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he Pharmacovigilance Branch, HSA has received six serious adverse drug reactions (ADR) reports and 246 non-serious reports of patients who were labelled as being allergic to sulphur over the period July 2007 to July 2008. Some patients who have suffered hypersensitivity to sulphonamide antimicromials such as co-trimoxazole may have been labelled as hypersensitive to sulphur. As there are important distinctions between sulphonamide antimicrobials, sulphonamide non-antimicrobials, sulphites, sulphates and sulphur allergy, this article is intended to clarify this misnomer and to discourage the use of the term as it may be imprecise and misleading.
These differences form the basis for classification of sulphonamide drugs (see Table 1 for details).
III. Sulphonamides
A sulphonamide is any compound with a SO 2NH 2 moiety. Sulphonamide antimicrobials contain an aromatic amine (arylamine) at the N4 position and a five or six member heterocyclic ring with one or more nitrogen at the sulphonamide N1 position. (see Fig. 1). Sulphonamide non-antimicrobials do not have both components.
Fig 2. This is a selection of non-antimicrobial sulphonamides with the SO2NH2 moiety labelled. It is clear that, besides the SO2NH2 moiety, there is no resemblance with sulphonamide antimicrobials.
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Sulphur allergy A common misnomer in ADR reporting CPE accreditation of ADR News Bulletin Abacavir hypersensitivity reactions associated with HLA-B*5701 allele Slimming health products (Relacore & Lami) adulterated with sibutramine
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CONTENTS
Fentanyl transdermal patch & overseas reports of fatality Haemorrhagic or necrotizing pancreatitis associated with Byetta Summary of advisories issued by HSA & pharmaceutical companies Package insert amendments reflecting safety issues Biosimilar products
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Continuing Professional Education (CPE) accreditation of the HSA ADR News Bulletin for pharmacists
he editorial team of the HSA Adverse Drug Reactions (ADR) News Bulletin is pleased to a n n o u n c e t h a t t h e S i n g a p o re Pharmacy Council has approved the inclusion of the news bulletin to the list of publications which pharmacists can read to obtain their Continuing Professional Education (CPE) points. Pharmacists can apply for one p a t i e n t - c a re C P E p o i n t u n d e r category 3A for reading each issue of the news bulletin. The CPE points can be logged in via the Singapore Pharmacy Council website at http://www.spc.gov.sg
toxic epidermal necrolysis (TEN). The oxidative formation of these metabolites occurs by means of the cytochrome P450 system. These reactive metabolites act by forming immunogenic structures for antibodies or T cells and also by direct cytotoxicity to lymphocytes and other immune cells.3 Although non-antimicrobial sulphonamides have the potential to cause allergic reactions, the predominance of scientific evidence suggests that cross-reactivity with antimicrobial sulphonamides is unlikely. However, patients with sulphonamide antimicrobial allergies may develop subsequent allergies to a sulphonamide nonantimicrobial. This association appears to be due to a predisposition of such patients to allergic reactions rather than to cross- reactivity with sulphonamide antimicrobial.7
Fig 3. Two sulphonamide antimicrobials and the common site that interacts with IgE antibodies. All illustrations (Figs 1-3) are abstracted with permission from Dr Leong KPs article published in the Medical Digest: The Truth about Sulpha Drug Allergy. 1
Table 1
Drug groups (and examples of drugs in these groups) 1. Aromatic amides a. Sulphonamide antimicrobials: sulphadiazine, sulphamethoxazole, sulphisoxazole b. Sulphonamide antivirals: amprenavir, fosamprenavir 2. Nonaromatic amides a. Diuretics: hydrochlorothiazide, chlorthiazide, furosemide, bumetanide b. Sulphonylureas: chlorpropamide, tolbutamide, glibenclamide, glipizide c. Carbonic anhydrase inhibitors : acetazolamide d. COX-2 selective inhibitors: celecoxib Cross-reactivity with sulphonamide antimicrobial Cross-reactivity within this group is likely based on structural similarities
Based on current information, there is lack of documentation for cross-reactivity between the two drug groups, i.e. aromatic amides and nonaromatic amides. Allergies when they do occur appears to be due to a predisposition of the patient to allergic reactions rather than cross-reactivity between these two groups of drugs
References 1. Medical Digest. Tan Tock Seng Hospital, Oct-Dec 2001; 14-16. 2. Ann Allergy Asthma Immunol 2008 Feb; 100(2):91-100; quiz 100-3, 111. 3. Australian Prescriber Vol 31 No: 1 Feb 2008 http://www.australianprescriber.com/ upload/pdf/articles/933.pdf 4. Pharmacotherapy 2004;24(7):857-70. 5. Ann Pharmacother 2006 Jun;40(6):1040-6. 6. Drug Safety 2001;24(4):239-47. 7. N Eng J Med 2003; 349:1628-35.
Conclusion
Accurate reporting of ADRs is crucial in the management of allergies. Being labelled as allergic to sulphur often creates confusion for both the patient and the attending healthcare professional. The term sulphur allergy should thus be avoided. Instead, the specific drug name should be identified.
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HLA-B*5701 resulted in a reduction in the incidence of clinically-suspected HSR of approximately 60% compared with no screening. The SHAPE study is a retrospective, case-control study designed to evaluate Prospective screening for relevant alleles the sensitivity of HLA-B*5701 allele with respect to abacavir HSR in black and white subjects in the United States. In this study, the data supports the strong association between HLA-B*5701 and clinically-suspected abacavir HSR in both black and white patients as well as the pre-screening for the HLA-B*5701 allele in the broader United States population to improve the safety profile of abacavir.
Local situation
HSA has not received any local reports pertaining to abacavir HSR. However, physicians who prescribe abacavir-containing medications are encouraged to advise their patients to look out for signs and symptoms of abacavir hypersensitivity reactions. If they develop signs and symptoms suggestive of hypersensitivity reactions, they should be advised to stop their medication and seek prompt medical attention. Although our Asian population has a low prevalence of the HLA-B*5701 allele, it is important to bear in mind the potential risk of abacavir HSR associated with this allele. The local package insert for Ziagen has recently been updated to reflect the safety information on HLA-B*5701 allele associated abacavir HSR and the recommendation to do pre-therapy screening for this allele. The package insert of Kivexa is in the process of being updated with this safety information. Healthcare professionals are encouraged to report suspected adverse drug reactions associated with abacavir to the Pharmacovigilance Branch of HSA.
References
1. FDA alert. Information for Healthcare Professionals Abacavir (marketed as Ziagen) and Abacavir-containing Medications. http://www.fda.gov/cder/drug/InfoSheets/HCP/abacavirHCP.htm. 2. European Public Assessment Report for Abacavir (Ziagen) http://www.emea.europa.eu/humandocs/PDFs/EPAR/Ziagen/101999en8b.pdf. 3. N Eng J Med 2008 Feb 7;358:568-79 4. CID 2008 Apr 1; 46: 1111-8
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n recent months, the Pharmacovigilance Branch, HSA has received three reports of adverse drug re a c t i o n s (ADR) associated with two slimming health p ro d u c t s . O n f u r t h e r investigation, the p ro d u c t s n a m e l y, Relacore and Lami, w e re found to contain sibutramine, an u n d e c l a re d w e s t e r n drug ingredient used as an appetite s u p p re s s a n t i n t h e m a n a g e m e n t o f obesity.
A) Relacore
I n J u n e 2 0 0 8 , H S A i s s u e d a p re s s statement to alert the public of the a d u l t e r a t e d p ro d u c t l a b e l l e d a s Relacore. This was prompted by two ADR reports involving two adult patients (a male and female) in their early 20s, that were brought to HSA s attention by doctors at a hospital. Noteworthy was that both patients admitted to purchasing the slimming product over the Internet. One of the patient provided samples of Relacore, which was ordered from a Chinese website. The product was subsequently tested by H S A s a n a l y t i c a l l a b o r a t o r y t o c o n t a i n 1 2 . 2 2 m g o f sibutramine in each capsule. The adulterated product labelled as Relacore (could be a counterfeit of the product sold in the US) was promoted as a dietary supplement and claimed to contain stress mitigating compound for belly fat and stress control.
Sibutramine-induced psychosis
Sibutramine is a noradrenaline a n d s e ro t o n i n re u p t a k e inhibitor indicated for weight loss. The commonly reported a d v e r s e re a c t i o n s i n c l u d e insomnia, headache and a n x i e t y. Ta c h y c a rd i a a n d hypertension have also been reported in some patients. Sibutramine is also known to exhibit significant dopamine reuptake inhibition and some authors have postulated that this could possibly lead to the development of psychotic symptoms, especially in the event of an overdose. 1 This is based on the postulation that the dopamine reuptake inhibition could result in excess dopamine in the synaptic c l e f t s a n d a c o n s e q u e n t i n c re a s e d d o p a m i n e rg i c neurotransmission, in line with the dopamine hypothesis of psychosis. 2, 3
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overdose, intentional overdose or suicide, drug interactions with CYP 3A4 inhibitors (eg. grapefruit juice, ketoconazole, erythromycin, diltiazem) and the sharing of the patch with another patient who was not prescribed the treatment. Fentanyl transdermal products available in Canada include Duragesic, Ratio-Fentanyl and Ran-Fentanyl. The Health Canada had in earlier warnings issued in 2004 and 2005 described fatal outcomes in opioid-nave adolescents and when fentanyl patches were abused by adolescents, leading the agency to revise the Canadian product monograph for Duragesic to emphasize the safe and appropriate use of the patch.
Local situation
To date, no adverse reaction of the nature described above has been reported to the Pharmacovigilance Branch of HSA. However, due to the seriousness and occurrence of fatalities associated with the inappropriate use and abuse of the patch reported overseas, healthcare professionals are advised to be aware of the potential serious and fatal adverse effects associated with the use of fentanyl patches. They are also advised to instruct patients and caregivers on the appropriate and safe use of fentanyl patches as well as educate them on the signs and symptoms of fentanyl overdose (see table 1 for list of symptoms). Healthcare professionals are also encouraged to report all adverse events suspected to be associated with fentanyl patches to the Pharmacovigilance Branch of HSA. Table 1: Some signs and symptoms of fentanyl overdose
Troubled breathing or shallow breathing Slow heartbeat Cold, clammy skin Tiredness Extreme sleepiness or sedation Inability to think, walk or talk normally Feeling faint, dizzy or confused
References 1. Drug Safety Update Vol. 2 Issue 2 September 2008 from MHRA and CHM 2. Canadian Adverse Reaction Newsletter Vol. 18, Issue 3, July 2008 3. Dear Healthcare Professional Letter issued by Health Canada on Duragesic, September 13, 2005. 4. Canadian Adverse Reaction Newsletter Vol. 15, Issue 3, July 2005 5. Canadian Adverse Reaction Newsletter Vol. 14, Issue 4, Oct 2004 6. http://www.fda.gov/cder/drug/infopage/fentanyl/default.htm
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xenatide (Byetta, Eli Lilly) is an incretin mimetic agent that mimics the enhancement of glucose-dependent insulin secretion and several other antihyperglycaemic actions of incretins. It is licensed as an adjunctive therapy in the treatment of patients with type 2 diabetes mellitus and was recently registered in Singapore in May 2008.
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Update on risk of suicidal ideation and behaviour with lamotrigine (Lamictal) tablets and chewable dispersable tablets [GSK] HSA alerts on wider spread of harmful illegal health products Reports of progressive multifocal leukoencephalopathy (PML) in mycophenolate mofetil (Cellcept) treated patients [Roche] Abacavir sulphate-containing medicinal products (Ziagen tablets and oral solution; Kivexa tablets; Trizivir tablets) communication on results pertaining to abacavir from the D:A:D study [GSK] Important prescribing information on exenatide (Byetta) [Eli Lilly] Safety information regarding the combined use of bevacizumab (Avastin) and sunitinib malate Direct healthcare professional communication on a report of progressive multifocal leukoencephalopathy (PML) in a patient with rheumatoid arthritis treated with rituximab (Mabthera) [Roche] US FDA s actions on products manufactured by two of Ranbaxys manufacturing plants in India New formulation of Eltroxin (Levothyroxine) tablets [GSK] Recall of hot/cold packs
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H
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SA has approved the following package insert changes due to safety updates from May 2008 to September 2008. 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: http://www.hsa.gov.sg/ safetyinfo_and_recalls. Please also note that there might be some lag time in the availability of the package insert which reflects the latest change(s).
Carbamazepine (Tegretol, Novartis) Special warning: Strong correlation between SJS/TEN associated with carbamazepine & presence of Human Leukocyte Antigen (HLA)-B*1502 allele found in Han Chinese. Consider testing for allele in genetically at-risk patients with Asian ancestry. Avoid use of carbamazepine, anti-epileptic drugs & other drugs associated with SJS/TEN in patients positive for HLA-B*1502. Cefepime (Maxipime injection, Bristol-Myers) Caution: Hypersensitivity to beta-lactam antibiotics, GI disease esp. colitis, neutropenia, renal-impairment, & in the elderly. New ADRs: Urticaria, renal dysfunction, hepatic dysfunction including cholestasis. Cyproterone, ethinylestradiol (Diane-35, Schering), Drospirenone, ethinylestradiol (Yasmin, Schering) & Levonorgestrel, ethinylestradiol (Microgynon, Schering) Special warning: The most important risk factor for cervical cancer is persistent HPV infection. Long term COC use may further increase this risk. The extent to which this finding is attributable to factors e.g. cervical screening & sexual behaviour remains controversial. Interactions: HIV protease inhibitors (e.g. ritonavir), non-nucleoside reverse transcriptase inhibitors (e.g. nevirapine) & combinations may affect hepatic metabolism, increasing plasma & tissue concentrations of cyclosporine & decreasing lamotrigine concentrations. New ADRs: May induce or exacerbate symptoms of angioedema in women with hereditary angioedema. Dactinomycin (Lyovac Cosmegen, Merck) New ADRs: Neutropenia, febrile neutropenia. Duloxetine (Cymbalta, Eli Lilly) Special warnings: Caution in patients whose conditions are compromised by increased heart rate or blood pressure. Suicidal ideation & behaviours reported during therapy or early after discontinuation. Not for patients < 18 years old. Hyponatremia may occur as a result of SIADH. Patients at risk include the elderly, those taking diuretics and those with volume depletion. New ADRs: Creatine phosphokinase increased, blood cholesterol increased, atrial fibrillation, akathisia, palpitations, tachycardia, dyskinesia, gastroenteritis, myoclonus convulsions, acute liver injury, tinnitus, angioneurotic oedema. Erythromycin (Eryc, Hospira) Warning: Prolonged QT observed in elderly. Precautions: Infantile hypertrophic pyloric stenosis (IHPS) reported. Erythromycin may aggravate the weakness of patients with myasthenia gravis. Interactions: Uncorrected electrolyte disorders (hypokalaemia), QTc interval prolonged or drugs that prolong the QTc interval. Monitor closely when oral erythromycin & quinidine are administered concomitantly as QT prolongation, torsades de pointes & cardiac arrest have been reported. Myalgia, neutropenia & fever reported with concurrent administration of erythromycin & vinblastine. ADRs: Pancreatitis, QT prolongation ventricular arrhythmias & convulsions. Etanercept (Enbrel injection, Wyeth) New ADRs: Erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis.
Ezetimibe, simvastatin (Vytorin, MSD) Precautions: Risk of myopathy/rhabdomyolysis increased by concomitant use of Vytorin with danazol, fibrates, niacin or fusidic acid. When used with gemfibrozil, dose of Vytorin should not exceed 10/10mg (ezetimibe/ simvastatin) daily. Monitor INRs If Vytorin is added to coumarin anticoagulant, or fluindione therapy. New ADRs: Cholelithiasis, cholecystitis, depression, increased creatine phosphokinase, elevations of liver transaminases, anaphylaxis, hepatic failure.
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Levonorgestrel, ethinylestradiol (Nordette, Wyeth) Contraindications: Hereditary or acquired thrombophilias, headache with focal neurological symptoms (such as aura) & undiagnosed vaginal bleeding. Precautions: adverse lipid changes. Elevations of plasma triglycerides may lead to pancreatitis & other complications. Interaction: Lamotrigine. Lorazepam (Ativan, Wyeth) Special warnings: Severe & potentially fatal anaphylactic/anaphylactoid reactions reported. Reports of angioedema involving the tongue, glottis or larynx after first or subsequent doses & sometimes dyspnoea, throat closing, or nausea & vomiting. Such patients should not be rechallenged. Dependence potential of lorazepam reduced when used at appropriate dose for short duration. Withdrawal symptoms can appear after discontinuation of one week of therapy. Avoid abrupt discontinuation after extended therapy. Convulsions more common in patients with pre-existing seizures disorders or in those taking drugs that lower convulsive threshold. Possible tolerance to sedative effects. Abuse potential esp. in patients with a history of drug &/ or alcohol abuse. Precaution: Compromised respiratory function. Pregnancy: Increased risk of congenital malformations during 1st trimester. New ADRs: Angioedema, diplopia, blurred vision. Mesalazine (Salofalk, IDS) Special warnings: Caution in hepatic dysfunction. Do not administer to patients with renal dysfunction Monitor renal function for possibility of mesalazine-induced nephrotoxicity during treatment. Not for children <6 years old. Mesalazine suppositories may cause contact dermatitis. Interaction: Possible potentiation of the myelosuppressive effects of azathioprine or 6-mercaptopurine. ADRs: Acute & chronic interstitial nephritis, renal insufficiency, allergic exanthema, pancolitis, elevated parameters of cholestasis, cholestatic hepatitis, alopecia. Pregnancy & lactation: Report of renal failure in neonate born to woman on long-term treatment with 24g/day oral doses during pregnancy. Stop breastfeeding if infant develops diarrhoea as hypersensitivity reactions may occur in infant. Mycophenolic acid (Myfortic, Novartis) Special warning: Occasional fatal cases of progressive multifocal leukoencephalopathy (PML) reported. Risk factors: immunosuppressant therapies & immune deficiency. Consider reducing total immunosuppression in patients with PML. In transplant patients, reduced immunosuppression may place graft at risk. Pramipexole (Sifrol, Boehringer Ingelheim) New ADRs: Amnesia, compulsive shopping, restlessness, visual disturbance including blur vision & reduced visual acuity, vomiting, weight loss.
Fentanyl (Durogesic Transdermal System, Janssen-Cilag) Special warnings: Patients at increased risk of opioid abuse may be treated with modified-release opioid formulations but monitor for signs of misuse, abuse or addiction. Withdrawal symptoms possible when converting from previous opioid analgesic to Durogesic or if therapy is abruptly stopped. Avoid exposing application site to tanning lamps & prolonged hot baths. New ADRs: Anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, drug withdrawal syndrome. Pregnancy: Neonatal withdrawal syndrome reported in newborn infants with chronic maternal use of Durogesic during pregnancy. Fluvastatin (Lescol, Novartis) ADR: Anaphylactic reactions. Glipizide (Glucotrol XL, Pfizer) Special warning: Treatment of patients with G6PD-deficiency may lead to haemolytic anaemia. Interaction: Voriconazole. Hydroxyzine (Atarax, UCB) Contraindications: 1) Hypersensitivity to cetirizine, piperazine derivatives, aminophylline, ethylenediamine, 2) porphyria, 3) pregnancy & breast-feeding. Special warnings: Caution in young children with increased potential for convulsions, glaucoma, bladder outflow obstruction, decreased GI motility, myasthenia gravis, or dementia, when used simultaneously with CNS depressants or anticholinergics. Avoid alcohol. Caution in patients with predisposing factor to cardiac arrhythmia, or those concomitantly treated with a potentially arrhythmogenic drug. Reduce dosage in elderly, patients with hepatic dysfunction & moderate/severe renal impairment. Stop treatment at least 5 days before allergy testing or metacholine bronchial challenge. Interactions: CNS depressants, anticholinergics, alcohol, betahistine, anticholinesterase drugs, MAOIs, adrenaline, cimetidine. Pregnancy & lactation: Hypotonia, movement disorders (extrapyramidal disorders, clonic movements), CNS depression, neonatal hypoxic conditions, or urinary retention observed in neonates of mothers who received Atarax during late pregnancy &/or labour. New ADRs: Tachycardia, accommodation disorder, blurred vision , pyrexia, hypersensitivity, anaphylactic shock, liver function test abnormal, insomnia, dyskinesia, agitation, confusion, disorientation, hallucination, urinary retention, bronchospasm, hypotension, dermatitis, fixed drug eruption, increased sweating. Iloprost Trometamol (Ventavis, Berlimed SA) Special warnings: Inhalation might induce bronchospasm. Patients with concomitant acute pulmonary infections, COPD, & severe asthma should be carefully monitored. Not for pregnant or lactating women. Women of child bearing potential should use effective contraceptive measures during treatment. New ADRs: Pain in jaw, back pain, vomiting, dizziness, diarrhoea, dyspnoea, bronchospasm, wheezing. Influenza vaccine (Fluad, Novartis) Contraindication: Children & elderly patients on warfarin.
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Simvastatin (Zocor, MSD) Precaution: Concomitant administration with fusidic acid may increase risk of myopathy. Consider temporary suspension of simvastatin. New ADR: Hepatic failure. Telmisartan (Micardis, Boehringer Ingelheim) Interactions: Treatment with NSAIDs associated with potential for acute renal insufficiency in dehydrated patients. Reduced effect during combined treatment with NSAIDs. New ADRs: Cystitis, syncope/faint, abnormal hepatic function/ liver disorder, renal impairment including acute renal failure, hyperkalaemia, anaemia, angioneurotic oedema, increased blood creatine phosphokinase.
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Laronidase (Aldurazyme, Genzyme) Warning: Lifethreatening anaphylactic reactions up to 3 hours after infusions. In patients with Mucopolysaccharidosis I, preexisting upper airway obstruction may have contributed to severity of reactions. Patients with acute illness at time of infusion may be at greater risk for infusion-related reactions. New ADRs: Chills, vomiting, nausea, arthralgia, diarrhoea, tachycardia, abdominal pain, blood pressure increased, decreased oxygen saturation.
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Vardenafil (Levitra, Bayer) Special warnings: With alpha blockers besides tamsulosin, separate timing of dose. When used with clarithromycin, do not exceed 5mg of vardenafil. Interaction: nicorandil. New ADRs: Sudden deafness or loss of hearing, transient global amnesia, seizures. Zanamivir (Relenza, GSK) Special warning: Seizures, delirium, hallucination & abnormal behaviour observed mainly early in the therapy & often has an abrupt onset & rapid resolution.
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Biosimilar products
A regulatory update
biosimilar medicine is a medicinal product which is similar to a biological medicine that has already been registered with a drug regulatory authority and is submitted for medicinal product registration by an independent applicant after the patent period for the original product has expired. As the cost of innovative biological products are generally high, thereby limiting their use, the expiration of the patents on many biological products such as human growth hormone and erythropoietin has prompted the development and licensing of biosimilar products. A biosimilar product would have an abbreviated non-clinical and clinical development programme leveraging on the existing information of the original product and focusing on demonstration of similarity with the original product, also known as the reference product. Biosimilar products such as Valtropin and Omnitrope (both are somatropin) and Binocrit (which contains epoetin alpha) are registered in the European Union. There are no biosimilar products registered in Singapore as yet but such products will eventually enter the market, subject to approval by HSA. This article serves to provide healthcare professionals with more information on biosimilars and what to take note of when prescribing and reporting ADRs associated with biosimilar products when these products become available locally in the future.
to the patient and the institution which he practises in. However when prescribing such products, it is important to use the brand name of the selected product. A biosimilar product may have the same international non-proprietary name (INN) as the reference biological product but they should not be presumed to be identical. Using the brand name will help avoid the issue of automatic substitution of the product when dispensed in the pharmacy, or during administration of the product.
A biosimilar product may have the same or a more restricted indication for use compared to the existing biological product When prescribing a biosimilar product, the brand name of the product should be clearly stated on the prescription When dispensing/administering a biosimilar product, only the product with the correct brand name should be dispensed/administered. There should NOT be any substitution with another product with the same international non-proprietary name without seeking clarification with the prescribing doctor When reporting an adverse reaction, the brand name and batch number of the product should be clearly stated
References 1. http://www3.niaid.nih.gov/research/resources/DAIDSClinRsrch/ Glossary.htm 2. Drug Safety Update Vol. 1, Issue 7 February 2008 from MHRA and CHM
Enquiries, comments and suggestions to: Pharmacovigilance Branch 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 2008 Health Sciences Authority of Singapore. All Rights Reserved.