reports alone, it was unable to estimate the frequency with which QT prolongation or TdP occur following administration of haloperidol and will continue to monitor post-marketing reports for such adverse events and further regulatory actions and communications will be effected as additional information becomes available. It advised that healthcare professionals should take into consideration the above new safety information when making individual treatment decisions for their patients.
References 1. FDA information for healthcare professionals, 17 September 2007. http://www.fda.gov/Cder/drug/InfoSheets/HCP/haloperidol.htm 2. Reuter s. FDA warns of heart risks with schizophrenia drug.
http://www.reuters.com/article/governmentFilingsNews/idUSWBT00759220070917

Reports of adverse reactions to Beauty Express Miracle Pigmentation Scar Cream

he Pharmacovigilance Unit, HSA has received local reports of adverse reactions resulting from use of adulterated cosmetic products. The cases below relate to the experience of some patients. Local case reports The cosmetic product, Beauty Express Miracle Pigmentation Scar Cream was tested by HSA to contain betamethasone dipropionate 0.023%, a potent steroid, following reports of adverse drug reactions to the product. A few female patients who purchased the product from a retail shop in Singapore as skin whitener for skin pigmentation developed rashes, redness and skin sensitivity on their face after using the creams for several years. These patients became very dependent on the cream and suffered flares of skin redness and soreness whenever they stopped application of the creams. Clinically, the rashes on their face were very suggestive of steroid facies as the skin on their face were red and atrophied with surface telangiectasia. The reporting physician suspected steroid facies and symptoms of steroid withdrawal syndrome when they stopped using the cream. Steroid facies is caused by prolonged use of fluorinated topical steroids on the face. Other side effects of topical fluorinated steroids on the face include perioral and periorbital dermatitis (which manifest as acneiform eruptions around the mouth and eyes). Betamethasone dipropionate is a very potent corticosteroid as compared to other topical corticosteroids such as hydrocortisone and betamethasone valerate. It can result in Cushing's syndrome, skin atropy and hyperglycaemia. Prolonged and widespread use may also result in reversible hypothalamic-pituitary-adrenal (HPA) axis suppression. The local company marketing Beauty Express Miracle Pigmentation Scar Cream was prosecuted by HSA for adulterating the product with betamethasone dipropionate. When diagnosing an adverse reaction in patients, healthcare professionals are encouraged to take a detailed medical history which may take into consideration the patients use of cosmetic products.

Summary of advisories issued by HSA and companies

Summary of Dear Healthcare Professional Letters issued by HSA and/or pharmaceutical companies from January 2006 to November 2007. For details, please log on to http://www.hpp.moh.gov.sg using your professional board register number or Singpass.

9 Jan 2006

Rosiglitazone (Avandia or Avandamet): Rare reports of macular oedema

24 May 2007 Zolendronic acid (Zometa): Reports of atrial fibrillation observed in clinical study 11 Jun 2007 Nimesulide: Suspension of sales following signals of liver toxicities 14 Jun 2007 Deferasirox (Exjade): Risk of acute renal failure and blood cytopenias 5 Jul 2007 Tegaserod (Zelmac)/ Restrictions on the supply of tegaserod and special access for patients who have no therapeutic alternatives

14 Feb 2006 Aprotinin (Trasylol): Literature reports on the possible risk of serious renal and cardiovascular toxicity following Trasylol administration to patients undergoing coronary artery bypass grafting surgery (CABG) 22 Feb 2006 Gatifloxacin (Tequin): Safety update and product labelling changes of serious cases of hypoglycaemia and hyperglycaemia 23 Jun 2006 Lamotrigine (Lamictal): Risk of oral clefts 21 Jun 2006 Infliximab (Remicade): Risk of hepatosplenic T-cell lymphoma 8 Feb 2007 Ranibizumab (Lucentis): Risk of stroke 21 Feb 2007 Entecavir (Baraclude): Risk of developing HIV resistance cannot be excluded with entecavir therapy in HIV/HBV co-infected patients not receiving HAART 12 Mar 2007 Rosiglitazone (Avandia): Clinical trial observation of an increased incidence of fractures in female patients receiving long-term treatment with rosiglitazone for type 2 diabetes mellitus 3 Apr 2007 Tegaserod (Zelmac): Temporary withdrawal of sales

21 Aug 2007 Rosiglitazone (Avandia)/ Rosiglitazone and metformin (Avandamet): Advisory for patients with congestive heart failure 23 Aug 2007 Lopinavir and ritonavir (Kaletra): Accidental overdose in children 04 Sep 2007 Clobutinol (Silomat): Withdrawal of sales 07 Sep 2007 Salbutamol: Risk of myocardial ischaemia when used during premature labour in pregnant women 30 Oct 2007 Advisory on the use of cough and cold medicines in children 7 Nov 2007 Aprotinin (Trasylol): Temporary suspension of sales 9 Nov 2007 Mycophenolate mofetil (Cellcept): Increased risk of congenital malformations observed following use in pregnancy
Adverse Drug Reaction News December 2007 Vol.9 No.3

9 May 2007 Bevacizumab (Avastin): Risk of tracheoesophageal fistula

Package insert amendments reflecting safety issues

HSA has approved the following package insert changes due to safety updates from June 2007 to October 2007. Please note that due to space constraints, the list published is not exhaustive and you are encouraged to refer to the following website for the complete listing with details: www.hsa.gov.sg/safetyinfo_and_recalls. Please also note that there might be a time lag in the availability of the package insert which reflects the latest change(s). 1. Adefovir (Hepsera, GSK) Caution: Elderly. Warning: Lactic acidosis (in the absence of hypoxemia), sometimes fatal, usually associated with severe hepatomegaly & hepatic steatosis may occur, hence treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic lactic acidosis of unknown etiology occur & caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, or other known risk factors for liver disease. New ADRs: Vomiting, mild to moderate increases in serum creatinine levels, hypophosphatemia & a decrease in carnitine concentrations. 2. Alendronate (Fosamax, MSD) Cautions: Discontinuation should be considered in patients with osteonecrosis of jaw (ONJ) based on individual benefit / risk assessment, especially for patients requiring invasive dental surgery. Dental surgery may exacerbate ONJ. Known risk factors for ONJ include co-morbid disorders like periodontal disease. 3. Anagrelide (Agrylin, IDS) Elderly patients had twice the incidence of serious adverse events, mainly cardiac-related events. Contraindication: Moderate/severe hepatic impairment or moderate/severe renal impairment (ClCr <50ml/min). Potential risks & benefits of anagrelide therapy in patients with mild hepatic impairment should be assessed before treatment is started. Warning: Cardiomegaly & congestive heart failure reported. Cautions: Patients with known or suspected heart disease. Pre-treatment cardiovascular examination (echocardiography, electrocardiogram) & continued monitoring of CV function is recommended. Not recommended in patients with elevated transaminases (>5 times ULN). Concomitant use with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone & cilostazol is not recommended. Potential risks & benefits of concomitant use of anagrelide with acetylsalicylic acid in patients with a platelet count >1500 x 109/L &/or a history of haemorrhage should be assessed before starting treatment. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not be given with anagrelide. 4. Baclofen (Lioresal, Novartis) Signs & symptoms of overdosage have been reported with doses >5mg/day in patients undergoing chronic haemodialysis as baclofen concentrations in plasma are elevated. Cautions: i) Patients suffering from depressive, manic disorders or Parkinson's disease; ii) Discontinuation or cases of overdosage as lowering of convulsion threshold may occur & seizures have occasionally been reported; iii) Abrupt withdrawal as dyskinesia & hyperthermia have been reported. Clinical characteristics of withdrawal of intrathecal Lioresal may resemble autonomic dysreflexia, infection (sepsis), malignant hyperthermia, neuroleptic malignant syndrome, or other conditions associated with a hypermetabolic state or widespread rhabdomyolysis. Drug interactions: Synthetic opiates, alcohol, morphine & levodopa. Careful monitoring of respiratory & cardiovascular functions is essential, especially cardiopulmonary disease & respiratory muscle weakness. ADRs: Hypothermia, pollakiuria & erectile dysfunction. 5. Cabergoline (Dostinex, Pfizer) Warnings: Chest x-ray is recommended when new clinical symptoms of respiratory disorders are presented. Discontinue therapy in the case of x-ray signs of pleural effusion/pulmonary fibrosis or in the diagnosis of valvulopathy. Pathological gambling, increased libido & hypersexuality (reversible upon reduction of dose or treatment discontinuation) reported. ADRs: Alopecia, aggression & psychotic disorder. 6. Carbamazepine (Tegretol, Novartis) Warning: Toxic epidermal necrolysis & SJS have been rarely reported with Tegretol. Drug interactions: Paroxetine & levetiracetam. ADR: Hypogammaglobulinaemia. 7. Ceftibuten (Cedax, Schering-Plough) Ceftibuten can rarely lead to prolonged prothrombin time (PT), especially in patients previously stabilised on oral anticoagulant therapy. PT or INR should be monitored in patients at risk & treated as required. ADRs: Bronchospasm, dyspnoea, rash, urticaria, photosensitivity reaction, pruritus, angioneurotic oedema & pseudomembranous colitis. 8. Cholestyramine (PMS-Cholestyramine, Apotheca) Caution: May cause steatorrhea or accentuate pre-existing steatorrhea & this may require reduction & adjustment of dosage. Drug interactions: Digitalis & estrogens that undergo enterohepatic recirculation. Cholestyramine has been shown to reduce the bioavailability of HMG-CoA reductase inhibitors; the clinical cholesterol-lowering effects of an HMG-CoA reductase inhibitor & cholestyramine have been shown to be additive. ADRs: Dental bleeding, diuresis, weight loss/gain, increased libido, swollen glands, edema & dental caries. 9. Ciclosporin (Sandimmun Neoral, Novartis) Warnings: Avoid excess UV light exposure; monitor renal function in elderly. There is only limited experience with the use in children with endogenous uveitis. Drug interactions: Oxcarbazepine, bosentan, voriconazole & colchicine. Methotrexate exhibits nephrotoxic synergy with ciclosporin. Following concomitant administration of ciclosporin & lercanidipine, AUC of lercanidipine was increased 3 times & AUC of ciclosporin was increased 21%. Concomitant use of potassium sparing drugs e.g. p o t a s s i u m s p a r i n g d i u r e t i c s , AC E i n h i b i t o r s , a n g i o t e n s i n I I receptor antagonists or potassium containing drugs may lead to significant increases in serum potassium. 10. Clobetasol (Univate, Apex Pharmacy) Contraindication: Treatment of dermatoses, peri-anal & genital pruritus in children <1yr, including dermatitis& nappy eruption. Severe ADRs are likely to happen if application of more than 50g/week is used. 11. Diclofenac (Cataflam, Novartis) Caution: Breastfeeding. Drug interactions: Concomitant use of topical diclofenac & topical steroids in patients with significant pre-existing corneal inflammation may increase risk of developing corneal complications. ADRs: Conjunctival hyperaemia, allergic conjunctivitis, eyelid erythema, urticaria, rash, eczema, erythema, pruritus, hypersensitivity, cough & rhinitis. 12. Diphtheria, haemophilius influenzae, pertussis, polio & tetanus (InfanrixIPV+Hib, GSK) Warning: For children with progressive neurological disorders like infantile spasms, uncontrolled epilepsy or progressive encephalopathy, to defer pertussis immunization until condition is corrected. ADRs: Local or diffuse swelling at injection site, sometimes involving adjacent joint. Large swelling reactions more likely when children primed with acellular pertussis vaccines vs whole cell vaccine; local swelling & diffuse swelling may be more frequent when booster dose is administered between 4 & 6 years, resolving over an average of 4 days. Swelling of the entire injected limb has been reported. 13. Eletriptan (Relpax, Pfizer) Caution: Co-administering with other drugs having serotonergic activity, such as SNRIs & SSRIs due to possible development of serotonin syndrome. Thus, careful observation of the patient is warranted particularly during treatment initiation or dose increase of either eletriptan or SSRIs/SNRIs. Concomitant use with potent CYP3A4 inhibitors e.g. ketoconazole, itraconazole, erythromycin, clarithromycin & protease inhibitors is not recommended. 14. Epoetin alfa (Eprex, Johnson & Johnson) Warnings: Monitor haemoglobin (Hb) levels closely due to a potential increased risk of thromboembolic events & fatal outcomes when patients are treated at Hb levels above the target for the indication of use. In patients with chronic renal failure, maintenance Hb concentration should not exceed the upper limit of the target Hb concentration. Hb levels >12g/dL may be associated with a higher risk of cardiovascular events, including death. ADRs: Increase in blood pressure, aggravation of existing hypertension, myalgia, hypertensive crisis with encephalopathy & seizures, shunt thromboses, & porphyria. 15. Estramustine (Estracyt, Pfizer) Warnings: Patients with prostate cancer & osteoblastic metastases are at risk for hypocalcemia. Monitor calcium levels. 16. Etoricoxib (Arcoxia, MSD) Warnings: Long-term administration of NSAIDs has resulted in renal papillary necrosis & other renal injury. Perforations, ulcers or bleeds can occur at any time during use & without warning symptoms though the results of the MEDAL Program demonstrate that risk of GI toxicity in patients treated with Arcoxia 60mg or 90mg once daily is significantly less than with diclofenac 150mg daily. ADR: Shock. Serious skin reactions, some of them fatal, may occur. 17. Gadoxetic acid (Primovist, Zuellig) Warnings: Occurrence of nephrogenic systemic fibrosis (NSF) / nephrogenic fibrosing dermopathy (NFD) in patients with severe renal impairment (GFR <30ml/min/1.73m 2 ) were reported. No robust evidence that haemodialysis can prevent or treat the development of NSF but haemodialysis shortly after Primovist administration in patients currently recently receiving haemodialysis may be useful at removing Primovist from the body. No evidence to support the initiation of haemodialysis for prevention or treatment of NSF in patients not already undergoing haemodialysis. 18. Ibandronic acid (Bonviva, Roche) Osteonecrosis of the jaw, associated with tooth extraction &/or local infection has been reported in cancer patients receiving mainly IV bisphosphonates & in patients with osteoporosis receiving oral bisphosphonates. Consider dental examination with appropriate preventive dentistry in those with concomitant risk factors e.g. cancer, chemotherapy, radiotherapy, corticosteroids, & poor oral hygiene. Avoid in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. 19. Isradipine (Dynacirc SRO, Novartis) Warnings: Angina pectoris may occur, predominantly in patients with pre-existing coronary artery disease. In patients with pre-existing angina pectoris, frequency, duration & severity of anginal attacks may be increased by rapid dosage increments or at the start of treatment. Food interaction: Grapefruit juice may increase bioavailability of isradipine. ADRs: Polyuria, malaise, weight increased, stroke, syncope, transient ischaemic attack, lethargy, dry mouth, constipation, diarrhoea, insomnia, & chest pain. 20. Lansoprazole (Prevacid, Luen Wah Medical) Contraindication: Patients on atazanavir therapy. Drug interactions: Theophylline & atazanavir. ADRs: Anaphylactic reactions, dyspnea, shock, toxic epidermal necrolysis (Lyell syndrome), oculomucocutaneous syndrome, Stevens Johnson syndrome, severe hepatic dysfunction with jaundice, hepatitis, agranulocytosis, pancytopenia, haemolytic anaemia, nausea, vomiting, anorexia, abdominal pain, candidiasis, stomatitis, glossitis, taste abnormality, interstitial nephritis, acute renal failure, interstitial pneumonia, gynaecomastia, blurred vision, oedema, weakness, malaise, numbness of tongue or lips, numbness of limbs, arthralgia, muscle pain, & alopecia.

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Adverse Drug Reaction News December 2007 Vol.9 No.3

Package insert amendments reflecting safety issues

HSA has approved the following package insert changes due to safety updates from June 2007 to October 2007. Please note that due to space constraints, the list published is not exhaustive and you are encouraged to refer to the following website for the complete listing with details: www.hsa.gov.sg/safetyinfo_and_recalls. Please also note that there might be a time lag in the availability of the package insert which reflects the latest change(s). Discontinue lansoprazole in the following cases: i) Diarrhoea persists. ii) Abdominal pain & frequent diarrhoea occurring in H.pylori eradication. iii) Abnormalities in renal function test values e.g. increases in BUN, creatinine, etc. iv) Fever, coughing, dyspnoea, abnormal lung sound (crepitation) etc. When such symptoms arise, chest X-ray should be performed immediately & patient treated with corticosteroid. 21. Lopinavir & ritonavir (Kaletra, Abbott) Precautions: Coadministration of ritonavir & digoxin may result in significantly increased digoxin levels, therefore monitoring of serum digoxin levels is recommended. Drug interactions: Rifampin, fluticasone & tipranavir. ADRs: Myocardial infarct, hepatomegaly, liver fatty deposit, liver tenderness, joint disorder, myasthenia, extrapyramidal syndrome, increased cough, neoplasm, skin striae, & impotence. 22. Naftidrofuryl (Praxilene, Merck) Contraindication: History of hyperoxaluria. Warnings: Taking Praxilene without liquid before going to bed may cause local oesophagitis. Recommended to drink large volumes of liquid during the whole treatment period to maintain an adequate level of diuresis and to reduce the formation of calcium oxalate kidney stones. ADRs: Nausea & hepatitis. 23. Nifedipine (Adalat LA, Bayer) Warnings: Bezoars can occur rarely & may require surgical intervention. ADRs: Anaphylactoid reaction, anxiety reactions, migraine, par-/dysaesthesia, visual disturbances, palpitations, nosebleed, nasal congestion, GI & abdominal pain, erythema, joint swelling, & erectile dysfunction. 24. Octreotide (Sandostatin LAR & Sandostatin multidose, Novartis) Warnings: Uncommon cases of bradycardia have been reported hence dose adjustments of drugs like beta blockers, calcium channel blockers, or agents to control fluid & electrolyte balance may be necessary. Octreotide may alter absorption of dietary fats in some patients. Depressed vitamin B12 levels & abnormal Schilling's tests observed in some patients on octreotide hence to monitor vitamin B12 levels in patients on Sandostatin LAR & who have a history of vitamin B12 deficiency. ADRs: Anaphylaxis, tachycardia, dyspnoea, cholecystitis, thyroid dysfunction, dyspepsic signs, symptoms & episodes of arrhythmia, ECG changes e.g. QT prolongation. 25. Oxybutynin (Lyrinel, J&J) Warnings: Monitor patients for signs of anticholinergic CNS effects, particularly in the first few months after beginning treatment or increasing the dose. ADRs: Psychotic disorder & agitation. 26. Paricalcitol (Zemplar, Abbott) Chronic renal failure subjects showed a decreased clearance & increased half-life of paricalcitol. ADRs: Facial & oral oedema. 27. Pimecrolimus (Elidel, Novartis) Use of Elidel cream in patients <2 yrs old is not recommended until further data becomes available. ADRs: Anaphylactic reactions, alcohol intolerance (flushing, rash, burning, itching or swelling), allergic reactions & skin discoloration (e.g. hypopigmentation, hyperpigmentation). 28. Pneumococcal 7-valent conjugate (Prevenar, Wyeth) When Prevenar is co-administered with hexavalent vaccines (DTaP-Hib-IPV-HepB), the rate of febrile reactions was higher compared to that occurring following administration of hexavalent vaccines alone. Reactions were mostly moderate (39oC) & transient. ADR: Urticaria-like rash. 29. Procaterol (Meptin, Luen Wah Medical) Precautions: Pregnancy. Use only as additional therapy for patients whose symptoms are not adequately controlled & not as a substitute for inhaled corticosteroids & other anti-inflammatory agents. Use short-acting inhaled beta2 stimulants in episodes of acute asthma. 30. Raloxifene (Evista, Eli Lilly) Caution: Postmenopausal women with a history of stroke or other significant stroke factors such as transient ischaemic attack or atrial fibrillation. ADRs: Thrombocytopenia, peripheral oedema, venous & arterial thromboembolic reaction. 31. Ropinirole (Requip, GSK) Warnings: Compulsive behaviours such as pathological gambling & hypersexuality have been reported in Parkinson's disease patients treated with ropinirole, especially at high doses & were generally reversible upon dose reduction or treatment discontinuation. In some cases, other factors like a history of compulsive behaviours or concurrent dopaminergic treatment were present. ADRs: Constipation, peripheral oedema & hypersexuality. 32. Sulfasalazine (PMS-Sulfasalazine, IDS) Contraindications: Intestinal & urinary obstructions. Not to be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other NSAIDs as fatal anaphylactic reactions have occurred in such individuals. Cautions: Patients with hepatic or renal damage, blood dyscrasias, severe allergy or bronchial asthma. Pancreatitis has been observed in some susceptible individuals. Deaths associated with the use of sulfasalazine have been reported from hypersensitivity reactions, agranulocytosis, aplastic anemia, other blood dyscrasias, renal & liver damage, irreversible neuromuscular & CNS changes & fibrosing alveolitis. Presence of clinical signs like sore throat, fever, pallor, purpura or jaundice may be indications of serious blood disorders. Bone marrow depression has been reported usually within the first 3 months of starting treatment & is usually reversible on stopping sulfasalazine. A full blood count, including differential white blood cell count, should be carried out before starting therapy & monitored closely during the first few months of treatment, thereafter patients should be screened if their condition changes or if they have symptoms of infection. Oligospermia with infertility have been observed in men treated with sulfasalazine. Adequate fluid intake must be maintained in order to prevent crystalluria & stone formation. 33. Ziprasidone (Zeldox, Pfizer) Cautions: Patients with severe hepatic insufficiency; concomitant use with other centrally acting agents & drugs acting on the dopaminergic & serotonergic systems. Warnings: Rare post-marketing reports of torsade de pointes in patients with multiple confounding risk factors taking ziprasidone reported. Discontinue drug if signs of neuroleptic malignant syndrome occurred. Zeldox is not approved for elderly patients with dementia-related psychosis. Women of childbearing potential receiving ziprasidone should use an appropriate contraceptive. ADRs: Seizures, body weight gain & loss, transient elevation of prolactin, mania/hypomania, serotonin syndrome, syncope, torsade de pointes, angioedema, galactorrhea, & priapism. 34. Zoledronic acid (Zometa, Novartis) Warnings: Renal deterioration, progression to renal failure & dialysis have been reported in patients after the initial dose or a single dose of Zometa. ADRs: Atrial fibrillation, somnolence & bronchoconstriction.

Voluntary withdrawal of clobutinol (Silomat) cough syrup

lobutinol (Silomat, Boehringer Ingelheim) was licenced in Singapore in 1999. It is an orally active non-opioid antitussive agent, and is indicated for the treatment of irritable, non-productive cough and inflammatory disorders of the airways. In September 2007, Boehringer Ingelheim voluntarily withdrew Silomat from the Singapore market as a precautionary measure due to concerns of a potential increased risk of cardiac arrhythmias that could be associated with the active ingredient. Published experimental data have indicated the potential of clobutinol affecting the hERG (human ether-a-go-go related gene) potassium channels. Preliminary findings from a recent clinical trial with clobutinol in adult healthy volunteers have shown a prolongation of the QTc interval in the ECG. As clobutinol is indicated for a non-serious disease condition and in view of the potentially life-threatening adver se effects, HSA agreed with the actions of Boehringer Ingelheim to withdraw clobutinol from the worldwide market. A Dear Healthcare Professional Letter (DHCPL) was issued by the company to alert healthcare professionals to the findings and the decision to recall and suspend the sales of Silomat. For details of the DHCPL, please log on to the Health Professionals Portal at http://www.hpp.moh.gov.sg.
Adverse Drug Reaction News December 2007 Vol.9 No.3

Voluntary suspension of sales of aprotinin (Trasylol)

International measures As a result of the findings of the BART study, and in consultation with the German Federal Institute for Drugs and Medical Devices (BfArM), the US Food and Drug Administration (FDA), Health Canada and other regulatory authorities, Bayer protinin (Trasylol, Bayer HealthCare) is an antifibrinolytic agent used to reduce blood loss and the need for blood transfusion in adult patients at risk of blood loss who are undergoing cardiopulmonary bypass in the course of coronary artery bypass graft surgery. It has been registered in Singapore since 1994. Recent safety findings Recent findings have raised concerns regarding the safety issues associated with the use of aprotinin in cardiac surgery. Earlier observational studies have suggested that aprotinin may increase the risk of mortality when compared against other antifibrinolytic agents. The latest Canadian study, BART (Blood conservation using antifibrinolytics: A randomized trial in high risk cardiac surgery patients), a trial comparing the safety and efficacy of aprotinin (2 million units bolus + 2 million units in pump prime + 2 million units via infusion over 4 hours) against epsilon-aminocaproic acid (10g bolus + 250 mL NaCl in pump prime + 2g/hr infusion) or tranexamic acid (30mg/kg bolus + 2mg/kg/hr in pump prime + 16mg/kg/hr infusion) suggested an increase in all-cause mortality among patients in the aprotinin arm of the study compared to the other two drugs: the 30 days mortality of aprotinin compared to the two drugs were relative risks of 1.5 at p=0.06 and p=0.08. Although statistical significance was not reached, a trend towards an increase in mortality in the aprotinin-treated group was present throughout most of the trial.
References 1. FDA early communication about an ongoing safety review aprotinin injection, 25 October 2007. http://www.fda.gov/cder/drug/early_comm/aprotinin.htm 2. N Engl J Med Jan 2006; 354(4):353-65. 3. Transfusion Mar 2006; 46(3):327-338.

HealthCare decided to temporarily suspend the worldwide sales of Trasylol until the final data from the study can be compiled and evaluated. HSAs action and advisory In consultation with the Health Sciences Authority (HSA), the sales of Trasylol was temporarily suspended in Singapore on 6 November 2007 pending further evaluation of information from the BART study. A final regulatory decision on Trasylol will be made in due course and healthcare professionals will be informed accordingly. As an interim measure, HSA has worked with Bayer to allow supply of Trasylol through restricted access under certain conditions, to a small group of patients who have been assessed by their physicians to have no other therapeutic options, and where the benefits of the drug may outweigh its risks. Physicians are required to discuss the risks associated with using Trasylol and obtain written consent from either the patient or the next of kin should the patient be incapable or incompetent in doing so before prescribing Trasylol.

Editor-in-Chief Ms Chan Cheng Leng, BSc (Pharm) Hons Executive Editor Ms Ang Pei San, BSc (Pharm) Staff Editors Mr Choong Chih Tzer, BPharm Dr Yvonne Koh, BSc (Pharm) Hons, PhD Ms Adena Lim, BSc (Pharm) Hons, MPharm (Clin Pharm) Ms Belinda Tan, BSc (Pharm) Editorial Board Clinical Prof. Goh Chee Leok Prof. Edmund Lee Joo Deoon Clinical A/Prof. Chng Hiok Hee Clinical A/Prof. Gilbert Lau Kwang Fatt Dr Lee Kheng Hock

Enquiries, comments and suggestions to: Pharmacovigilance Unit Centre for Drug Administration Health Products Regulation Group Health Sciences Authority 11 Biopolis Way, #11-03, Helios, Singapore 138667 Tel: (65) 6866 3538 Fax: (65) 6478 9069 Website: http://www.hsa.gov.sg Email: HSA_drugsafety@hsa.gov.sg

The contents are not to be reproduced in part or in whole, without prior written approval from the editor. Whilst every effort is made in compiling the content of this publication,the publishers, editors and authors accept no liability whatsoever for the consequences of any inaccurate or misleading data, opinions or statements. The mention of any product by the authors does not imply any official endorsement of the product by the Health Sciences Authority.

Copyright 2007 Health Sciences Authority of Singapore. All Rights Reserved.

Adverse Drug Reaction News December 2007 Vol.9 No.3