Vortimal

Voriconazole.

White to off-white lyophilized powder.
After reconstitution and dilution: The solution for infusion is clear, colourless and free from visible particles.
Each vial contains 200 mg Voriconazole.
After reconstitution, each ml contains 10 mg of voriconazole.

Pharmacology: Pharmacodynamics: Mechanism of action: Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P 450-mediated 14 alpha-lanosterol demethylations, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.
Clinical efficacy and safety: In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition, voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.
Clinical efficacy defined as a partial or complete response has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans, Candida spp., including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and limited numbers of C. dubliniensis, C. inconspicua, and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.
Other treated fungal infections (often with either partial or complete response) included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections.
In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 μg/ml.
In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.
Breakpoints: Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.
The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit minimal inhibitory concentration (MICs) of less than 1 mg/L for voriconazole.
However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). (See Table 1.)

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Pharmacokinetics: General pharmacokinetic characteristics: The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUCτ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice-daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by Day 6 in the majority of patients.
Long-term safety of hydroxypropylbetadex in humans is limited to 21 days (250 mg/kg/day).
Absorption: Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96%. When multiple doses of voriconazole are administered with high-fat meals, C_max and AUCτ are reduced by 34% and 24%, respectively. The absorption of voriconazole is not affected by changes in gastric pH.
Distribution: The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%.
Biotransformation: Voriconazole is metabolised by the hepatic cytochrome P 450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.
The inter-individual variability of voriconazole pharmacokinetics is high.
The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.
Elimination: Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.
After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (>94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.
The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally).
Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.
Pharmacokinetics in special patient groups: Gender: The safety profile and plasma concentrations observed in male and female were similar. Therefore, no dosage adjustment based on gender is necessary.
Older people: A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the older (see Dosage & Administration).
Paediatric population: The higher intravenous maintenance dose in paediatric relative to adults reflects the higher elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in paediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children's doses (see Dosage & Administration).
Renal impairment: The plasma protein binding of voriconazole was similar with different degrees of renal impairment. See Dosage & Administration and Precautions.
In patients with normal renal function, the pharmacokinetic profile of hydroxypropylbetadex, an ingredient of Voriconazole 200 mg powder for solution for infusion, has a short half-life of 1 to 2 hours and demonstrates no accumulation following successive daily doses. In patients with mild to severe renal insufficiency, the majority (>85%) of an 8 g dose of hydroxypropylbetadex is eliminated in the urine. In patients with mild, moderate, and severe renal impairment, half-life values were increased over normal values by approximately two-, four-, and six-fold, respectively. In these patients, successive infusions may result in accumulation of hydroxypropylbetadex until steady state is reached. Hydroxypropylbetadex is removed by haemodialysis, with a clearance of 37.5 ± 24 ml/min.
Hepatic impairment: Protein binding of voriconazole was not affected by impaired hepatic function. (See Dosage & Administration and Precautions.)

Voriconazole is a broad spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows: Treatment of invasive aspergillosis; Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei); Treatment of serious Candida infections including esophageal candidiasis; Treatment of candidemia in non-neutropenic patients and the following Candida infections: disseminated infection in skin and infections in abdomen, kidney, bladder wall and wounds; Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.
Prevention of breakthrough fungal infections in febrile high-risk neutropenic patients.
Prophylaxis in patients ≥12 years old who are at high risk of developing invasive fungal infections. The indication is based on a study which includes patients ≥12 years old undergoing haematopoietic stem cell transplantation.
Voriconazole should be administered primarily to immunocompromised patients with progressive, possibly life-threatening infections.

Adults: Therapy must be initiated with the specified intravenous loading dose regimen of voriconazole to achieve adequate plasma concentrations on Day 1. Intravenous treatment should be continued for at least 7 days before switching to oral treatment. Once the patient is clinically improved and can tolerate medication given by mouth, the oral tablet form or oral suspension form of voriconazole may be utilized. On the basis of the high oral bioavailability (96%), switching between intravenous and oral administration is appropriate when clinically indicated. (See Table 2.)

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Dosage Adjustment: Intravenous Administration: If patient response at 3 mg/kg every 12 hours is inadequate, the intravenous maintenance dose may be increased to 4 mg/kg every 12 hours.
If patients are unable to tolerate 4 mg/kg every 12 hours, reduce the intravenous maintenance dose to a minimum of 3 mg/kg every 12 hours.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously every 12 hours (see Precautions and Interactions).
Treatment duration depends upon patients' clinical and mycological response.
Elderly: No dose adjustment is necessary for elderly patients.
Patients with Renal Impairment: In patients with moderate to severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the intravenous vehicle, hydroxypropylbetadex, 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.
Voriconazole is hemodialyzed with a clearance of 121 mL/min. A four-hour hemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
The intravenous vehicle, hydroxypropylbetadex, is hemodialyzed with a clearance of 37.5 ± 24 mL/min.
Patients with Hepatic Impairment: No dose adjustment is necessary for patients with acute hepatic injury, manifested by elevated liver function tests (ALT, AST). Continued monitoring of liver function tests for further elevations is recommended.
It is recommended that the standard loading dose regimens be used but that the maintenance dose is 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).
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. (See Table 3.)

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It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
Safety and effectiveness in pediatric patients below the age of 2 years have not been established. Therefore, voriconazole is not recommended for children less than 2 years of age. Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see Pharmacology: Pharmacokinetics under Actions and Side Effects).
Use in All Other Adolescents (12 to 14 Years and ≥50 kg; 15 to 16 Years Regardless of Bodyweight): Voriconazole should be dosed as adults.
Dosage Adjustment: If patient response is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patients are unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).
Prophylaxis in Adults and Children: Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. It may only be continued up to 180 days after transplantation in case of continuing immunosuppression or graft versus host disease (GvHD).
Dosage: The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. Refer to treatment Tables previously mentioned.
Duration of Prophylaxis: The safety and efficacy of voriconazole use for longer than 180 days has not been adequately studied in clinical trials.
Administration: Voriconazole requires reconstitution and dilution (see Instructions for Use under Cautions for Usage) prior to administration as an intravenous infusion.
Voriconazole powder for solution for infusion is not recommended for bolus injection.
It is recommended that voriconazole is administered at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.
Route of Administration: Intravenous.

A single adverse reaction of photophobia of 10 minutes duration was reported to be associated with overdose of voriconazole.
There is no known antidote to voriconazole.
Voriconazole is haemodialysed with a clearance of 121 ml/min. The intravenous vehicle, hydroxypropylbetadex, is haemodialysed with a clearance of 37.5 ± 24 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole and hydroxypropylbetadex from the body.

Hypersensitivity to the active substance or to any of the excipients used in Vortimal.
Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see Interactions).
Coadministration with rifampicin, carbamazepine and phenobarbital since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see Interactions).
Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (see Interactions, for lower doses see Precautions).
Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose (see Interactions, for lower doses see Precautions).
Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicinal products can lead to ergotism (see Interactions).
Coadministration with sirolimus since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see Interactions).
Coadministration with St John's Wort (see Interactions).

Hypersensitivity: Caution should be used in prescribing Vortimal to patients with hypersensitivity to other azoles (see also Side Effects).
Duration of treatment: The duration of treatment with the intravenous formulation should be no longer than 6 months.
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 a 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 intervals Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see Dosage & Administration).
Infusion-related reactions: 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 (see Side Effects).
Visual adverse reactions: There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see Side Effects).
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 voriconazole treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.
Dermatological adverse reactions: Patients have rarely developed exfoliative cutaneous reactions, such as Stevens-Johnson syndrome, during treatment with voriconazole. If a patient develops a rash he should be monitored closely and voriconazole discontinued if lesions progress.
In addition, voriconazole has been associated with phototoxicity 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).
Long-term treatment: Long-term exposure treatment or prophylaxis) grated 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 voriconazole (see Pharmacology: Pharmacodynamics under Actions and Dosage & Administration). The following severe adverse events have been reported in relation to long-term voriconazole treatment.
Squamous cell carcinoma of the skin (SCC) has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur, multidisciplinary advice should be sought and the patient should be referred to a dermatologist. Voriconazole discontinuation and use of alternative antifungal agents should be considered. Dermatologic evaluation should be performed on a systematic and regular basis, whenever voriconazole is continued despite the occurrence of phototoxicity-related lesions, to allow early detection and management of premalignant lesions. Voriconazole should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified.
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 voriconazole discontinuation should be considered after multidisciplinary advice.
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 agents must be considered.
Phenytoin (CYP2C9 substrate and potent CYP450 inducer): Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (see Interactions).
Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate): When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see Dosage & Administration, Contraindications and Interactions).
Rifabutin (potent CYP450 inducer): Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g. uveitis) is recommended when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk (see Interactions).
Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate): Coadministration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see Contraindications and Interactions).
Everolimus (CYP3A4 substrate, P-gp substrate): Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently, there are insufficient sub to allow dosing recommendations in this situation (see Interactions).
Methadone (CYP3A4 substrate): Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with voriconazole since methadone levels increased following coadministration of voriconazole. Dose reduction of methadone may be needed (see Interactions).
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 coadministered with voriconazole (see Interactions). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is coadministered with voriconazole, and in an independent published study, concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC 0-∞ 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 metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for opiate-associated adverse reactions may be necessary (see Interactions).
Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor): Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUCτ of voriconazole. 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 (see Interactions).
Sodium content: Each vial of Vortimal contains 225.6 mg of sodium chloride. This should be taken into consideration for patients on a controlled sodium diet.
Effects on Ability to Drive and Use Machine: Vortimal has a 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.
Hepatic toxicity: There have been uncommon 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 Side Effects).
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, is based on the benefit-risk assessment the treatment is continued (see Dosage & Administration), 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.
Renal adverse reactions: 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 (see Side Effects).
Monitoring of renal function: Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Use in Children: Safety and effectiveness in paediatric subjects below the age of two years have not been established (see Pharmacology: Pharmacodynamics under Actions and Side Effects). Voriconazole is indicated for paediatric patients aged two years or older. 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.
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.

Pregnancy: There are no adequate data from the use of voriconazole in pregnant women. Vortimal must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.
Women of child-bearing potential: Women of child-bearing potential must always use effective contraception during treatment.
Breastfeeding: The excretion of voriconazole into breast milk has not been investigated. Breastfeeding must be stopped on initiation of treatment with Vortimal.

(See Table 4.)

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Description of selected adverse reactions: Visual disturbances: Visual impairments with voriconazole were very common. The visual disturbances include altered/enhanced visual perception, blurred vision, colour vision change or photophobia. These visual disturbances 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 disturbances were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual disturbances 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.
There have been post-marketing reports of prolonged visual adverse events (see Precautions).
Dermatological reactions: Dermatological reactions were common in patients treated with voriconazole and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have rarely developed serious cutaneous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme during treatment with voriconazole.
If a patient develops a rash they should be monitored closely and voriconazole discontinued if lesions progress. Photosensitivity reactions have been reported, especially during long-term therapy (see Precautions).
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 (see Precautions).
Liver function tests: 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 infrequently associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, and rare cases of hepatitis and hepatic failure leading to death (see Precautions).
Infusion-related reactions: During infusion of the intravenous formulation of voriconazole, 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 (see Precautions).
Prophylaxis: Discontinuation of voriconazole treatment has been reported in other study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, following adverse effects and treatment-emergent hepatic side effects.
Paediatric population: The adverse reaction profile of the paediatric patients was similar to that in adults. Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults.

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, drug 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.
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) co-administration is contraindicated (see as follows and Contraindications).
Interaction table: Interactions between voriconazole and other medicinal products are listed in the table as follows (once daily as "QD", twice daily as "BID", three times daily as "TID" and not determined as "ND"). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUCτ, AUC_t and AUC0-∞ 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 a 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. (See Tables 5a, 5b and 5c.)

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Instructions for Use: The powder is reconstituted with about 19 ml Water for Injections to obtain an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of voriconazole. Discard the vial if the vacuum does not pull the diluent into the vial. This medicinal product is for single use only and any unused solution should be discarded and only clear solutions without particles should be used.
For administration, the required volume of the reconstituted concentrate is added to a recommended compatible infusion solution (detailed in the table as follows) to obtain a final voriconazole solution containing 0.5-5 mg/ml.
The reconstituted solution can be diluted with: 0.9% Sodium Chloride Intravenous Infusion, Compound Sodium Lactate Intravenous Infusion, 5% Glucose and Compound Sodium Lactate Intravenous Infusion, 5% Glucose and 0.45% Sodium Chloride Intravenous Infusion, 5% Glucose Intravenous Infusion, 5% Glucose in 20 mEq Potassium Chloride Intravenous Infusion, 0.45% Sodium Chloride Intravenous Infusion, 5% Glucose and 0.9% Sodium Chloride Intravenous Infusion. (See Table 6.)

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The final voriconazole solution must be infused at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.
The compatibility of voriconazole with diluents other than described previously or in Incompatibilities as follows is unknown.
Incompatibilities: Vortimal must not be infused into the same line or cannula concomitantly with other intravenous products. When the Vortimal infusion is complete, the line may be used for administration of other intravenous products.
Blood Products and Concentrated Electrolytes: Voriconazole must not be infused concomitantly with any blood product or any short-term infusion of concentrated electrolytes, even if the two infusions are running in separate intravenous lines (or cannulas). Electrolyte disturbances such as hypokalaemia, hypomagnesemia and hypocalcaemia should be corrected prior to initiation of voriconazole therapy (see Precautions).
Intravenous Solutions Containing (Non-Concentrated) Electrolytes: Voriconazole can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.
Total Parenteral Nutrition (TPN): Voriconazole can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole (see Interactions).
Vortimal must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.
This medicinal product must not be mixed with other medicinal products except those mentioned previously.

Store at below 30°C. Store in the original package in order to protect from light.
After reconstitution: Store at 2-8°C for 24 hours.
After further dilution: Store at 25°C for 24 hours.
Shelf Life: 2 years.
After reconstitution: 24 hours at 2-8°C.
After further dilution: 24 hours at 25°C.

Antifungals

J02AC03 - voriconazole ; Belongs to the class of triazole and tetrazole derivatives. Used in the systemic treatment of mycotic infections.

B