Revised: 11 February 2016
Safety Information
Medicines
Monitoring
Outcomes of Medicines Previously on
- Melatonin and Hallucinations
- Guaifenesin (guaiphenesin) and tinnitus
- Bisphosphonates and optic neuritis
- Allopurinal and lichenoid-type skin reactions
- Doxazosin and paroniria (nightmare)
- Amitriptyline - Peripheral coldness/Raynaud's phenomenon
- Ornidazole and adverse effects on the eye
- Statins (atorvastatin, simvastatin, pravastatin, rosuvastatin) and acute kidney injury without rhabdomyolysis
- Varenicline and interaction with alcohol
- Ondansetron and serotonin syndrome (toxicity)
- Ibuprofen and hypokalaemia and/or renal tubular acidosis
- Serotonin reuptake inhibitors or triptans and thunderclap headache or reversible cerebral vasoconstriction Syndrome (RCVS)
- Lithium and diabetes mellitus type 2
- Lansoprazole/Pantoprazole/Omeprazole and hypocalcaemia
- Pantoprazole/Lansoprazole and hypomagnesaemia
- Cetirizine and Severe Mood Disorder
- Sildenafil and thromboembolism
- Rivaroxaban - atrial fibrilation
- Simvastatin - joint pain and swelling
- Quetiapine and cardiomyopathy
| Medicine-reaction combination | Melatonin and Hallucinations |
|---|---|
| Date of entry to
|
20 July 2015 |
| Date of removal from
|
31 January 2016 |
| Number of reports before listing on
|
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
|
0 |
| Review of reports |
N/A |
| Biological Plausibility | N/A |
| Conclusion | No action required |
| Recommendation | No action |
| Medicine-reaction combination | Guaifenesin (guaiphenesin) and tinnitus |
|---|---|
| Date of entry to
|
7 April 2015 |
| Date of removal from
|
31 October 2015 |
| Number of reports before listing on
|
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
|
0 |
| Review of reports |
N/A |
| Biological Plausibility | Unknown. |
| Conclusion | No action required |
| Recommendation | No action |
| Medicine-reaction combination | Bisphosphonates (alendronic acid, etidronic acid, pamidronic acid, risedronic acid, zoledronic acid) and optic neuritis |
|---|---|
| Date of entry to
|
8 July 2014 |
| Date of removal from
|
31 December 2014 |
| Number of reports before listing on
|
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
|
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 |
| Medicine-reaction combination | Allopurinol and lichenoid-type skin reactions |
|---|---|
| Date of entry to
|
1 April 2014 |
| Date of removal from
|
31 October 2014 |
| Number of reports before listing on
|
Four cases, three of dermatitis lichenoid and one of lichen planus-like dermatitis |
| Number of reports whilst on
|
0 |
| Review of reports |
N/A |
| Biological Plausibility | Unknown |
| Conclusion | No action required |
| Recommendation | No action |
| Medicine-reaction combination | Doxazosin and paroniria (nightmare) |
|---|---|
| Date of entry to
|
1 April 2014 |
| Date of removal from
|
31 October 2014 |
| Number of reports before listing on
|
CARM has received seven cases of nightmare associated with the use of doxazosin |
| Number of reports whilst on
|
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 |
| Medicine-reaction combination | Amitriptyline and peripheral coldness/Raynaud's phenomenon |
|---|---|
| Date of entry to
|
3 February 2014 |
| Date of removal from
|
31 July 2014 |
| Number of reports before listing on
|
The Centre for Adverse Reactions Monitoring (CARM) had received two reports of localised numbness with the use of amitriptyline. |
| Number of reports whilst on
|
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 |
| Medicine-reaction combination | Ornidazole and adverse effects on the eye |
|---|---|
| Date of entry to
|
1 December 2013 |
| Date of removal from
|
30 June 2014 |
| Number of reports before listing on
|
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
|
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 |
| Medicine-reaction combination | Statins (atorvastatin, simvastatin, pravastatin, rosuvastatin) and acute kidney injury without rhabdomyolysis |
|---|---|
| Date of entry to
|
1 November 2013 |
| Date of removal from
|
30 June 2014 |
| Number of reports before listing on
|
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
|
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 |
| Medicine-reaction combination | Varenicline and interaction with alcohol |
|---|---|
| Date of entry to
|
1 June 2013 |
| Date of removal from
|
31 December 2013 |
| Number of reports before listing on
|
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
|
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. |
| Medicine-reaction combination | Ondansetron and serotonin syndrome (toxicity) |
|---|---|
| Date of entry to
|
1 December 2012 |
| Date of removal from
|
30 June 2013 |
| Number of reports before listing on
|
CARM received two cases of serotonin syndrome in association with ondansetron taken with other serotonergic medicines |
| Number of reports whilst on
|
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 |
| Medicine-reaction combination | Ibuprofen and hypokalaemia and/or renal tubular acidosis |
|---|---|
| Date of entry to
|
1 September 2012 |
| Date of removal from
|
31 March 2013 |
| Number of reports before listing on
|
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
|
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. |
| Medicine-reaction combination | Serotonin reuptake inhibitors or triptans and thunderclap headache or reversible cerebral vasoconstriction syndrome (RCVS) |
|---|---|
| Date of entry to
|
June 2012 |
| Date of removal from
|
December 2012 |
| Number of reports before listing on
|
1 |
| Number of reports whilst on
|
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. |
| Medicine-reaction combination | Lithium and Diabetes Mellitus Type 2 |
|---|---|
| Date of entry to
|
1 June 2012 |
| Date of removal from
|
31 December 2012 |
| Number of reports before listing on
|
3 (2 cases of diabetes mellitus where lithium was suspect and 1 case where lithium was co-suspect) |
| Number of reports whilst on
|
0 |
| Review of reports | N/A |
| Biological Plausibility | N/A |
| Conclusion | No action required |
| Recommendation | No action |
| Medicine-reaction combination | Lansoprazole/Pantoprazole/Omeprazole and Hypocalcaemia |
|---|---|
| Date of entry to
|
1 June 2012 |
| Date of removal from
|
31 December 2012 |
| Number of reports before listing on
|
6 cases |
| Number of reports whilst on
|
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. |
| Medicine-reaction combination | Pantoprazole/Lansoprazole and hypomagnaesamia |
|---|---|
| Date of entry to
|
1 September 2011 |
| Date of removal from
|
31 March 2012 |
| Number of reports before listing on
|
1 -pantoprazole 0 -lansoprazole |
| Number of reports whilst on
|
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. |
| Medicine-reaction combination | Cetirizine and Severe Mood Disorder |
|---|---|
| Date of entry to
|
1 March 2012 |
| Date of removal from
|
30 September 2012 |
| Number of reports before listing on
|
4 |
| Number of reports whilst on
|
0 |
| Review of reports | N/A |
| Biological Plausibility | N/A |
| Conclusion | No action required |
| Recommendation | No action |
| Medicine-reaction combination | Sildenafil and thromboembolism |
|---|---|
| Date of entry to
|
1 September 2011 |
| Date of removal from
|
30 September 2012 |
| Number of reports before listing on
|
0, signal identified by the Netherlands Pharmacovigilance Centre (Lareb) |
| Number of reports whilst on
|
0 |
| Review of reports | N/A |
| Biological Plausibility | N/A |
| Conclusion | No action required |
| Recommendation | No action |
| Medicine-reaction combination | Rivaroxaban - atrial fibrillation |
|---|---|
| Date of entry to
|
January 2011 |
| Date of removal from
|
September 2011 |
| Number of reports before listing on
|
3 |
| Number of reports whilst on
|
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 |
| Medicine-reaction combination | Simvastatin - joint pain and swelling |
|---|---|
| Date of entry to
|
January 2011 |
| Date of removal from
|
September 2011 |
| Number of reports before listing on
|
78 (including related terms of arthralgia) |
| Number of reports whilst on
|
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 |
| Medicine-reaction combination | Quetiapine and cardiomyopathy |
|---|---|
| Date of entry to
|
January 2011 |
| Date of removal from
|
September 2011 |
| Number of reports before listing on
|
3 (+3 IMMP reports) |
| Number of reports whilst on
|
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 |
|
