VORITEK Tablets/Injection (Voriconazole)

Table of Content

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

In vitro, voriconazole displays broad-spectrum antifungal activity 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, such as Scedosporium or Fusarium, which have limited susceptibility to existing antifungal agents.

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:

  1. Treatment of invasive aspergillosis.
  2. Treatment of candidaemia in non-neutropenic patients.
  3. Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).
  4. 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:

Infection
Loading Dose
I.V.
Maintenance Dose a,b
I.V.
Oralc
Invasive
Aspergillosis
6 mg/kg q12h for the
first 24 hours
4 mg/kg q12h
200 mg q12h
Candidaemia in
non-neutropenic
patients and other
deep-tissue
Candida infections
6 mg/kg q12h for the
first 24 hours
3-4 mg/kg
q12h
200 mg q12h
Oesophageal
Candidiasis
d
d
200 mg q12h
Scedosporiosis
and Fusariosis
6 mg/kg q12h for the
first 24 hours
4 mg/kg q12h
200 mg q12h

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:

 
I.V.
Oral
Loading Dose Regimen
(first 24 hours)
9 mg/kg every 12 hours
Not recommended
Maintenance Dose (after
first 24 hours)
8 mg/kg twice daily
9 mg/kg twice daily (a
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.

Required Volumes of 10 mg/mL VORITEK Concentrate
Body
Weight
(kg)
Volume of VORITEK Concentrate (10 mg/mL) required for:
3 mg/kg
Dose
(number of
vials)
4 mg/kg Dose
(number of
vials)
6 mg/kg Dose
(number of
vials)
8 mg/kg Dose
(number of
vials)
9 mg/kg Dose
(number of
vials)
10
-
4.0 mL (1)
-
8.0 mL (1)
9.0 mL (1)
15
-
6.0 mL (1)
-
12.0 mL (1)
13.5 mL (1)
20
-
8.0 mL (1)
-
16.0 mL (1)
18.0 mL (1)
25
-
10.0 mL (1)
-
20.0 mL (1)
22.5 mL (2)
30
9.0 mL (1)
12.0 mL (1)
18.0 mL (1)
24.0 mL (2)
27.0 mL (2)
35
10.5 mL (1)
14.0 mL (1)
21.0 mL (2)
28.0 mL (2)
31.5 mL (2)
40
12.0 mL (1)
16.0 mL (1)
24.0 mL (2)
32.0 mL (2)
36.0 mL (2)
45
13.5 mL (1)
18.0 mL (1)
27.0 mL (2)
36.0 mL (2)
40.5 mL (3)
50
15.0 mL (1)
20.0 mL (1)
30.0 mL (2)
40.0 mL (2)
45.0 mL (3)
55
16.5 mL (1)
22.0 mL (2)
33.0 mL (2)
44.0 mL (3)
49.5 mL (3)
60
18.0 mL (1)
24.0 mL (2)
36.0 mL (2)
48.0 mL (3)
54.0 mL (3)
65
19.5 mL (1)
26.0 mL (2)
39.0 mL (2)
52.0 mL (3)
58.5 mL (3)
70
21.0 mL (2)
28.0 mL (2)
42.0 mL (3)
-
-
75
22.5 mL (2)
30.0 mL (2)
45.0 mL (3)
-
-
80
24.0 mL (2)
32.0 mL (2)
48.0 mL (3)
-
-
85
25.5 mL (2)
34.0 mL (2)
51.0 mL (3)
-
-
90
27.0 mL (2)
36.0 mL (2)
54.0 mL (3)
-
-
95
28.5 mL (2)
38.0 mL (2)
57.0 mL (3)
-
-
100
30.0 mL (2)
40.0 mL (2)
60.0 mL (3)
-
-

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.

Medicinal Product
Interaction
Geometric Mean
Changes (%)
Recommendations
Concerning Co-
Administration

Astemizole, cisapride,
pimozide, quinidine and
terfenadine

Although not studied,
increased plasma concentrations
of these medicinal
products can lead to QTc
prolongation and rare
occurrences of torsades
de pointes
.
Contraindicated
Carbamazepine and long
-acting barbiturates
(e.g. phenobarbital,
mephobarbital)
Although not studied,
carbamazepine and long
-acting barbiturates
are likely to
significantly decrease
plasma voriconazole
concentrations.
Contraindicated

Efavirenz (a non-nucleoside
reverse transcriptase inhibitor)

High dose (400 mg q.d.)*

Low dose (300 mg q.d., co-
administered with voriconazole
400 mg b.i.d.)

Efavirenz Cmax ↑ 38%
Efavirenz AUCτ ↑ 44%

Voriconazole Cmax 61%
Voriconazole AUCτ 77%

Compared to efavirenz
600 mg q.d.

Efavirenz Cmax ↔Efavirenz
AUCτ ↑ 17%Compared to
voriconazole 200 mg
b.i.d.Voriconazole
Cmax ↑ 23%Voriconazole
AUCτ 7%

Standard doses of
voriconazole and standard
doses of efavirenz (400
mg q.d. or above)
is contraindicated.

Voriconazole may be co-
administered with
efavirenz if the
voriconazole maintenance
dose is increased to 400
mg b.i.d. and the
efavirenz dose is
decreased to 300 mg q.d.

When voriconazole
treatment is stopped, the
initial dose of efavirenz
should be restored.

Ergot alkaloids (e.g.
ergotamine and
dihydroergotamine)

Although not studied,
voriconazole is likely
to increase the plasma
concentrations of ergot alkaloids and lead to ergotism.
Contraindicated

Rifabutin

300 mg q.d.

300 mg q.d. (co-administered
with voriconazole 350 mg
b.i.d.)*

300 mg q.d. (co-administered
with voriconazole 400 mg
b.i.d.)*

Voriconazole Cmax↓ 69%
Voriconazole AUCτ ↓ 78%
Compared to
voriconazole 200 mg b.i.d.
Voriconazole Cmax↓ 4%
Voriconazole
AUCτ 32%

Rifabutin Cmax ↑ 195%
Rifabutin AUCτ ↑ 331%

Compared to
voriconazole 200 mg b.i.d.
Voriconazole Cmax ↑ 104%
Voriconazole AUCτ ↑ 87%

Concomitant use of
voriconazole and rifabutin
should be avoided unless
the benefit outweighs the risk.

The maintenance dose of
voriconazole may be increased
to 5 mg/kg I.V. b.i.d. or
from 200 mg to 350 mg
orally b.i.d. (100 mg
to 200 mg orally b.i.d.
in patients less
than 40 kg).

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

Rifampicin (600 mg q.d.)

Voriconazole Cmax↓ 93%

Voriconazole AUCτ ↓ 96%

Contraindicated

Ritonavir (protease inhibitor)

High dose (400 mg b.i.d.)

Low dose (100 mg b.i.d.)*

Ritonavir Cmax and AUCτ ↔
Voriconazole Cmax ↓ 66%
Voriconazole AUC ↓τ 82%

Ritonavir Cmax ↓ 25%
Ritonavir AUCτ ↓13%
Voriconazole Cmax ↓24%
Voriconazole AUCτ ↓39%

Co-administration of
voriconazole and high
doses of ritonavir (400 mg
and above b.i.d.)
is contraindicated.

Co-administration of
voriconazole and low-
dose ritonavir (100 mg
b.i.d.) should be avoided,
unless an assessment of
the benefit/risk to the
patient justifies the use of
voriconazole.

St John's wort

300 mg t.i.d. (co-administered
with voriconazole 400 mg
single dose)
In an independent
published study,
Voriconazole AUC0
infinity
↓59%
Contraindicated
Everolimus
Although not studied,
voriconazole is likely
to significantly
increase the plasma
concentrations of
everolimus.
Co-administration of
voriconazole with
everolimus is not
recommended because
voriconazole is expected
to significantly increase
everolimus concentrations.
Fluconazole (200 mg q.d.)

Voriconazole Cmax ↑ 57%
Voriconazole AUCτ ↑ 79%

Fluconazole Cmax ND
Fluconazole AUCτ ND

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.

Phenytoin

300 mg q.d.

300 mg q.d. (co-administered
with voriconazole 400 mg
b.i.d.)*

Anticoagulants

Warfarin (30 mg single dose,
co-administered with 300 mg
b.i.d. voriconazole)

Other Oral Coumarins

(e.g. phenprocoumon, acenocoumarol)

Voriconazole Cmax↓ 49%

Voriconazole AUCτ ↓ 69%

Phenytoin Cmax ↑ 67%

Phenytoin AUCτ ↑ 81%

Compared to voriconazole
200 mg b.i.d.,
Voriconazole Cmax ↑ 34%

Voriconazole AUCτ ↑ 39%

Maximum increase in prothrombin
time was approximately 2-fold

Although not studied,
voriconazole may increase
the plasma concentrations
of coumarins that may cause
an increase in prothrombin
time.

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

Phenytoin may be co-
administered with
voriconazole if the
maintenance dose of
voriconazole is increased
to 5 mg/kg I.V. b.i.d.
or from 200 mg to 400 mg
oral b.i.d., (100 mg to
200 mg oral b.i.d.
in patients less than
40 kg).

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

Benzodiazepines
(e.g. midazolam, triazolam, alprazolam)
Although not studied clinically, voriconazole
is likely to increase the plasma
concentrations of benzodiazepines that
are metabolized by CYP3A4 and
lead to a prolonged sedative effect.
Dose reduction of benzodiazepines should be considered.

Immunosuppressants

Sirolimus (2 mg single dose)

Ciclosporin (in stable renal
transplant recipients receiving
chronic ciclosporin therapy)

Tacrolimus (0.1 mg/kg single
dose)

In an independent
published study,

Sirolimus Cmax ↑ 6.6-foldSirolimus
AUC0 infinity↑ 11-fold
Ciclosporin Cmax ↑ 13%
Ciclosporin AUC ↑ 70%
Tacrolimus Cmax ↑ 117%
Tacrolimus AUCt ↑ 221%

Co-administration of voriconazole
and sirolimus is contraindicated.

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

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

Long-acting Opiates

Oxycodone (10 mg single
dose)

In an independent
published study,

Oxycodone Cmax↑ 1.7-fold

Oxycodone AUC0 infinity ↑ 3.6-fold

Dose reduction in oxycodone
and other long-acting opiates
metabolized by CYP3A4 (e.g.
hydrocodone) should be
considered. Frequent monitoring
for opiate-associated adverse
reactions may be necessary.
Methadone (32 100 mg q.d.)

R-methadone
(active) Cmax ↑ 31%

R-methadone
(active) AUCτ ↑ 47%

S-methadone Cmax ↑ 65%
S-methadone AUCτ ↑ 103%

Frequent monitoring for
adverse reactions and
toxicity related to
methadone, including QT
prolongation, is recommended.
Dose reduction of methadone
may be needed.

Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs)

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%

Frequent monitoring for adverse
reactions and toxicity related
to NSAIDs is recommended.
Dose reduction of NSAIDs may
be needed.
Omeprazole (40 mg q.d.)*

Omeprazole Cmax↑ 116%

Omeprazole AUCτ ↑ 280%

Voriconazole Cmax ↑ 15%

Voriconazole AUCτ ↑ 41%

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

No dose adjustment of voriconazole
is recommended.

When initiating voriconazole
in patients already
receiving omeprazole
doses of 40 mg or
above, it is recommended
that the omeprazole dose
be halved.

Oral Contraceptives*

Norethisterone/ethinyloestradiol
(1 mg/0.035 mg q.d.)

Ethinyloestradiol Cmax ↑ 36%

Ethinyloestradiol AUCτ ↑ 61%

Norethisterone Cmax ↑ 15%

Norethisterone AUCτ ↑ 53%

Voriconazole Cmax ↑ 14%

Voriconazole AUCτ ↑ 46%

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

Short-acting Opiates

Alfentanil (20 μg/kg single dose,
with concomitant naloxone)

Fentanyl (5 μg/kg single dose)

In an independent
published study,

Alfentanil AUC0 infinity
6-fold

In an independent published
study,

Fentanyl AUC0 infinity
↑ 1.34-fold

Dose reduction of alfentanil,
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.

Statins
(e.g. lovastatin)

Although not studied
clinically, voriconazole
is likely to
increase the plasma
concentrations of
statins that are
metabolized by
CYP3A4 and could
lead to
rhabdomyolysis.
Dose reduction of statins
should be considered.

Sulphonylureas (e.g.
tolbutamide, glipizide,
glyburide)

Although not studied,
voriconazole is likely
to increase the plasma
concentrations of sulphonylureas and
cause hypoglycaemia.
Careful monitoring of
blood glucose is recommended.
Dose reduction of
sulphonylureas should be
considered.

Vinca Alkaloids
(e.g. vincristine and vinblastine)

Although not studied,
voriconazole is likely
to increase the plasma
concentrations of
vinca alkaloids
and lead to
neurotoxicity.
Dose reduction of vinca
alkaloids should be
considered.

Other HIV Protease Inhibitors
(e.g. saquinavir, amprenavir
and nelfinavir)*

Not studied clinically.
In vitro'studies show
that voriconazole may
inhibit the metabolism
of HIV protease inhibitors
and the metabolism
of voriconazole may
also be inhibited
by HIV protease
inhibitors.
Careful monitoring for
any occurrence of drug
toxicity and/or lack of
efficacy, and dose
adjustment may be
needed.

Other Non-Nucleoside Reverse
Transcriptase Inhibitors
(NNRTIs)
(e.g. delavirdine, nevirapine)*

Not studied clinically.
In vitro'studies show that the
metabolism of voriconazole
may be inhibited by
NNRTIs and voriconazole
may inhibit the metabolism
of NNRTIs.

The findings of the
effect of efavirenz
on voriconazole suggest
that the metabolism of
voriconazole may be
induced by a NNRTI

Careful monitoring
for any occurrence
of drug toxicity and/or
lack of efficacy,
and dose adjustment
may be needed.
Cimetidine (400 mg b.i.d.)
Voriconazole Cmax ↑ 18%
Voriconazole AUCτ ↑ 23%
No dose adjustment
Digoxin (0.25 mg q.d.)
Digoxin Cmax
Digoxin AUCτ ↔
No dose adjustment
Indinavir (800 mg t.i.d.)
Indinavir Cmax
Indinavir AUCτ ↔
Voriconazole Cmax
Voriconazole AUCτ ↔
No dose adjustment

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
on either erythromycin
or azithromycin is
unknown.

No dose adjustment

Mycophenolic acid (1 g single
dose)

Mycophenolic acid Cmax
Mycophenolic acid
AUCt
No dose adjustment

Prednisolone (60 mg single
dose)

Prednisolone Cmax ↑ 11%

Prednisolone AUC0 infinity ↑ 34%

No dose adjustment
Ranitidine (150 mg b.i.d.)
Voriconazole
Cmax and AUCτ ↔
No dose adjustment

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.

Undesirable Effects Reported in Subjects Receiving Voriconazole
System Organ Class
Adverse Drug Reactions
Infections and Infestation
Common
Gastroenteritis, influenza-like illness
Rare
Pseudomembranous colitis
Blood and Lymphatic System Disorders
Common
Pancytopenia, bone marrow depression, leucopenia,
thrombocytopenia, anaemia, purpura
Uncommon
Disseminated intravascular coagulation, agranulocytosis,
lymphadenopathy, eosinophilia
Immune System Disorders
Common
Sinusitis
Uncommon
Anaphylactoid reaction, hypersensitivity
Endocrine Disorders
Uncommon
Adrenal insufficiency
Rare
Hyperthyroidism, hypothyroidism
Metabolism and Nutrition Disorders
Common
Hypoglycaemia, hypokalaemia
Psychiatric Disorders
Common
Depression, hallucination, anxiety
Rare
Insomnia
Nervous System Disorders
Very common
Headache
Common
Dizziness, confusional state, tremor, agitation, paraesthesia
Uncommon
Brain oedema, ataxia, diplopia, vertigo, hypoaesthesia
Rare
Convulsion, encephalopathy, Guillain-Barr syndrome, extra-
pyramidal symptoms, peripheral neuropathy
Eye Disorders
Very common
Visual disturbances (including blurred vision, chromotopsia
and photophobia)
Uncommon
Papilloedema, optic nerve disorder (including optic neuritis),
nystagmus, scleritis, blepharitis
Rare
Optic atrophy, retinal haemorrhage, oculogyration, corneal
opacity
Ear and Labyrinth Disorders
Rare
Hypoacusis, tinnitus
Cardiac Disorders
Very common
Oedema peripheral
Uncommon
Ventricular fibrillation, ventricular arrhythmia,
syncope, supraventricular arrhythmia,
supraventricular tachycardia, tachycardia, bradycardia
Rare
Torsades de pointes, ventricular tachycardia, atrioventricular
complete block, bundle-branch
block, nodal rhythm
Vascular Disorders
Common
Thrombophlebitis, hypotension, phlebitis
Rare
Lymphangitis
Respiratory, Thoracic and Mediastinal Disorders
Common
Acute respiratory distress syndrome, pulmonary oedema, respiratory distress, chest pain
Gastrointestinal Disorders
Very common
Abdominal pain, nausea, vomiting, diarrhoea
Uncommon
Pancreatitis, peritonitis, duodenitis, gingivitis, glossitis, swollen
tongue, dyspepsia, constipation
Rare
Dysgeusia
Hepato-biliary Disorders
Common
Jaundice, cholestatic jaundice
Uncommon
Hepatic failure, hepatitis, hepatomegaly, cholecystitis,
cholelithiasis
Rare
Hepatic coma
Skin and Subcutaneous Tissue Disorders
Very common
Rash
Common
Exfoliative dermatitis, face oedema, phototoxic reaction,
maculo-papular rash, macular rash, papular rash, cheilitis,
pruritus, alopecia, erythema
Uncommon
Stevens-Johnson syndrome, angioneurotic oedema, allergic
dermatitis, urticaria, drug hypersensitivity, psoriasis
Rare
Toxic epidermal necrolysis, erythema multiforme, discoid lupus erythematosis, pseudoporphyria
Musculoskeletal and Connective Tissue Disorders
Common
Back pain
Uncommon
Arthritis
Rare
Hypertonia
Renal and Urinary Disorders
Common
Renal failure acute, haematuria
Uncommon
Proteinuria, nephritis
Rare
Renal tubular necrosis
General Disorders and Administrative Site Conditions
Very common
Pyrexia
Common
Injection site reaction/inflammation, chills, asthenia
Investigations
 
Common
Elevated liver function tests (including AST, ALT, alkaline
phosphatase, GGT, LDH, bilirubin), blood creatinine increased
Uncommon
Electrocardiogram QT corrected interval prolonged, blood urea
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