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Published by the Centre for Drug Administration, HSA and the HSA Pharmacovigilance Advisory Committee

Letter from Editor

Adulterated illegal sexual enhancement products

he Health Sciences Authoritys recent investigations involving Power 1 Walnut and several other illegal sexual enhancement products found adulterated with toxic doses of glibenclamide is the most serious case of adverse dug reactions to illegal health products that we have encountered. If not for our astute healthcare professionals who promptly reported their suspicions about these products to us, potentially many more of our consumers could have been harmed by the serious health hazards posed by these products. We would like to take this opportunity to express our sincere appreciation to our doctors, pharmacists, nurses and healthcare administrators who have contributed to this investigation in many ways. These include reporting of adverse drug reactions reports to us, retrieving suspected samples of products from patients or their relatives for analytical testing and interviewing patients on the source of the products. We feel that it is also opportune to provide an update on our investigations to keep our healthcare professionals informed.

also consumed health products adulterated with glibenclamide as they exhibited similar symptoms of hypoglycaemia (e.g. giddiness, seizures, unconsciousness). These patients also have positive laboratory findings of glibenclamide (or its metabolites) in either their blood or urine. Ten of the patients presented in a coma state of which six have since passed away and the remaining four have permanent neurological damage. All the patients were males except for one female. Their ages range between 21-97 years, comprising 69% residents and 31% foreigners; 57% were Chinese, 17% Malay, 13% Indian and 13% of other races. Hypocounts of these patients upon presentation were reported to be as low as 0.7mmol/L. Clinical investigations revealed findings of positive urine/blood test for glibenclamide, high insulin and C-peptide levels.

HSAs assessment and actions


We have assessed that the adulteration with glibenclamide is not limited to these four products and potentially can affect a wider range of illegal sexual enhancement products. It is likely that there could have been a mix-up at the source of manufacturing as we found that in products where glibenclamide was detected, the sildenafil concentration was present in very low levels. For instance, one particular batch of Power 1 Walnut from a patient contained 98mg glibenclamide and only 1mg of sildenafil. HSA officers have intensified our surveillance and enforcement activities in this area. To date, more than 100,000 units of illegal health products have been seized and eight peddlers caught dealing in such products have been charged in court. As part of our educational efforts to reduce demand of these products, we have also produced posters in foreign languages and depiction in cartoons to reach out to a wider audience.

Adulterated products
In addition to Power 1 Walnut, the other three illegal health products found to contain glibenclamide are counterfeit Cialis, Santi Bovine Penis Erecting Capsule and (Zhong Hua Niu Bian). The amount of glibenclamide was found to vary among the different products and among different batches. The amount of glibenclamide detected from the samples obtained from patients were between the range of 14-100mg per tablet. The other adulterants detected in these products include varying concentrations of sildenafil, tadalafil and sibutramine.

Conclusion
We look forward to your continued support of reporting adverse drug reactions to the Pharmacovigilance Unit, HSA. A high level of vigilance by our healthcare professionals is essential in ensuring safer drugs on the market. Editor-in-Chief

Summary of adverse drug reactions cases


As of 16 June 2008, we have 47 confirmed cases of adverse reactions to adulterated illegal products and another 98 suspected cases where it is highly probable that the patient

Chan Cheng Leng

ISSN: 0219 - 2152 July 2008 Vol.10 No.2

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Adulterated illegal sexual enhancement products Tumor necrosis factor alpha antagonists & serious skin reactions Update on aprotinin (Trasylol) Withdrawal of indication of primary nocturnal enuresis for desmopressin nasal preparations

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CONTENTS

Clozapine-induced gastrointestinal hypomotility PDE5 inhibitors associated sensorineural hearing loss Updates on mycophenolate group of drugs Package insert amendments reflecting safety issues Varenicline (Champix) & neuropsychiatric adverse events

Adverse Drug Reaction News July 2008 Vol.10 No.2

Tumor necrosis factor-alpha antagonists & serious skin reactions


FDA reported that there was a time related relationship between the first dose or the most recent dose of TNF- antagonists and the time to onset of the skin reaction.

umor necrosis factor-alpha (TNF-) is a cytokine produced by monocytes and macrophages and has a role in promoting an inflammatory response which may lead to the development of certain autoimmune disorders such as rheumatoid arthritis or Crohns disease. TNF- antagonists are biological protein molecules designed to block the TNF-s inflammatory responses. Since 2002, HSA has registered three TNF- antagonists: Adalimumab (Humira 40mg/0.8mL, Abbott) Etanercept (Enbrel 25mg, Wyeth) Infliximab (Remicade 100mg, Centocor BV)

Table 1: Summary of demographics and characteristics of the serious dermatological cases reported by US FDA
Infliximab
Male Female Unknown 5 16 54 27-70 (data provided for 20 patients)

Etanercept
7 14 1 53 16-84

Adalimumab
1 6 51 23-61

Age
Median Range

Skin reactions
Erythema multiforme (EM) Stevens Johnson syndrome (SJS) Toxic epidermal necrolysis (TEN) SJS/TEN EM/SJS Median Range 15 5 1 28 4 days - 18 months (Data provided for 11 patients) 15 (71%) were on concomitant medications e.g. carbamazepine, diltiazem, frusemide/ hydrochlorothiazide, leflunomide, methotrexate, mercaptopurine, meloxicam, naproxen, rofecoxib, sulfasalazine, sertraline 13 4 4 1 50 5 days - 52 months 4 2 1 60 6 days - 3 years

TNF- antagonists are currently locally approved for the management of severe arthritic conditions and Crohns disease (infliximab only). As TNF- antagonists are protein molecules, they have the capability to elicit an immune response possibly leading to hypersensitivity reactions.

Serious dermatological adverse reactions


Since August 1998, following the first marketing authorization of infliximab, the US Food and Drug Administration (FDA) has been receiving adverse drug reports (ADR) of serious cutaneous adverse reactions associated with the use of adalimumab, etanercept and infliximab. The adverse reactions, from both domestic and overseas reports include erythema multiforme (EM), Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) (refer to Table 1 for details). To date, there are: 7 reports associated with adalimumab 22 reports associated with etanercept 21 reports associated with infliximab

Time to onset since first dose (days)

Other medications

15 (68%) were on concomitant medications e.g. aspirin, amoxicillin, celecoxib, ciprofloxacin, diclofenac, etoricoxib, ethinyl estradiol/ levonorgestrol, flurbiprofen, hydroxychloroquine, methotrexate, indapamide, isoniazid, lamotrigine, meloxicam, naproxen, rofecoxib, sulfasalazine, terbinafine, venlafaxine, warfarin

2 (29%) on methotrexate

Actions taken in the US


The US product label for infliximab has been updated to include these post-marketing findings of serious skin adverse drug reactions. The FDA is currently reviewing whether there is a need to revise the product labels for etanercept and adalimumab and will continue to monitor the situation through their MedWatch program. Healthcare professionals and patients have been advised to maintain vigilance for such skin reactions associated with the use of adalimumab, etanercept and infliximab.

The evaluation of the potential of TNF- antagonists capability to elicit serious dermatological reactions are difficult as other confounding factors were present. A significant number of these patients were co-administered with one or more medications such as carbamazepine, amoxicillin, ciprofloxacin, methotrexate and celecoxib, which are also known to be associated with EM, SJS and TEN. However, a certain number of these cases yielded positive rechallenge and dechallenge outcomes, supporting the association of serious skin reactions with the use of adalimumab, etanercept and infliximab. Despite the lack of information,

Local findings and regulatory actions


In Singapore, the local package insert of infliximab has been updated to reflect these recent post-marketing findings of serious skin reactions. HSA is currently reviewing the package inserts of the other two TNF- antagonists. HSA has not received any local reports of serious skin-related adverse drug reactions associated with the use of TNF- antagonists. Healthcare professionals are encouraged to report any suspected adverse drug reactions associated with TNF- antagonists to HSA.
Reference 1. FDA Drug Safety Newsletter. Winter 2008.

July 2008 Vol.10 No.2 Adverse Drug Reaction News

Update on aprotinin (Trasylol)

he findings of the Blood Conservation Using Antifibrinolytics Randomized Trial (BART) that compared the use of aprotinin against lysine analogues, tranexamic acid and aminocaproic acid, conducted by the Ottawa Health Institute in Canada on 2,331 high risk cardiac surgery patients from August 2002 to October 2007 was recently published in the New England Journal of Medicine . 1 In this study, 781 patients were administered aprotinin, 770 were given tranexamic acid and 780 patients were given aminocaproic acid. The study was terminated early upon the recommendation of the independent data and safety monitoring committee in October 2007 due to the interim data suggesting a strong trend toward higher mortality in the aprotinin group compared with the tranexamic acid and the aminocaproic acid groups.

The study, however, noted that the use of aprotinin did not significantly increase the risk of renal failure or the need for postoperative renal replacements despite an increase in the proportion of patients who were experiencing a doubling of their serum creatinine levels. The investigators of the BART trial concluded that, although aprotinin is potentially more effective in controlling haemostasis than other agents, their results from this trial only noted a possible trend suggesting aprotinin may decrease massive bleeding. The authors also noted that only repeat surgeries and important blood losses through chest tubes, one of the main indications for surgery, were potentially improved with the use of aprotinin. Aprotinin did not appear to prevent massive bleeding or save the lives of patients who had massive bleeding.

International regulatory actions


The UK Medicines and Healthcare products Regulatory Agency has suspended the marketing authorization of aprotinin in the UK on 7 December 2007, pending the outcome of a full Europe-wide review of the balance of the risks and benefits of aprotinin. Currently, a limited access route has been established in Australia, Canada and the US, as well as several other countries, for patients undergoing coronary artery bypass graft (CABG) surgery requiring cardiopulmonary bypass who are at increased risk of blood loss and transfusion and who may still require aprotinin. In such cases, when the benefits of aprotinin use outweigh the risks, the patients are able to obtain aprotinin through limited access e.g. Australias Special Access Scheme or Canadas limited access program. In the US, a limited access protocol has been agreed to with the US Food and Drug Administration (FDA), in which aprotinin treatment is limited to patients undergoing CABG surgery requiring cardiopulmonary bypass who are at increased risk of blood loss and transfusion and who do not have any acceptable alternative therapies. 2 In the meantime, the Australian Therapeutic Goods Administration, FDA and Health Canada are conducting their safety reviews on aprotinin before taking any further regulatory actions.

Results of the BART trial


The findings of the BART trial revealed that high-risk cardiac surgery patients using aprotinin had fewer incidents of massive bleeding as defined by the investigators but had a higher 30-day mortality when compared with the other patients given tranexamic acid or aminocaproic acid. These trends were not statistically significant (see Table 1). In the aprotinin group, 74 (9.5%) patients experienced massive bleeding, as compared to 93 (12.1%) patients in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk of aprotinin for both comparisons was 0.79; 95% CI, 0.59 to 1.05). The 30-day mortality rate from any cause for patients on aprotinin was 6%, which were 2% points higher than the 3.9% among the patients on tranexamic acid (relative risk, 1.55; 95% CI, 0.99 to 2.42) or 4% among patients on aminocaproic acid (relative risk, 1.52; 95% CI, 0.98 to 2.36). In a post hoc analysis that combined the groups receiving tranexamic acid and aminocaproic acid, the relative increase in the percent of deaths in the aprotinin group was 53% compared with the other groups combined (relative risk, 1.53; 95% CI, 1.06 to 2.22). The use of aprotinin was associated with a higher risk of death from a cardiac cause when compared to both tranexamic acid and aminocaproic acid groups combined (relative risk, 2.19; 95% CI, 1.25 to 3.84). The number of deaths due to a cardiac cause totaled 25 (3.2%) in the aprotinin group as compared to 10 (1.3%) cases recorded in the tranexamic acid (relative risk, 2.47; 95% CI, 1.19 to 5.10) and 13 (1.7%) cases in the aminocaproic acid (relative risk, 1.93; 95% CI 0.99 to 3.74) groups respectively.

Local regulatory actions


HSA temporarily suspended the sales of aprotinin in Singapore in November 2007 following the earlier findings of BART. As an interim measure, the supply of aprotinin is made available locally through a restricted access programme. Aprotinin is available to a small group of patients, for whom their physicians have determined that the benefits of aprotinin may outweigh the risks associated with its use. Physicians are reminded that they are required to discuss the risks associated with the use of aprotinin and obtain written consent from the patient or the next of kin should the patient be incapable or incompetent of doing so before prescribing aprotinin. In the meanwhile, HSA is reviewing the recent findings of the BART trial and will be monitoring the situation closely both locally and internationally to decide whether further regulatory actions are needed to safeguard the use of this product locally.
References 1. N Engl J Med. 2008 May 14;358(22):2319-2331. 2. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01834.html

Table1: Risks of bleeding and deaths in BART


Study outcomes 30 day mortality Massive bleeding Death due to cardiac causes Aprotinin vs. tranexamic acid Aprotinin vs. aminocaproic acid

1.55 1.52 (95% CI, 0.99 - 2.42) (95% CI, 0.98 - 2.36) 0.79 0.79 (95% CI, 0.59 - 1.05) (95% CI, 0.59 - 1.05) 2.47 1.93 (95% CI, 1.19 - 5.10) (95% CI, 0.99 - 3.74)

Adverse Drug Reaction News July 2008 Vol.10 No.2

Withdrawal of indication of primary nocturnal enuresis for desmopressin nasal preparations


Post-marketing adverse reports
FDA reviewed 61 post-marketing cases of hyponatraemic-related seizures associated with the use of desmopressin. Fifty-five cases reported sodium levels ranging from 104 to 130mEq/L during the seizure event. Of these cases, two died. Both patients experienced hyponatraemia and seizures but the direct contribution of desmopressin to the deaths was unclear. Thirty-six cases were associated with intranasal formulations, of which 25 cases occurred in paediatric patients (<17 years old). The most commonly reported indication of use in these 25 paediatric cases was nocturnal enuresis. Thirty-nine of the 61 cases were associated with at least one concomitant drug or disease that was also associated with hyponatraemia and/or seizures. In addition to the removal of the indication of PNE for nasal desmopressin preparations, FDA also requested that the manufacturers update the prescribing information of desmopressin products to include important new safety information about severe hyponatraemia and seizures. Recommendations included that desmopressin nasal preparations should not be used in hyponatraemic patients or patients with a history of hyponatraemia; treatment with desmopressin tablets should be interrupted during episodes of fluid and/or electrolyte imbalance, such as fever, recurrent vomiting or diarrhoea, vigorous exercise or other conditions associated with increased water consumption; fluid intake should be restricted one hour before to eight hours after administration of desmopressin tablets. FDA also recommended that all desmopressin preparations should be used cautiously in patients at risk for water intoxication with hyponatraemia.

he UK Medicines and Healthcare products Regulatory Agency and the US Food and Drug Administration (FDA) have recently requested the companies marketing desmopressin products in their respective countries to remove the indication for the treatment of primary noctural enuresis (PNE) from all their nasal preparations. This was due to concerns of a higher incidence of hyponatraemia reported with desmopressin nasal preparations compared to oral preparations when used for the treatment of primary nocturnal enuresis.

Background
Desmopressin is a synthetic analogue of 8-arginine vasopressin (ADH), a natural pituitary hormone that prevents excessive water loss in the urine. It is indicated for the treatment of central diabetes insipidus; polyuria and polydipsia following hypophysectomy or surgery in the hypophyseal area; primary nocturnal enuresis (PNE) from the age of 5 years; and for the diagnosis of diabetes insipidus. Desmopressin has increased antidiuretic activity and prolonged duration of action compared with the natural peptide. In the presence of an inappropriate fluid intake, the sustained decrease in urine output and decrease in urine osmolality can cause hyponatraemia, water intoxication and convulsions.

Local actions
To date, HSA has not received any local adverse drug reactions of hyponatraemia associated with desmopressin nasal preparations. In line with the regulatory actions taken internationally, United Italian Trading which markets Minirin has also sought approval from HSA to remove the approved licensed indication of PNE from its nasal preparation in Singapore. HSA will also be working with the manufacturers of the other brands of desmopressin (namely Octostim and Presinex) to ensure the prescribing information is updated to highlight this safety information.

Clozapine-induced gastrointestinal hypomotility

SA would like to bring the attention of healthcare professionals to a study recently published (online ahead of print) in the Journal of Clinical Psychiatry1 to raise awareness of rare but potentially lethal clozapine-induced gastrointestinal hypomotility (CIGH). Although the adverse reaction of constipation with clozapine is not a new safety signal and there have been publications about this since the 1990s, CIGH is not readily distinguishable leading to its under-recognition.

unknown in 32 cases. From the review, the dose of clozapine was known for 92 patients, with a range of 12 to 1000mg/day (mean of 428mg/day). The doses were noted to be higher among the fatal cases at 250 900mg/day (mean of 535mg/day). The treatment duration with clozapine prior to onset of symptoms ranged from 3 days to 15 years with 20% of patients developing serious CIGH within the first month of treatment, 36.3% within the first 4 months, and just over 50% occurred within the first year of treatment. The mortality rate was found to be at 27.5% with considerable morbidity mainly due to bowel resection. Probable risk factors for CIGH were identified as new to clozapine therapy, higher doses of clozapine, co-prescription with other anticholinergic medication, concomitant medical illness, fever, and medications such as cytochrome P450 enzyme inhibitors which may inhibit metabolism of clozapine, thus increasing its serum concentration. History of bowel surgery, constipation or gastrointestinal pathology may also contribute to the risk of developing CIGH.

Details of study
The electronic adverse drug reactions database of the Therapeutic Goods Administration, Australia and the New Zealand Intensive Medicines Monitoring Program (IMMP), which cited clozapinerelated gastrointestinal side effects were analysed. In addition, databases like PsycINFO, MEDLINE and EMBASE were searched using relevant key words. A total of 102 cases were identified for analysis; 66.7% of the patients were male and the age reported for 96 of the patients ranged from 17 to 73 years, with a median of 42 years. Of these 102 patients, 28 patients died, 42 recovered and the outcome was

Pathophysiology
The paper postulated three main mechanisms whereby CIGH can have a fatal outcome:
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July 2008 Vol.10 No.2 Adverse Drug Reaction News

PDE5 inhibitors associated sensorineural hearing loss

that can occur all at once or over a period of up to three days. The mechanism behind how PDE5 inhibitors may be associated with SSHL remains unclear. There is not enough information to determine whether any specific type of patient is at increased risk for this possible adverse effect. In addition, it is uncertain whether these events are caused by medication use, underlying medical conditions, or a combination of both or other factors.

hree phosphodiesterase type 5 (PDE5) inhibitors are currently registered in Singapore - sildenafil (Viagra and Revatio, Pfizer), tadalafil (Cialis, Eli Lilly) and vardenafil (Levitra, Bayer). Viagra, Cialis and Levitra are all indicated for the treatment of erectile dysfunction (ED) while Revatio is indicated for the treatment of pulmonary arterial hypertension (PAH). PDE5 inhibitors work to block the type 5-mediated catabolism of cyclic guanosine monophosphate (cGMP), allowing the build up of cGMP, which causes smooth muscle relaxation. Smooth muscle relaxation in the penile vasculature and pulmonary arteries is responsible for the PDE5 inhibitor effects seen in ED and PAH, respectively.

Regulatory actions by FDA


Following FDAs warning, the product label for this class of drugs was revised to reflect this information and guidance was also provided in the label for patients who experience sudden hearing loss.

Local situation
HSA has not received any adverse drug reaction reports pertaining to hearing loss associated with the use of PDE5 inhibitors. However, physicians who prescribe Viagra, Levitra or Cialis for ED are encouraged to advise their patients to immediately stop taking the drug if they experience any sudden decrease in hearing and to seek prompt medical attention. Physicians should also advise their patients with PAH, who experience a sudden decrease or loss of hearing while taking Revatio to seek prompt medical attention. In addition, these patients should be told not to discontinue the medication without consulting their physician about other treatment options as PAH can be a life-threatening condition. Both the local package inserts of Viagra and Revatio have recently been updated to reflect the warning on hearing loss. The package insert of Levitra is in the process of being updated with this safety warning. Healthcare professionals are encouraged to report suspected PDE5 inhibitors related adverse events to the Pharmacovigilance Unit of HSA.
References 1. FDA Drug Safety Newsletter, Vol.1 No.2, 2008. http://www.fda.gov/cder/dsn/ default.htm 2. National Institute on Deafness and Other Communication disorders: Sudden Deafness. http://www.nidcd.nih.gov/health/ hearing/sudden.htm 3. Information for Healthcare Professionals: Sildenafil, vardenafil & tadalafil. http://www.fda.gov/cder/drug/ InfoSheets/HCP/ED_HCP.htm

Post-marketing reports
Recently, the US Food and Drug Administration (FDA) warned of a reasonably plausible temporal relationship of sudden sensorineural hearing loss (SSHL) with the use of sildenafil, tadalafil and vardenafil. This warning was based on 29 post-marketing cases that occurred with patients on sildenafil, tadalafil and vardenafil. Of these 29 reports, sildenafil accounted for 19 of these cases, while vardenafil and tadalafil each accounted for five of them. In approximately one-third of the cases, the hearing loss was temporary, with majority of the cases reporting onset of SSHL within 24 hours of PDE5 inhibitors use. In some reports, the sudden loss or decrease in hearing was accompanied by vestibular symptoms such as tinnitus, vertigo, and dizziness.

Mechanism of SSHL
According to the National Institute on Deafness and Other Communication Disorders (NIDCD), SSHL, more commonly known as sudden deafness, is a rapid loss of hearing
continued from Page 4 Clozapine-induced gastrointestinal hypomotility

i) Untreated bowel obstruction/pseudoobstruction leading to distension, necrosis, perforation, or sepsis. ii) Aspiration from inhalation of feculent vomitus or dysphagia. iii) Faecal stasis leading to infection.

Avoid prescribing concomitant medicines which may cause constipation Regular screening for change in bowel habit during the first four months of treatment which is thought to be the higher-risk period

Conclusion of study
Even though it is known that clozapine can affect the entire digestive system causing oesophageal to rectal hypomotility, the authors emphasized the need to prevent and manage CIGH-related constipation as it can result in bowel obstruction, ischaemia and necrosis, perforation, and aspiration pneumonia. Suggestions for prevention include: Take gastrointestinal history and perform abdominal examination Treat pre-existing constipation before starting clozapine treatment Inform patients about the risks of constipation and provide them with information regarding diet, fluid intake, and exercise

Local situation
There are three brands of clozapine registered in Singapore Clozaril (Novartis), Clozapine (Delfi), Clozapin Hexal (Novem Healthcare), and they are indicated for the management of treatment-resistant schizophrenia. The package inserts of all three products carry precautionary warnings of constipation and paralytic ileus, with Clozaril and Clozapin Hexal mentioning the association of clozapine with intestinal obstruction and faecal impaction, which on rare occasions have proven fatal. HSA has not received any local report pertaining to clozapine and impairment of intestinal peristalsis.
Reference 1. J Clin Psychiatry. 2008 April 29;e1-e10

Adverse Drug Reaction News July 2008 Vol.10 No.2

Updates on the mycophenolate group of drugs

here are currently two types of mycophenolate preparations available in Singapore mycophenolate mofetil (MMF) (Cellcept, Roche) and mycophenolic acid (MPA) as sodium salt (Myfortic, Novartis). MMF is approved for use in combination with ciclosporin and corticosteroids for the prophylaxis of acute transplant rejection in adults receiving allogenic renal, cardiac or hepatic transplants while MPA is approved for use in combination with ciclosporin microemulsion and corticosteroids for the prophylaxis of acute transplant rejection in patients receiving allogenic renal transplants.

A) Teratogenic risks associated mycophenolate group of drugs

with

Based on the publication by Sifontis et al1, post-marketing data from the US National Transplant Pregnancy Registry (NTPR), and MMF worldwide adverse event reporting, use of MMF during pregnancy is associated with an increased risk of first trimester pregnancy loss and an increased risk of congenital malformations. External ear and other facial abnormalities including cleft lip and palate, and anomalies of the distal limbs, heart, oesophagus, and kidney were the main congenital malformations observed. In December 2006, the NTPR published data about the pregnancy outcomes of 24 female transplant patients exposed to MMFcontaining regimens. A total of 33 pregnancies were reported by these patients to the registry, of which there were 15 spontaneous abortions (45%). Of the 18 live-born infants, four had structural malformations (22%). Three of the four of these structural malformations include microtia.2 In post-marketing data collected worldwide from 1995 to 2007, of the 77 women exposed to systemic MMF during pregnancy, 25 had spontaneous abortions and 14 had a malformed infant or foetus. Six of these 14 malformed offsprings had ear abnormalities. As these post-marketing data were reported voluntarily, it was not always possible to reliably estimate the frequency of any particular adverse outcomes. Similar structural malformations have been observed in preclinical animal reproductive toxicology studies.

PML cases reported with mycophenolate group of drugs


PML has been described in transplant patients involving different immunosuppressant medicines. Seventy-five percent of all the PML cases reported in transplant recipients presented subacutely: haemiparesis, apathy, confusion, cognitive deficiencies, and ataxia were the most frequently presented features. Roche has confirmed that in the Roche worldwide adverse event reporting system, there are currently 17 cases of PML that are potentially associated with MMF . To date, Novartis global safety database for MPA has no cases of PML.

Conclusion
In view that MMF is converted to MPA following oral or intravenous administration, both drugs would be deemed to carry the same potential risks for teratogenicity and PML. The local package inserts of Cellcept and Myfortic have been amended to include the updated safety information on teratogenic risks and PML associated with the use of these products. Roche and Norvartis have separately issued Dear Healthcare Professional Letters to alert healthcare professionals about the labelling update regarding the teratogenic risks with Cellcept. The letters also reiterated that these drugs are not recommended in pregnancy unless the benefit outweighs the potential risk to the foetus. Roche has updated the local Cellcept package inserts with information on PML and issued a Dear Healthcare Professional Letter to provide more information about this matter. The product insert of Myfortic is in the process of being updated with safety information on PML. Healthcare professionals are advised to consider PML in the differential diagnosis of any transplant recipient who develops neurological symptoms. Consideration should also be given to reducing the amount of immunosuppression if a patient develops PML whilst balancing against the possible risk of graft rejection.
References 1. Transplantation Dec 2006;82:1698-1702 2. FDA Information for Healthcare Professionals. http://www.fda.gov/cder/drug/InfoSheets/HCP/ mycophelolateHCP .htm 3. Communication About an Ongoing Safety Review of CellCept and Myfortic. http://www.fda.gov/cder/drug/early_comm/mycophenolate.htm

B) Post-marketing reports of progressive multifocal leukoencephalopathy


The US Food and Drug Administration recently issued a class-label request to all US manufacturers of marketed mycophenolate group of drugs with respect to the risk of progressive multifocal leukoencephalopathy (PML).

Background information on PML


PML is a rare, progressive, demyelinating disease of the central nervous system (CNS) that usually leads to death or severe disability.3 PML is caused by the reactivation of the JC virus, a polyomavirus that resides in latent form in 70%-90% of the adult population worldwide. JC virus usually remains latent, typically only causing PML in immunocompromised patients. The factors leading to activation of the latent infection are not fully understood although abnormalities in T-cells have been described as important for reactivation of JC virus and PML. Patients usually present with focal CNS abnormalities and radiographic evidence of white matter disease without mass effect.

July 2008 Vol.10 No.2 Adverse Drug Reaction News

Package insert amendments reflecting safety issues


SA has approved the following package insert changes due to safety updates from January 2008 to May 2008. 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: 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).

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11 12 13 14

1 2 3 4

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Abacavir (Ziagen, GSK) Special warning: Carriage of HLA-B*5701 allele is associated with increased risk of hypersensitivity to abacavir. Screening for allele carrier should be performed in all HIV-infected patients before initiating treatment. Not to be used in patients carrying HLA-B*5701 allele. Non-carriers can still develop a severe or fatal hypersensitivity reaction. Activated charcoal (Charcodote, IDS) Interaction: Not for diabetics unless recommended by a physician. Atovaquone, proguanil (Malarone, GSK) Interaction: Proguanil may potentiate the anticoagulant effect of all coumarin based anticoagulants. ADRs: Vasculitis & cholestasis. Budesonide (Pulmicort, AstraZeneca) Special warnings: Caution in patients with risk of impaired adrenal function, severely compromised liver function, requiring high dose emergency corticosteroid therapy, on prolonged treatment at the highest recommended dose or patients on concomitant CYP3A-metabolised medication. Consider additional systemic glucocorticosteroid cover for these patients during stress, severe asthma attack or elective surgery. Patients may suffer from lassitude & depression when switching from oral corticosteroid to Pulmicort. Interaction: Itraconazole increases systemic exposure to budesonide. ADRs: Cataracts & glaucoma. Cefoperazone (Cefobid, Pfizer) Special warnings: Monitor for organ system dysfunction (renal, hepatic & haematopoietic) during extended therapy with Cefobid particularly in neonates & infants. Clostridium difficile associated diarrhea (CDAD) reported, occurring over two months after administration & ranging from mild diarrhoea to fatal colitis. Darunavir (Prezista, J&J) Special warnings: A history of sulphonamide allergy was not shown (in clinical studies) to be related to incidence and severity of rash. Caution in severe hepatic impairment. Interactions: 1) Medicinal products that affect CYP3A activity may affect the clearance & plasma concentrations of darunavir. 2) Digoxin & pravastatin - titrate digoxin & pravastatin from the lowest dose upwards; 3) Carbamazepine (CBZ) - reduce CBZ 25% to 50% & observe for CBZ-related side effects; 4) Methadone - monitor patient during maintenance therapy; 5) Ethinylestradiol & norethindrone - consider non-hormonal contraceptives when using hormonal contraceptive; 6) Rifabutin - reduce dose of rifabutin by 75% of usual dose of 300mg/day & increase monitoring for rifabutin-related adverse events. Deferasirox (Exjade, Novartis) Special warnings: 1) Elevations of transaminases (>10x ULN) is suggestive of hepatitis. Reports of hepatic failure mostly involved those with significant co-morbidities including liver cirrhosis & multi-organ failure; some with fatal outcomes; 2) Upper GI ulceration & haemorrhage (also in children & adolescents). Caution when in combination with anticoagulants; 3) Inappropriately high doses given in patients with a low iron burden or with slightly elevated serum ferritin levels may increase toxicity of Exjade. Interactions: CYP3A4 substrates e.g. ciclosporin, simvastatin, hormonal contraceptive agents. A decrease of midazolam exposure by 17% observed. Increased risk of GI irritation with NSAIDs & corticosteroids. ADRs: Optic neuritis, oesophagitis, renal tubulopathy (Fanconis syndrome), hepatic failure. Desferrioxamine (Desferal, Novartis) Special warning: Rare cases (some fatal) of mucormycosis reported. ADR: Lung infiltration. Diclofenac (Voltaren emulgel, Novartis) Contraindications: Hypersensitivity to diclofenac usually manifests as asthma, respiratory problems, rashes, urticaria, swelling of the face & tongue, runny nose. Special precautions: Avoid application of gel for long periods of time over large areas of skin. ADRs: Serious skin rash with blisters, urticaria, wheezing, shortness of breath, asthma, swelling of the face, lips, tongue & throat.

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Domperidone (Motilium, J&J) ADRs: Anaphylactic shock, angioneurotic oedema, agitation, nervousness, convulsion, somnolence, headache, pruritus, rash, abnormal liver function test. Very rare: Convulsion, agitation, somnolence (primarily reported in infants & children). Epoprostenol (Flolan, GSK) Warning: Increased risk for haemorrhagic complications particularly for patients with other risk factors for bleeding. Interaction: Patients on digoxin may show transient elevations of digoxin concentrations after initiation of therapy with Flolan, may be clinically significant in patients prone to digoxin toxicity. ADR: Bleeding at various sites. Estradiol (Estrofem, Novo Nordisk) Special warning: Safety of added progestagens have not been studied for estradiol doses >2mg. ADRs: Venous thromboembolism, oestrogen-dependent neoplasms. Estradiol, cyproterone (Climen, Schering) Special warning: In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. ADRs: Erythema nodosum, urticaria, hirsutism, acne. Estradiol, dydrogesterone (Femoston, Solvay Pharma) Contraindications: Known or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer), undiagnosed genital bleeding, untreated endometrial hyperplasia, angina, myocardial infarction, porphyria, known or suspected pregnancy in non-postmenopausal women. Warnings & special precautions in patients with: 1) risk factors for estrogen dependent tumours, cholelithiasis or a history of endometrial hyperplasia; 2) deterioration in liver function; 3) fluid retention & cardiac/renal dysfunction; 4) terminal renal insufficiency; 5) pre-existing hypertriglyceridemia in women; 6) rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption; 7) perimenopausal phase. Circulating total thyroid hormone also increased. Interactions: Phenobarbital, rifabutin, ritonavir, nelfinavir, St. Johns Wort. ADRs: Breast pain, pelvic pain, estrogen dependent neoplasms e.g. endometrial cancer, nervousness, venous thromboembolism, gall bladder disease, back pain, alterations in liver function, haemolytic anaemia, myocardial infarction, stroke, vascular purpura, angioedema, probable dementia. Gestodene, ethinyl estradiol (Minulet, Wyeth) Contraindications: Hereditary or acquired thrombophilias, headache with focal neurological symptoms such as aura, undiagnosed vaginal bleeding. Special warnings: Discontinue four weeks prior to & for two weeks after elective surgery with increased risk of thrombosis. May increase the risk of transient ischaemic attack. Precaution: Minority of women will have adverse lipid changes while taking OCs. Consider nonhormonal contraception in women with uncontrolled dyslipidaemias. Elevations of plasma triglycerides may lead to other complications besides pancreatitis. Interaction: Ethinyl estradiol may induce hepatic drug conjugation & plasma/tissue concentrations of lamotrigine may be decreased. ADRs: Hepatic adenomas, hepatocellular carcinomas. Heparin (DBL Heparin, Hospira) Precaution: Heparininduced thrombocytopenia (HIT) & heparin-induced thrombocytopenia & thrombosis (HITT) can occur up to several weeks after discontinuation of heparin therapy. Patients presenting with thrombocytopenia or thrombosis after discontinuation of heparin should be evaluated for HIT & HITT. Iodixanol (Visipaque, GE healthcare) & Iohexol (Omnipaque, GE healthcare) Special warning: No evidence that haemodialysis protects patients with impaired renal function from contrast media induced nephropathy. Patients on haemodialysis may receive Visipaque for radiological procedures. ADRs: Dyspnoea, non-cardiogenic pulmonary oedema, cough. Itraconazole (Sporanox, J&J) Contraindication: Concurrent use with quinidine. Special warning: Transient or permanent hearing loss reported. Hearing loss usually resolves when treatment is stopped, but can persist in some. Interaction: Fluticasone - monitor side effect & reduce dose if necessary. Lamotrigine (Lamictal, GSK) Warnings & precautions: Patients with epilepsy have an elevated risk for suicidality. Patients with a history of suicidal behaviour or thoughts, young adults, & those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, may be at a greater risk of suicidal thoughts or suicide attempts, & should receive careful monitoring during treatment. Interactions: Lopinavir/ritonavir.

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Lapatinib (Tykerb, GSK) Precaution: Hepatotoxicity has occurred (rarely severe). Monitor liver function before initiation of treatment & monthly thereafter. Discontinue therapy if changes in liver function are severe & patients should not be retreated. Lidocaine (Xylocaine inj, AstraZeneca) Precautions: Treat hypotension due to epidural anaesthesia promptly with IV sympathomimetic & repeated as necessary. Xylocaine injection is probably porphyrinogenic. ADRs: CV toxicity is generally preceded by signs of CNS toxicity, unless the patient is receiving general anaesthetics or is heavily sedated with drugs such as a benzodiazepine or barbiturate. In children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during general anaesthesia. Meropenem (Meronem, AstraZeneca) Special warning: May reduce serum valproic acid levels leading to subtherapeutic levels. ADR: Haemolytic anaemia. Mycophenolate mofetil (Cellcept, Roche) Warnings & precautions: Progressive multifocal leukoencephalopathy (sometimes fatal) reported. Interaction: Ciclosporin, rifampicin, combination of norfloxacin & metronidazole, sevelamer. ADRs: Decrease in renal function, elevated serum creatinine, metabolic or respiratory acidosis, elevated LFTs, actinic keratosis, elevated PTH, congenital ear malformations. Olanzapine (Zyprexa, Eli Lilly) Special warnings: Undesirable alterations in lipids, hepatitis, cholestatic or mixed liver injury have been observed. ADRs: Fasting borderline to high total cholesterol/triglycerides/glucose, glycosuria, pulmonary embolism, deep vein thrombosis, hyperglycaemia, jaundice, alopecia, increased alkaline phosphatase, increased total bilirubin. Phenytoin (Phenytoin inj, Hospira) Interaction: Capecitabine or metabolite fluorouracil reported to increase phenytoin plasma concentrations. Serum levels of phenytoin above optimal range may produce encephalopathy, confusional states (delirium psychosis), or rarely irreversible cerebellar dysfunction. Ropivacaine (Naropin, AstraZeneca) Precautions: Naropin is possibly porphyrinogenic. ADRs: Anaphylactoid reactions, angioneurotic oedema & urticaria. Total spinal block may occur if an epidural dose is inadvertently administered intrathecally, or if a too large intrathecal dose is administered. Bradycardia, headache, vomiting, urinary retention, hypoaesthesia, syncope, dyspnoea, hypothermia are more frequent after spinal anaesthesia. Sodium polystyrene sulfonate (pms-Sodium polystyrene sulfonate, IDS) Interactions: May bind with magnesium or calcium found in nonsystemic antacids & laxatives, preventing neutralization of bicarbonate ions & leading to systemic alkalosis that may be severe. Concurrent use not recommended. Risk may be less with rectal administration. May reduce potassium concentrations by replacing potassium with sodium & fluid retention may occur. Sotalol (pms-Sotalol, IDS) Precaution: If vagal dominance occurs during use of pms-Sotalol with anaesthetic agents that depress the myocardium, it may be corrected with atropine. Interaction: Concomitant use with calcium blocking drugs may lead to hypotension. ADRs: Colon problem, extremity/back/localized pain, perspiration, altered consciousness, appetite disorder, stroke, genitourinary disorder, infection, pulmonary/ upper respiratory tract problem, asthma, weight change. Sultamicillin (Unasyn, Pfizer) Special warning: Clostridium difficile associated diarrhoea reported, ranging from mild diarrhea to fatal colitis, & may occur over two months after administration. Sumatriptan (Imigran, GSK) Warnings & precautions: Rare cases of patients with serotonin syndrome reported following use of selective serotonin reuptake inhibitors (SSRIs) & sumatriptan. Serotonin syndrome has also been reported following concomitant treatment with triptans & serotonin noradrenaline reuptake inhibitors (SNRIs). Concomitant administration of any triptan/5-HT1 agonist with sumatriptan is not recommended. Overuse of acute migraine treatments has been associated with the exacerbation of headache in susceptible patients & withdrawal of treatment may be necessary. ADRs: Sensory disturbance including paraesthesia & hypoaesthesia, dyspnoea, sensations of cold, angina. Telbivudine (Sebivo, Novartis) Special warning: Increased risk of developing peripheral neuropathy observed with combination use of telbivudine & pegylated interferon alfa-2a. ADR: Peripheral neuropathy. Zoledronic acid (Zometa, Novartis) Do not mix with calcium or other divalent cation-containing infusion solutions, e.g. Lactated Ringers solution. ADRs: Anaphylactic reaction/shock, urticaria.

Adverse Drug Reaction News July 2008 Vol.10 No.2

Varenicline (Champix) & neuropsychiatric adverse events


recently approved a patient medication guide designed to highlight important safety information to patients who are prescribed varenicline. Similarly, Health Canada has recently revised the Canadian Product Monograph of varenicline to include these post-marketing neuropsychiatric adverse events. In Europe, the European Medicines Agency has reviewed the case reports of suicidal ideation or attempted suicide while taking varenicline and have requested that the product information of Champix to include warnings of behavioural changes noted in post-marketing reports.

HSAs advisory
Champix was recently launched locally in April 2008 and HSA has not received any local adverse reaction reports. In view of the nature of adverse events observed overseas, prescribers are advised to carefully assess patients suitability (e.g. medical history, lifestyle, occupation) for treatment with Champix before prescribing this medication to them. As a risk management strategy to enhance the safe use of Champix, HSA is working with Pfizer (Singapore) to develop a patient medication guide for patients taking the medication with the aim of providing information on possible adverse reactions associated its use so that patients can identify these reactions and seek medical help if they experience these effects. In line with this risk management strategy, prescribers are strongly encouraged to discuss the potential neuropsychiatric adverse effects associated with Champix or smoking cessation with their patients. HSA continues to monitor the overseas and local situation closely and requests that healthcare professionals report any adverse reactions suspected to be associated with Champix to the Pharmacovigilance Unit.
References 1. JAMA 2006 Jul;296(1):56-63. 2. Health Canadas Advisory to Healthcare Professionals on Champix (varenicline tartrate), 3 June 2008. http://www.hc-sc.gc.ca/dhpmps/medeff/advisories-avis/prof/_2008/champix_hpc-cps eng.php 3. FDA Press Release: Early Communication About an Ongoing Safety Review: Varenicline (marketed as Chantix), 20 November 2007. 4. FDA News: Early Communication About an Ongoing Safety Review Varenicline (marketed as Chantix), 1 February 2008. http://www.fda.gov/cder/drug/early_comm/varenicline.htm 5. FDA Public Health Advisory: Important Information on Chantix (varenicline), 1 February 2008. http://www.fda.gov/cder/drug/advisory/varenicline.htm 6. FDA Alert: Information for Healthcare Professionals Varenicline (marketed as Chantix), 1 February 2008. http://www.fda.gov/cder/drug/infopage/varenicline/default.htm

arenicline (Champix, Pfizer), a partial nicotinic acetylcholine receptor agonist, is licensed as an aid to smoking cessation treatment and was registered in Singapore in August 2007.

Post-marketing neuropsychiatric adverse events


Since the drug was approved in May 2006 in the United States, the US Food and Drug Administration (FDA) had received postmarketing adverse event reports describing serious neuropsychiatric symptoms, which include changes in behaviour, agitation, depressed mood, suicidal ideation, and cases of attempted and completed suicide associated with the use of varenicline. FDAs preliminary assessment of these adverse drug reaction reports (ADRs) revealed that in many of the cases, the neuropsychiatric symptoms occurred within days to weeks after the initiation of varenicline therapy. However, the causal role of varenicline in these cases remained unclear as smoking cessation (with or without treatment) is associated with nicotine withdrawal symptoms and has been linked with the exacerbation of underlying psychiatric illness. Nevertheless, not all patients described in FDAs cases had preexisting psychiatric illness and not all had discontinued smoking. Since the introduction of Champix in Canada, Health Canada has received a total of 226 cases of neuropsychiatric adverse events over the period between April 2007 and April 2008. The types of reports include events of depressed mood, agitation, hostility, changes in behaviour, suicidal ideation and suicide, as well as worsening of pre-existing psychiatric illness regardless of whether it was previously diagnosed.

International regulatory actions


The US FDA has recently included these serious post-marketing neuropsychiatric symptoms in the warnings and precautions section of vareniclines prescribing information. Additionally, the FDA has

Editor-in-Chief Ms Chan Cheng Leng, BSc (Pharm) Hons Executive Editor Ms Ang Pei San, BSc (Pharm) Editorial Board Clinical Prof. Goh Chee Leok Prof. Edmund Lee Joo Deoon Clinical Prof. Chng Hiok Hee Clinical A/Prof. Gilbert Lau Kwang Fatt Dr Lee Kheng Hock

Staff Editors Mr Choong Chih Tzer, BPharm Ms Christine Ho, BSc (Pharm) Hons Dr Yvonne Koh, BSc (Pharm) Hons, PhD Ms Adena Lim, BSc (Pharm) Hons, MPharm Ms Belinda Tan, BSc (Pharm) Ms Liesbet Tan, BSc (Pharm) Hons Ms Tan Wei Chuen, BSc (Pharm)

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 2008 Health Sciences Authority of Singapore. All Rights Reserved.

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