Package leaflet: Information for the user

Voriconazole 200mg Powder for Solution for Infusion

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

•    Keep this leaflet You may need to read it again.

•    If you have anyfurther questions, askyour doctor, pharmacist or nurse. •This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.

•    If you getany side effects, talkto your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

•The full name of this medicine is Voriconazole 200mg Powder for Solution for Infusion but within the leaflet itwill be referred to as Voriconazole.

What is in this leaflet

1.    What Voriconazole is and what it is used for

2.    What you need to know before you use Voriconazole

3.    How to use Voriconazole 4 Possible side effects

5.    How to store Voriconazole

6.    Contents of the packand other information

1. What Voriconazole is and what it is used for

Voriconazole 200mg Powder for Solution for Infusion contains the active substance voriconazole. Voriconazole is an antifungal medidne. Itworks by killing or stopping the growth of the fungi that cause infections.

t is used for the treatment of patients (adults and children over the age jf 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 Candidasp. infections when the fungus is resistant to fluconazole (another antifungal medicine) serious fungal infections caused by Scedosporiumsp. or Fusariumsp. (two different species of fungi).

foriconazole is intended for patients with worsening, possibly life-hreatening,fungal infections.

’revention of fungal infections in high risk bone marrow transplant ecipients.

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

!. What you need to know before you use Voriconazole )o not use Voriconazole

if you are allergic to the active ingredientvoriconazole, or to hydroxypropylbetadex or any of the other ingredients of this medicine (listed in section 6).

t is very important that you inform your doctor or pharmacist if you are akingor have taken any other medicines, even those that are obtained vithouta prescription, or herbal medicines.

"he medicines in the following list must not be taken during your course )f Voriconazole treatment Terfenadine (used for allergy)

Astemizole (used for allergy)

Cisapride (used for stomach problems)_

Pimozide (used tor treating mental illness)

Quinidine (used for irregular heart beat)

Rifampicin (used for treating tuberculosis)

Efavirenz (used for treating HIV) in doses of400mg 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 of400mg and more twice daily St John's Wort (herbal supplement).

Warnings and precautions

Talk to your doctor, pharmadstor nurse before using Voriconazole

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

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

i/Vhile being treated with Voriconazole: tell your doctor immediately if you develop -sunburn

-severe skin rash or blisters -bone pain.

t you develop skin disorders as described above, your doctor may refer /ou to a dermatologist, who after consultation may deade that it is mportant for you to be seen on a regular basis.There is a small chance that skin cancer could develop with long-term use of Voriconazole.

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

Children and adolescents

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

Other medianes and Voriconazole

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

some medianes, when taken at the same time as Voriconazole, may affect the way Voriconazole works or Voriconazole may affect the way they work

Tell your doctor if you are taking the following medicine, as treatment with Voriconazole at the same time should be avoided if possible: Ritonavir (used for treating HIV) in doses of lOOmg twice daily.

Tell your doctor if you are taking either of the following medicines, as treatmentwith Voriconazole at the same time should be avoided if aossible 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 treatmentwith Voriconazole and your dose may be adjusted.

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

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

■    Cidosporin (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 Voriconazole 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-nudeoside 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 Voriconazole)

■    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).

Pregnancy and breast-feeding

Voriconazole 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 pregnantwhile being treated with Voriconazole, f you are pregnant or breast-feeding think you may be pregnant or are planning to have a baby, ask your doctor or pharmacistfor advice before taking this medicine.

Driving and using machines

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

Voriconazole contains sodium

This medicinal product contains less than 1 mmol sodium (23mg) per vial, Le. essentially'sodium- freet

3. How to use Voriconazole

Always use 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:

Intravenous

Dose for the first 24 hours

(Loading Dose)

6mg/kg every 12 hoursfor the first 24 hours

Dose after the first 24 hours

(Maintenance Dose)_

4mg/kgtwiceaday

A

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Depending on your response to treatment your doctor may decrease the dose to 3mg/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 ncrease or decrease the daily dose.

Voriconazole Powder for Solution for Infusion will be reconstituted and further diluted to the correct concentration by your hospital oharmadst or nurse. (Please refer to the end of this leafletfor further nformation).

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

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Die following information is intended for healthcare professionals only:

Voriconazole 200mg Powder for Solution for Infusion

Teconstrtution and Dilution information

Voriconazole Powderfor Solution for Infusion needs to first be reconstituted with either 19ml of Water for Injections or 19ml of 9mg/ml (0.9%) Sodium Chloridefor Infusion to obtain an extractable volume of 20ml of clear concentrate containing lOmg/ml voriconazole.

Discard the Voriconazole vial if the vacuum does not pull the diluent into the vial.

It is recommended that a standard 20ml (non-automated) syringe be used to ensure that the exact amount (19.0ml) of Water for Injections or of 9mg/ml (0.9%) Sodium Chloridefor Infusion isdispensed.

The required volumeof the reconstituted concentrate is then added to a recommended compatible infusion solution listed belowto obtain a final Voriconazole solution containing 0.5 to 5mg/ml of voriconazole.

This medicinal product isfor single use only and any unused solution should bediscarded and only clear solutions without particles should be used. For intravenous infusion only.

For storage information, please refer to Section 5 'How to store Voriconazole.

tequired Volumes of 10mg/ml Voriconazole Concentrate

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70

75

85

90

95

100

210ml (2)

22.5ml (2)

24.0ml (2)

25.5ml (2)

27.0ml (2)

28.5ml (2)

30.0ml (2)

28.0ml (2)

30.0ml (2)

32.0ml (2)

34.0ml (2)

36.0ml (2)

38.0ml (2)

40.0ml (2)

42.0ml (3)

45.0ml (3)

48.0ml (3)

51,0ml (3)

54.0ml (3)

57.0ml (3)

60.0ml (3)

Voriconazole is a single dose unpreserved sterile lyophilisate.Therefore, from a microbiological point ofview, 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 (in a refrigerator), unless reconstitution has taken place in controlled and validated aseptic conditions.

Compatible Infusion Solutions:

The reconstituted solution can be diluted with:

Sodium Chloride 9mg/ml (0.9%) Solution for Injection

5% (50mg/ml) Glucose and Lactated Ringer's Intravenous Infusion

5% (50mg/ml) Glucose and 0.45% (4.5mg/ml) Sodium Chloride Intravenous Infusion

5% (50mg/ml) Glucose Intravenous Infusion

5% (50mg/ml) Glucose in 20 mEq Potassium Chloride Intravenous Infusion

5% (50mg/ml) Glucose and 0.9% (9mg/ml) Sodium Chloride Intravenous Infusion

The compatibility of Voriconazole with diluents other than listed above (or listed below under'lncompatibilities') is unknown.

Incompatibilities:

Voriconazole must not be infused into the same line or cannula concomitantly with other drug infusions, including parenteral nutrition.

Infusions of blood products must not occur simultaneously with Voriconazole.

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

Voriconazole must not be diluted with 4.2% (42mg/ml) Sodium Bicarbonate Infusion.

When reconstituted with Water for Injections, Voriconazole cannot be used in combination with Sodium Chloride 0.45%

(45mg/ml) Solution for Injection and Compound Sodium Lactate Intravenous Infusion, due to low osmolality.

actavis

Actavis, Barnstaple, EX32 8NS, UH _BBBAQQ23

t you or your child are taking Voriconazole tor prevention of fungal nfections, your doctor may stop giving Voriconazole if you or your child develop treatment related side effects.

If a dose of Voriconazole has been forgotten

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

If you stop using Voriconazole

i/oriconazole treatmentwill continue for as long as your doctor advises, lowever duration of treatmentwith Voriconazole Powder for Solutionfor nfusion should be no more than 6 months.

³atients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning. Vou may be switched from the intravenous infusion to tablets once your condition improves.

When Voriconazole treatment is stopped by your doctor you should not experience any effects.

f you have any further questions on the use of this medidne, askyour doctor, pharmacist or nurse.

4. Possible side effects

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

fany side effects occur, mostare likely to be minor and temporary. Howeve some may be serious and need medical attention.

Serious side effects - Stop using Voriconazole and see a doctor immediately

■    Rash

■    Jaundice; Changes in blood tests of liver function

■    Pancreatitis.

Other side effects

Very common side effects (may affect more than 1 in 10 people):

■Visual impairment (change in vision including blurred vision, visual colour 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 ofvision, spots before the eyes)

■    Fever

■    Rash

■    Nausea,vomiting,diarrhoea

■    Headache

■    Swelling of the extremities

■    Stomach pains

■    Breathing difficulties

■    Elevated liver enzymes.

Common side effects (may affect up to 1 in 10 people):

■    Inflammation of the sinuses, inflammation of the gums, chilly 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

■    Allergic reaction or exaggerated immune response

■    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

. Rlppdinginthppyp_

Heart rhythm problems induding very fast heartbeat, very slow heartbeat, fainting

Low blood pressure, inflammation of a vein (which may be associated with theformationofa 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

characterised by a flat red area on the skin that is covered with small

confluent bumps, redness of the skin

Itchiness

Hair loss

Back pain

Kidneyfailure, blood in the urine, changes in kidney function tests.

Uncommon side effects (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_

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Page 4

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 Veryfast heart rate or skipped heartbeats, sometimes with erratic electrical impulse

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.

Taresideeffects(mayaffectupto 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 theeye Bullous photosensitivity

Adisorder 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 ot thick, red skin with silvery scales ot 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 know (frequency cannot be estimated from he available data):

Freckles and pigmented spots.

Dther significant side effects whose frequency is not known, but should be eported 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 roriconazole (including flushing, fever, sweating, increased heart rate and shortness of breath). Your doctor may stop the infusion if this occurs.

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

(here have been reports of skin cancer in patients treated with voriconazole or long periods of time.

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

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

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You an also report side effects directly via the Yellow Card Scheme Website: www.mhra.aov.uk/velloward

By reporting side effects you an help provide more information on the safety of this medicine.

5. Howto store Voriconazole

Keep this medicine out of the sightand reach of children.

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

Do not store above 30°C Store in the original package in order to protect from light

Once reconstituted, Voriconazole should be used immediately, but if necessary may be stored for up to 24 hours at 2°C - 8°C (in a refrigerator) or in room temperature (15°C-25°C). Reconstituted Voriconazole needs to be further diluted with a compatible infusion solution first before it is infused. (Please refer to the end of this leafletfor further information).

Once diluted, the solutions an be stored for up to 48 hours at 2°C - 8°C (in a refrigerator) or up to 24 hours at 15-25°C (room temperature).

From a microbiological point of view, the product 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°C to 8°C, unless reconstitution/dilution has taken

place in controlled and validated a^ptir conditions_

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

5. Contents of the packand other information What Voriconazole contains

■The active substance is voriconazole.

■The other ingredients are hyd roxypro pyI beta dex, arginine hydrochloride, sodium hydroxide (for pH adjustment), hydrochloric acid concentrated (for pH adjustment).

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

What Voriconazole looks like and contents of the pack

Voriconazole is a white or almostwhite powder for solution for infusion oresented in 30ml single use glass vials

Marketing Authorisation Holder

Actavis Group PTC ehf, Reykjavikurvegi 76-78,220 Hafnarfjordur, Iceland Manufacturer

Actavis ItalyS.p.A, Nerviano Plant,Via Pasteur 10,20014 Nerviano (Milan) This leaflet was last revised in October 2016.

(^actavis

Actavis, Barnstaple, EX32 8NS, UK _BBBA0023