Safety Information

Revised: 11 February 2016

M² logoMedicines Monitoring

Outcomes of Medicines Previously on M² logo

Medicine-reaction combination Melatonin and Hallucinations
Date of entry to M² logo 20 July 2015
Date of removal from M² logo 31 January 2016
Number of reports before listing on M² logo CARM has received three cases of hallucinations associated with the use of melatonin, of which one reported the brand name Circadin.
Number of reports whilst on M² logo 0
Review of reports

N/A

Biological Plausibility N/A
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Guaifenesin (guaiphenesin) and tinnitus
Date of entry to M² logo 7 April 2015
Date of removal from M² logo 31 October 2015
Number of reports before listing on M² logo

Two reports to the Centre for Adverse Reactions Monitoring (CARM). One report described reactions of tinnitus, deafness and facial and outer ear numbmess. The other report described hearing loss.

Number of reports whilst on M² logo 0
Review of reports

N/A

Biological Plausibility Unknown.
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Bisphosphonates (alendronic acid, etidronic acid, pamidronic acid, risedronic acid, zoledronic acid) and optic neuritis
Date of entry to M² logo 8 July 2014
Date of removal from M² logo 31 December 2014
Number of reports before listing on M² logo 11 reports to the Uppsala Monitoring Centre (UMC) of optic neuritis in association with pamidronic acid, one of which originated from New Zealand.
Number of reports whilst on M² logo 0
Review of reports

N/A

Biological Plausibility Unknown. However, bisphosphonates have been associated with other inflammatory ocular reactions.
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Allopurinol and lichenoid-type skin reactions
Date of entry to M² logo 1 April 2014
Date of removal from M² logo 31 October 2014
Number of reports before listing on M² logo Four cases, three of dermatitis lichenoid and one of lichen planus-like dermatitis
Number of reports whilst on M² logo 0
Review of reports

N/A

Biological Plausibility Unknown
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Doxazosin and paroniria (nightmare)
Date of entry to M² logo 1 April 2014
Date of removal from M² logo 31 October 2014
Number of reports before listing on M² logo CARM has received seven cases of nightmare associated with the use of doxazosin
Number of reports whilst on M² logo 0
Review of reports

N/A

Biological Plausibility Effect not fully understood; may be due to action as an α1-selective alpha blocker
Conclusion No action required at this time
Recommendation No action

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Medicine-reaction combination Amitriptyline and peripheral coldness/Raynaud's phenomenon
Date of entry to M² logo 3 February 2014
Date of removal from M² logo 31 July 2014
Number of reports before listing on M² logo The Centre for Adverse Reactions Monitoring (CARM) had received two reports of localised numbness with the use of amitriptyline.
Number of reports whilst on M² logo One
Review of reports

Patient with pre-existing Raynaud’s syndrome noticed increasing coldness and discolouration in hands; feet unaffected. Amitriptyline may have contributed.

Biological Plausibility Amitriptyline is a serotonin-norepinephrine reuptake inhibitor. Increased levels of norepinephrine may increase stimulation of peripheral alpha-1 and alpha-2 receptors, resulting in vasoconstriction. Tricyclic antidepressants also act as direct antagonists of alpha-1 adrenergic function, therefore this mechanism may not fully explain the action.
Conclusion Peripheral neuropathy, and numbness, tingling and paraesthesias of the extremities are included in data sheets as possible adverse reactions; no action required at this time
Recommendation No action

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Medicine-reaction combination Ornidazole and adverse effects on the eye
Date of entry to M² logo 1 December 2013
Date of removal from M² logo 30 June 2014
Number of reports before listing on M² logo 4 cases of visual impairment; 3 cases of vision blurred; 1 case of diplopia; 1 case of periorbital oedema; 1 case of mydriasis in New Zealand
Number of reports whilst on M² logo 1
Review of reports

One additional report described vision blurred and other events.  Two additional medicines were also suspected.

No case reports were identified in the scientific literature.

Biological Plausibility Unknown
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Statins (atorvastatin, simvastatin, pravastatin, rosuvastatin) and acute kidney injury without rhabdomyolysis
Date of entry to M² logo 1 November 2013
Date of removal from M² logo 30 June 2014
Number of reports before listing on M² logo Total of 38 reports relating to abnormal renal function or renal failure in patient taking statins. Twenty-four of the reports also list rhabdomyolysis or CK elevations
Number of reports whilst on M² logo Total of 48 reports for statins were received during the medicines monitoring period. There was one report of acute renal failure and one of renal failure aggravated – both cases were secondary to rhabdomyolysis experienced by the patient
Review of reports N/A
Biological Plausibility N/A
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Varenicline and interaction with alcohol
Date of entry to M² logo 1 June 2013
Date of removal from M² logo 31 December 2013
Number of reports before listing on M² logo CARM has received five reports involving patients taking varenicline who also consumed alcohol. CARM classified one of these reports as being an interaction.
Number of reports whilst on M² logo One additional report of a patient who experienced a neuropsychiatric reaction after drinking several glasses of wine whilst taking varenicline.
Review of reports The Medicines Adverse Reaction Committee (MARC) reviewed the New Zealand reports and available information on a possible interaction between varenicline and alcohol consumption at the March 2014 meeting (www.medsafe.govt.nz/profs/adverse/Minutes157.htm).
Biological Plausibility Animal models indicate a potential interaction between alcohol and varenicline but no mechanism has been determined. However, this interaction may depend on the history of alcohol consumption and the amount of varenicline exposure.
Conclusion The MARC’s majority decision was that the information regarding the potential interaction between varenicline and alcohol should be strengthened in the varenicline data sheet.
Recommendation The MARC recommended inclusion of information in the data sheet about occasional reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients drinking alcohol during varenicline treatment.

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Medicine-reaction combination Ondansetron and serotonin syndrome (toxicity)
Date of entry to M² logo 1 December 2012
Date of removal from M² logo 30 June 2013
Number of reports before listing on M² logo CARM received two cases of serotonin syndrome in association with ondansetron taken with other serotonergic medicines
Number of reports whilst on M² logo 0
Review of reports N/A
Biological Plausibility Ondansetron acts on serotonin receptors (selective 5-HT3 receptor antagonist).
It has been proposed that as some selective serotonin reuptake inhibitors inhibit CYP2D6 activity and ondansetron is metabolised by CYP2D6, concomitant use may increase ondansetron levels.
Conclusion No action required at this time
Recommendation No action

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Medicine-reaction combination Ibuprofen and hypokalaemia and/or renal tubular acidosis
Date of entry to M² logo 1 September 2012
Date of removal from M² logo 31 March 2013
Number of reports before listing on M² logo No previous reports to CARM of hypokalaemia or renal tubular acidosis in which ibuprofen was considered a suspect medicine.

There have been at least 10 literature reports primarily in patients who have taken excessive doses of combination ibuprofen 200mg/codeine 12.5mg products. At least two reports involved ibuprofen alone and one report involved therapeutic doses of ibuprofen.
Number of reports whilst on M² logo 0
Review of reports N/A
Biological Plausibility It has been proposed that ibuprofen may cause renal tubular acidosis and hypokalaemia through inhibition of carbonic anhydrase.
Conclusion There is insufficient evidence to determine if therapeutic doses of ibuprofen are associated with the development of hypokalaemia and/or renal tubular acidosis.
Recommendation No action required at this time.

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Medicine-reaction combination Serotonin reuptake inhibitors or triptans and thunderclap headache or reversible cerebral vasoconstriction syndrome (RCVS)
Date of entry to M² logo June 2012
Date of removal from M² logo December 2012
Number of reports before listing on M² logo 1
Number of reports whilst on M² logo 3 reports of severe (thunderclap) headache.
None of the cases fulfilled the diagnostic criteria for RCVS as angiogram results were not reported.
Two of the reports were for SSRIs (citalopram and fluoxetine).
There was one report for a triptan (rizatriptan).
Review of reports Number of serious reports: 3
Age range: 25–53
Sex: 1 male, 2 females
Indications: Depression, migraine and unknown
Onset times: A few hours to 14 days. Unknown in one report.
Number recovered: All three patients had improved or recovered at the time of the report.
Treatment: Supportive care. No reports described use of calcium channel blockers or steroids.
Test Results: None reported
Positive dechallenge: Headache improved in two patients.
Other information: Headache improved in one patient who continued on citalopram. However, no follow-up data is available on whether headache recurred or citalopram was stopped.
Negative rechallenge: N/A
Confounding factors: One patient had a history of migraines.
Any risk factors identified: Nil
Biological Plausibility No mechanism has yet been proposed.
MARC Conclusions The available data supports an association between the use of some serotonin reuptake inhibitors and the development of thunderclap headache and/or RCVS.
The available data supports an association between the use of triptan therapy and the development of thunderclap headache and/or RCVS.
However, the available data is insufficient to determine whether this association is causal.
MARC Recommendation Thunderclap headaches and/or RCVS should be listed in selected SSRI and triptan data sheets.

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Medicine-reaction combination Lithium and Diabetes Mellitus Type 2
Date of entry to M² logo 1 June 2012
Date of removal from M² logo 31 December 2012
Number of reports before listing on M² logo 3 (2 cases of diabetes mellitus where lithium was suspect and 1 case where lithium was co-suspect)
Number of reports whilst on M² logo 0
Review of reports N/A
Biological Plausibility N/A
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Lansoprazole/Pantoprazole/Omeprazole and Hypocalcaemia
Date of entry to M² logo 1 June 2012
Date of removal from M² logo 31 December 2012
Number of reports before listing on M² logo 6 cases
Number of reports whilst on M² logo 0
Review of reports All the reports in the CARM database were reported in conjunction with hypomagnesamia. No current evidence that PPIs cause hypocalcaemia other than secondary to hypomagnesaemia.
Biological Plausibility Change in stomach pH may affect calcium absorption.
Conclusion No evidence of a direct association.
Recommendation No action required.

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Medicine-reaction combination Pantoprazole/Lansoprazole and hypomagnaesamia
Date of entry to M² logo 1 September 2011
Date of removal from M² logo 31 March 2012
Number of reports before listing on M² logo 1 -pantoprazole
0 -lansoprazole
Number of reports whilst on M² logo 1 additional report for pantoprazole
Review of reports An elderly male experienced hypomagnesaemia whilst taking omeprazole (magnesium 0.3). On discontinuation of omeprazole magnesium levels increased to 0.9 within 5 days. Whilst on treatment with ranitidine magnesium levels remained stable, however the patient experienced persisting GI symptoms. Pantoprazole 40mg daily was started with magnesium monitoring. Within three weeks magnesium levels had dropped to 0.6 and by about 9 weeks had fallen to 0.5 at which point pantoprazole treatment was discontinued
This case is suggestive of a class effect.
Biological Plausibility This effect has been noted for omeprazole and there are cases in the literature
Conclusion There is sufficient evidence for an association.
Recommendation Include information in the relevant data sheets.
Communicate this outcome in Prescriber Update.

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Medicine-reaction combination Cetirizine and Severe Mood Disorder
Date of entry to M² logo 1 March 2012
Date of removal from M² logo 30 September 2012
Number of reports before listing on M² logo 4
Number of reports whilst on M² logo 0
Review of reports N/A
Biological Plausibility N/A
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Sildenafil and thromboembolism
Date of entry to M² logo 1 September 2011
Date of removal from M² logo 30 September 2012
Number of reports before listing on M² logo 0, signal identified by the Netherlands Pharmacovigilance Centre (Lareb)
Number of reports whilst on M² logo 0
Review of reports N/A
Biological Plausibility N/A
Conclusion No action required
Recommendation No action

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Medicine-reaction combination Rivaroxaban - atrial fibrillation
Date of entry to M² logo January 2011
Date of removal from M² logo September 2011
Number of reports before listing on M² logo 3
Number of reports whilst on M² logo No additional reports for atrial fibrillation
Review of reports N/A
Biological Plausibility N/A
Conclusion No action required at this time
Recommendation No action

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Medicine-reaction combination Simvastatin - joint pain and swelling
Date of entry to M² logo January 2011
Date of removal from M² logo September 2011
Number of reports before listing on M² logo 78 (including related terms of arthralgia)
Number of reports whilst on M² logo No additional reports for joint pain and swelling
Review of reports N/A
Biological Plausibility N/A
Conclusion No action required at this time
Recommendation No action

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Medicine-reaction combination Quetiapine and cardiomyopathy
Date of entry to M² logo January 2011
Date of removal from M² logo September 2011
Number of reports before listing on M² logo 3 (+3 IMMP reports)
Number of reports whilst on M² logo 1 (Medsafe informed 4 April 2011)
Overview of reports Number of serious reports:  7
Age range:  20-52
Sex:  5 males and 2 females
Indications:  Depression (3), BPAD (2), Schizophrenia (2)
Onset times:  6 months to 5 years
Number recovered:  2 patients experienced improvement.  No patients recovered.
Treatment:  Withdrawal of quetiapine and initiation of appropriate treatment for congestive cardiac failure
Test Results:  Negative autoimmune, metabolic and viral screening.  Cardiomyopathy diagnosed on echocardiogram.
Positive dechallanges:  None (although 2 patients experienced improvement in symptoms after discontinuation)
Positive rechallenges:  None
Negative rechallenges:  1 patients had improvement in symptoms despite continuing quetiapine
Confounding factors:  Concomitant clozapine use in 1 patients.  Possible alcoholic cardiomyopathy in 1 patient.
Any risk factors identified:  No
Biological Plausibility Quetiapine is a benzazepine derivative that is structurally related to clozapine, which is known to be associated with the development of both myocarditis and cardiomyopathy. As cases of cardiomyopathy have also been reported with olanzapine (another benzazepine derivative) this raises the possibility of a class effect.
Conclusion There is sufficient evidence for an association between quetiapine and cardiomyopathy; however, there is insufficient evidence to determine whether this association is causal.
Recommendation
  • Cardiomyopathy and/or myocarditis should be added to the adverse effects section of the quetiapine data sheet
  • The outcome of the M-squared review should be communicated in Prescriber Update