Consumer medicine information

Voriconazole Wockhardt

Voriconazole

BRAND INFORMATION

Brand name

Voriconazole Wockhardt

Active ingredient

Voriconazole

Schedule

What is in this leaflet

This leaflet answers some common questions about VORICONAZOLE WOCKHARDT.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking VORICONAZOLE WOCKHARDT against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Read this leaflet carefully before taking VORICONAZOLE WOCKHARDT and keep this leaflet. You may need to read it again.

What VORICONAZOLE WOCKHARDT is used for

Voriconazole is used to treat fungal and yeast infections such as:

invasive aspergillosis (as-pur-jilosis), a fungal infection caused by a fungus called Aspergillus (as-pur-jilus), which usually begins in the respiratory tract (the nose, sinuses or lungs). Aspergillus is harmless in most healthy people; however, in people with poor immune systems (such as people who have had organ transplants and people with cancer or HIV/AIDS) invasive aspergillosis can be serious and spread to other tissues and organs.
serious Candida (can-did-da) infections, those that have spread into the blood stream.
serious fungal infections caused by Scedosporium (ski-doe-sporerium) species and Fusarium (fewsaa-rium) species.
other serious fungal infections in patients who do not respond to, or cannot tolerate, other antifungal medicines.

VORICONAZOLE WOCKHARDT is also used to prevent invasive fungal infections in patients who are at risk of developing such infections.

This medicine belongs to a group of medicines called triazole antifungals.

This medicine works by preventing the growth of fungal and yeast organisms causing your infection.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you start to use it

When you must not use it

Do not take VORICONAZOLE WOCKHARDT if you have ever had an allergy to:

any medicine containing voriconazole.
any of the ingredients listed at the end of this leaflet.
any other similar medicines.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; skin rash, itching or hives.

Do not take VORICONAZOLE WOCKHARDT if you are taking any of the following medicines:

pimozide (e.g. Orap), a medicine used to treat mental illness.
quinidine (e.g. Kinidin Durules), a medicine used to treat irregular heartbeat.
ivabradine (e.g., Coralan), a medicine used to treat heart problems.
rifampicin (e.g. Rifadin, Rimycin), a medicine used to treat tuberculosis and other infections.
carbamazepine (e.g. Tegretol, Teril), a medicine used to treat seizures.
long-acting barbiturates such as phenobarbitone, medicines used to treat severe insomnia and seizures.
rifabutin (e.g. Mycobutin) an antibiotic.
ergotamine (e.g. Cafergot) or dihydroergotamine (e.g. Dihydergot), medicines used to treat migraine.
sirolimus (e.g. Rapamune), a medicine used in transplant patients.
efavirenz (e.g. Stocrin) (a medicine used to treat HIV infection) in doses of 400 mg or more once a day.
ritonavir (e.g. Norvir, Kaletra) (a medicine used to treat HIV infection) in doses of 400 mg or more twice a day.
St John's Wort (a herbal medicine).

VORICONAZOLE WOCKHARDT should not be given to a child under the age of 2 years. Safety and effectiveness in children younger than 2 years has not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor first.

Before you start to take it

Tell your doctor if you have allergies to any foods, preservatives or dyes or any other medicines, especially antifungal medicines such as itraconazole (Sporanox), fluconazole (Diflucan), posaconazole (Noxafil) or ketoconazole (Nizoral) (not all brands given).

Tell your doctor if you have or have had any of the following medical conditions:

heart problems.
any problems affecting your kidneys.
any problems affecting your liver. If you have liver disease your doctor may prescribe a lower dose.
recent chemotherapy or stem cell transplant.

Tell your doctor if you are pregnant or plan to become pregnant. VORICONAZOLE WOCKHARDT should not be taken during pregnancy, unless indicated by your doctor. Effective contraception should be used in women of childbearing potential. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breastfeeding. VORICONAZOLE WOCKHARDT should not be taken whilst breastfeeding, unless indicated by your doctor. It is not known if the active ingredient voriconazole passes into breast milk. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell your doctor before you start taking VORICONAZOLE WOCKHARDT.

Taking other medicines

Tell your doctor if you are taking any other medicines including any that you have bought without a prescription from a pharmacy, supermarket or health food shop.

Some medicines should not be taken with VORICONAZOLE WOCKHARDT. These include (not all brands given):

pimozide (e.g. Orap), a medicine used to treat mental illness.
quinidine (e.g. Kinidin Durules), a medicine for irregular heartbeat.
ivabradine (e.g., Coralan), a medicine used to treat heart problems.
rifampicin (e.g. Rifadin, Rimycin), a medicine used to treat tuberculosis and other infections.
carbamazepine (e.g. Tegretol, Teril), a medicine used to treat seizures.
long-acting barbiturates such as phenobarbitone, medicines used to treat severe insomnia and seizures.
rifabutin (e.g. Mycobutin) an antibiotic.
ergotamine (e.g. Cafergot) or dihydroergotamine (e.g. Dihydergot), medicines used to treat migraine.
sirolimus (e.g. Rapamune) a medicine used in transplant patients.
efavirenz (Stocrin) (a medicine used to treat HIV infection) in doses of 400 mg or more once a day.
ritonavir (e.g. Norvir, Kaletra) (a medicine used to treat HIV infection) in doses of 400 mg or more twice a day.
St John's Wort, (a herbal medicine).

Some medicines and VORICONAZOLE WOCKHARDT may interfere with each other. These include (not all brands given):

efavirenz (Stocrin) (a medicine used to treat HIV infection) in doses below 400 mg once a day.
ritonavir (Norvir, Kaletra) (a medicine used to treat HIV infection) in doses of 100 mg twice a day.
warfarin (e.g. Marevan, Coumadin), a medicine used to stop blood clots.
everolimus (e.g. Afinitor, Certican), a medicine used to treat cancer.
venetoclax (e.g., Venclexta), a medicine used to treat blood cancers
naloxegol, (e.g., Movantik), a medicine used to treat constipation caused by opioids (narcotic pain medicines).
ivacaftor, (e.g., Kalydeco, Orkambi, Symdeko), a medicine used to treat cystic fibrosis.
fluconazole (e.g. Diflucan), a medicine used to treat fungal infections.
phenytoin (e.g. Dilantin), a medicine used to treat epilepsy.
ciclosporin (e.g. Sandimmun, Neoral), a medicine used to prevent organ transplant rejection or to treat certain problems with the immune system.
sulphonylureas, medicines used to treat diabetes such as glibenclamide, gliclazide and glipizide (e.g. Daonil, Diamicron, Minidiab).
some antihistamines, medicines used to treat hayfever, allergic skin reactions, itching.
theophylline (e.g. Nuelin), a medicine used to treat asthma.
benzodiazepines (e.g.Valium), medicines used to treat insomnia or anxiety.
statins (e.g. Zocor, Lipitor, Crestor), medicines used for lowering cholesterol.
tacrolimus (e.g. Prograf), a medicine used in patients who have had a liver or kidney transplant.
indinavir (e.g. Crixivan) and some other medicines used to treat HIV infection.
omeprazole (e.g. Losec), a medicine used to treat indigestion, reflux and stomach or duodenal ulcers.
methadone (used to treat heroin addiction).
oral contraceptives (the Pill).
vincristine, vinblastine or vinorelbine, medicines used in treating cancer (e.g.Vepesid).
strong pain killers such as alfentanil (e.g. Rapifen), fentanyl (e.g. Durogesic, Actiq, Sublimaze) and oxycodone (e.g. Endone, Proladone).
non-steroidal anti-inflammatory drugs, medicines used to treat pain and inflammation such as ibuprofen and diclofenac (e.g. Nurofen, Advil, Voltaren).
tolvaptan (e.g., Jinarc, Samsca) used to treat low levels of sodium in your blood or for kidney problems).
letermovir (e.g., Prevymis) used to prevent viral infections after bone marrow transplant).

These medicines may be affected by VORICONAZOLE WOCKHARDT or may affect how well it works. You may need different amounts of your medicines or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take VORICONAZOLE WOCKHARDT

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box or bottle, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much to take depending on your weight.

Adults

Treatment of invasive fungal infections
The usual dose of VORICONAZOLE WOCKHARDT is 6 mg/kg every 12 hours for the first day. The dose is then adjusted to 3 mg/kg or 4 mg/kg every 12 hours, depending on the type of infection you have.

Prevention of invasive fungal infections.
The usual dose is 6 mg/kg every 12 hours for the first day, given by injection. The dose is then adjusted to 4 mg/kg every 12 hours by injection.

Children

VORICONAZOLE WOCKHARDT should not be given to a child under the age of 2 years.

Your doctor will determine the dose of VORICONAZOLE WOCKHARDT required for your child.

Depending on how serious the infection is and how your child reacts to the medicine, your doctor may increase or decrease the dose.

Adolescents (12-16 years of age)

Adolescents aged 12-16 years of age are usually given the same dose as adults.

How to take it

VORICONAZOLE WOCKHARDT needs to be taken regularly to be effective.

VORICONAZOLE WOCKHARDT is given as an injection by a doctor or trained nurse.

VORICONAZOLE WOCKHARDT is a powder which is mixed with Water for Injections and then diluted by your pharmacist or doctor. It is then given by injection into a vein.

When to take it

Take your medicine regularly at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

The length of time you take VORICONAZOLE WOCKHARDT will depend on the type of infection you have.

If you have a weakened immune system or a difficult infection, you may need long-term treatment to prevent the infection from returning.

You may be switched from the injection to Voriconazole Tablets or Oral Suspension once your condition improves.

Continue taking VORICONAZOLE WOCKHARDT for as long as your doctor or pharmacist recommends. Do not stop taking VORICONAZOLE WOCKHARDT because you are feeling better. If you do not complete the full course prescribed by your doctor, the infection may not clear completely or your symptoms may return.

If you forget to take it

If you forget to take one dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

VORICONAZOLE WOCKHARDT will be given to you under close medical supervision. It is unlikely that a dose would be missed.

However, tell your doctor or pharmacist if you think that a dose has been forgotten.

If you take too much (Overdose)

Immediately telephone your doctor or Poisons Information Centre (Phone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much VORICONAZOLE WOCKHARDT. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of an overdose may include upset stomach, diarrhoea, headache and sensitivity to light.

While you are using VORICONAZOLE WOCKHARDT

Things you must do

Tell your doctor immediately if you develop a rash or blisters while taking VORICONAZOLE WOCKHARDT. If this rash worsens, VORICONAZOLE WOCKHARDT may need to be stopped.

Avoid going out in the sun for long periods of time while you are taking VORICONAZOLE WOCKHARDT. VORICONAZOLE WOCKHARDT can cause sensitivity to light.

Tell your doctor if you notice any changes to your skin while you are taking VORICONAZOLE WOCKHARDT.

If the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.

Make sure you follow your doctor's instructions and keep all appointments, including blood tests. Your doctor should monitor the function of your liver and kidneys using blood tests. If you have liver disease, your doctor might lower your dose of VORICONAZOLE WOCKHARDT or stop your VORICONAZOLE WOCKHARDT treatment. Your doctor might also monitor the function of your pancreas.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking VORICONAZOLE WOCKHARDT.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you are a woman of childbearing age, you should avoid becoming pregnant while taking VORICONAZOLE WOCKHARDT. If you become pregnant while taking VORICONAZOLE WOCKHARDT, tell your doctor immediately.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Things you must not do

Do not take VORICONAZOLE WOCKHARDT to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else even if they have the same condition as you or if their symptoms seem similar to yours.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you do not complete the full course prescribed by your doctor, the infection may not clear completely or your symptoms may return.

Things to be careful of

Be careful driving or operating machinery until you know how VORICONAZOLE WOCKHARDT affects you. You may experience changes to your vision, such as blurriness, colour changes or uncomfortable sensitivity to light.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous. Do not drive at night.

Children should be careful when riding bicycles or climbing.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking VORICONAZOLE WOCKHARDT. This medicine helps most people with fungal infections, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. If they occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Do not be alarmed by the following lists of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

changes to your vision, such as blurred vision, colour changes or sensitivity to light
irregular heartbeat
nausea or feeling sick, vomiting
headache
stomach pain, indigestion, diarrhoea
back pain in middle or upper back
swelling of the arms or legs
rash
changes to your skin, such as skin eruptions or small lumps on the skin
soreness at the injection site.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
asthma, wheezing, shortness of breath
sudden or severe itching, skin rash, hives or blisters
fainting, seizures or fits
flaking of the skin
yellowing of the skin or eyes, also called jaundice
signs of frequent or worsening infections such as fever, severe chills, sore throat or mouth ulcers
blood in urine
signs of kidney failure such as tiredness, lack of appetite and reduced or greatly increased amount of urine
convulsions, fits

These may be signs of a serious allergic reaction or side effect. You may need urgent medical attention or hospitalisation. These side effects are rare.

Tell your doctor if you notice any other side effects.

Other side effects not listed above may also occur in some people.

Storage

VORICONAZOLE WOCKHARDT will be stored in the pharmacy or on the hospital ward and is kept below 25°C. Do not Freeze.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

VORICONAZOLE WOCKHARDT comes as a white to off-white lyophilized powder in a clear, colourless, glass vial which contains 200 mg of voriconazole.

Ingredients

VORICONAZOLE WOCKHARDT contains 200 mg of voriconazole as the active ingredient in each 25 mL vial.

Inactive Ingredients

Hydroxypropylbetadex (HP-β-CD),
sodium chloride,
hydrochloric acid
Water for Injections

Sponsor

Wockhardt Bio Pty Ltd
Suite 103,
39 East Esplanade
Manly NSW 2095, Australia
Tel: +61 29976 6876
Web:www.interpharma.com.au

Australian Registration Numbers

AUST R 267013

Date of preparation

This leaflet was updated in January 2021.

Published by MIMS March 2021

BRAND INFORMATION

Brand name

Voriconazole Wockhardt

Active ingredient

Voriconazole

Schedule

1 Name of Medicine

Voriconazole.

2 Qualitative and Quantitative Composition

Voriconazole Wockhardt is a white lyophilised powder containing nominally 200 mg voriconazole in a 25 mL Type I clear glass vial. Voriconazole Wockhardt is intended for administration by intravenous infusion. It is a single dose, unpreserved product.
It contains following excipients: hydroxypropylbetadex (HP-β-CD), sodium chloride, hydrochloric acid q.s. for pH adjustment and water for injection.
The lyophilised powder contents of the Voriconazole Wockhardt 200 mg vials are intended for reconstitution with Water for Injections or (0.9%) Sodium Chloride for Infusion to produce a solution containing 10 mg/mL voriconazole. The resulting solution is further diluted prior to administration as an intravenous infusion (see Section 4.2 Dose and Method of Administration).

3 Pharmaceutical Form

White, sterile lyophilised 200 mg powder for injection in single use clear glass vials.

4 Clinical Particulars

4.1 Therapeutic Indications

Voriconazole Injection is indicated for treatment of the following fungal infections:
Invasive aspergillosis.
Serious Candida infections (including C. krusei), including systemic Candida infections (hepatosplenic candidiasis, disseminated candidiasis, candidaemia).
Serious fungal infections caused by Scedosporium spp and Fusarium spp.
Other serious fungal infections, in patients intolerant of, or refractory to, other therapy.
Prophylaxis in patients who are at high risk of developing invasive fungal infections. The indication is based on studies including patients undergoing haematopoietic stem cell transplantation.

4.2 Dose and Method of Administration

* Voriconazole powder for oral suspension and tablet are unavailable in Voriconazole Wockhardt brand, however are available in other brands. Where correct dosing requires oral voriconazole, the oral formulations available from other suppliers should be used. Refer to the Product Information for oral voriconazole medicines for specific dosage recommendations.
Voriconazole Wockhardt requires reconstitution and dilution prior to administration as an intravenous infusion (see Section 4.2 Dose and Method of Administration).
Voriconazole Wockhardt is not recommended for bolus injection.
It is recommended that Voriconazole Wockhardt is administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiation of voriconazole therapy (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular).

Use in adults.

Therapy must be initiated with the specified loading dose regimen of either intravenous or *oral voriconazole to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oral bioavailability (96%; see Section 5.2 Pharmacokinetic Properties), switching between intravenous and oral administration is appropriate when clinically indicated.
Intravenous administration is not recommended for the treatment of oesophageal candidiasis; refer to the Product Information for oral voriconazole medicines for dosage recommendations for oesophageal candidiasis.
Dosage recommendations for other indications are provided in Tables 1 and 2.

Dosage adjustment.

Intravenous administration.

If patient response at 3 mg/kg every 12 hours is inadequate, the intravenous maintenance dose may be increased to 4 mg/kg every 12 hours.
If patients are unable to tolerate 4 mg/kg every 12 hours, reduce the intravenous dose to 3 mg/kg every 12 hours.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV every 12 hours. The loading dose regimen remains unchanged (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The dose recommendation for concomitant use of intravenous voriconazole and oral efavirenz has not been determined (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment duration depends upon patients' clinical and mycological response.

Use in the elderly.

No dose adjustment is necessary for elderly patients.

Use in patients with renal impairment.

The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment.
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), including dialysis patients, accumulation of the intravenous vehicle, HP-β-CD, occurs. Oral voriconazole should be administered to these patients, unless an assessment of the risk benefit to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients and, if increases occur, consideration should be given to changing to oral voriconazole therapy (see Section 5.2 Pharmacokinetic Properties, Renal impairment).

Use in patients with hepatic impairment.

No dose adjustment is necessary in patients with acute hepatic injury, manifested by elevated liver function tests (ALT, AST) (but continued monitoring of liver function tests for 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 severe hepatic impairment must be carefully monitored for drug toxicity (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in children.

Safety and efficacy in paediatric subjects below the age of 2 years has not been established. Therefore, voriconazole is not recommended for children less than 2 years of age. Use in paediatric patients aged 2 to < 12 years with hepatic or renal insufficiency has not been studied (see Section 4.4 Special Warnings and Precautions for Use).
Limited data are currently available to determine the optimal dosing regimen. Multiple intravenous doses (3, 4, 6 and 8 mg/kg twice daily) and oral doses (4 and 6 mg/kg twice daily) have been used in pharmacokinetic studies conducted in children 2 to 12 years.
The study results showed that 4 mg/kg IV twice daily in children achieved exposure comparable to that in adults receiving 3 mg/kg IV twice daily. The average voriconazole exposure in children receiving 6 mg/kg IV doses twice daily was slightly lower than in adults receiving 4 mg/kg IV doses twice daily. Based on the data, physicians may initiate therapy in children with 6 mg/kg IV twice daily. The dose may be increased to 7 mg/kg IV twice daily if clinically indicated.
Further study is required to determine the optimal oral dose for children 2 to < 12 years.
Limited data on the intravenous vehicle, HP-β-CD, are currently available to determine the optimal dosing regimen for Voriconazole Wockhardt. Intravenous treatment should not exceed 21 days. Children can be switched to oral tablets or suspension at any time, neither of which contains HP-β-CD.
Adolescents (12-16 years of age) should be dosed as adults.

Administration - intravenous.

Intravenous administration.

Voriconazole Wockhardt powder for injection is supplied in single use vials. The powder should be reconstituted with 19 mL of Water for Injections. Shake thoroughly to give a clear concentrate containing 10 mg/mL of voriconazole and an extractable volume of 20 mL. 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 Injections is dispensed. Discard the vial if a vacuum does not pull the diluent into the vial.
For administration, the required volume of the reconstituted concentrate is added to a recommended compatible infusion solution (detailed below) to obtain a final solution containing voriconazole at a concentration between 0.5 mg/mL and 5 mg/mL. Voriconazole Wockhardt IV should be administered at a maximum rate of 3 mg/kg per hour over 1 to 2 hours and must not be given as a bolus injection.
Voriconazole Wockhardt contains no preservative. To reduce microbiological hazard, use as soon as practicable after reconstitution. If storage is necessary, hold at 2°C to 8°C for not more than 24 hours. Product is for single use in one patient only. Discard any residue. Only clear solutions without particles should be used.
Chemical and physical in use stability has been demonstrated for 72 hours at 2°C to 8°C.
The reconstituted solution can be diluted with:
0.9% Sodium Chloride Intravenous Infusion;
Compound Sodium Lactate Intravenous Infusion;
5% Glucose and Compound Sodium Lactate Intravenous Infusion;
5% Glucose and 0.45% Sodium Chloride Intravenous Infusion;
5% Glucose Intravenous Infusion;
5% Glucose in 20 mEq Potassium Chloride Intravenous Infusion;
0.45% Sodium Chloride Intravenous Infusion;
5% Glucose and 0.9% Sodium Chloride Intravenous Infusion.
The compatibility of Voriconazole Wockhardt with diluents other than those described above is unknown (see Section 6.2 Incompatibilities).

4.3 Contraindications

Voriconazole Wockhardt is contraindicated in patients with known hypersensitivity to voriconazole or to any of the excipients.
Co-administration of the CYP3A4 substrates, terfenadine, pimozide, quinidine or ivabradine with voriconazole is contraindicated since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration of voriconazole with rifabutin, rifampicin, carbamazepine and long-acting barbiturates (e.g. phenobarbitone) is contraindicated since these medicinal products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration of standard doses of voriconazole with patients receiving efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). For information pertaining to lower doses of efavirenz (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration of voriconazole with patients receiving high doses of ritonavir (400 mg and higher twice daily) is contraindicated, because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at these doses (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). For information pertaining to lower doses of ritonavir (see Section 4.4 Special Warnings and Precautions for Use).
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 (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration of voriconazole and sirolimus is contraindicated, since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Co-administration of voriconazole with St John's Wort is contraindicated (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Caution should be used in prescribing voriconazole to patients with hypersensitivity to other azoles.

Cardiovascular.

Some azoles, including voriconazole have 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 history of cardiotoxic chemotherapy, cardiomyopathy, hypokalemia and concomitant medications that may have been contributory. Voriconazole should be administered with caution to patients with potentially pro-arrhythmic conditions, such as:
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 QT interval (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation of and during voriconazole therapy (see Section 4.2 Dose and Method of Administration).

Infusion related reactions.

Anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred during the administration of the intravenous formulation of voriconazole. Depending on the severity of symptoms, consideration should be given to stopping treatment.

Monitoring of pancreatic function.

Adults and children, with risk factors for acute pancreatitis (e.g. recent chemotherapy, haematopoietic stem cell transplantation (HSCT)), should be monitored closely during Voriconazole Wockhardt treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Dermatological adverse events.

Severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a suspected SCAR, voriconazole should be discontinued immediately and an alternative treatment should be considered.
In addition, voriconazole has been associated with photosensitivity skin reaction. It is recommended that patients, including children, avoid exposure to direct sunlight during voriconazole treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF) (see Squamous cell carcinoma).
The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution towards squamous cell carcinoma has been reported, stringent measures for the photo-protection are warranted in this population of patients. In children experiencing photo-aging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Adrenal events.

Adrenal insufficiency has been reported in patients receiving other azoles (e.g. ketoconazole).
Reversible cases of adrenal insufficiency have been reported in patients receiving voriconazole.
Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g. budesonide) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Long-term treatment.

The following severe adverse events have been reported in relation with long-term voriconazole treatment:

Squamous cell carcinoma (SCC).

In patients with photosensitivity skin reactions and additional risk factors (including immuno-suppression), squamous cell carcinoma of the skin and melanoma have been reported during long-term therapy. 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. If a patient develops a skin lesion consistent with premalignant skin lesions, squamous cell carcinoma or melanoma, voriconazole discontinuation should be considered.

Non-infectious periostitis.

Periostitis has been reported in transplant patients during long-term voriconazole therapy. If a patient develops skeletal pain and radiologic findings compatible with periostitis, voriconazole should be discontinued.

Visual adverse events.

There have been post-marketing reports of prolonged visual adverse events, including optic neuritis and papilloedema. These events occurred primarily in ill patients who had underlying conditions and/or concomitant medications which may have caused or contributed to these events (see Section 4.8 Adverse Effects (Undesirable Effects), Visual impairment).

Methadone (CYP3A4 substrate).

Increased plasma concentrations of methadone have been associated with toxicity including QT prolongation. Frequent monitoring for adverse events and toxicity related to methadone is recommended during co-administration. Dose reduction of methadone may be needed (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Short acting opiates (CYP3A4 substrate).

Reduction in the dose of alfentanil and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. sufentanil, fentanyl, remifentanil) should be considered when co-administered with voriconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is co-administered with voriconazole, frequent monitoring for opiate associated adverse events (including a longer respiratory monitoring period) may be necessary.

Oxycodone (CYP3A4 substrate).

Reduction in the dose of oxycodone and other long-acting opiates metabolised by CYP3A4 (e.g. hydrocodone) should be considered when co-administered with voriconazole. Frequent monitoring for opiate associated adverse events may be necessary (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Everolimus (CYP3A4 substrate, P-gp substrate).

Co-administration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Naloxegol (CYP3A4 substrate).

Coadministration of voriconazole with naloxegol is not recommended because voriconazole is expected to significantly increase naloxegol concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

Co-administration of oral voriconazole and oral fluconazole resulted in significant increase in C_max and AUC_T of voriconazole in healthy subjects. The clinical significance of this drug interaction has not been established and the co-administration of voriconazole and oral fluconazole is not recommended.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer).

Careful monitoring of phenytoin levels is recommended when phenytoin is co-administered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate).

Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk justifies the use of voriconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Co-administration of voriconazole and ritonavir 400 mg and higher twice daily is contraindicated (see Section 4.3 Contraindications).

Sodium content.

Each vial of Voriconazole Wockhardt Powder for Injection contains 225.6 mg of sodium. This should be taken into consideration for patients on a controlled sodium diet.

Use in hepatic impairment.

In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy). Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy.
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. If treatment is continued, 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 (see Section 4.2 Dose and Method of Administration).

Use in renal impairment.

The pharmacokinetic parameters of orally administered voriconazole are not affected by renal impairment. However, 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.
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), including dialysis patients, accumulation of the intravenous vehicle, HP-β-CD, occurs. Oral voriconazole should be administered to these patients unless an assessment of the risk to the patient justifies the use of intravenous voriconazole.
Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Use in the elderly.

No data available.

Paediatric use.

Safety and efficacy in paediatric subjects below the age of two years has not been established (see Section 5.1 Pharmacodynamic Properties, Clinical trials). A higher frequency of liver enzyme elevations was observed in the paediatric population (see Section 4.8 Adverse Effects (Undesirable Effects)).
Hepatic function and pancreatic function should be monitored.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Unless otherwise specified, drug interaction studies have been performed in healthy male subjects, using multiple dosing to steady state with oral voriconazole at 200 mg twice daily. These results are relevant to other populations and routes of administration.
This section addresses the effects of other medicinal products on voriconazole, the effects of voriconazole on other medicinal products and two-way interactions. The interactions for the first two sections are presented in the following order: contraindications, those requiring dosage adjustment, those requiring careful clinical and/or biochemical monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

Effects of other medicinal products on voriconazole.

Voriconazole is metabolised by cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively.

The exposure to voriconazole is significantly reduced by the concomitant administration of the following agents.

Rifampicin (CYP450 inducer).

Rifampicin (600 mg once daily) decreased the C_max (maximum plasma concentration) and AUC_T (area under the plasma concentration time curve within a dose interval) of voriconazole by 93% and 96%, respectively. Co-administration of voriconazole and rifampicin is contraindicated (see Section 4.3 Contraindications).

Rifabutin (potent CYP450 inducer).

Rifabutin (300 mg once daily) decreased the C_max and AUC_T of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During co-administration with rifabutin, the C_max and AUC_T of voriconazole at 350 mg twice daily were 96% and 68% of the levels when administered alone at 200 mg twice daily. At a voriconazole dose of 400 mg twice daily C_max and AUC_T were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. Voriconazole at 400 mg twice daily increased C_max and AUC_T of rifabutin by 195% and 331%, respectively. Co-administration of voriconazole with rifabutin is contraindicated (see Section 4.3 Contraindications).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate).

The effect of the co-administration of oral voriconazole (200 mg twice daily) and high dose (400 mg) and low dose (100 mg) oral ritonavir was investigated in two separate studies in healthy volunteers. High doses of ritonavir (400 mg twice daily) decreased the steady state C_max and AUC_T of oral voriconazole by an average of 66% and 82% respectively, whereas low doses of ritonavir (100 mg twice daily) decreased the C_max and AUC_T of oral voriconazole by an average of 24% and 39% respectively. Administration of voriconazole did not have a significant effect on mean C_max and AUC_T of ritonavir in the high dose study, although a minor decrease in steady state C_max and AUC_T of ritonavir with an average of 25% and 13% respectively was observed in the low dose ritonavir interaction study. One outlier subject with raised voriconazole levels was identified in each of the ritonavir interaction studies. Co-administration of voriconazole and high doses of ritonavir (400 mg and higher twice daily) is contraindicated (see Section 4.3 Contraindications). Co-administration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see Section 4.4 Special Warnings and Precautions for Use).

Carbamazepine and phenobarbitone (CYP450 inducers).

Although not studied, carbamazepine or phenobarbitone are likely to significantly decrease plasma voriconazole levels. Co-administration of voriconazole with carbamazepine and long acting barbiturates are contraindicated (see Section 4.3 Contraindications).

Letermovir (CYP2C9 and CYP2C19 inducer).

Letermovir decreased the C_max, AUC0-12 and C12 of voriconazole by 39%, 44% and 51%, respectively. If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for loss of voriconazole effectiveness.

Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole related adverse events/toxicity.

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

Minor or no significant pharmacokinetic interactions that require no dosage adjustment.

Cimetidine (non-specific CYP450 inhibitor and increases gastric pH).

Cimetidine (400 mg twice daily) increased voriconazole C_max and AUC_T by 18% and 23%, respectively. No dosage adjustment of voriconazole is recommended.

Ranitidine (increases gastric pH).

Ranitidine (150 mg twice daily) had no significant effect on voriconazole C_max and AUC_T.

Macrolide antibiotics.

Erythromycin (CYP3A4 inhibitor; 1 g twice daily) and azithromycin (500 mg once daily) had no significant effect on voriconazole C_max and AUC_T.

Effects of voriconazole on other medicinal products.

Voriconazole inhibits the activity of cytochrome P450 isoenzymes, CYP2C19, CYP2C9 and CYP3A4. Therefore, there is potential for voriconazole to increase the plasma levels of drugs metabolised by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since voriconazole is a moderate to strong CYP3A4 inhibitor (substrate dependent).
Voriconazole should be administered with caution in patients receiving concomitant medication that is known to prolong QT interval. When there is also a potential for voriconazole to increase the plasma levels of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, pimozide, ivabradine) co-administration is contraindicated (see below and see Section 4.3 Contraindications).

Concomitant use of the following agents with voriconazole is contraindicated.

Terfenadine, pimozide, quinidine and ivabradine (CYP3A4 substrates).

Although not studied, co-administration of voriconazole with terfenadine, pimozide, quinidine or ivabradine is contraindicated, since increased plasma concentrations of these drugs can lead to QTc prolongation and rare occurrences of torsades de pointes (see Section 4.3 Contraindications).

Sirolimus (CYP3A4 substrate).

Voriconazole increased sirolimus (2 mg single dose) C_max and AUC_T by 556% and 1014%, respectively. Co-administration of voriconazole and sirolimus is contraindicated (see Section 4.3 Contraindications).

Ergot alkaloids (CYP3A4 substrates).

Although not studied, voriconazole may increase the plasma concentrations of ergot alkaloids (ergotamine and dihydroergotamine) and lead to ergotism. Co-administration of voriconazole with ergot alkaloids is contraindicated (see Section 4.3 Contraindications).

St John's Wort (CYP450 inducer; P-gp inducer).

In an independent published study in healthy volunteers, St John's Wort exhibited a short initial inhibitory effect followed by induction of voriconazole metabolism. After 15 days of treatment with St John's Wort (300 mg three times daily), plasma exposure following a single 400 mg dose of voriconazole decreased by 40-60%. Therefore, concomitant use of voriconazole with St John's Wort is contraindicated (see Section 4.3 Contraindications).

Interaction of voriconazole with the following agents may result in increased exposure to these drugs. Careful monitoring and/or dosage adjustment should be considered.

Ciclosporin (CYP3A4 substrate).

In stable, renal transplant recipients, voriconazole increased ciclosporin C_max and AUC_T by at least 13% and 70% respectively. When initiating voriconazole in patients already receiving 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.

Tacrolimus (CYP3A4 substrate).

Voriconazole increased tacrolimus (0.1 mg/kg single dose) C_max and AUC_T by 117% and 221%, respectively. When initiating voriconazole in patients already receiving tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus levels 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.

Methadone (CYP3A4 substrate).

Repeat dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 4 days) increased the C_max and AUC_T of pharmacologically active R-methadone by 31% (90% CI: 22%, 40%) and 47% (90% CI: 38%, 57%) respectively in subjects receiving a methadone maintenance dose (30-100 mg daily) (see Section 4.4 Special Warnings and Precautions for Use).

Short acting opiates (CYP3A4 substrates).

Alfentanil: In an independent publication, steady-state administration of oral voriconazole increased the mean AUC_0-∞ of a single dose of alfentanil by 6-fold. Reduction in the dose of alfentanil and other short acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g. fentanyl, sufentanil, remifentanil), should be considered when co-administered with voriconazole.
Fentanyl: In an independent published study, concomitant use of voriconazole (400 mg q12h on Day 1, then 200 mg q12h on Day 2) with a single intravenous dose of fentanyl (5 microgram/kg) resulted in an increase in the mean AUC_0-∞ of fentanyl by 1.4-fold (range 1.12- to 1.60-fold). When voriconazole is co-administered with fentanyl, extended and frequent monitoring of patients for respiratory depression and other fentanyl-associated adverse events is recommended, and the fentanyl dose should be reduced if warranted.

Long acting opiates (CYP3A4 substrates).

Oxycodone: In an independent published study, co-administration of multiple doses of oral voriconazole (400 mg q12h on Day 1, followed by five doses of 200 mg q12h on Days 2 to 4) with a single 10 mg oral dose of oxycodone on Day 3 resulted in an increase in the mean C_max and AUC_0-∞ of oxycodone by 1.7-fold (range 1.4- to 2.2-fold) and 3.6-fold (range 2.7- to 5.6-fold), respectively. The mean elimination half-life of oxycodone was also increased by 2.0-fold (range 1.4- to 2.5-fold). A reduction in oxycodone dosage may be needed during voriconazole treatment to avoid opioid related adverse effects. Extended and frequent monitoring for adverse effects associated with oxycodone and other long-acting opiates metabolised by CYP3A4 is recommended.

Everolimus (CYP3A4 substrate, P-gP substrate).

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of everolimus. Co-administration of voriconazole and everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations.

Venetoclax (CYP3A substrate).

Although not studied clinically, voriconazole is likely to significantly increase the plasma concentrations of venetoclax. Concomitant administration of voriconazole should be avoided during venetoclax dose titration phase. Dose reduction of venetoclax is required as instructed in venetoclax prescribing information during steady daily dosing; close monitoring for signs of toxicity is recommended.

Naloxegol (CYP3A4 substrate).

Co-administration of voriconazole and naloxegol is not recommended, as there is insufficient data to allow dosing recommendations of naloxegol in this situation. Although not studied, voriconazole is likely to significantly increase the plasma concentrations of naloxegol.

Warfarin (CYP2C9 substrate).

Co-administration of voriconazole (300 mg twice daily) with warfarin (30 mg single dose) increased maximum prothrombin time by 93%. Close monitoring of prothrombin time is recommended if warfarin and voriconazole are co-administered.

Other oral anticoagulants (CYP2C9, CYP3A4 substrates).

Although not studied, voriconazole may increase the plasma concentrations of coumarins and therefore may cause an increase in prothrombin time. If patients receiving coumarin preparations are treated simultaneously with voriconazole, the prothrombin time should be monitored at close intervals and the dosage of anticoagulants adjusted accordingly.

Ivacaftor (CYP3A4 substrate).

Although not studied, voriconazole is likely to increase the plasma concentrations of ivacaftor with risk of increased adverse effects.
Dose reduction of ivacaftor is recommended.

Sulphonylureas (CYP2C9 substrates).

Although not studied, voriconazole may increase the plasma levels of sulphonylureas, (e.g. tolbutamide, glipizide, and glyburide) and therefore cause hypoglycaemia. Careful monitoring of blood glucose is recommended during co-administration.

Statins (CYP3A4 substrates).

Although not studied clinically, voriconazole has been shown to inhibit lovastatin metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase plasma levels of statins that are metabolised by CYP3A4. It is recommended that dose adjustment of the statin be considered during co-administration. Increased statin levels have been associated with rhabdomyolysis.

Benzodiazepines (CYP3A4 substrates).

Although not studied clinically, voriconazole has been shown to inhibit midazolam metabolism in vitro (human liver microsomes). Therefore, voriconazole is likely to increase the plasma levels of benzodiazepines that are metabolised by CYP3A4 (e.g. midazolam, triazolam and alprazolam) and lead to a prolonged sedative effect. It is recommended that dose adjustment of the benzodiazepine be considered during co-administration.

Tolvaptan (CYP3A substrate).

Although not studied clinically, voriconazole is likely to significantly increase the plasma concentrations of tolvaptan. If concomitant administration of voriconazole with tolvaptan cannot be avoided, dose reduction of tolvaptan is recommended.

Vinca alkaloids (CYP3A4 substrates).

Although not studied, voriconazole may increase the plasma levels of the vinca alkaloids (e.g. vincristine and vinblastine) and lead to neurotoxicity. It is therefore recommended that dose adjustment of the vinca alkaloid be considered.

Non-steroidal anti-inflammatory drugs (CYP2C9 substrates).

Voriconazole increased C_max and AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased C_max and AUC of diclofenac (50 mg single dose) by 114% and 78%, respectively. Frequent monitoring for adverse events and toxicity related to NSAIDs is recommended. Adjustment of dosage of NSAIDs may be needed.

No significant pharmacokinetic interactions were observed when voriconazole was co-administered with the following agents. No dosage adjustment for these agents is recommended.

Corticosteroids.

Prednisolone (CYP3A4 substrate): Voriconazole increased C_max and AUC_T of prednisolone (60 mg single dose) by 11% and 34%, respectively. No dosage adjustment is recommended.
Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g. budesonide) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued (see Section 4.4 Special Warnings and Precautions for Use).

Digoxin (P-glycoprotein mediated transport).

Voriconazole had no significant effect on C_max and AUC_T of digoxin (0.25 mg once daily).

Mycophenolic acid (UDP-glucuronyl transferase substrate).

Voriconazole had no effect on the C_max and AUC_T of mycophenolic acid (1 g single dose).

Two-way interactions.

Phenytoin (CYP2C9 substrates and potent CYP450 inducer).

Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk.
Phenytoin (300 mg once daily) decreased the C_max and AUC_T of voriconazole by 49% and 69%, respectively. Voriconazole (400 mg twice daily) increased C_max and AUC_T of phenytoin (300 mg once daily) by 67% and 81%, respectively.
Phenytoin may be co-administered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg intravenously twice daily or from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg). Careful monitoring of phenytoin plasma levels is recommended when phenytoin is co-administered with voriconazole.

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate).

Omeprazole (40 mg once daily) increased voriconazole C_max and AUC_T by 15% and 41%, respectively. No dosage adjustment of voriconazole is recommended. Voriconazole increased omeprazole C_max and AUC_T by 116% and 280%, respectively. When initiating voriconazole in patients already receiving omeprazole, it is recommended that the omeprazole dose be halved. The metabolism of other proton pump inhibitors which are CYP2C19 substrates may also be inhibited by voriconazole.

Oral contraceptives (CYP3A4 substrate).

Co-administration of voriconazole and an oral contraceptive (norethisterone 1 mg and ethinylestradiol 0.035 mg once daily) in healthy female subjects resulted in increases in the C_max and AUC_T of ethinylestradiol (36% and 61% respectively) and norethisterone (15% and 53% respectively). Voriconazole C_max and AUC_T increased by 14% and 46% respectively. Oral contraceptives containing doses other than norethisterone 1 mg and ethinylestradiol 0.035 mg have not been studied. As the ratio between norethisterone and ethinylestradiol remained similar during interaction with voriconazole, their contraceptive activity would probably not be affected. Monitoring for adverse events related to oral contraceptives is recommended during co-administration.

Indinavir (CYP3A4 inhibitor and substrate).

Indinavir (800 mg three times daily) had no significant effect on voriconazole C_max and AUC_T. Voriconazole did not have a significant effect on C_max, C_min and AUC_T of indinavir.

Other HIV protease inhibitors (CYP3A4 substrates and inhibitors).

In vitro studies suggest that voriconazole may inhibit the metabolism of HIV protease inhibitors (e.g. saquinavir, amprenavir and nelfinavir). In vitro studies also show that the metabolism of voriconazole may be inhibited by HIV protease inhibitors. Patients should be carefully monitored for drug toxicity during the co-administration of voriconazole and HIV protease inhibitors.

Efavirenz (a non-nucleoside reverse transcriptase inhibitor [CYP450 inducer; CYP3A4 inhibitor and substrate]).

Use of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated (see Section 4.3 Contraindications).
In healthy subjects, steady state efavirenz (400 mg oral once daily) decreased the steady state C_max and AUC_T of voriconazole by an average of 61% and 77%, respectively. In the same study, voriconazole at steady state (400 mg orally every 12 hours for 1 day, then 200 mg orally every 12 hours for 8 days) increased the steady state C_max and AUC_T of efavirenz by an average of 38% and 44%, respectively, in the same subjects.
In a separate study in healthy subjects, voriconazole dose of 300 mg twice daily in combination with low dose efavirenz (300 mg once daily) did not lead to sufficient voriconazole exposure.
Following co-administration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once daily in healthy subjects, the AUC_T of voriconazole was decreased by 7% and C_max was increased by 23% compared to voriconazole 200 mg twice daily alone. The AUC_T of efavirenz was increased by 17% and C_max was equivalent compared to efavirenz 600 mg once daily alone. These differences were not considered to be clinically significant.
Voriconazole may be co-administered with efavirenz if the voriconazole maintenance dose is increased to 400 mg twice daily and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily (see Section 4.2 Dose and Method of Administration). When treatment with voriconazole is stopped, the initial dose of efavirenz should be restored.
The concomitant use of intravenous voriconazole and oral efavirenz has not been studied.

Other non-nucleoside reverse transcriptase inhibitors (NNRTIs) (CYP3A4 substrates, inhibitors or CYP450 inducers).

In vitro studies show that the metabolism of voriconazole may be inhibited by delavirdine. Although not studied, the metabolism of voriconazole may be induced by nevirapine. Voriconazole may also inhibit the metabolism of NNRTIs. Patients should be carefully monitored for drug toxicity during the co-administration of voriconazole and NNRTIs. See Table 3.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Fertility of male and female rats was not affected at oral doses of up to 50 mg/kg/day, corresponding to exposures 4-6 times the expected human exposure (based on AUC) at the maintenance dose.
(Category B3)
There are no adequate studies in pregnant women. Studies in rats have shown reproductive toxicity, including teratogenicity (cleft palates) at oral doses of ≥ 10 mg/kg/day and disturbance of parturition (dystocia) at oral doses of ≥ 3 mg/kg/day, with exposures similar to or below those expected in humans at maintenance dosing. Voriconazole was not teratogenic in rabbits at oral doses of up to 100 mg/kg/day, but produced an increase in post-implantation loss and a decrease in foetal body weight, with exposures approximately 4 times the expected human exposure. Voriconazole must not be used during pregnancy except in patients with severe or potentially life-threatening fungal infections in whom voriconazole may be used if the benefit to the mother clearly outweighs the potential risk to the foetus.

Women of childbearing potential.

Women of childbearing potential must always use effective contraception during treatment (see Use in pregnancy).
It is not known whether voriconazole is excreted in the milk of laboratory animals or in human breast milk. Breast-feeding must be stopped on initiation of treatment with voriconazole.

4.7 Effects on Ability to Drive and Use Machines

Voriconazole may cause changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery whilst experiencing these symptoms. Patients should be advised not to drive at night while taking voriconazole.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

The safety of voriconazole in adults is based on an integrated safety database of more than 2000 subjects (1603 adult patients in therapeutic studies). This represents a heterogeneous population, containing patients with haematological malignancy, HIV infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers.
In addition, the safety of voriconazole was investigated in 279 patients (including 270 adults) who were treated with voriconazole in prophylaxis studies. The adverse event profile in these prophylaxis studies was similar to the established safety profile from 2000 subjects in voriconazole clinical trials.
Table 4 includes all causality adverse reactions in 1873 adults from pooled therapeutic (1603) and prophylaxis (270) studies. The most commonly reported adverse events were visual impairment, liver function test abnormal, 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.

See Table 5.

Visual impairment.

In clinical trials, visual impairment (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters and xanthopsia) with voricanzole were very common. These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes. There was evidence of attenuation with repeated doses of voriconazole. The visual impairment were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairment may be associated with higher plasma concentrations and/or doses.
There have been post-marketing reports of prolonged visual adverse events (see Section 4.4 Special Warnings and Precautions for Use).
The mechanism of action is unknown, although the site of action is most likely to be within the retina.
In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of voriconazole.
The long-term effect of voriconazole (median 169 days; range 5-353 days) on visual function was evaluated in subjects with paracoccidioidomycoses. Voriconazole had no clinically relevant effect on visual function as assessed by testing of visual acuity, visual fields, colour vision and contrast sensitivity. There were no signs of retinal toxicity. 17/35 voriconazole subjects experienced visual adverse events. These events did not lead to discontinuation, were generally mild, occurred in the first week of therapy and resolved during continued voriconazole therapy.

Dermatological reactions.

Dermatological reactions were very common in patients treated with voriconazole. In clinical trials, rashes were reported by 19% (278/1493) of voriconazole treated patients, but these patients had serious underlying diseases and were receiving multiple concomitant medications. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous reactions (SCARs), including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) which was reported post-marketing (rare) and erythema multiforme (rare) during treatment with voriconazole (see Section 4.4 Special Warnings and Precautions for Use).
If patients develop a rash they should be monitored closely and voriconazole discontinued if lesions progress. Photosensitivity reactions have been reported, especially during long-term therapy (see Section 4.4 Special Warnings and Precautions for Use).
Dermatological adverse reactions potentially related to phototoxicity (pseudoporphyria, cheilitis, and cutaneous lupus erythematosus) are also reported with voriconazole. Sun avoidance and photo-protection are recommended for all patients. If phototoxicity occurs, voriconazole discontinuation and dermatological evaluation should be considered (see Section 4.4 Special Warnings and Precautions for Use).
There have been post-marketing reports of cutaneous lupus erythematosus and squamous cell carcinoma (SCC) (see Section 4.4 Special Warnings and Precautions for Use).

Liver function tests.

The overall incidence of clinically significant transaminase abnormalities in the voriconazole clinical program was 13.4% (200/1493) of subjects treated with voriconazole. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.
Voriconazole has been associated with cases of serious hepatic toxicity, in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death (see Section 4.4 Special Warnings and Precautions for Use).

Paediatric use.

The safety of voriconazole was investigated in 245 paediatric patients aged 2 to < 12 years who were treated with voriconazole in pharmacokinetic studies (87 paediatric patients) and in compassionate use programs (158 paediatric patients). The adverse event profile of these 245 paediatrics was similar to adults. A higher frequency of liver enzyme elevations reported as adverse events was observed in paediatric patients as compared to adults.
Post-marketing data suggest there might be a higher occurrence of skin reactions in the paediatric population compared to adults.
There have been post-marketing reports of pancreatitis in paediatric patients.

Infusion-related reactions.

During infusion of the intravenous formulation of voriconazole in healthy subjects, anaphylactoid-type reactions, including flushing, fever, sweating, tachycardia, chest tightness, dyspnoea, faintness, nausea, pruritus and rash have occurred. Symptoms appeared immediately upon initiating the infusion (see Section 4.4 Special Warnings and Precautions for Use).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Clinical data on overdose with this agent is scant.
In clinical trials there were three cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse event of photophobia of 10 minutes duration was reported.
There is no known antidote to voriconazole. It is recommended that treatment of overdose is symptomatic and supportive.
Monitor potassium, full blood count and liver function following an overdose.
Consider administration of activated charcoal in the event of a potentially toxic ingestion. Activated charcoal is most effective when administered within one hour of ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via nasogastric tube once the airway is protected.
Voriconazole is haemodialysed with a clearance of 121 mL/min. The intravenous vehicle, HP-β-CD, is haemodialysed with a clearance of 37.5 ± 24 mL/min. In an overdose, haemodialysis may assist in the removal of voriconazole and HP-β-CD from the body.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Voriconazole is a triazole antifungal agent. Voriconazole's primary mode of action is the inhibition of fungal cytochrome P450-mediated 14α-sterol demethylation, an essential step in ergosterol biosynthesis. Voriconazole is more selective than some other azole drugs for fungal as opposed to various mammalian cytochrome P450 enzyme systems. The subsequent loss of normal sterols correlates with the accumulation of 14α-methyl sterols in fungi and may be responsible for its fungistatic/fungicidal activity.
In vitro, voriconazole displays broad-spectrum antifungal activity with high antifungal potency against Candida species (including fluconazole resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition, voriconazole shows in vitro activity against emerging fungal pathogens, such as Scedosporium or Fusarium, some isolates of which have limited susceptibility to existing antifungal agents. In addition, voriconazole exhibits in vitro fungicidal activity against some strains within these species.
In animal studies there is a correlation between minimum inhibitory concentration values and efficacy against experimental mycoses. Furthermore, there appears to be a correlation between minimum inhibitory concentration values and clinical outcome for Candida species.

Microbiology.

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. dubliniensis, C. glabrata, C. inconspicua, C. krusei, C. parapsilosis, C. tropicalis and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans and Fusarium spp.
Other successfully treated fungal infections included isolated cases of Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp including T. beigelii infections.
In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp., Cladophialophora spp, Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 microgram/mL.
In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.
Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained to isolate and identify causative organisms prior to therapy. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

Susceptibility testing.

See Tables 6 and 7.

Clinical trials.

Duration of treatment.

In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 subjects receiving voriconazole for over 6 months.

Clinical experience.

Successful outcome in this section is defined as complete or partial response.

Invasive aspergillosis.

The efficacy and survival benefit of voriconazole compared to conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study. The total duration of treatment was 12 weeks. Patients could be switched to Other Licensed Antifungal Therapy (OLAT) during the 12 week study period, either due to lack of efficacy of the initial randomised treatment (IRT) or for safety/tolerability reasons. Efficacy was assessed at 12 weeks (primary endpoint) and at the end of IRT by a Data Review Committee. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of seven days, after which the oral formulation at a dose of 200 mg twice daily could be used. Patients in the comparator group received conventional amphotericin B as a slow infusion at a daily dose of 1.0-1.5 mg/kg/day.
In this study, 277 immunocompromised patients with invasive aspergillosis (modified intent to treat population) were evaluated. At week 12, a satisfactory global response (complete or partial resolution of all attributable symptoms, signs, radiographic/ bronchoscopic abnormalities present at baseline) was seen in 53% of patients in the voriconazole group compared to 31% of patients in the comparator group. At the end of IRT, a satisfactory global response was seen in 53.5% of voriconazole treated patients compared to 21.8% of conventional amphotericin B treated patients. Subjects in the voriconazole group were treated longer than subjects in the amphotericin B group before switching to OLAT (median duration of IRT was 73 vs. 12 days respectively). OLAT included liposomal amphotericin B formulations, itraconazole and flucytosine. Survival in the voriconazole group (71%) was greater than in the comparator group (58%) at week 12. See Table 8.

The results of this comparative trial confirmed the results of an earlier trial in the primary treatment of patients with acute invasive aspergillosis (Study 304). In this study, an overall success rate of 54% was seen in patients treated with voriconazole.
Voriconazole successfully treated cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrow and solid organ transplants, haematological malignancies, cancer and AIDS.

Serious candida infections.

Systemic candida infections.

The efficacy of voriconazole compared to the regimen of (conventional) amphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open comparative study (Study 150-608). Three hundred and seventy (370) non-neutropenic patients with documented candidaemia (positive blood culture and clinical signs of infection) were included in the study, of which 248 were treated with voriconazole. The patient population was seriously ill, with approximately 50% of subjects in the intensive care unit and 40% mechanically ventilated at baseline. The median treatment duration was 15 days in both treatment arms. A successful response (resolution/improvement in all clinical signs and symptoms of infection, blood cultures negative for Candida, infected deep tissue sites negative for Candida) was seen in 41% of patients in both treatment arms 12 weeks after the End of Therapy (EOT). In this analysis, patients who did not have an assessment 12 weeks after EOT were set to failure. According to a secondary analysis, which compared response rates at the latest time point most relevant to the evaluation of the patient (EOT, or 2, 6, or 12 weeks after EOT, which is more appropriate for this type of study), voriconazole and the regimen of amphotericin B followed by fluconazole had response rates of 65% and 71%, respectively. Forty-seven percent of isolated pathogens in the voriconazole treatment group were from non-albicans species, including C. glabrata and C. krusei, although C. albicans was the most commonly isolated species in the small subgroup of patients (n = 14) with confirmed deep tissue infections. When considering response at 12 weeks after EOT by pathogen, the success rates were comparable between voriconazole (43%) and amphotericin B followed by fluconazole (46%) for baseline Candida albicans infections. Success rates were more favourable with voriconazole (38.6%) than with amphotericin followed by fluconazole (32.3%) for baseline non-albicans infections.

Refractory candida infections.

Study 309/604 (the combined results of 2 open-label, non-comparative trials) assessed voriconazole in the treatment of fungal infections in patient's refractory to, or intolerant of, other antifungal medications. Of the 301 patients assessed for efficacy, 87 patients had serious candidiasis: 38 had oesophageal candidiasis and 47 had invasive candidiasis, of which 26 patients had deep tissue Candida infections. The median duration of IV therapy was 11 days (range 1-138 days) and of oral therapy was 81 days (range 1-326 days). Overall, 25/47 (53.2%) of invasive candidiasis subjects had a successful response, with 16/47 (34.0%) having a complete response and 9/47 (19.1%) having a partial response; 6/47 (12.8%) were assessed as stable. Of the subjects with deep tissue Candida infection, 14/26 (53.8%) had a successful response, with 8/26 (30.8%) having a complete response, 6/26 (23.1%) having a partial response and 5/26 (19.2%) assessed as stable.

Oesophageal candidiasis.

Study 150-305 was a randomised, double-blind, comparative study versus oral fluconazole in immunocompromised patients with endoscopically-proven oesophageal candidiasis. 200 patients were randomised to receive voriconazole (200 mg twice daily) and 191 to receive fluconazole (400 mg once daily on day 1 followed by 200 mg once daily from day 2 onwards). Over half of the patients in each group had advanced AIDS with CD4 cell counts < 50 cells/microL. Outcome was assessed by repeat endoscopy at day 43 or the end of therapy. Voriconazole and fluconazole showed equivalent efficacy against oesophageal candidiasis in the per protocol and intention to treat analysis. See Table 9.

Other serious fungal pathogens.

The efficacy, safety and tolerability of voriconazole in the treatment of systemic and invasive fungal infections in patients failing, or intolerant to other therapy, or for invasive fungal infections due to pathogens for which there is no licensed therapy was assessed in two, open, non-comparative studies (Studies 309/604). A total of 301 patients were evaluated for efficacy, of whom 72 cases had invasive infections due to fungal pathogens other than Aspergillus spp. or Candida spp.
Patients received an initial intravenous loading dose of 6 mg/kg q12h or an oral loading dose of 400 mg for the first 24 hours, followed by maintenance dosing with 4 mg/kg q12h or 200 mg twice daily, respectively, for up to 12 weeks. The primary endpoint was satisfactory global response at End of Therapy, defined as 'complete' or 'partial' global response.
Overall 39/72 (54.2%) subjects with other (non-Aspergillus, non-Candida) serious fungal infections had a satisfactory global outcome at end of voriconazole therapy.
In pooled analyses of patients enrolled across the development program, including those from the combined 309/604 studies, voriconazole was shown to be effective against the following additional fungal pathogens:

Scedosporium spp.

Successful response to voriconazole therapy was seen in 16 of 28 patients with S. apiospermum and in 2 of 7 patients with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with mixed organism infections.

Fusarium spp.

Seven of 17 patients were successfully treated with voriconazole. Of these seven patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; two of them had a successful outcome.
The majority of patients receiving voriconazole treatment for rare fungal infections were intolerant of, or refractory to, prior antifungal therapy.
Other successfully treated fungal infections included isolated cases of: Alternaria spp., Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis, and Trichosporon spp. including T. beigelii infections.

Primary prophylaxis of invasive fungal infections - efficacy in haematopoietic stem cell transplant (HSCT) recipients without prior proven or probable invasive fungal infection (IFI).

Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI (Study A1501073). Patients were aged ≥ 12 years and receiving allogeneic HSCT for acute leukaemia (AML, ALL, or myelodysplastic syndrome), failure of therapy for lymphoma or transformation of chronic myeloid leukaemia. Patients with possible, probable or proven IFI during the 6 months prior to study entry, a history of zygomycosis, impaired hepatic function, use of systemic antifungals within 7 days before study entry, or patients who received concomitant medications with major interactions with azoles were excluded from the study. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for > 14 days) and survival with no proven or probable IFI for 180 days after HSCT. The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients, with myeloablative (58%) or reduced-intensity (42%) conditioning regimens. Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241 received itraconazole. The median duration of study drug prophylaxis in the MITT group was 96 days for voriconazole and 68 days for itraconazole.
The primary endpoint was the success of antifungal prophylaxis at 180 days post-transplant. To be a success at this time point, the patient had to meet all of the following conditions:
survive until Day 180 post-transplant with no breakthrough IFI;
not discontinue study drug for > 14 days during the first 100 days of prophylaxis;
for patients randomised to itraconazole, not receive > 14 days of itraconzole capsules during the first 100 days of prophylaxis.
Success rates were 48.7% (109/224) for voriconazole, and 33.2% (80/241) for itraconazole (p=0.0002). The number and proportion of patients with insufficient prophylaxis i.e. those who missed > 14 days of prophylaxis during the first 100 days after transplant (or if randomised to itraconazole, took > 14 days of itraconazole capsules during this period) was 104/224 (46.4%) in the voriconazole group and 147/241 (61.0%) in the itraconazole group, resulting in a treatment difference of -14.6% (95% CI: -23.5%, -5.6%; p=0.0015). Proven or probable IFI developed in 1.3% (3/224) of voriconazole patients and 2.1% (5/241) itraconazole patients during the 180 days after HSCT. The survival rate at Day 180 was 82.1% (184/224) vs 81.7% (197/241) and at 1 year was 73.7% (165/224) vs 68.5% (165/241) for voriconazole and itraconazole, respectively.

Secondary prophylaxis of IFI - efficacy in HSCT recipients with prior proven or probable IFI.

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI (Study A1501038). The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis in the MITT group was 95.5 days. Nine patients (22.5%) received empiric antifungal therapy for between 9 and 365 days.
Recurrent proven or probable IFIs in the MITT population was reported in 3/28 (10.7%) [95% CI (2, 28)] of evaluable patients during the first year after HSCT, including one candidaemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

Paediatric use.

Sixty four (64) paediatric patients aged 9 months up to 15 years who had definite or probable invasive fungal infections were treated with voriconazole. This population included 34 patients 2 to < 12 years old and 23 patients 12-15 years of age. The majority (59/64) had failed previous antifungal therapies. Therapeutic trials included eight patients aged 12-15 years, the remaining patients received voriconazole in the compassionate use programs. Underlying diseases in these patients included haematologic malignancies and aplastic anaemia (27 patients) and chronic granulomatous disease (14 patients). The most commonly treated fungal infection was aspergillosis (46/64; 71%). In addition, a successful response was seen in one patient with infection caused by Aspergillus fumigatus and Phialophora richardsiae. Other fungal infections were caused by Scedosporium, Candida, Fusarium, Conidiobolus, Alternaria and Trichosporon spp. See Table 10.

Clinical studies examining QT interval.

A placebo-controlled, randomised, single-dose, crossover study to evaluate the effect on the QT interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No subject in any group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically relevant threshold of 500 msec. Subjects who were CYP2C19 genotype poor metabolisers were excluded from this study; however, the dose of 1600 mg voriconazole achieved plasma concentrations of approximately 5,400 to 16,900 nanogram/mL which covered the exposure seen in 95% of patients in Phase 2/3 trials where poor metabolisers were not excluded.

5.2 Pharmacokinetic Properties

Voriconazole tablets and powder for oral suspension are unavailable in Voriconazole Wockhardt brand. Pharmacokinetic information obtained using voriconazole oral formulations have been retained in the following subsections for continuity and prescriber information.

General pharmacokinetic characteristics.

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at 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 are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUC_T) (area under the plasma concentration time curve over the 12-hour dosing interval) while increasing the intravenous dose from 3 mg/kg twice daily to 4 mg/kg twice daily produces a 2.3-fold increase in exposure. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by day 6 in the majority of subjects.

Absorption.

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (C_max) achieved 1 to 2 hours after dosing. The oral bioavailability of voriconazole in adults is estimated to be 96%. Bioequivalence has been established between the 200 mg tablet and the 40 mg/mL oral suspension when administered as a 200 mg dose to adults.
When multiple doses of voriconazole are administered with high fat meals, C_max and AUC_T of the tablets are reduced by 34% and 24% respectively, and C_max and AUC_T of the suspension are reduced by 58% and 37%, respectively.
The absorption of voriconazole is not affected by changes in gastric pH.

Distribution.

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%.
Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.

Metabolism.

In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 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 metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (AUC_T) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.
The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radio-labelled 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 radio-labelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (> 94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.
The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 3 mg/kg (intravenously) or 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.

Pharmacokinetic-pharmacodynamic (PK/PD) relationships.

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2425 nanogram/mL (inter-quartile range 1193 to 4380 nanogram/mL) and 3742 nanogram/mL (inter-quartile range 2027 to 6302 nanogram/mL), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found.
PK/PD analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both LFT abnormalities and visual disturbances.

Pharmacokinetics in special patient groups.

Gender.

In an oral multiple dose study, C_max and AUC_T for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in C_max and AUC_T were observed between healthy elderly males and healthy elderly females (≥ 65 years).
In the clinical program, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.

Elderly.

In an oral multiple dose study C_max and AUC_T in healthy elderly males (≥ 65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in C_max and AUC_T were observed between healthy elderly females (≥ 65 years) and healthy young females (18-45 years).
In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly.

Paediatrics.

A population pharmacokinetic analysis was conducted on data from 35 immunocompromised subjects aged 2 to < 12 years old who were included in the intravenous single or multiple dose pharmacokinetic studies. Twenty-four of these subjects received multiple doses of voriconazole. Average steady state plasma concentrations in children receiving a maintenance dose of 4 mg/kg twice daily were similar to those in adults receiving 3 mg/kg twice daily, with medians of 1186 nanogram/mL in children and 1155 nanogram/mL in adults. Therefore, intravenous maintenance doses of 4 mg/kg twice daily in children aged between 2 to < 12 years of age matched the exposure in adults receiving intravenous doses of 3 mg/kg twice daily.
Another pharmacokinetic study in 47 immunocompromised subjects aged 2 to < 12 years old evaluated intravenous doses of 4, 6 and 8 mg/kg twice daily and multiple oral suspension doses of 4 and 6 mg/kg twice daily. The majority of patients received more than one dose level with a maximum duration of dosing of 30 days. The non-linearity of the pharmacokinetics of voriconazole in children is less pronounced than that in adults. On average, the exposure achieved in adults receiving maintenance doses of 4 mg/kg twice daily is approximately 30 microgram.h/mL. The average voriconazole exposures (AUC_T) in children following multiple intravenous doses of 6 and 8 mg/kg twice daily were approximately 20 and 29.8 microgram.h/mL, respectively, with high inter-subject variability. A great percentage of children in the 8 mg/kg intravenous dose group had higher exposure than the typical range observed in adults receiving intravenous 4 mg/kg dose. Average absolute bioavailability of the oral suspension was 66% in children with high inter-subject variability. Bioavailability was lower in children aged 2 to < 6 years old (43.6%-63.4%) than in children aged 6 to < 12 years old (66.7%-90.9%).

Renal impairment.

In a single oral dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 mL/min) to severe (creatinine clearance < 20 mL/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment.
In patients with moderate to severe renal dysfunction (creatinine clearance < 50 mL/min), accumulation of the intravenous vehicle, HP-β-CD, occurs. Oral voriconazole should be administered to patients with moderate to severe renal dysfunction including dialysis patients, unless an assessment of the benefit risk to the patient justifies the use of intravenous voriconazole. Serum creatinine levels should be closely monitored in these patients, and if increases occur, consideration should be given to changing to oral voriconazole therapy (see Section 4.2 Dose and Method of Administration).
A pharmacokinetic study in subjects with renal failure undergoing haemodialysis showed that voriconazole is dialysed with clearance of 121 mL/min. A 4-hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.
Mean voriconazole plasma concentrations were measured at the end of infusion on study days 3, 4 and 5 for both dialysis and normal subjects. Exposure to voriconazole was lower in the dialysis subjects. Combining the Day 3, 4 and 5 data, the ratio of the post infusion means (dialysis/normal subjects) was 50% (95% CI: 32%, 80%) for voriconazole.
The intravenous vehicle, HP-β-CD, is haemodialysed with clearance of 37.5 ± 24 mL/min. A pharmacokinetic study in subjects with renal failure undergoing haemodialysis showed that exposure to HP-β-CD was higher in dialysis subjects. There was no evidence of HP-β-CD accumulation in normal subjects and the study demonstrated that hemodialysis is capable of clearing HP-β-CD as efficiently as a patient with normal renal function.

Hepatic impairment.

After a single oral dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.
In a multiple oral dose study, AUC_T was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given maintenance doses of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C) (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Voriconazole showed no mutagenic potential in gene-mutation assays in bacterial (Salmonella typhimurium) and mammalian (Chinese hamster ovary) cells. While in vitro exposure of human lymphocytes to voriconazole produced equivocal effects on chromosomes, in vivo treatment of male and female mice at doses up to and including the maximum tolerated dose produced no evidence of chromosome damage as determined by the micronucleus assay.

Carcinogenicity.

Carcinogenic potential was studied in mice and rats at oral doses of up to 100 mg/kg/day and 50 mg/kg/day for 24 months, respectively. Hepatocellular adenoma appeared in male and female mice at 100 mg/kg/day and in female rats at 50 mg/kg/day. There was also an increased incidence of hepatocellular carcinoma in mice at 100 mg/kg/day. Although mean plasma drug concentrations indicated there is no safety margin in humans in terms of exposure, adenoma and carcinoma (as well as non-neoplastic changes) are known to occur in rodents after chronic administration of compounds that are hepatic enzyme inducers.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Intravenous incompatibilities.

Blood products and concentrated electrolytes.

Voriconazole must not be infused concomitantly with any blood product or any short-term infusion of concentrated solution of electrolytes, even if the two infusions are running in separate lines. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be corrected prior to initiation of voriconazole therapy (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular).

Intravenous solutions containing (non-concentrated) electrolytes.

Voriconazole can be infused at the same time as other intravenous solutions containing (non-concentrated) electrolytes, but must be infused through a separate line.

Total parenteral nutrition (TPN).

Voriconazole can be infused at the same time as total parenteral nutrition, but must be infused in a separate line. If infused through a multiple-lumen catheter, TPN needs to be administered using a different port from the one used for voriconazole.
Voriconazole must not be diluted with 4.2% Sodium Bicarbonate Infusion. Compatibility with other concentrations is unknown.
Voriconazole Wockhardt must not be mixed with other medicinal products except those mentioned under Intravenous administration.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Voriconazole Wockhardt is a single dose unpreserved sterile lyophile powder that should be stored below 25°C. Do not Freeze.
Following reconstitution of the lyophile with Water for Injections to 10 mg/mL, Voriconazole Wockhardt reconstituted concentrate can be stored at 2°C to 8°C in a refrigerator for up to 24 hours prior to use (see Section 4.2 Dose and Method of Administration, Intravenous administration).

6.5 Nature and Contents of Container

Voriconazole Wockhardt is a white lyophilised powder containing nominally 200 mg voriconazole in a 25 mL Type I clear glass vial. Packs of 1.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

CAS number.

137234-62-9.
Voriconazole is designated chemically as (2R, 3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4- pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol with an empirical formula of C₁₆H₁₄F₃N₅O and a molecular weight of 349.3.
Voriconazole, a broad-spectrum, triazole antifungal agent, is available as a lyophilised powder for solution for intravenous infusion.
Voriconazole drug substance is a white to off white powder. Its aqueous solubility is very low at 0.7 mg/mL at 25°C.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Medicine).

Log in

Consumer medicine information

Voriconazole Wockhardt

Voriconazole

Keep track of your medicines

BRAND INFORMATION