Composition
VORITEK-200 Tablets
Each film-coated tablet contains:
Voriconazole …............ 200 mg
Colour: Titanium Dioxide
VORITEK I.V.
Each vial contains:
Voriconazole …............. 200 mg
(as a sterile, freeze-dried powder for reconstitution with 20 mL Sterile Water for Injection, IP)
Dosage Form/S
Oral tablet and lyophilized powder for intravenous solution.
Pharmacology
Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome (CY) P450-mediated 14-alpha-lanosterol demethylation, 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 CYP450 enzymes than for various mammalian CYP450 enzyme systems.
Pharmacodynamics
Clinical efficacy 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 (with often partial or complete response) include 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 of 0.05 to 2 mcg/mL.
In vitro activity against Curvularia spp. and Sporothrix spp. has been shown, but the clinical significance is unknown.
Clinical isolates with decreased susceptibility to voriconazole have been identified. However, elevated minimum inhibitory concentrations did not always correlate with clinical failure and clinical success has been observed in patients infected with organisms resistant to other azoles. Correlation of In vitro activity with clinical outcome is difficult owing to the complexity of the patients studied in clinical trials; breakpoints for voriconazole remain to be established.
Pharmacokinetics
The pharmacokinetics of voriconazole has been characterized in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at a risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.
The pharmacokinetics of voriconazole is non-linear due to the 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). When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to the 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 subjects.
Absorption
Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (Cmax) 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, the Cmax and the AUC are reduced by 34% and 24%, respectively. The absorption of voriconazole is not affected by changes in the gastric pH.
Bioequivalence was established between the 200 mg tablets and the 40 mg/mL oral suspension when administered as a 200 mg dose.
Distribution
The volume of distribution for voriconazole at the steady state is estimated to be 4.6 l/kg, suggesting extensive distribution into the tissues. Plasma protein-binding is estimated to be 58%. Cerebrospinal fluid samples from 8 patients in a compassionate programme showed detectable voriconazole concentrations in all patients.
Metabolism
In vitro studies showed that voriconazole is metabolized by the hepatic CYP450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4.
The inter-individual variability of voriconazole pharmacokinetics is high.
In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15 20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3 5%. Studies conducted in healthy Caucasian and Japanese subjects have shown that poor metabolizers have, on average, a 4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, a 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts.
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.
Excretion
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 I.V. 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 I.V. dosing.
The terminal half-life of voriconazole depends on the dose and is approximately 6 hours at 200 mg (orally). Because of the non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.
Indications
VORITEK-200 Tablets and I.V. are indicated in adults and children aged 2 years and above for the following:
- Treatment of invasive aspergillosis.
- Treatment of candidaemia in non-neutropenic patients.
- Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).
- Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium\ spp.
VORITEK-200 Tablets and I.V. should be administered primarily to patients with progressive, possibly life-threatening infections
Dosage and Administration
Dosage
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see WARNINGS AND PRECAUTIONS).
VORITEK I.V. requires reconstitution and dilution prior to administration as an I.V. infusion. Not for bolus injection.
It is recommended that VORITEK I.V. be administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours.
Adults and Adolescents (aged 12 to 14 years and ≥50 kg; aged 15 to 17 years, regardless of body weight)
Therapy must be initiated with the specified loading dose regimen of either I.V. or oral VORITEK to achieve plasma concentrations close to the steady state on day 1. On the basis of the high oral bioavailability, switching between I.V. and oral administration is appropriate when clinically indicated.
Detailed information on dosage recommendations is provided in the following table:
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I.V. |
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Aspergillosis |
first 24 hours |
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non-neutropenic patients and other deep-tissue Candida infections |
first 24 hours |
q12h |
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Candidiasis |
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and Fusariosis |
first 24 hours |
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b In healthy volunteer studies, the 200 mg oral q12h dose provided an exposure (AUCτ) similar to a 3 mg/kg I.V. q12h dose; the 300 mg oral q12h dose provided an exposure (AUCτ) similar to a 4
mg/kg I.V. q12h dose.
c Adult patients who weigh less than 40 kg should receive half of the oral maintenance dose.
d Not evaluated in patients with oesophageal candidiasis.
Dosage adjustment
VORITEK-200 tablets
If patient response is inadequate, the maintenance dose may be increased to 300 mg every 12 hours. For adult patients weighing less than 40 kg, the oral maintenance dose may be increased to 150 mg every 12 hours.
If a patient is unable to tolerate 300 mg orally every 12 hours, the oral maintenance dose should be reduced by 50 mg steps to 200 mg every 12 hours (or to 100 mg every 12 hours for adult patients weighing less than 40 kg).
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg (see WARNINGS AND PRECAUTIONS, Drug Interactions).
The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg) (see WARNINGS AND PRECAUTIONS, Drug Interactions).
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see WARNINGS AND PRECAUTIONS, Drug Interactions).
VORITEK I.V.
If patients are unable to tolerate treatment at 4 mg/kg twice daily, the I.V. dose should be reduced to 3 mg/kg twice daily.
Rifabutin or phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg I.V. twice daily (see WARNINGS AND PRECAUTIONS, Drug Interactions).
Efavirenz may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see WARNINGS AND PRECAUTIONS, Drug Interactions).
Children (aged 2 to <12 years) and Young Adolescents (aged 12 to 14 years and <50 kg)
Use in paediatric patients aged 2 to <12 years with hepatic or renal impairment has not been studied.
The recommended dosing regimen is as follows:
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(first 24 hours) |
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first 24 hours) |
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maximum dose of 350 mg twice daily) |
It is recommended to initiate the therapy with the I.V regimen, and the oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg I.V. dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.
If the child is able to swallow tablets, the dose should be administered to the nearest mg/kg dose possible, using whole 50 mg tablets.
Other Adolescents (aged 12 to 14 years and ≥50 kg; 15 to 16 years, regardless of age)
Should be dosed as adults.
Dose 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).
Duration of Treatment
Treatment should be as short as possible, depending on the patient's clinical and mycological response.
The duration of treatment with the I.V. formulation should be no longer than 6 months. For voriconazole in general, long-term treatment greater than 6 months requires careful assessment of the benefit-risk balance (see WARNINGS AND PRECAUTIONS).
Geriatric Use
No dose adjustment is necessary for elderly patients.
Renal Impairment
VORITEK Tablets
The pharmacokinetics of orally administered voriconazole is not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild-to-severe renal impairment.
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.
VORITEK I.V.
In patients with moderate-to-severe renal dysfunction (creatinine clearance <50 mL/min), accumulation of the I.V. vehicle, HPBCD, occurs. Hence, oral voriconazole should be administered to these patients unless an assessment of the benefit/risk to the patient justifies the use of I.V. 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 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.
Hepatic Impairment
No dose adjustment is necessary in 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 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).
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 hepatic impairment must be carefully monitored for drug toxicity.
Method of Reconstitution and Dilution
VORITEK I.V.
The powder should be reconstituted with 19 mL of Water for Injection to obtain an extractable volume of 20 mL of clear concentrate containing 10 mg/mL of voriconazole. Discard the VORITEK vial if the vacuum does not pull the diluent into the vial. It is recommended that a standard 20 mL (non-automated) syringe be used to ensure that the exact amount (19.0 mL) of Water for Injection is dispensed. This medicinal product is for single use only and any unused solution should be discarded; also, only clear solutions without particulates should be used.
For administration, the required volume of the reconstituted concentrate is added to a recommended compatible infusion solution (detailed below) to obtain a finalsolution containing 0.5-5 mg/mL of voriconazole.
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Dose (number of vials) |
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The reconstituted solution can be diluted with the following:
- Sodium Chloride 9 mg/mL (0.9%) Solution for Injection
- Compound Sodium Lactate I.V. Infusion 5% Glucose and Lactated Ringer's I.V. Infusion
- 5% Glucose and 0.45% Sodium Chloride I.V. Infusion
- 5% Glucose I.V. Infusion
- 5% Glucose in 20 mEq Potassium Chloride I.V. Infusion
- 0.45% Sodium Chloride I.V. Infusion
- 5% Glucose and 0.9% Sodium Chloride I.V. Infusion
The compatibility of voriconazole with diluents other than described above and those mentioned under INCOMPATIBILITY is unknown
Voriconazole is a single-dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, the reconstituted solution must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should normally not be longer than 24 hours at 2-8 ºC, unless reconstitution has taken place in controlled and validated aseptic conditions.
Contraindications
VORITEK-200 Tablets and I.V. are contraindicated in patients with a known hypersensitivity to voriconazole or its excipients.
Co-administration of the CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine, along with voriconazole are contraindicated since increased plasma concentrations of these drugs can lead to QTc prolongation and rare occurrences of torsades de pointes.
Co-administration of voriconazole with rifampicin, carbamazepine and phenobarbital is contraindicated since these medicinal products are likely to decrease plasma voriconazole concentrations significantly.
Co-administration of voriconazole with ritonavir ((400 mg and above twice daily) is contraindicated because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects.
Co-administration of voriconazole with sirolimus is contraindicated because voriconazole significantly increases sirolimus concentrations in healthy subjects.
Co-administration of voriconazole with efavirenz (400 mg and above once daily) is contraindicated because efavirenz significantly decreases plasma voriconazole concentrations while voriconazole also significantly increases favirnez plasma concentrations.
The concomitant use of voriconazole with St John's wort is contraindicated.
Co-administration of ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, is contraindicated since increased plasma concentrations of these medicinal products can lead to ergotism.
Warnings and Precautions
General
Caution should be used in prescribing VORITEK-200 Tablets and I.V. to patients with a hypersensitivity to other azoles.
Duration of I.V. Treatment
The duration of treatment with the I.V. formulation should be no longer than 6 months.
Cardiovascular
Voriconazole has been associated with QT 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 pro-arrhythmic conditions, such as the following:
- Congenital or acquired QT prolongation.
- Cardiomyopathy, in particular when heart failure is present.
- Sinus bradycardia.
- Existing symptomatic arrhythmias.
- Concomitant medicinal product that is known to prolong the QT interval.
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy.
Infusion-related Reactions
Infusion-related reactions, predominantly flushing and nausea, have been observed during administration of the I.V. formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment (see UNDESIRABLE EFFECTS).
Visual Adverse Reactions
There have been rare reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see UNDESIRABLE EFFECTS).
Monitoring of Pancreatic Function
Patients, especially children, with risk factors for acute pancreatitis (e.g. recent chemotherapy, haematopoietic stem cell transplantation ), 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 patients develop a rash, they should be monitored closely and voriconazole discontinued if lesions progress.
In addition, voriconazole has been associated with phototoxicity and pseudoporphyria. It is recommended that patients avoid intense or prolonged exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen, when appropriate. In patients with phototoxicity and additional risk factors, including immunosuppression, squamous cell carcinoma of the skin has been reported during long-term therapy. Physicians should, therefore, consider the need to limit the exposure to voriconazole. If phototoxic reactions occur, voriconazole discontinuation should be considered after multidisciplinary advice and the patient should be referred to a dermatologist.
Long-Term Treatment
The following severe adverse events have been reported in relation with long-term treatment with voriconazole, physicians should therefore consider the need to limit the exposure to voriconazole (see DOSAGE AND ADMINISTRATION):
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 and the patient should be referred to a dermatologist. Voriconazole discontinuation 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.
Paediatric Population
Safety and effectiveness in paediatric subjects aged <2 years has not been established. Voriconazole is indicated for paediatric patients aged 2 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, I.V. voriconazole administration is recommended.
VORITEK-200 Tablets contain lactose and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.
Sodium Content
Each vial of VORITEK I.V. contains 217.6 mg of sodium. This should be taken into consideration for patients on a controlled sodium diet.
Drug Interactions
Voriconazole is metabolized by, and inhibits the activity of CYP450 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 metabolized 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 (b.i.d.). These results are relevant to other populations and routes of administration.
Interactions between voriconazole and other medicinal products are listed in the table below.
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.
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Geometric Mean Changes (%) |
Concerning Co- Administration |
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Astemizole, cisapride,
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increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes. |
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-acting barbiturates (e.g. phenobarbital, mephobarbital) |
carbamazepine and long -acting barbiturates are likely to significantly decrease plasma voriconazole concentrations. |
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Efavirenz (a non-nucleoside
High dose (400 mg q.d.)* Low dose (300 mg q.d., co- |
Efavirenz Cmax ↑ 38% Voriconazole Cmax 61% Compared to efavirenz Efavirenz Cmax ↔Efavirenz |
Standard doses of Voriconazole may be co- When voriconazole |
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Ergot alkaloids (e.g.
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voriconazole is likely to increase the plasma concentrations of ergot alkaloids and lead to ergotism. |
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Rifabutin 300 mg q.d. (co-administered 300 mg q.d. (co-administered |
Voriconazole Cmax↓ 69% Rifabutin Cmax ↑ 195% Compared to |
Concomitant use of The maintenance dose of Careful monitoring of full |
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Voriconazole Cmax↓ 93% Voriconazole AUCτ ↓ 96% |
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Ritonavir (protease inhibitor) High dose (400 mg b.i.d.) Low dose (100 mg b.i.d.)* |
Ritonavir Cmax and AUCτ ↔ Ritonavir Cmax ↓ 25% |
Co-administration of Co-administration of |
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300 mg t.i.d. (co-administered with voriconazole 400 mg single dose) |
published study, Voriconazole AUC0 infinity ↓59% |
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voriconazole is likely to significantly increase the plasma concentrations of everolimus. |
voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. |
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Voriconazole Cmax ↑ 57% Fluconazole Cmax ND |
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. |
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Phenytoin
300 mg q.d. 300 mg q.d. (co-administered Anticoagulants Warfarin (30 mg single dose,
Other Oral Coumarins (e.g. phenprocoumon, acenocoumarol) |
Voriconazole Cmax↓ 49% Voriconazole AUCτ ↓ 69% Phenytoin Cmax ↑ 67% Phenytoin AUCτ ↑ 81% Compared to voriconazole Voriconazole AUCτ ↑ 39% Maximum increase in prothrombin Although not studied, |
Concomitant use of voriconazole Phenytoin may be co- Close monitoring of prothrombin |
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(e.g. midazolam, triazolam, alprazolam) |
is likely to increase the plasma concentrations of benzodiazepines that are metabolized by CYP3A4 and lead to a prolonged sedative effect. |
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Immunosuppressants Sirolimus (2 mg single dose) Ciclosporin (in stable renal Tacrolimus (0.1 mg/kg single |
In an independent Sirolimus Cmax ↑ 6.6-foldSirolimus |
Co-administration of voriconazole When initiating voriconazole When initiating |
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Long-acting Opiates
Oxycodone (10 mg single |
In an independent Oxycodone Cmax↑ 1.7-fold Oxycodone AUC0 infinity ↑ 3.6-fold |
and other long-acting opiates metabolized by CYP3A4 (e.g. hydrocodone) should be considered. Frequent monitoring for opiate-associated adverse reactions may be necessary. |
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R-methadone R-methadone S-methadone Cmax ↑ 65% |
adverse reactions and toxicity related to methadone, including QT prolongation, is recommended. Dose reduction of methadone may be needed. |
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Non-Steroidal Anti- Ibuprofen (400 mg single dose) Diclofenac (50 mg single dose) |
S-Ibuprofen Cmax ↑ 20% S-Ibuprofen AUC0 infinity ↑ 100% Diclofenac Cmax ↑ 114% Diclofenac AUC0 infinity ↑ 78% |
reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed. |
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Omeprazole Cmax↑ 116% Omeprazole AUCτ ↑ 280% Voriconazole Cmax ↑ 15% Voriconazole AUCτ ↑ 41% Other proton-pump inhibitors |
No dose adjustment of voriconazole When initiating voriconazole |
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Oral Contraceptives* Norethisterone/ethinyloestradiol |
Ethinyloestradiol Cmax ↑ 36% Ethinyloestradiol AUCτ ↑ 61% Norethisterone Cmax ↑ 15% Norethisterone AUCτ ↑ 53% Voriconazole Cmax ↑ 14% Voriconazole AUCτ ↑ 46% |
related to oral contraceptives , in addition to those for voriconazole, is recommended. |
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Short-acting Opiates
Alfentanil (20 μg/kg single dose, Fentanyl (5 μg/kg single dose) |
In an independent Alfentanil AUC0 infinity ↑ In an independent published Fentanyl AUC0 infinity |
fentanyl and other short- acting opiates similar in structure to alfentanil and metabolized by CYP3A4 (e.g. sufentanil) should be considered. Extended and frequent monitoring for respiratory depression and other opiate -associated adverse reactions is recommended. |
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Statins
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clinically, voriconazole is likely to increase the plasma concentrations of statins that are metabolized by CYP3A4 and could lead to rhabdomyolysis. |
should be considered. |
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Sulphonylureas (e.g.
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voriconazole is likely to increase the plasma concentrations of sulphonylureas and cause hypoglycaemia. |
blood glucose is recommended. Dose reduction of sulphonylureas should be considered. |
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Vinca Alkaloids
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voriconazole is likely to increase the plasma concentrations of vinca alkaloids and lead to neurotoxicity. |
alkaloids should be considered. |
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Other HIV Protease Inhibitors
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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. |
any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed. |
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Other Non-Nucleoside Reverse
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Not studied clinically. The findings of the |
for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed. |
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Voriconazole AUCτ ↑ 23% |
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Digoxin AUCτ ↔ |
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Indinavir AUCτ ↔ Voriconazole Cmax ↔ Voriconazole AUCτ ↔ |
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Macrolide Antibiotics Erythromycin (1 g b.i.d.)
Azithromycin (500 mg q.d.) |
Voriconazole Cmax and AUCτ ↔ Voriconazole Cmax and AUCτ ↔ The effect of voriconazole |
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Mycophenolic acid (1 g single
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Mycophenolic acid AUCt ↔ |
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Prednisolone (60 mg single
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Prednisolone Cmax ↑ 11% Prednisolone AUC0 infinity ↑ 34% |
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Cmax and AUCτ ↔ |
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(Once daily is indicated as 'q.d.', twice daily as 'b.i.d.', three times daily as 't.i.d.' 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, AUCt and AUC0 infinity 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.
Renal impairment
See DOSAGE AND ADMINISTRATION. 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 medications and have concurrent conditions that may result in decreased renal function (see UNDESIRABLE EFFECTS).
Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.
Hepatic Impairment
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 should be as short as possible; however, if based on the benefit-risk assessment, the treatment is continued (see DOSAGE AND 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.
Pregnancy
No adequate information on the use of voriconazole in pregnant women is 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.
Lactation
The excretion of voriconazole into human breast milk has not been investigated. Breastfeeding should be stopped on initiation of treatment with voriconazole. Voriconazole should not be used in nursing mothers unless the benefit clearly outweighs the risk.
Paediatric Use
Safety and effectiveness in paediatric subjects below the age of 2 years have not been established. Voriconazole is indicated for paediatric patients aged 2 years or older. Hepatic function should be monitored. Oral bioavailability may be limited in paediatric patients, aged 2 to
Geriatric Use
No dose adjustment is necessary for elderly patients.
Undesirable Effects
The most commonly reported adverse events were visual disturbances, pyrexia, 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 analysed by age, race, or gender.
Tabulated List of Adverse Reactions
In the table below, adverse events by system organ class and frequency are listed. Frequency categories are expressed as follows:
Very common (≥1/10); common (≥1/100 and <1/10); uncommon (≥1/1,000 and <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000); and, not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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thrombocytopenia, anaemia, purpura |
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lymphadenopathy, eosinophilia |
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pyramidal symptoms, peripheral neuropathy |
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and photophobia) |
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nystagmus, scleritis, blepharitis |
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opacity |
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syncope, supraventricular arrhythmia, supraventricular tachycardia, tachycardia, bradycardia |
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complete block, bundle-branch block, nodal rhythm |
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tongue, dyspepsia, constipation |
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cholelithiasis |
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maculo-papular rash, macular rash, papular rash, cheilitis, pruritus, alopecia, erythema |
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dermatitis, urticaria, drug hypersensitivity, psoriasis |
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phosphatase, GGT, LDH, bilirubin), blood creatinine increased |
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increased, blood cholesterol increased |
Overdosage
In clinical trials, there were three cases of accidental overdose. All occurred in paediatric patients who received up to five times the recommended I.V. dose of voriconazole. A single adverse event 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 I.V. vehicle, HPBCD, is haemodialysed with a clearance of 55 mL/min. In an overdose, haemodialysis may assist in the removal of voriconazole and HPBCD from the body.
Incompatibility
VORITEK-200 tablets
Not applicable.
VORITEK I.V.
VORITEK I.V. must not be infused into the same line or cannula concomitantly with other I.V. products. When the VORITEK I.V. infusion is complete, the line may be used for administration of other I.V. products.
Blood Products and Short-Term Infusion of Concentrated Solutions of Electrolytes
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiation of voriconazole therapy. VORITEK I.V. must not be administered simultaneously with any blood product or any short-term infusion of concentrated solutions of electrolytes, even if the two infusions are running in separate lines.
Total Parenteral Nutrition (TPN)
TPN need not be discontinued when prescribed with VORITEK I.V. but does need to be infused through a separate line. If infused through a multiple-lumen catheter, TPN should be administered using a different port from the one used for voriconazole. Voriconazole must not be diluted with 4.2% Sodium Bicarbonate Infusion.
This medicinal product must not be mixed with other medicinal products except those mentioned under DOSAGE AND ADMINISTRATION
Storage and Handling Instructions
VORITEK-200 tablets
No special precautions for storage.
VORITEK I.V.
Before Opening
Store below 30ºC.
Reconstitution Solution
Voriconazole is a single-dose, unpreserved sterile lyophile. Therefore, from a microbiological point of view, the reconstituted solution must be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8ºC, unless reconstitution has taken place in controlled and validated aseptic conditions.
Packaging Information
VORITEK-200 tablets: Blister pack of 4 tablets
VORITEK I.V.: Vial of 30 mL
Last reviewed: September 2013
Last updated: October 2013