VFEND (Voriconazole)

VFEND belongs to a group of medicines called triazole antifungal agents. VFEND works by killing or stopping the growth of the fungi that cause infections. VFEND is used to treat serious fungal infections caused by Aspergillus, Scedosporium, Fusarium, fluconazole-resistant Candida, and candidaemia in patients with normal white blood cell counts. This product should only be used under the supervision of a doctor. VFEND is mainly for use in seriously ill patients.

Uses

Aspergillosis

Voriconazole is used for the treatment of invasive aspergillosis. Clinical studies have demonstrated efficacy in treating primary, and or intolerant of invasive aspergillosis, for primary and salvage therapy of invasive aspergillosis, and for treatment of invasive aspergillosis in patients whose disease was refractory to, or who were intolerant of, other antifungal therapy. Aspergillus fumigatus was the most frequent isolate in patients with aspergillosis participating in clinical trials with the drug.

The efficacy of voriconazole as primary or salvage therapy for invasive aspergillosis was evaluated in an open-label, noncomparative study in 116 patients 18-79 years of age with definite or probable invasive aspergillosis. A complete or partial response was achieved in 48% of patients in this study, with lower response rates observed in patients with definite disease (38%) than in those with probable disease (58%). In a randomized, nonblinded study of voriconazole as primary therapy for invasive aspergillosis, 277 patients 12-79 years of age with definite or probable invasive aspergillosis received either voriconazole (6 mg/kg IV twice daily for 2 doses and then 4 mg/kg IV twice daily for at least 7 days, at which time therapy could be switched to voriconazole 200 mg orally twice daily) or amphotericin B (1-1.5 mg/kg IV once daily) for up to 12 weeks.

At the end of the study, a complete or partial response was achieved in 53% of patients randomized to receive voriconazole compared with 32% of those randomized to receive amphotericin B; the survival rate at the end of the study was 71 or 58% in patients randomized to receive voriconazole or amphotericin B, respectively. Pooled analysis of data from this study and an additional study demonstrated response rates of 44 or 40% in patients with invasive infections caused by A. fumigatus or other Aspergillus species, respectively, whose disease was refractory to, or who were intolerant of, other antifungal therapy.

Other Fungal Infections

Voriconazole is also used to treat serious fungal infections caused by Scedosporium apiospermum and Fusarium spp., including F. solani, in patients who are intolerant of or whose disease is refractory to other therapies.

Empiric Therapy in Febrile Neutropenic Patients

Voriconazole has also been used for empiric therapy of presumed fungal infections in febrile neutropenic patients. The efficacy of this therapy has been evaluated in an open-label, randomized, multicenter study of patients 12-82 years of age who were neutropenic following therapy or stem cell transplantation. In this study, patients received voriconazole or amphoteric. 

A response (based on a composite assessment including no breakthrough infections within 7 days of the completion of therapy, survival for 7 days following completion of therapy, discontinuance of the drug because of toxicity or lack of efficacy prior to recovery from neutropenia, resolution of fever during neutropenia, and complete or partial response in patients with baseline fungal infections by the completion of therapy) was obtained in 26 or 31% of patients receiving voriconazole or amphotericin B liposomal, respectively. The composite results failed to meet protocol-defined statistical criteria for concluding that voriconazole was not inferior to amphotericin B liposomal.

Exploratory analyses of the individual elements of the composite measure suggested that breakthrough infections occurred in a smaller proportion of patients receiving voriconazole (1.9%) compared with amphotericin B liposomal (5%); exploratory analyses of the other individual elements of the composite measure failed to identify other substantial differences between the 2 regimens.

Ingredients

• The active substance is voriconazole.
• The other ingredient is sulphobutylether beta cyclodextrin sodium.

Each vial of VFEND contains 217.6 mg of sodium per vial. This should be taken into consideration if you are on a strictly controlled sodium diet.

Dosage and Administration

Voriconazole is administered orally or by IV infusion. For IV infusion, it is administered at a maximum rate of 3 mg/kg per hour over 1-2 hours.

The drug should not be administered by rapid IV infusion. Commercially available voriconazole powder for injection should be stored at 15-30°C. The contents of a single-use vial labeled as containing 200 mg of voriconazole should be reconstituted with exactly 19 mL of sterile water for injection to prepare a solution containing 10 mg/mL of the drug. The vial should be shaken until all the powder is dissolved.

The manufacturer recommends that reconstituted voriconazole solutions be used immediately following reconstitution since they contain no preservative; if not used immediately, reconstituted solutions should be stored for no longer than 24 hours at 2-8°C.

Reconstituted drug solutions must be further diluted in a compatible IV infusion solution prior to administration. The reconstituted voriconazole solution is prepared for infusion by calculating the volume required to administer the appropriate weight-based dose and then withdrawing and discarding a volume of diluent from the final infusion container that equals or exceeds that volume.

The volume of diluent remaining in the container should be sufficient to achieve a final concentration of at least 0.5 mg/mL but not greater than 5 mg/mL after the reconstituted solution is added. The appropriate dose should then be withdrawn from the required number of vials and added to the infusion container.

Any unused portion of the reconstituted solution should be discarded. Whenever the solution and container permit, voriconazole solutions should be inspected visually for particulate matter and discoloration prior to administration. IV solutions of voriconazole should not be admixed or administered through the same catheter as other drugs. Orally administered voriconazole should be given at least one hour before or one hour after meals.

General Dosage

The recommended initial adult IV dosage of voriconazole in patients with invasive aspergillosis or infections caused by Scedosporium apiospermum or Fusarium spp. is 6 mg/kg by IV infusion every 12 hours for 2 doses. This is followed by a maintenance dosage of 4 mg/kg by IV infusion every 12 hours until the patient can be switched to oral therapy. If this dosage cannot be tolerated, the IV maintenance dosage can be decreased to 3 mg/kg every 12 hours.

Patient Weight	Initial Oral Dosage	Increased Dosage (if inadequate response)	Minimum Dosage (if not tolerated)
40 kg or more	200 mg every 12 hours	300 mg every 12 hours	200 mg every 12 hours
Less than 40 kg	100 mg every 12 hours	150 mg every 12 hours	100 mg every 12 hours

The duration of therapy should be based on the severity of the patient’s underlying disease, recovery from immunosuppression, and response to the drug. Always take VFEND exactly as your doctor has instructed. If you are not sure, check with your doctor. Your doctor will determine your dose based on your weight and the type of infection you have. 

Required Volumes of 10 mg/ml VFEND Concentrate

BodyWeight (kg)	Volume of VFE1ND 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)	7 mg/kg dose(number of vials)
10	–	4.0 ml (1)	–	7.0 ml (1)
15	–	6.0 ml (1)	–	10.5 ml (1)
20	–	8.0 ml (1)	–	14.0 ml (1)
25	–	10.0 ml (1)	–	17.5 ml (1)
30	9.0 ml (1)	12.0 ml (1)	18.0 ml (1)	21.0 ml (2)
35	10.5 ml (1)	14.0 ml (1)	21.0 ml (2)	24.5 ml (2)
40	12.0 ml (1)	16.0 ml (1)	24.0 ml (2)	28.0 ml (2)
45	13.5 ml (1)	18.0 ml (1)	27.0 ml (2)	31.5 ml (2)
50	15.0 ml (1)	20.0 ml (1)	30.0 ml (2)	35.0 ml (2)
55	16.5 ml (1)	22.0 ml (2)	33.0 ml (2)	–
60	18.0 ml (1)	24.0 ml (2)	36.0 ml (2)	–
65	19.5 ml (1)	26.0 ml (2)	39.0 ml (2)	–
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)	–

VFEND 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, the user is responsible for in-use storage times and conditions prior to use. These would normally not be longer than 24 hours at 2 to 8°C unless reconstitution has taken place in controlled and validated aseptic conditions.

The usual dose for children aged 2 to less than 12 years is 7 mg/kg twice daily. VFEND should not be given to children younger than 2 years of age. The usual dose for teenagers (aged 12 to 16 years) is the same as for adults.

Patients with a weakened immune system or those with difficult infections may require long.

You may be switched from the intravenous infusion to tablets once your condition improves.

Compatible Infusion Solutions

The reconstituted solution can be diluted with: 9 mg/ml (0.9 %) Sodium Chloride for Infusion Lactated Ringer’s Intravenous Infusion 5 % Glucose and Lactated Ringer’s 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

VFEND is not compatible with diluents other than those listed above (or listed below under ‘Incompatibilities’).

Incompatibilities

VFEND must not be infused into the same line or cannula concomitantly with other drug infusions, including parenteral nutrition (e.g., Aminofusin 10 % Plus).

Blood product infusions must not occur simultaneously with VFEND. However, total parenteral nutrition infusions can occur simultaneously with VFEND, but not in the same line or cannula.

VFEND must not be diluted with 4.2 % Sodium Bicarbonate Infusion.

If You Forgot to Take a Dose

As you will be given this medicine under close medical supervision, it is unlikely that you will miss a dose. However, tell your doctor or pharmacist if you think you have forgotten a dose.

If You Stop Taking VFEND

When your doctor stops VFEND treatment, you should not experience any effects. However, if you were taking medicines containing ciclosporin or tacrolimus, you must mention this to your doctor, as the dose will need to be adjusted. 

Special Populations

In patients with mild-to-moderate hepatic cirrhosis (Child-Pugh class A or B), usual IV or oral loading dosages of voriconazole should be used, but IV or oral maintenance dosages should be decreased by 50%. Voriconazole has not been studied in patients with severe hepatic cirrhosis (Child-Pugh class C) or in those with chronic hepatitis B or hepatitis C virus infection. In patients with moderate-to-severe renal impairment (creatinine clearance less than 50 mL/minute), IV voriconazole should be used only when clearly needed because of potential accumulation of the IV vehicle, sulfobutyl ether β-cyclodextrin sodium. No adjustment of oral voriconazole dosage is necessary in patients with renal impairment.

Important Safety Information

Laboratory Monitoring

Liver function tests should be performed before and during voriconazole therapy, and renal function (e.g., serum creatinine concentrations) should be monitored in patients receiving it.

Acute renal failure has occurred in severely ill patients receiving voriconazole; such patients are likely to have other factors (e.g., underlying conditions, concomitant drugs) predisposing to impaired renal function.

Warnings Ocular Effects

The effect of voriconazole on visual function is unknown if the duration of therapy exceeds 28 days. Monitor visual function (visual acuity, visual field, and color perception) if the duration of therapy exceeds 28 days.

Hepatic Effects

Serious hepatic effects, including hepatitis, cholestasis, and fulminant hepatic failure, have been reported rarely in clinical trials. Hepatic effects usually are reversible when voriconazole therapy is discontinued; however, fatalities have occurred. If abnormal liver function test results occur during voriconazole therapy, the patient should be monitored for the development of more severe hepatic injury. Voriconazole therapy should be discontinued if signs and symptoms consistent with liver disease develop.

Galactose Intolerance

Patients with a history of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not be given voriconazole tablets, as lactose is used in their manufacture.

Sensitivity Reactions

Anaphylactoid reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnea, faintness, nausea, pruritus, and rash, that occur immediately upon initiating the infusion, have been reported rarely.

Dermatologic Effects

Serious cutaneous reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis) have rarely occurred in patients receiving voriconazole. If a rash develops, discontinuation of the drug should be considered.

Photosensitivity reactions have occurred infrequently in patients receiving voriconazole, particularly during long-term therapy. Avoidance of strong, direct sunlight during voriconazole therapy is recommended.

Pregnancy and Breastfeeding

VFEND must not be used during pregnancy unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while being treated with VFEND.

VFEND must not be used during breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine whilst breastfeeding.

Pediatric Use

Safety and efficacy are not established in children younger than 12 years of age. However, a limited number of pediatric patients 9 months to 15 years of age whose disease was refractory to, or who were intolerant of, other antifungal therapy have received voriconazole IV (6 mg/kg every 12 hours for 2 doses, followed by 4 mg/kg every 12 hours) or orally (100 mg twice daily in patients weighing less than 40 kg or 200 mg twice daily in patients weighing 40 kg or more) in the treatment of aspergillosis, infections caused by Scedosporium spp., candidiasis, or other invasive fungal infections.

At the completion of therapy, 45% of pediatric patients receiving voriconazole had a complete or partial response. Adverse effects in children receiving voriconazole were similar to those reported in adults.

Based on a comparison of pharmacokinetic data from pediatric patients (2 years to less than 12 years of age) with data from adults, the manufacturer states that the predicted steady-state plasma voriconazole concentrations were similar in pediatric patients or adults (median concentration of 1.19 or 1.16 mcg/mL, respectively) at a maintenance IV dosage of 4 mg/kg every 12 hours in children or 3 mg/kg every 12 hours in adults.

Geriatric Use

Clinical experience with voriconazole in geriatric patients is limited. Plasma voriconazole concentrations are increased, but the overall safety profile is similar to that in younger adults. Patients with hepatic impairment should be monitored carefully for voriconazole toxicity. Voriconazole should be used in patients with severe hepatic impairment only when the benefits outweigh the risks. Patients with moderate-to-severe renal impairment receiving IV voriconazole should be monitored carefully for increases in serum creatinine concentrations. If such increases occur, consideration should be given to switching the patient to oral voriconazole therapy.

Contraindications

Known hypersensitivity to voriconazole or any ingredient in the formulation. Concomitant therapy with terfenadine (no longer commercially available in the US), astemizole (no longer commercially available in the US), cisapride, pimozide, quinidine, sirolimus, rifampin, carbamazepine, long-acting barbiturates (e.g., phenobarbital, mephobarbital), rifabutin, or ergot alkaloids (e.g., ergotamine, dihydroergotamine).

Do not take VFEND if you are allergic to the active ingredient voriconazole, or to sulphobutylether beta cyclodextrin sodium.

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription. Some medicines affect the way VFEND works, or VFEND may affect the way they work.

Medicines in the following list must not be taken during your VFEND treatment:

• Terfenadine (used for allergy);
• Astemizole (used for allergy);
• Cisapride (used for stomach problems);
• Pimozide (used for treating mental illness);
• Quinidine (used for irregular heart beat);
• Rifampicin (used for treating tuberculosis);
• Carbamazepine (used to treat seizures);
• Phenobarbital (used for severe insomnia and seizures);
• Ergot alkaloids (e.g. ergotamine, dihydroergotamine; used for migraine);
• Sirolimus (used in transplant patients);
• Ritonavir (used for treating HIV) in doses of 400mg and more twice daily;
• St John’s Wort (herbal supplement).

Take special care with VFEND:

• to avoid sunlight and sun exposure while being treated. It is important to cover sun-exposed areas of skin and use sunscreen, as an increased sensitivity of skin to the sun’s UV rays can occur;
• if you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QT syndrome’.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should be avoided if possible or dose adjustment may be required:

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily;
• Rifabutin (used for treating tuberculosis);
• Phenytoin (used to treat epilepsy);
• Warfarin and other anticoagulants (e.g. phenprocoumon, acenocoumarol; used to slow down clotting of the blood);
• Ciclosporin (used in transplant patients);
• Tacrolimus (used in transplant patients);
• Sulphonylureas (e.g. tolbutamide, glipizide, and glyburide) (used for diabetes);
• Statins (e.g. atorvastatin, simvastatin) (used for lowering cholesterol);
• Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress);
• Omeprazole (used for treating ulcers)
• Oral contraceptives (if you take VFEND whilst using oral cont; receptive, you may get side effects such as nausea and menstrual disorders);
• Vinca alkaloids (e.g. vincristine and vinblastine) (used in treating cancer);
• Indinavir and other HIV protease inhibitors (used for treating HIV);
• Non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz, delavirdine, nevirapine) (used for treating HIV);
• Methadone (used to treat heroin addiction);
• Efavirenz (used for treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND);
• Alfentanil and fentanyl, and other short-acting opiates such as sufentanil (painkillers used for surgical procedures);
• Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain);
• Non-steroidal anti-inflammatory drugs (e.g. ibuprofen, diclofenac) (used for treating pain and inflammation);
• Fluconazole (used for fungal infections).

Before being treated with VFEND, tell your doctor if:

1. You have had an allergic reaction to other azoles.
2. You are suffering from, or have ever suffered from kidney disease. Depending upon the degree of kidney disease, the doctor may decide to give you VFEND tablets. Your doctor should monitor your renal function while you are being treated with VFEND by doing blood tests.
3. You are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function while you are being treated with VFEND by doing blood tests.
4. You are already being treated with phenytoin (used to treat epilepsy). Your blood concentration of phenytoin will need to be monitored during your treatment with VFEND, and your dose may be adjusted.
5. You are already being treated with rifabutin (used for treating tuberculosis). Your blood counts, and side effects of rifabutin will need to be monitored.

While being treated with VFEND:

• tell your doctor immediately if you develop a severe skin rash or blisters;
• Avoid sunlight and sun exposure while being treated with VFEND. Cover sun-exposed areas of the skin and use sunscreen, as the skin can become more sensitive to the sun’s UV rays.
• your doctor should monitor the function of your liver and kidney by doing blood tests.
• reactions during the infusion have occurred uncommonly with VFEND (including flushing and nausea). Your doctor may stop the infusion of VFEND if this occurs.

Driving and Using Machines

VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Tell your doctor if you experience this.

Side Effects

Like all medicines, VFEND can cause side effects, although not everybody gets them. If any side effects occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Very common side effects (occurring in at least 1 in 10 patients):

• visual disturbances (change in vision);
• fever;
• rash;
• nausea, vomiting, diarrhea;
• headache;
• swelling of the extremities;
• stomach pains.

Common side effects (occurring in at least 1 in 100 patients) are:

• Flu-like symptoms, sinusitis, chills, weakness.
• Anemia is a low number of cells called platelets that help blood clot. It can also be caused by low numbers of some or all types of white blood cells, red or purple skin discoloration, which may be caused by low platelet count, or other blood cell changes.
• Low blood sugar, low blood potassium.
• Anxiety, depression, tingling, confusion, dizziness, agitation, trembling, hallucinations, and other nervous symptoms.
• Low blood pressure and inflammation of a vein (which may be associated with the formation of a blood clot).
• Breathing difficulty, chest pain, fluid accumulation in the lungs.
• Jaundice, redness of the skin.
• Swelling of the lips or face.
• Allergic reactions (sometimes severe), including widespread blistering rash and skin peeling, severe skin reaction following exposure to light or sun.
• Itchiness.
• Hair loss.
• Back pain.
• Kidney failure, blood in the urine, changes in blood tests of kidney function.
• Inflammation at injection sites -Changes in blood tests of liver function.

Uncommon side effects (occurring in at least 1 in 1,000 patients):

• Enlarged lymph glands (sometimes painful).
• An increase in a type of white blood cell may be associated with an allergic reaction, a disorder of the blood clotting system.
• Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting.
• Depressed function of the adrenal gland.
• Problem with coordination.
• Swelling of the brain.
• Double vision pain and inflammation of the eyes and eyelids, involuntary movement of the eye.
• Decreased sensitivity to touch.
• Constipation, inflammation of the upper small intestine, dyspepsia, pancreatitis, peritonitis.
• Gingivitis.
• Swelling and inflammation of the tongue.
• Enlarged liver, hepatitis, liver failure, gallbladder disease, gallstones.
• Joint pain.
• Inflammation of the kidney, proteins in the urine -Abnormal electrocardiogram (ECG).
• Blood chemistry changes.

Rare side effects (occurring in at least 1 in 10,000 patients):

• Inability to sleep.
• Hearing difficulties, ringing in the ears.
• Abnormal sense of taste.
• Increase in muscle tone and muscle weakness caused by an abnormal immune system response.
• Abnormal brain function, Parkinson-like symptoms, convulsion, nerve injury resulting in numbness, pain, tingling, or burning in the hands or feet.
• Sleepiness during infusion.

Reactions during the infusion have occurred uncommonly with VFEND (including flushing, fever, sweating, increased heart rate, and shortness of breath). Your doctor may stop the infusion if this occurs.

As VFEND has been known to affect the liver and kidneys, your doctor should monitor their function through blood tests. Please advise your doctor if you have stomach pains or if your stools have a different consistency.

If any of these side effects persist or are troublesome, please tell your doctor.

If any of the side effects get serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Interactions

The pharmacokinetics of voriconazole are similar following IV or oral administration. Voriconazole exhibits nonlinear, dose-dependent pharmacokinetics, apparently because of saturable first-pass metabolism or systemic clearance. In vitro studies indicate that voriconazole is extensively metabolized in the liver by cytochrome P-450 (CYP) isoenzymes 2C19, 2C9, and 3A4.

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors or inducers of cytochrome P-450 (CYP) isoenzymes 2C19, 2C9, or 3A4 may increase or decrease plasma voriconazole concentrations, respectively. Voriconazole and its major metabolite inhibit the metabolic activity of CYP isoenzymes 2C19, 2C9, and 3A4 and may increase plasma concentrations of other drugs metabolized by these hepatic enzymes.

Rifampin and Rifabutin

Potential pharmacokinetic interaction (decrease in plasma voriconazole concentrations and/or increase in plasma rifabutin concentrations). Concomitant use of rifampin or rifabutin with voriconazole is contraindicated.

Drugs that Prolong the QT Interval

Potential pharmacokinetic interaction with CYP3A4 substrates that prolong the QT interval (e.g., terfenadine [no longer commercially available in the US], astemizole [no longer commercially available in the US], cisapride, pimozide, quinidine).

Potential increase in plasma concentrations of the concomitantly administered CYP3A4 substrate, which can result in QT interval prolongation and rarely, torsades de pointes. Concomitant use of these drugs with voriconazole is contraindicated.

Immunosuppressants

Potential pharmacokinetic interaction (increase in plasma concentrations of sirolimus, cyclosporine, or tacrolimus). Concomitant use of sirolimus with voriconazole is contraindicated. When initiating voriconazole therapy in patients currently receiving cyclosporine or tacrolimus, the dosage of cyclosporine or tacrolimus should be reduced by one-half or one-third, respectively. When voriconazole is discontinued, plasma concentrations of cyclosporine or tacrolimus should be monitored frequently, and the dosage of this drug should be adjusted as necessary.

Ergot Alkaloids

Potential pharmacokinetic interaction (increase in plasma concentrations of ergot alkaloid). Concomitant use of ergot alkaloids (e.g., ergotamine, dihydroergotamine) with voriconazole is contraindicated.

Carbamazepine and Barbiturates

Potential pharmacokinetic interaction (decrease in plasma voriconazole concentrations) with carbamazepine or long-acting barbiturates (e.g., phenobarbital, mephobarbital). Concomitant use of carbamazepine or long-acting barbiturates with voriconazole is contraindicated.

Phenytoin

Potential pharmacokinetic interaction (decreased plasma voriconazole concentrations and/or increased plasma phenytoin concentrations). When phenytoin and voriconazole are used concomitantly, the IV maintenance dosage of voriconazole should be increased to 5 mg/kg every 12 hours, and the oral maintenance dosage should be increased to 400 mg every 12 hours in patients weighing 40 kg or more or 200 mg every 12 hours in those weighing less than 40 kg. Plasma phenytoin concentrations should be monitored frequently, and the patient should be observed for potential phenytoin adverse effects.

HIV Protease Inhibitors

Potential pharmacokinetic interaction. Potential increase in plasma voriconazole concentrations with concomitant use of certain HIV protease inhibitors (e.g., ritonavir, saquinavir, amprenavir). Potential increase in plasma concentrations of certain HIV protease inhibitors (e.g., saquinavir, amprenavir, nelfinavir). Monitor the patient for manifestations of voriconazole or HIV protease inhibitor toxicity. No pharmacokinetic interaction was observed between indinavir and voriconazole.

Nonnucleoside Reverse Transcriptase Inhibitors

Potential pharmacokinetic interaction. Potential increase in plasma concentrations of nonnucleoside reverse transcriptase inhibitor (NNRTI). Plasma voriconazole concentrations may be increased (e.g., with concomitant use of delaviridine or efavirenz) or decreased (e.g., with concomitant use of efavirenz or nevirapine). Monitor patient for manifestations of voriconazole or NNRTI toxicity, as well as for clinical response to voriconazole.

Coumarin Anticoagulants

Potential pharmacokinetic interaction (increased prothrombin time). Monitor prothrombin time closely if coumarin anticoagulants (e.g., warfarin) are used concomitantly with voriconazole; reduction of anticoagulant dosage may be necessary.

Proton-Pump Inhibitors

Potential pharmacokinetic interaction (increased plasma concentrations of omeprazole and voriconazole) with omeprazole. In patients currently receiving omeprazole in dosages of 40 mg or more daily, reduce omeprazole dosage by one-half when voriconazole therapy is initiated. Potential increase in plasma concentrations of other proton-pump inhibitors that are metabolized by CYP2C19 isoenzyme.

Benzodiazepines

Potential pharmacokinetic interaction (increased plasma benzodiazepine concentrations) with benzodiazepines that are metabolized by CYP3A4 isoenzyme (e.g., midazolam, triazolam, alprazolam). Monitor the patient for manifestations of benzodiazepine toxicity and adjust benzodiazepine dosage as necessary.

Antilipemic Agents

Potential pharmacokinetic interaction (increased plasma concentrations of antilipemic agent) with HMG-CoA reductase inhibitors (i.e., statins) that are metabolized by CYP3A4 isoenzyme (e.g., lovastatin). Monitor patient for manifestations of statin toxicity and adjust statin dosage as necessary.

Calcium-Channel Blocking Agents

Potential pharmacokinetic interaction (increased plasma concentrations of calcium-channel blocker) with calcium-channel blocking agents that are metabolized by CYP3A4 isoenzyme (e.g., felodipine). Monitor the patient for manifestations of calcium-channel blocker toxicity and adjust dosage as necessary.

Sulfonylurea Antidiabetic Agents

Potential pharmacokinetic interaction (increased plasma concentrations of antidiabetic agent) with sulfonylurea antidiabetic agents (e.g., tolbutamide, glipizide, glyburide). Monitor blood glucose concentrations and monitor the patient for signs and symptoms of hypoglycemia; adjust the dosage of the antidiabetic agent as necessary.

Vinca Alkaloids

Potential pharmacokinetic interaction (increased plasma concentrations of vinca alkaloid). Monitor patient for manifestations of vinca alkaloid toxicity (i.e., neurotoxicity) and adjust dosage as necessary.

Advice to Patients

Importance of taking oral voriconazole at least 1 hour before or 1 hour after meals. Possibility of visual changes, including blurred vision and photophobia. Avoid driving, operating machinery, or performing hazardous tasks if visual changes occur; importance of not driving at night while taking voriconazole. Importance of avoiding exposure to strong, direct sunlight during voriconazole therapy. Importance of women informing clinicians if they are or plan to become pregnant or to breast-feed. Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.

Storage

Keep VFEND out of the reach and sight of children. Do not use VFEND after the expiry date which is stated on the label. The expiry date refers to the last day of the month.

Once reconstituted, VFEND should be used immediately, but if necessary, it may be stored for up to 24 hours at 2°C —8°C (in a refrigerator). Before infusion, reconstituted VFEND needs to be diluted with a compatible infusion solution. (Please refer to the end of this leaflet for further information.)

Medicines should not be disposed of in wastewater or household waste. Ask your pharmacist how to dispose of medicines that are no longer required. These measures will help protect the environment.

Preparations

Dosage Form	Strength	Brand Name	Composition/Features	Manufacturer
Oral Tablets, film-coated	50 mg	Vfend®	With povidone	Pfizer
Oral Tablets, film-coated	200 mg	Vfend®	With povidone	Pfizer
Parenteral Injection, for IV infusion only	200 mg	Vfend®	With sulfonyl ether β-cyclodextrin sodium (3.2 g)	Pfizer