Adverse Reaction Reporting and IMMP

Adverse Reactions of Current Concern

Web page: last updated 30 May 2006

The Medicines Adverse Reactions Committee (MARC) first initiated the list of Adverse reactions of current concern in 1994, as a means of bringing particular medicine adverse reactions to the attention of prescribers. The purpose of the list is also to encourage prescribers to report the reactions to the Centre for Adverse Reactions Monitoring (CARM) so that more information can be gathered, and further action taken if necessary. The reports provide a New Zealand perspective on emerging medicine safety issues.

Since initiation, the number of reactions listed has grown, and is revised from time to time. Amendments are made either in response to reactions reported in New Zealand or international pharmacovigilance issues.

As with any adverse reactions monitoring scheme, analysis can only be based on reports that are received. Prescribers are therefore encouraged to continue reporting adverse reactions to CARM so that the MARC can make the best possible recommendations based on information reflecting the New Zealand situation.

Updates on listings
Background on previous reactions of concern

Current list as at June 2006

Please report all cases of these adverse reactions, to the Centre for Adverse Reactions Monitoring (CARM), PO Box 913, Dunedin.

Medicine	Adverse reactions	Date of addition to list
Complementary and alternative medicines* (previously listed as Herbal medicines)	all adverse reactions	October 1996
Leflunomide (Arava^®)	all adverse reactions	April 2004
Pioglitazone and Rosiglitazone	all adverse reactions	June 2006

* includes herbal medicines, bee products, homoeopathic products, dietary supplements, minerals, and any other medicines containing animal or plant extracts.

Updates on listings

Pioglitazone or Rosiglitazone and all adverse reactions - June 2006 addition
Serious and unexpected adverse reactions (such as macular oedema and congestive heart failure) associated with rosiglitazone use are being increasingly reported in the literature. It is possible that these are therapeutic class effects. Currently pioglitazone is fully funded and therefore likely to be prescribed more than rosiglitazone. For these reasons and so that more complete adverse reaction data can be gathered, all adverse reactions with pioglitazone or rosiglitazone are now included in the list of adverse reactions of current concern.

SSRI antidepressants and severe agitation, severe restlessness/akathisia, and/or increased suicidality - June 2006 deletion
The removal of these reactions has been recommended by the MARC due to a good level of prescriber awareness having been achieved. However, the MARC will continue to closely monitor these reactions, including regularly reviewing the published literature and overseas regulatory activity. See below for background on original listing.

Leflunomide (Arava^®) and all adverse reactions - April 2004 addition
Due to increasing use of this disease-modifying agent in the management of rheumatoid arthritis, and the serious nature of some adverse reactions reported both locally and internationally, the Medicines Adverse Reactions Committee requests that prescribers report all adverse reactions associated with leflunomide regardless of severity or seriousness.

The following adverse reactions of current concern have been removed - effective from April 2004:

Atypical antipsychotics and hyperglycaemia
Celecoxib and cardiovascular events
Diane-35/35ED^® and Estelle-35/35ED^®, and venous thromboembolism
Fluticasone (inhaled) and adrenal insufficiency, hypoglycaemia, or seizure
Hormone replacement therapy (HRT) and venous thromboembolism
Rofecoxib and cardiovascular events

The removal of the above reactions has been recommended by the Medicines Adverse Reactions Committee (MARC) due to a good level of prescriber awareness having been achieved. However, MARC encourages prescribers to continue reporting the other adverse reactions of current concern.

These five adverse reactions of current concern have been removed - effective from March 2003:

Celecoxib and warfarin interaction
Nefazodone and hepatic reactions
NSAIAs and serious soft-tissue infection
Oral contraceptives and venous thromboembolism
Rofecoxib and warfarin interaction

Herbal medicines - July 2002 update
These were first listed as adverse reactions of current concern in October 1996 when CARM received increasing numbers of reports of adverse reactions to herbal medicines. Prior to 1996, there had been 17 reports to CARM for herbal products. This has now grown to a total of 153 reports encompassing 172 products. These reports cover a range of products, such as echinacea and bee pollen. Hence from July 2002, the term 'herbal medicines' has been widened to 'complementary and alternative medicines' (CAMs), to include any medicines containing plant or animal extracts.
In 72 of the reports the CAM was the sole suspected agent, and for 21 reports more than one CAM was suspected of causing the adverse reaction. The most common reports are for bee products (29) and St Johns Wort (17).
Obvious hypersensitivity reactions are reflected in at least 28% of all reports (n=43) for CAMs, and drug interactions account for 15% (n=23). The most common reactions include the skin (51), neuro-psychiatric (40), alimentary (34), hepatic (26) and cardiovascular (25). Of note, there are 14 reactions affecting the haematological system, nine endocrine/metabolic reactions and five uterine bleeding disorders.
These findings highlight the potential for adverse events with complementary and alternative medicines, some of which are both severe and serious. These include one death, four reports of anaphylaxis, two of hepatic failure and seven reports of abnormal bleeding disorders.
The presence of hypersensitivity reactions, and in recent time increasing numbers of reports suggesting interactions with prescribed (or 'conventional') medicines, highlight the ongoing need for caution regarding the use of CAMs. Prescribers are encouraged to be mindful of potential use by patients, and to continue reporting any suspected events with complementary and alternative medicines so more can become known.

Adverse reactions associated with herbal medicines - Dec 1999 update
From January 1992 to December 1999, 122 reports of adverse reactions occurring in association with complementary therapies have been received. For most alternative therapies insufficient is known about the product’s pharmacology or adverse reactions profile to be able to assign causality with confidence. Some exceptions are those cases where a positive rechallenge has occurred or the reaction was a hypersensitivity reaction with rapid onset, and no other apparent cause such as concomitant medication.
Interactions between prescription medicines and St John’s wort, usually resulting in loss of potency of the prescription medicine, are well-recognised.¹ Six cases have been reported to CARM. Three cases involved intermenstrual bleeding with an oral contraceptive. In one case the contraceptive was the progestogen-only product, Femulen^®, for which there is no known pharmacological basis for an interaction. In the other two cases the patient was taking Microgynon 30^®. St John’s wort is thought to increase the rate of metabolism of oestrogens with resulting lowered contraceptive efficacy. Two other cases involved interaction with warfarin with an increase in potency resulting in a rise in INR in patients whose INR had been stable previously. These cases are at variance with published reports in which a decrease in potency was observed,² and with the understanding of the mechanism of the St John’s wort interaction. The sixth case involved a possible mild serotonin syndrome in a patient taking St John’s wort along with clomipramine.

Background on previous reactions of concern

Agitation, restlessness, akathisia and/or increased suicidality with SSRIs - October 2002 addition (NB. removed from listing in June 2006)
The possibility of SSRIs* being associated with suicidal ideation and suicide remains an open question. However, as described in the September 2002 Prescriber Update article, the more common cause of suicidal tendency during treatment with an antidepressant is inadequate treatment of depression.
For fluoxetine, the CARM database holds eights reports of suicidal tendency, one of suicide and five of suicide attempt; for paroxetine there are three reports of suicide and two of suicide attempt. No cases of similar events have been reported with the other SSRIs, but the total number of reports of any adverse reactions with these medicines is much lower. The MARC has listed severe agitation, severe restlessness/akathisia, and/or increased suicidality with SSRIs as adverse reactions of current concern. The intention is to obtain further information to clarify whether there may be a causal association between SSRIs and suicidal tendencies in some, probably rare, cases.
* SSRIs currently available in New Zealand: citalopram, clomipramine (a tricyclic antidepressant with potent serotonergic activity), fluoxetine, fluvoxamine, paroxetine and sertraline.

Nefazodone (Serzone^®) and hepatic reactions - removed March 2003
This has been an adverse reaction of current concern since February 2000. During this period, up until February 2003, CARM has received 14 reports of hepatic reactions including seven cases of hepatocellular liver injury and five of abnormal liver function test results occurring during treatment with nefazodone. Doses ranged from 200mg to 500mg daily (recommended dose range is 300mg to 600mg/day³), and onset of the adverse event occurred between nine days and 15 months from when nefazodone therapy was initiated. Of the 14 cases, 11 had an onset time of four months or less. While hepatic reactions with nefazodone are no longer an adverse reaction of current concern, nefazodone continues to be monitored in the Intensive Medicines Monitoring Programme. This will enable MARC to maintain a watching brief. At this stage, no additional safety advice is being issued by MARC however, prescribers are reminded that patients should be alerted to signs and symptoms suggestive of liver dysfunction, such as jaundice, dark urine, anorexia, nausea, malaise, gastrointestinal complaints, or abdominal pain and told to report these to their doctor immediately. If signs, symptoms or evidence of hepatocellular injury occur during treatment with nefazodone, it should be withdrawn. These patients should be presumed to be at increased risk of liver injury if nefazodone is reintroduced. Accordingly, such patients should not be considered for re-treatment with nefazodone. Initiation of treatment with nefazodone is not recommended in patients with active liver disease or elevated baseline serum transaminases.^3,1
Original reason for listing in Feb 2000: Evidence suggests that nefazodone (Serzone^®) may be associated with hepatic reactions. Most cases occur after one or two months of therapy. The incidence of mild hepatotoxicity with nefazodone is around 2%, but more serious toxicity is rare (around 0.1%). Nefazodone is also being monitored on the Intensive Medicines Monitoring Programme.

Adrenal insufficiency, hypoglycaemia, or seizure with fluticasone - March 2003 addition (NB. removed from listing in April 2004)
Due to concerns arising from international reports of these adverse reactions occuring in association with inhaled fluticasone, MARC would like to bring them to the attention of New Zealand prescribers. The intention is to obtain a local perspective on an emerging medicine safety issue. Adrenal insufficiency associated with inhaled corticosteroid use can occur due to systemic absorption of the corticosteroid and consequent suppression of endogenous glucocorticoids, leaving insufficient adrenal reserve to respond to stress (for example, infection). Adrenal insufficiency may also result from abrupt discontinuation or non-compliance with treatment, leading to acute steroid deficiency. It may present as hypoglycaemia, abdominal pain, tiredness or vomiting, with or without seizures or coma. Although adrenal insufficiency can occur with any inhaled corticosteroid, it may be more common with fluticasone because of its greater potency.⁴

Hormone replacement therapy and venous thromboembolism - Oct 2002 update (NB. removed from listing in April 2004)
Since the listing of hormone replacement therapy (HRT) and venous thromboembolism (VTE) in April 1999 as an adverse reaction of current concern, there have been 13 further reports of deep vein thrombosis and two of pulmonary embolism. There have been no deaths but one patient with a pulmonary embolism also had right heart failure. VTE has occurred with oestrogen-only preparations, combined continuous and combined sequential preparations, and with most of the major oestrogens and oestrogen/progestogen combinations used as HRT in New Zealand. Premarin^® (conjugated equine oestrogens), followed by the combined continuous preparation Kliogest^® (2mg 17-beta-oestradiol and 1mg norethisterone), have the greatest number of reports, but as yet total numbers are small and these figures probably reflect sales. While the relative risk of VTE is similar to that with the combined oral contraceptive, the absolute risk with HRT is likely to be greater as the likelihood of VTE increases with age.
The results of the Women’s Health Initiative⁵ randomised controlled trial of 161,809 women found a 2-fold increase in risk of pulmonary embolism and deep vein thrombosis with use of conjugated equine oestrogens and medroxyprogesterone acetate, compared with women not using HRT. This represents a rate of 34 cases per 10,000 women each year compared with 16 for non-users.
Original reason for listing in April 1999 - From 1989 to 2000, six cases of pulmonary embolism and five of deep vein thrombosis with hormone replacement therapies have been reported to CARM. Death was the outcome in one case of pulmonary embolism which occurred with deep vein thrombosis. Three of the women were reported to have predisposing conditions.
Hormone replacement therapy increases the risk of venous thromboembolism by a factor of > 4 in the first year of use. The relative risk (an increase of 2-4 times compared with non-users) is similar to that with oral contraceptives, but the incidence of venous thromboembolism increases with age.⁶

NSAIAs and serious soft tissue infection - Oct 2002 update (NB. removed from listing in March 2003)
This was first listed as an adverse reaction of current concern in November 2000 following publication of a study⁷ showing an association between the use of non-steroidal anti-inflammatory agents (NSAIAs) in children with primary varicella (chicken pox) and the development of necrotising fasciitis (NF) and serious complications of this disorder.
CARM received nine reports of soft tissue infection associated with NSAIAs up to November 2000. These included three reports of NF, five of sepsis and one of cellulitis. Since listing serious soft tissue infection with NSAIAs as a reaction of current concern, CARM has received three further reports (one each of cellulitis, sepsis and NF). One of the patients was diabetic and developed NF at the site of a burn. He had received diclofenac for symptoms due to the burn. He required cardiorespiratory support and several surgical interventions as a result of the NF. The second patient had an undiagnosed streptococcal septicaemia, possibly due to a muscle abscess, and died. He had experienced non-specific symptoms and pain, and been given diclofenac prior to his death. The patient with cellulitis had an ischiorectal abscess, and was taking piroxicam and methotrexate. Duration of NSAIA use was unknown in the first patient, less than 24 hours in the second, and nine months in the third patient.
There have been many published case reports of NF and serious soft tissue infection occurring in patients taking NSAIAs. Two New Zealand case series⁸^,⁹ have been published; one⁸ showed that five out of seven consecutive patients admitted to hospital with NF had taken NSAIAs, while the other⁹ showed that five out of 13 similar patients had taken these medicines. Diabetes, obesity and/or multiple co-morbidities were present in the majority of patients in the second study⁹, and the authors concluded that the role of NSAIAs remained unclear.
There are plausible reasons why NSAIAs may increase the severity of streptococcal infections. They have an inhibitory effect on several biological responses to infection and may also mask the symptoms of early infection. A fuller discussion can be found in the February 2001 issue of Prescriber Update.¹⁰
The small number of reports received by CARM suggests that if NSAIAs do precipitate or worsen soft tissue infection, they do so only rarely. Caution should be exercised when considering the use of NSAIAs in soft tissue injuries at risk of infection, and they should not be given to children with chicken pox. This reaction will remain of current concern as it is still controversial, the disorders of interest are serious, and it may be possible to build a profile of susceptible patients.

Hyperglycaemia with all atypical antipsychotics - Feb 2002 addition (NB. removed from listing in April 2004)
Local and international adverse reaction reports suggest that all atypical antipsychotics (clozapine, olanzapine, quetiapine and risperidone) may be associated with impaired glucose metabolism, causing hyperglycaemia or new onset diabetes mellitus.¹¹^,¹² Hence, the MARC has decided to extend the adverse reaction of current concern of hyperglycaemia with clozapine to include all of the atypical antipsychotics, effective from February 2002.
In February 2002, the CARM/IMMP database held four reports of diabetes mellitus or hyperglycaemia with clozapine, two reports of diabetes mellitus with olanzapine and one of hyperglycaemia with risperidone. Up to the same date the numbers of reports of these events, plus aggravated or reactivated diabetes mellitus, in the WHO database were 616 for clozapine, 391 for olanzapine, 18 for quetiapine and 141 for risperidone.

Cardiovascular events with COX-2 inhibitors - Feb 2002 addition (NB. removed from listing in April 2004)
There is some preliminary evidence, needing confirmation, that the COX-2 inhibitors (celecoxib and rofecoxib) may be associated with cardiovascular events. The first indication of this association came from a surprise result of the VIGOR study¹³ in which 0.4% of the rofecoxib group and 0.1% of the naproxen group developed myocardial infarction. This result was extended by a between-study comparison conducted by Mukherjee et al.¹⁴ The comparison, which included celecoxib and rofecoxib, implicated both medicines as being associated with a significantly higher rate of myocardial infarction than placebo. These authors postulated that COX-2 inhibitors may have a prothrombotic effect through inhibition of prostacyclin.¹⁴
As at January 2002, 8% of the celecoxib reactions reported to CARM and 15% of those for rofecoxib were of cardiovascular events. Although rofecoxib and celecoxib are being monitored in the IMMP, the interest in the cardiovascular effects of these medicines is such that the MARC decided to include them in the list of adverse reactions of current concern, effective from February 2002.

Cardiac arrhythmia with cisapride - removed from listing in Feb 2002
Cisapride was listed in May 1999 following overseas reports of deaths from QT-prolongation, which prompted several countries to withdraw cisapride from the market or restrict its use. Since being listed, there have been no specific local reports of arrhythmia, but one report each of supraventricular tachycardia (SVT) and tachycardia. Prescribing restrictions placed on the use of cisapride during 2000¹⁵ may have contributed to the lack of reactions reported. As from February 2002, Cisapride and cardiac arrhythmia is no longer an adverse reaction of current concern.

Neutropenia/thrombocytopenia with ticlopidine - removed from listing in Feb 2002
This was added to the list in December 1998, following a case reported to CARM of rapid onset neutropenia caused by ticlopidine. The MARC had also reviewed a study describing 60 cases of thrombotic thrombocytopenic purpura with ticlopidine.¹⁶ Since the listing, there has been only one report of granulocytopenia. No reports of neutropenia have ever been received in New Zealand. As from February 2002, neutropenia/thrombocytopenia with ticlopidine has been delisted. The low number of reports could be explained by the increasing preferential use of clopidogrel, which has a lower incidence of blood dyscrasias.¹⁷ The CARM database holds three reports for clopidogrel, none of which involve the haematological system.

Thromboembolism with oral contraceptives - February 2002 update (NB. removed from listing in April 2004)
Oral contraceptives were added to the list of adverse reactions of current concern in February 1996¹⁸ after international studies¹⁹^-²² found that third generation oral contraceptives (OCs) were associated with a higher risk of venous thromboembolism, compared to second generation OCs. Since listing, CARM has received 32 reports of pulmonary embolism (nine fatal) and 48 reports of other venous thrombotic events with combined OCs. No fatal cases have been reported since 1999, possibly reflecting reduced prescribing of the third generation OCs, greater attention to risk factors, and higher index of suspicion for early diagnosis and treatment of VTE.
Diane 35/35ED^® (cyproterone acetate and ethinyloestradiol), for use in women with androgenic disorders who require contraception, were added to the list in February 2001 following reports of venous thromboembolism in women taking Diane-35, in New Zealand. Estelle 35/35ED^® (a generic brand) were also added to the list of adverse reactions of current concern in October 2001.
Prescribers are encouraged to keep reporting venous thromboembolism with all OCs to CARM as the reactions remain under active surveillance by the MARC.

COX-2 inhibitors (celecoxib, rofecoxib) and warfarin interaction - Oct 2001 addition (NB. removed from listing in March 2003)
In October 2001, this interaction was added as an adverse reaction of current concern. Celecoxib and rofecoxib may interact with warfarin to increase the international normalised ratio (INR) and cause serious haemorrhagic events. CARM has received one report of an interaction between celecoxib and warfarin resulting in haematuria, in a patient whose INR had risen to 3.1. Patients taking warfarin who are prescribed celecoxib or rofecoxib should have their INR checked in the first few days and monitored closely in the first two weeks of combined treatment. A Prescriber Update article provides further detail.

References