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ADVERSE REACTION
NEWSLETTER 1999:2
This newsletter contains information reported to information reported does not necessarily reflect the official views, decisions or policies of the International Drug Monitoring; however, the NATIONALLY CIRCULATED
mainly associated with the dihydropyridine calcium channelblockers (CCBs) INFORMATION
Brunet L, Miranda J, Farré M, Berini L, Mendieta C.
Gingival enlargement induced by drugs. Drug Safety Australia
Lawrence D, Weart W, Laro JJ, Neville BW. Calciumchannel blocker-induced gingival hyperplasia: case Depression with inteferon
report and review of this iatrogenic disease. J Fam Interferon alfa (2a-Roferon-A and 2b-Intron A) is used in a variety of conditions including leukaemias, some carcinomas, multiple myeloma, non-Hodgkin's lymphoma, malignant overgrowth. Ann Pharmacother 1997; 31: 935.
melanoma and more recently, hepatitis B and C. The mostcommonly reported adverse reactions in association with A comparison of dicloxacillin with flucloxacillin
interferon alfa are flu-like symptoms such as fever, fatigue, Early in 1997 dicloxacillin was introduced onto the myalgia, joint pain, and headache. Serious effects Australian market to provide an alternative to flucloxacillin documented include severe hypersensitivity reactions, and in the treatment of staphylococcal infections. haematological, hepatic, cardiovascular and neurological Table below shows the results after the first two calendar effects, particularly at high dose. Psychiatric effects have been described and include depression and suicidal ideation. ADRAC has received 19 reports of depression or suicidal Dicloxacillin versus Flucloxacillin in 1997-98
ideation associated with interferon alfa therapy. Eleven patients had depression alone, four had depression and suicidal ideation or attempt and there were four additional reports of suicidal attempts. Three of the reports of suicidal Renault PF, Hoofnagle JH, Park Y et al. Psychiatric complications of long-term interferon alfa therapy.
The table shows total reports, reports of hepatic reactions including those of cholestasis, reports of renal reactions andan estimate of community usage. Drug-induced gingival overgrowth
Drugs of Current Interest
Gingival overgrowth or enlargement has been reported in 114 of the 128,000 reports contained in the ADRAC database. Those 114 cases are dominated by the presence of five drugs which account for 68% of the reports, as shown Gelatin succinylated (Gelofusine) Trovaflocaxin(Trovan) Table 1: Reports of Gingival overgrowth
It has been estimated that gingival overgrowth occurs inabout 50% of patients taking phenytoin, 25-80% of patientstaking cyclosporin, and 15-20% of patients receivingnifedipine, but severe cases with nifedipine occur in less than1%. ADRAC has received only 2 reports each with diltiazemand verapamil so it is possible that gingival overgrowth is In both cases, symptoms disappeared after bupropiontherapy was stopped.
Canadian Adverse Drug Reaction Newsletter, Vol. 9, No 2,April 1999 Bupropion is a new pharmacological alternative for patientswho want to quit smoking. It can be used alone or incombination with transdermal nicotine patches; the Bupropion (Zyban®), sustained-release tablets):
recommended duration of therapy is 7 to 12 weeks.
reported adverse reactions
Bupropion is, however, associated with certain adverse Bupropion (Zyban®), has been available in Canada since reactions and precautions, which must be observed before August 1998. Its use is recommended, in combination with administering it. According to the product monograph, the the introduction of behavioural changes, to help people quit most frequent adverse reactions -- insomnia and dry mouth occur in 31% and 11% of patients respectively. The adverse Sustained-release bupropion is also sold under the name reactions that most often lead to a cessation of bupropion Wellbutrin SR® for the relief of symptoms of depression.
therapy include central nervous system disturbances Between Aug. 18 and Dec. 1, 1998, the Canadian Adverse (especially tremors) and dermatological reactions.
Drug Reaction Monitoring Program (CADRMP) received The combined use of Zyban® and Wellbutrin SR® or any 48 reports of suspected adverse reactions to bupropion taken other drug containing bupropion is contraindicated, since to quit smoking (patients included 15 men, 31 women and the occurrence of convulsions is related to the bupropion 2 people sex unknown; average age 36 [range 27 to 81] years).
In the 48 reports, 144 adverse reactions were noted, the mostfrequent of which were pruritus (9), urticaria (7), edema (7), Tolcapone (TasmarTM)
tremors (6), dizziness (5), insomnia (5) and anxiety (5).
On Nov. 20, 1998, Health Canada suspended the sale of Sixteen of the reports described serious events. tolcapone (TasmarTM), the first approved reversible There is a risk of convulsions associated with taking catechol-O-methyl transferase inhibitor indicated as an bupropion to quit smoking. The CADRMP received 3 adjunct to levodopa-decarboxylase inhibitors in the reports of convulsions in patients taking Zyban®. One of treatment of Parkinson's disease. This action was based on the patients had a history of alcohol dependence and was emerging safety concerns regarding hepatotoxicity and taking 600 mg of Zyban® daily for 15 days before potentially fatal fulminant hepatitis associated with experiencing convulsions. In general, convulsions are associated with the Zyban® dose, the use of the drug in Continued availability of tolcapone through the Special conjunction with other drugs and/or the patient's medical Access Programme (SAP) was organized on a limited and exceptional basis for 1) the safe discontinuation of tolcapone Adverse cardiovascular reactions were also reported. Patients therapy and 2) extraordinary cases involving patients already taking Zyban® experienced palpitations (2), tachycardia (2), receiving tolcapone therapy for whom, in the opinion of angina (1) and myocardial infarction (1). In the last case, a their physician, the benefits of continued treatment 52-year-old man died following myocardial infarction. He outweighed the risks. As of January 1999, SAP has received had a history of alcohol dependence and serious coronary artery disease. He had taken 300 mg/d (higher initial dosethan that recommended by the manufacturer) for 2 days See also reference from Portugal below.
before he died. The patient was not taking other drugs.
Finally, extreme caution must be observed beforeadministering Zyban® in conjunction with certain otherdrugs. Two suspected cases of adverse reactions to abupropion-paroxetine combination were reported. Nausea,vomiting, visual hallucinations and dizziness were reported2 days after bupropion therapy was started in a 48-year-oldwoman who had also been taking paroxetine and estrogenreplacement therapy for about a year. In the other case, a27-year-old man experienced tachycardia, anxiety, tremors,mydriasis, blurred vision and photophobia while takingcombination therapy with bupropion and paroxetine(duration of therapy unknown). He was also takingclobazam and trazodone.
syndrome, and multiorgan hypersensitivity with fulminantliver failure resulting in death. Three published incidence studies have investigated thefrequency and seriousness of cutaneous or haematological Pulmonary oedema after anaesthesia with
reactions with carbamazepine. Rash was found to occur in sevoflurane
around 10% of patients. Most occurred in the first 2 weeks Two cases of lung oedema after anaesthesia with sevo- of treatment and were mild. In each of 2 studies one patient flurane have been reported in Denmark. The first case refers developed a serious reaction - erythema multiforme and to a 15 years-old boy who was operated and hence put under anaesthesia with sevoflurane. Approximately 100 minutes Blood dyscrasias (moderate and severe leucopenia and 1 case after awakening the patient was short of breath and pale.
of thrombocytopenia) occurred with an incidence of 2% with Tests showed that he had a pulmonary oedema. He was mild changes detected in up to 30% of patients. Most cases treated with furosemide and recovered. The second case was developed within the first month of therapy. To reduce the risk of serious adverse effects, a blood screenand physical examination should be conducted during thefirst 4-6 weeks of therapy, and repeated where there areclinical reasons for concern. Carbamazepine should be New Zealand
withdrawn or the dose reduced if the white cell count falls Information for Health Professionals, March 1999 below 3000/mm3 or the neutrophil count below1000/mm3.
Tamoxifen and venous thromboembolism
Evidence now strongly supports the suspicion that
tamoxifen increases the risk of venous thromboembolism
(VTE). This observation is consistent with the fact that Clozapine and Hyperglycaemia
Hyperglycaemia, sometimes leading to ketoacidosis or One study, based on a sub-population of 10,000 women glycosuria, has been reported in association with clozapine.
with breast cancer, identified 25 cases of VTE with an In some cases the condition has been of new onset, and in adequately confirmed diagnosis, and calculated a relative risk others exacerbation of pre-existing diabetes mellitus has of VTE with tamoxifen use of 7.1 (95% CI 1.5-33). Another occurred. Hyperglycaemia appears to be of early onset (2 study used data from a Scottish trial of tamoxifen in the weeks to 3 months after initiation of clozapine) and to occur treatment of breast cancer in 1312 women. In this study the without predisposing factors. Clozapine-induced risk of VTE in users compared with non-users was higher hyperglycaemia may be serious leading to coma, but it is by a factor of 2.50 (95% CI 1.11-5.56). In addition, the reversible on discontinuation of clozapine. In some cases American Breast Cancer Prevention Study involving 13,388 continuation of clozapine is possible by controlling serum women found the rate of pulmonary embolism among the glucose levels with the use of hypoglycaemic agents. This tamoxifen group to be three times that in recipients of approach may be useful in refractory schizophrenia placebo (relative risk 3.01; 95% CI 1.15-9.27).
responsive to clozapine. In those with diabetes mellitus, These results do not greatly affect the benefit-risk assessment glucose monitoring should be conducted in conjunction for tamoxifen in the treatment of breast cancer. However, with the obligatory haematological monitoring. All patients women with an elevated risk of breast cancer should not be should be advised to report altered consciousness, polyuria treated with tamoxifen as a preventive measure (an unapproved indication) without an assessment of thepersonal risk factors for VTE.
Potentially serious adverse effects of
carbamazepine: Blood dyscrasias and skin rash
The Centre for Adverse Reactions Monitoring recently
received 3 reports of serious adverse reactions with
carbamazepine: severe cholestatic jaundice, Stevens Johnson
between echocardiographic valvular abnormalities of the Adverse respiratory reactions to long-acting beta-
aortic and mitral valves and treatment with dexfenfluramine agonists
There have been occasional reports of deterioration in Evidence now favours a causal connection between asthma control, and even respiratory arrest, following the dexfenfluramine (Adifax) and fenfluramine (Ponderax) commencement of a long-acting beta-agonist (Serevent, when used alone and the development of heart valve Foradil, Oxis). Several mechanisms need to be considered to abnormalities on echocardiography. Both medicines were explain such reactions including paradoxical bronchospasm, withdrawn in 1997. The incidence, severity and likelihood of increased bronchial responsiveness and tolerance, but none progression of the valve abnormalities is poorly defined. of these has been identified in prospective studies.
The risk appears to be minimal with use < 3 months; most Practitioners using long-acting beta-agonists need to be abnormalities were reported as mild. The risk is presently aware of the possibility of such sporadic adverse reactions.
not quantifiable, but appears to increase with duration of Careful monitoring of patients is advised, particularly during use. The major consequence of concern is the development of endocarditis in the damaged valve. As a large number ofpatients have been exposed to these medications sincePonderax first became available in 1966, and the Adverse reactions of current concern
development of endocarditis is preventable, guidelines have A list of adverse reactions of current concern was first been drawn up in consultation with the Cardiac Society of There are two reasons for this list.
Patients who took dexfenfluramine or fenfluramine To raise the level of awareness of these adverse for < 3 months need not be examined.
Those who took either or both agents for 3 months To evoke reports so that more information may be should be examined by a GP for evidence of a heart murmur or other abnormal cardiac signs.
If a murmur or other abnormality is found, or the Medicine Adverse reactions Date of addition
heart cannot be examined due to obesity, refer the patient to a cardiologist for echocardiography.
Carbamazepine skin and haematological December 1998 Until a cardiologist is able to advise on the risk of endocarditis, appropriate prophylactic antibiotics should be given to patients requiring dental or other surgical procedures that put them at risk of Practitioners should send an adverse reaction report for valve abnormalities requiring antibiotic prophylaxis in patients exposed to these medicines to the Centre for The medicines currently being monitored are:
Medicine Indications/Action
contraceptives venous thromboembolism February 1996 Eformoterol Potent long-acting b2-agonist Levonorgestrelintrauterine system Progestogen-releasing intrauterine Valvular abnormalities with dexfenfluramine and
fenfluramine
Montelukast Antiasthmatic/leukotriene inhibitor In September 1997 dexfenfluramine (Adifax ®) andfenfluramine (Ponderax ®) were withdrawn from the marketworld-wide because of a series of cases of valvularabnormalities in individuals who had taken one of theseagents in combination with phentermine. More recently,studies have been published demonstrating an association in August 1997 for the adjuvant treatment of Parkinson's disease, in combination with levodopa/ benserazide or levodopa/carbidopa, especially in patients with motor fluctuations (end-of-dose phenome-non) who cannot be In October 1998, a total of 9 cases of severe hepatic dysfunction (two of which were fatal) had been reported in100.000 patients treated until then. The EMEA consideredthat tolcapone could no longer be safely used in clinical Portugal
practice, given the inability to prevent the development of Boletim de FarmacoVigiláncia Vol 2, No 2, 1998 severe (and even fatal) adverse hepatic reactions by frequentliver function monitoring, and the possible occurrence ofneuroleptic malignant-like syndrome and rhabdomiolysis, Minocycline - risk of hepatotoxicity and
which had meanwhile also been reported. The risk-benefit lupus
ratio of Tolcapone was therefore considered to be Minocycline is a broad-spectrum semi-synthetic tetracycline, unfavourable for the authorised indication. It has not been widely used as a first line antibiotic in the treatment of acne.
possible to restrict its indi-cations in such a way as to allow Several advantages over other tetracyclines are usually ascribed to minocycline, such as faster absorption; absorption not The INFARMED, similarly to the authorities from the other member states, took the necessary measures to intake frequency due to longer half-life; fewer gastrointestinal side-effects; possible efficacy in cases of resistence totetracyclines in general.
Terfenadine 120 mg and association with
In 1996, given the suspicion of serious adverse reactions pseudoephedrine
- hepatotoxicity and systemic lupus erythematous (SLE) Terfenadine is a non-sedative, H1-receptor-specific anti- with higher frequency than with other tetracyclines, the safety histamine. It is known since it was first marketed that it has profile of minocycline was re-evaluated in the UnitedKingdom. Thus, adverse hepatic reactions and lupus-like an arrhythmogenic potential when used simultaneouslywith certain antifungal agents (imidazoles, such as ketoco- reactions associated with minocycline are rare but can occur nazole and itraconazole), or antibiotics (macrolides, like with higher frequency than with other tetracyclines. On the erythromycin or clarithromycin), or still in patients with liver other hand, with tetracyclines in general these reactions occurwithin a period of 6 months from the beginning of therapy and/or renal failure.
These conditions are associated with an inhibition of (81% in the first 2 weeks), whereas with minocycline only terfenadine's main metabolic pathway (isoenzyme CYP3A4 one half of the cases occurred in the first 6 months.
of cytochrome P450) which, under normal conditions, Based on the evaluation made it was decided to limit the useof minocycline to 6 month treatments. These should only be allows terfenadine's levels to remain relatively low. A rise inits plasma concentration may lead to a prolongation of the continued if a satisfactory response of acne is observed and QT interval with an attendant risk of dysrhythmia.
if liver function tests remain within normal limits.
Terfenadine's safety profile was re-assessed in the EU sub- sequently to the enforcement of article 12 of Directive75/319/CE (see Boletim de Farmacovigilância, vol. 1, nº 2).
Elias E - Minocycline induced autoimmune Consequently, two decisions were made concerning hepatitis and systemic lupus erythematosus-like medicines containing this active substance.
Ferner RE, Moss C - Minocycline for acne. First On the one hand, marketing authorisations for terfenadinein 120 mg-strength tablets and in any strength in association line antibacterial treatment of acne should be with pseudoephedrine have been withdrawn.
tetracycline or oxytetracycline. BMJ 1996; 312: 138.
On the other hand, marketing authorisations are kept validfor 60 mg tablets, as well as for the 6 mg/ml oral suspen- Tolcapone: Marketing suspended
sions. Their SPCs (Summary of Product Characteristics), Tolcapone (Tasmar ® ) is a COMT (Cathecol-O- however, were changed in accordance with the EMEA's Methyltransfe rase) inhibitor both at peripheral and central advice, emphasising the risk of cardiotoxicity in the levels. It has been authorised by the European Commission Contraindications and in the Drug Interactions section.
Sweden
Information from the MPA, Vol 10, No 1, 1999
Nimesulide Adverse Reactions Reported to the
CNF
Nimesulide is a non-steroid anti-inflammatory (NSAID)
Acute renal failure and quinine
sulphonanilide whose mechanism of action is characterised A 57-year-old woman on naproxen and aceclofenac started by selective inhibition of cyclo-oxigenase 2 (COX2).
treatment with quinine 100 mg due to nightly akathisia.
This pharmacodynamic profile is compatible with a lower Two days later she experienced abdominal pain and incidence of adverse GI reactions in comparison with other vomiting. The next day she had diarrhoea, yellow eyeballs NSAIDs, although this has not been clearly demonstrated.
and dark urine. Laboratory tests showed increased level of Some studies show that the incidence of this type of ADRs creatinine, decreasing diuresis, trombocytopenia and mild with nimesulide is similar to that of patients trea-ted with a anaemia. The doctor suspected NSAID induced renal failure control NSAID. Furthermore, there may appear and all drugs were suspended. There was no evidence of endoscopically visible lesions of the gastric mucosa with renal necrosis. She underwent dialysis once. One month nimesulid, and the selectivity of COX2 inhibition may be later her renal function was normalised. A short time after she took quinine 100 mg. A couple of hours later she had The National Pharmacovigilance Centre (CNF) has received, fever, diarrhoea, vomiting and acute renal failure. Between since 1993, 17 ADR reports ascribed to nimesulide. The these two incidences she had had diarrhoea and nausea most frequent ones were skin (5) and liver (4) ADRs. Others when drinking Tonic water containing quinine.
were: peripheral oedema (2), stomatitis (2), paresthesia (1),thrombocytopaenic purpura (1), irritability (1), and hea-daches/ reduced visual acuity (1). No adverse GI reactions Donezepil - possible hepatotoxicity
have been reported. The adverse skin reactions reported Donezepil is a selective acetylcholine inhibitor used for included three cases of rash, one case of treatment of Alzheimers disease. Some of the known urticaria/angioedema, and one case of necrotising fasciitis adverse reactions are: insomnia, diarrhoea, anorexia, which evolved to septicaemia and death. Except for the case syncope, bradycardia and AV-block. The drug was approved of necrotising fasciitis, these ADRs have been previously in Sweden in July 1997. During review of ADR reports , described with the administration of nimesulide. Several several cases of suspected liver reactions was found.
cases of necrotising fasciitis are described in association with According to the manufacturer more than 500 000 patients various NSAIDs, but this association has never been clearly have been treated. 50 patients have had liver or biliary demonstrated. Of the hepatic ADRs reported, two cases reactions. The MPA doesn't think it is motivated to were compatible with Reye's syndrome. They occurred in monitor the liver status continously but asks doctors to children and were both fatal. One case of cholestasis, and investigate possible liver reactions in patients taking another of liver enzyme elevation and coagulopathy were donepezil and to report them to the MPA.
also reported, the latter being fatal. Liver enzyme elevationand acute hepatitis in patients on nimesulide are mentionedin the literature.
In the cases reported to the CNF, all patients were Tinidazole and liver damage
concomitantly medicated with amoxicillin+clavulanate.
In 1997 a 37-year-old man stayed several months in Africa.
Similarly, one of the patients who died of Reye's syndrome He took proguanil and chloroquine for malaria prophylaxis.
had also been given lisine salicylate. Although the reporting When he returned to Europe he received tinidazole and professionals ascribed a causal relationship to nimesulide, possibly also metronidazole due to diarrhoea. A short time one cannot firmly exclude the direct role of the after he was hospitalized due to signs of icterus. Drug amoxicillin+clavulanate association in causing liver damage, induced hepatitis was confirmed by laboratory tests and liver whose occurrence has been described with the use of this biopsy. 1998 the man once more returned from Africa and antibiotic (see Vol.1, n.o 4). On the other hand, it is not received tinidazole for diarrhoea. A week later he noticed known whether there may be an interaction between dark urine, fatigue, weight loss and vomiting. Toxic liver nimesulide and amoxicillin+clavulanate which may damage was suspected but no liver biopsy was taken. In potentiate the hepatic dysfunction induced by any one of Nefazodone - a serious case of fulminant liver
damage
A woman aged 44, with one previous episode of depression
EMEA public statement on Trovan/Trovan IV/
started treatment with nefazodone 200 mg daily. After one Turvel/Turvel IV
month the dose was 400 mg daily. After three months the The European Commission granted marketing dose was decreased to 300 mg daily. The patient didn't authorisations for the whole European Union to Pfizer receive any other medication during that time. After three Limited on 3 July 1998 for Trovan ® (trovafloxacin) and months she expreienced nausea, blurred vision and coldness.
Trovan IV ® (alatrofloxacin) and to Roerig Farmaceutici The symptoms continued and the fatigue increased. When Italiana S.p.A. on 8 July 1998 for Turvel ® (trovafloxacin) her husband saw that she had yellow eyeballs she was and on 3 July 1998 for Turvel IV ® (alatrofloxacin).
submitted to hospital where it was confirmed that she had The Scientific Committee for Proprietary Medicinal Products acute liver damage. The patient's condition rapidly got (CPMP) of the European Medicines Evaluation Agency worse. She was unconscious and put in a respirator. Lab- (EMEA) during its extraordinary meeting on 10 June 1999, tests, anamnesis and course of event pointed towards drug has adopted an Opinion recommending the suspension of induced fulminant liver damage. The patient underwent two the marketing of Trovan/Trovan IV and Turvel/Turvel IV.
liver transplantations but died later on.
This was due to increased concern over 152 documentedreports of cases of serious hepatic events, including 9 caseswhere patients died or required a liver trasplant.
Latanoprost and trichiasis
Two cases of trichiasis in patients treated with latanoprost
for glaucoma has been reported to the Medical Products
Agency. In total, the MPA has received 43 reports for
latanoprost of which 17 concerned eye reactions. Of these 17
reports, 11 referred to longer, darker and more marked
eyelashes.
USA
FDA Talk paper, May 12, 1999
New warning for arthritis drug, Enbrel
Enbrel was approved last November with labeling that says
that it should not be given to patients with sepsis and
should be discontinued if a patient develops a serious
infection.
FDA is advising physicians about new safety concerns
regarding the use of etanercept (Enbrel), a product recently
approved to treat moderate to severe rheumatoid arthritis
(RA). New postmarketing reports indicate that certain
patients receiving Enbrel have developed serious infections,
including sepsis, and that several of these patients have died
from their infections.
DRUG WITHDRAWALS

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