Consumer medicine information

Cresemba

Isavuconazole

BRAND INFORMATION

Brand name

Cresemba

Active ingredient

Isavuconazole

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cresemba.

What is in this leaflet

This leaflet answers some common questions about CRESEMBA.

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 CRESEMBA against the benefits they expect it will have for you.

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

Read this leaflet carefully before taking CRESEMBA and keep this leaflet with the medicine. You may need to read it again.

What CRESEMBA is used for

This medicine used to treat fungal infections such as:

  • Invasive aspergillosis (as-pur-ji-losis), an infection caused by a fungus called Aspergillus (as-pur-jilus).
  • Mucormycosis (mu-cor-mi-cosis), an infection caused by a fungus called Mucorales (mu-cor-alus) where the treatment with amphotericin (am-fo-teri-cin) B is not appropriate.

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

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

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

This medicine is not addictive.

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

This medicine may affect your ability to drive a car or operate machinery. You may feel confused, tired or sleepy.

There is not enough information to recommend the use of this medicine for children under the age of 18 years.

Before you start to use it

When you must not take it

Do not take CRESEMBA if you have an allergy to:

  • any medicine containing isavuconazole (as isavuconazonium sulfate).
  • any of the ingredients listed at the end of this leaflet.
  • any other similar medicines such as ketoconazole, fluconazole, itraconazole, voriconazole or posaconazole .

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

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

  • ketoconazole (e.g. Nizoral), a medicine used to treat fungal infections.
  • ritonavir (e.g. Norvir, Kaletra), a medicine used to treat HIV infection where the dose is greater than 200 mg or more twice a day.
  • rifabutin (e.g. Mycobutin), an antibiotic used to treat tuberculosis.
  • rifampicin (e.g. Rifadin, Rimycin), a medicine used to treat tuberculosis and other infections.
  • carbamazepine (e.g. Tegretol), a medicine used to treat epilepsy.
  • long acting barbiturates such as phenobarbital, medicines used to treat severe insomnia and seizures.
  • phenytoin (e.g. Dilantin), a medicine used to treat epilepsy.
  • efavirenz (e.g. Stocrin) and etravine (e.g. Intelence), medicines used to treat HIV infection.
  • St. John's Wort, a herbal medicine.
  • nafcillin (e.g. Nafcil), a medicine used to bacterial infections.

Do not take this medicine if you have familial short QT syndrome (Disorder of the heart). It may cause your heart to beat irregularly.

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

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

Before you start to take it

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

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

  • heart problems
  • any problems affecting your liver
  • any problems affecting your kidneys

Your doctor should do blood tests to check your liver before you start and while you are having treatment with CRESEMBA.

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

Tell your doctor if you are breast-feeding. CRESEMBA should not be taken whilst breastfeeding, unless indicated by your doctor. Your doctor can discuss with you the risks and benefits involved.

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

Taking other medicines

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

Some medicines should not be taken with CRESEMBA. These include:

  • ketoconazole (e.g Nizoral), a medicine used to treat fungal infections.
  • ritonavir (e.g. Norvir, Kaletra), a medicine used to treat HIV infection where the dose is greater than 200 mg or more twice a day.
  • rifabutin (e.g. Mycobutin), an antibiotic used to treat tuberculosis.
  • rifampicin (e.g. Rifadin, Rimycin), a medicine used to treat tuberculosis and other infections.
  • carbamazepine (e.g. Tegretol), a medicine used to treat epilepsy.
  • long acting barbiturates such as phenobarbital, medicines used to treat severe insomnia and seizures.
  • phenytoin (e.g. Dilantin), a medicine used to treat epilepsy.
  • efavirenz (e.g. Stocrin) and etravine (e.g. Intelence), medicines used to treat HIV infection.
  • St. John's Wort, a herbal medicine used to treat depression.
  • nafcillin (e.g. Nafcil), a medicine used to bacterial infections.

Some medicines and CRESEMBA may interfere with each other. These include:

  • rufinamide (e.g. Banzel), a medicine used to treat seizures.
  • aprepitant (e.g. Emend), a medicine used to treat nausea and vomiting.
  • prednisone (e.g. Panafcort), a steroidal medicine use to treat a variety of conditions.
  • pioglitazone (e.g. Actos), a medicine use in the treatment of diabetes.
  • ciclosporin (e.g Sandimmun), sirolimus (e.g. Rapamune) and tacrolimus (e.g. Prograf), medicines used to prevent organ transplant rejection or to treat certain problems with the immune system.
  • digoxin (e.g. Lanoxin, Sigmaxin), medicine used to various heart conditions.
  • colchicine (e.g. Colgout), a medicine used in the treatment of gout.
  • dabigatran etexilate (e.g. Pradaxa), a medicine used in the treatment of blood clots (Deep Vein Thrombosis and Pulmonary Embolism).
  • clarithromycin (e.g. Klacid) used to treat bacterial infections.
  • saquinavir, indinavir, nevirapine, fosamprenavir, lopinavir/ritonavir combination (e.g. Invirase, Crixvan, Viramune, Kaletra, Telzir) used to treat HIV infection.
  • alfentanil, fentanyl (e.g. Rapifen, Fentora, Sublimaze, Actiq, Abstral), used to treat strong pain.
  • vincristine, vinblastine, used to treat cancer.
  • mycophenolate mofetil (e.g. Cellcept), used in transplant patients.
  • midazolam (e.g. Hypnovel), used to treat severe insomnia.
  • bupropion (e.g. Zyban) used for smoking cessation and to treat depression.
  • metformin (e.g. Diabex, Formet, Glucophage), a medicine used in the treatment of diabetes
  • daunorubicin (e.g. Cerubidine), cyclophosphamide (e.g. Endoxan), doxorubicin (e.g. Adriamycin), irinotecan (e.g. Campto), topotecan (e.g. Hycamtin) and mitoxantrone (e.g. Onkotrone), medicines used in treating cancer.
  • imatinib (e.g. Glivec) and lapatinib (e.g. Tyverb) medicines used in the treatment of cancer.
  • lovastatin (e.g. Mevacor), a medicine used in the treatment of high cholesterol (Hypercholesterolaemia).

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

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

How to take CRESEMBA

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

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

How much to take

Your doctor will tell you how much to take during the loading and maintenance phase.

Adults
The usual dose of CRESEMBA Capsules in adults is 200 mg (2 capsules) every 8 hours for 6 doses (First 48 hours - Starting Dose). Then 200 mg (2 capsules) ONCE daily thereafter (Usual Dose).

The usual dose of CRESEMBA IV Injection in adults is 200 mg (1 reconstituted vial, diluted further for IV infusion) every 8 hours for 6 doses (First 48 hours - Starting Dose). Then 200mg (1 reconstituted vial, diluted further for IV infusion) ONCE daily thereafter (Usual Dose).

How to take it

CRESEMBA needs to be taken regularly to be effective.

CRESEMBA Capsules

CRESEMBA can be taken with or without food.

CRESEMBA capsules should be swallowed whole with a full glass of water. Do not chew, crush, dissolve or open the capsules.

CRESEMBA IV Injection

CRESEMBA IV Injection is given as a slow injection into a vein (intravenous infusion). It must only be given by a doctor or trained nurse. It is a powder which is mixed with sterile water for injections and diluted further by your pharmacist, nurse or doctor.

When to take it

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

How long to take it

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

If you have weakened immune system or a difficult infection, you may need to be on CRESEMBA for longer periods of time (maybe longer than 6 months).

You doctor may switch you from CRESEMBA IV Injection to CRESEMBA Capsules once your condition improves.

Continue taking CRESEMBA for as long as your doctor tells you. Do not stop taking CRESEMBA because you are feeling better.

If you do not complete the full course prescribed by your doctor, the infection may not clear completely or your symptoms may return.

If you forget to take it

If it is nearly time to take your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

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

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

CRESEMBA IV Injection will be given to you under close medical supervision. It is unlikely that a dose would be missed.

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

If you take too much (overdose)

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

Symptoms of an overdose may include: headache, feeling dizzy, restless or sleepy, tingling, reduced sense of touch or sensation in the mouth, problems being aware of things, hot flushes, anxiety, joint pain, changes in the way things taste, dry mouth, diarrhoea, vomiting, feeling your heart beat, faster heart rate, being more sensitive to light.

While you are using CRESEMBA

Things you must do

Stop taking CRESEMBA and tell your doctor immediately if you develop: a rash or blisters, swelling of your lips, mouth, tongue or throat with difficulty breathing - these may be signs of an allergic reaction while taking CRESEMBA.

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

Make sure you follow your doctor's instructions and keep all appointments, including blood tests. Your doctor should monitor the function of your liver and kidneys using blood tests.

If you are about to be started on any medicine, remind your doctor and pharmacists who treat you that you are taking CRESEMBA.

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

If you become pregnant while taking this medicine, tell your doctor immediately.

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

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

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

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor. If you stop taking it suddenly or not complete the course as prescribed by your doctor, your condition may worsen or your symptoms may return.

Things to be careful of

Be careful driving or operating machinery until you know how CRESEMBA affects you. This medicine may cause confusion, tiredness and sleepiness in some people.

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

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking CRESEMBA.

This medicine helps most people with fungal infections, but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

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

Tell your doctor as soon as possible if you notice any of the following:

  • low potassium in your blood,
  • decreased appetite,
  • hallucinations (delirium),
  • headache,
  • sleepiness,
  • inflamed veins that could lead to blood clots,
  • shortness of breath or sudden and severe difficulty breathing
  • feeling sick (nausea), being sick (vomiting), diarrhoea, stomach pain,
  • changes in blood tests of liver function,
  • rash, itching,
  • kidney failure,
  • chest pain, feeling tired or sleepy.

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

  • reduced white blood cells - can increase your risk of infection and fever,
  • reduced blood cells called 'platelets' - can increase your risk for bleeding or bruising,
  • reduced red blood cells - can make you feel weak or short of breath or make your skin pale,
  • severe reduction in blood cells - can make you feel weak, cause bruising or make infections more likely,
  • rash, swelling of your lips, mouth, tongue or throat with difficulty breathing (hypersensitivity),
  • low blood sugar levels,
  • low blood levels of magnesium,
  • low levels in the blood of a protein called 'albumin',
  • not getting the right goodness from your diet (malnutrition),
  • depression, difficulty sleeping,
  • seizure, fainting or feeling faint, dizziness,
  • sensation of tingling, tickling, or pricking of the skin (paraesthesia),
  • altered mental state (encephalopathy),
  • changes in taste (dysgeusia),
  • feeling of 'spinning' or being dizzy (vertigo),
  • heart beat problems - may be too fast or uneven, or extra heart beats – this may show in your heart tracing (electrocardiogram or ECG),
  • problems with the blood circulation,
  • low blood pressure,
  • wheezing, very fast breathing, coughing up blood or blood-stained sputum, nose bleeding,
  • indigestion,
  • constipation,
  • feeling bloated (abdominal distension),
  • enlarged liver,
  • inflammation of the liver,
  • problems with the skin, red or purple spots on the skin (petechiae), inflamed skin (dermatitis), hair loss,
  • back pain,
  • feeling weak, very tired, or sleepy or generally out of sorts (malaise).

The above list includes serious side effects that may require medical attention.

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

  • swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing
  • sudden and severe difficulty breathing
  • fainting, confusion, seizures or fits
  • sudden or severe itching, skin rash, hives or blisters
  • signs of kidney failure such as tiredness, lack of appetite and reduced or greatly increased amount of urine

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

Tell your doctor if you notice any other side effects.

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

After using CRESEMBA

Storage

CRESEMBA Capsules

Keep your capsules in the original pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store CRESEMBA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep your medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

CRESEMBA IV Injection

CRESEMBA IV Injection will be stored in the pharmacy or on the hospital ward. It is kept in a refrigerator where the temperature stays between 2-8°C.

Disposal

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

Product description

What it looks like

CRESEMBA Capsules

CRESEMBA Capsules come in one strength, 100 mg.

The capsules have a reddish-brown body marked with '100' in black ink and a white cap marked with "C" in black ink.

CRESEMBA Capsules 100 mg are available in cartons that contain 14 capsules. Each carton contains 2 aluminium/aluminium blisters pack, with 7 capsules each.

Each capsule pocket is connected to a pocket that contains 'desiccant' to protect the capsule from moisture.

Do not puncture the blister containing the desiccant.

Do not swallow or use the desiccant.

CRESEMBA Powder for Injection

CRESEMBA IV comes as a white to yellow powder in a clear glass vial with a rubber stopper and an aluminium cap with a plastic seal which contains 200 mg isavuconazole.

Ingredients

Active Ingredients

CRESEMBA Capsules 100 mg contains 100 mg of isavuconazole (as 186.3 mg isavuconazonium sulfate) as the active ingredient.

CRESEMBA IV Injection 200 mg contains 200 mg of isavuconazole (as 372.6 mg isavuconazonium sulfate) as the active ingredient.

Inactive Ingredients

CRESEMBA Capsules 100 mg contains the following other ingredients:

Capsule Contents

  • magnesium citrate
  • microcrystalline cellulose
  • purified talc
  • colloidal anhydrous silica
  • stearic acid

Capsule Shell

  • hypromellose
  • purified water
  • iron oxide red (E172) (capsule body only)
  • titanium dioxide (E171)
  • gellan gum
  • potassium acetate
  • disodium edetate
  • sodium lauryl sulfate

Printing Ink

  • shellac
  • propylene glycol
  • potassium hydroxide
  • iron oxide black (E172)

CRESEMBA IV Injection 200 mg contains the following other ingredients:

  • mannitol
  • sulfuric acid (for pH-adjustment)

Supplier

CRESEMBA is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

Australian Registration Numbers

CRESEMBA Capsules 100 mg AUST R 305452

CRESEMBA IV Injection 200 mg AUST R 305480

Date of Preparation

This leaflet was prepared in January 2022

® = Registered Trademark

© Pfizer Australia Pty Ltd

Published by MIMS March 2022

BRAND INFORMATION

Brand name

Cresemba

Active ingredient

Isavuconazole

Schedule

S4

 

1 Name of Medicine

Isavuconazole (as isavuconazonium sulfate).

2 Qualitative and Quantitative Composition

Powder for injection.

Each vial contains 200 mg isavuconazole (as 372.6 mg isavuconazonium sulfate).

Capsules.

Each capsule contains 100 mg isavuconazole (as 186.3 mg isavuconazonium sulfate).
Each capsule contains 40 mg isavuconazole (as 74.5 mg isavuconazonium sulfate).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection.

Powder for injection; white to yellow powder for intravenous administration following reconstitution and dilution.

Capsules.

For oral administration.

100 mg.

Swedish orange (reddish-brown) capsule body marked with "100" in black ink and a white cap marked with "C" in black ink.

40 mg.

Swedish orange (reddish-brown) capsules marked with "CR40" on the capsule cap in black ink.

4 Clinical Particulars

4.1 Therapeutic Indications

Cresemba is indicated in adults and paediatric patients from 1 year of age for the treatment of invasive aspergillosis; mucormycosis in patients for whom amphotericin B is inappropriate (see Section 4.4 Special Warnings and Precautions for Use; Section 5.1 Pharmacodynamic Properties).
Consideration should be given to official guidance on the appropriate use of antifungal agents.

4.2 Dose and Method of Administration

Dosage.

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.
The recommended loading and maintenance dose for both the powder for injection and capsule formulations for adult and paediatric patients are shown in Table 1 and Table 2 respectively.
The maximum of any individual loading or daily maintenance dose to be administered to any paediatric patient is 200 mg isavuconazole.
All capsules per dose must be taken at the same time.
Paediatric patients from one year to below 6 years of age, or who have a bodyweight less than 16 kg or are not able to swallow Cresemba hard capsules may receive Cresemba as an intravenous infusion.
The use of Cresemba 100 mg capsules has not been studied in paediatric patients (see Section 4.4 Special Warnings and Precautions For Use).
The safety and efficacy of Cresemba in paediatric patients aged below 1 year has not been established.
Duration of therapy should be determined by the clinical response (see Section 5.1 Pharmacodynamic Properties).
For long-term treatment beyond 6 months, the benefit-risk balance should be carefully considered (see Section 5.1 Pharmacodynamic Properties; Section 5.3 Preclinical Safety Data).

Switching between powder for injection and capsule formulations.

Cresemba is available as powder for concentrate for solution for infusion containing 200 mg isavuconazole for adults and paediatric patients from 1 year of age.
Cresemba is also available as 40 mg and 100 mg hard capsules. Cresemba 40 mg hard capsules are intended for use for paediatric patients from 6 years of age and with body weight 16 kg or above. The use of Cresemba 40 mg hard capsules in adults is not indicated.
On the basis of the high oral bioavailability (98%, see Section 5.2 Pharmacokinetic Properties), switching between intravenous and oral administration is appropriate when clinically indicated.

Elderly.

No dose adjustment is necessary for elderly patients; however, the clinical experience in elderly patients is limited.

Renal impairment.

No dose adjustment is necessary in adult patients with renal impairment, including patients with end-stage renal disease (see Section 5.2 Pharmacokinetic Properties).
No data are available in paediatric patients with renal impairment.

Hepatic impairment.

No dose adjustment is necessary in adult patients with mild or moderate hepatic impairment (Child-Pugh Classes A and B) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Cresemba has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks. See Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties.
No data are available in paediatric patients with hepatic impairment.

Paediatric population.

No dose recommendation can be made for paediatric patients from 1 year of age with renal or hepatic impairment, since no data are available.
Paediatric patients from 6 years to less than 18 years of age and with a bodyweight at least 32 kg may receive Cresemba 100 mg capsules for ease of dosing. However, the use of Cresemba 100 mg capsules has not been studied in paediatric patients.
The safety and efficacy of isavuconazole in paediatric patients below 1 year of age has not been established.

Method of administration.

Powder for injection. Cresemba powder for injection must be reconstituted and then further diluted to a concentration corresponding to a range of 0.4 to 0.8 mg/mL isavuconazole prior to administration by intravenous infusion over a minimum of 1 hour to reduce the risk of infusion-related reactions. Higher concentrations should be avoided as these may cause local irritation at the site of infusion. The infusion must be administered via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) and with a pore size of 0.2 micrometer to 1.2 micrometer. Cresemba powder for injection must only be given as an intravenous infusion.

Reconstitution.

One vial of the powder for concentrate for solution for infusion should be reconstituted by addition of 5 mL water for injections to the vial. The reconstituted concentrate contains 40 mg isavuconazole per mL. The vial should be shaken to dissolve the powder completely. The reconstituted solution should be inspected visually for particulate matter and discolouration. Reconstituted concentrate should be clear and free of visible particulate. It must be further diluted prior to administration.

Dilution.

Adults and paediatric patients with bodyweight more than 37 kg:
After reconstitution, the entire content of the reconstituted concentrate should be removed from the vial and added to an infusion bag containing 250 mL of either sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) dextrose solution. The infusion solution contains approximately 1.5 mg/mL isavuconazonium sulfate (corresponding to approximately 0.8 mg isavuconazole per mL).
Paediatric patients with bodyweight 37 kg or less:
The final concentration of the infusion solution should be in the range of 0.4 to 0.8 mg isavuconazole per mL. Higher concentrations should be avoided as these may cause local irritation at the site of infusion.
To obtain the final concentration, the appropriate volume of the reconstituted concentrate based on paediatric dosing recommendations should be removed from the vial and added to an infusion bag containing the appropriate amount of diluent.
The appropriate volume of the infusion bag is calculated as follows:
[Required dose (mg)/final concentration (mg/mL)] - Volume of the concentrate (mL).
The concentrate can be diluted with either 9 mg/mL (0.9%) sodium chloride solution for injection or 50 mg/mL (5%) dextrose solution.

Administration.

After the reconstituted concentrate is further diluted, the diluted solution may show fine white-to-translucent particulates of isavuconazole, that do not sediment (but will be removed by in-line filtration). The diluted solution should be mixed gently, or the bag should be rolled to minimise the formation of particulates. Unnecessary vibration or vigorous shaking of the solution should be avoided.The solution for infusion must be administered via an infusion set with an in-line filter (pore size 0.2 micrometer to 1.2 micrometer) made of polyether sulfone (PES). Infusion pumps can be used and must be placed before the infusion set. Regardless of the infusion solution container size utilised, the entire volume of the container should be administered to ensure the complete intended dose of the product is administered.
Isavuconazole should not be infused into the same line or cannula concomitantly with other intravenous products.
Storage conditions after reconstitution and dilution are provided in Section 6.3 Shelf Life.
If possible, the intravenous administration of isavuconazole should be completed within 6 hours after reconstitution and dilution at room temperature. If this is not possible, the infusion solution should be immediately refrigerated after dilution, and infusion should be completed within 24 hours. Further information regarding the storage conditions after reconstitution and dilution of the medicinal product is provided in Section 6.3 Shelf Life.
An existing intravenous line should be flushed with sodium chloride 9 mg/mL (0.9%) solution for injection or 50 mg/mL (5%) dextrose solution.
The product is for single use in one patient only. Discard any residue.
Capsules. Cresemba capsules can be taken with or without food.
Cresemba capsules should be swallowed whole. Do not chew, crush, dissolve or open the capsules.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.
Coadministration with ketoconazole (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration with high dose ritonavir (> 200 mg every 12 hours) (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Coadministration with strong CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g. phenobarbital), phenytoin and St. John's wort or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Patients with familial short QT syndrome (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Hypersensitivity.

Hypersensitivity to isavuconazole may result in adverse reactions that include: anaphylactic reaction, hypotension, respiratory failure, dyspnoea, drug eruption, pruritus, and rash (see Section 4.8 Adverse Effects (Undesirable Effects)). In case of anaphylactic reaction, isavuconazole should be discontinued immediately and appropriate medical treatment should be initiated.
Caution should be used in prescribing isavuconazole to patients with hypersensitivity to other azole antifungal agents.

Infusion-related reactions.

During intravenous administration of isavuconazole, infusion-related reactions including hypotension, dyspnoea, dizziness, paraesthesia, nausea, and headache were reported (see Section 4.8 Adverse Effects (Undesirable Effects)). The infusion should be stopped if these reactions occur.

Severe cutaneous adverse reactions.

Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, have been reported during treatment with azole antifungal agents. If a patient develops a severe cutaneous adverse reaction, Cresemba should be discontinued.

Cardiovascular.

QT shortening.

Cresemba is contraindicated in patients with familial short QT syndrome (see Section 4.3 Contraindications).
In a QT study in healthy human subjects, isavuconazole shortened the QTc interval in a concentration-related manner. For the 200 mg dosing regimen, the least squares mean (LSM) difference from placebo was 13.1 ms at 2 hours postdose [90% CI: 17.1, 9.1 ms]. Increasing the dose to 600 mg resulted in an LSM difference from placebo of 24.6 ms at 2 hours postdose [90% CI: 28.7, 20.4 ms].
Caution is warranted when prescribing Cresemba to patients taking other medicinal products known to decrease the QT interval, such as rufinamide.

Elevated liver transaminases or hepatitis.

Elevated liver transaminases have been reported in clinical studies (see Section 4.8 Adverse Effects (Undesirable Effects)). The elevations in liver transaminases rarely required discontinuation of Cresemba. Monitoring of hepatic enzymes should be considered, as clinically indicated. Serious hepatic reactions have been reported. Evaluate liver-related laboratory tests at the start and during the course of Cresemba therapy.

Severe hepatic impairment.

Cresemba has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks. These patients should be carefully monitored for potential drug toxicity. See Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.2 Pharmacokinetic Properties.

Concomitant use with other medicinal products.

CYP3A4/5 inhibitors.

Ketoconazole is contraindicated (see Section 4.3 Contraindications). For the strong CYP3A4 inhibitor lopinavir/ritonavir, a twofold increase in isavuconazole exposure was observed. For other strong CYP3A4/5 inhibitors, a less pronounced effect can be expected. No dose adjustment of Cresemba is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactions may increase (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP3A4/5 inducers.

Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone, and pioglitazone, may result in mild to moderate decreases of isavuconazole plasma levels; co-administration with mild CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP3A4/5 substrates including immunosuppressants.

Isavuconazole can be considered a moderate inhibitor of CYP3A4/5, and systemic exposure to medicinal products metabolised by CYP3A4 may be increased when co-administered with Cresemba. Concomitant use of Cresemba with CYP3A4 substrates such as the immunosuppressants tacrolimus, sirolimus or ciclosporin may increase the systemic exposure to these medicinal products. Appropriate therapeutic drug monitoring and dose adjustment may be necessary during co-administration (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

CYP2B6 substrates.

Isavuconazole is an inducer of CYP2B6. Systemic exposure to medicinal products metabolised by CYP2B6 may be decreased when co-administered with Cresemba. Therefore, caution is advised when CYP2B6 substrates, especially medicinal products with a narrow therapeutic index such as cyclophosphamide, are co-administered with Cresemba. The use of the CYP2B6 substrate efavirenz with Cresemba is contraindicated because efavirenz is a moderate inducer of CYP3A4/5 (see Section 4.3 Contraindications).

P-gp substrates.

Isavuconazole may increase the exposure of medicinal products that are P-gp substrates. Dose adjustment of medicinal products that are P-gp substrates, especially medicinal products with a narrow therapeutic index such as digoxin, colchicine and dabigatran etexilate, may be needed when concomitantly administered with Cresemba (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Limitations of the clinical data.

The clinical data for isavuconazole in the treatment of mucormycosis are limited to one prospective non-controlled clinical study in 37 adult patients with proven or probable mucormycosis who received isavuconazole for primary treatment, or because other antifungal treatments (predominantly amphotericin B) were inappropriate.
For individual Mucorales species, the clinical efficacy data are very limited, often to one or two patients (see Section 5.1 Pharmacodynamic Properties). Susceptibility data were available in only a small subset of cases. These data indicate that concentrations of isavuconazole required for inhibition in vitro are very variable between genera/species within the order of Mucorales, and generally higher than concentrations required to inhibit Aspergillus species. It should be noted that there was no dose-finding study in mucormycosis, and patients were administered the same dose of isavuconazole as was used for the treatment of invasive aspergillosis.

Use in the elderly.

No data available.

Paediatric population.

Paediatric patients from 6 years to less than 18 years of age and with a bodyweight at least 32 kg may receive Cresemba 100 mg capsules. However, the use of Cresemba 100 mg capsules has not been studied in paediatric patients.
The safety and efficacy of Cresemba in paediatric patients aged below 1 year has not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects), Laboratory effects.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Potential of medicinal products to affect the pharmacokinetics of isavuconazole.

Isavuconazole is a substrate of CYP3A4 and CYP3A5 (see Section 5.2 Pharmacokinetic Properties). Co-administration of medicinal products which are inhibitors of CYP3A4 and/or CYP3A5 may increase the plasma concentrations of isavuconazole. Co-administration of medicinal products which are inducers of CYP3A4 and/or CYP3A5 may decrease the plasma concentrations of isavuconazole.

Medicinal products that inhibit CYP3A4/5.

Co-administration of Cresemba with the strong CYP3A4/5 inhibitor ketoconazole is contraindicated, since this medicinal product can significantly increase plasma concentrations of isavuconazole (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
For the strong CYP3A4 inhibitor lopinavir/ritonavir, a twofold increase in isavuconazole exposure was observed. For other strong CYP3A4 inhibitors, such as clarithromycin, indinavir and saquinavir, a less pronounced effect can be expected, based on their relative potency. No dose adjustment of Cresemba is necessary when co-administered with strong CYP3A4/5 inhibitors, however caution is advised as adverse drug reactions may increase (see Section 4.4 Special Warnings and Precautions for Use).
No dose adjustment is warranted for moderate to mild CYP3A4/5 inhibitors.

Medicinal products that induce CYP3A4/5.

Co-administration of Cresemba with potent CYP3A4/5 inducers such as rifampicin, rifabutin, carbamazepine, long-acting barbiturates (e.g. phenobarbital), phenytoin and St. John's wort, or with moderate CYP3A4/5 inducers such as efavirenz, nafcillin and etravirine, is contraindicated, since these medicinal products can significantly decrease plasma concentrations of isavuconazole (see Section 4.3 Contraindications).
Co-administration with mild CYP3A4/5 inducers such as aprepitant, prednisone and pioglitazone, may result in mild to moderate decreases of isavuconazole plasma levels; co administration with mild CYP3A4/5 inducers should be avoided unless the potential benefit is considered to outweigh the risk (see Section 4.4 Special Warnings and Precautions for Use).
Co-administration with high-dose ritonavir (> 200 mg twice daily) is contraindicated, as at high doses ritonavir may induce CYP3A4/5 and decrease isavuconazole plasma concentrations (see Section 4.3 Contraindications).

Potential for Cresemba to affect exposures of other medicines.

Medicinal products metabolised by CYP3A4/5.

Isavuconazole is a moderate inhibitor of CYP3A4/5; co-administration of Cresemba with medicinal products which are substrates of CYP3A4/5 may result in increased plasma concentrations of these medicinal products.

Medicinal products metabolised by CYP2B6.

Isavuconazole is a mild CYP2B6 inducer; co-administration of Cresemba may result in decreased plasma concentrations of CYP2B6 substrates.

Medicinal products transported by P-gp in the intestine.

Isavuconazole is a mild inhibitor of P-glycoprotein (P-gp); co-administration with Cresemba may result in increased plasma concentrations of P-gp substrates.

Medicinal products transported by BCRP.

Isavuconazole is an inhibitor in vitro of BCRP, and plasma concentrations of substrates of BCRP may therefore be increased. Caution is advised when Cresemba is given concomitantly with substrates of BCRP.

Medicinal products renally excreted via transport proteins.

Isavuconazole is a mild inhibitor of the organic cation transporter 2 (OCT2). Co-administration of Cresemba with medicinal products which are substrates of OCT2 may result in increased plasma concentrations of these medicinal products.

Uridine diphosphate-glucuronosyltransferases (UGT) substrates.

Isavuconazole is a mild inhibitor of UGT. Co-administration of Cresemba with medicinal products which are substrates of UGT may result in mildly increased plasma concentrations of these medicinal products.

Interaction table.

Interactions between isavuconazole and co-administered medicinal products are listed in Table 3 (increase is indicated as "↑", decrease as "↓"), ordered by therapeutic class. Unless otherwise stated, studies detailed in Table 3 have been performed in adults with the recommended dose of Cresemba.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no data on the effect of isavuconazole on human fertility. Oral administration of isavuconazonium sulfate did not affect the fertility in male or female rats treated at doses up to 90 mg/kg/day (less than a half the clinical dose based on AUC comparisons).
Cresemba is not recommended for women of childbearing potential who are not using contraception.
(Category D)
There are no data from the use of Cresemba in pregnant women. Isavuconazonium chloride administration was associated with dose-related increases in the incidences of rudimentary cervical ribs in rats and rabbits at 30 and 45 mg/kg, respectively, doses equivalent to about one fifth and one tenth of the clinical exposures based on AUC comparisons. In rats, dose-related increases in the incidences of zygomatic arch fusion and supernumerary ribs/rudimentary supernumerary ribs were also noted at 30 mg/kg and above, equivalent to one fifth the clinical dose based on AUC comparisons. The potential risk for humans is unknown.
Cresemba must not be used during pregnancy except in patients with severe or potentially life-threatening fungal infections, in whom isavuconazole may be used if the anticipated benefits outweigh the possible risks to the fetus.
 Intravenous administration of 14C-labelled isavuconazonium sulfate to lactating rats resulted in the recovery of radiolabel in the milk.
A risk to newborns and infants cannot be excluded.
Breast-feeding should be discontinued during treatment with Cresemba.

4.7 Effects on Ability to Drive and Use Machines

Isavuconazole has a moderate potential to influence the ability to drive and use machines. Patients should avoid driving or operating machinery if symptoms of confusional state, somnolence, syncope, and/or dizziness are experienced.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The frequency of adverse reactions shown in Table 4 is based on data from 403 patients with invasive fungal infections treated with Cresemba in phase 3 studies.
The most common treatment-related adverse reactions in adults were elevated liver chemistry tests (7.9%), nausea (7.4%), vomiting (5.5%), dyspnoea (3.2%), abdominal pain (2.7%), diarrhoea (2.7%), injection site reaction (2.2%), headache (2.0%), hypokalaemia (1.7%) and rash (1.7%).
The adverse reactions which most often led to permanent discontinuation of Cresemba treatment in adults were confusional state (0.7%), acute renal failure (0.7%), increased blood bilirubin (0.5%), convulsion (0.5%), dyspnoea (0.5%), epilepsy (0.5%), respiratory failure (0.5%) and vomiting (0.5%).

Tabulated list of adverse reactions.

Table 4 presents adverse reactions with isavuconazole in the treatment of invasive fungal infections in adults, by System Organ Class and frequency.
The frequency of adverse reactions is defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); and not known (frequency cannot be estimated from available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions.

Delirium includes reactions of confusional state.
Elevated liver chemistry tests includes events of alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood bilirubin increased, blood lactate dehydrogenase increased, gamma-glutamyltransferase increased, hepatic enzyme increased, hepatic function abnormal, hyperbilirubinaemia, liver function test abnormal, and transaminases increased.

Laboratory effects.

In a double-blind, randomised, active-controlled clinical study of 516 patients with invasive fungal disease caused by Aspergillus species or other filamentous fungi, elevated liver transaminases (alanine aminotransferase or aspartate aminotransferase) > 3 x upper limit of normal (ULN) were reported at the end of study treatment in 4.4% of patients who received Cresemba. Marked elevations of liver transaminases > 10 x ULN developed in 1.2% of patients on isavuconazole.
Table 5 includes selected treatment-emergent adverse reactions which were reported at an incidence of more than 5% during Cresemba therapy in study 9766-CL-0104 (invasive aspergillosis).

Paediatric population.

The clinical safety of isavuconazole was assessed in 77 paediatric patients who received at least one dose of intravenous or oral isavuconazole. This included 46 paediatric patients who received isavuconazole as a single dose and who also received other antifungals for prophylaxis, and 31 patients with suspected or confirmed invasive aspergillosis or mucormycosis who received isavuconazole as primary therapy for up to 181 days. Overall, the safety profile of isavuconazole in the paediatric population was similar to that in adults.

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/safety/reporting-problems.

4.9 Overdose

Symptoms.

Symptoms reported more frequently at supratherapeutic doses of Cresemba (equivalent to isavuconazole 600 mg/day) evaluated in a QT study than in the therapeutic dose group (equivalent to isavuconazole 200 mg/day dose) included: headache, dizziness, paraesthesia, somnolence, disturbance in attention, dysgeusia, dry mouth, diarrhoea, oral hypoaesthesia, vomiting, hot flush, anxiety, restlessness, palpitations, tachycardia, photophobia and arthralgia.

Management of overdose.

Isavuconazole is not removed by haemodialysis. There is no specific antidote for isavuconazole. In the event of an overdose, supportive treatment should be instituted.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole and tetrazole derivative, ATC code: J02AC05.

Mechanism of action.

Isavuconazonium sulfate is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazole inhibits the synthesis of ergosterol, a key component of the fungal cell membrane, through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14-alpha-demethylase. This enzyme is responsible for the conversion of lanosterol to ergosterol. An accumulation of methylated sterol precursors and a depletion of ergosterol within the fungal cell membrane weakens the membrane structure and function. Mammalian cell demethylation is less sensitive to isavuconazole inhibition.

Microbiology.

In animal models of disseminated and pulmonary aspergillosis, the pharmacodynamic (PD) index important in efficacy is exposure divided by minimum inhibitory concentration (MIC) (AUC/MIC).
No clear correlation between in vitro MIC and clinical response for the different species (Aspergillus and Mucorales) could be established.
Concentrations of isavuconazole required to inhibit Aspergillus species and genera/species of the order Mucorales in vitro have been very variable. Generally, concentrations of isavuconazole required to inhibit Mucorales are higher than those required to inhibit the majority of Aspergillus species.
Clinical efficacy has been demonstrated for the following Aspergillus species: Aspergillus fumigatus, A. flavus, A. niger, and A. terreus (see further below).

Drug resistance.

There is a potential for development of resistance to isavuconazole. The mechanism of resistance to isavuconazole, like other azole antifungals, is likely due to multiple mechanisms that include substitutions in the target gene CYP51. Changes in sterol profile and elevated efflux pump activity were observed, however, the clinical relevance of these findings is unclear. In vitro and animal studies suggest cross-resistance between isavuconazole and other azoles. The relevance of cross resistance to clinical outcome has not been fully characterized. However, patients failing prior azole therapy may require alternative antifungal therapy.

EUCAST breakpoints.

See Table 6.
There are currently insufficient data to set clinical breakpoints for other Aspergillus species or for any Mucorales species.

Clinical trials.

Treatment of invasive aspergillosis.

The safety and efficacy of isavuconazole for the treatment of adult patients with invasive aspergillosis were evaluated in a double-blind, active controlled clinical study in 516 patients with invasive fungal disease caused by Aspergillus species or other filamentous fungi. In the intent-to-treat (ITT) population, 258 patients received isavuconazole and 258 patients received voriconazole. Cresemba was administered intravenously (equivalent to 200 mg isavuconazole) every 8 hours for the first 48 hours, followed by once-daily intravenous or oral treatment (equivalent to 200 mg isavuconazole). The protocol-defined maximum treatment duration was 84 days. Median treatment duration was 45 days.
The overall response at end-of-treatment (EOT) in the myITT population (patients with proven and probable invasive aspergillosis based on cytology, histology, culture or galactomannan testing) was assessed by an independent blinded Data Review Committee. The myITT population comprised 123 patients receiving isavuconazole and 108 patients receiving voriconazole. The overall response in this population was n = 43 (35%) for isavuconazole and n = 42 (38.9%) for voriconazole. The adjusted treatment difference (isavuconazole-voriconazole) was -4.0 (95% confidence interval: -16.3, 8.4).
The all cause mortality at Day 42 in this population was 18.7% for isavuconazole and 22.2% for voriconazole. The adjusted treatment difference (isavuconazole-voriconazole) was -2.7% (95% confidence interval: -13.6, 8.2) (see Table 7).
Overall success at End-of-Treatment (EOT) was assessed by a blinded, independent Data Review Committee (DRC) using pre-specified clinical, mycological, and radiological criteria. In the subgroup of patients with proven or probable invasive aspergillosis confirmed by serology, culture or histology, overall success at EOT was seen in 35% of Cresemba-treated patients compared to 38.9% of voriconazole-treated patients (see Table 8).

Treatment of mucormycosis.

In an open-label non-controlled study, 37 adult patients with proven or probable mucormycosis received isavuconazole at the same dose regimen as that used to treat invasive aspergillosis. Median treatment duration was 84 days for the overall mucormycosis patient population, and 102 days for the 21 patients not previously treated for mucormycosis. For patients with probable or proven mucormycosis as defined by the independent Data Review Committee (DRC), all-cause mortality at Day 84 was 43.2% (16/37) for the overall patient population, 42.9% (9/21) for mucormycosis patients receiving isavuconazole as primary treatment, and 43.8% (7/16) for mucormycosis patients receiving isavuconazole who were refractory to, or intolerant of, prior antifungal therapy (mainly amphotericin B based treatments). The DRC assessed overall success rate at EOT was 11/35 (31.4%), with 5 patients considered completely cured and 6 patients partially cured. A stable response was observed in an additional 10/35 patients (28.6%). In 9 patients with mucormycosis due to Rhizopus spp., 4 patients showed a favourable response to isavuconazole. In 5 patients with mucormycosis due to Rhizomucor spp., no favourable responses were observed. The clinical experience in other species is very limited (Lichtheimia spp. n = 2, Cunninghamella spp. n = 1, Actinomucor elegans n = 1). Baseline risk factors are presented in Table 9.
Patients were treated with Cresemba intravenously or via oral administration at the recommended doses. Median treatment duration was 102 days for patients classified as primary, 33 days for refractory, and 85 days for intolerant (see Section 4.2 Dose and Method of Administration).
For patients with invasive mucormycosis, all-cause mortality through day 42 and success in overall response at the End-of-Treatment as assessed by the independent Data Review Committee is shown in Table 10. These results provide evidence that Cresemba is effective for the treatment for mucormycosis, in light of the natural history of untreated mucormycosis. However, the efficacy of Cresemba for the treatment for invasive mucormycosis has not been evaluated in concurrent, controlled clinical trials.

5.2 Pharmacokinetic Properties

Isavuconazonium sulfate is a water-soluble prodrug that can be administered as an intravenous infusion or orally as hard capsules. Following administration, isavuconazonium sulfate is rapidly hydrolysed by plasma esterases to the active moiety isavuconazole; plasma concentrations of the prodrug are very low, and detectable only for a short time after intravenous dosing.

Absorption.

Following oral administration of Cresemba in healthy adult subjects, the active moiety isavuconazole is absorbed and reaches maximum plasma concentrations (Cmax) approximately 2-3 hours after single and multiple dosing (see Table 11).
As shown in Table 12, the absolute bioavailability of isavuconazole following oral administration of a single dose of Cresemba is 98%. Based on these findings, intravenous and oral dosing can be used interchangeably.

Effect of food on absorption.

Oral administration of Cresemba equivalent to 400 mg isavuconazole with a high-fat meal reduced isavuconazole Cmax by 9% and increased AUC by 9%. Cresemba can be taken with or without food.

Distribution.

Isavuconazole is extensively distributed, with a mean steady state volume of distribution (Vss) of approximately 450 L. Isavuconazole is highly bound (> 99%) to human plasma proteins, predominantly to albumin.

Metabolism.

In vitro/ in vivo studies indicate that CYP3A4, CYP3A5, and subsequently uridine diphosphate-glucuronosyltransferases (UGT), are involved in the metabolism of isavuconazole.
Following single doses of [cyano-14C] isavuconazonium and [pyridinylmethyl-14C] isavuconazonium sulfate in humans, in addition to the active moiety (isavuconazole) and the inactive cleavage product, a number of minor metabolites were identified. Except for the active moiety isavuconazole, no individual metabolite was observed with an AUC > 10% of total radio labelled material.

Excretion.

Following oral administration of radio-labelled isavuconazonium sulfate to healthy subjects, a mean of 46.1% of the radioactive dose was recovered in faeces, and 45.5% was recovered in urine.
Renal excretion of intact isavuconazole was less than 1% of the dose administered.
The inactive cleavage product is primarily eliminated by metabolism and subsequent renal excretion of the metabolites.

Linearity/non-linearity.

Studies in healthy subjects have demonstrated that the pharmacokinetics of isavuconazole are proportional up to 600 mg per day.

Pharmacokinetics in special populations.

Paediatric patients.

The paediatric dosage regimens were confirmed using a population pharmacokinetic (popPK) model developed using data from three clinical studies (N = 97); this included two clinical studies (N = 73) conducted in paediatric patients aged 1 to < 18 years, of whom 31 received isavuconazole for treating invasive aspergillosis or mucormycosis.
The predicted exposures to isavuconazole for paediatric patients at steady-state based on different age groups, weight, route of administration, and dose are shown in Table 13.
The predicted exposures for paediatric patients, regardless of route of administration and age group, were comparable to exposures at steady-state (AUCss) from a clinical study conducted in adult patients with infections caused by Aspergillus species and other filamentous fungi (mean AUCss = 101.2 h.mg/L with standard deviation (SD) = 55.9, see Table 13).
The predicted exposures under the paediatric dosing regimen were lower than the exposures of adults who received multiple daily supratherapeutic doses of 600 mg isavuconazole (Table 11), where there was a greater occurrence of adverse events (see Section 4.9 Overdose).

Renal impairment.

No clinically relevant changes were observed in the total Cmax and AUC of isavuconazole in adult patients with mild, moderate or severe renal impairment compared to subjects with normal renal function. Of the 403 patients who received Cresemba in the Phase 3 studies, 79 (20%) of patients had an estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2. No dose adjustment is required in patients with renal impairment, including those patients with end-stage renal disease. Isavuconazole is not readily dialysable (see Section 4.2 Dose and Method of Administration).
No data are available in paediatric patients with renal impairment (see Section 4.2 Dose and Method of Administration).

Hepatic impairment.

After a single 100 mg dose of isavuconazole was administered to 32 adult patients with mild (Child-Pugh Class A) hepatic insufficiency and 32 patients with moderate (Child-Pugh Class B) hepatic insufficiency (16 intravenous and 16 oral patients per Child-Pugh class), the least square mean systemic exposure (AUC) increased 64% in the Child-Pugh Class A group, and 84% in the Child-Pugh Class B group, relative to 32 age- and weight-matched healthy subjects with normal hepatic function. Mean plasma concentrations (Cmax) were 2% lower in the Child-Pugh Class A group and 30% lower in the Child-Pugh Class B group. The population pharmacokinetic evaluation of isavuconazole in healthy subjects and patients with mild or moderate hepatic dysfunction demonstrated that the mild and moderate hepatic impairment populations had 40% and 48% lower isavuconazole clearance (CL) values, respectively, than the healthy population.
No dose adjustment is required in adult patients with mild to moderate hepatic impairment.
Cresemba has not been studied in adult patients with severe hepatic impairment (Child-Pugh Class C). Use in these patients is not recommended unless the potential benefit is considered to outweigh the risks. See Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use.
No data are available in paediatric patients with hepatic impairment (see Section 4.2 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Isavuconazole has no discernible mutagenic or genotoxic potential. Isavuconazole was negative in a bacterial reverse mutation assay, was weakly clastogenic at cytotoxic concentrations in the L5178Y tk+/- mouse lymphoma chromosome aberration assay, and showed no biologically relevant or statistically significant increase in the frequency of micronuclei in an in vivo rat micronucleus test.

Carcinogenicity.

Isavuconazole has demonstrated carcinogenic potential in liver, thyroid, skin and endometrium when administered to rodents in long term (2 years) carcinogenicity studies.
Hepatocellular adenomas and carcinomas were noted in mice and rats, and thyroid follicular cell adenomas and carcinomas in rats at exposures below the clinical exposure at the maintenance dose of 200 mg isavuconazole, based on AUC. This pattern of tumours is known to result from prolonged hepatocellular enzyme induction in rodents, and is considered an adaptive response that is not relevant to humans.
A significant increase in the incidence of skin fibromas was noted in male rats (exposure below the clinical exposure based on AUC) but not in female rats or mice. Similarly, the incidence of uterine adenocarcinoma was significantly increased in rats (but not mice) at exposure below the clinical exposure. Given that these findings occurred in only one sex (fibromas) or one species (uterine carcinomas) after close to lifetime exposure, and the limited treatment duration in patients, the carcinogenic risk in humans for these tumours is considered low.

Juvenile animal studies.

Isavuconazonium sulfate, when administered to juvenile rats, demonstrated a similar toxicological profile to that observed in adult animals. In juvenile rats, treatment-related toxicity considered rodent specific was observed in the liver (increased liver weights and hepatocellular hypertrophy at ≥ 30 mg/kg (0.19-0.37-times the exposure at MRHD). Effects on the adrenal glands (increases in adrenal weights in female rats), thyroid (increased thyroid gland weight and thyroid follicular cell hypertrophy/hyperplasia) and blood and lymphatic system (anaemia and prolongation of activated partial thromboplastin time in female rats) was observed at 90 mg/kg (0.4-0.5-times the exposure at MRHD). The thyroid effects are considered rodent-specific and not clinically relevant. Based on the no-observed-adverse-effect level in juvenile rats, the safety margins for isavuconazonium sulfate were approximately 0.2 to 0.4-fold the systemic exposure at the clinical maintenance dose for paediatric patients, similar to those observed in adult rats.

6 Pharmaceutical Particulars

6.1 List of Excipients

Powder for injection.

Mannitol, sulfuric acid (for pH-adjustment).

Capsules.

Capsule contents 100 mg and 40 mg.

Magnesium citrate, microcrystalline cellulose, purified talc, colloidal anhydrous silica, stearic acid.

Capsule shell 100 mg.

Hypromellose, iron oxide red (capsule body only), titanium dioxide, gellan gum, potassium acetate, disodium edetate, sodium lauryl sulfate.

Capsule shell 40 mg.

Hypromellose, iron oxide red, titanium dioxide.

Printing ink 100 mg and 40 mg.

Shellac, propylene glycol, strong ammonia solution, potassium hydroxide, iron oxide black.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Powder for injection.

Unopened vials.

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.

Reconstituted solution.

Chemical and physical in-use stability after reconstitution and dilution has been demonstrated for 24 hours at 2°C to 8°C, or 6 hours at room temperature.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2°C to 8°C.

Capsules.

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

Powder for injection.

Unopened vials: Store in a refrigerator (2°C to 8°C).
For storage conditions after reconstitution and dilution of the medicinal product, see Section 6.3 Shelf Life.

Capsules.

Store below 25°C. Store in the original packaging in order to protect from moisture.

6.5 Nature and Contents of Container

Powder for injection.

One 10 mL Type I glass vial with teflon coated butyl rubber stopper and an aluminium flip-off cap with plastic seal.

Capsules.

100 mg: 14 hard capsules (in two aluminium/aluminium blisters), with each capsule pocket connected to a pocket with desiccant.
40 mg: 35 hard capsules (in seven aluminium/aluminium blisters), with each capsule pocket connected to a pocket with desiccant.

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

Cresemba contains isavuconazonium sulfate, which is the prodrug of isavuconazole, an azole antifungal drug. Isavuconazonium sulfate drug substance is an amorphous, white to yellowish-white powder. The chemical name of isavuconazonium sulfate is 1-{(2R,3R)-3-[4-(4-Cyanophenyl)-1,3-thiazol-2-yl]-2-(2,5-difluorophenyl)-2-hydroxybutyl}-4-[(1RS)-1-({methyl[3-({[(methylamino)acetyl]oxy}methyl)pyridin-2-yl]carbamoyl}oxy)ethyl]-1H-1,2,4-triazol-4-ium monosulfate. The empirical formula is C35H35F2N8O5S.HSO4, the molecular weight is 814.84.

Chemical structure.


CAS number.

946075-13-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4 Prescription Only Medicine.

Summary Table of Changes