Vfend - patient leaflet, side effects, dosage

B. PACKAGE LEAFLET

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.

What is in this leaflet

• 1. What VFEND is and what it is used for

• 2. What you need to know before you take VFEND

• 3. How to take VFEND

• 4. Possible side effects

• 5. How to store VFEND

• 6. Content of the pack and other information

1. What VFEND is and what it is used for

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:

• invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
• candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients (patients without abnormally low white blood cells count),
• serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another antifungal medicine),
• serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be taken under the supervision of a doctor.

2. What you need to know before you take VFEND

Do not take VFEND

If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription, or herbal medicines.

The medicines in the following list must not be taken during your course of VFEND treatment:

• Terfenadine (used for allergy)
• Astemizole (used for allergy)

Cisapride (used for stomach problems)

Pimozide (used for treating mental illness)

Quinidine (used for irregular heart beat)

Ivabradine (used for symptoms of chronic heart failure)

Rifampicin (used for treating tuberculosis)

Efavirenz (used for treating HIV) in doses of 400 mg and above once daily

Carbamazepine (used to treat seizures)

Phenobarbital (used for severe insomnia and seizures)

Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine)

Sirolimus (used in transplant patients)

Ritonavir (used for treating HIV) in doses of 400mg and more twice daily

St. John’s Wort (herbal supplement)

Naloxegol (used to treat constipation specifically caused by pain medicines, called opioids, (e.g., morphine, oxycodone, fentanyl, tramadol, codeine))

Tolvaptan (us ed to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline in patients with polycystic kidney disease)

Lurasidone (used to treat depression)

Venetoclax (used to treat patients with chronic lymphocytic leukaemia-CLL)

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking VFEND if:

• you have had an allergic reaction to other azoles.
• you are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function while you are being treated with VFEND by doing blood tests.
• you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QTc syndrome’.

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND:

• tell your doctor immediately if you develop

o sunburn

o severe skin rash or blisters

o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that skin cancer could develop with long-term use of VFEND.

If you develop signs of ‘adrenal insufficiency’ where the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol which may lead to symptoms such as: chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, please tell your doctor.

If you develop signs of ‘Cushing’ s syndrome’ where the body produces too much of the hormone cortisol which may lead to symptoms such as: weight gain, fatty hump between the shoulders, a rounded face, darkening of the skin on the stomach, thighs breasts, and arms, thinning skin, bruising easily, high blood sugar, excessive hair growth, excessive sweating, please tell your doctor.

Your doctor should monitor the function of your liver and kidney by doing blood tests.

Children and adolescents

VFEND should not be given to children younger than 2 years of age.

Other medicines and VFEND

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those that are obtained without a prescription.

Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or VFEND may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should be avoided if possible:

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily
• Glasdegib (used for treating cancer) – if you need to use both drugs your doctor will monitor your

heart rhythm frequently

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same time should be avoided if possible, and a dose adjustment of voriconazole may be required:

• Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood counts and side effects to rifabutin will need to be monitored.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood concentration of phenytoin will need to be monitored during your treatment with VFEND and your dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be required to check that the medicines and/ or VFEND are still having the desired effect:

Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting of the blood)

Ciclosporin (used in transplant patients)

Tacrolimus (used in transplant patients)

Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes)

Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol)

Benzodiazepines (e.g., midazolam, triazolam) (used for severe insomnia and stress)

Omeprazole (used for treating ulcers)

Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects such as nausea and menstrual disorders)

Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer)

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used for treating cancer)

Tretinoin (used to treat leukaemia)

Indinavir and other HIV protease inhibitors (used for treating HIV)

Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND) Methadone (used to treat heroin addiction)

Alfentanil and fentanyl_and other short-acting opiates such as sufentanil (painkillers used for surgical procedures)

Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)

Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and inflammation)

Fluconazole (used for fungal infections)

Everolimus (used for treating advanced kidney cancer and in transplant patients)

Letermovir (used for preventing cytomegalovirus (CMV) disease after bone marrow transplant) Ivacaftor: used to treat cystic fibrosis

Pregnancy and breast-feeding

VFEND must not be taken during pregnancy, unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while taking VFEND.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Contact your doctor if you experience this.

VFEND contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before taking VFEND.

VFEND contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per 50 mg tablet, that is to say essentially ‘sodium-free’.

This medicine contains less than 1 mmol sodium (23 mg) per 200 mg tablet, that is to say essentially ‘sodium-free’.

3. How to take VFEND

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Your doctor will determine your dose depending on your weight and the type of infection you have.

The recommended dose for adults (including elderly patients) is as follows:

Depending on your response to treatment, your doctor may increase the daily dose to 300 mg twice a day.

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis.

Use in children and adolescents

The recommended dose for children and teenagers is as follows:

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

Tablets must only be given if the child is able to swallow tablets.

Take your tablet at least one hour before, or one hour after a meal. Swallow the tablet whole with some water.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving VFEND if you or your child develop treatment related side effects.

If you take more VFEND than you should

If you take more tablets than prescribed (or if someone else takes your tablets) you must seek medical advice or go to the nearest hospital casualty department immediately. Take your box of VFEND tablets with you. You may experience abnormal intolerance to light as a result of taking more VFEND than you should.

If you forget to take VFEND

It is important to take your VFEND tablets regularly at the same time each day. If you forget to take one dose, take your next dose when it is due. Do not take a double dose to make up for a forgotten dose.

If you stop taking VFEND

It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of your medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep taking VFEND correctly, as described above.

Continue taking VFEND until your doctor tells you to stop. Do not stop treatment early because your infection may not be cured. Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning.

When VFEND treatment is stopped by your doctor 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 side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Serious side effects – Stop taking VFEND and see a doctor immediately

• - Rash

• - Jaundice; Changes in blood tests of liver function

• - Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

• - Visual impairment (change in vision including blurred vision, visual color alterations, abnormal

intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of the usual field of vision, spots before the eyes)

• - Fever

• - Rash

• - Nausea, vomiting, diarrhoea

• - Headache

• - Swelling of the extremities

• - Stomach pains

• - Breathing difficulties

Elevated liver enzymes

Common: may affect up to 1 in 10 people

• - Inflammation of the sinuses, inflammation of the gums, chills, weakness

• - Low numbers of some types, including severe, of red (sometimes immune-related) and/or white blood

cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot

• - Low blood sugar, low blood potassium, low sodium in the blood

• - Anxiety, depression, confusion, agitation, inability to sleep, hallucinations

• - Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin sensations,

increase in muscle tone, sleepiness, dizziness

• - Bleeding in the eye

• - Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting

• - Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood

clot)

• - Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid

accumulation in the lungs

• - Constipation, indigestion, inflammation of the lips

• - Jaundice, inflammation of the liver and liver injury

• - Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red

area on the skin that is covered with small confluent bumps, redness of the skin

• - Itchiness

• - Hair loss

• - Back pain

• - Kidney failure, blood in the urine, changes in kidney function tests

Uncommon: may affect up to 1 in 100 people

• - Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the

gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

• - Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal

organ

• - Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil

• - Depressed function of the adrenal gland, underactive thyroid gland

• - Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, tingling

or burning in the hands or feet

• - Problems with balance or coordination

• - Swelling of the brain

• - Double vision, serious conditions of the eye including: pain and inflammation of the eyes and eyelids,

abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic disc swelling

• - Decreased sensitivity to touch

• - Abnormal sense of taste

• - Hearing difficulties, ringing in the ears, vertigo

• - Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the

tongue

• - Enlarged liver, liver failure, gallbladder disease, gallstones

• - Joint inflammation, inflammation of the veins under the skin (which may be associated with the

formation of a blood clot)

• - Inflammation of the kidney, proteins in the urine, damage to the kidney

• - Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses

• - Abnormal electrocardiogram (ECG)

• - Blood cholesterol increased, blood urea increased

• - Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes

painful blisters and sores of the skin and mucous membranes, especially in the mouth, inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by low platelet count, eczema

• - Infusion site reaction

• - Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

• - Overactive thyroid gland

• - Deterioration of brain function that is a serious complication of liver disease

• - Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye

• - Bullous photosensitivity

• - A disorder in which the body’s immune system attacks part of the peripheral nervous system

• - Heart rhythm or conduction problems (sometimes life threatening)

• - Life threatening allergic reaction

• - Disorder of blood clotting system

• - Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of skin below

• - Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:

• - Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor immediately:

• - Skin cancer

• - Inflammation of the tissue surrounding the bone

• - Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease

called cutaneous lupus erythematosus

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains or if your stools have a different consistency.

There have been reports of skin cancer in patients treated with VFEND for long periods of time.

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND

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

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

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What VFEND contains

• The active substance is voriconazole. Each tablet contains either 50 mg voriconazole (for VFEND 50 mg film-coated tablets) or 200 mg voriconazole (for VFEND 200 mg film-coated tablets).
• The other ingredients are lactose monohydrate, pregelatinised starch, croscarmellose sodium, povidone and magnesium stearate which make up the tablet core and hypromellose, titanium dioxide (E171), lactose monohydrate and glycerol triacetate which make up the film-coat (see section 2, VFEND 50 mg film-coated tablets or VFEND 200 mg film-coated tablets contains lactose and sodium).

What VFEND looks like and contents of the pack

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.

What is in this leaflet

• 1. What VFEND is and what it is used for

• 2. What you need to know before you take VFEND

• 3. How to use VFEND

• 4. Possible side effects

• 5. How to store VFEND

• 6. Content of the pack and other information

1. What VFEND is and what it is used for

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:

• invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
• candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients (patients without abnormally low white blood cells count),
• serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another antifungal medicine),
• serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be used under the supervision of a doctor.

2. What you need to know before you take VFEND

Do not take VFEND

• - If you are allergic to the active ingredient voriconazole, or to sulfobutylether beta cyclodextrin sodium

(listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription, or herbal medicines.

The medicines in the following list must not be taken during your course of VFEND treatment:

• Terfenadine (used for allergy)
• Astemizole (used for allergy)
• Cisapride (used for stomach problems)

Pimozide (used for treating mental illness)

Quinidine (used for irregular heart beat)

Ivabradine (used for symptoms of chronic heart failure)

Rifampicin (used for treating tuberculosis)

Efavirenz (used for treating HIV) in doses of 400 mg and above once daily

Carbamazepine (used to treat seizures)

Phenobarbital (used for severe insomnia and seizures)

Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine)

Sirolimus (used in transplant patients)

Ritonavir (used for treating HIV) in doses of 400mg and more twice daily

St. John’s Wort (herbal supplement)

Naloxegol (used to treat constipation specifically caused by pain medicines, called opioids, (e.g., morphine, oxycodone, fentanyl, tramadol, codeine))

Tolvaptan (us ed to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline in patients with polycystic kidney disease)

Lurasidone (used to treat depression)

Venetoclax (used to treat patients with chronic lymphocytic leukaemia-CLL)

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking VFEND if:

• you have had an allergic reaction to other azoles.
• you are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function while you are being treated with VFEND by doing blood tests.
• you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QTc syndrome’.

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND:

• tell your doctor immediately if you develop

o sunburn

o severe skin rash or blisters

o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that skin cancer could develop with long-term use of VFEND.

If you develop signs of ‘adrenal insufficiency’ where the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol which may lead to symptoms such as: chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, please tell your doctor.

If you develop signs of ‘Cushing’ s syndrome’ where the body produces too much of the hormone cortisol which may lead to symptoms such as: weight gain, fatty hump between the shoulders, a rounded face, darkening of the skin on the stomach, thighs breasts, and arms, thinning skin, bruising easily, high blood sugar, excessive hair growth, excessive sweating, please tell your doctor.

Your doctor should monitor the function of your liver and kidney by doing blood tests.

Children and adolescents

VFEND should not be given to children younger than 2 years of age.

Other medicines and VFEND

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those that are obtained without a prescription.

Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or VFEND may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should be avoided if possible:

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily
• Glasdegib (used for treating cancer) – if you need to use both drugs your doctor will monitor your

heart rhythm frequently

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same time should be avoided if possible, and a dose adjustment of voriconazole may be required:

Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood counts and side effects to rifabutin will need to be monitored.

Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood concentration of phenytoin will need to be monitored during your treatment with VFEND and your dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be required to check that the medicines and/ or VFEND are still having the desired effect:

Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting of the blood)

Ciclosporin (used in transplant patients)

Tacrolimus (used in transplant patients)

Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes)

Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol)

Benzodiazepines (e.g., midazolam, triazolam) (used for severe insomnia and stress)

Omeprazole (used for treating ulcers)

Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects such as nausea and menstrual disorders)

Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer)

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used for treating cancer)

Tretinoin (used to treat leukaemia)

Indinavir and other HIV protease inhibitors (used for treating HIV)

Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND) Methadone (used to treat heroin addiction)

Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical procedures)

Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)

Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and inflammation)

Fluconazole (used for fungal infections)

Everolimus (used for treating advanced kidney cancer and in transplant patients)

Letermovir (used for preventing cytomegalovirus (CMV) disease after bone marrow transplant) Ivacaftor: used to treat cystic fibrosis

Pregnancy and breast-feeding

VFEND must not be used during pregnancy, unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while being treated with VFEND.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Tell your doctor if you experience this.

VFEND contains sodium

This medicine contains 221 mg of sodium (main component of cooking/table salt) per vial. This is equivalent to 11% of the recommended maximum daily dietary intake of sodium for an adult.

VFEND contains cyclodextrins

This medicine contains 3,200 mg cyclodextrins in each vial which is equivalent to 160 mg/ml when reconstituted in 20 ml. If you have a kidney disease, talk to your doctor before you receive this medicine.

3. How to use VFEND

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Your doctor will determine your dose depending on your weight and the type of infection you have.

Your doctor may change your dose depending on your condition.

The recommended dose for adults (including elderly patients) is as follows:

Depending on your response to treatment, your doctor may decrease the dose to 3 mg/kg twice daily.

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis.

Use in children and adolescents

The recommended dose for children and teenagers is as follows:

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

VFEND powder for solution for infusion will be reconstituted and diluted to the correct concentration by your hospital pharmacist or nurse. (Please refer to the end of this leaflet for further information)

This will be given to you by intravenous infusion (into a vein) at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving VFEND if you or your child develop treatment related side effects.

If a dose of VFEND has been forgotten

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

If you stop taking VFEND

VFEND treatment will continue for as long as your doctor advises, however duration of treatment with VFEND powder for solution for infusion should be no more than 6 months.

Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning. You may be switched from the intravenous infusion to tablets once your condition improves.

When VFEND treatment is stopped by your doctor 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 side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Serious side effects – Stop taking VFEND and see a doctor immediately

• - Rash

• - Jaundice; Changes in blood tests of liver function

• - Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

• - Visual impairment (change in vision including blurred vision, visual color alterations, abnormal

intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of the usual field of vision, spots before the eyes)

• - Fever

• - Rash

• - Nausea, vomiting, diarrhoea

• - Headache

• - Swelling of the extremities

• - Stomach pains

• - Breathing difficulties

• - Elevated liver enzymes

Common: may affect up to 1 in 10 people

• - Inflammation of the sinuses, inflammation of the gums, chills, weakness

• - Low numbers of some types, including severe, of red (sometimes immune-related) and/or white blood

cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot

• - Low blood sugar, low blood potassium, low sodium in the blood

• - Anxiety, depression, confusion, agitation, inability to sleep, hallucinations

• - Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin sensations, increase in

muscle tone, sleepiness, dizziness

• - Bleeding in the eye

• - Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting

• - Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood

clot)

• - Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid

accumulation in the lungs

• - Constipation, indigestion, inflammation of the lips

• - Jaundice, inflammation of the liver and liver injury

• - Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red area

on the skin that is covered with small confluent bumps, redness of the skin

• - Itchiness

• - Hair loss

• - Back pain

• - Kidney failure, blood in the urine, changes in kidney function tests

Uncommon: may affect up to 1 in 100 people

• - Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the

gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

• - Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal

organ

• - Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil

• - Depressed function of the adrenal gland, underactive thyroid gland

• - Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, tingling

or burning in the hands or feet

• - Problems with balance or coordination

• - Swelling of the brain

• - Double vision, serious conditions of the eye including: pain and inflammation of the eyes and eyelids,

abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic disc swelling

• - Decreased sensitivity to touch

• - Abnormal sense of taste

• - Hearing difficulties, ringing in the ears, vertigo

• - Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the

tongue

• - Enlarged liver, liver failure, gallbladder disease, gallstones

• - Joint inflammation, inflammation of the veins under the skin (which may be associated with the

formation of a blood clot)

• - Inflammation of the kidney, proteins in the urine, damage to the kidney

• - Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses

• - Abnormal electrocardiogram (ECG)

• - Blood cholesterol increased, blood urea increased

• - Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes

painful blisters and sores of the skin and mucous membranes, especially in the mouth, inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by low platelet count, eczema

• - Infusion site reaction

• - Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

• - Overactive thyroid gland

• - Deterioration of brain function that is a serious complication of liver disease

• - Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye

• - Bullous photosensitivity

• - A disorder in which the body’s immune system attacks part of the peripheral nervous system

• - Heart rhythm or conduction problems (sometimes life threatening)

• - Life threatening allergic reaction

• - Disorder of blood clotting system

• - Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of skin below

• - Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:

• - Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor immediately:

• - Skin cancer

• - Inflammation of the tissue surrounding the bone

• - Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease

called cutaneous lupus erythematosus

Reactions during the infusion have occurred uncommonly with VFEND (including flushing, fever, sweating, increased heart rate and shortness of breath). Your doctor may stop the infusion if this occurs.

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains or if your stools have a different consistency.

There have been reports of skin cancer in patients treated with VFEND for long periods of time.

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND

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

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

Once reconstituted, VFEND should be used immediately, but if necessary may be stored for up to 24 hours at 2°C – 8°C (in a refrigerator). Reconstituted VFEND needs to be diluted with a compatible infusion solution first before it is infused. (Please refer to the end of this leaflet for further information).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What VFEND contains

• – The active substance is voriconazole.

• – The other ingredient is sulfobutylether beta cyclodextrin sodium (see section 2, VFEND 200 mg

powder for solution for infusion contains cyclodextrin and sodium).

Each vial contains 200 mg voriconazole, equivalent to a 10 mg/ml solution when reconstituted as directed by your hospital pharmacist or nurse (see the information at the end of this leaflet).

What VFEND looks like and contents of the pack

For storage information, please refer to Section 5 ‘How to store VFEND’.

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.

What is in this leaflet

• 1. What VFEND is and what it is used for

• 2. What you need to know before you take VFEND

• 3. How to use VFEND

• 4. Possible side effects

• 5. How to store VFEND

• 6. Content of the pack and other information

1. What VFEND is and what it is used for

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:

• invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
• candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients (patients without abnormally low white blood cells count),
• serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another antifungal medicine),
• serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be used under the supervision of a doctor.

2. What you need to know before you take VFEND

Do not take VFEND

• – If you are allergic to the active ingredient voriconazole, or to sulfobutylether beta cyclodextrin sodium

(listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription, or herbal medicines.

The medicines in the following list must not be taken during your VFEND treatment:

• Terfenadine (used for allergy)
• Astemizole (used for allergy)
• Cisapride (used for stomach problems)

Pimozide (used for treating mental illness)

Quinidine (used for irregular heart beat)

Ivabradine (used for symptoms of chronic heart failure)

Rifampicin (used for treating tuberculosis)

Efavirenz (used for treating HIV) in doses of 400 mg and above once daily

Carbamazepine (used to treat seizures)

Phenobarbital (used for severe insomnia and seizures)

Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine)

Sirolimus (used in transplant patients)

Ritonavir (used for treating HIV) in doses of 400mg and more twice daily

St. John’s Wort (herbal supplement)

Naloxegol (used to treat constipation specifically caused by pain medicines, called opioids, (e.g., morphine, oxycodone, fentanyl, tramadol, codeine))

Tolvaptan (us ed to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline in patients with polycystic kidney disease)

Lurasidone (used to treat depression)

Venetoclax (used to treat patients with chronic lymphocytic leukaemia-CLL)

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking VFEND if:

• you have had an allergic reaction to other azoles.
• you are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function while you are being treated with VFEND by doing blood tests.
• you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QTc syndrome’.

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND:

• tell your doctor immediately if you develop

o sunburn

o severe skin rash or blisters

o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that skin cancer could develop with long-term use of VFEND.

If you develop signs of ‘adrenal insufficiency’ where the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol which may lead to symptoms such as: chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, please tell your doctor.

If you develop signs of ‘Cushing’ s syndrome’ where the body produces too much of the hormone cortisol which may lead to symptoms such as: weight gain, fatty hump between the shoulders, a rounded face, darkening of the skin on the stomach, thighs breasts, and arms, thinning skin, bruising easily, high blood sugar, excessive hair growth, excessive sweating, please tell your doctor.

Your doctor should monitor the function of your liver and kidney by doing blood tests.

Children and adolescents

VFEND should not be given to children younger than 2 years of age.

Other medicines and VFEND

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those that are obtained without a prescription.

• Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or

VFEND may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should be avoided if possible:

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily
• Glasdegib (used for treating cancer) – if you need to use both drugs your doctor will monitor your

heart rhythm frequently

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same time should be avoided if possible, and a dose adjustment of voriconazole may be required:

• Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood counts and side effects to rifabutin will need to be monitored.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood concentration of phenytoin will need to be monitored during your treatment with VFEND and your dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be required to check that the medicines and/ or VFEND are still having the desired effect:

Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting of the blood)

Ciclosporin (used in transplant patients)

Tacrolimus (used in transplant patients)

Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes)

Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol)

Benzodiazepines (e.g., midazolam, triazolam) (used for severe insomnia and stress)

Omeprazole (used for treating ulcers)

Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects such as nausea and menstrual disorders)

Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer)

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used for treating cancer)

Tretinoin (used to treat leukaemia)

Indinavir and other HIV protease inhibitors (used for treating HIV)

Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND) Methadone (used to treat heroin addiction)

Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical procedures)

Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)

Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and inflammation)

Fluconazole (used for fungal infections)

Everolimus (used for treating advanced kidney cancer and in transplant patients)

Letermovir (used for preventing cytomegalovirus (CMV) disease after bone marrow transplant) Ivacaftor: used to treat cystic fibrosis

Pregnancy and breast-feeding

VFEND must not be used during pregnancy, unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while being treated with VFEND.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Tell your doctor if you experience this.

VFEND contains sodium

This medicine contains 221 mg of sodium (main component of cooking/table salt) per vial. This is equivalent to 11% of the recommended maximum daily dietary intake of sodium for an adult.

VFEND contains cyclodextrins

This medicine contains 3,200 mg cyclodextrins in each vial which is equivalent to 160 mg/ml when reconstituted in 20 ml. If you have a kidney disease, talk to your doctor before you receive this medicine.

3. How to use VFEND

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.

Your doctor will determine your dose depending on your weight and the type of infection you have.

Your doctor may change your dose depending on your condition.

The recommended dose for adults (including elderly patients) is as follows:

Depending on your response to treatment, your doctor may decrease the dose to 3 mg/kg twice daily.

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis.

Use in children and adolescents

The recommended dose for children and teenagers is as follows:

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

VFEND powder and solvent for solution for infusion will be reconstituted and diluted to the correct concentration by your hospital pharmacist or nurse. (Please refer to the end of this leaflet for further information)

This will be given to you by intravenous infusion (into a vein) at a maximum rate of 3 mg/kg per hour over 1 to 3 hours.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving VFEND if you or your child develop treatment related side effects.

If a dose of VFEND has been forgotten

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

If you stop taking VFEND

VFEND treatment will continue for as long as your doctor advises, however duration of treatment with VFEND powder for solution for infusion should be no more than 6 months.

Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning. You may be switched from the intravenous infusion to tablets once your condition improves.

When VFEND treatment is stopped by your doctor 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 side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Serious side effects – Stop taking VFEND and see a doctor immediately

• - Rash

• - Jaundice; Changes in blood tests of liver function

• - Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

• - Visual impairment (change in vision including blurred vision, visual color alterations, abnormal

intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of the usual field of vision, spots before the eyes)

• - Fever

• - Rash

• - Nausea, vomiting, diarrhoea

• - Headache

• - Swelling of the extremities

• - Stomach pains

• - Breathing difficulties

• - Elevated liver enzymes

Common: may affect up to 1 in 10 people

• - Inflammation of the sinuses, inflammation of the gums, chills, weakness

• - Low numbers of some types, including severe, of red (sometimes immune-related) and/or white blood

cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot

• - Low blood sugar, low blood potassium, low sodium in the blood

• - Anxiety, depression, confusion, agitation, inability to sleep, hallucinations

• - Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin sensations, increase in

muscle tone, sleepiness, dizziness

• - Bleeding in the eye

• - Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting

• - Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood

clot)

• - Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid

accumulation in the lungs

• - Constipation, indigestion, inflammation of the lips

• - Jaundice, inflammation of the liver and liver injury

• - Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red area

on the skin that is covered with small confluent bumps, redness of the skin

• - Itchiness

• - Hair loss

• - Back pain

• - Kidney failure, blood in the urine, changes in kidney function tests

Uncommon: may affect up to 1 in 100 people

• - Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the

gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

• - Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal

organ

• - Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil

• - Depressed function of the adrenal gland, underactive thyroid gland

• - Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, tingling

or burning in the hands or feet

• - Problems with balance or coordination

• - Swelling of the brain

• - Double vision, serious conditions of the eye including: pain and inflammation of the eyes and eyelids,

abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic disc swelling

• - Decreased sensitivity to touch

• - Abnormal sense of taste

• - Hearing difficulties, ringing in the ears, vertigo

• - Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the

tongue

• - Enlarged liver, liver failure, gallbladder disease, gallstones

• - Joint inflammation, inflammation of the veins under the skin (which may be associated with the

formation of a blood clot)

• - Inflammation of the kidney, proteins in the urine, damage to the kidney

• - Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses

• - Abnormal electrocardiogram (ECG)

• - Blood cholesterol increased, blood urea increased

• - Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes

painful blisters and sores of the skin and mucous membranes, especially in the mouth, inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by low platelet count, eczema

• - Infusion site reaction

• - Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

• - Overactive thyroid gland

• - Deterioration of brain function that is a serious complication of liver disease

• - Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye

• - Bullous photosensitivity

• - A disorder in which the body’s immune system attacks part of the peripheral nervous system

• - Heart rhythm or conduction problems (sometimes life threatening)

• - Life threatening allergic reaction

• - Disorder of blood clotting system

• - Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of skin below

• - Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:

• - Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor immediately:

• - Skin cancer

• - Inflammation of the tissue surrounding the bone

• - Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease

called cutaneous lupus erythematosus

Reactions during the infusion have occurred uncommonly with VFEND (including flushing, fever, sweating, increased heart rate and shortness of breath). Your doctor may stop the infusion if this occurs.

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains or if your stools have a different consistency.

There have been reports of skin cancer in patients treated with VFEND for long periods of time.

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND

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

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

Once the powder in the vial has been reconstituted, VFEND should be used immediately, but if necessary may be stored for up to 24 hours at 2°C – 8°C (in a refrigerator) with the infusion bag. Reconstituted VFEND concentrate needs to be further diluted with sodium chloride (0.9%) infusion solution within the infusion bag before it is infused. The bag containing the reconstituted and diluted VFEND should be used immediately, but if necessary may be stored for up to a total of 24 hours at 2°C – 8°C (in a refrigerator) or at room temperature. (Please refer to the end of this leaflet for further information).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What VFEND contains

• - The active substance is voriconazole.

• - The other ingredient is sulfobutylether beta cyclodextrin sodium (see section 2, VFEND 200 mg

powder and solvent for solution for infusion contains cyclodextrin and sodium).

Each vial contains 200 mg voriconazole, equivalent to a 10 mg/ml solution when reconstituted as directed by your hospital pharmacist or nurse (see the information at the end of this leaflet).

Each bag contains 50 ml of sodium chloride 0.9% in Water for Injections.

What VFEND looks like and contents of the pack

VFEND powder and solvent for solution for infusion is presented as an administration kit containing:

• VFEND powder for solution for infusion in single use glass vial.
• VFEND solvent for solution for infusion in an overwrapped, sterile, single use, polypropylene

infusion bag.

• A sterile, single use, syringe.
• A sterile, single use vial adapter.

Marketing Authorisation Holder

Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

Manufacturer

Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France.

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

Nederland

Pfizer bv

Tel: +31 (0)10 406 43 01

Norge

Pfizer AS

Tlf: +47 67 52 61 00

Österreich

Pfizer Corporation Austria Ges.m.b.H.

Tel: +43 (0)1 521 15–0

Polska

Pfizer Polska Sp. z o.o.,

Tel.: +48 22 335 61 00

Portugal

Laboratórios Pfizer, Lda.

Tel: + 351 214 235 500

România

Pfizer România S.R. L

Tel: +40 (0)21 207 28 00

Slovenija

Pfizer Luxembourg SARL

Pfizer, podružnica za svetovanje s področja farmacevtske dejavnosti, Ljubljana

Tel: + 386 (0)152 11 400

Slovenská republika

Pfizer Luxembourg SARL, organizačná zložka

Tel: +421–2–3355 5500

Suomi/Finland

Pfizer Oy

Puh/Tel: +358(0)9 43 00 40

Sverige

Pfizer AB

Tel: +46 (0)8 5505 2000

United Kingdom (Northern Ireland)

Pfizer Limited

Tel: +44 (0)1304 616161

This leaflet was last approved in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:

<-----------------------------------------------------------------------------------------------------------------

The following information is intended for medical or healthcare professionals only:

Required Volumes of 10 mg/ml VFEND Concentrate

VFEND is a single dose unpreserved sterile lyophile. Therefore, from a microbiological point of view, the reconstituted solution must be used immediately.

If not used immediately, in-use storage times and conditions of the reconstituted vial prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Incompatibili­ties:

VFEND must not be infused into the same line or cannula concomitantly with other drug infusions, including parenteral nutrition (e.g., Aminofusin 10% Plus).

Infusions of blood products must not occur simultaneously with VFEND.

Infusion of total parenteral nutrition can occur simultaneously with VFEND but not in the same line or cannula.

VFEND must not be diluted with 4.2% Sodium Bicarbonate Infusion.

Kit Operating Instructions for Use:

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.

What is in this leaflet

• 1. What VFEND is and what it is used for

• 2. What you need to know before you take VFEND

• 3. How to take VFEND

• 4. Possible side effects

• 5. How to store VFEND

• 6 Content of the pack and other information

1. What VFEND is and what it is used for

VFEND contains the active substance voriconazole. VFEND is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections.

It is used for the treatment of patients (adults and children over the age of 2) with:

• invasive aspergillosis (a type of fungal infection due to Aspergillus sp),
• candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients (patients without abnormally low white blood cells count),
• serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another antifungal medicine),
• serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of fungi).

VFEND is intended for patients with worsening, possibly life-threatening, fungal infections.

Prevention of fungal infections in high risk bone marrow transplant recipients.

This product should only be taken under the supervision of a doctor.

2. What you need to know before you take VFEND

Do not take VFEND

If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription, or herbal medicines.

The medicines in the following list must not be taken during your course of VFEND treatment:

• Terfenadine (used for allergy)
• Astemizole (used for allergy)
• Cisapride (used for stomach problems)

Pimozide (used for treating mental illness)

Quinidine (used for irregular heart beat)

Ivabradine (used for symptoms of chronic heart failure)

Rifampicin (used for treating tuberculosis)

Efavirenz (used for treating HIV) in doses of 400 mg and above once daily

Carbamazepine (used to treat seizures)

Phenobarbital (used for severe insomnia and seizures)

Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine)

Sirolimus (used in transplant patients)

Ritonavir (used for treating HIV) in doses of 400mg and more twice daily

St. John’s Wort (herbal supplement)

Naloxegol (used to treat constipation specifically caused by pain medicines, called opioids, (e.g., morphine, oxycodone, fentanyl, tramadol, codeine))

Tolvaptan (us ed to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline in patients with polycystic kidney disease)

Lurasidone (used to treat depression)Ve­netoclax (used to treat patients with chronic lymphocytic leukaemia-CLL)

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking VFEND if:

• you have had an allergic reaction to other azoles.
• you are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function while you are being treated with VFEND by doing blood tests.
• you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QTc syndrome’.

You should avoid any sunlight and sun exposure while being treated. It is important to cover sun exposed areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children.

While being treated with VFEND:

• tell your doctor immediately if you develop

o sunburn

o severe skin rash or blisters

o bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that skin cancer could develop with long-term use of VFEND.

If you develop signs of ‘adrenal insufficiency’ where the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol which may lead to symptoms such as: chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, please tell your doctor.

If you develop signs of ‘Cushing’ s syndrome’ where the body produces too much of the hormone cortisol which may lead to symptoms such as: weight gain, fatty hump between the shoulders, a rounded face, darkening of the skin on the stomach, thighs breasts, and arms, thinning skin, bruising easily, high blood sugar, excessive hair growth, excessive sweating, please tell your doctor.

Your doctor should monitor the function of your liver and kidney by doing blood tests.

Children and adolescents

VFEND should not be given to children younger than 2 years of age.

Other medicines and VFEND

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those that are obtained without a prescription.

Some medicines, when taken at the same time as VFEND, may affect the way VFEND works or VFEND may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with VFEND at the same time should be avoided if possible:

• Ritonavir (used for treating HIV) in doses of 100 mg twice daily
• Glasdegib (used for treating cancer) – if you need to use both drugs your doctor will monitor your

heart rhythm frequently

Tell your doctor if you are taking either of the following medicines, as treatment with VFEND at the same time should be avoided if possible, and a dose adjustment of voriconazole may be required:

• Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood counts and side effects to rifabutin will need to be monitored.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood concentration of phenytoin will need to be monitored during your treatment with VFEND and your dose may be adjusted.

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be required to check that the medicines and/ or VFEND are still having the desired effect:

Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting of the blood)

Ciclosporin (used in transplant patients)

Tacrolimus (used in transplant patients)

Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes)

Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol)

Benzodiazepines (e.g., midazolam, triazolam) (used for severe insomnia and stress)

Omeprazole (used for treating ulcers)

Oral contraceptives (if you take VFEND whilst using oral contraceptives, you may get side effects such as nausea and menstrual disorders)

Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer)

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used for treating cancer)

Tretinoin (used to treat leukaemia)

Indinavir and other HIV protease inhibitors (used for treating HIV)

Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for treating HIV) (some doses of efavirenz can NOT be taken at the same time as VFEND) Methadone (used to treat heroin addiction)

Alfentanil and fentanyl-and other short-acting opiates such as sufentanil (painkillers used for surgical procedures)

Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain)

Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and inflammation)

Fluconazole (used for fungal infections)

Everolimus (used for treating advanced kidney cancer and in transplant patients)

Letermovir (used for preventing cytomegalovirus (CMV) disease after bone marrow transplant) Ivacaftor: used to treat cystic fibrosis

Pregnancy and breast-feeding

VFEND must not be taken during pregnancy, unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while taking VFEND.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

VFEND may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Contact your doctor if you experience this.

VFEND contains sucrose

This medicine contains 0.54g sucrose per ml of suspension. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking VFEND. This should be taken into account in patients with diabetes mellitus. May be harmful to the teeth.

VFEND contains sodium

This medicine contains less than 1 mmol sodium (23 mg) per 5 ml of suspension, that is to say essentially ‘sodium-free’.

VFEND contains benzoate salt/sodium

This medicine contains 12 mg benzoate salt (E211) in each 5 ml dose.

3. How to take VFEND

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

Your doctor will determine your dose depending on your weight and the type of infection you have.

The recommended dose for adults (including elderly patients) is as follows:

Depending on your response to treatment, your doctor may increase the daily dose to 300 mg twice a day.

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis.

Use in children and adolescents

The recommended dose for children and teenagers is as follows:

Depending on your response to treatment, your doctor may increase or decrease the daily dose.

Take your suspension at least one hour before, or two hours after a meal.

If you or your child are taking VFEND for prevention of fungal infections, your doctor may stop giving VFEND if you or your child develop treatment related side effects.

VFEND suspension should not be mixed with any other medicine. The suspension should not be further diluted with water or any other liquids.

Instructions to constitute the suspension:

It is recommended that your pharmacist constitutes VFEND suspension before giving it to you. VFEND suspension is constituted if it is in a liquid form. If it appears to be a dry powder you should constitute the oral suspension by following the instructions below.

• 1. Tap the bottle to release the powder.

• 2. Remove the cap.

• 3. Add 2 measuring cups (measure cup included in the carton) of water (total of 46 ml) to the bottle. Fill the measuring cup to the top of the marked line then pour the water into the bottle. You should always add a total of 46 ml of water irrespective of the dose you are taking.

• 4. Replace the cap and shake the bottle vigorously for about 1 minute. Following constitution, the total volume of the suspension must be 75 ml.

• 5. Remove the cap. Press the bottle adaptor into the neck of the bottle (as shown on figure below). The adaptor is provided so that you can fill the oral syringe with medicine from the bottle. Replace the cap on the bottle.

• 6. Write the date of expiry of the constituted suspension on the bottle label (the shelf-life of the constituted suspension is 14 days). Any unused suspension should be discarded after this date.

Instructions for use:

Your pharmacist should advise you how to measure the medicine using the multi-dosing oral syringe provided in the pack. Please see instructions below before using VFEND suspension.

• 1. Shake the closed bottle of constituted suspension for approximately 10 seconds before use. Remove the cap.

• 2. While the bottle is upright, on a flat surface, insert the tip of the oral syringe into the adaptor.

• 3. Turn the bottle upside down while holding the oral syringe in place. Slowly pull back the plunger of the oral syringe to the graduation mark that marks the dose for you. To measure the dose accurately, the top edge of the black ring should be lined up with the graduated mark on the oral syringe.

• 4. If large bubbles can be seen, slowly push the plunger back into the syringe. This will force the medicine back into the bottle. Repeat step 3 again.

• 5. Turn the bottle back upright with the oral syringe still in place. Remove the oral syringe from the bottle.

• 6. Put the tip of the oral syringe into the mouth. Point the tip of the oral syringe towards the inside of the cheek. SLOWLY push down the plunger of the oral syringe. Do not squirt the medicine out quickly. If the medicine is to be given to a child, make sure the child is sitting, or is held, upright before giving the medicine.

• 7. Replace the cap on the bottle, leaving the bottle adaptor in place. Wash the oral syringe as instructed below.

1 2 3/4 5 6

Cleaning and storing the syringe:

• 1. The syringe should be washed after each dose. Pull the plunger out of the syringe and wash both parts in warm soapy water. Then rinse with water.

• 2. Dry the two parts. Push the plunger back in to the syringe. Keep it in a clean safe place with the medicine.

If you take more VFEND than you should

If you take more suspension than prescribed (or if someone else takes your suspension) you must seek medical advice or go to the nearest hospital casualty department immediately. Take your bottle of VFEND suspension with you. You may experience abnormal intolerance to light as a result of taking more VFEND than you should.

If you forget to take VFEND

It is important to take your VFEND suspension regularly at the same time each day. If you forget to take one dose, take your next dose when it is due. Do not take a double dose to make up for the forgotten dose.

If you stop taking VFEND

It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of your medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep taking VFEND correctly, as described above.

Continue taking VFEND until your doctor tells you to stop. Do not stop treatment early because your infection may not be cured. Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning.

When VFEND treatment is stopped by your doctor 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 side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.

Serious side effects – Stop taking VFEND and see a doctor immediately

• - Rash

• - Jaundice; Changes in blood tests of liver function

• - Pancreatitis

Other side effects

Very common: may affect more than 1 in 10 people

• - Visual impairment (change in vision including blurred vision, visual color alterations, abnormal

intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of the usual field of vision, spots before the eyes)

• - Fever

• - Rash

• - Nausea, vomiting, diarrhoea

• - Headache

• - Swelling of the extremities

• - Stomach pains

• - Breathing difficulties

• - Elevated liver enzymes

Common: may affect up to 1 in 10 people

• - Inflammation of the sinuses, inflammation of the gums, chills, weakness

• - Low numbers of some types, including severe, of red (sometimes immune-related) and/or white blood

cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot

• - Low blood sugar, low blood potassium, low sodium in the blood

• - Anxiety, depression, confusion, agitation, inability to sleep, hallucinations

• - Seizures, tremors or uncontrolled muscle movements, tingling or abnormal skin sensations, increase in

muscle tone, sleepiness, dizziness

• - Bleeding in the eye

• - Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting

• - Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood

clot)

• - Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid

accumulation in the lungs

• - Constipation, indigestion, inflammation of the lips

• - Jaundice, inflammation of the liver and liver injury

• - Skin rashes which may lead to severe blistering and peeling of the skin characterized by a flat, red area

on the skin that is covered with small confluent bumps, redness of the skin

• - Itchiness

• - Hair loss

• - Back pain

• - Kidney failure, blood in the urine, changes in kidney function tests

Uncommon: may affect up to 1 in 100 people

• - Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the

gastrointestinal tract causing antibiotic associated diarrhoea, inflammation of the lymphatic vessels

• - Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal

organ

• - Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil

• - Depressed function of the adrenal gland, underactive thyroid gland

• - Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in numbness, pain, tingling

or burning in the hands or feet

• - Problems with balance or coordination

• - Swelling of the brain

• - Double vision, serious conditions of the eye including: pain and inflammation of the eyes and eyelids,

abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic disc swelling

• - Decreased sensitivity to touch

• - Abnormal sense of taste

• - Hearing difficulties, ringing in the ears, vertigo

• - Inflammation of certain internal organs- pancreas and duodenum, swelling and inflammation of the

tongue

• - Enlarged liver, liver failure, gallbladder disease, gallstones

• - Joint inflammation, inflammation of the veins under the skin (which may be associated with the

formation of a blood clot)

• - Inflammation of the kidney, proteins in the urine, damage to the kidney

• - Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses

• - Abnormal electrocardiogram (ECG)

• - Blood cholesterol increased, blood urea increased

• - Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes

painful blisters and sores of the skin and mucous membranes, especially in the mouth, inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by low platelet count, eczema

• - Infusion site reaction

• - Allergic reaction or exaggerated immune response

Rare: may affect up to 1 in 1000 people

• - Overactive thyroid gland

• - Deterioration of brain function that is a serious complication of liver disease

• - Loss of most fibers in the optic nerve, clouding of the cornea, involuntary movement of the eye

• - Bullous photosensitivity

• - A disorder in which the body’s immune system attacks part of the peripheral nervous system

• - Heart rhythm or conduction problems (sometimes life threatening)

• - Life threatening allergic reaction

• - Disorder of blood clotting system

• - Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis,

subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition that causes large portions of the epidermis, the skin's outermost layer, to detach from the layers of skin below

• - Small dry scaly skin patches, sometimes thick with spikes or ‘horns’

Side effects with frequency not known:

• - Freckles and pigmented spots

Other significant side effects whose frequency is not known, but should be reported to your doctor immediately:

• - Skin cancer

• - Inflammation of the tissue surrounding the bone

• - Red, scaly patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease

called cutaneous lupus erythematosus

As VFEND has been known to affect the liver and the kidney, your doctor should monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains or if your stools have a different consistency.

There have been reports of skin cancer in patients treated with VFEND for long periods of time.

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who after consultation may decide that it is important for you or your child to be seen on a regular basis. Elevated liver enzymes were also observed more frequently in children.

If any of these side effects persist or are troublesome, please tell your doctor.

Reporting of side effects

If you get any side effects, talk to your doctor or, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store VFEND

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

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

Powder for oral suspension: store at 2°C – 8°C (in a refrigerator) before constitution.

For the constituted suspension:

Do not store above 30°C.

Do not refrigerate or freeze.

Store in the original container

Keep the container tightly closed.

Any remaining suspension should be discarded 14 days after constitution.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What VFEND contains:

• - The active substance is voriconazole. Each bottle contains 45 g of powder providing 70 ml of

suspension when constituted with water as recommended. One ml of the constituted suspension contains 40 mg voriconazole. (See section 3 ‘How to take VFEND’).

• - The other ingredients are sucrose; silica colloidal; titanium dioxide; xanthan gum; sodium citrate;

What VFEND looks like and contents of the pack

VFEND is supplied as a white to off-white powder for oral suspension providing a white to off-white, orange flavoured suspension when constituted with water.

Marketing Authorisation Holder

Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

Manufacturer

Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Poce-sur-Cisse, France.

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Latvija

Pfizer Luxembourg SARL

Filiale Latvija

Tel: +371 670 35 775

This leaflet was last approved in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site:

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for voriconazole, the scientific conclusions of CHMP are as follows:

In view of available data on spontaneous reports including cases with a close temporal relationship, and current labelling on SCC, the PRAC Rapporteur considers a causal relationship between voriconazole and cutaneous SCC, or Bowen’s disease is at least a reasonable possibility. In order to increase the knowledge of voriconazole risks, additional wording regarding Bowen’s disease should be included in sections 4.4 and 4.8 of the SmPC to reinforce the level of awareness of physicians.

During the current reporting interval, there were 28 cases reporting 28 serious events matching the search criteria for SCC and corresponding to 0.5% of total PM cases compared to 20 cases (1.0%) in the previous reporting interval. Out of these 28 SCC cases, there were 4 Bowen’s dise­ase cases.

Based on the 4 additional Bowen’s disease cases reported during this interval (26 cumulatively) the MAHs should amend/further specify the current labelling on SCC following post-marketing reports of Bowen’s disease. Cumulatively, 26 reports of Bowen’s disease, which is a distinct clinical-pathologic variant of SCC in situ were identified. Considering that Bowen’s disease and invasive SCC represent different steps within the disease continuum of squamous neoplasia, but also that the incidence of Bowen’s disease is similar to SCC in the general population, these cases may suggest under-reporting of these reactions. A disproporti­onality was found for the PT “Bowen’s disease” from EVDAS, ROR (-) = 32.35 cumulatively.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for voriconazole the CHMP is of the opinion that the benefit-risk balance of the medicinal product(s) containing voriconazole is unchanged subject to the proposed changes to the product information.

The CHMP recommends that the terms of the marketing authorisation(s) should be varied.

170