Voriconazole accord

Patient Information Leaflet

Voriconazole Accord, 200 mg, powder for solution for infusion
Voriconazolum
Please read all of this leaflet carefully before using this medicine, because it contains
important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the leaflet

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

1. What Voriconazole Accord is and what it is used for

Voriconazole Accord contains the active substance voriconazole. Voriconazole Accord is an antifungal medicine. It works by killing the fungi causing infections or by stopping their growth.
The medicine is used to treat patients (adults and children aged over 2 years) with:

• invasive aspergillosis (a type of fungal infection caused by Aspergillus fungi),
• candidaemia (another type of fungal infection caused by Candida fungi) in patients without concomitant neutropenia (patients who do not have abnormally low levels of white blood cells),
• serious, invasive fungal infections caused by Candida fungi that are resistant to fluconazole (another antifungal medicine),
• serious fungal infections caused by Scedosporium and Fusarium fungi (two different species of fungi).

Voriconazole Accord is intended for patients with progressive, potentially life-threatening fungal infections.
The medicine is also indicated for the prevention of fungal infections in high-risk patients following allogeneic hematopoietic stem cell transplantation.
This medicine should only be used under the supervision of a doctor.

2. Important information before using Voriconazole Accord

When not to use Voriconazole Accord

• if the patient is allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

It is very important to inform your doctor or pharmacist about all medicines currently or recently taken by the patient, including those obtained without a prescription or herbal medicines.
The following medicines must not be taken during treatment with Voriconazole Accord:

• terfenadine (used to treat allergies),
• astemizole (used to treat allergies),
• cisapride (used for gastrointestinal disorders),
• pimozide (used to treat psychiatric disorders),
• quinidine (used for heart rhythm disorders),
• ivabradine (used to treat symptoms of chronic heart failure),
• rifampicin (used to treat tuberculosis),
• efavirenz (used to treat HIV infections) at doses of 400 mg or higher once daily,
• carbamazepine (used to treat epilepsy),
• phenobarbital (used for insomnia and treatment of epilepsy),
• ergot alkaloids (e.g. ergotamine, dihydroergotamine used for migraine),
• sirolimus (used in transplant patients),
• ritonavir (used to treat HIV infections) at doses of 400 mg or higher twice daily,
• St John’s wort (herbal medicine),
• naloxegol [used to treat constipation specifically caused by opioid pain medicines (e.g. morphine, oxycodone, fentanyl, tramadol, codeine)],
• tolvaptan [used to treat hyponatraemia (low sodium levels in the patient’s blood) or to slow the decline in kidney function in patients with autosomal dominant polycystic kidney disease],
• lurasidone (used to treat depression),
• finerenone (used to treat chronic kidney disease),
• venetoclax [used to treat patients with chronic lymphocytic leukaemia (CLL)].

Warnings and precautions
Before starting treatment with Voriconazole Accord, discuss with your doctor, pharmacist, or nurse if:

• the patient has had hypersensitivity to other azoles.
• the patient has liver disease, including past history of liver disease. In case of liver disease, the doctor may prescribe a lower dose of Voriconazole Accord. The doctor should also monitor liver function during treatment with Voriconazole Accord by ordering appropriate blood tests.
• the patient has cardiomyopathy, heart rhythm disorders, slow heart rate, or changes in the electrocardiogram (ECG) known as “prolonged QTc interval”.

Avoid any exposure to sunlight during treatment. It is important to wear protective clothing and use sunscreen products with a high sun protection factor (SPF) against ultraviolet (UV) radiation.
This risk may be further increased by other medicines that make the skin more sensitive to sunlight, such as methotrexate. These precautions also apply to children.
During treatment with Voriconazole Accord:

• contact your doctor immediately if you experience
  • sunburn
  • severe skin rash or blisters
  • bone pain

If the above skin disorders occur, the doctor may refer the patient to a dermatologist, who after consultation may decide on the need for regular follow-up visits. There is a small risk that long-term use of Voriconazole Accord may lead to skin cancer.
If the patient develops symptoms of “adrenal insufficiency”, in which the adrenal glands do not produce sufficient amounts of certain steroid hormones, such as cortisol, including: chronic or prolonged fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, inform the doctor.
If the patient develops symptoms of “Cushing's syndrome”, in which the body produces too much of the hormone cortisol, leading to symptoms such as: weight gain, development of a fatty hump between the shoulders, rounded face, darkening of the skin on the abdomen, thighs, chest and arms, thinning of the skin, increased tendency to bruising, elevated blood sugar levels, excessive hair growth, increased sweating, inform the doctor.
The doctor should regularly monitor the patient’s liver and kidney function through blood tests.

Children and adolescents
Voriconazole Accord must not be used in children under 2 years of age.

Voriconazole Accord and other medicines
Tell your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines the patient plans to take, including those available without a prescription.

• Some medicines taken together with Voriconazole Accord may alter its effect, and Voriconazole Accord may also affect the action of other medicines.

Tell your doctor if you are taking the following medicine, as concomitant use with Voriconazole Accord should be avoided if possible:

• ritonavir (used to treat HIV infections) at doses of 100 mg twice daily.
• glasdegib (used to treat cancers) – if co-administration is necessary, the doctor will order frequent monitoring of heart rhythm.

Tell your doctor if you are taking any of the following medicines, as concomitant use with Voriconazole Accord should be avoided if possible (if co-administration is necessary, the voriconazole dose may need adjustment):

• rifabutin (used to treat tuberculosis). If the patient is being treated with rifabutin, blood parameters and adverse effects of rifabutin should be monitored.
• phenytoin (used to treat epilepsy). If the patient is being treated with phenytoin during Voriconazole Accord therapy, its blood levels should be monitored and dose adjustment considered.

Tell your doctor if you are taking any of the following medicines, as dose adjustment or monitoring of these medicines and/or Voriconazole Accord may be necessary to ensure they remain effective:

• warfarin and other anticoagulants (e.g. phenprocoumon, acenocoumarol; used to reduce blood clotting),
• cyclosporine (used in transplant patients),
• tacrolimus (used in transplant patients),
• sulfonylureas (e.g. tolbutamide, glipizide, glyburide) (used in diabetes),
• statins (e.g. atorvastatin, simvastatin) (used to lower cholesterol levels),
• benzodiazepines (e.g. midazolam, triazolam) (used for severe insomnia and anxiety),
• omeprazole (used to treat ulcers),
• oral contraceptives (if Voriconazole Accord is taken together with oral contraceptives, adverse effects such as nausea and menstrual irregularities may occur),
• Vinca alkaloids (e.g. vincristine, vinblastine) (used to treat cancers),
• tyrosine kinase inhibitors (e.g. axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used to treat cancers),
• tretinoin (used to treat leukaemia),
• indinavir and other HIV protease inhibitors (used to treat HIV infection),
• non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz, delavirdine, nevirapine) (used to treat HIV infection) (certain doses of efavirenz must not be used concomitantly with Voriconazole Accord),
• methadone (used to treat heroin addiction),
• alfentanil, fentanyl, and other short-acting opioids such as sufentanil (pain medicines used during surgical procedures),
• oxycodone and other long-acting opioids such as hydrocodone (used for moderate to severe pain),
• non-steroidal anti-inflammatory drugs (e.g. ibuprofen, diclofenac) (used to treat pain and inflammatory conditions),
• fluconazole (used to treat fungal infections),
• everolimus (used to treat advanced renal cell carcinoma and in transplant patients),
• letermovir [used to prevent cytomegalovirus (CMV) disease after allogeneic haematopoietic stem cell transplantation],
• ivacaftor (used to treat cystic fibrosis).

Pregnancy and breastfeeding
Voriconazole Accord must not be used during pregnancy unless otherwise decided by the doctor. Women of childbearing potential must use effective contraception during treatment with Voriconazole Accord.
If pregnancy occurs during treatment with Voriconazole Accord, contact your doctor immediately.
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to become pregnant, she should consult her doctor or pharmacist before using this medicine.

Driving and operating machinery
Voriconazole Accord may cause visual disturbances and abnormal reaction to light. In such cases, driving and operating machinery should be avoided. Contact your doctor if such disturbances occur.

Voriconazole Accord contains hydroxypropylbetadex (cyclodextrin)
This medicine contains 3595.20 mg of cyclodextrin per vial, equivalent to 179.76 mg/mL after reconstitution in 20 mL. If the patient has kidney disease, they should contact their doctor before taking this medicine.

3. How to use Voriconazole Accord

This medicine should always be used exactly as your doctor has told you. If you are unsure, you should contact your doctor.
Your doctor will decide the dose based on body weight and type of infection. Your doctor may change the recommended dose depending on your clinical condition.
The usual recommended dosing for adults (including elderly patients) is shown in the table below:

Depending on the response to treatment, the doctor may reduce the dose to 3 mg/kg body weight twice daily.
If mild to moderate liver cirrhosis is diagnosed, the doctor may decide to reduce the dose of the medicine.
Use in children and adolescents
The usual recommended dosing in children and adolescents is shown in the table below:

Depending on the response to treatment, the doctor may increase or decrease the daily dose.
The Voriconazole Accord medication, powder for solution for infusion, will be reconstituted and diluted to the appropriate concentration by a nurse or pharmacist (see information provided at the end of the leaflet).
The medication will be administered as an intravenous infusion at a maximum rate of 3 mg/kg body weight per hour over 1 to 3 hours.
If a patient is receiving Voriconazole Accord to prevent fungal infections, and treatment-related adverse reactions occur, the treating physician may discontinue administration of Voriconazole Accord.

Missed dose of Voriconazole Accord
Since the medication will be administered under strict medical supervision, missing a dose seems unlikely. However, if a dose is suspected to have been missed, always inform the doctor or pharmacist.

Discontinuation of Voriconazole Accord treatment
The duration of treatment with Voriconazole Accord is determined by the doctor; however, treatment with Voriconazole Accord, powder for solution for infusion, should not exceed 6 months.
Patients with weakened immune systems or severe infections may require long-term treatment to prevent disease recurrence. Upon clinical improvement, the route of administration of Voriconazole Accord may be switched from intravenous to oral.
If the doctor decides to discontinue therapy with Voriconazole Accord, there is no need to worry about consequences of stopping the treatment.

If you have any further questions regarding the use of this medication, consult your doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them. If
adverse reactions do occur, they are mostly mild and transient. However, some of them may be serious and
may require medical intervention.
Severe adverse reactions – stop taking Voriconazole Accord immediately and contact your doctor

• Rash
• Jaundice; changes in blood test results related to liver function
• Pancreatitis

Other adverse reactions
Very common (may affect more than 1 in 10 people):

• Visual disturbances (changes in vision, including blurred vision, changes in colour vision, abnormal light sensitivity, loss of colour vision, eye disorders, seeing halos, night blindness, perception of image vibration, seeing sparks, visual aura, reduced visual acuity, bright vision, loss of part of the normal visual field, floaters)
• Fever
• Rash
• Nausea, vomiting, diarrhoea
• Headache
• Peripheral oedema
• Abdominal pain
• Difficulty breathing
• Increased liver enzyme activity

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

• Sinusitis, gingivitis, chills, fatigue
• Low number of certain types of blood cells, including severe cases, red blood cells (sometimes immune-mediated) and (or) white blood cells (sometimes accompanied by fever), low number of blood cells called platelets which help blood to clot
• Low blood sugar, low blood potassium, low blood sodium
• Anxiety, depression, confusion, agitation, insomnia, hallucinations
• Seizures, tremor or uncontrolled muscle movements, tingling or unusual skin sensations, increased muscle tone, drowsiness, dizziness
• Eye haemorrhage
• Heart rhythm disorders, including very fast heartbeat, very slow heartbeat, fainting
• Low blood pressure, phlebitis (which may be associated with blood clots)
• Acute breathing difficulties, chest pain, facial swelling (of the mouth, lips, and around the eyes), fluid accumulation in the lungs
• Constipation, indigestion, cheilitis (inflammation of the lips)
• Jaundice, hepatitis and liver damage
• Skin rashes that may lead to severe blistering and skin peeling characterised by flat, red areas of skin covered with small merging bumps, skin redness
• Itching
• Hair loss
• Back pain
• Kidney failure, blood in urine, changes in kidney function tests
• Sunburn or severe skin reaction following exposure to light or sunlight
• Skin cancer

Uncommon (may affect up to 1 in 100 people):

• Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, antibiotic-associated diarrhoea due to gastrointestinal inflammation, lymphangitis (inflammation of lymphatic vessels)
• Inflammation of the thin tissue lining the abdominal wall and covering abdominal organs (peritonitis)
• Enlarged lymph nodes (sometimes painful), bone marrow failure, increased number of eosinophils
• Adrenal gland dysfunction, hypothyroidism
• Brain function disorders, Parkinson-like symptoms, nerve damage causing numbness, pain, tingling or burning sensations in hands or feet
• Balance or coordination disorders
• Brain oedema
• Double vision, severe eye disorders, including: eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage leading to vision disturbances, optic disc swelling
• Reduced sensitivity to touch
• Taste disturbances
• Hearing loss, tinnitus, dizziness
• Inflammation of certain internal organs – pancreas and duodenum, tongue swelling and inflammation
• Liver enlargement, liver failure, gallbladder disorders, gallstones
• Arthritis, phlebitis under the skin (which may be associated with blood clots)
• Kidney inflammation, proteinuria, kidney damage
• Very fast heartbeat or skipped heartbeats, sometimes with abnormal electrical impulses
• Abnormal electrocardiogram (ECG) findings
• Increased blood cholesterol levels, increased blood urea levels
• Allergic skin reactions (sometimes severe), including life-threatening skin disease characterised by painful blisters with associated skin and mucosal pain, particularly in the mouth, skin inflammation, urticaria, skin redness and irritation, red or purple skin discolourations which may be caused by low platelet count, rash
• Infusion site reaction
• Allergic reaction or excessive immune response
• Inflammation of tissue surrounding bone (periostitis)

Rare (may affect up to 1 in 1,000 people):

• Hyperthyroidism
• Worsening of brain function which is a serious complication of liver disease
• Loss of most of the optic nerve fibres, corneal opacity, involuntary eye movements
• Blistering skin rash due to photosensitivity
• Disorders in which the immune system attacks parts of the peripheral nervous system
• Heart rhythm or conduction disorders (sometimes life-threatening)
• Life-threatening allergic reaction
• Blood coagulation disorders
• Allergic skin reactions (sometimes severe), including sudden swelling (acute oedema) of the dermis, subcutaneous tissue, mucous membranes and submucosal tissues, itchy or painful thickened red skin patches with silvery scales, skin and mucosal irritation, life-threatening skin disease involving detachment of large sheets of the epidermis (outer skin layer) from deeper skin layers
• Small, dry, peeling skin patches, sometimes thickened with sharp projections or "horns"

Frequency not known (cannot be estimated from available data):

• Freckles and pigmented spots

Other important adverse reactions, frequency unknown, but which should be reported to the doctor immediately:

• Red, peeling skin patches or ring-shaped skin lesions, which may indicate an autoimmune disease called cutaneous lupus erythematosus

During intravenous infusion of Voriconazole Accord, adverse symptoms (hot flushes, fever, sweating, increased heart rate, and shortness of breath) occurred uncommonly. If these symptoms occur, the doctor may decide to discontinue the infusion.
Due to the known effects of Voriconazole Accord on the liver and kidneys, the function of these organs should be monitored with appropriate blood tests. You should also inform your doctor if you experience abdominal pain or changes in stool consistency.
Cases of skin cancer have been reported in patients treated with Voriconazole Accord for a prolonged period.
Sunburn or severe skin reactions following exposure to light or sunlight occurred more frequently in children. If skin disorders occur, the doctor may refer the patient to a dermatologist, who after consultation may decide that regular follow-up visits to the dermatologist are necessary. Increased liver enzyme activity has also been observed more frequently in children.
If any of these adverse reactions persist or become troublesome, inform your doctor.
Reporting of adverse reactions
If you experience any adverse reactions, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions, Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al. Jerozolimskie 181C,
02-222 Warsaw,
tel.: +48 22 49 21 301,
fax: +48 22 49 21 309,
website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
By reporting adverse reactions, additional information on the safety of this medicine can be collected.

5. How to store Voriconazole Accord

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton after EXP.
The expiry date refers to the last day of the stated month.
There are no special requirements for the storage conditions of this medicinal product.
After reconstitution, chemical and physical stability has been demonstrated for 24 hours at 2-8°C.
From a microbiological point of view, the product should be used immediately. If not used immediately,
the user is responsible for the storage time and conditions.
After dilution, chemical and physical stability has been demonstrated for 6 hours at 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately,
the user is responsible for the storage time and conditions.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. Such measures help protect the environment.

6. Contents of the pack and other information

What Voriconazole Accord contains
The active substance is voriconazole.
The other components are hydroxypropylbetadex (HPBCD) and monohydrate lactose.
Each vial contains 200 mg of voriconazole. After reconstitution according to instructions provided by the hospital pharmacist or nurse, the concentration of voriconazole is 10 mg/mL (see information provided at the end of the leaflet).

What Voriconazole Accord looks like and contents of the pack
Voriconazole Accord is a white, lyophilized powder for solution for infusion.
The medicine is available in single-use glass vials.
The pack contains 1 vial.

Marketing Authorisation Holder
Accord Healthcare Polska Sp. z o.o.
ul. Taśmowa 7
02-677 Warsaw
Tel: + 48 22 577 28 00

Manufacturer/Importer
Accord Healthcare Polska Sp. z o.o.
ul. Lutomierska 50
95-200 Pabianice
Pharmadox Healthcare Ltd.
KW20A Kordin Industrial Park
Paola, PLA 3000
Malta

This medicinal product is authorised for marketing in the Member States of the European Economic Area under the following names:

| Member State | Name of the medicinal product | |------------------|-----------------------------------| | Austria | Voriconazol Accord 200 mg Pulver zur Herstellung einer Infusionslösung | | Belgium | Voriconazole Accord Healthcare 200 mg, Poeder voor oplossing voor infusie | | Bulgaria | Voriconazole Accord 200 mg Powder for solution for infusion | | Cyprus | Voriconazole Accord 200 mg Powder for solution for infusion | | Czech Republic | Voriconazole Accord 200 mg, prášek pro infuzní roztok | | Denmark | Voriconazole Accord 200 mg | | Estonia | Voriconazole Accord | | Finland | Voriconazole Accord 200 mg infuusiokuiva-aine, liuosta varten | | France | Voriconazole Accord 200 mg, poudre pour solution pour perfusion | | Spain | Voriconazole Accord 200 mg, polvo para solución para infusión | | Netherlands | Voriconazol Accord 200 mg Poeder voor oplossing voor infusie | | Ireland | Voriconazole Accord 200 mg Powder for Solution for Infusion | | Iceland | Vórikónazóli 200 mg innrennslisstofn, lausn | | Lithuania | Voriconazole Accord 200 mg milteliai infuziniam tirpalui | | Latvia | Voriconazole Accord 200 mg pulveris infūziju šķīduma pagatavošanai | | Germany | Voriconazol Accord 200 mg Pulver zur Herstellung einer Infusionslösung | | Norway | Voriconazole Accord 200 mg | | Poland | Voriconazole Accord | | Portugal | Voriconazol Accord 200 mg | | Romania | Voriconazol Accord 200 mg pulbere pentru soluție perfuzabilă | | Slovenia | Vorikonazol Accord 200 mg prašek za raztopino za infundiranje | | Sweden | Voriconazole 200 mg Pulver till infusionsvätska, lösning | | Hungary | Voriconazole Accord 200 mg Por oldatos infúzióhoz |

Information intended solely for healthcare professionals:
Instructions for reconstitution (preparation of concentrate) and dilution:

• Voriconazole Accord powder for solution for infusion must be reconstituted with 19 mL of Water for Injections or 19 mL of 9 mg/mL (0.9%) Sodium Chloride for Injections to obtain 20 mL of a clear concentrate containing 10 mg/mL of voriconazole.
• Reconstitution may take up to 4 minutes.
• The Voriconazole Accord vial should be discarded if, during addition of the solvent, the solvent is not drawn in automatically due to the vacuum present in the vial.
• To ensure accurate measurement of the volume (19 mL) of Water for Injections or 9 mg/mL (0.9%) Sodium Chloride for Injections, the use of standard 20 mL (non-automated) syringes is recommended.
• To obtain an infusion solution containing 0.5 mg/mL to 5 mg/mL of voriconazole, the required volume of the prepared concentrate should be added to the recommended compatible infusion solution (see below).
• This medicinal product is for single use only. Any unused solution should be discarded. Do not use solutions that are not clear or that contain any cloudiness or particulate matter.
• The solution is not intended for rapid intravenous injection (bolus).
• Information on storage instructions is provided in section 5 “How to store Voriconazole Accord”.

Required volumes of Voriconazole Accord concentrate 10 mg/mL

Voriconazole Accord is an unpreserved, sterile lyophilisate for single use. After reconstitution, chemical and physical stability has been demonstrated for 24 hours at 2–8°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions.
After dilution, chemical and physical stability has been demonstrated for 6 hours at 25°C. From a microbiological point of view, the product should be used immediately. If not used immediately, the user is responsible for the storage duration and conditions.

Compatible solutions for preparing infusion solution:
The prepared concentrate may be diluted with:

• 9 mg/mL (0.9%) sodium chloride solution for injection
• Sodium lactate solution for intravenous infusion
• 5% glucose solution and Ringer's lactate solution for intravenous infusion
• 5% glucose solution with 0.45% sodium chloride solution for intravenous infusion
• 5% glucose solution for intravenous infusion
• 5% glucose solution with 20 mEq potassium chloride solution for intravenous infusion and 0.45% sodium chloride solution for intravenous infusion
• 5% glucose solution and 0.9% sodium chloride solution for intravenous infusion
• Ringer's lactate solution for intravenous infusion

Compatibility of Voriconazole Accord with solutions other than those listed above (or mentioned in the section "Incompatibilities" below) has not been established.

Incompatibilities:
Voriconazole Accord must not be administered together with other medicinal products in the same infusion line or intravenous access, including parenteral nutrition (e.g., Aminofusin 10% Plus).
Voriconazole Accord must not be co-administered simultaneously with blood products.
Intravenous infusions for parenteral nutrition may be administered simultaneously with voriconazole, but not through the same intravenous access or cannula.
4.2% sodium bicarbonate solution for intravenous infusion must not be used to dilute Voriconazole Accord.