Vicomyl 200 Mg IV Powder for solution for infusion.

VICOMYL 200 MG IV is indicated for:

• 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.

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.4).

Posology: It is recommended that VICOMYL 200 MG IV is administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours. Not for bolus injection. (See u2018Method of administrationu2019 below and u2018Instructions for reconstitutionu2019, section 6.6)

Special populations:

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 voriconazole therapy. VICOMYL 200 MG IV is haemodialysed with a clearance of 121 ml/min. A four-hour haemodialysis session does not remove a sufficient amount of VICOMYL 200 MG IV 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. 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 VICOMYL 200 MG IV. VICOMYL 200 MG IV has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C). VICOMYL 200 MG IV 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 (also see section 4.8).

VICOMYL 200 MG IV is contraindicated in:

• Patients with known hypersensitivity to voriconazole or to any of the excipients (see section 6.1).
• Co-administration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine since increased plasma concentrations of these medicines can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.5).
• Co-administration with rifampicin, carbamazepine and phenobarbital since these medicines are likely to decrease plasma voriconazole concentrations significantly (see section 4.5).
• Co-administration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose (see section 4.5, for lower doses see section 4.4).
• Co-administration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicines can lead to ergotism (see section 4.5).
• Co-administration with sirolimus since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5).
• Co-administration with St. John's Wort (see section 4.5).
• Co-administration with rifabutin since VICOMYL 200 MG IV is likely to increase plasma concentrations of rifabutin significantly (see section 4.5).
• Patients with prolonged QT syndrome.
• Pregnancy and lactation.
• Severe impairment of hepatic function (Child-Pugh Class C).
• Co-administration of standard doses of VICOMYL 200 MG IV with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations. Voriconazole also significantly increases efavirenz plasma concentrations (see section 4.5, for lower doses see section 4.4).
• Co-administration of VICOMYL 200 MG IV with naloxegol, a CYP3A4 substrate, is contraindicated since increased plasma concentrations of naloxegol can precipitate opioid withdrawal symptoms (see section 4.5).
• Co-administration of VICOMYL 200 MG IV with tolvaptan is contraindicated since strong CYP3A4 inhibitors such as VICOMYL 200 MG IV significantly increase plasma concentrations of tolvaptan (see section 4.5).
• Co-administration of VICOMYL 200 MG IV with lurasidone is contraindicated since significant increases in lurasidone exposure have the potential for serious adverse reactions (see section 4.5).
• Co-administration with venetoclax at initiation and during the venetoclax dose titration phase is contraindicated since VICOMYL 200 MG IV is likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysis syndrome (see section 4.5).

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

Caution should be used in prescribing VICOMYL 200 MG IV to patients with hypersensitivity to other azoles (see also section 4.8).

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. Depending on the severity of the symptoms, consideration should be given to stopping treatment.

Voriconazole has been associated with QTc interval prolongation. There have been cases of torsades de pointes in patients taking voriconazole who had risk factors, such as a history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicines that may have been contributory. VICOMYL 200 MG IV should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• Congenital or acquired QTc-prolongation (see section 4.3). Voriconazole may prolong the QT interval without a clear relationship to plasma concentration. VICOMYL 200 MG IV should not be used concomitantly with other medicines which prolong the QT interval.
• Cardiomyopathy, in particular when heart failure is present.
• Sinus bradycardia.
• Existing symptomatic arrhythmias.

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).

Patients receiving VICOMYL 200 MG IV 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 VICOMYL 200 MG IV and at least weekly for the first month of treatment. Treatment duration should be as short as possible. 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, VICOMYL 200 MG IV should be discontinued. Monitoring of hepatic function should be carried out in both children and adults.

Serious dermatological adverse reactions:

• Phototoxicity: In addition, VICOMYL 200 MG IV has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudo porphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during VICOMYL 200 MG IV treatment and use measures such as protective clothing and sunscreen with a 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, VICOMYL 200 MG IV discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If VICOMYL 200 MG IV is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. VICOMYL 200 MG IV 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) 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 VICOMYL 200 MG IV discontinued if lesions progress.

Visual adverse reactions: There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see section 4.8). These visual disturbances may be transient and fully reversible, with the majority spontaneously resolving within 60 minutes (see section 4.8).

Renal adverse reactions: Acute renal failure has been observed in severely ill patients undergoing treatment with VICOMYL 200 MG IV. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicines 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 or haematopoietic stem cell transplantation [HSCT]), should be monitored closely during VICOMYL 200 MG IV treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Careful monitoring of phenytoin levels is recommended when phenytoin is co-administered with VICOMYL 200 MG IV. Concomitant use of VICOMYL 200 MG IV and phenytoin should be avoided (see section 4.5).

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate): When VICOMYL 200 MG IV is co-administered with efavirenz the dose of VICOMYL 200 MG IV should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.3 and 4.5).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Co-administration of VICOMYL 200 MG IV and low-dose ritonavir (100 mg twice daily) should be avoided (see section 4.3 for higher doses and section 4.5).

Everolimus (CYP3A4 substrate, P-gp substrate): Co-administration of VICOMYL 200 MG IV with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see section 4.5).

Methadone (CYP3A4 substrate): Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when co-administered with voriconazole since methadone levels increased following co-administration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).

Short-acting opiates (CYP3A4 substrate): Reduction in the dose of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. sufentanil) should be considered when co-administered with voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is co-administered with voriconazole, and in an independent published study concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC 0-u221e of fentanyl, frequent monitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

Long-acting opiates (CYP3A4 substrate): Reduction in the dose of oxycodone and other long-acting opiates metabolised by CYP3A4 (e.g. hydrocodone) should be considered when co-administered with VICOMYL 200 MG IV. Frequent monitoring for opiate-associated adverse reactions may be necessary (see section 4.5).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Co-administration of oral voriconazole and oral fluconazole resulted in a significant increase in C max and AUC of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for VICOMYL 200 MG IV -associated adverse reactions is recommended if VICOMYL 200 MG IV is used sequentially after fluconazole (see section 4.5).

Ciclosporin and tacrolimus (CYP3A4 substrates): Clinically significant medicine interactions with VICOMYL 200 MG IV may occur in patients who are receiving treatment with ciclosporin or tacrolimus (see section 4.5).

Glasdegib (CYP3A4 substrate): Co-administration of VICOMYL 200 MG IV is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation (see section 4.5). If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrate): Co-administration of VICOMYL 200 MG IV with tyrosine kinase inhibitors metabolised by CYP3A4 is expected to increase tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close monitoring is recommended (see section 4.5).

Adrenal events: Adrenal insufficiency has been reported in patients receiving azoles, as contained in VICOMYL 200 MG IV. Adrenal insufficiency has been reported in patients receiving VICOMYL 200 MG IV with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, VICOMYL 200 MG IV -associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression (see section 4.5). Cushingu2019s syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving VICOMYL 200 MG IV concomitantly with corticosteroids. Patients on long-term treatment with VICOMYL 200 MG IV and corticosteroids (including inhaled corticosteroids e.g. budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during treatment and when VICOMYL 200 MG IV is discontinued (see section 4.5). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushingu2019s syndrome or adrenal insufficiency.

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.

Unless otherwise specified, interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration.

VICOMYL 200 MG IV 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), co-administration is contraindicated (see below and section 4.3).

Interaction table: Interactions between voriconazole and other medicines are listed in the table below (once daily as u201cQDu201d, twice daily as u201cBIDu201d, three times daily as u201cTIDu201d and not determined as u201cNDu201d). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (u2194), below (u2193) or above (u2191) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUC, AUC t and AUC0-u221e represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively. The interactions in the table are presented in the following order: contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

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

Pregnancy: There are no adequate data on the use of VICOMYL 200 MG IV in pregnant women available. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. VICOMYL 200 MG IV must not be used during pregnancy.

Breastfeeding: The excretion of voriconazole into breast milk has not been investigated. Breastfeeding must be stopped on initiation of treatment with VICOMYL 200 MG IV.

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

VICOMYL 200 MG IV 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.

a) Summary of adverse effects: 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 frequently reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhoea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

b) Tabulated list of adverse reactions: In the table 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: Frequent, Less frequent and Frequency unknown (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported. There is no known antidote to voriconazole. 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.