VORICONAZOLE ADAMED

Package leaflet: Information for the user

Voriconazol Adamed, 200 mg, powder for concentrate 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.
• This medicine has been prescribed for a specific individual. Do not pass it on to others. It may harm other people, even if their symptoms are the same.
• If you experience any side effects, including any not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of the leaflet:
What Voriconazol Adamed is and what it is used for
Important information before using Voriconazol Adamed
How to use Voriconazol Adamed
Possible side effects
How to store Voriconazol Adamed
Contents of the pack and other information

What Voriconazol Adamed is and what it is used for
Voriconazol Adamed contains the active substance voriconazole. Voriconazol Adamed is an antifungal medicine. It works by killing the fungi causing infections or by inhibiting their growth.
The medicine is used to treat patients (adults and children over 2 years of age) with:

• invasive aspergillosis (a type of fungal infection caused by fungi of the genus Aspergillus),
• candidaemia (another type of fungal infection caused by fungi of the genus Candida) in patients without concomitant neutropenia (patients without abnormally low white blood cell count),
• severe, invasive fungal infections caused by Candida species resistant to fluconazole (another antifungal medicine),
• severe fungal infections caused by Scedosporium and Fusarium species (two different types of fungi).

Voriconazol Adamed is intended for patients with progressive, potentially life-threatening fungal infections.
The medicine is also used for prevention of fungal infections in high-risk patients following bone marrow transplantation.
This medicine should only be used under the supervision of a doctor.

Important information before using Voriconazol Adamed

When not to use Voriconazol Adamed

• if you are allergic to the active substance voriconazole or to 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 you are currently taking or have recently taken, including those obtained without a prescription or herbal medicines.
Do not take Voriconazol Adamed together with:

• 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 infection) at doses of 400 mg or higher once daily,
• Carbamazepine (used to treat epilepsy),
• Phenobarbital (used for insomnia and epilepsy treatment),
• Ergot alkaloids (e.g. ergotamine, dihydroergotamine used for migraine),
• Sirolimus (used after organ transplantation),
• Ritonavir (used to treat HIV infection) at doses of 400 mg or higher twice daily,
• St. John’s wort (herbal preparation),
• Naloxegol [used to treat constipation caused by opioid pain medicines (e.g. morphine, oxycodone, fentanyl, tramadol, codeine)],
• Tolvaptan [used to treat hyponatremia (low blood sodium levels) or to slow the worsening of kidney function in patients with autosomal dominant 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 starting treatment with Voriconazol Adamed if:

Avoid exposure to sunlight during treatment. It is important to wear protective clothing against sunlight and use sunscreen creams with a high protection factor (SPF), as skin symptoms of photosensitivity (UV) may occur. These precautions also apply to children.

During treatment with Voriconazol Adamed:

Immediately inform the doctor if any of the following occur:

• Sunburn
• Severe skin rash or blistering
• Bone pain

If the above skin disorders occur, the doctor may refer the patient to a dermatologist, who after consultation may decide on the necessity of regular visits. There is a small risk that long-term use of Voriconazol Adamed 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, for example cortisol, leading to symptoms such as: 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 a hormone called cortisol, leading to symptoms such as: weight gain, development of a fatty hump between the shoulders, facial rounding, 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, and excessive sweating, inform the doctor.

The doctor should regularly monitor the patient's liver and kidney function through blood tests.

Children and adolescents

Voriconazol Adamed must not be used in children under 2 years of age.

Voriconazol Adamed and other medicines

Inform the doctor or pharmacist about all medicines currently taken or recently taken, as well as any medicines the patient plans to take, including those available without a prescription.

Some medicines taken concurrently with Voriconazol Adamed may alter its effect, and Voriconazol Adamed may also affect the action of other medicines.

Inform the doctor if the following medicine is being taken, as its concomitant use with Voriconazol Adamed should be avoided if possible:

• Ritonavir (used in the treatment of HIV infection) at doses of 100 mg twice daily.
• Glasdegib (used in the treatment of cancers) – if administration of both medicines is necessary, the doctor will order frequent monitoring of heart rhythm.

Inform the doctor if any of the following medicines are being taken, as their concomitant use with Voriconazol Adamed should be avoided if possible (if concomitant use is necessary, the voriconazole dose may need to be adjusted):

• Rifabutin (used in the treatment of tuberculosis). If the patient is being treated with rifabutin, blood counts and possible adverse effects of rifabutin should be monitored.
• Phenytoin (used in the treatment of epilepsy). If the patient is being treated with phenytoin during Voriconazol Adamed therapy, its blood concentration should be monitored and dose adjustment considered.

Inform the doctor if any of the following medicines are being taken, as dose adjustment or monitoring of these medicines and/or Voriconazol Adamed may be necessary to ensure they remain effective:

• Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to reduce blood clotting),
• Cyclosporine (used after organ transplantation),
• Tacrolimus (used after organ transplantation),
• Sulfonylurea derivatives (e.g., tolbutamide, glipizide, and glyburide) (used in diabetes),
• Statins (e.g., atorvastatin, simvastatin) (used to lower cholesterol levels),
• Benzodiazepines (e.g., midazolam, triazolam) (used in severe insomnia and stress),
• Omeprazole (used in the treatment of peptic ulcer disease),
• Oral contraceptives (if Voriconazol Adamed is used concurrently with oral contraceptives, adverse effects such as nausea and menstrual disturbances may occur),
• Vinca alkaloids (Vinca), e.g., vincristine and vinblastine (used in cancer treatment),
• Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used in cancer treatment),
• Tretinoin (used in the treatment of leukemia),
• Indinavir and other HIV protease inhibitors (used in the treatment of HIV infection),
• Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used in the treatment of HIV infection) (certain doses of efavirenz must NOT be used concurrently with Voriconazol Adamed),
• Methadone (used in heroin addiction treatment),
• Alfentanil, fentanyl, and other short-acting opioid analgesics, such as sufentanil (analgesics used during surgical procedures),
• Oxycodone and other long-acting opioid analgesics, such as hydrocodone (used in moderate to severe pain),
• Non-steroidal anti-inflammatory drugs, e.g., ibuprofen, diclofenac (used in the treatment of pain and inflammatory conditions),
• Fluconazole (used in fungal infections),
• Everolimus (used in advanced renal cancer and in patients after organ transplantation),
• Letermovir (used to prevent cytomegalovirus (CMV)-related disease after bone marrow transplantation),
• Ivacaftor: used in the treatment of cystic fibrosis.

Pregnancy and breastfeeding

Voriconazol Adamed must NOT be used during pregnancy, unless the doctor decides otherwise.

Women of childbearing potential must use effective contraception during treatment with Voriconazol Adamed. If pregnancy occurs during treatment with Voriconazol Adamed, contact the doctor immediately.

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to have a child, she should consult a doctor or pharmacist before using this medicine.

Driving and operating machinery

Voriconazol Adamed may cause visual disturbances and abnormal reaction to light. In such cases, driving and operating machinery should be avoided. Contact the doctor if such disturbances occur.

Voriconazol Adamed contains hydroxypropylbetadex

The medicine contains 2600 mg of hydroxypropylbetadex per 200 mg of voriconazole.

Do not use in children under 2 years of age without medical advice.

If the patient has kidney disease, contact the doctor before using this medicine.

3. How to use Voriconazol Adamed

This medicine should always be used exactly as prescribed by the doctor. If in doubt, consult the doctor.

The doctor determines the dose based on body weight and type of infection.

The doctor may adjust the recommended dose depending on the patient's clinical condition.

The usual recommended dosing in adults (including elderly patients) is shown in the table below:

Depending on the response to treatment, the physician may increase the daily dose to 3 mg/kg body weight twice daily.
In cases of mild or moderate liver cirrhosis, the physician may decide to reduce the dose of the medicinal product.

Use in children and adolescents
The usual recommended dosing in children and adolescents is presented in the table below:

Intravenous
Children aged 2 to 12 years and Adolescents aged 12 to 14 years with body weight below 50 kg
Adolescents aged 12 to 14 years with body weight above 50 kg or greater, and adolescents above 14 years of age

Dosing during the first 24 hours (loading dose):
9 mg/kg body weight every 12 hours
6 mg/kg body weight every 12 hours
6 mg/kg body weight every 12 hours

Dosing after the first 24 hours (maintenance dose):
8 mg/kg body weight twice daily
4 mg/kg body weight twice daily

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

Voriconazol Adamed, powder for solution for infusion, will be dissolved before administration and the resulting solution will be diluted to the appropriate concentration by a nurse or pharmacist (see information provided at the end of this leaflet).

The medicinal product 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 the patient is receiving Voriconazol Adamed for prevention of fungal infections, in case of treatment-related adverse reactions, the treating physician may discontinue administration of Voriconazol Adamed.

Missed dose of Voriconazol Adamed
Since the medicinal product will be administered under strict medical supervision, a missed dose seems unlikely. However, if a dose is suspected to have been missed, always inform the physician or pharmacist.

Discontinuation of Voriconazol Adamed treatment
The duration of Voriconazol Adamed treatment is determined by the physician; however, treatment with Voriconazol Adamed, powder for solution for infusion, should not exceed 6 months.

Patients with weakened immunity or severe infections may require long-term treatment to prevent disease recurrence. In case of clinical improvement, the route of administration of Voriconazol Adamed may be changed from intravenous to oral.

If the physician decides to discontinue therapy, there is no need to worry about consequences of discontinuation.

If you have any further doubts regarding the use of this medicinal product, consult your physician, pharmacist, or nurse.

4. Possible adverse reactions

Rash
Jaundice; changes in blood test results related to liver function
Pancreatitis
Other adverse reactions
Very common: may occur in more than 1 in 10 patients
Visual disturbances (changes in vision, including blurred vision, changes in color vision, abnormal light intolerance, loss of color vision, eye disorders, seeing halos, night blindness, sensation of vibrating images, seeing sparks, visual aura, reduced visual acuity, bright vision, loss of part of the normal visual field, floaters) • fever • rash • nausea, vomiting, diarrhea • headache • extremities • abdominal pain • difficulty breathing • increased liver enzyme activity

Common: may occur in no more than 1 in 10 patients
Sinusitis, gingivitis, chills, weakness • 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 platelet count which helps blood clotting • 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 • bleeding in the eye • heart rhythm disorders, including very fast heartbeat, very slow heartbeat, fainting • low blood pressure, phlebitis (which may be associated with blood clot formation) • acute breathing difficulties, chest pain, facial swelling (oral cavity, lips and around eyes), fluid accumulation in the lungs • constipation, indigestion, cheilitis • jaundice, hepatitis and liver damage • rashes which may lead to severe blistering and skin peeling, characterized by flat, red areas on the skin covered with small merging bumps, skin redness • itching • hair loss • back pain • kidney failure, blood in urine, changes in kidney function tests

Uncommon: occur in no more than 1 in 100 patients
Influenza-like symptoms, gastrointestinal irritation and inflammation, gastrointestinal inflammation causing antibiotic-associated diarrhea, lymphangitis • inflammation of the thin membrane lining the abdominal cavity and covering abdominal organs • enlarged lymph nodes (sometimes painful), bone marrow failure, increased eosinophil count • 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 swelling • double vision, severe eye disorders, including: eye pain and inflammation of eyeballs and eyelids, abnormal eye movements, optic nerve damage leading to visual disturbances, optic disc swelling • reduced sensitivity to touch • taste disturbances • hearing loss, tinnitus, dizziness • inflammation of certain internal organs – pancreas and duodenum, swelling and inflammation of the tongue • liver enlargement, liver failure, gallbladder disorders, gallstones • arthritis, phlebitis under the skin (which may be associated with blood clot formation) • nephritis, proteinuria, kidney damage • very rapid heartbeat or skipped beats, sometimes with abnormal electrical impulses • abnormal electrocardiogram (ECG) reading • increased blood cholesterol levels, increased blood urea levels • skin allergic reactions (sometimes severe), including life-threatening skin disease characterized by painful blisters with accompanying skin and mucosal pain, particularly in the oral cavity, dermatitis, urticaria, sunburn or severe skin reaction after exposure to light or sun, redness and skin irritation, red or purplish skin discolorations which may be caused by low platelet count, rash • infusion site reaction • allergic reaction or excessive immune response.

Rare: occurring in no more than 1 in 1000 patients
Hyperthyroidism • worsening of brain function which is a serious complication of liver disease

• loss of most optic nerve fibers, corneal opacity, involuntary eye movements • blistering rash due to photosensitivity • disorders in which the immune system attacks part of the peripheral nervous system • heart rhythm or conduction disorders (sometimes life-threatening) • life-threatening allergic reaction • blood coagulation disorders • skin allergic reactions (sometimes severe), including sudden swelling (acute edema) of the dermis, subcutaneous tissue, mucous membranes and submucosal tissues, itchy or painful patches of thickened, red skin with silvery scales, skin and mucous membrane irritation, life-threatening skin disease characterized by peeling off large sheets of the epidermis (outer skin layer) from deeper skin layers • small, dry, scaling skin lesions, sometimes thickened with sharp projections or "horns"

Frequency unknown (cannot be estimated from available data)

• Moles and pigmented spots

Other important adverse reactions whose frequency is unknown but which should be reported to a doctor immediately:

• Skin cancer
• Inflammation of the tissue surrounding the bone
• Red, peeling skin patches or ring-shaped skin lesions, which may be symptoms of an autoimmune disease called cutaneous lupus erythematosus

When administering Voriconazole Adamed by infusion, adverse symptoms (hot flushes, fever, excessive 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 Adamed 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.

Sunburns or severe skin reactions after exposure to light or sunlight occurred more frequently in children. If a patient develops skin disorders, the physician may refer them to a dermatologist, who after consultation may decide that regular follow-up visits to the dermatologist are necessary. Increased liver enzyme activity was also observed more frequently in children.

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed in
the leaflet, inform your doctor, pharmacist, or nurse. Adverse reactions can
be reported directly to the Department for Monitoring Adverse Reactions to Medicinal Products,
Office for Registration of Medicinal Products, Medical Devices and Biocidal Products, Al.
Jerozolimskie 181C, PL-02-222 Warsaw, Tel.: + 48 22 49 21 301, Fax: + 48 22 49 21 309, website: https://smz.ezdrowie.gov.pl

5. How to store Voriconazol Adamed

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

The dissolved Voriconazol Adamed solution should be used immediately, but if necessary, it may be stored for no longer than 24 hours at 2°C - 8°C (refrigerator).
The prepared solution must be diluted with a compatible intravenous infusion solution, always immediately before administration (see information provided at the end of the leaflet).
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the package and other information

What Voriconazol Adamed contains

• The active substance is voriconazole. Each vial contains 200 mg of voriconazole, which, after reconstitution, gives a concentration of 10 mg/ml, as recommended by the hospital pharmacist or nurse (see information provided at the end of the leaflet).
• Other ingredients are: hydroxypropylbetadex and monohydrate lactose.

What Voriconazol Adamed looks like and contents of the pack
Voriconazol Adamed is available as a powder for solution for infusion in single-use glass vials.
Marketing Authorisation Holder
Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicza 6A
05-152 Czosnów
Manufacturer
Synthon BV
Microweg 22
6545 CM, Nijmegen
The Netherlands
Synthon Hispania S.L.
C/Castelló 1
Polígono Las Salinas
08830 Sant Boi de Llobregat, Barcelona
Spain
Adamed Pharma S.A.
Pieńków, ul. M. Adamkiewicza 6A
05-152 Czosnów

Information intended exclusively for medical professionals:

Information on reconstitution (preparation of concentrate) and dilution:

• Voriconazol Adamed, powder for solution for infusion, should 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.
• The Voriconazol Adamed vial should be discarded if vacuum (negative pressure) does not assist in drawing the solvent into the vial.
• To ensure accurate measurement of 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 solution 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 intravenous bolus injection.
• Information on storage is provided in section 5 "How to store Voriconazol Adamed".

Required volumes of Voriconazol Adamed concentrate 10 mg/mL

Voriconazol Adamed is an unpreserved, sterile lyophilisate intended for single use. Therefore, from a microbiological standpoint, the prepared concentrate should be used immediately. If the concentrate is not used immediately, the user is responsible for the storage conditions and duration prior to administration. The storage time of the concentrate should not exceed 24 hours at a temperature of 2°C - 8°C, provided that reconstitution was performed under controlled and validated aseptic conditions.

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

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

Compatibility of Voriconazol Adamed with solutions other than those listed above (or mentioned under "Incompatibilities" below) has not been established.

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