Consumer medicine information

Vzole

Voriconazole

BRAND INFORMATION

Brand name

Vzole

Active ingredient

Voriconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vzole.

SUMMARY CMI

VZOLE

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using VZOLE?

VZOLE contains the active ingredient voriconazole. VZOLE is used to treat fungal and yeast infections.

For more information, see Section 1. Why am I using VZOLE? in the full CMI.

2. What should I know before I use VZOLE?

Do not use if you have ever had an allergic reaction to voriconazole, any similar medicines, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant, or are breastfeeding. VZOLE should NOT be used during pregnancy or breastfeeding, unless indicated by your doctor. Effective contraception should be used in women of childbearing potential.

For more information, see Section 2. What should I know before I use VZOLE? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VZOLE and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use VZOLE?

  • Your doctor will prescribe the amount required of VZOLE based on your weight. The dose will be based on the form being prescribed.
  • More instructions can be found in Section 4. How do I use VZOLE? in the full CMI.

5. What should I know while using VZOLE?

Things you should do
  • Remind any doctor or dentist you visit that you are using VZOLE.
  • Avoid going out in the sun for long periods of time while you are taking VZOLE. VZOLE can cause sensitivity to sunlight.
  • Make sure you follow your doctor's instructions and keep all appointments, including blood tests.
  • If you are about to have any blood tests, tell your doctor that you are taking this medicine.
Things you should not do
  • 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
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how VZOLE affects you.
  • You may experience changes to your vision, such as blurriness, colour changes or uncomfortable sensitivity to light.
Looking after your medicine
  • VZOLE Tablets: Keep your tablets in the pack until it is time to take them, and stored below 30°C.

For more information, see Section 5. What should I know while using VZOLE? in the full CMI.

6. Are there any side effects?

Common side effects maybe headache, nausea or rash. More serious side effects maybe sudden skin symptoms or changes, allergic reaction, changes to urine colour or seizures.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

VZOLE

Active ingredient(s): VORICONAZOLE (vori-con-a-zole)

Consumer Medicine Information (CMI)

This leaflet provides important information about using VZOLE. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using VZOLE.

Where to find information in this leaflet:

1. Why am I using VZOLE?
2. What should I know before I use VZOLE?
3. What if I am taking other medicines?
4. How do I use VZOLE?
5. What should I know while using VZOLE?
6. Are there any side effects?
7. Product details

1. Why am I using VZOLE?

VZOLE contains the active ingredient voriconazole.

VZOLE belongs to a group of medicines called triazole antifungals.

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

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

  • invasive aspergillosis (as-pur-ji-losis), a fungal infection caused by a fungus called Aspergillus (as-pur-jilus), which usually begins in the respiratory tract (in 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, including Candida infections of the oesophagus (food pipe or gullet) and those that have spread into the blood stream or to other parts of the body.
  • serious fungal infections caused by Scedosporium (ski-doe-spore-rium) species and Fusarium (few-saa-rium) species.
  • other serious fungal infections in patients who do not respond to, or cannot tolerate, other antifungal medicines.

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

2. What should I know before I use VZOLE?

Warnings

Do not use VZOLE if:

  1. you are allergic to voriconazole, any similar medicines, or any of the ingredients listed at the end of this leaflet.
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.
  1. Always check the ingredients to make sure you can use this medicine.
  2. Do not use VZOLE if you are taking any of the following medicines:
  • Medicines to treat mental illness:
    - pimozide, a medicine used to treat mental illness.
    - St John's Wort (a herbal medicine).
    - lurasidone, a medicine to treat schizophrenia and bipolar disorder.
  • Medicines used to manage heart health
    - quinidine, a medicine used to treat irregular heartbeat.
    - ivabradine, a medicine used to treat heart problems.
  • Medicines used to treat infections
    - rifampicin, a medicine used to treat tuberculosis and other infections.
    - rifabutin an antibiotic.
    - efavirenz (e.g., Stocrin) (a medicine used to treat HIV infection) in doses of 400 mg or more once a day.
    - ritonavir (a medicine used to treat HIV infection) in doses of 400 mg or more twice a day.
  • Medicines used for seizures, insomnia or migraines
    - carbamazepine, a medicine used to treat seizures.
    - long-acting barbiturates such as phenobarbitone, medicines used to treat severe insomnia and seizures.
    - ergotamine or dihydroergotamine, medicines used to treat migraine.
  • Other medicines:
    - sirolimus, a medicine used in transplant patients.
    - naloxegol, a medicine used to treat constipation caused by opioids (narcotic pain medicines).
    - tolvaptan used to treat low levels of sodium in your blood or for kidney problems).
    - venetoclax, a medicine used to treat blood cancers.
    - Lemborexant, a medicine used to help manage insomnia

VZOLE 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 use 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.

Check with your doctor if you:

  • have any other medical conditions, including:
    - 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.
    - take any medicines for any other condition
  • have allergies to foods, preservatives or dyes or any other medicines, especially antifungal medicines such as itraconazole, fluconazole, posaconazole or ketoconazole.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

VZOLE should not be used 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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

VZOLE should not be used 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.

3. What if I am taking other medicines?

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

Some medicines should NOT be taken with VZOLE. Please see Section 2 above for a list of those medicines.

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

  • Medicines used to treat infections
    - fluconazole, a medicine used to treat fungal infections.
    - flucloxacillin, a medicine used to treat bacterial infections.
    - indinavir and some other medicines used to treat HIV infection.
  • Medicines used for cancer treatment:
    - everolimus, a medicine used to treat cancer
    - other cancer drugs such as glasdegib, axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib, sunitinib.
    - tretinoin, a medicine used for the treatment of acne and acute promyelocytic leukemia.
    - Vincristine, vinblastine or vinorelbine, medicines used in treating cancer.
  • Medicines used in management of organ transplant:
    - ciclosporin, a medicine used to prevent organ transplant rejection or to treat certain problems with the immune system.
    - tacrolimus, a medicine used in patients who have had a liver or kidney transplant.
    - letermovir used to prevent viral infections after bone marrow transplant).
  • Medicines for management of diabetes and other heart-related conditions:
    - warfarin, a medicine used to stop blood clots.
    - sulphonylureas, medicines used to treat diabetes such as glibenclamide, gliclazide and glipizide.
    - statins, medicines used for lowering cholesterol.
  • Medicines for management of mental health
    - benzodiazepines, medicines used to treat insomnia or anxiety.
    - eszopiclone, a medicine used to treat insomnia.
  • Medicines used for pain management:
    - strong pain killers such as alfentanil, fentanyl and oxycodone.
    - non-steroidal anti-inflammatory drugs, medicines used to treat pain and inflammation such as ibuprofen and diclofenac.
  • Other medicines:
    - ivacaftor, a medicine used to treat cystic fibrosis.
    - phenytoin, a medicine used to treat epilepsy. osome antihistamines, medicines used to treat hayfever, allergic skin reactions, itching.
    - theophylline, a medicine used to treat asthma.
    - omeprazole, a medicine used to treat indigestion, reflux and stomach or duodenal ulcers.
    - methadone (used to treat heroin addiction).
    - oral contraceptives (the Pill).
  • methotrexate, a medicine used to treat arthritis and cancers.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect VZOLE.

4. How do I use VZOLE?

How much to take / use

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

Adults

Treatment of invasive fungal infections

The usual dose of VZOLE tablets in adults weighing 40 kg and greater is 400 mg (two 200 mg tablets twice a day) for the first day and then 200 mg to 300 mg twice a day thereafter.

Prevention of invasive fungal infections.

The usual dose in adults weighing 40 kg and greater is one 200 mg tablet twice a day.

In adults weighing less than 40 kg the dose of VZOLE tablets is halved.

Children

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

Your doctor will determine the dose of VZOLE 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.

Oral voriconazole should be administered to these patients unless an assessment of the risk to the patient justifies the use of intravenous voriconazole.

Adolescents (12-16 years of age)

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

How to take / use VZOLE

Swallow the tablets whole with a full glass of water.

Take VZOLE tablets at least one hour before or one hour after a meal.

VZOLE needs to be taken regularly to be effective.

When to take / use VZOLE

  • Take your medicine 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.
  • Take your medicine 1 hour before food after a meal.

How long to take it

  • The length of time you take VZOLE 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.
  • Continue taking VZOLE for as long as your doctor or pharmacist recommends. Do not stop taking VZOLE 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 VZOLE

If it is almost time for your next 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 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.

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

If you take too much VZOLE

If you think that you have taken too much VZOLE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

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

5. What should I know while using VZOLE?

Things you should do

  • 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.
  • Avoid going out in the sun for long periods of time while you are taking VZOLE. VZOLE can cause sensitivity to sunlight.
  • 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 VZOLE or stop your VZOLE treatment. Your doctor might also monitor the function of your pancreas.
  • 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.

Call your doctor straight away if you:

  • notice any changes to your skin while you are taking VZOLE.
  • develop a rash or blisters while taking VZOLE. If this rash worsens, VZOLE may need to be stopped.
  • suffer from chronic, or long-lasting fatigue, muscle weakness, loss of appetite, weight loss or abdominal pain while on VZOLE.
  • notice the symptoms of your infection do not improve within a few days, or if they become worse, tell your doctor.
  • become pregnant while taking VZOLE, tell your doctor immediately. If you are a woman of child-bearing age, you should avoid becoming pregnant while taking VZOLE.

Remind any doctor or dentist you visit that you are using VZOLE.

Things you should not do

  • 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
  • Do not use VZOLE 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how VZOLE 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.

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the blister pack, they may not keep well.

Keep your tablets in a cool dry place where the temperature stays below 30°C.

Do not use this medicine after the expiry date.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Symptoms at injection site:
  • soreness at the injection site
Gastrointestinal symptoms:
  • stomach pain, indigestion, diarrhoea
  • nausea or feeling sick, vomiting
Pain:
  • headache
Vision and skin symptoms:
  • changes to your vision, such as blurred vision, colour changes or sensitivity to light
  • rash
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Skin changes:
  • sudden or severe itching, skin rash, hives or blisters
  • severe skin reaction such as painful red areas, large blisters, flaking of your skin
  • yellowing of the skin or eyes, also called jaundice
  • changes to your skin, such as skin eruptions or small lumps on the skin
Urine and kidney related effects:
  • blood in urine
  • signs of kidney failure such as tiredness, lack of appetite and reduced or greatly increased amount of urine
Allergic reaction related symptoms:
  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • asthma, wheezing, shortness of breath
Other:
  • fainting, seizures, convulsions or fits
  • bleeding in the lips, eyes, mouth, nose and genitals.
  • signs of frequent or worsening infections such as fever, severe chills, sore throat or mouth ulcers
  • irregular heartbeat
  • back pain in middle or upper back
  • swelling of the arms or legs
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What VZOLE contains

Active ingredient
(main ingredient)
  • VZOLE 50 mg Tablets contain 50 mg of voriconazole as the active ingredient.
  • VZOLE 200 mg Tablets contain 200 mg of voriconazole as the active ingredient.
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • pregelatinised maize starch
  • maize starch
  • croscarmellose sodium
  • povidone
  • magnesium stearate
  • silicon dioxide
  • magnesium stearate
  • OPADRY II Complete Film Coating System 33K18618 White (proprietary ingredient number 110208)
Potential allergensThis medicine contains sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What VZOLE looks like

VZOLE tablets come in two strengths, 50 mg and 200 mg.

VZOLE 50 mg tablets are white, round, biconvex, film coated tablets with ‘V50’ debossed on one side and plain on other side.

  • VZOLE 50 mg blister pack - AUST R 238239
  • VZOLE 50 mg bottle - AUST R 238240

VZOLE 200 mg tablets are white, caplet shaped, film coated tablets with ‘V200’ debossed on one side and plain on other side.

  • VZOLE 200 mg blister pack - AUST R 238242
  • VZOLE 200 mg bottle - AUST R 238241

Who distributes VZOLE

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121

This leaflet was prepared in February 2024

Published by MIMS March 2024

BRAND INFORMATION

Brand name

Vzole

Active ingredient

Voriconazole

Schedule

S4

 

1 Name of Medicine

Voriconazole.

2 Qualitative and Quantitative Composition

Vzole 50 mg film-coated tablets contain 50 mg of voriconazole.
Vzole 200 mg film-coated tablets contain 200 mg of voriconazole.
Voriconazole, a broad-spectrum, triazole antifungal agent, is available as film-coated tablets for oral administration.

Excipients with known effects.

Vzole tablets contain sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Vzole 50 mg film-coated tablets are white, round, biconvex film coated 7 mm tablet with 'V50' debossed on one side and plain on other side.
Vzole 200 mg film-coated tablets are white, caplet shaped film coated 15.6 mm tablet with 'V200' debossed on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Voriconazole is indicated for treatment of the following fungal infections:
Invasive aspergillosis.
Serious Candida infections (including C. krusei), including oesophageal and 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

Vzole tablets are to be taken at least one hour before, or one hour following, a meal.
Voriconazole powder for oral suspension is unavailable in this brand, however is available in other brands. Where correct dosing requires oral suspension in paediatric or adult patients, the oral suspension available from other suppliers should be used. For intravenous specific dosing requirements, please refer to the voriconazole IV powder for injection product information.

Dosage in adults.

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral Vzole 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; dosage recommendations for oesophageal candidiasis are provided in Table 1.
Dosage recommendations for other indications are provided in Tables 2 and 3.

Dosage adjustment.

Oral administration.

If patient response is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration. For patients less than 40 kg, the oral dose may be increased to 150 mg twice daily. If patients are unable to tolerate treatment at these higher doses reduce the oral dose by 50 mg steps to a minimum 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.
Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally twice daily (100 mg to 200 mg orally twice daily in patients less than 40 kg). 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).
When voriconazole is coadministered with efavirenz, the voriconazole maintenance dose should be increased to 400 mg every 12 hours and the efavirenz dose should be decreased to 300 mg every 24 hours (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Treatment duration depends upon patients' clinical and mycological response.

Dosage adjustment in the elderly.

No dose adjustment is necessary for elderly patients.

Dosage adjustment 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).

Dosage adjustment 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)).

Dosage 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.

Adolescents (12-16 years of age).

Should be dosed as adults.

4.3 Contraindications

Vzole is contraindicated in patients with known hypersensitivity to voriconazole or to any of the excipients.
Coadministration 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).
Coadministration of voriconazole with rifabutin, rifampicin, carbamazepine and long-acting barbiturates (including but not limited to: phenobarbital) and St. John's wort is contraindicated since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration 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.
Coadministration 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.
Coadministration 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).
Coadministration 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).
Coadministration of voriconazole with naloxegol is contraindicated because voriconazole may significantly increase plasma concentrations of naloxegol which may precipitate opioid withdrawal symptoms (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration of voriconazole with tolvaptan is contraindicated because voriconazole may significantly increase plasma concentrations of tolvaptan (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration of voriconazole with venetoclax is contraindicated at initiation and during the venetoclax dose titration phase since voriconazole is likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysis syndrome (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration of voriconazole with lurasidone is contraindicated since it may result in significant increases in lurasidone exposure and the potential for serious adverse reactions (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 proarrhythmic 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 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. An increased risk of skin toxicity with concomitant use of methotrexate, a drug associated with ultraviolet (UV) reactivation has been observed. There is a potential for this risk to be observed with other drugs associated with UV reactivation. 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 (SCC) later in this section).
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.

Reversible cases of adrenal insufficiency have been reported in patients receiving azoles, including voriconazole. Adrenal insufficiency has been reported in patients receiving azoles with or without concomitant corticosteroids. In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids. 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). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.

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 immunosuppression), squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen's disease) 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).

Visual impairment and effect 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 (see Section 4.7 Effects on Ability to Drive and Use Machines).

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 coadministration. 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 coadministered 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 coadministered 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 coadministered 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).

Coadministration 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).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

Coadministration of oral voriconazole and oral fluconazole resulted in significant increase in Cmax and AUCT of voriconazole in healthy subjects. The clinical significance of this drug interaction has not been established and the coadministration of voriconazole and oral fluconazole is not recommended.

Glasdegib (CYP3A4 substrate).

Coadministration of voriconazole is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrate).

Coadministration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expected to increase tyrosine kinase inhibitors plasma concentrations and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring is recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Phenytoin (CYP2C9 substrate and potent CYP450 inducer).

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

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

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

Advice about lactose and sucrose.

Vzole tablets contain lactose monohydrate and should not be given to patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

Hepatic toxicity.

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 hepatic impairment.

See Section 4.2 Dose and Method of Administration, Dosage adjustment in patients with hepatic impairment.

Use in the elderly.

No data available.

Paediatric use.

Oral voriconazole should be administered to these patients unless an assessment of the risk to the patient justifies the use of intravenous voriconazole see Section 4.2 Dose and Method of Administration, Dosage in children.
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 Cmax (maximum plasma concentration) and AUCT (area under the plasma concentration time curve within a dose interval) of voriconazole by 93% and 96%, respectively. Coadministration of voriconazole and rifampicin is contraindicated (see Section 4.3 Contraindications).

Rifabutin (potent CYP450 inducer).

Rifabutin (300 mg once daily) decreased the Cmax and AUCT of voriconazole at 200 mg twice daily by 69% and 78%, respectively. During coadministration with rifabutin, the Cmax and AUCT 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 Cmax and AUCT were 104% and 87% higher, respectively, compared with voriconazole alone at 200 mg twice daily. Voriconazole at 400 mg twice daily increased Cmax and AUCT of rifabutin by 195% and 331%, respectively. Coadministration of voriconazole with rifabutin is contraindicated (see Section 4.3 Contraindications).

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

The effect of the coadministration 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 Cmax and AUCT of oral voriconazole by an average of 66% and 82%, respectively, whereas low doses of ritonavir (100 mg twice daily) decreased the Cmax and AUCT of oral voriconazole by an average of 24% and 39%, respectively. Administration of voriconazole did not have a significant effect on mean Cmax and AUCT of ritonavir in the high dose study, although a minor decrease in steady-state Cmax and AUCT 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. Coadministration of voriconazole and high doses of ritonavir (400 mg and higher twice daily) is contraindicated (see Section 4.3 Contraindications). Coadministration of voriconazole and low dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see Section 4.4 Special Warnings and Precautions for Use).

Carbamazepine and long acting barbiturates (potent CYP450 inducers - e.g. phenobarbital (phenobarbitone)).

Although not studied, carbamazepine or phenobarbital (phenobarbitone) are likely to significantly decrease plasma voriconazole levels. Coadministration of voriconazole with carbamazepine and long acting barbiturates are contraindicated (see Section 4.3 Contraindications).
Significant drug interactions that may require voriconazole dosage adjustment, or frequent monitoring of voriconazole related adverse events/toxicity.

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor).

Coadministration of oral voriconazole and oral fluconazole resulted in significant increase in Cmax and AUCT of voriconazole in healthy subjects. The clinical significance of this drug interaction has not been established and the coadministration of voriconazole and oral fluconazole is not recommended. Monitoring for voriconazole associated adverse events is recommended if voriconazole is used sequentially after fluconazole.

Letermovir (CYP2C9 and CYP2C19 inducer).

Letermovir decreased the Cmax, 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.

Flucloxacillin (CYP450 inducer).

Although not studied, flucloxacillin has been reported to significantly decrease plasma voriconazole concentrations. If concomitant administration of voriconazole with flucloxacillin cannot be avoided, monitor for potential loss of voriconazole effectiveness.
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 Cmax and AUCT 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 Cmax and AUCT.

Macrolide antibiotics.

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

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 strong CYP3A4 inhibitor though the increase in AUC is 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 and ivabradine) co-administration is contraindicated (see below; 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, coadministration 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) Cmax and AUCT by 556% and 1014%, respectively. Coadministration 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. Coadministration of voriconazole with ergot alkaloids is contraindicated (see Section 4.3 Contraindications).

Lurasidone (CYP3A4 substrate).

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of lurasidone. Coadministration of voriconazole with lurasidone is contraindicated (see Section 4.3 Contraindications).

Naloxegol (CYP3A4 substrate).

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of naloxegol. Coadministration of voriconazole with naloxegol 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).

Tolvaptan (CYP3A substrate).

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of tolvaptan. Coadministration of voriconazole with tolvaptan is contraindicated (see Section 4.3 Contraindications).

Venetoclax (CYP3A substrate).

Although not studied,, voriconazole is likely to significantly increase the plasma concentrations of venetoclax. Concomitant administration of voriconazole is contraindicated at initiation and during venetoclax dose titration phase (see Section 4.3 Contraindications). Dose reduction of venetoclax is required as instructed in venetoclax prescribing information during steady daily dosing; close monitoring for signs of toxicity is recommended.
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 Cmax and AUCT 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) Cmax and AUCT 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 Cmax and AUCT 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 AUC0-∞ 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 coadministered 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 AUC0-∞ of fentanyl by 1.4-fold (range 1.12- to 1.60-fold). When voriconazole is coadministered 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, coadministration 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 Cmax and AUC0-∞ 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. Coadministration of voriconazole and everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations (see Section 4.4 Special Warnings and Precautions for Use).

Lemborexant (CYP3A4 substrate).

Although not studied, voriconazole is likely to increase the plasma concentration of lemborexant. Concomitant use of voriconazole and lemborexant should be avoided.

Warfarin (CYP2C9 substrate).

Coadministration 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 coadministered.

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.

Glasdegib (CYP3A4 substrate).

Although not studied, voriconazole is likely to increase the plasma concentrations of glasdegib and increase risk of QTc prolongation. If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrates) (including but not limited to: axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib).

Although not studied, voriconazole may increase plasma concentrations of tyrosine kinase inhibitors metabolized by CYP3A4. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitors and close clinical monitoring is recommended.

Eszopiclone (CYP3A4 substrate).

Although not studied, voriconazole may increase the plasma concentrations and sedative effect of eszopiclone. Dose reduction of eszopiclone is recommended.

Tretinoin (CYP3A4 substrate).

Although not studied, voriconazole may increase tretinoin concentrations and increase risk of adverse reactions (pseudotumor cerebri, hypercalcaemia) Dose adjustment of tretinoin is recommended during treatment with voriconazole and after its discontinuation.

Sulphonylureas (CYP2C9 substrates).

Although not studied, voriconazole may increase the plasma levels of sulphonylureas, (including but not limited to: tolbutamide, glipizide, and glibenclamide) and therefore cause hypoglycaemia. Careful monitoring of blood glucose is recommended during coadministration.

Statins (CYP3A4 substrates).

Although not studied, 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. Increased statin levels have been associated with rhabdomyolysis. If concomitant administration of voriconazole with statins metabolized by CYP3A4 cannot be avoided, dose reduction of the statin should be considered.

Benzodiazepines (CYP3A4 substrates).

Midazolam (0.05 mg/kg IV single dose): In an independent published study, midazolam AUC0-∞ increased (↑) 3.7-fold.
Midazolam (7.5 mg oral single dose): In an independent published study, midazolam Cmax increased (↑) 3.8-fold, midazolam AUC0-∞ increased (↑) 10.3-fold.

Other benzodiazepines (including but not limited to: triazolam, alprazolam).

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 coadministration.

Vinca alkaloids (CYP3A4 substrates).

Although not studied, voriconazole may increase the plasma levels of the vinca alkaloids (including but not limited to: 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 Cmax and AUC of ibuprofen (400 mg single dose) by 20% and 100%, respectively. Voriconazole increased Cmax 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 coadministered with the following agents. No dosage adjustment for these agents is recommended.

Corticosteroids.

Prednisolone (CYP3A4 substrate): Voriconazole increased Cmax and AUCT 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 Cmax and AUCT of digoxin (0.25 mg once daily).

Mycophenolic acid (UDP-glucuronyl transferase substrate).

Voriconazole had no effect on the Cmax and AUCT 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 Cmax and AUCT of voriconazole by 49% and 69%, respectively. Voriconazole (400 mg twice daily) increased Cmax and AUCT of phenytoin (300 mg once daily) by 67% and 81%, respectively.
Phenytoin may be coadministered 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 coadministered with voriconazole.

Omeprazole (CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate).

Omeprazole (40 mg once daily) increased voriconazole Cmax and AUCT by 15% and 41%, respectively. No dosage adjustment of voriconazole is recommended. Voriconazole increased omeprazole Cmax and AUCT 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).

Coadministration 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 Cmax and AUCT of ethinylestradiol (36% and 61%, respectively) and norethisterone (15% and 53%, respectively). Voriconazole Cmax and AUCT 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 coadministration.

Indinavir (CYP3A4 inhibitor and substrate).

Indinavir (800 mg three times daily) had no significant effect on voriconazole Cmax and AUCT. Voriconazole did not have a significant effect on Cmax, Cmin and AUCT 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 coadministration 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 Cmax and AUCT 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 Cmax and AUCT 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 coadministration of voriconazole 400 mg twice daily with efavirenz 300 mg orally once daily in healthy subjects, the AUCT of voriconazole was decreased by 7% and Cmax was increased by 23% compared to voriconazole 200 mg twice daily alone. The AUCT of efavirenz was increased by 17% and Cmax was equivalent compared to efavirenz 600 mg once daily alone. These differences were not considered to be clinically significant.
Voriconazole may be coadministered 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 - including but not limited to: nevirapine).

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 coadministration of voriconazole and NNRTIs. See Table 4.

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 fetal 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.
 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

See Section 4.4 Special Warnings and Precautions for Use, Visual impairment and effect on ability to drive and use machines.

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 5 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 6.

Description of selected adverse reactions.

Visual impairment.

In clinical trials, visual impairments (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 voriconazole 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 impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments 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 paracoccidioidomycosis. 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 adverse 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 photoprotection 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 including cutaneous SCC in situ, or Bowen's disease) (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, and cases of 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, hydroxypropylbetadex, is haemodialysed with a clearance of 37.5 ± 24 mL/min. In an overdose, haemodialysis may assist in the removal of voriconazole and hydroxypropylbetadex from the body.
For information on the management of overdose, contact the Poison Information Centre on 131126 (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 7 and 8.

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 9.
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 patients 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 10.
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 itraconazole 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 11.
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

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 (AUCT) (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 (Cmax) 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, Cmax and AUCT of the tablets are reduced by 34% and 24%, respectively, and Cmax and AUCT 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 (AUCT) 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 radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Excretion.

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.
After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple 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, Cmax and AUCT 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 Cmax and AUCT 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 Cmax and AUCT in healthy elderly males (≥ 65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and AUCT 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 (AUCT) 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 postinfusion means (dialysis/normal subjects) was 50% (95% CI: 32%, 80%) for voriconazole.

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, AUCT 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

Vzole tablets contain the following inactive ingredients: lactose monohydrate, pregelatinised maize starch, maize starch, croscarmellose sodium, povidone, silicon dioxide, magnesium stearate and Opadry II Complete Film Coating System 33K18618 White (proprietary ingredient number 110208).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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

Store below 30°C. Protect from light.

6.5 Nature and Contents of Container

Vzole tablets are available in HDPE bottle packs with PP child resistant closures and PVC/Aluminium blisters of 2, 10, 14, 20, 28, 30, 50, 56 and 100 tablets. Not all pack sizes may be marketed.

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

Voriconazole drug substance is a white to off white powder. Its aqueous solubility is very low at 0.7 mg/mL at 25°C.

Chemical structure.

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.

CAS number.

137234-62-9.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Medicine).

Summary Table of Changes