NOXAFIL 300 MG CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the User

Noxafil 300 mg concentrate for solution for infusion

posaconazole

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

1. What is Noxafil and what is it used for
2. What you need to know before you use Noxafil
3. How to use Noxafil
4. Possible side effects
5. Storage of Noxafil
6. Contents of the pack and other information

1. What is Noxafil and what is it used for

Noxafil contains a medicine called posaconazole, which belongs to a group of medicines called “antifungals”. Noxafil is used to prevent and treat many different fungal infections.

Noxafil works by killing or stopping the growth of some types of fungi that can cause infections.

Noxafil can be used in adults to treat fungal infections caused by fungi of the Aspergillusfamily.

Noxafil can be used in adults and children from 2 years of age to treat the following types of fungal infections:

• infections caused by fungi of the Aspergillusfamily that have not improved during treatment with the antifungal medicines amphotericin B or itraconazole, or when treatment with these medicines has had to be stopped;
• infections caused by fungi of the Fusariumfamily that have not improved during treatment with amphotericin B, or when treatment with amphotericin B has had to be stopped;
• infections caused by fungi that cause diseases known as “chromoblastomycosis” and “mycetoma” that have not improved during treatment with itraconazole, or when treatment with itraconazole has had to be stopped;

• infections caused by a fungus called Coccidioidesthat have not improved during treatment with one or more medicines, amphotericin B, itraconazole or fluconazole, or when treatment with these medicines has had to be stopped.

Noxafil can also be used to prevent fungal infections in adults and children from 2 years of age who are at high risk of getting a fungal infection, such as:

• patients who have a weakened immune system as a result of having received chemotherapy for "acute myelogenous leukaemia" (AML) or "myelodysplastic syndromes" (MDS)

• patients who are receiving "high-dose immunosuppressive treatment" after a "haematopoietic stem cell transplant" (HSCT).

2. What you need to know before you use Noxafil

Do not use Noxafil

• if you are allergic to posaconazole or any of the other ingredients of this medicine (listed in section 6).

• if you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, any medicine that contains "ergot alkaloids", such as ergotamine or dihydroergotamine, or a "statin", such as simvastatin, atorvastatin or lovastatin.
• if you have recently started taking venetoclax or your dose of venetoclax is being slowly increased for the treatment of chronic lymphocytic leukaemia (CLL).

Do not use Noxafil if you are in any of the above situations. If in doubt, consult your doctor or pharmacist before taking Noxafil.

See the section “Using Noxafil with other medicines” below for information about other medicines that may interact with Noxafil.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you start taking Noxafil if:

• you have had an allergic reaction to another antifungal medicine, such as ketoconazole, fluconazole, itraconazole or voriconazole.
• you have or have had liver problems. You may need to have blood tests while you are taking Noxafil.
• you have a heart rhythm problem (ECG) that shows a problem called QTc interval prolongation.
• you have a weak heart or heart failure.
• you have a very slow heart rate.
• you have any heart rhythm problems.

• you have any problems with the levels of potassium, magnesium or calcium in your blood.
• you are taking vincristine, vinblastine and other "vinca alkaloids" (medicines used to treat cancer).
• you are taking venetoclax (a medicine used to treat cancer).

You should avoid exposure to the sun while you are being treated. It is important to cover areas of skin that are exposed to the sun with protective clothing and to use a sunscreen with a high sun protection factor (SPF), as you may get more sensitive to the UV rays of the sun.

If you are in any of the above situations (or if in doubt), talk to your doctor, pharmacist or nurse before using Noxafil.

Children

Noxafil should not be given to children under 2 years of age.

Using Noxafil with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

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

• terfenadine (used to treat allergies)
• astemizole (used to treat allergies)
• cisapride (used to treat stomach problems)
• pimozide (used to treat symptoms of Tourette's syndrome and mental illnesses)
• halofantrine (used to treat malaria)
• quinidine (used to treat heart rhythm problems).

Noxafil may increase the levels of these medicines in your blood, which could cause serious changes to your heart rhythm.

• any medicine that contains "ergot alkaloids", such as ergotamine or dihydroergotamine, used to treat migraines. Noxafil may increase the levels of these medicines in your blood, which could cause a serious reduction in blood flow to your fingers or toes and damage them.

• a "statin", such as simvastatin, atorvastatin or lovastatin, used to treat high cholesterol levels.
• venetoclax when used at the start of treatment for a type of cancer, chronic lymphocytic leukaemia (CLL).

Do not take Noxafil if you are in any of the above situations. If in doubt, consult your doctor or pharmacist before taking Noxafil.

Other medicines

See the list above of medicines that you should not use while taking Noxafil. In addition to the medicines mentioned above, there are other medicines that may increase the risk of heart rhythm problems, which may be greater when taken with posaconazole. Make sure you tell your doctor about all the medicines you are taking (with or without a prescription).

Some medicines may increase the risk of side effects of Noxafil by increasing the levels of Noxafil in your blood.

The following medicines may reduce the effectiveness of Noxafil by reducing its levels in the blood:

• rifabutin and rifampicin (used to treat certain infections). If you are already taking rifabutin, you will need to have a blood test, as well as be aware of some possible side effects of rifabutin.
• phenytoin, carbamazepine, phenobarbital or primidone (used to treat or prevent seizures).
• efavirenz and fosamprenavir, used to treat HIV infection.
• flucloxacillin (an antibiotic used to treat bacterial infections).

Noxafil may increase the levels of other medicines in your blood, which could increase the risk of side effects of these medicines. These medicines include:

• vincristine, vinblastine and other "vinca alkaloids" (used to treat cancer)
• venetoclax (used to treat cancer)
• ciclosporin (used during or after transplants)
• tacrolimus and sirolimus (used during or after transplants)
• rifabutin (used to treat certain infections)
• medicines used to treat HIV called protease inhibitors (including lopinavir and atazanavir, which are given with ritonavir)
• midazolam, triazolam, alprazolam or other "benzodiazepines" (used as sedatives or muscle relaxants)
• diltiazem, verapamil, nifedipine, nisoldipine or other "calcium channel blockers" (used to treat high blood pressure)
• digoxin (used to treat heart failure)
• glipizide or other "sulphonylureas" (used to treat high blood sugar levels)
• all-trans retinoic acid (ATRA), also called tretinoin (used to treat some blood cancers).

If you are in any of the above situations (or if in doubt), talk to your doctor or pharmacist before taking Noxafil.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant or think you might be pregnant before you start taking Noxafil. Do not use Noxafil if you are pregnant unless your doctor tells you to.

If you are a woman who can become pregnant, you must use effective contraception while you are taking Noxafil. If you become pregnant while taking Noxafil, contact your doctor immediately.

Do not breast-feed while you are taking Noxafil, as small amounts may pass into breast milk.

Driving and using machines

You may feel dizzy, sleepy or have blurred vision while you are taking Noxafil, which may affect your ability to drive or use tools or machines. If this happens, do not drive or use any tools or machines and contact your doctor.

Noxafil contains sodium

The maximum recommended daily dose of this medicine contains 924 mg of sodium (found in table salt). This is equivalent to 46% of the maximum recommended daily intake of sodium for an adult.

Consult your doctor or pharmacist if you need Noxafil 300 mg concentrate for solution for infusion or more than one dose per day for a long time, especially if you have been advised to follow a low-salt (sodium) diet.

Noxafil contains cyclodextrin

This medicine contains 6,680 mg of cyclodextrin per vial.

3. How to use Noxafil

Follow exactly the instructions given to you by your doctor or pharmacist. If you are not sure, talk to your doctor or pharmacist again.

The recommended dose for adults is 300 mg twice a day on the first day and then 300 mg once a day.

The recommended dose for children from 2 years to less than 18 years is 6 mg/kg up to a maximum of 300 mg twice a day on the first day and then 6 mg/kg up to a maximum of 300 mg once a day.

Your pharmacist or nurse will dilute Noxafil concentrate for solution for infusion to the correct concentration.

Noxafil concentrate for solution for infusion will always be prepared and given to you by a healthcare professional.

You will be given Noxafil:

• through a plastic tube inserted into a vein (intravenous infusion)
• usually over 90 minutes

The length of treatment may depend on the type of infection you have or the length of time your immune system is not working properly, and may be adjusted individually for you by your doctor. Do not change your dose yourself before talking to your doctor, or change your treatment schedule.

If you miss a dose of Noxafil

Since this medicine is given under close medical supervision, it is unlikely that you will miss a dose. However, if you think you may have missed a dose, tell your doctor or pharmacist.

If your doctor stops your treatment with Noxafil, you should not experience any effects.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

Severe Adverse Effects

Inform your doctor, pharmacist, or nurse immediately if you notice any of the following severe adverse effects; you may need urgent medical treatment:

• nausea or vomiting (feeling or being sick), diarrhea

• signs of liver problems, including yellowing of the skin or whites of the eyes, unusually dark urine or pale stools, feeling sick without apparent reason, stomach problems, loss of appetite or unusual fatigue or weakness, elevated liver enzymes detected in blood tests

• allergic reaction

Other Adverse Effects

Inform your doctor, pharmacist, or nurse if you notice any of the following adverse effects:

Frequent: the following may affect up to 1 in 10 patients

• a change in blood salt levels detected in blood tests, whose signs include a feeling of confusion or weakness

• abnormal sensations in the skin, such as numbness, tingling, itching, crawling, pinching, or burning
• swelling, redness, and pain along the vein where Noxafil was administered
• headache
• low potassium levels, detected in blood tests
• low magnesium levels, detected in blood tests
• high blood pressure

• loss of appetite, stomach pain or stomach discomfort, flatulence, dry mouth, changes in taste
• heartburn (a burning sensation in the chest that rises to the throat)
• low levels of "neutrophils", a type of white blood cell (neutropenia), which can make you more prone to infections and are detected in blood tests

• fever
• feeling of weakness, dizziness, fatigue, or somnolence

• rash
• itching
• constipation
• rectal discomfort

Infrequent: the following may affect up to 1 in 100 patients

• anemia, whose signs include headaches, feeling of fatigue or dizziness, difficult breathing, or paleness and low hemoglobin levels detected in blood tests
• low platelet levels (thrombocytopenia), detected in blood tests. This can cause bleeding
• low levels of "leukocytes", a type of white blood cell (leukopenia), detected in blood tests. This can make you more susceptible to infections
• high levels of "eosinophils", a type of white blood cell (eosinophilia). This can appear if you have an inflammatory process
• inflammation of blood vessels
• heart rhythm problems
• seizures (convulsions)
• nerve damage (neuropathy)
• abnormal heart rhythm, detected in an electrocardiogram (ECG), palpitations, slow or fast heartbeat, high or low blood pressure
• low blood pressure
• inflammation of the pancreas (pancreatitis). This can cause severe stomach pain
• interruption of oxygen supply to the spleen (splenic infarction), which can cause severe stomach pain
• severe kidney problems, whose signs include increased or decreased urination with urine of a different color than usual
• high blood creatinine levels, detected in blood tests
• cough, hiccups
• nasal bleeding
• sharp and intense chest pain when breathing (pleuritic pain)
• inflammation of the lymph nodes (lymphadenopathy)
• decreased sensitivity, especially in the skin
• tremors
• high or low blood sugar levels
• blurred vision, sensitivity to light
• hair loss (alopecia)
• mouth ulcers
• chills, feeling of discomfort
• pain, back pain or neck pain, pain in arms or legs
• fluid retention (edema)
• menstrual problems (abnormal vaginal bleeding)
• inability to sleep (insomnia)
• inability to speak totally or partially
• mouth swelling
• abnormal dreams or sleep problems
• coordination or balance problems
• mucosal inflammation
• nasal congestion
• breathing difficulties
• chest discomfort
• feeling bloated
• nausea, vomiting, cramps, and diarrhea from mild to severe, usually caused by a virus, stomach pain
• belching
• feeling of restlessness
• inflammation or pain at the injection site

Rare: the following may affect up to 1 in 1,000 patients

• pneumonia, whose signs include shortness of breath and production of discolored phlegm
• high blood pressure in the blood vessels of the lungs (pulmonary hypertension), which can cause serious damage to the lungs and heart
• blood problems such as unusual blood clotting or prolonged bleeding
• severe allergic reactions, including widespread skin rash with blisters and skin peeling
• mental problems, such as hearing voices or seeing things that are not there
• fainting
• problems thinking or speaking, sudden movements, especially in your hands, that you cannot control
• stroke, whose signs include pain, weakness, numbness, or tingling in the limbs
• presence of a blind spot or dark spot in the field of vision
• heart failure or heart attack, which can cause cardiac arrest and death, heart rhythm problems with sudden death
• blood clots in the legs (deep vein thrombosis), whose signs include intense pain or swelling of the legs
• blood clots in the lungs (pulmonary embolism), whose signs include shortness of breath or pain when breathing
• bleeding in the stomach or intestine, whose signs include vomiting blood or blood in the stool
• intestinal blockage (intestinal obstruction), especially of the "ileum". This blockage prevents the contents of the intestine from passing through the colon and whose signs include feeling bloated, vomiting, severe constipation, loss of appetite, and cramps
• "hemolytic uremic syndrome" that appears when there is destruction of red blood cells (hemolysis), which can occur with or without kidney failure
• "pancytopenia", low levels of all blood cells (red, white, and platelets), detected in blood tests
• large purple spots on the skin (thrombocytopenic purpura)
• inflammation of the face or tongue
• depression
• double vision
• breast pain
• inadequate functioning of the adrenal glands, which can cause weakness, fatigue, loss of appetite, skin discoloration
• inadequate functioning of the pituitary gland, which can cause low blood levels of some hormones that affect the function of male or female sexual organs
• hearing problems
• pseudoaldosteronism, which causes high blood pressure with low potassium levels (appears in blood tests)

Frequency not known: cannot be estimated from available data

• some patients have also reported feeling confused after taking Noxafil

• skin redness

Inform your doctor, pharmacist, or nurse if you experience any of the adverse effects described above.

Adverse Effect Reporting

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Noxafil

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date that appears on the label after CAD. The expiration date is the last day of the month indicated.

Store in the refrigerator (between 2°C and 8°C).

Once prepared, the medicine must be used immediately. If not used immediately, the solution can be stored for up to 24 hours between 2°C and 8°C (in the refrigerator). This medicine is for single use and any unused solution must be discarded.

Medicines should not be thrown down the drain or into the trash. Ask your pharmacist how to dispose of the packaging and medicines that are no longer needed. This will help protect the environment.

6. Package Contents and Additional Information

Noxafil Composition

• The active ingredient is posaconazole. Each vial contains 300 mg of posaconazole.
• The other components are: sulfobutyl ether beta-cyclodextrin sodium (SBECD), disodium edetate, hydrochloric acid (concentrated), sodium hydroxide, water for injectable preparations.

Product Appearance and Package Contents

Noxafil concentrated solution for infusion is a clear, colorless to yellow liquid. Color variations within this range do not affect the quality of the medicine.

This medicine is available in a single-use glass vial closed with a bromobutyl rubber stopper and an aluminum cap.

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Revision of this Prospectus:<{MM/AAAA}><{mes AAAA}>.

Other Sources of Information

Detailed information about this medicine is available on the European Medicines Agency website: https://www.ema.europa.eu.

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This information is intended only for healthcare professionals:

Instructions for Administration of Noxafil Concentrate for Solution for Infusion

• Allow the refrigerated Noxafil vial to reach room temperature.
• Transfer 16.7 ml of posaconazole aseptically to an intravenous infusion bag (or bottle) containing a compatible mixing solvent (see below for list of solvents) using a volume range of 150 ml to 283 ml depending on the desired final concentration (not less than 1 mg/ml and not more than 2 mg/ml).
• Administer through a central venous line, including a central venous catheter or a peripherally inserted central catheter (PICC), by slow intravenous infusion over approximately 90 minutes. Noxafil concentrate for solution for infusion should not be administered as a bolus.
• If a central venous catheter is not available, a single infusion can be administered through a peripheral venous catheter with the appropriate volume to achieve a dilution of approximately 2 mg/ml. In this case, the infusion should be administered over approximately 30 minutes.

Note: In clinical studies, multiple peripheral infusions performed through the same vein resulted in the appearance of infusion site reactions (see section4.8).

• Noxafil is for single use.

The following medicines can be infused at the same time as Noxafil concentrate for solution for infusion and through the same intravenous line (or cannula):

Do not administer any medicine with Noxafil through the same intravenous line (or cannula) unless it is included in this table.

Before administration, the infusion solution should be visually inspected for particulate matter. The Noxafil solution ranges from colorless to pale yellow. Color variations within this range do not affect the quality of the medicine.

Disposal of unused medicine and all materials that have come into contact with it will be carried out in accordance with local regulations.

Noxafil should not be diluted with:

This medicine should not be mixed with other medicines, except for those mentioned below:

5% Glucose in water

0.9% Sodium Chloride

0.45% Sodium Chloride

5% Glucose and 0.45% Sodium Chloride

5% Glucose and 0.9% Sodium Chloride

5% Glucose and 20 mEq of KCl