Kwartaalbericht 4e kwartaal 2010 8 november 2010 Contents Voorwoord 3 1. Observations 4 1.1. Bisphosphonates and depressive reactions 4 1.2. Norfloxacin and hypoglycaemia 12 1.3. Inhaled fluticasone and epistaxis 16 1.4. Oxaliplatin and laryngospasm 20 2. Short notes 2.1. 24 Baclofen and constipation 24 3. Publications 25 2 Voorwoord Op 22 september jl. heeft het Europees Parlement een aantal wijzigingen aangenomen die van belang zijn voor de farmacovigilantie in Europa. Sleutelbegrippen waren onder meer: transparantie en de positie van de patiënt. Het is duidelijk dat de patiënt een centrale positie heeft: het gaat er om dat de gebruiker van geneesmiddelen zo veilig mogelijke geneesmiddelen krijgt en toegang heeft tot alle relevante informatie daarover. Vertrouwen is daarbij dus een derde sleutelbegrip. Het melden door patiënten zal in heel Europa gestimuleerd worden. Nederland loopt daarin voorop, zowel in aantal meldingen als in het analyseren van de bijdrage die deze meldingen leveren aan signaaldetectie. De bij dit Kwartaalbericht gevoegde literatuur illustreert dat. Ook voorzien de nieuwe regels erin dat op de bijsluiters wordt aangegeven dat gebruikers bijwerkingen bij het nationale meldcentrum kunnen melden, iets waar Lareb al jaren voor pleit. Ook transparantie is een sleutelbegrip in de nieuwe regelgeving. De Nederlandse meldingen zijn voor iedereen op de website van Lareb zichtbaar en we weten dat zorgverleners daar ook gebruik van maken. De signalen in dit Kwartaalbericht zullen ook op de website zichtbaar gemaakt worden. Bij de verschillende bronnen die Lareb gebruikt bij de analyse van mogelijke signalen ontbreekt het Risk Management Plan. Hoewel het formeel openbaar schijnt te zijn, is het voor ons en anderen niet makkelijk toegankelijk. Wellicht moet hier de transparantie nog verder geïmplementeerd worden, want het is van groot belang dat bekend is welke risico’s van bijwerkingen er mogelijk zijn. Kees van Grootheest directeur Lareb 3 1. Observations 1.1. Bisphosphonates and depressive reactions Introduction Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis [1]. Alendronate (Fosamax®) is indicated for the treatment and prevention of osteoporosis in postmenopausal women, treatment to increase bone mass in men with osteoporosis, treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and who have low bone mineral density, and treatment of Paget’s disease of bone in men and women [2]. Alendronate with colecalciferol (vitamin ® D3) (Fosavance ) is indicated for the treatment of postmenopausal osteoporosis in patients at risk of vitamin D insufficiency [3]. Risedronate (Actonel®) is used for the same indications as alendronate [4]. ® Risedronate with calcium (Actokit ) is indicated for the treatment and prevention of osteoporosis in postmenopausal women [5]. Etidronate with calciumcarbonate (Didrokit®) is indicated for the prevention and treatment of osteoporosis in post-menopausal women and the prevention of corticosteroid induced osteoporosis [6]. ® Ibandronate (Bonviva ) is indicated for the treatment of osteoporosis in postmenopausal women at increased risk of fracture [7]. Pamidronate (Pamipro®) is used intravenously for a different indication than most other bisphosphonates, namely tumour-induced hypercalcaemia, osteolytic lesions in patients with breast cancer related bone metastasis and multiple myeloma stage III [8]. Intravenous pamidronate is also used as APD infusion for the indication osteoporosis. ® Zoledronate (Zometa ) is indicated for prevention of skeletal related events in patients with advanced malignancies involving bone or treatment of tumourinduced hypercalcaemia [9]. The most commonly used bisphosphonate in the Netherlands [10], alendronate ® (Fosamax ), was granted marketing authorization in 1996 [2]. Lareb received several reports of depression, depressed state or mood with the use of the bisphosphonates alendronate, etidronate and pamidronate. Although no reports of depressive reactions were received for other bisphosphonates, we included these in the overview of the literature. According to the DSM-IV criteria [11] depressive disorders can be divided in major depressive disorder, dysthymic disorder and depressive disorder not otherwise specified. The essential feature of a major depressive episode is a period of at least two weeks during which there is either depressed mood or the lost of interest or pleasure in nearly all activities. The individual must also experience four symptoms drawn from a list which includes changes in appetite or weight, sleep, psychomotor activity, decreased energy, feelings of worthlessness or guilt, difficulty thinking, concentrating or making decisions, or recurrent thoughts of death or suicidal ideation or plans or attempts [11]. Depression or depressed mood is not described in the SmPC of alendronate (Fosamax®) [2], alendronate with colecalciferol (Fosavance®) [3], risedronate (Actonel®) [4], risedronate with calcium carbonate (Actokit®) [5], etidronate with ® ® calcium carbonate (Didrokit ) [6], ibandronate (Bonviva ) [7], pamidronate ® ® (Pamipro ) [8] or zoledronate (Zometa ) [9]. 4 Reports On July 22, 2010, the database of the Netherlands Pharmacovigilance Centre Lareb contained 14 reports concerning depression with the use of alendronate, etidronate or pamidronate. Table 1. Reports of depression associated with the use of bisphosphonates Patient, Sex, Age Drug Indication for use Concomitant medication Suspected adverse drug reaction Time to onset, Action with drug outcome A 16425 F, 61 – 70 years alendronate 10 mg daily, osteoporosis spironolactone, furosemide, ipratropium, budesonide depressed state, hoarseness, drowsiness, abdominal discomfort 6 weeks discontinued not reported B 17110 F, 70 years and older alendronate 10 mg daily, unspecified hydrophilic cream depressed state (‘lanette’), calcium carbonate 6 weeks no change not reported beclomethasone depressed state 3 weeks discontinued recovered after one month ranitidine, isradipine, triamterene/ epitizide depressed state 4 years discontinued recovered C 19211 etidronate cyclical use M, 41 – 50 of 400 mg daily during years 14 days followed by 72 days of calcium carbonate, osteoporosis D* 19212 F, 51 – 60 years etidronate cyclical use of 400 mg daily during 14 days followed by 72 days of calcium carbonate, osteoporosis D* 19212 F, 51 – 60 years pamidronate 90 mg per IV, osteoporosis depressed state, agitation quickly after start discontinued recovered E 22487 F, 31 – 40 years alendronate 10 mg daily, osteoporosis fluvoxamine 50 mg 3 times daily drug level decreased, depression aggravated not reported discontinued not reported F 28069 F, 70 years and older alendronate 10 mg daily, osteoporosis depressed state not reported discontinued recovered G 45315 F, 61 – 70 years alendronate 70 mg weekly, osteoporosis depression, gastro-intestinal disorder, bone pain, peripheral oedema, fatigue not reported exactly, gradual onset discontinued recovering H 47307 F, 51 – 60 years alendronate 70 mg weekly, osteoporosis depression, restlessness, emotional lability couple of days discontinued, recovered, positive rechallenge ibuprofen, temazepam diazepam 5 Patient, Sex, Age Drug Indication for use Concomitant medication I 48815 alendronate 70 mg M, 51 – 60 weekly, years unspecified J 65558 F, 70 years and older alendronate with colecalciferol 70 mg/2800 ie weekly, osteopenia K, 104474 F, 61 – 70 years alendronate 70 mg weekly, osteoporosis L 88028 F, 61 – 70 years alendronate 70 mg weekly, osteoporosis diazepam, maprotiline, nitrazepam, vitamin C + garlic pantoprazole, salbutamol M 101865 etidronate cyclical use M, 41 – 50 of 400 mg daily during years 14 days followed by 72 days of calcium carbonate, osteoporosis N 70459 F, 31 – 40 years anastrozole 1 mg, breast cancer, goserelin 3.6 mg in injection, breast cancer, alendronate 70 mg weekly, prevention ibandronate calcium carbonate/ colecalciferol, zolpidem Suspected adverse drug reaction Time to onset, Action with drug outcome depressed state, bone pain, oedema legs, fatigue, allergic reaction not reported discontinued not reported depressed state 5 hours discontinued recovered depressed mood, anxiety not reported discontinued recovered depressed mood month discontinued recovered depressed mood within a day discontinued and replaced by risedronate recovered depressed mood, arthralgia, cough, insomnia, nausea 2 weeks discontinued, recovered, rechallenge only for the anastrozole and goserelin * Patient D appears twice in table 1. See the description of this case below. Patient A uses budesonide as concomitant medication. For this drug depression is listed in the SmPC as a rare adverse drug reaction (incidence 0.1 - 0.01%) [12]. The cases of patient C en D were previously published by Wolffenbuttel &.van der Klauw [13] and also reported to Lareb. Patiënt C is male aged 41 – 50 years who was treated with etidonate for osteoporosis. He had a medical history of chronic obstructive pulmonary disease and had been treated with corticosteroids for a prolonged period. The patient suffered from fatigue, concentration impairment, irritation, spontaneous crying and depressed feelings. The reaction occurred after each cycle of etidronate use and recovered within weeks. Each following time etidronate was used again, the reaction reoccurred. The blood calcium level was within the normal range in this patient. Etidronate was withdrawn and the reaction did not occur again for the following five years. Patient D appears twice in table 1, this case had not been divided into two separate case reports with their own ID-numbers at the time of reporting (1997). Patient D had been treated for osteoporosis with etidronate since she was 50. At the age of 54 changes in her mood, memory impairment and difficulties with concentration occurred. She felt depressed and emotionally drained. The blood calcium level was within the normal range in this patient. After withdrawal of etidronate the patient recovered within two months. Her other medication had not been changed during this period. 6 When the patient was 56 pamidronate 90 mg per IV was started to treat her osteoporosis. Quickly after start of pamidronate the same reactions occurred again and the patient became depressed and agitated. Pamidronate was withdrawn and she recovered. Treatment with bisphosphonates was not started again; the patient was treated with colecaliferol, vitamin D and calcium. Patient E had a history of depression. Fluvoxamine had been used for years and every time this drug was discontinued a relapse of the depression occurred. The last six years the patient had been using fluvoxamine constantly and had not suffered from a relapse of the depression. After alendronate was started, the depression worsened again. In hospital the blood level of fluvoxamine was determined; this had decreased without a known cause. A possible interaction between alendronate and fluvoxamine was reported to the pharmacovigilance centre. At the time of reporting (12-10-1998), alendronate was discontinued but the patient had not recovered. Patient J (consumer report) reported that the first couple of weeks after alendronate with colecaliferol she only suffered from complaints a few hours after intake. Gradually the depressed state prolonged and she also suffered from fatigue. In her report the patient asked if there was a possibility for an interaction between maprotiline and alendronate with colecalciferol. After withdrawal of the suspect drug she recovered. The indication for the use of maprotiline, a tricyclic antidepressant, is not given in this report. Patient M only suffered from a depressed mood during the 14 days of etidronate use during a cycle. During the following 72 days of calcium carbonate use the reaction recovered. Patient N (consumer report) reported that she thinks the combination between anastrozole and goserelin was the main cause for her depressed mood. There was a positive dechallenge for all suspected drugs (anastrozole, goserelin and alendronate) but a positive rechallenge was only reported for anastrozole and goserelin. The patients’ serious illness could also be a factor in the occurrence of the depressed state. Other sources of information SmPC Depressive reactions including depression or depressed state or mood are not described in the Dutch SmPC’s of the various bisphosphonates [2-9]. The Dutch SmPC of pamidronate [8] describes some psychiatric adverse drug reactions like agitation and visual hallucinations. The Dutch SmPC of zoledronate mentions anxiety, sleep disturbance and confusion as possible psychiatric reactions [9]. Depression is not described in the US SmPC of alendronate (Fosamax®) [14]. ® The US SmPC of etidronate (Didronel ) mentions neuropsychiatric events including amnesia, confusion, depression and hallucination as events based on worldwide postmarketing experience [15]. The US SmPC of risedronate (Actonel®) mentions that depression occurred with an incidence of 6.8% compared to 6.1% with placebo in combined phase 3 postmenopausal osteoporosis treatment trials [16]. Four randomized, doubleblind, placebo-controlled multinational trials of 3232 women aged 38 to 85 years with postmenopausal osteoporosis were combined. The duration of the trials was up to three years, with 1619 patients exposed to placebo and 1613 patients exposed to risedronate 5 mg. Based on the numbers on the SmPC, this 2 difference is not statistically significant (2-sided Χ -test p-value = 0.43) 7 During a study which compared risedronate 5 mg daily and 35 mg weekly for the treatment of osteoporosis in postmenopausal women (n=965), the incidence of depression was 2.3% for both groups [17]. ® The US SmPC of zoledronate (Zometa ) describes that in 3 randomized, doubleblind, active, and placebo-controlled clinical trials in patients with multiple myeloma and bone metastases, the incidence of depression in patients receiving zoledronic acid 4 mg (n=1,031) compared to pamidronate 90 mg (n=556) and to placebo (n=455) was 14% versus 17% versus 11%, respectively [18]. Based on the numbers in the SmPC, the difference between zoledronate and 2 placebo is not statistically significant (2-sided Χ -test p-value = 0.13). The difference between pamidronate and placebo is statistically significant (2-sided 2 Χ -test p-value = 0.007) Literature In the article by Wolffenbuttel &.van der Klauw [13] a third patient is presented, whose case was not reported to Lareb. This patient was a female, aged 67 who also suffered from a depressed mood, agitation and impaired concentration with cyclical use of etidronate. The blood calcium level was within the normal range in this patient. Shortly after withdrawal of etidronate, she recovered. There were no other emotional or psychosocial problems. Alendronate was started and the depressed mood reoccurred together with insomnia, palpitations and rash. Alendronate was withdrawn and the patient recovered. Three monthly intravenous pamidronate was started without reoccurrence of the reactions. To the best of our knowledge no other case reports about bisphosphonateinduced depressive reactions have been published. Databases Table 2. Reports of depressive reactions associated with bisphosphonates in the Lareb database Drug Number of reports ROR (95% CI) Alendronate 11 1.3 (0.7 - 2.5) Etidronate 3 2.5 (0.8 – 7.9) Bisphosphonates in total 14 1.5 (0.9 - 2.6) For the Lareb database the MedDRA Preferred terms depression and depressed mood in association with bisphosphonates, with and without calcium or colecalciferol were taken into account. One patient also suffered from depressed feelings during the use of pamidronate, a reporting odds ratio was not calculated for pamidronate. Table 3. Reports of depressive reactions associated with bisphosphonates in the WHO database Drug Number of reports ROR (95% CI) Alendronate 638 2.3 (2.1 - 2.5) Etidronate 18 0.7 (0.5 - 1.1) Pamidronate 89 1.9 (1.5 – 2.3) Bisphosphonates in 986 1.5 (1.4 - 1.6) 8 Drug Number of reports ROR (95% CI) total For the WHO database the terms WHO-ART terms depression, depression aggravated and depression psychotic in association with bisphosphonates, with and without calcium or colecalciferol were taken into account. On August 3rd the Eudravigilance database contained 753 reports of depression associated with use of one of the bisphosphonates. Specified for individual bisfosfonates results in the following number of reports of depression: alendronate 636, risedronate 42, zoledronate 214, etidronate 1, clodronate, ibandronate 46, pamidronate 116. Because in some reports, more than one bisphosphonate was reported as a suspect drug the total number exceeds 777. Prescription data The number of patients using bisphosphonates in the Netherlands is shown in table 4. Table 4. Number of patients using bisphosponates in the Netherlands between 2006 and 2009* [10] Drug 2006 2007 2008 2009 Etidronate 2 . . . Etidronate with calcium 12,735 9,295 7,133 5,742 Alendronate 144,080 139,770 141,250 149,300 Aledronate with colecalciferol 12,567 17,883 21,309 25,610 Ibandronate 4,855 8,481 10,756 12,083 Risedronate 59,033 61,755 66,077 72,343 Risedronate with calcium 10,973 12,400 12,798 12,763 603 1,367 275 452 Zoledronate * There are no data for pamidronate available Mechanism The mechanism through which bisphosphonates might induce depressive symptoms is unknown. Bisphosphonates, including alendronate, can cause hypocalcaemia. Acute hypocalcaemia is commonly associated with symptoms of breathlessness, palpitations, tingling, and spasm. In comparison, chronic hypocalcaemia is more commonly associated with fatigue, irritability, memory loss, depression, confusion, delusions, and hallucinations. However, the decrease in serum calcium is generally mild and occurs with the start of therapy and then plateaus over time [19]. In the patients that were described by Wolffenbuttel &.van der Klauw [13], the blood calcium levels were within the normal range. The authors of a case report of hallucinations associated with alendronate described the hypothesis that changing from the once-daily to the once-weekly formulation of alendronate, although resulting in similar values for the area under the concentration-time curve, yields a greater maximum serum concentration of the drug, ultimately precipitating the adverse reaction their patient experienced. However, this could not be confirmed in their patient since the poor bioavailability 9 with oral administration of alendronate results in serum concentrations below the lower limit of quantification (5 ng/ml) [19]. There were two cases reported to Lareb where a possible drug interaction between alendronate (with colecalciferol) and fluvoxamine (patient E) or maprotiline (Patient J) was mentioned. An interaction between bisphosphonates and antidepressant drugs such as SSRI’s or TCA’s is not described in Stockley’s Drug interactions [20]. Discussion Lareb received 14 reports concerning depressive reactions with the use of alendronate or etidronate. In nine cases there was a positive dechallenge and in one patient also a positive rechallenge. In the other four cases the outcome was not reported. A close temporal relationship with the start of each cycle of use of etidronate was reported in patient D and M. In the literature information about this association is scarce, although the US SmPCs of certain bisphosphonates mention the occurrence of depression as an adverse drug event [15,17,18]. However, for risedronate and zoledronate the occurrence of depression was similar in the placebo and the treated group [16]. Lareb has received only reports about three of the bisphosphonates available on the Dutch market namely etidronate, pamidronate and alendronate. In the WHO database there are also reports of depression with other bisphosphonates. This association could possibly be a class-effect for all the bisphosphonates. However, a possible class-effect is not fully supported by the cases Lareb received. Depression is mentioned in the literature as one of the possible risk factors for osteoporosis [21]. Conclusion These cases illustrate a possible signal of depressive reactions occurring with alendronate, pamidronate and etidronate. This association could possibly be a class-effect for all the bisphosphonates. • Possible new signal of alendronate, pamidronate and etidronate associated with depressive reactions References 1. Strampel W, Emkey R, Civitelli R. Safety considerations with bisphosphonates for the treatment of osteoporosis. Drug Saf 2007;30(9):755-63. 2. Dutch SmPC Fosamax®. (version date: 12-9-2009, access date: 22-7-2010) http://db.cbgmeb.nl/IB-teksten/h18021.pdf. 3. Dutch SmPC Fosavance®. (version date: 8-7-2010, access date: 22-7-2010) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000619/WC500024251.pdf. 4. Dutch SmPC Actonel®. (version date: 24-2-2010, access date: 22-7-2010) http://db.cbgmeb.nl/IB-teksten/h24990.pdf. 10 5. Dutch SmPC Actokit®. (version date: 11-3-2010, access date: 22-7-2010) http://db.cbg-meb.nl/IBteksten/h31634.pdf. 6. Dutch SmPC Didrokit®. (version date: 4-3-2009, access date: 22-7-2010) http://db.cbg-meb.nl/IBteksten/h13739.pdf. 7. Dutch SmPC Bonviva®. (version date: 7-7-2010, access date: 22-7-2010) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000501/WC500052652.pdf. 8. Dutch SmPC Pamipro®. (version date: 5-6-2009, access date: 22-7-2010) http://db.cbg-meb.nl/IBteksten/h30331.pdf. 9. Dutch SmPC Zometa®. (version date: 5-6-2010, access date: 22-7-2010) http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000336/WC500051730.pdf. 10. College for Health Insurances. GIP database. (version date: 9-6-2009, access date: 10-2-2010) http://www.gipdatabank.nl/index.asp?scherm=tabellenFrameSet&infoType=g&tabel=01basis&item=J01FF. 11. American Psychiatric Association. DSM-IV Diagnostic and Statistical Manual of Mental Disorders. ed. Washington DC: American Psychiatric Association; 1994. 12. Dutch SmPC Pulmicort®. (version date: 18-9-2008, access date: 22-9-2010) http://db.cbgmeb.nl/IB-teksten/h13698.pdf. 13. Wolffenbuttel BH, van der Klauw MM. [Psychiatric side effects associated with diphosphonate treatment]. Ned Tijdschr Geneeskd 2003;147(1):35-7. 14. US SmPC Fosamax®. (version date: 1-3-2010, access date: 23-7-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020560s051s055s057,021575s012s0 16s018lbl.pdf. 15. US SmPC Didronel®. (version date: 31-12-2010, access date: 23-7-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017831s055lbl.pdf. 16. US SmPC Actonel®. (version date: 31-12-2009, access date: 23-7-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020835s036lbl.pdf. 17. US SmPC Actonel with calcium (Copacked)®. (version date: 22-8-2006, access date: 23-7-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/021823s004_LBL.pdf. 18. US SmPC Zometa®. (version date: 9-11-2009, access date: 23-7-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021223s018lbl.pdf. 19. Coleman CI, Perkerson KA, Lewis A. Alendronate-induced auditory hallucinations and visual disturbances. Pharmacotherapy 2004;24(6):799-802. 20. Baxter, K ed. Stockley's Drug Interactions [online]. (version date: 2010, access date: 26-7-2010) http://www.medicinescomplete.com/. 21. Cizza G, Primma S, Coyle M, Gourgiotis L, Csako G. Depression and osteoporosis: a research synthesis with meta-analysis. Horm.Metab.Res 2010;42(7):467-82. 11 1.2. Norfloxacin and hypoglycaemia Introduction Norfloxacin is a fluoroquinolone antibiotic. It inhibits bacterial deoxyribonucleic acid synthesis and can therefore be used as a wide spectrum antibiotic. Norfloxacin is registered for therapeutic use in acute recurrent urinary tract infections, prostatitis, bacterial gastroenteritis, gonorrhoeic urethritis, proctitis and cervicitis as well for prophylactic use in neutropenic patients [1-5]. Norfloxacin has been used internationally since 1983. Fluoroquinolones have both hypoglycemic and hyperglycemic effects in diabetic as well as non-diabetic patients [7]. Although a class effect is suspected, some fluoroquinolones have a more profound effect on glucose homeostasis, for example gatifloxacin [7-9] and temafloxacin [8], which were withdrawn due to this effect. Levofloxacin is also believed to have hypoglycemic effects [9]. Evidence of ciprofloxacin effects on hypoglycemia is sparser and only based on case reports in patients using sulfonylurea in a pre-existing diabetes mellitus [8]. Hypoglycaemia is not mentioned in the SmPCs of norfloxacin [1-5] Hypoglycaemia not related to diabetes treatment, salicylate intoxication or use of alcohol occurs seldom. Besides endogenous hyperinsulinism or rare malignancies or paraneoplastic effects, sepsis or starvation may induce hypoglycaemia [10]. Five cases of norfloxacin and hypoglycamia associated with norfloxacin use, including two cases of hypoglycaemia in non-diabetic subjects, are presented in this report. Reports On July 7, 2010 the database of the Netherlands Pharmacovigilance Centre Lareb contained five reports (Table 1) concerning hypoglycemia associated with norfloxacin use. Table 1. Reports of hypoglycemia associated with the use of norfloxacin. Patient, Number, Sex, Age Drug Indication for use Concomitant medication Suspected adverse drug reaction Time to onset, Action with drug Outcome A 21494 F, 21 – 30 years norfloxacin urinary tract infection OAC (Mercilon®), ibuprofen hypoglycaemia (2.9 mmol/l, postprandial 3.3 mmol/l) two days; withdrawn; recovered glucose 4.4 mmol/l and 5.9 mmol/l prior hypoglycaemia during earlier norfloxacin treatment betahistine estriol ibuprofen magnesium hydroxide, paracetamol, haloperidole, rosuvastatin, omeprazole, rivastigmine hypoglycaemia three days withdrawn, glucagon therapy, recovered B, 104591 norfloxacin 400mg bd F, 70 years urinary tract infection and older 12 Patient, Number, Sex, Age Drug Indication for use C 73853 M, 31 – 40 years Concomitant medication Suspected adverse drug reaction Time to onset, Action with drug Outcome norfloxacin 400mg not reported urinary tract infection insulin diabetes mellitus type 1 hypoglycaemia glucose blood levels were not specified, however 20 units reduction of daily insulin need one day; norfloxacin withdrawn; recovered D, 75154 F, 61 – 70 years norfloxacin 400mg cystitis metformin 1000mg bd insulin (lispro and glargin) ipratropium salbutamole salmeterole/fluticasone montelukast prednisolone hypoglycaemia (2.7mmol/l one day, withdrawn, outcome unclear due to unstable diabetes and infections unresponsive to antibiotic treatment, weeks later patient died due to non-related cause (cerebrovascular accident) E 21415 F, 61 – 70 years norfloxacin urinary tract infection 400mg daily glimepiride type 2 diabetes mellitus 3mg metoprolol, valsartan, hydrochlorothiazide, triamterene, pravastatin hypoglycaemia (2.9 mmol/l 75 minutes discontinued, replaced by nitrofurantoin recovered despite ongoing glimepiride use Lareb received five reports of norfloxacin associated hypoglycaemia, all reported by health care professionals and objectified by glucose levels or need of insulin, or given the administration of glucagon in patient B, most probably objectified. In all five cases the reported reaction consisted of both subjective symptoms and a measured low blood glucose. Three cases are particularly interesting due to short latencies, (Case E), a positive rechallenge (Case A) and an objectified increase in insulin need (Case C). Three patients (C, D, E) have been diagnosed with type 2 diabetes, so other DMrelated factors cannot be excluded. No indication of other alternative causes like excessive use of alcohol or salicylates was reported. Two patients involved had no history of diagnosed diabetes mellitus (A and B). However in both patients, glucose metabolism and counter balancing hepatic function may have been altered. Patient B is diagnosed with a chronic liver disease. Patient B has been shown to have an impaired glucose metabolism with a HbA1C slightly above reference levels (4.0-5.9%) and increased glucose levels in both postprandial and sober state. Causality assessment in Case D is complex. Patient D was known with recurrent urinary tract infections not responsive to several antibiotics, however without indication of complications which may lead to hypoglycaemia. Norfloxacin has been used in a prior antibiotic course without inducing hypoglycaemia. Since blood glucose levels were fluctuating over a prolonged period, it is difficult to assess the contribution of norfloxacin to decreased glucose levels. Weeks after the event patient died unexpectedly due to a cerebrovascular accident. No blood glucose levels after norfloxacin treatment were accessible to reporter. 13 Other sources of information SmPC Hypoglycaemia is not mentioned in the Dutch norfloxacin SmPCs. However in the US SmPC, the warning is given to use norfloxacin with caution because of an increased hypoglycaemic risk in patients using glibenclamide [11]. Literature Despite extensive coverage of hypoglycaemia related to other fluoroquinolones, no publications on norfloxacin-induced hypoglycaemia are accessible through Medline. Databases Hypoglycaemia associated with norfloxacin use is disproportionally present in the rd Netherlands Pharmacovigilance Centre database on August 3 2010. The World Health Organization (WHO) pharmacovigilance database however did not support causality on November 4th 2010. Results are shown in Table 2. Table 2. Reporting odds ratios of norfloxacin and hypoglycaemia in the Netherlands’ and WHO Pharmacovigilance database. Drug and ADR Number of reports ROR (95% CI) Lareb database 5 5.3 (2.2-13.0) WHO database 18 0.6 (0.4-1.0) On August 3rd the Eudravigilance database contained two serious reports of hypoglycaemia associated with norfloxacin use and one of a hypoglycaemic coma. One case was deemed life threatening but causality was blurred by the presence of an insulinoma. The second case lead to decease of an eighty-year old female with an insulin dependent form of diabetes. An additional twelve preparations including insulin, pioglitazone and glibenclamide were also suspected. The case of a hypoglycaemic coma occurred in an 81-year old female, also known with insulin dependent diabetes. Insulin and pioglitazone were listed under the additional suspect medications. Prescription data The number of patients using norfloxacin in the Netherlands is shown in table 3. Table 3. Number of norfloxacin users in the Netherlands between 2005 and 2008 [6] Drug 2005 2006 2007 2008 Norfloxacin 125,220 130,220 123,080 118,890 Mechanism Serum glucose regulation is a complex process in which insulin secretion and counteracting balances lead to a tight regulation of serum glucose levels. Both in in-vitro and in animal studies, fluoroquinolones had inhibitory effects on the ATPsensitive K+ channels in pancreatic β cells, which regulate insulin secretion. This effect is similar to the acting mechanism of sulfonylurea antidiabetics and leads eventually to increased insulin secretion [8]. Quinine which contains a quinolone group is believed to have similar effects exerted through its quinolone component. Normally, hypoglycaemia due to increased insulin secretion, is counterbalanced by molecules acting opposite to insulin like glucagon, however in people with an altered glucose homoeostasis, as in type 2 diabetes or hepatic disease, 14 symptomatic hypoglycaemia may develop due to an impaired compensatory function [7]. Discussion and Conclusion Norfloxacin-induced hypoglycaemia is supported by five reports and is disproportionally present in the Netherlands Pharmacovigilance Centre Lareb’s database. Two patients involved had no history of diagnosed diabetes mellitus. Conversely, this association is not disproportionally present in the database of the World Health Organisation (WHO), where the reported numbers indicate a ‘protective effect’. Hypoglycemia due to some fluoroquinolones is well established in literature and is supported by a plausible mechanism. In addition to the reports about norfloxacin, Lareb has received reports of hypoglycaemia in association with moxifloxacin (1 report), ciprofloxacin (1 report) and levofloxacin (1 report). The potential to induce hypoglycaemia differs between fluoroquinolones and due to the absence of reports in literature, norfloxacin is likely to be one of the fluoroquinolones with a lesser potential to induce hypoglycaemia. Attention of norfloxacin-induced hypoglycaemia is warranted, including mentioning of glucose lowering effects in the SmPC. • Attention of norfloxacin-induced hypoglycaemia is warranted References 1. Dutch SmPC norfloxacine 400 PCH. (version date: 15-5-2008, access date: 15-7-2010) http://db.cbg-meb.nl/IB-teksten/h22824.pdf. 2. Dutch SmPC Norfloxacine ratiopharm 400 mg. (version date: 6-1-2008, access date: 15-7-2010) http://db.cbg-meb.nl/IB-teksten/h23358.pdf. 3. Dutch SmPC Norfloxacine CF 400 mg. (version date: 23-6-2008, access date: 15-7-2010) http://db.cbg-meb.nl/IB-teksten/h24265.pdf. 4. Dutch SmPC Norfloxacine Sandoz tablet 400 mg. (version date: 24-11-2009, access date: 15-72010) http://db.cbg-meb.nl/IB-teksten/h26800.pdf. 5. Dutch SmPC Norfloxacine Mylan 400 mg. (version date: 16-4-2010, access date: 15-7-2010) http://db.cbg-meb.nl/IB-teksten/h29846.pdf. 6. GIP/college voor zorgverzekeringen. www.gipdatabank.nl. 2007(access date: 15-7-2010) 7. Lewis RJ, Mohr JF, III. Dysglycaemias and fluoroquinolones. Drug Saf 2008;31(4):283-92. 8. Saraya A, Yokokura M, Gonoi T, Seino S. Effects of fluoroquinolones on insulin secretion and beta-cell ATP-sensitive K+ channels. Eur J Pharmacol 2004;497(1):111-7. 9. Aspinall SL, Good CB, Jiang R, McCarren M, Dong D, Cunningham FE. Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis 2009;49(3):402-8. 10. Cryer PE. Kaspar DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL, editors.Harrison's Principles of Internal Medicine. 16th ed. New York: McGraw-Hill; 2005; 324, Hypoglycemia. p. 2180-5. 11. FDA SmPC Noroxin®. (version date: 27-4-2009, access date: 30-7-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/019384s054lbl.pdf. 12. Smith, KM and Lomaestro, BM. What role do fluoroquinolone antimicrobial agents play in cardiac dysfunction and altered glycemic control? (version date: 2010, access date: Journal of Pharmacy Practice 5. 13. Menzies DJ, Dorsainvil PA, Cunha BA, Johnson DH. Severe and persistent hypoglycemia due to gatifloxacin interaction with oral hypoglycemic agents. Am J Med 2002;113(3):232-4. 14. LeBlanc M, Belanger C, Cossette P. Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. Pharmacotherapy 2004;24(7):926-31. 15 1.3. Inhaled fluticasone and epistaxis Introduction Fluticasone is a locally acting potent corticosteroid and is registered in the Netherlands since 1990. It is marketed as nasal drops and nasal spray ® ® (Flixonase , Avamys ) for the indications vasomotor and allergic rhinitis, nasal polyps, and as inhalation corticosteroid (ICS) (Flixotide®) in both an inhalation dosisaerosol and a powder inhalation form for indications asthma and chronic obstructive pulmonary disease (COPD). Epistaxis, or nose bleed, is estimated to occur in 60% of persons during their lifetime with a higher incidence during the winter months. The prevalence is increased for children less than 10 years of age, is lower for adolescents and young adults and then rises again after the age of 35 years. Nose bleeds are more common in older patients; a mean age of 64 is mentioned [1]. Among hospitalized patient with nose bleeds, male patient are more presented in the age of 20-49 years. From the age of 50, no sex differences were found [2]. Approximately 6% of the patients with nosebleeds seek medical treatment. More than 90% of episodes of epistaxis occur along the anterior nasal septum, at a site called Kiesselbach’s area [1]. Systemic adverse drug reactions can occur during nasal and inhaled administration of fluticasone. Epistaxis is a well known ADR during nasal use of fluticasone [3], but it is not mentioned in the Dutch SmPCs of orally inhaled fluticasone products [4-6]. Reports On July 29, 2010, the database of the Netherlands Pharmacovigilance Centre Lareb contained eight reports of epistaxis associated with the use of orally inhaled fluticasone. These reports concerned male as well as female patients in varying ages. The reports are listed in Table 1. Table 1. Reports of epistaxis associated with the use of fluticasone Patient, Number, Sex, Age Drug (daily dose) Indication for use Concomitant medication Suspected adverse drug reaction Time to onset, Action with drug outcome A 19187 F, 8 – 10 years fluticasone dose unknown asthma salbutamol epistaxis several hours discontinued recovered, positive de- and rechallenge B 23740 fluticasone F, 70 years 2 dd 500 mcg and older asthma ipratropium, salmeterol, nifedipine, nedocromil, ranitidine epistaxis unknown discontinued recovered, positive de- and rechallenge C 24936 M, 70 years and older fluticasone 2 dd 500 mcg ipratropium, famotidine, captopril, salbutamol epistaxis (3 to 4 times a day) 7 days discontinued recovered D 26684 M, 5 – 7 years fluticasone 2 dd 250 mcg loratadine, salbutamol, salmeterol epistaxis unknown continued not recovered 16 Patient, Number, Sex, Age Drug (daily dose) Indication for use Concomitant medication Suspected adverse drug reaction Time to onset, Action with drug outcome E 48448 M, 61 – 70 years fluticasone chronic bronchitis 2 dd 250 mcg losartan epistaxis (one sided) several hours unknown unknown similar symptoms during nasal use of fluticasone F 82593 F, 31 – 40 years fluticasone dose unknown respiratory disorder - epistaxis several days continued recovered G 82930 M, 41 – 50 years fluticasone asthma 2 dd 250 mcg - epistaxis several days continued recovering H 107529 M, 11 – 20 years fluticasone 2 dd 250 mcg asthma - epistaxis; blood in snot after noose blowing 1 day discontinued recovered, positive de- and rechallenge Time to onset varied from several hours to several days. In four cases a positive dechallenge was reported, two of them with positive rechallenge as well. In five cases the nose bleeds occurred in the winter (B, D-G). Other sources of information Literature Epistaxis is mentioned as a possible adverse reaction of orally inhaled fluticasone ® in the US SmPC of Flovent discus [7]. To the best of our knowledge, there are no other publications on a possible association between orally inhaled fluticasone and epistaxis. In Micromedex [8] and Pubmed publications epistaxis is only described in association with the use of nasal administration of fluticasone. The relationship between skin bruising and inhaled corticosteroid (ICS) therapy is described in several studies. In a large double-blind, randomized, placebocontrolled clinical trial with 1116 participants (544 ICS, 542 placebo) it was found that a significantly higher proportion of ICS than placebo participants reported easy bruising (11.2% vs 3.5%, respectively) and the slow healing of skin cuts or sores (2.4% vs 0.5%, respectively) [9]. Lareb previously described the association between inhaled fluticasone and haematoma in a quarterly report [10] and a publication [11]. By now, bruising is mentioned as a possible adverse drug reaction in the SmPCs of inhaled fluticasone, but epistaxis is not described. Databases The eight Lareb reports of epistaxis during use of orally inhaled fluticasone lead to a reporting odds ratio (ROR) of 6.3 (95% CI 3.1-12.9). It should be noted that this ROR includes the cases that occurred during the winter. On July 29, 2010, the WHO database of the Uppsala Monitoring Centre contained 573 reports of epistaxis and orally inhaled fluticasone. This resulted in a disproportional ROR of 26.2 (95% CI 24.1-28.6). This ROR also includes the cases that occurred during the winter. 17 On August 3rd the Eudravigilance database contained six reports of epistaxis associated with use of inhaled fluticasone. All six cases were rated serious (one report of a life threatening event due to a combined nose and throat bleeding, three additional reports of hospital admission, other in two cases). There are three Portuguese cases which all concern 65-year old women. However, the reported clinical event differs in each three cases, which most plausibly implies that these cases concern separate events. Prescription data The number of patients using inhaled fluticasone in the Netherlands is shown in Table 2. Table 2. Number of users of inhaled fluticasone in the Netherlands between 2005 and 2008 [12] Drug Fluticasone 2006 302,320 2007 295,140 2008 276,110 2009 281,660 Mechanism Thinning and bruising of the skin may occur while taking inhaled corticosteroids, with evidence of a dose-response effect [13]. The presence of skin bruising can be considered a visible marker of the adverse effects of corticosteroids on collagen turnover in connective tissue, and serial skin examinations therefore can be used to monitor potential systemic adverse effects in patients taking high-dose therapy [14]. Inhaled corticosteroids most probably repress skin collagen synthesis. In a small study with 18 asthma patients, both types I and III procollagen propeptide concentrations decreased significantly after 6 weeks of even a low dose of inhaled corticosteroids [15]. Epistaxis caused by inhaled corticosteroids may well be caused by the same mechanism; repressed skin collagen synthesis, resulting in an increased vulnerability of the skin and the cutaneous blood vessels. Discussion and conclusion Epistaxis is associated with several factors, including rhino-sinusitis, systemic conditions associated with coagulopathy, septal perforations, dry mucosa, OslerWeber-Rendu syndrome and neoplasm [1]. The eight Lareb cases may all be more susceptible to epistaxis due to their asthmatic condition, which is often attended with or induced by (allergic) rhinitis [16]. Furthermore, the concomitant medication of three patients (B, C and E) is most probably indicated for hypertension. Hypertension may also contribute to epistaxis, although this theory is controversial [1]. It should also be considered that there is an increased incidence of nose bleeds during the winter months, probable due to dehumidification of the nasal mucosa [1]. Since five of the eight case reports occurred during the winter months (December to March), the contribution of this factor cannot be excluded. However, the positive de- (and re-)challenge in four cases - including cases B and C - strongly supports the causal relation with use of fluticason. The association between inhaled fluticasone and epistaxis is supported by the disproportional number of reports both in the Lareb and WHO database, the 18 known effects of inhaled corticosteroids on skin haematoma, and the fact that epistaxis is a known adverse drug reaction for nasal administration of fluticasone. • Possible signal of epistaxis in association with orally inhaled fluticasone References 1. Schlosser RJ. Clinical practice. Epistaxis. N Engl J Med 2009;360(8):784-9. 2. Tomkinson A, Roblin DG, Flanagan P, Quine SM, Backhouse S. Patterns of hospital attendance with epistaxis. Rhinology. 1997;35(3):129-31. 3. Dutch SmPC Flixonase neusspray. (version date: 29-2-2008, access date: 5-8-2010) http://db.cbgmeb.nl/IB-teksten/h14424.pdf. 4. Dutch SmPC Flixotide Inhalator / Flixotide Volumatic. (version date: 22-7-2009, access date: 5-82010) http://db.cbg-meb.nl/IB-teksten/h16212.pdf. 5. Dutch SmPC Flixotide Diskus. (version date: 1-4-2009, access date: 5-8-2010) http://db.cbgmeb.nl/IB-teksten/h18192.pdf. 6. Dutch SmPC Flixotide Nebules. (version date: 23-2-2010, access date: 5-8-2010) http://db.cbgmeb.nl/IB-teksten/h21834.pdf. 7. US SmPC Flovent Diskus. (version date: 2010, access date: 5-8-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020833s021lbl.pdf. 8. Thomson Micromedex, Greenwood Village Colorado USA. Micromedex® Healthcare Series, (electronic version). (version date: 2010, access date: 5-8-2010) http://www.thomsonhc.com. 9. Tashkin DP, Murray HE, Skeans M, Murray RP. Skin manifestations of inhaled corticosteroids in COPD patients: results from Lung Health Study II. Chest 2004;126(4):1123-33. 10. Inhaled and intranasal fluticasone propionate and haematoma. (version date: 2007, access date: 5-8-2010) http://www.lareb.nl/documents/kwb_2007_4_flut.pdf. 11. Gerritsen RF, Borgsteede SD, Harmark L. Hematoom als bijwerkingen fluticason. Pharmaceutisch Weekblad 2008;143(36):38-9. 12. College for health insurances. GIP database. (version date: 9-6-2009, access date: 6-8-2010) http://www.gipdatabank.nl/. 13. Capewell S, Reynolds S, Shuttleworth D, Edwards C, Finlay AY. Purpura and dermal thinning associated with high dose inhaled corticosteroids. BMJ 1990;300(6739):1548-51. 14. Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: A systematic review and meta-analysis. Arch Intern Med 1999;159(9):941-55. 15. Autio P, Karjalainen J, Risteli L, Risteli J, Kiistala U, Oikarinen A. Effects of an inhaled steroid (budesonide) on skin collagen synthesis of asthma patients in vivo. Am J Respir Crit.Care Med 1996;153(3):1172-5. 16. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, Wjst M, Cerveri I, Pin I, Bousquet J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet 2008;372(9643):1049-57. 19 1.4. Oxaliplatin and laryngospasm Introduction Oxaliplatin (Eloxatin®) is a platinum compound with antineoplasmatic properties and is registered in the Netherlands since 2005. Oxaliplatin is used in combination with 5-fluorouracil and folinic acid in the treatment of metastatic colorectal cancer. It is also indicated as adjuvant therapy in the treatment of colon carcinoma (stage III) after a complete resection of the primary tumor [1]. The platinum compound in oxaliplatin forms a complex with 1,2-diaminocyclohexane and an oxalate group [1] which interferes with DNA synthesis [2]. The complex is more hydrophobic than the complex formed by cisplatin and carboplatin, other platinum compounds and is therefore less nephro-ototoxic than cisplatin and less myelotoxic than carboplatin [3]. Laryngospasm is characterized as a brief episode of uncontrolled muscular contraction of the laryngeal cords [4,5]. This can lead to episodes of complete upper-airway occlusion [5]. Risk factors for laryngospasm are laryngopharyngeal reflux [6] (sleep-related [7]) and as post-surgery complication, especially in pediatrics [8]. Reports On August 10, 2010 the database of the Netherlands Pharmacovigilance Centre Lareb contained four reports concerning laryngospasm in association with the use of oxaliplatin. Of these four reports, report A is reported by a health professional and the other three are reported by the Marketing Authorization Holder (MAH). Table 1. Reports of laryngospasm associated with the use of oxaliplatin. Patient, Number, Sex, Age, Reporter Drug Indication for use Concomitant medication Suspected adverse drug reaction Time to onset, number of cycle, action with drug outcome A 106930 oxaliplatin 200 mg F, 70 years metastatic colon and older carcinoma thiamazole, levothyroxin, sotalol, dorzolamide, candesartan, enalapril laryngospasm 1 minute 45 days after first cycle drug withdrawn recovered B 56403 F, 51 – 60 years clemastine, diazepam, ondansetron, dexamethasone laryngospasm muscle spasm few hours after oxaliplatin infusion second cycle drug withdrawn outcome unknown estrogen with levonorgestrel, fentanyl laryngospasm nausea vomiting immediately after oxaliplatin infusion second cycle action and outcome unknown oxaliplatin 270 mg once per 3 weeks colorectal carcinoma cetuximab capecitabine bevacizumab C 54749 = 54751 F, 41 – 50 years oxaliplatin 178 mg once per 3 weeks unknown capecitabin irinotecan 20 Patient, Number, Sex, Age, Reporter Drug Indication for use Concomitant medication Suspected adverse drug reaction Time to onset, number of cycle, action with drug outcome D 82048 F, 61 – 70 years oxaliplatin unknown diazepam, ondansetron, metformin, imipramine, paracetamol with codein, dexamethasone, bevacizumab, glimepiride. laryngeal spasm, wheezing, pale, clammy within 1 day third cycle administration time enlarged to 6 hours recovered Case A was reported by a medical specialist. The laryngeal spasm occurred 45 days after the first infusion of the drug and 1 minute after the last infusion. The patient recovered after treatment with adrenaline, clemastine, ranitidine, hydrocortisone, intubation and admission to the intensive care. Case B was reported by the Marketing Authorization Holder. The therapy date, route of administration and daily dose are unknown for the concomitant medication diazepam. There is no further information about the reported muscle spasms. Latency time was in all cases within a day of the last oxaliplatin infusion. All patients experienced laryngospasm after administration of oxaliplatin. Other sources of information SmPC The Dutch SmPC of oxaliplatin [1] does mention subjective feelings of dysphagia and dyspnoea and/ or feeling to choke, without any objective evidence with problems to breathe or laryngospasm or bronchospasm (no stridor or wheezing). Laryngospasm with objective evidence is not mentioned in the Dutch SmPC of oxaliplatin [1]. The US SmPC [9] mentions an acute syndrome of pharyngolaryngeal dysesthesia in 1-2% of patients. This syndrome is characterized by subjective sensations of dysphagia or dyspnea, without any laryngospasm or bronchospasm (no stridor or wheezing). Laryngospasm is mentioned as a clinical symptom when an overdosage of oxaliplatin is given [9]. Literature Brandi et al [3] described hypersensitivity reactions related to oxaliplatin. Laryngospasm is mentioned as severe form of a hypersensitivity reaction. A total of 17 patients with hypersensitivity reactions were described, two of them experienced laryngospasm after their second and third infusion number. The infusion of oxaliplatin was stopped and replaced by a saline infusion. Antihistaminics and 100 -1000 mg hydrocortisone was administered. In this article, no difference was made between subjective or objective evidence for laryngospasm. 21 Databases On August 10, 2010 the Lareb database contained four reports on oxaliplatin and laryngospasm. In respect to the other reports in the database this association is disproportionally reported (ROR 56.2, 95% CI 18.4- 171). Lareb also received reports of symptoms that can be part of laryngospams. Dyspnoea (10 reports), bronchospams (1 report) and the feeling to choke (1 report) was reported with the use of oxaliplatin. These events were also reported with the use of carboplatin or cisplatin, other cytostatic drugs with a platinum compound. Laryngospasm is not reported before in associations with the use of carboplatin or cisplatin. On August 10, 2010 the WHO Collaborating Centre had received 85 reports of oxaliplatin and laryngospasm which was disproportionally present in the database (ROR 13.6, 95% CI 10.5-16.2). On August 3rd the Eudravigilance database contained 155 reports of laryngospasm associated with oxaliplatin use. All cases but four were rated serious. In three cases the reported reaction lead to the death of the patient involved. In 29 cases life-threatening aspects were indicated. Ages when specified ranged from 28 to 77 years. Fifty male patients were involved, 99 women. In the remaining six cases no sex was specified. Prescription data The prescription data for oxaliplatin are not available through the GIP database of the College for health insurances. Mechanism Laryngospasm can be part of a hypersensitivity reaction [3]. Because patients developed laryngospasm after multiple infusions of oxaliplatin, sensitization is likely [3]. The reactions occurred fast after the infusion. Therefore a type I hypersensitivity Ig-E mediated reaction is suggested [3]. There are also different hypothesis for hypersensitivity with the use of oxaliplatin suggesting the platinum salt can induce a cascade of reactions leading to cytokines of forming a major histocompatibility complex (MHC) [3]. Discussion The four cases reported to the Netherlands Pharmacovigilance Centre Lareb suggest oxaliplatin can induce laryngospasm. This is also mentioned in the SmPC but without any objective evidence. In at least one report (patient A) objective evidence (intubation) was present. In addition three cases of laryngospasm were reported. In reports B and C, there were also other suspected drugs. However, laryngospasm started within a few hours after oxaliplatin infusion so oxaliplatin is most likely for the events. Although other factors for laryngospasm can not be excluded, risk factors like laryngopharyngeal reflux were not mentioned in the reports. The reported latency times also supports a causal relationship. Conclusion Lareb received four reports of laryngospasm associated with the use of oxaliplatin. Subjective feeling of laryngospasm is described in the SmPC. However, in at least one report there was also intubation and therefore objective 22 evidence for laryngospasm. Therefore, laryngospasm should not only be mentioned as a subjective event in the SmPC of oxaliplatin. • Laryngospasm should be mentioned as an objective event in the SmPC of oxaliplatin References 1. Dutch SmPC Eloxatin®. (version date: 16-4-2010, access date: 9-8-2010) http://db.cbg-meb.nl/IBteksten/h32774.pdf. 2. CVZ. Farmacotherapeutisch Kompas. (version date: 1-7-2009, access date: 14-9-2009) www.fk.cvz.nl. 3. Brandi G, Pantaleo MA, Galli C, Falcone A, Antonuzzo A, Mordenti P, Di Marco MC, Biasco G. Hypersensitivity reactions related to oxaliplatin (OHP). Br J Cancer. 2003;89(3):477-81. 4. Jochems AAF; Joosten FWMG. Coelho. Zakwoordenboek der Geneeskunde. 29 ed. 2009. 497p. 5. Gdynia HJ, Kassubek J, Sperfeld AD. Laryngospasm in neurological diseases. Neurocrit.Care 2006;4(2):163-7. 6. Obholzer RJ, Nouraei SA, Ahmed J, Kadhim MR, Sandhu GS. An approach to the management of paroxysmal laryngospasm. J Laryngol.Otol. 2008;122(1):57-60. 7. Roland MM, Baran AS, Richert AC. Sleep-related laryngospasm caused by gastroesophageal reflux. Sleep Med 2008;9(4):451-3. 8. Flick RP, Wilder RT, Pieper SF, van KK, Ellison KM, Marienau ME, Hanson AC, Schroeder DR, Sprung J. Risk factors for laryngospasm in children during general anesthesia. Paediatr.Anaesth 2008;18(4):289-96. 9. American SmPC Eloxatin®. (version date: 13-3-2009, access date: 10-8-2010) http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/021492s011,021759s009lbl.pdf. 23 2. Short notes 2.1. Baclofen and constipation On August 10, 2010, the Netherlands Pharmacovigilance Centre Lareb had received four reports of constipation in association with baclofen. The Dutch SmPCs of baclofen are inconsistent with regard to mentioning constipation as adverse drug reaction. Some SmPCs [1,2] do mention constipation, while others [3] do not mention this adverse reaction. Constipation should be mentioned in the SmPCs of all baclofen containing products. References 1. Dutch SmPC baclofen Actavis. (version date: 29-11-2006, access date: 10-8-2010) http://db.cbgmeb.nl/IB-teksten/h21618.pdf. 2. Dutch SmPC Lioresal®. (version date: 16-10-2007, access date: 10-8-2010) http://db.cbgmeb.nl/IB-teksten/h06347.pdf. 3. Dutch SmPC baclofen Ratiopharm, PCH, Sandoz and Mylan. (version date: 29-10-2004, access date: 10-8-2010) http://db.cbg-meb.nl/IB-teksten/h12153.pdf. 24 3. Publications 1. Mannesse CK, Van Puijenbroek EP, Jansen PA, van Marum RJ, Souverein PC, Egberts TC. Hyponatraemia as an adverse drug reaction of antipsychotic drugs: a case-control study in VigiBase. Drug Saf 2010;33(7):569-78. 2. Plouvier A. Selectieve serotonine-heropnameremmers en hypoglykemie bij patiënten met diabetes mellitus. Gebu 2010;44(6):67-8. 3. Passier JL, Van Puijenbroek EP, Jonkers GJ, van Grootheest AC. Pancreatitis associated with the use of itraconazole. Neth J Med 2010;68(6):285-9. 4. Blokpoel RGT, Broos N, de Jong-van den Berg LTW, de Vries TW. Waarde omeprazol bij huilende zuigelingen beperkt. Ned Tijdschr Geneeskd 2010;154(A1850):1-4. 5. Tengstrand M, Star K, Van Puijenbroek EP, Hill R. Alopecia in association with lamotrigine use: an analysis of individual case safety reports in a global database. Drug Saf 2010;33(8):653-8. 6. van Hunsel F, van der Welle C, Passier A, van Puijenbroek E, van Grootheest K. Motives for reporting adverse drug reactions by patient-reporters in the Netherlands. Eur J Clin Pharmacol 2010; Nov;66(11):1143-50. 7. Broos N, Van Puijenbroek EP. Interaction between topical miconazole and coumarins. Eur J Clin Pharmacol 2010; 2010 Nov;66(11):1171-2 8. Oosterhuis I, Puijenbroek EP. Lareb Intensive Monitoring onder de loep. Pharmaceutisch Weekblad 2010;35:24-5. 25
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