Consumer medicine information

Posaconazole Dr. Reddy's Modified Release Tablets

Posaconazole

BRAND INFORMATION

Brand name

Posaconazole Dr. Reddy's

Active ingredient

Posaconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Posaconazole Dr. Reddy's Modified Release Tablets.

What is in this leaflet

This leaflet answers some common questions about POSACONAZOLE DR.REDDY’S. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking POSACONAZOLE DR.REDDY’S against the benefits this medicine is expected to have for you.

If you have any concerns about taking POSACONAZOLE DR.REDDY’S, ask your doctor or pharmacist.

Read this leaflet carefully before taking POSACONAZOLE DR.REDDY’S.

Keep this leaflet with the medicine. You may need to read it again.

What POSACONAZOLE DR.REDDY’S is used for

POSACONAZOLE DR.REDDY’S contains the active ingredient, posaconazole.

Posaconazole is a medicine that belongs to the triazole group of antifungal medicines.

POSACONAZOLE DR.REDDY’S works by killing or stopping the growth of the fungi causing these infections.

POSACONAZOLE DR.REDDY’S Modified Release Tablets are 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 POSACONAZOLE DR.REDDY’S is usually reserved for patients who do not respond to or cannot tolerate other medicines used to treat these types of fungal infections.

POSACONAZOLE DR.REDDY’S is also used to treat coccidioidomycosis, a rare and serious fungal infection.

POSACONAZOLE DR.REDDY’S 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.

Your doctor may have prescribed POSACONAZOLE DR.REDDY’S for another reason.

Ask your doctor if you have any questions about why POSACONAZOLE DR.REDDY’S has been prescribed for you.

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

Before you take POSACONAZOLE DR.REDDY’S

When you must not take it

Do not take POSACONAZOLE DR.REDDY’S if:

  1. you have an allergy to:
  • posaconazole or any other triazole antifungal medicines
  • any of the ingredients listed at the end of this leaflet (See Product Description)
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.
  1. you are pregnant or may become pregnant.

Do not take POSACONAZOLE DR.REDDY’S 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 heart beat
  • 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.

POSACONAZOLE DR.REDDY’S is not recommended for children below the age of 13 years.

Do not take POSACONAZOLE DR.REDDY’S if the packaging is torn or shows signs of tampering.

Do not take POSACONAZOLE DR.REDDY’S if the expiry date (EXP) printed on the pack has passed. If you take POSACONAZOLE DR.REDDY’S after the expiry date has passed, it may not work (as well). Return this medicine to your pharmacist for disposal if it has expired or is damaged.

If you are not sure whether you should start taking POSACONAZOLE DR.REDDY’S, talk to your doctor.

Before you start to take it

Tell your doctor if:

  1. you have any allergies to any other medicines, especially other antifungal medicines such as itraconazole (Sporanox®), fluconazole (Diflucan®), voriconazole (Vfend®), ketoconazole (Nizoral®) or any other substances such as foods, preservatives or dyes.
  2. you 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.
  1. you are pregnant or plan to become pregnant
POSACONAZOLE DR.REDDY’S should not be taken during pregnancy unless indicated by your doctor. Women who are of childbearing potential should use effective contraception while taking POSACONAZOLE DR.REDDY’S and for 2 weeks after completing treatment.
Your doctor will discuss the possible risks and benefits to you and your unborn baby.
  1. You are breastfeeding
POSACONAZOLE DR.REDDY’S should not be taken by 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.

If you have not told your doctor or pharmacist about any of the above, tell them before you start taking POSACONAZOLE DR.REDDY’S.

Taking other medicines

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

Some medicines may increase the risk of side effects of POSACONAZOLE DR.REDDY’Sby increasing the amount of posaconazole in the blood. Similarly, some medicines may decrease the effectiveness of POSACONAZOLE DR.REDDY’S by decreasing the amount of posaconazole in the blood.

Medicines that can decrease the effectiveness of POSACONAZOLE DR.REDDY’S 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

POSACONAZOLE DR.REDDY’S may possibly increase the risk of side effects of some medicines by increasing the amount of these medicines in the blood. These are:

  • 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

These medicines may be affected by POSACONAZOLE DR.REDDY’S or may affect how well it works. You may need different amounts of your medicine or you may need to take different medicines. Your doctor will advise you.

Taking POSACONAZOLE DR.REDDY’S

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

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

Children
POSACONAZOLE DR.REDDY’S is not recommended for children below the age of 13 years.

POSACONAZOLE DR.REDDY’S Modified Release Tablets

How much to take

For treatment and prevention of invasive fungal infections:

The usual dose is three tablets twice a day on the first day, then three tablets once a day, thereafter.

The dose may vary from one patient to another. Your doctor may recommend a different dose depending on your condition.

How to take POSACONAZOLE DR.REDDY’S Modified Release Tablets

  • Swallow the tablet whole with some water.
  • Do not crush, chew, break or dissolve the tablet.
  • POSACONAZOLE DR.REDDY’S modified release tablets may be taken with or without food.

How long to take POSACONAZOLE DR.REDDY’S

Your doctor will advise how long you should take POSACONAZOLE DR.REDDY’S.

Continue taking POSACONAZOLE DR.REDDY’S for the length of time that your doctor recommends.

If you forget to take POSACONAZOLE DR.REDDY’S

Take the dose you missed as soon as you remember, then continue to take it as you normally would.

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 have missed.

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

If you have taken too much (overdose)

Immediately telephone your doctor or Poisons Information Centre or go to Accident and Emergency at your nearest hospital, if you think you or anyone else may have taken too much POSACONAZOLE DR.REDDY’S. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Keep these telephone numbers handy:

Poisons Information Centres:

  • Australia: 13 11 26
  • New Zealand: 0800 POISON or 0800 764 766

While you are taking POSACONAZOLE DR.REDDY’S

Things you must 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 POSACONAZOLE DR.REDDY’S, continue using contraception until your next period.
  • If you become pregnant while you are taking POSACONAZOLE DR.REDDY’S, tell your doctor immediately.
  • If you are about to start any other new medicine, tell your doctor that you are taking POSACONAZOLE DR.REDDY’S.
  • If you need to have any blood tests, tell your doctor you are taking POSACONAZOLE DR.REDDY’S. It may affect the results of some laboratory tests.

Tell all doctors, dentists and pharmacists who are treating you that you are taking POSACONAZOLE DR.REDDY’S.

Things you must not do

  • Do not give POSACONAZOLE DR.REDDY’S to anyone else, even if they have the same condition as you.
  • Do not use POSACONAZOLE DR.REDDY’S to treat any other medical complaints unless your doctor tells you to.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking POSACONAZOLE DR.REDDY’S.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them. Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you experience any of the following:

  • Loss of appetite
  • Sleeplessness
  • Headache, dizziness, sleepiness
  • Tingling in fingers or toes
  • Hot flushes
  • Upset stomach, nausea, vomiting, stomach pain, diarrhoea, gas from stomach or bowel, dry mouth, altered sense of taste.
  • Dry skin, rash, itchiness
  • Back pain
  • Fever.

If any of the following happen, stop taking POSACONAZOLE DR.REDDY’S and tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

  • rash, itchiness, hives
  • swelling of the face, lips, mouth, throat or neck which may cause difficulty swallowing or breathing
  • tingling or numbness of the hands or feet, or muscle weakness.

These are very serious side effects. You may need urgent medical attention. These side effects are rare.

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

Tell your doctor if you notice anything else that is making you feel unwell.

After taking POSACONAZOLE DR.REDDY’S

Storage

POSACONAZOLE DR.REDDY’S Modified Release Tablets

  • Store POSACONAZOLE DR.REDDY’S Modified Release Tablets below 30°C.
  • Store in original container.

Do not store POSACONAZOLE DR.REDDY’S or any other medicine in the bathroom or near a sink. Do not leave it in the car or on window sills. Heat and dampness can destroy some medicines.

Keep POSACONAZOLE DR.REDDY’S and all other medicines where children cannot reach them. A locked cupboard at least one-and- a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking POSACONAZOLE DR.REDDY’S, or if it has passed the expiry date, ask your pharmacist what to do with any left over medicine.

Product description

What it looks like

POSACONAZOLE DR.REDDY’S Modified Release Tablets

POSACONAZOLE DR.REDDY’S Tablets are brown, capsule shaped, bevelled edge, film coated tablet, debossed with ‘470’ on one side and plain on other side.

POSACONAZOLE DR.REDDY’S tablets are available in blister packs of 24 or 96 tablets.

Ingredients

POSACONAZOLE DR.REDDY’S Modified Oral Release Tablets

Each tablet contains 100 mg of posaconazole.

Other inactive ingredients are: hypromellose acetate succinate, microcrystalline cellulose, hyprolose, croscarmellose sodium, magnesium stearate, silicon dioxide, hypromellose, triacetin, Macrogol 400, titanium dioxide, purified talc, iron oxide red.

Sponsor

Dr Reddy’s Laboratories (Australia) Pty Ltd
Suite 3.03, Level 3, 390 St Kilda Road
Melbourne, Victoria, Australia
Phone: 1800 733 397

Australian Registration Number:

Modified Release Tablet AUST R 317443

This leaflet was prepared in January 2020.

Published by MIMS April 2021

BRAND INFORMATION

Brand name

Posaconazole Dr. Reddy's

Active ingredient

Posaconazole

Schedule

S4

 

1 Name of Medicine

Posaconazole.

2 Qualitative and Quantitative Composition

Each modified release tablet contains 100 mg of posaconazole.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Posaconazole Dr. Reddy's modified release tablet is a brown, capsule shaped, bevelled edge, film coated tablet, debossed with '470' on one side and plain on other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Posaconazole Dr. Reddy's (posaconazole) is indicated for use in the treatment of the following invasive fungal infections in patients 13 years of age or older:
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.
Posaconazole Dr. Reddy's is also indicated for the prophylaxis of invasive fungal infections among patients 13 years of age and older, 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

Posaconazole Dr. Reddy's Modified Release Tablets should be swallowed whole, and not be divided, crushed, or chewed. Posaconazole Dr. Reddy's Modified Release Tablets may be taken without regard to food intake.
Coadministration of drugs that can decrease the plasma concentrations of posaconazole should generally be avoided unless the benefit outweighs the risk. If such drugs are necessary, patients should be monitored closely for breakthrough fungal infections (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Administration instructions for Posaconazole Dr. Reddy's modified release tablets.

Refractory invasive fungal infections (IFI)/ intolerant patients with IFI.

Loading dose of 300 mg (three 100 mg modified release tablets) twice a day on the first day, then 300 mg (three 100 mg modified release tablets) once a day thereafter. Each dose may be taken without regard to food intake. Duration of therapy should be based on the severity of the underlying disease, recovery from immunosuppression, and clinical response.

Prophylaxis of invasive fungal infections.

Loading dose of 300 mg (three 100 mg modified release tablets) twice a day on the first day, then 300 mg (three 100 mg modified release tablets) once a day thereafter. Duration of therapy is based on recovery from neutropenia or immunosuppression.
Posaconazole Dr. Reddy's modified release tablets can be taken without regard to food intake.

Use in renal impairment.

No dose adjustment is required for renal dysfunction and as posaconazole is not significantly renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is not expected and no dose adjustment is recommended (see Section 5.2 Pharmacokinetic Properties). Due to variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

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

Use in paediatrics.

Safety and efficacy in adolescents and children below the age of 13 years have not been established.

Use in the elderly.

No dosage adjustment is recommended for elderly patients (see Section 5.2 Pharmacokinetic Properties).

4.3 Contraindications

Posaconazole 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

Identified precautions.

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.

In clinical trials, there were infrequent cases of hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis) during treatment with posaconazole. 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 1 for hepatic enzyme abnormalities in healthy volunteers.

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.

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

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 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 4.2 Dose and Method of Administration, Use in hepatic impairment; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Hepatic impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Use in renal impairment; Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Renal impairment.

Use in the elderly.

No dosage adjustment is recommended for geriatric patients (see Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Elderly).
Of the 230 patients treated with posaconazole modified release tablets, 38 (17%) were greater than 65 years of age. The pharmacokinetics of posaconazole modified release tablets are comparable in young and elderly subjects. No overall differences in safety were observed between the geriatric patients and younger patients; therefore, no dosage adjustment is recommended for geriatric patients.

Paediatric use.

(See Section 5.2 Pharmacokinetic Properties, Pharmacokinetics in special populations, Paediatric). Safety and effectiveness in paediatric patients below the age of 13 years have not been established. Clinical experience of posaconazole oral suspension in paediatric patients 13 - 17 years of age is very limited (n=16), therefore pharmacology, efficacy and safety profiles have not been completely characterised in children within this age group. Available data suggest a similar profile in children 13 - 17 years of age and adults.
Use of posaconazole modified release tablets in patients 13 to 17 years of age is supported by evidence from adequate and well-controlled studies of posaconazole oral suspension (available in other brands).

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

Posaconazole oral suspension is unavailable in this brand, however, is available in other brands. Information obtained using posaconazole oral suspension, including interactions, adverse effects, clinical trials and pharmacokinetics, is included in the following sections for prescriber information. See Table 2.
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. See below for further information.

Effect of other drugs on posaconazole.

Posaconazole is metabolised 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 oral suspension 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.

Posaconazole oral suspension: 20 mL single dose of liquid antacid, equivalent to 25.4 mEq acid neutralizing capacity/5 mL, had no clinically significant effect on posaconazole oral suspension Cmax and AUC. No dosage adjustments are required.
Posaconazole modified release tablet: No clinically relevant effects were observed when posaconazole modified release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole modified release tablets is required when posaconazole modified release tablets are concomitantly used with antacids, H2-receptor antagonists and proton pump inhibitors.

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, metabolised 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 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.

Repeat dose administration of oral posaconazole 200 mg or 400 mg twice daily with a high fat meal, significantly increased the midazolam Cmax by 2.2 fold (~7.03 to 15.4 nanogram/mL): AUC by approximately 5 fold (~31.9 to 159 h.nanogram/mL); and prolonged the mean terminal half-life of midazolam 8 to 10 hours in healthy subjects. It is recommended that dose adjustments of benzodiazepines, including midazolam metabolised by CYP3A4, be considered during coadministration with posaconazole.

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 metabolised 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 metabolised through CYP3A4 is contraindicated.
Interactions with HMG CoA reductase inhibitors that are not metabolised 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 metabolised 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 coadministration 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 had no effect on the fertility of male rats at doses up to 180 mg/kg/day (1.6 times the maximum recommended clinical dose (RCD) based on AUC at steady state in healthy volunteers fed a high fat meal). Like other azoles, male dogs administered oral posaconazole had findings consistent with reduced plasma testosterone levels, including spermatic giant cells (relative exposure 4.2). Posaconazole administered to female rats at doses up to 45 mg/kg/day (relative exposure 2.0) 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 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.
Posaconazole 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 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 oral suspension.

Drug-related adverse reactions observed in 2, 400 subjects dosed with posaconazole oral suspension are shown in Table 3. 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 4, 5, and 6.

Posaconazole modified release tablets.

In clinical trials, the type and frequency of adverse effects reported for posaconazole modified release tablets were generally similar to that reported in trials of posaconazole oral suspension.
The safety of posaconazole modified release tablets has been assessed in 230 patients in clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole modified release tablets when given as antifungal prophylaxis (P05615). Patients were immunocompromised with underlying conditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of patients were ≥ 65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 210 patients received 300 mg daily dose (following BD dosing on Day 1 in each cohort).
The most frequently reported treatment-related adverse reactions (≥ 5%) with posaconazole modified release tablets (300 mg once daily) were nausea and diarrhoea. The most frequently reported adverse reaction leading to discontinuation of posaconazole modified release tablets 300 mg once daily was nausea.
Table 7 presents treatment-emergent adverse reactions observed in patients treated with 300 mg daily dose at an incidence of ≥ 10% in posaconazole modified release tablet study.

Clinical laboratory values.

In (uncontrolled) trials of patients with invasive fungal infections treated with posaconazole 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 posaconazole 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 8 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 www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no experience with overdosage of posaconazole modified release tablets.
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.
There is no experience with overdosage of posaconazole modified release tablets.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Antiinfective 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 micro-organisms: (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.
Posaconazole 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 posaconazole 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 posaconazole 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 1x10-8 to 1x10-9. 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. Summary of posaconazole oral suspension studies.

Posaconazole oral suspension is unavailable in this brand, however, is available in other brands. Information obtained using Posaconazole oral suspension is included for prescriber information.
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 haematological 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 9, 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 non-meningeal 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.
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-randomisation 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-randomisation. 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 10 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 randomisation, 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. A total of 16 patients aged 8 to 17 years were included in the posaconazole oral suspension therapeutic trials of invasive fungal infections. Five patients were < 13 years of age and 11 were 13-17 years old. Infections included aspergillosis, candidiasis and fusariosis. Successful response after treatment with posaconazole at divided doses up to 800 mg/day was seen in 50% (8/16) of patients. Pharmacokinetic parameters obtained from 12 of these patients were not different from those obtained from the patients in the 18-65 year age group, and the safety profile appeared similar.
Additionally, 12 patients aged 13 to 17 years received 600 mg/day of posaconazole oral suspension for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these patients < 18 years of age appears to be similar to the safety profile observed in adults. Based on pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be similar to patients ≥ 18 years of age.
Safety and efficacy in paediatric patients below the age of 13 years have not been established.

Summary of posaconazole modified release tablet studies.

Study 5615 was a non-comparative multi-center study performed to evaluate the pharmacokinetic properties, safety, and tolerability of posaconazole modified release tablet. Study 5615 was conducted in a similar patient population to that previously studied in the pivotal posaconazole oral suspension clinical program. The pharmacokinetics and safety data from Study 5615 were bridged to the existing data (including efficacy data) with the oral suspension.
Study 5615 enrolled a total of 230 subjects. Part 1 of the study was designed to select a dose for further study in Part 2, after first evaluating pharmacokinetics, safety, and tolerability in the neutropenic patient population at high risk of a fungal infection. Part 2 of the study was designed to evaluate posaconazole modified release tablet in a more diverse patient population, and to confirm the exposure of posaconazole modified release tablet in additional subjects at risk of a fungal infection. Posaconazole modified release tablet was administered without regard to food intake in both Part 1 and Part 2 of the study.
The subject population for Part 1 included subjects with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) who had recently received chemotherapy and had developed or were anticipated to develop significant neutropenia. Two different dosing groups were evaluated in Part 1: 200 mg BD on Day 1, followed by 200 mg QD thereafter (Part 1A) and 300 mg BD on Day 1, followed by 300 mg QD thereafter (Part 1B).
The subject population in Part 2 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 Part 1, all subjects in Part 2 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 = 19-78 years), 93% were White, the major ethnicity was not Hispanic or Latino (84%), and 62% were male. The study treated 110 (48%) subjects with AML (new diagnosis), 20 (9%) subjects with AML (first relapse), 9 (4%) subjects with MDS, and 91 (40%) subjects with HSCT, as the primary diseases at study entry.
Serial PK samples were collected on Day 1 and at steady-state on Day 8 for all Part 1 subjects and a subset of Part 2 subjects. This serial PK analysis demonstrated that 90% of the subjects treated with the 300 mg QD dose attained steady state Cavg between 500-2500 nanogram/mL. [Cavg was the average concentration of posaconazole at steady state, calculated as AUC/dosing interval (24 hours).] 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 Cavg at steady state of 1580 nanogram/mL. The PK findings from the pivotal study (Study 5615) support a 300-mg daily dose of posaconazole modified release tablet for use in prophylaxis.

5.2 Pharmacokinetic Properties

Absorption.

Posaconazole oral suspension is absorbed with a median Tmax of 3 hours (patients) and ~ 5 hours (healthy volunteers). Intersubject variability in mean AUC and Cmax was high in healthy volunteers and patients despite the controlled conditions in pharmacokinetic studies. Steady-state is attained following 7 to 10 days of multiple-dose administration.
The pharmacokinetics of posaconazole are linear following single and multiple dose administration of up to 800 mg. No further increases in exposure are observed above a total daily dose of 800 mg in patients and healthy volunteers. There is no effect of altered pH on the absorption of posaconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Dividing the total posaconazole daily dose (800 mg) as 400 mg twice a day results in a 184% higher exposure relative to once-a-day administration in patients. Exposure further increased when posaconazole was given as 200 mg four times daily.
When given orally in healthy volunteers, posaconazole modified release tablets are absorbed with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 at the 300 mg dose (QD after BD loading dose at Day 1).
The absolute bioavailability of the oral modified release tablet is approximately 54%.
Relative bioavailability was investigated between the 100 mg modified release tablet under fasted conditions and the 100 mg oral suspension under fed conditions in healthy adults. Under these conditions, plasma exposure to posaconazole for the two treatments was similar.
Under fasted conditions, the exposure of posaconazole after single-dose modified release tablet administration was 3.7-fold higher than the oral suspension.

Effect of food on oral absorption in healthy volunteers.

The AUC of posaconazole oral suspension is about 2.6 times greater when administered with a nonfat meal or nutritional supplement (14 g fat) and 4 times greater when administered with a high-fat meal (~ 50 g fat) relative to the fasted state. Posaconazole oral suspension should be administered with food or a nutritional supplement.
In a single dose study (P112) investigating the effect of a high fat meal on the bioavailability of posaconazole following administration of posaconazole tablets 300 mg (3 x 100 mg) in healthy volunteers, the Cmax was 16% higher and the AUC0-72 hours was 51% higher with food relative to fasting. The results of the study are summarised in Table 11. The effect of food on the absorption of posaconazole modified release tablets is not considered clinically meaningful. Food effect was taken into consideration at the time of final dose selection of the 300 mg modified release tablet based on data from the pivotal clinical Phase 1b/Phase 3 pharmacokinetic/safety study P5615 in which patients took posaconazole modified release tablets without regard to food intake. Posaconazole modified release tablets can therefore be administered with or without food.

Distribution.

Posaconazole, after administration of the modified release tablet, has a mean apparent volume of distribution of 394 L (42% CV), ranging between 294-583 L among the studies in healthy volunteers.

Metabolism.

Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to be altered by inhibitors of CYP450 enzymes. 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.

Excretion.

Posaconazole modified release tablet is eliminated with a mean half-life (t1/2) ranging between 26 and 31 hours and a mean apparent clearance ranging from 7.5 to 11 L/hr.
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 general pharmacokinetic findings across the clinical program in both healthy volunteers and patients were consistent in that posaconazole oral suspension was slowly absorbed and slowly eliminated with an extensive volume of distribution. In addition, the phenomenon of dose-limited absorption of posaconazole at 800 mg/day was observed both in healthy volunteers and patients. The mean pharmacokinetic parameters in patients and healthy volunteers following administration of posaconazole 400 mg twice a day for 7 days are displayed in Table 12.
The exposure to posaconazole oral suspension following administration of 400 mg twice a day was ~ 3 times higher in healthy volunteers than in patients, without additional safety findings at the higher concentrations (Table 12).
The mean pharmacokinetic parameters in patients and healthy volunteers following administration of posaconazole modified release tablet 300 mg daily are displayed in Table 13. Patients have approximately 25% lower exposure as compared to healthy volunteers after multiple dosing of posaconazole modified release tablet.
Simulation based on the population pharmacokinetic model was performed in patients receiving posaconazole modified release tablet 300 mg daily (following 300 mg BD on Day 1). Simulated pharmacokinetics in patients and subpopulations of AML/MDS and HSCT patients are displayed in Table 14.
Coadministration of food, or medications known to alter gastric pH (antacid, ranitidine, esomeprazole) or motility (metoclopramide) shows no clinically meaningful effect on the pharmacokinetics of posaconazole when administered as a modified release tablet.
In Table 15 a comparison is shown of exposure (Cavg) in patients after administration of posaconazole modified release tablet and posaconazole oral suspension at therapeutic doses.

Pharmacokinetics in special populations.

Paediatric.

Following administration of 800 mg per day of posaconazole oral suspension as a divided dose for treatment of invasive fungal infections, mean trough plasma concentrations from 12 paediatric patients 8 - 17 years of age (776 nanogram/mL) were similar to concentrations from 194 patients 18 - 64 years of age (817 nanogram/mL). No pharmacokinetic data are available from paediatric patients less than 8 years of age. Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cavg) was comparable among ten adolescents (13 - 17 years of age) to Cavg achieved in adults (≥ 18 years of age).
Mean average steady-state plasma concentration was calculated for neutropenic paediatric patients aged between 11 months and 17 years treated with 12 mg/kg/day or 18 mg/kg/day of posaconazole oral suspension in two or three divided doses. Approximately 50% met the pre-specified target (Day 7 Cavg of 1200 nanogram/mL with acceptable range 500 nanogram/mL to 2500 nanogram/mL); 43% (30/70) of subjects fell below 500 nanogram/mL. In general, exposures tended to be closer to the target Day 7 Cavg in the older patients (7 to < 18 years n = 36) than in younger patients (2 to < 7 years; n = 33 and 3 to 23 months n = 1). (See Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Paediatric use.)

Gender.

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

Elderly.

Results from a multiple dose study of posaconazole oral suspension in healthy volunteers (N=48) indicated that at steady state, there was an increase in Cmax (26%) and AUC (29%) observed in elderly subjects (24 subjects ≥ 65 years of age) relative to younger subjects (24 subjects 18 - 45 years of age). A similar trend was observed in the clinical program based on a small proportion of elderly subjects ≥ 65 years of age (N=25 vs. 194 patients 18 - 64 years of age). However, in a population pharmacokinetic analysis (Study 1899), age did not influence the pharmacokinetics of posaconazole oral suspension. The safety profile of posaconazole oral suspension between the young and elderly patients was similar. Therefore no dose adjustment is required for age.

Race.

Results from a multiple dose study in healthy volunteers (n = 56) indicated that there was only a slight decrease (16%) in the AUC and Cmax of posaconazole oral suspension in Black subjects relative to Caucasian subjects, therefore, no dose adjustment for race is required.

Renal impairment.

Following single-dose administration of 400 mg of the oral suspension, there was no significant effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is required in patients with mild to moderate renal impairment. In subjects with severe renal impairment (eGFR: < 20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that in patients with normal renal function (eGFR: > 80 mL/min/1.73 m2); however, the range of the AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as compared to that in other renal groups (CV < 40%). Due to the variability in exposure, patients with severe renal impairment should be monitored closely for breakthrough fungal infections (see Section 4.2 Dose and Method of Administration).
Similar recommendations apply to posaconazole modified release tablets; however, a specific study has not been conducted with modified release tablets.

Hepatic impairment.

In a small number of subjects (n=12) studied with hepatic impairment (Child-Pugh class A, B or C) receiving 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 modified release tablets; however, a specific study has not been conducted with the posaconazole modified release tablets.

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 BD 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

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 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 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 oral suspension. The results of animal studies indicate little carcinogenic risk for posaconazole in clinical use.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hypromellose acetate succinate, hyprolose, croscarmellose sodium, microcrystalline cellulose, silicon dioxide, magnesium stearate, hypromellose, triacetin, purified talc, titanium dioxide, macrogol 400, iron oxide red.

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. Store in original container.

6.5 Nature and Contents of Container

Aluminium-Aluminium blister packs of 24 and 96 tablets.

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

Posaconazole is a white to off-white crystalline powder. It has a melting range of 164°C - 165°C and is insoluble in water.

Chemical structure.

The chemical structure, which possesses four chiral centres, two R and two S, and chemical name are illustrated below:
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.

171228-49-2.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Medicine.

Summary Table of Changes