Noxafil 300 mg concentrate for solution for infusion

Package leaflet: Information for the user

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 as you may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only; do not pass it on to other people, even if they have the same symptoms as you, because it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist or nurse, even if they are adverse effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Noxafil is and what it is used for

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

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

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

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 Aspergillus family that have not improved during treatment with the antifungal medicines amphotericin B or itraconazole, or when treatment with these medicines has had to be discontinued;
• infections caused by fungi of the Fusarium family that have not improved during treatment with amphotericin B, or when treatment with amphotericin B has had to be discontinued;
• infections caused by fungi that lead to diseases known as "chromoblastomycosis" and "mycetoma" that have not improved during treatment with itraconazole, or when treatment with itraconazole has had to be discontinued;
• infections caused by a fungus called Coccidioides that have not improved during treatment with one or more medicines, such as amphotericin B, itraconazole or fluconazole, or when treatment with these medicines has had to be discontinued.

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

• patients with a weakened immune system as a result of receiving chemotherapy for "acute myelogenous leukemia" (AML) or "myelodysplastic syndromes" (MDS);
• patients receiving "high-dose immunosuppressive therapy" following "haematopoietic stem cell transplantation" (HSCT).

2. What you need to know before using Noxafil

Do not use Noxafil

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

• if you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, any medicine containing "ergot alkaloids", such as ergotamine or dihydroergotamine, or a "statin", such as simvastatin, atorvastatin or lovastatin.

• if you have just started taking venetoclax or your venetoclax dose is being gradually increased for the treatment of chronic lymphocytic leukemia (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 “Use of 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 starting Noxafil if:

• you have ever had an allergic reaction to another antifungal medicine, such as ketoconazole, fluconazole, itraconazole, or voriconazole.

• you currently have or have ever had liver problems. You may need blood tests while taking Noxafil.

• you have a heart rhythm disorder (ECG) showing a condition called QTc interval prolongation.

• you have weakened heart muscle or heart failure.

• you have a very slow heartbeat.

• you have any heart rhythm disorder.

• you have any problems with levels of potassium, magnesium, or calcium in your blood.

• you are taking vincristine, vinblastine, or other "vinca alkaloids" (medicines used to treat cancer).

• you are taking venetoclax (a medicine used to treat cancer).

You should avoid exposure to sunlight during treatment. It is important to cover sun-exposed skin areas with protective clothing and use sunscreen with a high sun protection factor (SPF), as increased sensitivity of the skin to UV rays from the sun may occur.

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

Children

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

Use of Noxafil with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken, or might need to 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 syndrome and mental illnesses)
• halofantrine (used to treat malaria)
• quinidine (used to treat heart rhythm disorders)

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

• any medicine containing "ergot alkaloids", such as ergotamine or dihydroergotamine, used to treat migraines. Noxafil may increase the levels of these medicines in the blood, which could cause a serious reduction in blood flow to the fingers of the hands or feet, potentially causing damage.

• a "statin", such as simvastatin, atorvastatin, or lovastatin, used to treat high cholesterol levels.

• venetoclax when used at the beginning of treatment for a type of cancer, chronic lymphocytic leukemia (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

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

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

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

• rifabutin and rifampicin (used to treat certain infections). If you are already taking rifabutin, you will need a blood test and should watch for 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 against bacterial infections).

Noxafil may increase the risk of side effects from other medicines by increasing their levels in the blood. These medicines include:

• vincristine, vinblastine, and other "vinca alkaloids" (used to treat cancer)
• venetoclax (used to treat cancer)
• cyclosporine (used during or after organ transplants)
• tacrolimus and sirolimus (used during or after organ 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 "sulfonylureas" (used to treat high blood sugar levels)
• all-trans retinoic acid (ATRA), also called tretinoin (used to treat certain blood cancers)

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

Pregnancy and breastfeeding

Tell your doctor if you are or think you may be pregnant before starting Noxafil. Do not use Noxafil if you are pregnant, unless your doctor tells you to do so.

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

Do not breastfeed while using Noxafil, as small amounts may pass into breast milk.

Driving and using machines

You may feel dizzy, drowsy, or experience blurred vision while taking Noxafil, which may affect your ability to drive or use tools or machines. If this occurs, do not drive or use any tools or machines and contact your doctor.

Noxafil contains sodium

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

Consult your doctor or pharmacist if you need Noxafil 300 mg concentrate for infusion solution or higher daily doses for a prolonged period, 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 for administration of this medicine given by your doctor or pharmacist. If in doubt, consult your doctor or pharmacist again.

The recommended dose for adults is 300 mg twice daily on the first day, followed by 300 mg once daily thereafter.

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

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 administered by a healthcare professional.

You will be given Noxafil:

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

The duration of treatment may depend on the type of infection you have or the period during which your immune system is not functioning properly, and may be individually adjusted for you by your doctor. Do not adjust your dose yourself before consulting your doctor, nor change your treatment schedule.

If you miss a dose of Noxafil

Since this medicine is administered under strict medical supervision, it is unlikely that a dose will be missed. However, if you think a dose may have been omitted, inform your doctor or pharmacist.

When your doctor stops treatment with Noxafil, you should not experience any effect.

If you have any further questions about 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 everyone experiences them.

Serious adverse effects

Tell your doctor, pharmacist, or nurse immediately if you notice any of the following serious adverse effects; you may require urgent medical treatment:

• nausea or vomiting (feeling sick 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 unwell for no apparent reason, stomach problems, loss of appetite, or unusual tiredness or weakness, an increase in liver enzymes detected in blood tests

• allergic reaction

Other adverse effects

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

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

• a change in blood electrolyte levels detected in blood tests, which may include symptoms such as confusion or weakness

• abnormal skin sensations such as numbness, tingling, itching, crawling sensations, prickling, 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 discomfort, flatulence, dry mouth, changes in taste sensation

• heartburn (a burning sensation in the chest rising up to the throat)

• low levels of "neutrophils", a type of white blood cell (neutropenia), which may make you more prone to infections and is detected in blood tests

• fever

• feeling weak, dizzy, tired, or drowsy

• rash

• itching

• constipation

• rectal discomfort

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

• anemia, with signs including headaches, feeling tired or dizzy, shortness of breath, paleness, and low hemoglobin levels detected in blood tests

• low platelet levels (thrombocytopenia), detected in blood tests. This may cause bleeding

• low levels of "leukocytes", a type of white blood cell (leukopenia), detected in blood tests. This may make you more susceptible to infections

• high levels of "eosinophils", a type of white blood cell (eosinophilia). This may occur if you have an inflammatory condition

• inflammation of blood vessels

• heart rhythm problems

• seizures (fits)

• nerve damage (neuropathy)

• abnormal heart rhythm detected on an electrocardiogram (ECG), palpitations, slow or fast heartbeat, high or low blood pressure

• low blood pressure

• inflammation of the pancreas (pancreatitis). This may cause severe stomach pain

• interruption of oxygen supply to the spleen (splenic infarction), which may cause severe stomach pain

• serious kidney problems, with signs including increased or decreased urination and urine that appears different in color than usual

• high blood creatinine levels, detected in blood tests

• cough, hiccups

• nosebleeds

• sharp, severe chest pain when breathing (pleuritic pain)

• swelling of lymph nodes (lymphadenopathy)

• reduced sensation, especially in the skin

• tremors

• high or low blood sugar levels

• blurred vision, light sensitivity

• hair loss (alopecia)

• mouth ulcers

• chills, general feeling of being unwell

• pain, back or neck pain, pain in arms or legs

• fluid retention (edema)

• menstrual problems (abnormal vaginal bleeding)

• inability to sleep (insomnia)

• complete or partial inability to speak

• swelling of the mouth

• abnormal dreams or sleep problems

• coordination or balance problems

• inflammation of the mucosa

• nasal congestion

• difficulty breathing

• chest discomfort

• feeling bloated

• nausea, vomiting, cramps, and mild to severe diarrhea, usually caused by a virus, stomach pain

• burping

• feeling restless

• swelling or pain at the injection site

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

• pneumonia, with signs including shortness of breath and production of discolored mucus

• high blood pressure in the blood vessels of the lungs (pulmonary hypertension), which may cause serious damage to the lungs and heart

• blood disorders such as unusual blood clotting or prolonged bleeding

• severe allergic reactions, including widespread rash with blisters and skin peeling

• mental problems, such as hearing voices or seeing things that are not there

• fainting

• problems with thinking or speaking, sudden jerky movements, especially in the hands, that you cannot control

• stroke, with signs including 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 may lead to cardiac arrest and death, heart rhythm problems with sudden death

• blood clots in the legs (deep vein thrombosis), with signs including severe pain or swelling in the legs

• blood clots in the lungs (pulmonary embolism), with signs including shortness of breath or chest pain when breathing

• bleeding in the stomach or intestines, with signs including vomiting blood or blood in the stools

• intestinal blockage (intestinal obstruction), especially of the "ileum". This blockage prevents intestinal contents from passing through the colon, with signs including feeling bloated, vomiting, severe constipation, loss of appetite, and cramping

• "haemolytic uraemic syndrome" that occurs when red blood cells are destroyed (haemolysis), which may occur with or without kidney failure

• "pancytopenia", low levels of all blood cells (red cells, white cells, and platelets), detected in blood tests

• large purple spots on the skin (thrombotic thrombocytopenic purpura)

• swelling of the face or tongue

• depression

• double vision

• breast pain

• inadequate adrenal gland function, which may cause weakness, tiredness, loss of appetite, skin discoloration

• inadequate pituitary gland function, which may cause low blood levels of certain hormones affecting male or female sexual organ function

• hearing problems

• pseudoaldosteronism, causing high blood pressure with low potassium levels (detected in blood tests)

Frequency not known: cannot be estimated from available data

• some patients have also reported feeling confused after taking Noxafil

• redness of the skin

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

Reporting of adverse effects

If you experience any adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect not listed in this leaflet. You may also report them directly through the national reporting system detailed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of Noxafil

Keep this medicine out of the sight and reach of children.

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

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

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

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and containers you no longer need. This helps protect the environment.

6. Contents of the container and other information

Composition of Noxafil

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

Appearance of the product and contents of the container

Noxafil concentrate for solution for infusion is a clear, colourless to yellow liquid. Colour variations within this range do not affect the quality of the medicinal product.

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

You can request further information about this medicinal product by contacting the local representative of the marketing authorization holder:

Date of the most recent review of this leaflet: <{MM/YYYY}><{month YYYY}>.

Other sources of information

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

This information is intended for healthcare professionals only:

Instructions for administration of Noxafil concentrate for solution for infusion

• Allow the refrigerated Noxafil vial to reach room temperature.
• Aseptically transfer 16.7 ml of posaconazole to an intravenous infusion bag (or bottle) containing a compatible diluent (see list of diluents below), using a total volume ranging from 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 via a central venous line, including a central venous catheter or a peripherally inserted central catheter (PICC), as a slow intravenous infusion over approximately 90 minutes. Noxafil concentrate for solution for infusion must not be administered as an intravenous bolus.
• If a central venous catheter is not available, a single infusion may be administered through a peripheral venous catheter using an 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 administered through the same vein resulted in infusion site reactions (see section 4.8).

• Noxafil is for single use only.

The following medicines may be co-infused with Noxafil concentrate for solution for infusion and through the same intravenous line (or cannula):

Noxafil must not be administered intravenously through the same line (or cannula) together with any medication not listed in this table.

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

Any unused medicine and all materials that have come into contact with it must be disposed of in accordance with local regulations.

Noxafil must not be diluted with:

This medicine should not be mixed with other drugs except those listed 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