Voriconazole

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole.

Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).

There is limited data on the safety of voriconazole in patients with abnormal liver function tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], or total bilirubin >5 times the upper limit of normal).

Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity.

In patients with moderate to severe renal dysfunction (creatinine clearance <50 ml/min), accumulation of the intravenous vehicle, SBECD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy.

Interaction – Geometric mean changes (%):

Sulfonylureas (e.g. tolbutamide, glipizide, glyburide) [CYP2C9 substrates]: Although not studied, voriconazole is likely to increase the plasma concentrations of sulfonylureas and cause hypoglycaemia.

Recommendations concerning coadministration: Careful monitoring of blood glucose is recommended. Dose reduction of sulfonylureas should be considered.

Interaction – Geometric mean changes (%):

Oral coumarins (e.g. phenprocoumon, acenocoumarol) [CYP2C9 and CYP3A4 substrates]: Although not studied, voriconazole may increase the plasma concentrations of coumarins that may cause an increase in prothrombin time.

Recommendations concerning coadministration: Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended, and the dose of anticoagulants should be adjusted accordingly.

Interaction – Geometric mean changes (%):

Statins (e.g. lovastatin) [CYP3A4 substrates]: Although not studied clinically, voriconazole is likely to increase the plasma concentrations of statins that are metabolised by CYP3A4 and could lead to rhabdomyolysis.

Recommendations concerning coadministration: Dose reduction of statins should be considered.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Not studied clinically. In vitro studies show that voriconazole may inhibit the metabolism of HIV protease inhibitors and the metabolism of voriconazole may also be inhibited by HIV protease inhibitors.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Not studied clinically. In vitro studies show that the metabolism of voriconazole may be inhibited by NNRTIs and voriconazole may inhibit the metabolism of NNRTIs. The findings of the effect of efavirenz on voriconazole suggest that the metabolism of voriconazole may be induced by an NNRTI.

Dose reduction of vinca alkaloids should be considered.

Although not studied, voriconazole is likely to increase the plasma concentrations of vinca alkaloids and lead to neurotoxicity.

Interaction – Geometric mean changes (%):

Short-acting Opiates [CYP3A4 substrates]:

Recommendations concerning coadministration: Dose reduction of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. sufentanil) should be considered. Extended and frequent monitoring for respiratory depression and other opiateassociated adverse reactions is recommended.

Interaction – Geometric mean changes (%):

Immunosuppressants [CYP3A4 substrates] - Ciclosporin (in stable renal transplant recipients receiving chronic ciclosporin therapy):

• Ciclosporin
  • C_max: ↑13%
  • AUC_τ: ↑70%

Recommendations concerning coadministration: When initiating voriconazole in patients already on ciclosporin it is recommended that the ciclosporin dose be halved and ciclosporin level carefully monitored. Increased ciclosporin levels have been associated with nephrotoxicity. When voriconazole is discontinued, ciclosporin levels must be carefully monitored and the dose increased as necessary.

Interaction – Geometric mean changes (%):

Cimetidine (400 mg BID) [non-specific CYP450 inhibitor and increases gastric pH]:

• Voriconazole
  • C_max: ↑18%
  • AUC_τ: ↑23%

Recommendations concerning coadministration: No dose adjustment.

Interaction – Geometric mean changes (%):

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [CYP2C9 substrates]:

Diclofenac (50 mg single dose):

• Diclofenac
  • C_max: ↑114%
  • AUC: ↑78%

Recommendations concerning coadministration: Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

Everolimus [CYP3A4 substrate, P-gp substrate]. Although not studied, voriconazole is likely to significantly increase the plasma concentrations of everolimus.

Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations.

Interaction – Geometric mean changes (%):

Fluconazole (200 mg QD) [CYP2C9, CYP2C19 and CYP3A4 inhibitor]:

ND = not determined

Recommendations concerning coadministration: The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.

Interaction – Geometric mean changes (%):

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) [CYP2C9 substrates]:

Ibuprofen (400 mg single dose):

• S-Ibuprofen
  • C_max: ↑20%
  • AUC_0-∞: ↑100%

Recommendations concerning coadministration: Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

Interaction – Geometric mean changes (%):

Methadone (32-100 mg QD) [CYP3A4 substrate]:

Recommendations concerning coadministration: Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended. Dose reduction of methadone may be needed.

Interaction – Geometric mean changes (%):

Benzodiazepines (e.g. midazolam, triazolam, alprazolam) [CYP3A4 substrates]: Although not studied clinically, voriconazole is likely to increase the plasma concentrations of benzodiazepines that are metabolised by CYP3A4 and lead to a prolonged sedative effect.

Recommendations concerning coadministration: Dose reduction of benzodiazepines should be considered.

Interaction – Geometric mean changes (%):

Oral Contraceptives* [CYP3A4 substrate; CYP2C19 inhibitor]:

Norethisterone/ethinylestradiol (1 mg/0.035 mg QD):

* two-way interaction

Recommendations concerning coadministration: Monitoring for adverse reactions related to oral contraceptives, in addition to those for voriconazole, is recommended.

Interaction – Geometric mean changes (%):

Omeprazole (40 mg QD)* [CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate]:

* two-way interaction

Other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these medicinal products.

Recommendations concerning coadministration: No dose adjustment of voriconazole is recommended. When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or above, it is recommended that the omeprazole dose be halved.

Interaction – Geometric mean changes (%):

Long-Acting Opiates [CYP3A4 substrates]:

Oxycodone (10 mg single dose), in an independent published study:

• Oxycodone
  • C_max: ↑1.7-fold
  • AUC_0-∞: ↑3.6-fold

Recommendations concerning coadministration: Dose reduction in oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g. hydrocodone) should be considered. Frequent monitoring for opiateassociated adverse reactions may be necessary.

Interaction – Geometric mean changes (%):

Phenytoin [CYP2C9 substrate and potent CYP450 inducer]:

* two-way interaction

Recommendations concerning coadministration:

Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk. Careful monitoring of phenytoin plasma levels is recommended.

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV BID or from 200 mg to 400 mg oral BID (100 mg to 200 mg oral BID in patients less than 40 kg).

Interaction – Geometric mean changes (%):

Prednisolone (60 mg single dose) [CYP3A4 substrate]:

• Prednisolone
  • C_max: ↑11%
  • AUC_0-∞: ↑34%

Recommendations concerning coadministration: No dose adjustment.

Interaction – Geometric mean changes (%):

Rifabutin [potent CYP450 inducer]:

* two-way interaction

Recommendations concerning coadministration:

Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk. The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously BID or from 200 mg to 350 mg orally BID (100 mg to 200 mg orally BID in patients less than 40 kg).

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole.

Interaction – Geometric mean changes (%):

Immunosuppressants [CYP3A4 substrates]:

Tacrolimus (0.1 mg/kg single dose):

• Tacrolimus
  • C_max: ↑117%
  • AUC_t: ↑221%

Recommendations concerning coadministration: When initiating voriconazole in patients already on tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary.

Interaction – Geometric mean changes (%):

Warfarin (30 mg single dose, co-administered with 300 mg BID voriconazole) [CYP2C9 substrate]: Maximum increase in prothrombin time was approximately 2-fold.

Recommendations concerning coadministration: Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended, and the dose of anticoagulants should be adjusted accordingly.

Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory.

Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• Congenital or acquired QTc-prolongation.
• Cardiomyopathy, in particular when heart failure is present.
• Sinus bradycardia.
• Existing symptomatic arrhythmias.
• Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy. A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec.

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function.

Monitoring of renal function: patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Squamous cell carcinoma of the skin has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur multidisciplinary advice should be sought, voriconazole discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If voriconazole is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazole should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified.

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4-hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.

Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a rash he should be monitored closely and VFEND discontinued if lesions progress.

Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment.

In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy). Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy.

Monitoring of hepatic function

Patients receiving voriconazole must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with voriconazole and at least weekly for the first month of treatment. Treatment duration should be as short as possible; however, if based on the benefit-risk assessment the treatment is continued, monitoring frequency can be reduced to monthly if there are no changes in the liver function tests.

If the liver function tests become markedly elevated, voriconazole should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use.

Monitoring of hepatic function should be carried out in both children and adults.

In addition voriconazole has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

There are no adequate data on the use of voriconazole in pregnant women available.

Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown.

Voriconazole must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with voriconazole.

Women of child-bearing potential

Women of child-bearing potential must always use effective contraception during treatment.

Fertility

In an animal study, no impairment of fertility was demonstrated in male and female rats.

Voriconazole has moderate influence on the ability to drive and use machines. It may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms.

Summary of safety profile

The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis trials. This represents a heterogeneous population, containing patients with haematological malignancy, HIV-infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers.

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

List of adverse reactions

In the list below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class, are listed.

Frequency categories are expressed as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Infections and infestations

Common: sinusitis

Uncommon: pseudomembranous colitis

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Frequency not known: squamous cell carcinoma*

Blood and lymphatic system disorders

Common: agranulocytosis¹, pancytopenia, thrombocytopenia², leukopenia, anaemia

Uncommon: bone marrow failure, lymphadenopathy, eosinophilia

Rare: disseminated intravascular coagulation

Immune system disorders

Uncommon: hypersensitivity

Rare: anaphylactoid reaction

Endocrine disorders

Uncommon: adrenal insufficiency, hypothyroidism

Rare: hyperthyroidism

Metabolism and nutrition disorders

Very common: oedema peripheral

Common: hypoglycaemia, hypokalaemia, hyponatraemia

Psychiatric disorders

Common: depression, hallucination, anxiety, insomnia, agitation, confusional state

Nervous system disorders

Very common: headache

Common: convulsion, syncope, tremor, hypertonia³, paraesthesia, somnolence, dizziness

Uncommon: brain oedema, encephalopathy⁴, extrapyramidal disorder⁵, neuropathy peripheral, ataxia, hypoaesthesia, dysgeusia

Rare: hepatic encephalopathy, Guillain-Barre syndrome, nystagmus

Eye disorders

Very common: visual impairment⁶

Common: retinal haemorrhage

Uncommon: optic nerve disorder⁷, papilloedema, oculogyric crisis, diplopia, scleritis, blepharitis

Rare: optic atrophy, corneal opacity

Ear and labyrinth disorders

Uncommon: hypoacusis, vertigo, tinnitus

Cardiac disorders

Common: arrhythmia supraventricular, tachycardia, bradycardia

Uncommon: ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, electrocardiogram QT prolonged, supraventricular tachycardia

Rare: torsades de pointes, atrioventricular block complete, bundle branch block, nodal rhythm

Vascular disorders

Common: hypotension, phlebitis

Uncommon: thrombophlebitis, lymphangitis

Respiratory, thoracic and mediastinal disorders

Very common: respiratory distress⁹

Common: acute respiratory distress syndrome, pulmonary oedema

Gastrointestinal disorders

Very common: diarrhoea, vomiting, abdominal pain, nausea

Common: cheilitis, dyspepsia, constipation, gingivitis

Uncommon: peritonitis, pancreatitis, swollen tongue, duodenitis, gastroenteritis, glossitis

Hepatobiliary disorders

Very common: liver function test abnormal

Common: jaundice, jaundice cholestatic, hepatitis¹⁰

Uncommon: hepatic failure, hepatomegaly, cholecystitis, cholelithiasis

Skin and subcutaneous tissue disorders

Very common: rash

Common: dermatitis exfoliative, alopecia, rash maculo-papular, pruritus, erythema

Uncommon: Stevens-Johnson syndrome, phototoxicity, purpura, urticaria, dermatitis allergic, rash papular, rash macular, eczema

Rare: toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS), angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug eruption

Frequency not known: cutaneous lupus erythematosus*, ephelides*, lentigo*

Musculoskeletal and connective tissue disorders

Common: back pain

Uncommon: arthritis

Frequency not known: periostitis*

Renal and urinary disorders

Common: renal failure acute, haematuria

Uncommon: renal tubular necrosis, proteinuria, nephritis

General disorders and administration site conditions

Very common: pyrexia

Common: chest pain, face oedema¹¹, asthenia, chills

Uncommon: infusion site reaction, influenza like illness

Investigations

Common: blood creatinine increased

Uncommon: blood urea increased, blood cholesterol increased

* ADR identified post-marketing
¹ Includes febrile neutropenia and neutropenia.
² Includes immune thrombocytopenic purpura.
³ Includes nuchal rigidity and tetany.
⁴ Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.
⁵ Includes akathisia and parkinsonism.
⁶ See “Visual impairments” paragraph below.
⁷ Prolonged optic neuritis has been reported post-marketing.
⁹ Includes dyspnoea and dyspnoea exertional.
¹⁰ Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.
¹¹ Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

Visual impairments

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common. These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant long-term visual effects were observed. There was evidence of attenuation with repeated doses of voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments may be associated with higher plasma concentrations and/or doses.

The mechanism of action is unknown, although the site of action is most likely to be within the retina. In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of voriconazole.

There have been post-marketing reports of prolonged visual adverse events.

Dermatological reactions

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic epidermal necrolysis (TEN) (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatment with voriconazole.

If a patient develops a rash they should be monitored closely and voriconazole discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especially during long-term therapy.

There have been reports of squamous cell carcinoma of the skin in patients treated with voriconazole for long periods of time; the mechanism has not been established.

Liver function tests

The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18.0% (319/1,768) in adults and 25.8% (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death.

Infusion-related reactions

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion.

Prophylaxis

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years in compassionate use programs. Overall, the safety profile of voriconazole in paediatric population was similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% in adults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse reactions (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.