VFEND 200 mg powder for solution for infusion

VFEND belongs to a group of medicines called triazole antifungal agents. These medicines are used to treat a wide variety of fungal infections. VFEND works by killing or stopping the growth of the fungi that cause infections.

What fungal infections are treated with VFEND?
VFEND is used to treat serious fungal infections caused by Aspergillus, Scedosporium, Fusarium, fluconazole-resistant Candida, and candidaemia in patients with normal white blood cell counts.

This product should only be used under the supervision of a doctor.
VFEND is mainly for use in seriously ill patients.

Do not take VFEND:

• If you are allergic to the active ingredient voriconazole, or to sulphobutylether beta cyclodextrin sodium.

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. Some medicines affect the way VFEND works, or VFEND may affect the way they work.

A list of the medicines that may affect VFEND is shown in the section ?Taking other medicines with VFEND?. However, 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)
• Rifampicin (used for treating tuberculosis)
• 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)

Take special care with VFEND:

• to avoid sunlight and sun exposure while being treated. It is important to cover sun exposed areas of skin and use sunscreen, as an increased sensitivity of skin to the sun?s UV rays can occur.
• If you are known to have cardiomyopathy, irregular heart beat, slow heart rate or an abnormality of electrocardiogram (ECG) called ?long QT syndrome?.

Taking other medicines with VFEND:
Please tell your doctor or pharmacist if you are taking or have recently taken 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 any of the following medicines, as VFEND must not be taken if you are already taking any of these medicines (See also Section 2 above ?Do not take VFEND):

• Terfenadine (used for allergy)
• Astemizole (used for allergy)
• Carbamazepine (used to treat seizures)
• Cisapride (used for stomach problems)
• Pimozide (used for treating mental illness)
• Quinidine (used for irregular heart beat)
• Rifampicin (used for treating tuberculosis)
• 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 400 mg and more twice daily
• St John?s Wort (herbal supplement)

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

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)
• Phenytoin (used to treat epilepsy)

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

Before being treated with VFEND, tell your doctor if:

• you have had an allergic reaction to other azoles.
• you are suffering from, or have ever suffered from kidney disease. Dependent upon the degree of kidney disease the doctor may decide to give you VFEND tablets. Your doctor should monitor your renal function while you are being treated with VFEND by doing blood tests.
• 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 already being treated with phenytoin (used to treat epilepsy). Your blood concentration of phenytoin will need to be monitored during your treatment with VFEND and your dose may be adjusted.
• you are already being treated with rifabutin (used for treating tuberculosis). Your blood counts and side effects to rifabutin will need to be monitored.

While being treated with VFEND:

• tell your doctor immediately if you develop a severe skin rash or blisters.
• avoid sunlight and sun exposure while being treated with VFEND. Cover sun exposed areas of skin and use sunscreen, as an increased sensitivity of skin to the sun?s UV rays can occur.
• your doctor should monitor the function of your liver and kidney by doing blood tests.
• reactions during the infusion have occurred uncommonly with VFEND (including flushing and nausea). Your doctor may stop the infusion of VFEND if this occurs.

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.

VFEND must not be used during breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine whilst breast-feeding.

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.

Important information about some of the ingredients of VFEND
Each vial of VFEND contains 217.6 mg of sodium per vial. This should be taken into consideration if you are on a strictly controlled sodium diet.

Always take VFEND exactly as your doctor has told you. You should 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 usual dose for adults (including elderly patients) is as follows:
Intravenous

6 mg/kg every 12 hours for
Dose for the first 24 hours the
(Loading Dose) first 24 hours

4 mgkg twice a day Dose after the first 24 hours Maintenance Dose

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.

• The usual dose for children aged 2 to less than 12 years is 7 mg/kg twice daily.
• The usual dose for teenagers (aged 12 to 16 years) is the same as for adults. . VFEND should not be given to children younger than 2 years of age.

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 2 hours.

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.

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:
When VFEND treatment is stopped by your doctor you should not experience any effects. However if you were taking medicines containing ciclosporin or tacrolimus you must mention this to your doctor, as the dose will need to be adjusted.

If you have any further questions on the use of this product, ask your doctor.

Like all medicines, VFEND 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.

Very common side effects (occurring in at least 1 in 10 patients) are:

-Visual disturbances (change in vision)
-Fever
-Rash
-Nausea, vomiting, diarrhoea
-Headache
-Swelling of the extremities
-Stomach pains.

Common side effects (occurring in at least 1 in 100 patients) are:

-Flu-like symptoms, sinusitis, chills, weakness
-Anaemia, low numbers of cells called platelets that help the blood to clot, low numbers of some types of white blood cells or of all types of blood cells, red or purple discoloration of the skin which may be caused by low platelet count , other blood cell changes
-Low blood sugar, low blood potassium
-Anxiety, depression, tingling, confusion, dizziness, agitation, trembling, hallucinations and other nervous symptoms
-Low blood pressure, inflammation of a vein (which may be associated with the formation of a blood clot)
-Breathing difficulty, chest pain, fluid accumulation in the lungs
-Jaundice, redness of the skin
-Swelling of the lips or face
-Allergic reactions (sometimes severe), including widespread blistering rash and skin peeling, severe skin reaction following exposure to light or sun
-Itchiness
-Hair loss
-Back pain
-Kidney failure, blood in the urine, changes in blood tests of kidney function
-Inflammation at injection sites
-Changes in blood tests of liver function

Uncommon side effects (occurring in at least 1 in 1,000 patients) are:

-Enlarged lymph glands (sometimes painful)
-Increase in a type of white blood cell which may be associated with allergic reaction, disorder of blood clotting system
-Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting -Depressed function of the adrenal gland
-Problem with coordination
-Swelling of the brain
-Double vision pain and inflammation of the eyes and eyelids, involuntary movement of the eye -Decreased sensitivity to touch
-Constipation, inflammation of upper small intestine, dyspepsia, pancreatitis, peritonitis -Gingivitis,
-Swelling and inflammation of the tongue
-Enlarged liver, hepatitis, liver failure, gallbladder disease, gallstones
-Joint pain
-Inflammation of the kidney, proteins in the urine -Abnormal electrocardiogram (ECG) -Blood chemistry changes

Rare side effects (occurring in at least 1 in 10,000 patients) are:

• Inability to sleep -Hearing difficulties, ringing in the ears -Abnormal sense of taste -Increase in muscle tone, muscle weakness caused by an abnormal immune system response -Abnormal brain function, Parkinson-like symptoms, convulsion, nerve injury resulting in numbness, pain, tingling or burning in the hands or feet. -Sleepiness during infusion

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.

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

If any of the side effects gets serious or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep VFEND out of the reach and sight of children. Do not use VFEND after the expiry date which is stated on the label. The expiry date refers to the last day of the 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).

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What VFEND contains

-The active substance is voriconazole.
-The other ingredient is sulphobutylether beta cyclodextrin 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

VFEND is presented in single use glass vials as a powder for solution for infusion. The information in this leaflet is about VFEND 200 mg powder for solution for infusion only. For further information on VFEND 50 mg and 200 mg film-coated tablets or VFEND 40 mg/ml powder for oral suspension, please see the User Package Leaflet for these products.

Marketing Authorisation Holder

Pfizer Limited, Ramsgate Rd, Sandwich, Kent, CT13 9NJ, United Kingdom.
Manufacturer

Pfizer PGM, 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:

België BelgiqueBelgien Pfizer S.A.N.V. TélTel 32 02 554 62 11 LuxembourgLuxemburg Pfizer S.A. Tél 32 02 554 62 11

, . 359 2 970 4333 Magyarország Pfizer Kft. Tel. 36 1 488 37 00

eská republika Pfizer s.r.o. Tel 420-283-004-111 Malta V.J. Salomone Pharma Ltd. Tel 356 21 22 01 74

Danmark Pfizer ApS Tlf 45 44 20 11 00 Nederland Pfizer bv Tel 31 010 406 43 01

Deutschland Pfizer Pharma GmbH Tel 49 030 550055 51000 Norge Pfizer AS Tlf 47 67 52 61 00

Eesti Pfizer Luxembourg SARL Eesti filiaal Tel 372 6 405 328 Österreich Pfizer Corporation Austria Ges.m.b.H. Tel 43 01 521 15-0

Pfizer Hellas A.E. 30 210 6785 800 Polska Pfizer Polska Sp. z o.o., Tel. 48 22 335 61 00

España Pfizer S.A. Tel 34 91 490 99 00 Portugal Laboratórios Pfizer, Lda. Tel 351 214 235 500

France Pfizer Tél 33 01 58 07 34 40 România Pfizer România S.R.L Tel 40 021 207 28 00

Ireland Pfizer Healthcare Ireland Tel 1800 633 363 toll free 44 01304 616161 Slovenija Pfizer Luxembourg SARL Pfizer, podrunica za svetovanje s podroja farmacevtske dejavnosti, Ljubljana Tel 386 0152 11 400

Ísland Icepharma hf., Sími 354 540 8000 Slovenská republika Pfizer Luxembourg SARL, organizaná zloka Tel 421-2-3355 5500

Italia Pfizer Italia S.r.l. Tel 39 06 33 18 21 SuomiFinland Pfizer Oy PuhTel 35809 43 00 40

GEO. PAVLIDES ARAOUZOS LTD, 35722818087 Sverige Pfizer AB Tel 46 08 5505 2000

United Kingdom Pfizer Limited Tel 44 01304 616161 Latvija Pfizer Luxembourg SARL Filile Latvij Tel 371 670 35 775

Lietuva
Pfizer Luxembourg SARL
Filialas Lietuvoje
Tel. +3705 2514000

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

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

Reconstitution and Dilution information

• VFEND powder for solution for infusion needs to first be reconstituted with 19 ml of Water for Injections to obtain an extractable volume of 20 ml of clear concentrate containing 10 mg/ml voriconazole.
• Discard the VFEND vial if the vacuum does not pull the diluent into the vial.
• It is recommended that a standard 20 ml (non-automated) syringe be used to ensure that the exact amount (19.0 ml) of Water for Injections is dispensed.
• The required volume of the reconstituted concentrate is then added to a recommended compatible infusion solution listed below to obtain a final VFEND solution containing 0.5 to 5 mg/ml of voriconazole.
• This medicinal product is for single use only and any unused solution should be discarded and only clear solutions without particles should be used.
• Not for administration as a bolus injection.
• For storage information, please refer to Section 5 ?How to store VFEND?.

Required Volumes of 10 mg/ml VFEND Concentrate

Volume of VFEND Concentrate 10 mgml required for Body Weight kg 3 mgkg dose number of vials 4 mgkg dose number of vials 6 mgkg dose number of vials 7 mgkg dose number of vials 10 - 4.0 ml 1 - 7.0 ml 1 15 - 6.0 ml 1 - 10.5 ml 1 20 - 8.0 ml 1 - 14.0 ml 1 25 - 10.0 ml 1 - 17.5 ml 1 30 9.0 ml 1 12.0 ml 1 18.0 ml 1 21.0 ml 2 35 10.5 ml 1 14.0 ml 1 21.0 ml 2 24.5 ml 2 40 12.0 ml 1 16.0 ml 1 24.0 ml 2 28.0 ml 2 45 13.5 ml 1 18.0 ml 1 27.0 ml 2 31.5 ml 2 50 15.0 ml 1 20.0 ml 1 30.0 ml 2 35.0 ml 2

55 16.5 ml 1 22.0 ml 2 33.0 ml 2 - 60 18.0 ml 1 24.0 ml 2 36.0 ml 2 - 65 19.5 ml 1 26.0 ml 2 39.0 ml 2 - 70 21.0 ml 2 28.0 ml 2 42.0 ml 3 - 75 22.5 ml 2 30.0 ml 2 45.0 ml 3 - 80 24.0 ml 2 32.0 ml 2 48.0 ml 3 - 85 25.5 ml 2 34.0 ml 2 51.0 ml 3 - 90 27.0 ml 2 36.0 ml 2 54.0 ml 3 - 95 28.5 ml 2 38.0 ml 2 57.0 ml 3 - 100 30.0 ml 2 40.0 ml 2 60.0 ml 3 -

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 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.

Compatible Infusion Solutions:
The reconstituted solution can be diluted with: 9 mg/ml (0.9 %) Sodium Chloride for Infusion Lactated Ringer?s Intravenous Infusion 5 % Glucose and Lactated Ringer?s Intravenous Infusion 5 % Glucose and 0.45 % Sodium Chloride Intravenous Infusion 5 % Glucose Intravenous Infusion 5 % Glucose in 20 mEq Potassium Chloride Intravenous Infusion
0.45 % Sodium Chloride Intravenous Infusion 5 % Glucose and 0.9 % Sodium Chloride Intravenous Infusion

The compatibility of VFEND with diluents other than listed above (or listed below under ?Incompatibilities?) is unknown.

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.