Immanaz 200 mg Powder for solution for injection

Treatment of invasive aspergillosis.

Treatment of serious invasive infections caused by Candida spp (including C. krusei).

Voriconazole has been used in the treatment of serious fungal infections caused by Scedosporium spp and Fusarium spp.

Prevention of breakthrough of fungal infections in febrile high-risk patients (allogeneic bone marrow transplants, relapsed leukaemia patients) where liposomal amphotericin B cannot be used.

Posology

It is recommended that IMMANAZ is administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours. IMMANAZ requires reconstitution and dilution prior to administration as an intravenous infusion. Not for bolus injection.

Treatment

Adults

Therapy must be initiated with the specified loading dose of IMMANAZ to achieve plasma concentrations on Day 1 that are close to steady state. Detailed information on dosage recommendations is provided in the following table:

Intravenous Loading Dose Regimen for all Indications (first 24 hours)

• 6 mg/kg every 12 hours (for the first 24 hours)

Maintenance Dose (after first 24 hours)

• Prevention of breakthrough infections: 3 mg/kg every 12 hours
• Invasive aspergillosis, serious Candida infections, Scedosporium/Fusarium infections: 4 mg/kg every 12 hours

Dosage adjustment (Adults)

If patient response is inadequate, the maintenance dose may be increased to 4 mg/kg every 12 hours for intravenous administration. If patient is unable to tolerate intravenous treatment at 4 mg/kg twice daily, reduce the dose to 3 mg/kg twice daily. Phenytoin may be co-administered with IMMANAZ if the maintenance dose of IMMANAZ is increased to 5 mg/kg intravenously every 12 hours (see section 4.4 and 4.5).

Treatment duration depends upon patientsu2019 clinical and mycological response.

Use in the elderly

No dose adjustment is necessary for elderly patients.

Use in patients with renal impairment

In patients with moderate to severe renal dysfunction (creatinine clearance < 50 ml/min), accumulation of the intravenous vehicle, SBECD, occurs. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral IMMANAZ therapy. IMMANAZ is haemodialysed with a clearance of 121 ml/min. A four-hour haemodialysis session does not remove a sufficient amount of IMMANAZ to warrant dose adjustment. The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min.

Use in patients with hepatic impairment

No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver function tests (ALT, AST), but continued monitoring of liver function tests for future elevations is recommended. IMMANAZ has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C). IMMANAZ has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice. Patients with hepatic impairment must be carefully monitored for medicine toxicity (see also u2018Side effectsu2019).

Use in children

Safety and effectiveness in paediatric subjects below the age of 2 years has not been established. Therefore, IMMANAZ is not recommended for children less than 2 years of age. Limited data are currently available to determine the optimal posology. However, the following regimen has been used in paediatric studies.

Children (2 to <12 years)

Intravenous Loading Dose Regimen (first 24 hours)

• 6 mg/kg every 12 hours (for the first 24 hours)

Maintenance Dose (after first 24 hours)

• 4 mg/kg every 12 hours

The pharmacokinetics and tolerability of higher doses have not been characterised in paediatric populations. Adolescents (12 to 16 years of age) should be dosed as adults. Duration of Treatment Treatment duration depends on the patientu2019s clinical and mycological response.

IMMANAZ is contraindicated in patients with known hypersensitivity to voriconazole or to any of the excipients. Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide, quinidine or ivabradine with IMMANAZ is contraindicated since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of Torsades de Pointes (see section 4.5). Co-administration of IMMANAZ with rifampicin, carbamazepine and phenobarbitone is contraindicated since these medicines are likely to decrease plasma voriconazole concentrations significantly (see section 4.5). Co-administration of standard doses of IMMANAZ with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma IMMANAZ concentrations in healthy subjects at these doses. IMMANAZ also significantly increases efavirenz plasma concentrations. Co-administration of IMMANAZ with high dose ritonavir (400 mg and above twice daily) is contraindicated because ritonavir significantly decreased plasma IMMANAZ concentrations in healthy subjects at this dose (see section 4.5 for lower doses). Co-administration of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contraindicated since increased plasma concentrations of these drugs can lead to ergotism (see section 4.5). Co-administration of IMMANAZ and sirolimus is contraindicated, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5). Co-administration of IMMANAZ and rifabutin is contraindicated since IMMANAZ is likely to increase plasma concentrations of rifabutin significantly (see section 4.5). Co-administration of IMMANAZ with St Johnu2019s Wort is contraindicated (see section 4.5). Co-administration with venetoclax at initiation and during the venetoclax dose titration phase is contraindicated since IMMANAZ is likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysis syndrome. Patients with prolonged QT syndrome. Pregnancy and lactation. Severe impairment of hepatic function (Child-Pugh Class C).

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

Hypersensitivity

Caution should be used in prescribing IMMANAZ to patients with hypersensitivity to other azoles (see also section 4.8).

Infusion-related reaction

During infusion of the intravenous formulation of IMMANAZ 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. Depending on the severity of the symptoms, consideration should be given to stopping treatment.

Cardiovascular

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 (see section 4.2). 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 (see section 5.1).

Hepatic toxicity

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 (see section 4.8).

Monitoring of hepatic function

Patients receiving IMMANAZ 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 IMMANAZ 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 (see section 4.2), 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, IMMANAZ should be discontinued.

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

Serious dermatological adverse reactions

• Phototoxicity

In addition, IMMANAZ 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 IMMANAZ treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

• Squamous cell carcinoma of the skin (SCC)

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, IMMANAZ discontinuation and use of alternative antifungal medicines should be considered and the patient should be referred to a dermatologist. If IMMANAZ is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. IMMANAZ should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see below the section under Long-term treatment).

• Exfoliative cutaneous reactions

Severe cutaneous adverse reactions (SCARs) including 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 IMMANAZ discontinued if lesions progress.

Long-term treatment

Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to IMMANAZ (see sections 4.2 and 5.1). Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term IMMANAZ treatment. Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis IMMANAZ discontinuation should be considered after multidisciplinary advice.

Visual adverse reactions

There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see section 4.8).

Renal adverse reactions

Acute renal failure has been observed in severely ill patients undergoing treatment with IMMANAZ. 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 (see section 4.8).

Monitoring of renal function

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

Monitoring of pancreatic function

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, haematopoietic stem cell transplantation [HSCT], should be monitored closely during IMMANAZ treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Paediatric population

Safety and effectiveness in paediatric subjects below the age of two years has not been established (see sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population (see section 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 to <12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.

• Serious dermatological adverse reactions (including SCC)

The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution towards SCC has been reported, stringent measures for the photoprotection are warranted in this population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Prophylaxis

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of alternative antifungal medicines must be considered.

Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes.

Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide and ivabradine), coadministration is contraindicated. (see section 4.3)

Effects of other medicinal products on voriconazole

Concomitant use of the following medicines with IMMANAZ is contraindicated:

• St Johnu2019s Wort (CYP450 inducer; P-gp inducer): In an independent published study in healthy volunteers, St Johnu2019s Wort exhibited a short initial inhibitory effect followed by induction of IMMANAZ metabolism. Therefore, concomitant use of IMMANAZ with St Johnu2019s Wort is contraindicated (see section 4.3).
• Rifampicin (CYP450 inducer): Rifampicin (600 mg once daily) decreased the C max (maximum plasma concentration) and AUC t (area under the plasma concentration time curve within a dose interval) of voriconazole by 93 % and 96 %, respectively. Co-administration of IMMANAZ and rifampicin is contraindicated (see section 4.3).
• Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): The effect of the co-administration of oral IMMANAZ (200 mg twice daily) and high dose (400 mg) and low dose (100 mg) oral ritonavir was investigated in two separate studies in healthy volunteers. High doses of ritonavir (400 mg twice daily) decreased the steady state C max and AUC t of oral IMMANAZ by an average of 66 % and 82 %, whereas low doses of ritonavir (100 mg twice daily) decreased the C max and AUC t of IMMANAZ by an average of 24 % and 39 % respectively. Administration of IMMANAZ did not have a significant effect on mean C max and AUC t of ritonavir in the high dose study, although a minor decrease in steady state C max and AUC t of ritonavir with an average of 25 % and 13 % respectively was observed in the low dose ritonavir interaction study. One outlier subject with raised IMMANAZ levels was identified in each of the ritonavir interaction studies. Co-administration of IMMANAZ and high doses of ritonavir (400 mg and above twice daily) is contraindicated. Co-administration of IMMANAZ and low dose ritonavir (100 mg twice daily) should be avoided (see section 4.3 & see section 4.4).
• Carbamazepine and phenobarbital (potent CYP450 inducers): Although not studied, carbamazepine or phenobarbital are likely to significantly decrease plasma IMMANAZ concentrations. Co-administration of IMMANAZ with carbamazepine and phenobarbital is contraindicated (see section 4.3).

Due to minor or no significant pharmacokinetic interactions, no dosage adjustment is required with the following medicines:

• Cimetidine (non-specific CYP450 inhibitor and increases gastric pH): Cimetidine (400 mg twice daily) increased IMMANAZ C max and AUC t by 18 % and 23 %, respectively. No dosage adjustment of IMMANAZ is recommended.
• Ranitidine (increases gastric pH): Ranitidine (150 mg twice daily) had no significant effect on IMMANAZ C max and AUC t.
• Macrolide antibiotics: Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg once daily) had no significant effect on IMMANAZ C max and AUC t.

Effects of IMMANAZ on other medicinal products

Concomitant use of the following medicines with IMMANAZ is contraindicated:

• Astemizole, cisapride, pimozide and quinidine (CYP3A4 substrates): Although not studied, co-administration of IMMANAZ with astemizole, cisapride, pimozide, or quinidine is contraindicated, since increased plasma concentrations of these drugs can lead to QTc prolongation and rare occurrences of Torsades de Pointes (see section 4.3).
• Sirolimus (CYP3A4 substrate): IMMANAZ increased sirolimus (2 mg single dose) C max and AUC by 6 fold and 11 fold respectively. Co-administration of IMMANAZ and sirolimus is contraindicated (see section 4.3).
• Ergot alkaloids (CYP3A4 substrates): Although not studied, IMMANAZ may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Co-administration of IMMANAZ with ergot alkaloids is contraindicated (see section 4.3).

Interaction of IMMANAZ with the following medicines may result in increased exposure to these medicines. Therefore, careful monitoring and/or dosage adjustment should be considered.

• Ciclosporin (CYP3A4 substrate): In stable, renal transplant recipients, IMMANAZ increased cyclosporin C max and AUC t by at least 13 % and 70 % respectively. When initiating IMMANAZ in patients already receiving ciclosporin it is recommended that the ciclosporin dose be halved and ciclosporin level carefully monitored. Increased ciclosporin levels have been associated with nephrotoxicity. When IMMANAZ is discontinued, ciclosporin levels must be carefully monitored and the dose increased as necessary (see section 4.4).
• Tacrolimus (CYP3A4 substrate): IMMANAZ increased tacrolimus (0,1 mg/kg single dose) C max and AUC t (area under the plasma concentration time curve to the last quantifiable measurement) by 117 % and 221 %, respectively. When initiating IMMANAZ in patients already receiving 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 IMMANAZ is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary (see section 4.4).
• Methadone (CYP3A4 substrate): Repeat dose administration of oral IMMANAZ (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the C max and AUC t of pharmacologically active R-methadone by 31 % (90 % CI: 22 %, 40 %) and 47 % (90 % CI: 38 %, 57 %), respectively, in subjects receiving a methadone maintenance dose (30 - 100 mg daily) (see section 4.4).
• Short Acting Opiates (CYP3A4 substrate): In an independent publication, steady-state administration of oral IMMANAZ increased the AUCu221e of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4, should be considered when co-administered with IMMANAZ.
• Fentanyl (CYP3A4 substrate): In an independent published study, concomitant use of IMMANAZ (400 mg every 12 hours on Day 1, then 200 mg every 12 hours on Day 2) with a single intravenous dose of fentanyl (5 u03bcg/kg) resulted in an increase in the mean AUC0 - u221e of fentanyl by 1,4-fold (range 1,12 u2013 1,60-fold). When IMMANAZ is co-administered with fentanyl, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and fentanyl dosage should be reduced if warranted.
• Oxycodone (CYP3A4 substrate): In an independent published study, co-administration of multiple doses of oral IMMANAZ (400 mg every 12 hours, on Day 1 followed by five doses of 200 mg every 12 hours on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C max and AUC0u2013 u221e of oxycodone by 1,7 -fold (range 1,4- to 2,2-fold) and 3,6-fold (range 2,7- to 5,6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2,0-fold (range 1,4- to 2,5-fold). A reduction in oxycodone dosage may be needed during IMMANAZ treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolised by CYP3A4 is recommended.

Oral anticoagulants: Warfarin (CYP2C9 substrate): Co-administration of IMMANAZ (300 mg twice daily) with warfarin (30 mg single dose) increased maximum prothrombin time / international normalised ratio (INR) by 93 %. Close monitoring of prothrombin time/INR is recommended if warfarin and IMMANAZ are co-administered.

Sulphonylureas (CYP2C9 substrates): Although not studied, IMMANAZ may increase the plasma levels of sulphonylureas, (e.g. tolbutamide, glipizide, and glyburide) and therefore cause hypoglycaemia. Careful monitoring of blood glucose is recommended during co-administration.

Statins (CYP3A4 substrates): Although not studied clinically, IMMANAZ has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, IMMANAZ is likely to increase plasma levels of statins that are metabolised by CYP3A4. It is recommended that dose adjustment of the statin be considered during co-administration. Increased statin levels have been associated with rhabdomyolysis.

Benzodiazepines (CYP3A4 substrates): Although not studied clinically, IMMANAZ has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, IMMANAZ is likely to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (e.g. midazolam, triazolam and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during co-administration.

Vinca Alkaloids (CYP3A4 substrates): Although not studied, IMMANAZ may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity. It is therefore recommended that dose adjustment of the vinca alkaloid be considered.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDS): IMMANAZ increased C max and AUC of ibuprofen (400 mg single dose) by 20 % and 100 %, respectively. IMMANAZ increased C max and AUC of diclofenac (50 mg single dose) by 114 % and 78 %, respectively. Frequent monitoring for adverse events and toxicity related to NSAIDu2019s is recommended. Adjustment of dosage of NSAIDu2019s may be needed.

No significant pharmacokinetic interactions were observed when IMMANAZ was co-administered with the following medicines. Therefore, no dosage adjustment for these medicines is necessary.

• Prednisolone (CYP3A4 substrate): IMMANAZ increased C max and AUC t of prednisolone (60 mg single dose) by 11 % and 34 %, respectively. No dosage adjustment is recommended.
• Digoxin (P-glycoprotein mediated transport): IMMANAZ had no significant effect on C max and AUC t of digoxin (0,25 mg once daily).
• Mycophenolic acid (UDP-glucuronyl transferase substrate): IMMANAZ had no effect on the C max and AUC t of mycophenolic acid (1 g single dose).

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

Pregnancy

IMMANAZ must not be used during pregnancy. (see section 4.3). Studies in animals have shown reproductive toxicity and teratogenicity (see section 5.3). The potential risk to humans is unknown.

Breast-feeding

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

Fertility

In an animal study, no impairment of fertility was demonstrated in male and female rats (see section 5.3).

IMMANAZ 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 the safety profile

The safety profile of IMMANAZ is based on an integrated safety database of patients who participated in clinical 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. Duration of treatment ranged from 12 weeks to more than 6 months.

In the table below, since the majority of the studies were of an open nature, all causality adverse events, by system organ class and frequency. The most commonly reported adverse events were visual disturbances, fever, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema and abdominal pain. The severity of the adverse events was generally mild to moderate. No clinically significant differences were seen when the safety data were were analysed by age, race, or gender.

Tabulated list of adverse reactions

MedDRA System Organ Class Side effects

Infections and infestations

• Frequent Sinusitis, Pseudomembranous colitis

Blood and lymphatic system disorders

• Frequent Thrombocytopenia, anaemia (including macrocytic, microcytic, normocytic, megaloblastic, aplastic), leukopenia, pancytopenia, agranulocytosis
• Less Frequent Lymphadenopathy, eosinophilia, disseminated intravascular coagulation, bone marrow depression

Immune system disorders

• Less frequent Allergic reaction, anaphylactoid reaction

Endocrine disorders

• Less frequent Adrenal cortex insufficiency, hypothyroidism
• Frequency unknown Hyperthyroidism

Metabolism and nutrition disorders

• Frequent Peripheral oedema

Psychiatric disorders

• Frequent Hallucinations, confusion, depression, anxiety, agitation, insomnia

Nervous system disorders

• Frequent Headache
• Dizziness, tremor, paraesthesia, syncope, hypertonia, somnolence.
• Less Frequent Ataxia, brain oedema, hypertonia, hypoaesthesia, nystagmus
• Frequency unknown Guillain-Barre syndrome, oculogyric crisis, extrapyramidal syndrome, hepatic coma, insomnia, encephalopathy, somnolence during infusion

Eye disorders

• Frequent Visual disturbances (including altered/enhanced visual perception, blurred vision, colour vision change, photophobia)
• Less frequent Blepharitis, optic nerve disorder, papilloedema, oculogyric crisis, scleritis, diplopia
• Frequency unknown Corneal opacity, optic atrophy

Ear and labyrinth disorders

• Less frequent Vertigo, hypoacusis, tinnitus

Cardiac disorders

• Frequent Supraventricular dysrhythmia, atrial dysrhythmia, tachycardia, bradycardia
• Less frequent Ventricular dysrhythmia, ventricular fibrillation, supraventricular tachycardia, prolonged QT interval
• Frequency unknown Atrioventricular (AV) complete block, bundle branch block, nodal dysrhythmia, ventricular tachycardia (including Torsades de Pointes)

Vascular disorders

• Frequent Hypotension, thrombophlebitis, phlebitis
• Frequency unknown Lymphangitis

Respiratory, thoracic and mediastinal disorders

• Frequent Acute respiratory distress syndrome, pulmonary oedema

Gastrointestinal disorders

• Frequent Nausea, vomiting, diarrhoea, abdominal pain, cheilitis, gastroenteritis, dyspepsia, constipation, gingivitis
• Less frequent Duodenitis, glossitis, pancreatitis, tongue oedema, peritonitis
• Frequency unknown Pseudomembranous colitis

Hepatobiliary disorders

• Frequent Elevated liver function tests (including AST, ALT, alkaline phosphatase, GGT, LDH, bilirubin), jaundice, cholestatic jaundice, hepatitis
• Less frequent Cholecystitis, cholelithiasis, enlarged liver, hepatic failure

Skin and subcutaneous tissue disorders

• Frequent Rash
• Frequent Pruritus, maculopapular rash, photosensitivity, skin reaction, alopecia, exfoliative dermatitis, purpura
• Less frequent Fixed drug eruption, eczema, psoriasis, Stevens-Johnson syndrome, urticaria
• Frequency unknown Angioedema, discoid lupus erythematosus, erythema multiforme, toxic epidermal necrolysis, pseudoporphyria

Musculoskeletal, connective tissue and bone disorders

• Frequent Back pain
• Less frequent Arthritis

Renal and urinary disorders

• Frequent Acute kidney/renal failure, haematuria
• Less frequent Nephritis, renal/kidney tubular necrosis, proteinuria

General disorders and administration site conditions

• Frequent Pyrexia, peripheral oedema
• Chills, asthenia, chest pain, injection site reaction/inflammation, flu syndrome, facial oedema

Investigations

• Frequent Increased creatinine
• Less frequent Hypercholesterolemia, increased blood urea

Reporting of suspected adverse reactions

Healthcare professionals are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

There is no known antidote to IMMANAZ. Voriconazole is haemodialysed with a clearance of 121 ml/min. The intravenous vehicle, SBECD, is haemodialysed with a clearance of 55 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole and SBECD from the body.