Consumer medicine information

Noxafil Concentrated Injection

Posaconazole

BRAND INFORMATION

Brand name

Noxafil Concentrated Injection

Active ingredient

Posaconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Noxafil Concentrated Injection.

SUMMARY CMI

NOXAFIL® Concentrated Injection

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 NOXAFIL?

NOXAFIL contains the active ingredient posaconazole. Posaconazole is used to kill or stop the growth of fungi that can cause infections.

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

2. What should I know before I use NOXAFIL?

Do not use if you have ever had an allergic reaction to posaconazole 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. For more information, see Section 2. What should I know before I use NOXAFIL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with NOXAFIL 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 NOXAFIL?

NOXAFIL is usually diluted and given as a slow infusion or “drip” injection into your vein (intravenously).

More instructions can be found in Section 4. How do I use NOXAFIL? in the full CMI.

5. What should I know whilst using NOXAFIL?

Things you should do
  • If you are about to start any other new medicine, tell your doctor that you are taking NOXAFIL.
  • Remind any doctor, dentist or pharmacist you visit that you are being given NOXAFIL.
  • If you need to have any blood tests, tell your doctor you are taking NOXAFIL. NOXAFIL may affect the results of some laboratory tests.
Things you should not do
  • NOXAFIL should not be used during pregnancy or breastfeeding unless indicated by your doctor.
Driving or using machines
  • NOXAFIL may cause dizziness, sleepiness, or blurred vision in some people
  • There have been side effects reported with NOXAFIL that may affect your ability to drive or operate machinery. Individual responses to NOXAFIL may vary. Be careful before you drive or use any machines or tools until you know how NOXAFIL affects you.
Looking after your medicine
  • NOXAFIL concentrated injection is stored in a refrigerator (at 2°C - 8°C) in the pharmacy or on the ward in a hospital. Once prepared, the product should be used immediately. If not used immediately it can be stored for up to 24 hours at 2°C - 8°C.
  • NOXAFIL is for single use only and any unused solution should be discarded.

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

6. Are there any side effects?

Tell your doctor, pharmacist or nurse immediately if you notice any of the following serious side effects: Swelling of the face, lips, mouth, throat or neck which may cause difficulty swallowing or breathing, nausea or vomiting, diarrhoea, yellowing of the skin or whites of the eyes, unusually dark urine or pale faeces, feeling sick for no reason, stomach problems, loss of appetite or unusual tiredness or weakness (signs of liver problems).

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

NOXAFIL® Concentrated Injection

Active ingredient: Posaconazole


Consumer Medicine Information (CMI)

This leaflet provides important information about using NOXAFIL. 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 NOXAFIL.

Where to find information in this leaflet:

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

1. Why am I using NOXAFIL?

NOXAFIL contains the active ingredient posaconazole.

NOXAFIL is a medicine that belongs to the triazole group of antifungals. Noxafil is used to kill or stop the growth of fungi that can cause infections.

NOXAFIL Concentrated Injection is used for:

  • The treatment of invasive aspergillosis, a fungal infection caused by a fungus called aspergillus
  • The treatment of other serious fungal infections called fusariosis, zygomycosis, chromoblastomycosis and mycetoma.

These types of fungal infections usually occur in some patients who may have lowered resistance to infection due to poor immunity.

Treatment of these serious fungal infections with NOXAFIL is usually reserved for patients who do not respond to or cannot tolerate other medicines used to treat these types of fungal infections.

NOXAFIL is also used to treat coccidioidomycosis, a rare and serious fungal infection.

NOXAFIL is also used to prevent fungal infections, such as yeasts and moulds, from occurring in patients who are at high-risk of developing these infections.

NOXAFIL is only for use in adults (18 years of age and older).

2. What should I know before I use NOXAFIL?

Warnings

Do not use NOXAFIL if:

you are allergic to posaconazole (or any other triazole antifungal medicines) or any of the ingredients listed at the end of this leaflet.

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

Check with your doctor if you:

have any allergies to any other medicines, including other antifungal medicines such as:

  • itraconazole (Sporanox®)
  • fluconazole (Diflucan®)
  • voriconazole (Vfend®)
  • ketoconazole (Nizoral®)

or any other substances such as foods, preservatives or dyes.

have or have ever had any other health problems/ medical conditions including:

  • any kidney problems
  • any liver problems
  • any heart problems
  • any problems with potassium, magnesium or calcium levels in your blood.

Follow your doctor's advice if any blood tests to check on your kidney or liver are recommended.

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.

NOXAFIL should not be used during pregnancy unless indicated by your doctor. Women who are of childbearing potential should use effective contraception while being given NOXAFIL and for 2 weeks after completing treatment.

Once you have finished taking NOXAFIL, continue using contraception until your next period.

Your doctor will discuss the possible risks and benefits to you and your unborn baby.

If you become pregnant while you are being given NOXAFIL, contact your doctor straight away.

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

NOXAFIL should not be given to breastfeeding women. It is possible that the active ingredient, posaconazole, may be passed into the breast milk. Your doctor can discuss 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.

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

  • certain medicines used to treat allergy or hay fever (terfenadine or astemizole)
  • cisapride (a medicine used to treat certain stomach problems)
  • pimozide (a medicine used to treat certain mental disorders)
  • quinidine (a medicine used to treat irregular heartbeat)
  • ergotamine and dihydroergotamine, which are medicines used to treat migraine
  • halofantrine (a medicine used to treat malaria)
  • simvastatin, lovastatin, atorvastatin or similar medicines (called HMG-CoA reductase inhibitors or statins) that are used to treat high cholesterol levels.

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

Some medicines may increase the risk of side effects of NOXAFIL by increasing the amount of posaconazole in the blood. Similarly, some medicines may decrease the effectiveness of NOXAFIL by decreasing the amount of posaconazole in the blood.

Medicines that can decrease the effectiveness of NOXAFIL are:

  • rifabutin (used to treat tuberculosis)
  • phenytoin (used to treat fits or convulsions)
  • efavirenz and fosamprenavir (used to treat HIV infection)
  • medicines used to decrease stomach acid such as cimetidine, ranitidine and omeprazole

NOXAFIL may possibly increase the risk of side effects of some medicines by increasing the amount of these medicines in the blood. These include:

  • vincristine, vinblastine and other vinca alkaloids (used to treat cancer)
  • cyclosporine, tacrolimus and sirolimus (used to treat certain immune system problems or to prevent organ transplant rejection)
  • rifabutin (used to treat certain infections)
  • midazolam and other benzodiazepine medicines (used as sedatives or muscle relaxants)
  • calcium channel blockers, such as diltiazem, nifedipine and verapamil (used in certain heart conditions and to treat high blood pressure)
  • digoxin (used to treat certain heart conditions)
  • sulfonylureas such as glipizide (used to treat diabetes)
  • medicines used to treat HIV called protease inhibitors (including atazanavir which is given with ritonavir) and non-nucleoside reverse transcriptase inhibitors
  • venetoclax (used to treat certain blood cancers)

These medicines may be affected by NOXAFIL or may affect how well it works. You may need different amounts of these medicines or you may need to take different medicines. Your doctor or pharmacist will advise you.

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

4. How do I use NOXAFIL?

NOXAFIL concentrated injection will be diluted to the correct concentration by your pharmacist or nurse.

NOXAFIL is usually diluted and given as a slow infusion or ‘drip’ injection into your vein (intravenously).

The length of treatment may depend on the type of infection that you have and will be individually adapted for you by your doctor.

How much is given

The usual dose is 300 mg twice a day on the first day, then 300 mg once a day, thereafter.

How long will I be given it?

The length of treatment will depend on the type of infection you have and will be individually adapted for you by your doctor.

If a dose of NOXAFIL has been forgotten

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

If you use too much NOXAFIL

As you will be given this medicine under close medical supervision, it is unlikely that you will be given too much. However, if you think that you have been given too much NOXAFIL, 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.

5. What should I know whilst using NOXAFIL?

Things you should do

Always follow your doctor's instructions carefully.

If you are a woman of childbearing age, talk to your doctor about the need for effective contraception. Once you have finished taking NOXAFIL, continue using contraception until your next period.

If you are about to start any other new medicine, tell your doctor that you are taking NOXAFIL

If you need to have any blood tests, tell your doctor you are taking NOXAFIL. NOXAFIL may affect the results of some laboratory tests.

Tell all doctors, dentists and pharmacists who are treating you that you are being given NOXAFIL

Call your doctor straight away if you:

  • Have diarrhoea or vomiting
  • If you become pregnant or plan to get pregnant whilst you are using NOXAFIL
  • Do not feel well whilst you are using NOXAFIL, or after using NOXAFIL

Remind any doctor, dentist, pharmacist or nurse you visit that you are being given NOXAFIL.

Driving or using machines

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

You may feel dizzy, sleepy, or have blurred vision whilst being given NOXAFIL, which may affect your ability to drive or use tools or machines. If this happens, do not drive or use any tools or machines and contact your doctor.

Looking after your medicine

NOXAFIL concentrated injection is stored in a refrigerator (2 to 8°C) in the pharmacy or on the ward in a hospital.

Once prepared, the product should be used immediately. If not used immediately it can be stored for up to 24 hours at 2 to 8 degrees Celsius (in a refrigerator).

Keep it where young children cannot reach it.

When to discard your medicine

NOXAFIL is for single use only and any unused solution should be discarded.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last day of that month.

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
  • Abnormal skin sensations, such as numbness, tingling, itching, creeping prickling or burning, rash, swelling, redness and tenderness along the vein in which NOXAFIL was given.
  • Loss of appetite, stomach pain or upset stomach, passing wind, dry mouth, changes in your taste, constipation, rectal discomfort
  • Feeling confused or weak, dizzy, tired or sleepy, headache
  • Raised blood pressure with a low potassium level (shown in blood test)
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
  • Swelling of the face, lips, mouth, throat or neck which may cause difficulty swallowing or breathing, rash, itchiness, hives
  • Nausea or vomiting, diarrhoea
  • Yellowing of the skin or whites of eyes, unusually dark urine or pale faeces, feeling sick for no reason, stomach problems, loss of appetite or unusual tiredness or weakness (signs of liver problems)
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 NOXAFIL contains

Active ingredient
(main ingredient)
posaconazole
Other ingredients
(inactive ingredients)
Sulfobutyl betadex sodium.
disodium edetate.
hydrochloric acid and sodium hydroxide for pH adjustment.
Water for Injections.

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

What NOXAFIL Concentrated Injection looks like

NOXAFIL Concentrated Injection is a clear, colourless to yellow liquid.

Who distributes NOXAFIL Concentrated Injection?

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A, 26 Talavera Road
Macquarie Park, NSW 2113, Australia

Australian Registration Number:
NOXAFIL Concentrated Injection - AUST R 218702

This leaflet was prepared in November 2021.

RCN000020221

S-CCDS-MK5592-IV-042021

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Noxafil Concentrated Injection

Active ingredient

Posaconazole

Schedule

S4

 

1 Name of Medicine

Posaconazole.

2 Qualitative and Quantitative Composition

Posaconazole is a white to off-white crystalline powder.
Each vial of Noxafil concentrated injection contains 300 mg of posaconazole (18 mg per mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Noxafil (posaconazole) concentrated injection is a clear, colourless to yellow liquid.

4 Clinical Particulars

4.1 Therapeutic Indications

Noxafil (posaconazole) concentrated injection is indicated for use in the treatment of the following invasive fungal infections in adults:
invasive aspergillosis in patients intolerant of, or with disease that is refractory to, alternative therapy;
fusariosis, zygomycosis, coccidioidomycosis, chromoblastomycosis, and mycetoma in patients intolerant of, or with disease that is refractory to, alternative therapy.
Noxafil is also indicated for the:
prophylaxis of invasive fungal infections among adults, who are at high risk of developing these infections, such as patients with prolonged neutropenia or haematopoietic stem cell transplant (HSCT) recipients.

4.2 Dose and Method of Administration

Treatment should be initiated by a physician experienced in the management of fungal infections or in the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.
Recommended dose is shown in Table 1.

Method of administration.

Noxafil concentrated injection must be diluted before administration. Not for bolus injection.
Equilibrate the refrigerated vial of Noxafil to room temperature.
Aseptically transfer 16.7 mL of posaconazole to an IV bag (or bottle) containing a compatible infusion solution (see below for list of diluents) using a volume ranging from 150 mL to 283 mL depending on the final concentration to be achieved (not less than 1 mg/mL and not greater than 2 mg/mL).
Administer via a central venous line, including a central venous catheter or peripherally inserted central catheter (PICC) by slow intravenous (IV) infusion over approximately 90 minutes. Not for IV bolus administration.
If a central venous catheter is not available, a single infusion may be administered through a peripheral venous catheter. When administered through a peripheral venous catheter, the infusion should be administered over approximately 30 minutes.

Note.

In clinical trials, multiple peripheral infusions given through the same vein were not well tolerated (see Section 4.8 Adverse Effects (Undesirable Effects)).
Noxafil is a single dose unpreserved sterile solution. Therefore, from a microbiological point of view, once admixed, the product should be used immediately. If not used immediately, the solution can be stored up to 24 hours refrigerated 2°C-8°C. Noxafil is for single use only and any unused solution should be discarded.
Noxafil concentrated injection can be diluted with: 5% dextrose in water; 0.9% sodium chloride; 0.45% sodium chloride; 5% dextrose and 0.45% sodium chloride; 5% dextrose and 0.9% sodium chloride; 5% dextrose and 20 mEq KCl.
Noxafil concentrated injection should only be administered with these diluents.

Noxafil concentrated injection must not be diluted with Lactated Ringer's solution, 5% dextrose with Lactated Ringer's solution, 4.2% sodium bicarbonate.

Intravenous line compatibility.

A study was conducted to evaluate physical compatibility of Noxafil concentrated injection with injectable drug products and commonly used intravenous diluents during simulated Y-site infusion. Compatibility was determined through visual observations, measurement of particulate matter and turbidity.
Based on the results of the study, the following drug products can be infused at the same time through the same intravenous line (or cannula) as Noxafil concentrated injection (see Table 2):
Any products not listed in Table 2 should not be co-administered with Noxafil through the same intravenous line (or cannula).

Noxafil concentrated injection should be inspected visually for particulate matter prior to administration. The solution of Noxafil ranges from colourless to pale yellow. Variations of colour within this range do not affect the quality of the product.

Use in renal impairment.

In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2), receiving the Noxafil concentrated injection, accumulation of the intravenous vehicle, Sulfobutyl Betadex Sodium (SBECD), is expected to occur. Noxafil concentrated injection for IV infusion should be avoided in patients with moderate or severe renal impairment (eGFR < 50 mL/min/1.73 m2), unless an assessment of the benefit/ risk to the patient justifies the use of Noxafil concentrated injection. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to Noxafil oral suspension therapy. Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see Section 5.2 Pharmacokinetic Properties; Section 4.4 Special Warnings and Precautions for Use).

Use in hepatic impairment.

There is limited pharmacokinetic data in patients with hepatic insufficiency; therefore, no recommendation for dose adjustment can be made. In the small number of subjects studied who had hepatic insufficiency, there was an increase in half-life with a decrease in hepatic function (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

Use in paediatrics.

Safety and efficacy in children below the age of 18 years have not been established.
Noxafil concentrated injection should not be used in children because of pre-clinical safety concerns (see Section 5.3 Preclinical Safety Data, Pre-clinical safety).

Use in the elderly.

No dosage adjustment is recommended for elderly patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations).

4.3 Contraindications

Noxafil is contraindicated in patients with known hypersensitivity to posaconazole or to any of the excipients.
Coadministration of posaconazole and ergot alkaloids (ergotamine, dihydroergotamine) is contraindicated as posaconazole may increase the plasma concentration of ergot alkaloids, which may lead to ergotism (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration with the HMG-CoA reductase inhibitors that are primarily metabolised through CYP3A4 is contraindicated since increased plasma concentration of these drugs can lead to rhabdomyolysis.
Although not studied in vitro or in vivo, coadministration of posaconazole and certain drugs metabolised through the CYP3A4 system: terfenadine, astemizole, cisapride, pimozide, and quinidine may result in increased plasma concentrations of those drugs, leading to potentially serious and/or life threatening adverse events, such as QT prolongation and rare occurrences of torsade de pointes (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

There is no information regarding cross-sensitivity between posaconazole and other azole antifungal agents. Caution should be used when prescribing posaconazole to patients with hypersensitivity to other azoles. Subjects with severe or serious reactions to azoles were excluded from key studies of posaconazole.

Hepatic toxicity.

Hepatic reactions (e.g. mild to moderate elevations in alanine aminotransferase (ALT), aspartate transaminase (AST), alkaline phosphatase, total bilirubin, and/or clinical hepatitis) have been reported in clinical trials. Elevated liver function tests were generally reversible on discontinuation of therapy and in some instances these tests normalized without interruption of therapy and rarely required drug discontinuation. Rarely, more severe hepatic reactions (including cases that have progressed to fatal outcomes) were reported in patients with serious underlying medical conditions (e.g. haematological malignancy) during treatment with posaconazole. In the clinical pharmacology program, no healthy subject had CTC Grade 3 or Grade 4 (> 5 x ULN) elevations in their liver function test results. Most of these LFT changes were mild in severity and all were transient in nature, returned to baseline after the cessation of dosing, and rarely led to study discontinuation. See Table 3 for hepatic enzyme abnormalities in healthy volunteers.
Liver function tests should be evaluated at the start of and during the course of posaconazole therapy, particularly in treatment beyond 14 days with posaconazole concentrated injection. Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical experience and the possibility that posaconazole plasma levels may be higher in these patients. Patients who develop abnormal liver function tests during posaconazole therapy should be monitored for the development of more severe hepatic injury. Patient management should include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin). Discontinuation of posaconazole should be considered if clinical signs and symptoms are consistent with development of liver disease.

QT prolongation.

Some azoles have been associated with prolongation of the QTc interval on the electrocardiogram (ECG). Posaconazole should be administered with caution to patients with potentially proarrhythmic conditions and should not be administered with medicines that are known to prolong the QTc interval and are metabolised through the CYP3A4 (see Section 5.2 Pharmacokinetic Properties, Electrocardiogram evaluation; Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Electrolyte disturbances.

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should be monitored and corrected as necessary, before and during posaconazole therapy.

Midazolam and other benzodiazepines metabolised by CYP3A4.

Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered when posaconazole is administered with any benzodiazepine that is metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam).
Dose adjustment of benzodiazepine metabolised by CYP3A4 should be considered (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Vincristine toxicity.

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Venetoclax toxicity.

Concomitant administration of posaconazole with venetoclax (a CYP3A4 substrate) may increase venetoclax toxicities, including the risk of tumor lysis syndrome (TLS) and neutropenia (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Refer to the venetoclax prescribing information for the medical management of patients concomitantly administered venetoclax and posaconazole.

Effects on adrenal steroid hormones.

As observed with other azole antifungal agents, effects related to inhibition of adrenal steroid hormone synthesis were seen in repeat-dose toxicity studies with posaconazole. Adrenal suppressive effects were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained at therapeutic doses in humans.

Use in hepatic impairment.

See Section 4.4. Special Warnings and Precautions for Use, Hepatic toxicity; Section 4.2 Dose and Method of Administration, Use in hepatic impairment.

Use in renal impairment.

In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2), receiving the Noxafil concentrated injection, accumulation of the intravenous vehicle, Sulfobutyl Betadex Sodium (SBECD), is expected to occur. Noxafil concentrated injection should be avoided in patients with moderate or severe renal impairment (eGFR < 50 mL/min/1.73 m2), unless an assessment of the benefit/ risk to the patient justifies the use of Noxafil concentrated injection. Serum creatinine levels should be closely monitored in these patients, and, if increases occur, consideration should be given to changing to Noxafil oral suspension therapy.
Due to the variability in exposure, patients with severe renal impairment (eGFR: < 20 mL/min/1.73 m2) should be monitored closely for breakthrough fungal infections (see Section 5.2 Pharmacokinetic Properties; Section 4.2 Dose and Method of Administration).
A specific study has not been conducted with posaconazole concentrated injection.
Following single-dose administration of 400 mg of the oral suspension, there was no effect of mild and moderate renal impairment (n = 18, eGFR ≥ 20 mL/min/1.73 m2) on posaconazole pharmacokinetics, therefore, no dose adjustment is required. In subjects with severe renal insufficiency (n = 6, eGFR < 20 mL/min/1.73 m2), the exposure of posaconazole was highly variable (96% CV) compared to the exposure in the other renal groups (40% CV). However, as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected. Posaconazole is not removed by haemodialysis.

Use in the elderly.

Of the 279 patients treated with posaconazole concentrated injection, 52 (19%) were greater than 65 years of age. The pharmacokinetics of posaconazole concentrated injection are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients and age was not a significant covariate in the population PK model; therefore, no dosage adjustment is recommended for Noxafil concentrated injection in geriatric patients.

Paediatric use.

(See Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Children (< 18 years)). Safety and effectiveness in paediatric patients below the age of 18 years have not been established.
Noxafil concentrated injection should not be used in children because of pre-clinical safety concerns (see Section 5.3 Preclinical Safety Data, Pre-clinical safety).

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Clinical laboratory values.

4.5 Interactions with Other Medicines and Other Forms of Interactions

See Table 4.
Note that the majority of the interaction studies were carried out in healthy volunteers with repeat dose regimens of posaconazole 400 mg (oral suspension) twice daily administered with a meal or nutritional supplement. All drug interactions with posaconazole oral suspension, except for those that affect the absorption of posaconazole (via gastric pH and motility) are considered relevant to posaconazole concentrated injection as well. See below for further information.

Effect of other drugs on posaconazole.

Posaconazole is metabolized via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of these clearance pathways may affect posaconazole plasma concentrations.

Rifabutin.

(300 mg once a day) decreased the Cmax (maximum plasma concentration) and AUC (area under the plasma concentration time curve) of posaconazole by 43% and 49%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk.

Phenytoin.

(200 mg once a day) decreased the Cmax and AUC of posaconazole by 41% and 50%, respectively. Concomitant use of posaconazole and phenytoin should be avoided unless the benefit to the patient outweighs the risk.

Cimetidine.

(400 mg twice a day) decreased the Cmax and AUC of posaconazole 200 mg once a day each by 39%. Concomitant use of posaconazole and cimetidine should be avoided unless the benefit outweighs the risk. The effect of other H2 receptor antagonists and proton pump inhibitors that may suppress gastric acidity has not been studied. Reduction in bioavailability may occur, therefore co-administration of posaconazole with H2 receptor antagonists and proton pump inhibitors should be avoided if possible.

Antacids.

(20 mL single dose of liquid antacid equivalent to 25.4 mEq acid neutralizing capacity/5 mL) had no clinically significant effect on posaconazole Cmax and AUC. No posaconazole dosage adjustments are required.

Gastrointestinal motility agents.

No clinically meaningful effect on the pharmacokinetics of posaconazole was observed when oral posaconazole was concomitantly administered with metoclopramide. No dosage adjustment is required when given concomitantly with metoclopramide.

Glipizide.

(10 mg single dose) had no clinically significant effect on posaconazole Cmax and AUC. No posaconazole dosage adjustments are required.

Ritonavir.

(600 mg twice a day) had no clinically significant effect on posaconazole Cmax and AUC. No posaconazole dosage adjustments are required.

Efavirenz.

(400 mg once a day) decreased the Cmax and AUC of posaconazole by 45% and 50%, respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to the patient outweighs the risk.

Fosamprenavir.

Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma concentrations. If concomitant administration is required, close monitoring for breakthrough fungal infections is recommended. A study conducted in 20 healthy volunteers, repeat dose administration of fosamprenavir (700 mg twice a day for 10 days) decreased the Cmax and AUC of posaconazole (200 mg once a day on the 1st day, 200 mg twice a day on the 2nd day, then 400 mg twice a day for 8 days) by 21% and 23%, respectively. The GMRs of posaconazole Cmax and AUC when taken as posaconazole versus posaconazole/ fosamprenavir were 0.79 (0.71-0.89) and 0.77 (0.68-0.87), respectively.

Effects of posaconazole on other drugs.

Posaconazole is not metabolised to a clinically significant extent through the cytochrome P450 system. However, posaconazole is an inhibitor of CYP3A4 and thus the plasma levels of drugs that are metabolised through this enzyme pathway may increase when administered with posaconazole.

Terfenadine, astemizole, cisapride, pimozide, and quinidine.

Although not studied in vitro or in vivo, co-administration of posaconazole and certain drugs such as terfenadine, astemizole, cisapride, pimozide, and quinidine, metabolized through the CYP3A4 system may result in increased plasma concentrations of these drugs, leading to potentially serious and/or life threatening adverse events (QT prolongation and rare occurrences of torsade de pointes). Therefore, co-administration of these drugs with posaconazole is contraindicated (see Section 4.3 Contraindications).

Ergot alkaloids.

Although not studied in vitro or in vivo, posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and dihydroergotamine), which may lead to ergotism. Coadministration of posaconazole and ergot alkaloids is contraindicated (see Section 4.3 Contraindications).

Vinca alkaloids.

Most of the vinca alkaloids (e.g. vincristine and vinblastine) are substrates of CYP3A4. Concomitant administration of azole antifungals, including posaconazole, with vincristine has been associated with serious adverse reactions (see Section 4.4 Special Warnings and Precautions for Use). Posaconazole may increase the plasma concentrations of vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore, reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including vincristine, who have no alternative antifungal treatment options.

Cyclosporine.

In heart transplant patients on stable doses of cyclosporine, posaconazole 200 mg once daily increased cyclosporine concentrations requiring dose reductions. Cases of elevated cyclosporine levels resulting in serious adverse events, including nephrotoxicity and one fatal case of leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with posaconazole in patients already receiving cyclosporine, the dose of cyclosporine should be reduced (e.g. to about three quarters of the current dose). Thereafter blood levels of cyclosporine should be monitored carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose of cyclosporine should be adjusted as necessary.

Tacrolimus.

Posaconazole increased Cmax and AUC of tacrolimus (0.05 mg/kg single dose) by 121% and 358%, respectively. Clinically significant interactions resulting in hospitalisation and/or posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored carefully during co-administration, and upon discontinuation of posaconazole, and the dose of tacrolimus should be adjusted as necessary.

Sirolimus.

Repeat dose administration of oral posaconazole (400 mg twice daily for 16 days) increased the Cmax and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold, respectively, in healthy subjects. When initiating therapy in patients already taking sirolimus, the dose of sirolimus should be reduced (e.g. to about 1/10 of the current dose) with frequent monitoring of sirolimus whole blood trough concentrations. Sirolimus concentrations should be performed upon initiation, during coadministration, and at discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly.

Rifabutin.

Posaconazole increased the Cmax and AUC of rifabutin by 31% and 72%, respectively. Concomitant use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the risk. If the drugs are coadministered, careful monitoring of full blood counts and adverse effects related to increased rifabutin levels (e.g. uveitis) is recommended.

Midazolam and other benzodiazepines metabolised by CYP3A4.

In a study in healthy volunteers posaconazole oral suspension (200 mg once daily for 10 days) increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83%. In another study in healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily for 7 days) increased the Cmax and AUC of intravenous midazolam (0.4 mg single dose) by an average of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively. Posaconazole oral suspension 400 mg twice daily for 7 days increased the intravenous midazolam Cmax and AUC by 1.6 and 6.2-fold (range 1.6 to 7.6-fold), respectively. Both doses of posaconazole increased Cmax and AUC of oral midazolam (2 mg single oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mg or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to 8-10 hours during coadministration.
Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by CYP3A4 (e.g. midazolam, triazolam, alprazolam) (see Section 4.4 Special Warnings and Precautions for Use).

Zidovudine (AZT), lamivudine (3TC), ritonavir, indinavir.

In HIV infected patients on stable doses of zidovudine (300 mg twice a day or 200 mg every 8 hours), lamivudine (150 mg twice a day), ritonavir (600 mg twice a day) and/or indinavir (800 mg every 8 hours), posaconazole had no clinically significant effect on the Cmax and AUC of these medicinal products. Although not considered clinically significant, ritonavir exposure was increased by 30% with the addition of posaconazole.

HMG-CoA reductase inhibitors primarily metabolized through CYP3A4.

Repeat dose administration of oral posaconazole (50, 100, and 200 mg once daily for 13 days) increased the Cmax and AUC of simvastatin (40 mg single dose) an average of 7.4- to 11.4-fold, and 5.7- to 10.6-fold, respectively. Increased statins concentrations in plasma can be associated with rhabdomyolysis. Co-administration of posaconazole and HMG-CoA reductase inhibitors primarily metabolized through CYP3A4 is contraindicated.
Interactions with HMG-CoA reductase inhibitors that are not metabolized by CYP3A4 have not been investigated but clinically relevant drug interactions are not expected as posaconazole does not inhibit other CYP isoenzymes at relevant concentrations.

Calcium channel blockers metabolized through CYP3A4.

Although not studied in vitro or in vivo, frequent monitoring for adverse effects and toxicity related to calcium channel blockers is recommended during co-administration with posaconazole. Dose adjustment of calcium channel blockers may be required.

Digoxin.

Increased plasma concentrations of digoxin have been reported in patients receiving digoxin and posaconazole. Therefore, digoxin levels need to be monitored when initiating or discontinuing posaconazole treatment.

Sulfonylureas.

Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

HIV protease inhibitors.

As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase plasma levels of these antiretroviral agents. Repeat dose administration of oral posaconazole (400 mg twice daily for 7 days) increased the Cmax and AUC of atazanavir (300 mg once a day for 7 days) an average of 2.6-fold and 3.7-fold, respectively, in healthy subjects. Repeat dose administration of oral posaconazole (400 mg twice daily for 7 days) increased the Cmax and AUC of atazanavir to a lesser extent when administered as a boosted regimen with ritonavir (300 mg atazanavir plus ritonavir 100 mg once a day for 7 days) with an average of 1.5-fold and 2.5-fold, respectively, in healthy subjects. Frequent monitoring for adverse events and toxicity related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-administration with posaconazole.

Fosamprenavir.

The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with ritonavir is unknown. A study conducted in 20 healthy subjects, administration of posaconazole (200 mg once a day on the 1st day, 200 mg twice a day on the 2nd day, then 400 mg twice a day for 8 days) with fosamprenavir (700 mg twice a day for 10 days) resulted in a 36% and 65% lower Cmax and AUC for amprenavir compared to when fosamprenavir was administered with ritonavir. The GMRs of amprenavir Cmax and AUC when taken as fosamprenavir and posaconazole versus fosamprenavir/ ritonavir were 0.64 (0.55-0.76) and 0.35 (0.32-0.39), respectively.

Venetoclax.

Concomitant use of venetoclax (a CYP3A4 substrate) with posaconazole increases venetoclax Cmax and AUC0-INF, which may increase venetoclax toxicities (see Section 4.4 Special Warnings and Precautions for Use).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Posaconazole administered by the oral route had no effect on the fertility of male rats at doses up to 180 mg/kg/day (2.8 times the exposure achieved from a 300 mg IV dose in humans). Posaconazole administered by the oral route to female rats at doses up to 45 mg/kg/day (3.4 times the exposure from a 300 mg IV dose in patients) for 2 weeks prior to mating did not affect fertility, but disruption of oestrus cycling was seen in female rats treated for 4 weeks.
(Category B3)
There are no adequate studies in pregnant women. A total of three pregnancies have been reported in female subjects treated with posaconazole oral suspension. Two pregnancies were electively terminated; no examination was reported on the foetuses. Another pregnancy was diagnosed at a follow-up visit approximately 1 month after the completion of a full 16-week prophylactic treatment with POS oral suspension 200 mg TDS in a patient who had received an allogeneic haematopoietic stem cell transplant. The subject delivered a healthy full-term male infant via caesarean section.
Studies in rats with posaconazole administered by the oral route have shown reproductive toxicity including post implantation loss, increased skeletal variations, teratogenicity (craniofacial malformations), increased gestation length, dystocia, and reduced postnatal viability at exposure levels lower than those expected at the recommended doses in humans. An increase in post implantation loss and increased skeletal variations were seen in rabbits at plasma exposure levels greater than those of humans receiving therapeutic doses of posaconazole oral suspension.
Noxafil must not be used during pregnancy unless the benefit to the mother clearly outweighs the risk to the foetus. Women of childbearing potential must be advised to always use effective contraceptive measure during treatment and for at least 2 weeks after completing therapy.
Posaconazole administered by the oral route is excreted in milk of lactating rats. The excretion of posaconazole in human breast milk has not been investigated. Women taking posaconazole should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with posaconazole use, which potentially may affect driving/operating machinery, caution needs to be used.

4.8 Adverse Effects (Undesirable Effects)

Posaconazole concentrated injection.

In clinical trials, the type and frequency of adverse effects reported for posaconzole concentrated injection were generally similar to that reported in trials of posaconazole oral suspension.
In initial studies of healthy volunteers, administration of a single dose of posaconazole concentrated injection infused over 30 minutes via a peripheral venous catheter was well tolerated. However, multiple doses of posaconazole concentrated injection administered via a peripheral venous catheter were associated with thrombophlebitis (60% incidence). Therefore, in subsequent studies, posaconazole concentrated injection was administered via central venous catheter. If a central venous catheter was not readily available, patients could receive a single infusion over 30 minutes via a peripheral venous catheter.
The safety of posaconazole concentrated injection has been assessed in 268 patients in a clinical trial. Patients were enrolled in a noncomparative pharmacokinetic and safety trial of posaconazole concentrated injection when given as antifungal prophylaxis (Study 5520). Patients were immunocompromised with underlying conditions including haematological malignancy, neutropenia postchemotherapy, GVHD, and post HSCT. This patient population was 55% male, had a mean age of 51 years (range 18-82 years, 19% of patients were ≥ 65 years of age), and were 95% white and 8% Hispanic. Ten patients received a single dose of 200 mg posaconazole concentrated injection, 21 patients received 200 mg daily dose for a median of 14 days, and 237 patients received 300 mg daily dose for a median of 9 days. Each patient in the multiple dose cohorts received BD dosing on day 1. In each cohort, following posaconazole IV therapy, patients received posaconazole oral suspension to complete 28 days of total posaconazole therapy. Safety and efficacy of posaconazole concentrated injection at the recommended dose has not been assessed beyond 14 days in clinical trials.
Table 5 presents treatment emergent adverse reactions observed in patients treated with posaconazole IV solution 300 mg daily dose at an incidence of ≥ 10% in the posaconazole concentrated injection study.
The most frequently reported adverse effect (> 30%) with an onset during the posaconazole IV phase of dosing with 300 mg once daily was diarrhoea (32%).
The most common adverse effect (> 1%) leading to discontinuation of posaconazole IV solution 300 mg once daily was acute myelogenous leukemia (AML) (1%).

Posaconazole oral suspension.

Drug related, adverse reactions observed in 2400 subjects dosed with posaconazole oral suspension are shown in Table 6. 172 patients received posaconazole oral suspension therapy for ≥ 6 months; 58 of these received posaconazole oral suspension therapy for ≥ 12 months.
The most frequently reported adverse reactions reported across the whole population of healthy volunteers and patients were nausea (6%) and headache (6%).
Serious adverse events that were considered treatment related were reported in 8% (35/428) of patients in the refractory invasive fungal infection pool. Most individual treatment related serious adverse events were reported by < 1% of patients and are largely reflective of the serious underlying conditions that predisposed to the development of the invasive fungal infection. Treatment related serious adverse events reported in 1% of subjects (3 or 4 subjects each) included altered concentration of other medicinal products, increased hepatic enzymes, nausea, rash, and vomiting. Treatment related serious adverse events reported in 605 patients treated with posaconazole oral suspension for prophylaxis (1% each) included bilirubinaemia, increased hepatic enzymes, hepatocellular damage, nausea, and vomiting.
Uncommon and rare treatment related medically significant adverse events reported during clinical trials with posaconazole oral suspension have included adrenal insufficiency, pancreatitis, allergic and/or hypersensitivity reactions.
Some azoles have been associated with prolongation of the QT interval on the electrocardiogram. A pooled analysis of 173 posaconazole oral suspension dosed healthy volunteers utilizing time matched ECGs did not show a potential to prolong the QT interval. In addition, rare cases of torsade de pointes have been reported in patients taking posaconazole oral suspension.
In addition, rare cases of haemolytic uremic syndrome and thrombotic thrombocytopenic purpura have been reported primarily among patients who had been receiving concomitant cyclosporine or tacrolimus for management of transplant rejection or graft vs. host disease. (See Tables 7, 8 and 9.)

Clinical laboratory values.

In (uncontrolled) trials of patients with invasive fungal infections treated with Noxafil oral suspension doses of 800 mg/day, the incidence of clinically significant liver function test abnormalities was; ALT and AST (> 3 x upper limit normal {ULN}) 11% and 10%, respectively; total bilirubin (> 1.5 x ULN) 22%; and alkaline phosphatase (> 3 x ULN) 14%. In healthy volunteers, elevation of hepatic enzymes did not appear to be associated with higher plasma concentrations of posaconazole. In patients, the majority of abnormal liver function tests results showed minor and transient changes and rarely led to discontinuation of therapy.
In the comparative trials of patients infected with HIV treated with Noxafil at doses up to 400 mg, the incidence of clinically significant liver function test abnormalities was as follows; ALT and AST (> 3 x ULN), 3% and 6%, respectively; total bilirubin (> 1.5 x ULN), 3%; and alkaline phosphatase (> 3 x ULN), 3%.
The number of patients with changes in liver function tests from common toxicity criteria (CTC) grade 0, 1, or 2 at baseline to grade 3 or 4 during the study are presented in Table 10 for the prophylaxis studies 316 and 1899.

Post-marketing experience.

The following post-marketing adverse experience has been reported.

Endocrine disorders.

Pseudoaldosteronism.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdosage of posaconazole concentrated injection.
During clinical trials, patients who received posaconazole oral suspension doses up to 1600 mg/day had no noted adverse reactions different from those reported with patients at the lower doses. In addition, accidental overdose was noted in one patient who took 1200 mg posaconazole oral suspension twice a day for 3 days. No adverse reactions were noted by the investigator.
In a trial of patients with severe haemodialysis-dependent renal dysfunction (Clcr < 20 mL/min), posaconazole was not removed by haemodialysis. Thus, haemodialysis is unlikely to be effective in removing posaconazole from the systemic circulation.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Anti-infective for systemic use, triazole derivative, J02AC04.

Mechanism of action.

Posaconazole is a triazole antifungal agent. It is an inhibitor of the enzyme lanosterol 14α-demethylase, which catalyses an essential step in ergosterol biosynthesis. Ergosterol depletion, coupled with the accumulation of methylated sterol precursors, is thought to impair membrane integrity and the function of some membrane-associated proteins. This results in the inhibition of cell growth and/or cell death.

Microbiology.

Posaconazole has been shown in vitro and in clinical infections to be active against the following microorganisms (see Section 4.1 Therapeutic Indications): Aspergillus species (Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus, A. ochraceus), Candida species (Candida albicans, C. glabrata, C. krusei, C. parapsilosis), Cryptococcus neoformans, Coccidioides immitis, Fonsecaea pedrosoi, Histoplasma capsulatum, Pseudallescheria boydii and species of Alternaria, Exophiala, Fusarium, Ramichloridium, Rhizomucor, Mucor, and Rhizopus. While posaconazole has been used in a clinical setting against these microorganisms, sufficient evidence for efficacy has not been collected for all the listed microorganisms (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Posaconazole also exhibits in vitro activity against the following yeasts and moulds: Candida dubliniensis, C. famata, C. guilliermondii, C. lusitaniae, C. kefyr, C. rugosa, C. tropicalis, C. zeylanoides, C. inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis, Cryptococcus laurentii, Kluyveromyces marxianus, Saccharomyces cerevisiae, Yarrowia lipolytica, species of Pichia, and Trichosporon, Aspergillus sydowii, Bjerkandera adusta, Blastomyces dermatitidis, Epidermophyton floccosum, Paracoccidioides brasiliensis, Scedosporium apiospermum, Sporothrix schenckii, Wangiella dermatitidis and species of Absidia, Apophysomyces, Bipolaris, Curvularia, Microsporum, Paecilomyces, Penicillium, and Trichophyton. However, the safety and effectiveness of posaconazole in treating clinical infections due to these microorganisms have not been established in clinical trials.
Noxafil exhibits broad spectrum antifungal activity against some yeasts and moulds not generally responsive to azoles, or resistant to other azoles:
species of Candida (including C. albicans isolates resistant to fluconazole, voriconazole and itraconazole;
C. krusei and C. glabrata which are inherently less susceptible to fluconazole;
C. lusitaniae which is inherently less susceptible to amphotericin B);
Aspergillus (including isolates resistant to fluconazole, voriconazole, itraconazole and amphotericin B);
organisms not previously regarded as being susceptible to azoles such as the zygomycetes (e.g. species of Absidia, Mucor, Rhizopus and Rhizomucor).
In vitro Noxafil exhibited fungicidal activity against species of:
Aspergillus; dimorphic fungi (Blastomyces dermatitidis, Histoplasma capsulatum, Penicillium marneffei, Coccidioides immitis); some species of Candida.
In animal infection models Noxafil was active against a wide variety of fungal infections caused by moulds or yeasts. However, there was no consistent correlation between minimum inhibitory concentration and efficacy.
Specimens for fungal culture and other relevant laboratory studies (including histopathology) should be obtained prior to therapy to isolate and identify causative organism(s). Therapy may be instituted before the results of the cultures and other laboratory studies are known. However, once these results become available, antifungal therapy should be adjusted accordingly.

Drug resistance.

C. albicans strains resistant to posaconazole could not be generated in the laboratory; spontaneous laboratory Aspergillus fumigatus mutants exhibiting a decrease in susceptibility to posaconazole arose at a frequency of 1 x 10-8 to 1 x 10-9. Clinical isolates of Candida albicans and Aspergillus fumigatus exhibiting significant decreases in posaconazole susceptibility are rare. In those rare instances where decreased susceptibility was noted, there was no clear correlation between decreased susceptibility and clinical failure. Clinical success has been observed in patients infected with organisms resistant to other azoles; consistent with these observations posaconazole was active in vitro against many Aspergillus and Candida strains that developed resistance to other azoles and/or amphotericin B. Breakpoints for posaconazole have not been established for any fungi.

Antifungal drug combinations.

When combinations of posaconazole with either amphotericin B or caspofungin were tested in vitro and in vivo there was little or no antagonism and in some instances there was an additive effect. Clinical studies of posaconazole in combination with antifungal drugs including amphotericin B based drugs and caspofungin have not been conducted.

Clinical trials.

Posaconazole concentrated injection. Study 5520 was a non-comparative multicenter study performed to evaluate the pharmacokinetic properties, safety, and tolerability of posaconazole concentrated injection.
Study 5520 enrolled a total of 279 subjects, including 268 receiving at least one dose of posaconazole concentrated injection. Cohort 0 was designed to evaluate the tolerability of a single dose of posaconazole concentrated injection when administered via a central line. Cohorts 1 and 2 of the study were designed to select a dose for further evaluation in Cohort 3, after first evaluating pharmacokinetics, safety, and tolerability in the neutropenic patient population at high risk of a fungal infection. Cohort 3 of the study was designed to evaluate posaconazole concentrated injection in a more diverse patient population, and to confirm the exposure of posaconazole concentrated injection in additional subjects at risk of a fungal infection.
The subject population for Cohorts 0, 1, and 2 included subjects with AML or MDS who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia. Two different dosing groups were evaluated in Cohorts 1 and 2: 200 mg BD on Day 1, followed by 200 mg QD thereafter (Cohort 1) and 300 mg BD on Day 1, followed by 300 mg QD thereafter (Cohort 2).
The subject population in Cohort 3 included: 1) patients with AML or MDS who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patients who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or treatment of GVHD. These types of patients had been previously studied in a pivotal controlled trial of posaconazole oral suspension. Based on the pharmacokinetics and safety results of Cohorts 1 and 2, all subjects in Cohort 3 received 300 mg BD on Day 1, followed by 300 mg QD thereafter.
The total subject population had a mean age of 51 years (range = 18-82 years), 95% were White, the major ethnicity was not Hispanic or Latino (92%), and 55% were male. The study treated 155 (65%) subjects with AML or MDS, and 82 (35%) subjects with HSCT, as the primary diseases at study entry.
Serial pharmacokinetic samples were collected on Day 1 and at steady-state on Day 14 for all Cohort 1 and 2 subjects and on Day 10 for a subset of Cohort 3 subjects. This serial pharmacokinetic analysis demonstrated that 94% of the subjects treated with the 300 mg QD dose attained steady state Cav between 500-2500 nanogram/mL. [Cav was the average concentration of posaconazole at steady state, calculated as AUC/dosing interval (24 hours)]. This exposure was selected based on pharmacokinetic/ pharmacodynamic considerations with posaconazole oral suspension. Subjects with AML/MDS with neutropenia following chemotherapy or HSCT subjects receiving immunosuppressive therapy to prevent or treat GVHD who received 300 mg QD achieved a mean Cav at steady state of 1500 nanogram/mL. The PK findings from the pivotal study (Study 5520) support a 300 mg daily dose of posaconazole concentrated injection for use in prophylaxis.
Posaconazole oral suspension studies: invasive Aspergillosis.

Efficacy in patients with refractory disease or intolerance to prior therapy.

The efficacy and survival benefit of oral posaconazole for the treatment of invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal formulations), itraconazole or, in a small number of cases, voriconazole or echinocandins, and/or with intolerance to amphotericin B (including liposomal formulations) or itraconazole was demonstrated in 107 patients enrolled in a salvage therapy trial. Patients were administered posaconazole 800 mg/day in divided doses for up to 585 days. The median duration of posaconazole therapy was 56 days (1-585 days).
The majority of patients were severely immunocompromised with underlying conditions such as haematologic malignancies, including bone marrow transplantation; solid organ transplantation; solid tumours and/or AIDS. An independent expert panel reviewed all patient data, including diagnosis of invasive aspergillosis, refractoriness and intolerance to previous therapy, and clinical outcome in a parallel and blinded fashion with an external control group of 86 patients treated with standard salvage therapy (e.g. amphotericin B including liposomal formulations, and/or itraconazole) mostly at the same time and at the same sites as the patients enrolled in the posaconazole trial.
A success was defined as either complete resolution (complete response) or a clinically meaningful improvement (partial response) of all signs, symptoms and radiographic findings attributable to the fungal infection. Stable, non-progressive disease and failure were considered to be a non-success. Most of the cases of aspergillosis were considered to be refractory in both the posaconazole group (88%) and in the external control group (79%) while the remaining patients were intolerant to prior antifungal therapy (12% posaconazole; 21% external control group).
As shown in Table 11, a successful global response at end of treatment was seen in 42% of posaconazole-treated patients compared to 26% of the external group (P = 0.006).
Other serious fungal pathogens. Posaconazole has been shown to be effective against the following additional pathogens when other therapy had been ineffective or when the patient had developed intolerance of the prior therapy.

Zygomycosis.

Successful responses to posaconazole therapy were noted in 7/13 (54%) of patients with zygomycete infections. Sites of infection included the sinuses, lung, and skin. Organisms included Rhizopus, Mucor and Rhizomucor. Most of the patients had underlying haematological malignancies, half of which required a bone marrow transplant. Half of the patients were enrolled with intolerance to previous therapy and the other half as a result of disease that was refractory to prior therapy. Three patients were noted to have disseminated disease, one of which had a successful outcome after failing amphotericin B therapy.

Fusarium spp.

Successful responses to posaconazole therapy were seen in 11 of 24 (46%) of patients with fusariosis. Four of the responders had disseminated disease and one patient had disease localized to the eye; the remainder had a variety of sites of infection. Seven of 24 patients had profound neutropenia at baseline. In addition, 3/5 patients with infection due to F. solani which is typically resistant to most antifungal agents, were successfully treated.

Chromoblastomycosis/ mycetoma.

Successful responses to posaconazole therapy were seen in 9 of 11 (82%) of patients with chromoblastomycosis or mycetoma. Five of these patients had chromoblastomycosis due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis.

The efficacy of posaconazole in the primary treatment of nonmeningeal coccidioidomycosis was demonstrated in 15 clinically evaluable patients enrolled in an open label, non-comparative trial to receive posaconazole 400 mg daily for 6 months. Most patients were otherwise healthy and had infections at a variety of sites. A satisfactory response (defined as an improvement of at least 50% of the Cocci score as defined by the BAMSG Coccidioidomycosis trial group) was seen in 12 of 15 patients (80%) after an average of 4 months of posaconazole treatment. In a separate open-label, non-comparative trial, the safety and efficacy of posaconazole 400 mg twice a day was assessed in 16 patients with coccidioidomycosis infection refractory to standard treatment.
Most had been treated with amphotericin B (including lipid formulations) and/or itraconazole or fluconazole for months to years prior to posaconazole treatment. At the end of treatment with posaconazole, a satisfactory response (complete or partial resolution of signs and symptoms present at baseline) as determined by an independent panel was achieved for 11/16 (69%) of patients. One patient with CNS disease that had failed fluconazole therapy had a successful outcome following 12 months of posaconazole therapy.
Treatment of azole-susceptible oropharyngeal candidiasis (OPC) in HIV-infected patients. A randomised, double-blind, controlled study was completed in HIV-infected patients with azole susceptible oropharyngeal candidiasis. The primary efficacy variable was the clinical success rate (defined as cure or improvement) after 14 days of treatment. Patients were treated with posaconazole or fluconazole oral suspension (both posaconazole and fluconazole were given as follows: 100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).
The clinical and mycological response rates from the above study are shown in Table 12. Posaconazole and fluconazole demonstrated equivalent clinical success rates at Day 14 as well as 4 weeks after the end of treatment. However, posaconazole demonstrated a significantly better mycological response rate than fluconazole 4 weeks after the end of treatment.
Treatment of oropharyngeal candidiasis refractory to itraconazole and fluconazole (rOPC) in HIV-infected patients. The primary efficacy parameter in the short-term treatment study was the clinical success rate (cure or improvement) after 4 weeks of treatment. HIV-infected patients were treated with posaconazole 400 mg twice a day with an option for further treatment during a 3-month maintenance period. A 75% (132/176) clinical success rate and a 36.5% (46/126) mycological response rate (≤ 20 CFU/mL) were achieved after 4 weeks of posaconazole treatment. Clinical success rates ranged from 71% to 100%, inclusive, for all azole resistant Candida species identified at baseline, including C. glabrata and C. krusei.
In the long-term treatment study the primary efficacy endpoint was the clinical success rate (cure or improvement) after 3 months of treatment. A total of 100 HIV-infected patients with OPC and/or EC were treated with posaconazole 400 mg twice a day for up to 15 months. Sixty of these patients had been previously treated in study 330. An 85.6% (77/90) clinical success rate overall (cure or improvement) was achieved after 3 months of posaconazole treatment; 80.6% (25/31) for previously untreated subjects.
The mean exposure to posaconazole based on the actual days dosed was 102 days (range: 1-544 days). Sixty seven percent (67%, 10/15) of patients treated with posaconazole for at least 12 months had continued clinical success at the last assessment.
Prophylaxis of invasive fungal infections (IFIs) (studies 316 and 1899). Two large, randomised, controlled studies were conducted using posaconazole as prophylaxis for the prevention of IFIs among patients at high risk.
Study 316 was a randomised, double-blind trial that compared posaconazole oral suspension (200 mg three times a day) with fluconazole capsules (400 mg once daily) as prophylaxis against invasive fungal infections in allogeneic HSCT recipients with graft versus host disease (GVHD). The primary efficacy endpoint was the incidence of proven/ probable IFIs at 16 weeks post-randomization as determined by an independent, blinded external expert panel. A key secondary endpoint was the incidence of proven/ probable IFIs during the on-treatment period (first dose to last dose of study medication + 7 days). The mean duration of therapy was comparable between the two treatment groups (80 days, posaconazole; 77 days, fluconazole).
Study 1899 was a randomised, evaluator-blinded study that compared posaconazole oral suspension (200 mg three times a day) with fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg twice a day) as prophylaxis against IFIs in neutropenic patients who were receiving cytotoxic chemotherapy for acute myelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was the incidence of proven/ probable IFIs as determined by an independent, blinded external expert panel during the on-treatment period. A key secondary endpoint was the incidence of proven/ probable IFIs at 100 days post-randomization. The mean duration of therapy was comparable between the two treatment groups (29 days, posaconazole; 25 days, fluconazole/ itraconazole).
In both prophylaxis studies, aspergillosis was the most common breakthrough infection. There were significantly fewer breakthrough Aspergillus infections in patients receiving posaconazole prophylaxis when compared to control patients receiving fluconazole or itraconazole. See Table 13 for results from both studies.
In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed [POS 49/304 (16%) vs. FLU/ITZ 67/298 (22%) p = 0.048]. Based on Kaplan-Meier estimates, the probability of survival up to day 100 after randomization, was significantly higher for posaconazole recipients; this survival benefit was demonstrated when the analysis considered all causes of death (P = 0.0354) (Figure 1) as well as IFI-related deaths (P = 0.0209).
In Study 316, overall mortality was similar (POS, 25%; FLU, 28%); however, the proportion of IFI-related deaths was significantly lower in the POS group (4/301) compared with the FLU group (12/299; P = 0.0413).
Use in paediatric patients. There is no paediatric experience for posaconazole concentrated injection.

5.2 Pharmacokinetic Properties

Pharmacokinetic/ pharmacodynamic relationships.

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical outcome was observed. The critical ratio for subjects with Aspergillus infections was ~200. It is particularly important to try to ensure that maximal plasma levels are achieved in patients infected with Aspergillus (see Section 4.2 Dose and Method of Administration on recommended dose regimens).

Distribution.

Posaconazole exhibits dose proportional pharmacokinetics after single dosing in healthy volunteers and multiple dosing in patients in the therapeutic dose range (200-300 mg).
Following administration of 300 mg posaconazole concentrated injection, posaconazole has a distribution volume of 261 L, indicating extravascular distribution.
Posaconazole is highly protein bound (> 98.0%), predominantly to serum albumin.

Metabolism.

Posaconazole does not have any major circulating metabolites. Of the circulating metabolites, the majority are glucuronide conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolites observed. The excreted metabolites in urine and faeces account for approximately 17% of the administered radio-labelled dose of posaconazole oral suspension.

Excretion.

Posaconazole, after administration of 300 mg of posaconazole concentrated injection, is slowly eliminated with a mean half-life (t1/2) of 27 hours and a mean clearance of 7.3 L/hr.
Posaconazole, after oral suspension administration, is slowly eliminated with a mean half-life (t1/2) of 35 hours (range 20 to 66 hours) and an apparent total body clearance (Cl/F) of 32 L/hr. After administration of 14C-posaconazole as oral suspension, posaconazole is predominantly excreted in the faeces (77% of the radio-labelled dose) with the major component eliminated as parent drug (66% of the radio-labelled dose). Renal clearance is a minor elimination pathway, with 14% of the radio-labelled dose excreted in urine (< 0.2% of the radio-labelled dose is parent drug). Steady state is attained following 7 to 10 days of multiple dose administration.

Summary of the mean pharmacokinetic parameters in patients.

The pharmacokinetic parameters of posaconazole in patients following administration of posaconazole concentrated injection 300 mg once a day for 10 or 14 days following BD dosing on Day 1 are shown in Table 14.

Pharmacokinetics in special populations.

Children (< 18 years).

There is no paediatric experience with posaconazole concentrated injection (see Section 5.3 Preclinical Safety Data, Pre-clinical safety; Section 4.2 Dose and Method of Administration).

Gender.

The pharmacokinetics of posaconazole concentrated injection are comparable in men and women. No adjustment in the dosage of Noxafil is necessary based on gender.

Elderly.

The pharmacokinetics of posaconazole concentrated injection are comparable in young and elderly subjects. No overall differences in safety were observed between geriatric patients and younger patients and age was not a significant covariant in the population PK model; therefore no dosage adjustment is recommended for geriatric patients.

Race.

There is insufficient data among different races with posaconazole concentrated injection.

Weight.

Pharmacokinetic modelling with an oral tablet formulation suggests that patients weighing greater than 120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for breakthrough fungal infections in patients weighing more than 120 kg.

Renal impairment.

In patients with moderate or severe renal impairment (estimated glomerular filtration rate (eGFR) < 50 mL/min/1.73 m2), receiving the Noxafil concentrated injection, accumulation of the intravenous vehicle, Sulfobutyl Betadex Sodium (SBECD), is expected to occur. Noxafil concentrated injection should be avoided in patients with moderate or severe renal impairment (eGFR < 50 mL/min/1.73 m2), unless an assessment of the benefit/ risk to the patient justifies the use of Noxafil concentrated injection (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration). A specific study has not been conducted with posaconazole concentrated injection.
Following single-dose administration of 400 mg of the oral suspension, there was no effect of mild and moderate renal impairment (n = 18, eGFR ≥ 20 mL/min/1.73 m2) on posaconazole pharmacokinetics, therefore, no dose adjustment is required. In subjects with severe renal insufficiency (n = 6, eGFR < 20 mL/min/1.73 m2), the exposure of posaconazole was highly variable (96% CV) compared to the exposure in the other renal groups (40% CV). However, as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected. Posaconazole is not removed by haemodialysis (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Hepatic impairment.

A specific study has not been conducted with posaconazole concentrated injection.
In a small number of subjects (n = 12) studied with hepatic impairment (Child-Pugh class A, B or C) administered 200 mg posaconazole oral suspension, Cmax values generally decreased with the severity of hepatic dysfunction (545, 414 and 347 nanogram/mL for the mild, moderate, and severe groups, respectively), even though the Cmax values (mean 508 nanogram/mL) for the normal subjects were consistent with previous trials in healthy volunteers. In addition, an increase in half-life was also associated with a decrease in hepatic function (26.6, 35.3, and 46.1 hours for the mild, moderate, and severe groups, respectively), as all groups had longer half-life values than subjects with normal hepatic function (22.1 hours). Due to the limited pharmacokinetic data in patients with hepatic impairment, no recommendation for dose adjustment can be made.
Similar recommendations apply to posaconazole concentrated injection; however, a specific study has not been conducted with posaconazole concentrated injection.
Electrocardiogram evaluation. Multiple, time matched ECGs collected over a 12 hour period were recorded at baseline and steady state from 173 healthy male and female volunteers (18 to 85 years of age) administered posaconazole oral suspension 400 mg BID with a high-fat meal. In this pooled analysis, the mean QTc (Fridericia) interval change was -5 msec following administration of the recommended clinical dose. A decrease in the QTc (F) interval (-3 msec) was also observed in a small number of subjects (n = 16) administered placebo. No subject administered posaconazole oral suspension had a QTc (F) interval of ≥ 500 msec or an increase ≥ 60 msec in their QTc (F) interval from baseline.

5.3 Preclinical Safety Data

Pre-clinical safety.

In a nonclinical study using intravenous administration of posaconazole in very young dogs (dosed from 2-8 weeks of age) an increase in the incidence of brain ventricle enlargement was observed in treated animals as compared with concurrent control animals. No difference in the incidence of brain ventricle enlargement between control and treated animals was observed following the subsequent 5-month treatment-free period. There were no neurologic, behavioural or developmental abnormalities in the dogs with this finding, and a similar brain finding was not seen with oral posaconazole administration to juvenile dogs (4 days to 9 months of age). The clinical significance of this finding is unknown; therefore, the use of posaconazole concentrated injection in patients under 18 years of age is not recommended (see Section 4.2 Dose and Method of Administration).

Genotoxicity.

Posaconazole has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, mammalian mutation and human lymphocyte chromosomal aberration) and an in vivo mouse micronucleus test. Under the conditions of these assays, posaconazole did not cause genetic damage.

Carcinogenicity.

Posaconazole administered by the oral route caused an increase in hepatocellular adenomas in mice at plasma exposure levels ~7-times higher than anticipated in humans at the maximum recommended clinical dose. This finding is considered to have occurred secondary to liver toxicity in the species, and mice are known to be particularly susceptible to this neoplastic change.
Rats treated with posaconazole administered by the oral route at exposure levels ≥ 2.4-times that of humans developed adrenal cortical cell adenomas and/or carcinomas and phaeochromocytomas. The cortical tumours are consistent with endocrinological disruption following chronic impairment of adrenal steroidogenesis. The increase in phaeochromocytomas is considered to be a rat-specific phenomenon that follows changes in calcium homeostasis. Altered calcium homeostasis has not been observed in humans receiving posaconazole. The results of animal studies indicate little carcinogenic risk for posaconazole in clinical use.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each vial of Noxafil concentrated injection contains the following inactive ingredients: sulfobutyl betadex sodium (SBECD), disodium edetate, hydrochloric acid, sodium hydroxide and Water for Injections.

6.2 Incompatibilities

Noxafil concentrated injection must not be diluted with Lactated Ringer's solution, 5% dextrose with Lactated Ringer's solution, 4.2% sodium bicarbonate.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store at 2°C-8°C. (Refrigerate. Do not freeze.)

6.5 Nature and Contents of Container

Noxafil concentrated injection is available in a Type I glass vial closed with bromobutyl rubber stopper and aluminium seal containing 16.7 mL of solution (18 mg of posaconazole per mL).
Noxafil Concentrated Injection: AUST R 218702.

6.6 Special Precautions for Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Posaconazole is a broad spectrum triazole antifungal compound with a molecular formula of C37H42F2N8O4 yielding a molecular weight of 700.8.
The chemical structure, which possesses four chiral centres, two R and two S, and chemical name are illustrated below:

Chemical structure.


CAS index name: D-threo-Pentitol, 2,5-anhydro-1,3,4-trideoxy-2-C- (2,4-difluorophenyl)-4-[[ 4-[4-[4-[1-[(1S,2S)-1 -ethyl-2- hydropropyl]- 1,5-dihydro-5-oxo- 4H-1,2,4-triazol-4-yl] phenyl]-1-piperazinyl] phenoxy]methyl]-1- (1H-1,2,4-triazol-1-yl).
IUPAC name: 4-4-[4-(4-{(3R, 5R)-5- (2,4-difluorophenyl)-5- (1H-1,2,4-triazol-1-ylmethyl) tetrahydro-3-furanyl] methoxyphenyl)piperazino] phenyl-1-[(1S,2S)- 1-ethyl-2-hydroxypropyl] -4,5-dihydro-1H-1,2,4-triazol-5-one.

CAS number.

The CAS Registry Number is 171228-49-2.
Posaconazole has a melting range of 164°C - 165°C and is insoluble in water.

7 Medicine Schedule (Poisons Standard)

All states and ACT - Schedule 4.

Summary Table of Changes