Voriconazole accordpharma

Package leaflet: Information for the user

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

• Keep this leaflet as 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

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

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

Voriconazole Accordpharma is an antifungal medicine and contains the active substance
voriconazole. It works by killing or inhibiting the growth of fungi that cause infections.
It is used to treat patients (adults and children over 2 years of age) with:

• invasive aspergillosis (a type of fungal infection caused by Aspergillus species)
• candidaemia (another type of fungal infection caused by Candida species) in patients without neutropenia (those who do not have low white blood cell counts)
• serious invasive infections caused by Candida species resistant to fluconazole (another antifungal medicine)
• serious fungal infections caused by Scedosporium or Fusarium species (two different types of fungi).

Voriconazole Accordpharma is indicated for use in patients with progressive, potentially life-threatening fungal infections.
It is also used for prevention of fungal infections in patients at high risk following bone marrow transplantation.
This medicine should only be used under the supervision of a doctor.

2. Important information before taking Voriconazole Accordpharma

When not to take Voriconazole Accordpharma:

• if the patient is allergic to voriconazole or to hydroxypropylbetadex, 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 currently or recently taken by the patient, including those available without a prescription, or herbal medicines.

Do not take Voriconazole Accordpharma together with any of the following medicines:

• 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 a dose of 400 mg or higher taken once daily
• carbamazepine (used to treat epilepsy)
• phenobarbital (used to treat severe insomnia and epilepsy)
• ergot alkaloids (e.g. ergotamine, dihydroergotamine; used to treat migraine)
• sirolimus (used in organ transplant patients)
• ritonavir (used to treat HIV infection) at a dose of 400 mg or higher taken twice daily
• St John’s wort (herbal medicine)
• naloxegol [used to treat constipation caused by opioid pain medicines (e.g. morphine, oxycodone, fentanyl, tramadol, codeine)]
• tolvaptan [used to treat hyponatraemia (low blood sodium levels) or to slow the decline in kidney function in patients with 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 Accordpharma, discuss with your doctor, pharmacist or nurse if:

• the patient has previously experienced an allergic reaction to other azole medicines
• the patient has or has ever had liver disease; patients with liver disease may be prescribed a lower dose of Voriconazole Accordpharma; the doctor should also monitor liver function through appropriate blood tests
• the patient has been diagnosed with cardiomyopathy, irregular heartbeat, slow heart rate, or a heart test abnormality known as "prolonged QTc interval".

During treatment, avoid exposure to sunlight. It is important to cover skin areas exposed to the sun and to use sunscreen creams with a high sun protection factor (SPF), as increased sensitivity to UV radiation may occur. This 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 Accordpharma:

• immediately inform your doctor if any of the following symptoms occur:
• sunburn
• severe skin rash or blisters on the skin
• bone pain.

If the skin problems described above occur, the doctor may refer the patient to a dermatologist, who may recommend regular follow-up visits after consultation. There is a small risk of developing skin cancer during long-term treatment with Voriconazole Accordpharma.

If the patient develops symptoms of adrenal insufficiency—a condition in which the adrenal glands do not produce enough 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, a condition 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, a 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, and excessive sweating, inform the doctor.

The doctor should monitor the patient’s liver and kidney function through appropriate blood tests.

Children and adolescents
Voriconazole Accordpharma must not be given to children under 2 years of age.

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

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

Inform your doctor if the patient is taking the following medicine, as concomitant use with Voriconazole Accordpharma should be avoided if possible:

• ritonavir (used to treat HIV infection) at a dose of 100 mg taken 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 the patient is taking any of the following medicines, as concomitant use with Voriconazole Accordpharma should be avoided if possible. Dose adjustment of voriconazole may also be required:

• rifabutin (used to treat tuberculosis); if the patient is already being treated with rifabutin, monitoring of blood counts and observation for rifabutin-related adverse effects will be necessary
• phenytoin (used to treat epilepsy); if the patient is already being treated with phenytoin, monitoring of phenytoin blood levels during treatment with Voriconazole Accordpharma will be necessary, and dose adjustment may be required.

If the patient is taking any of the following medicines, inform the doctor, as dose adjustment or monitoring may be necessary to ensure these medicines and/or Voriconazole Accordpharma remain effective:

• warfarin and other anticoagulants (e.g. phenprocoumon, acenocoumarol; used to reduce blood clotting)
• cyclosporine (used in organ transplant patients)
• tacrolimus (used in organ transplant patients)
• sulfonylureas (e.g. tolbutamide, glipizide, glyburide; used to treat diabetes)
• statins (e.g. atorvastatin, simvastatin; used to lower cholesterol levels)
• benzodiazepines (e.g. midazolam, triazolam; used for severe insomnia and stress)
• omeprazole (used to treat peptic ulcer disease)
• oral contraceptives (if Voriconazole Accordpharma is taken together with oral contraceptives, adverse effects such as nausea or 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 taken with Voriconazole Accordpharma)
• 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 or severe pain)
• non-steroidal anti-inflammatory drugs (e.g. ibuprofen, diclofenac; used to treat pain and inflammation)
• fluconazole (used to treat fungal infections)
• everolimus (used to treat advanced kidney cancer and in organ transplant patients)
• letermovir [used to prevent cytomegalovirus (CMV) disease after bone marrow transplantation]
• ivacaftor (used to treat cystic fibrosis)
• flucloxacillin (an antibiotic used to treat bacterial infections)

Pregnancy and breastfeeding
Do not take Voriconazole Accordpharma during pregnancy unless your doctor decides otherwise.
Women of childbearing potential must use an effective method of contraception. If the patient becomes pregnant while taking Voriconazole Accordpharma, she should contact her 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 using machines
Voriconazole Accordpharma may cause blurred vision and discomfort due to light sensitivity. In such cases, do not drive, use tools, or operate machinery. If such symptoms occur, contact your doctor.

Voriconazole Accordpharma contains sodium
This medicine contains less than 1 mmol of sodium (23 mg) per vial, meaning the medicine is considered "sodium-free".

Voriconazole Accordpharma contains cyclodextrin
This medicine contains 2060.0 mg of cyclodextrin per vial, equivalent to 103 mg/ml dissolved in 20 ml.

3. How to take Voriconazole Accordpharma

This medicine should always be taken exactly as prescribed by your doctor. If in doubt,
you should consult your doctor.
The doctor will determine the dose based on body weight and type of infection.
The doctor may change the recommended dose depending on the patient's health condition.
The recommended dose for use in adults (including elderly patients) is shown below.

Depending on the response to treatment, the doctor may decide to reduce the dose to 3 mg/kg b.i.d.
If the patient has mild or moderate hepatic cirrhosis, the doctor may decide to reduce the dose of the medicinal product.
Use in children and adolescents
The recommended dose for use in children and adolescents is presented below.

Depending on the patient's response to treatment, the doctor may increase or decrease the daily dose.
Voriconazole Accordpharma, powder for solution for infusion, will be dissolved before administration, and the resulting solution will be diluted to the appropriate concentration by hospital staff (see information provided at the end of the leaflet).
The medicine will be administered as an intravenous infusion (into a vein) at a maximum rate of 3 mg/kg body weight per hour over 1 to 3 hours.
If a patient or child is receiving Voriconazole Accordpharma to prevent fungal infections, the treating doctor may decide to discontinue Voriconazole Accordpharma treatment in case of treatment-related adverse reactions.

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

Stopping Voriconazole Accordpharma
Voriconazole Accordpharma should be taken for as long as prescribed by the doctor. However, treatment with Voriconazole Accordpharma powder for solution for infusion should not exceed 6 months.
In patients with weakened immunity or severe infections, prolonged treatment may be necessary to prevent disease recurrence. When clinical improvement occurs, the route of administration may be changed from intravenous to oral.
If the doctor decides to stop treatment with Voriconazole Accordpharma, the patient should not experience any effects from stopping the medicine.
If you have any further questions about the use of this medicine, 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.
Most adverse reactions are mild and transient. However, some of them may be severe and require immediate medical attention.
Severe adverse reactions — discontinue use of Voriconazole Accordpharma immediately and contact a doctor

• Rash
• Jaundice, changes in blood test results indicating liver function abnormalities
• Pancreatitis.

Other adverse reactions
Very common: may occur in more than 1 in 10 people:

• Visual disturbances (vision changes including blurred vision, color vision changes, light sensitivity, color blindness, eye disorders, seeing halos around light sources, night blindness, oscillopsia, seeing flashes of light, visual aura, reduced visual acuity, bright vision, narrowed visual field, floaters)
• Fever
• Rash
• Nausea, vomiting, diarrhea
• Headache
• Swelling of limbs
• Abdominal pain
• Breathing difficulties
• Increased liver enzyme activity.

Common: may occur in no more than 1 in 10 people:

• Sinusitis, gingivitis, chills, fatigue
• Low blood cell counts, including significant reduction in red blood cells (sometimes immune-mediated) and/or white blood cells (sometimes associated with fever), low platelet count involved in 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
• Eye hemorrhage
• Heart rhythm disturbances, including very fast or very slow heartbeat, fainting
• Low blood pressure, phlebitis (which may be associated with blood clot formation)
• Acute breathing difficulties, chest pain, facial swelling (lips, eyelids, and around eyes), fluid accumulation in the lungs
• Constipation, indigestion, inflammation of the lips
• Jaundice, hepatitis, liver damage
• Skin rashes that may lead to severe blistering and skin peeling characterized by flat, red areas on the skin covered with small merging papules, 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 occur in no more than 1 in 100 people:

• Influenza-like symptoms, gastrointestinal irritation and inflammation, antibiotic-associated diarrhea due to gastrointestinal inflammation, lymphangitis
• Inflammation of the thin tissue lining the abdominal cavity and covering abdominal organs (peritonitis)
• 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 disturbances
• Brain edema
• Double vision, severe eye diseases including eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage leading to vision disturbances, optic disc edema
• 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 diseases, gallstones
• Arthritis, phlebitis under the skin (which may be associated with blood clot formation)
• Kidney inflammation, proteinuria, kidney damage
• Very rapid heartbeat or skipped beats, sometimes with abnormal electrical impulses
• Abnormal electrocardiogram (ECG) findings
• Increased blood cholesterol, increased blood urea
• Allergic skin reactions (sometimes severe), including life-threatening blistering rash and skin or mucosal ulceration, particularly in the mouth, dermatitis, urticaria, skin redness and irritation, red or purple skin discolorations possibly due to low platelet count, rash
• Reaction at the infusion site
• Allergic reaction or excessive immune response
• Inflammation of the tissue surrounding the bone (periostitis)

Rare: may occur in no more than 1 in 1,000 people:

• Hyperthyroidism
• Worsening of brain function as a serious complication of liver disease
• Optic nerve damage, corneal opacity, involuntary eye movements
• Photosensitivity reaction manifesting as blister formation
• Disease in which the immune system attacks part of the peripheral nervous system
• Heart rhythm or conduction disorders (sometimes life-threatening)
• Life-threatening allergic reaction
• Coagulation disorders
• Allergic skin reactions (sometimes severe), including rapidly progressive swelling of dermis, subcutaneous tissue, mucous membranes, and tissues beneath mucous membranes, itchy or painful areas of thickened, red skin with silvery scales, skin and mucous membrane irritation, life-threatening condition causing detachment of large areas of the epidermis, the outermost skin layer, from lower skin layers
• Scaly skin, sometimes with thickened, sharp projections or "horns."

Adverse reactions of unknown frequency (frequency cannot be estimated from available data):

• Skin freckles and pigmented spots.

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

• Red, scaly patches or ring-shaped skin lesions, which may indicate an autoimmune disease known as cutaneous lupus erythematosus.

During intravenous infusion of voriconazole, uncommon infusion-related adverse reactions occurred (e.g., hot flushes, fever, sweating, increased heart rate, and shortness of breath). If these symptoms occur, the doctor may decide to discontinue the infusion.
Due to the known effects of Voriconazole Accordpharma on the liver and kidneys, the doctor should monitor the function of these organs with appropriate blood tests.
Patients should also inform their doctor if they experience abdominal pain or changes in stool consistency.
Cases of skin cancer have been reported in patients receiving long-term treatment with Voriconazole Accordpharma.
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 may recommend regular monitoring.
Increased liver enzyme activity has also been observed more frequently in children.
If any of these adverse reactions persist or become bothersome, patients should inform their doctor.
Reporting of adverse reactions
If any adverse effects occur, including any not listed in this leaflet, patients should inform their 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 authorization holder.
Reporting adverse reactions helps provide more information on the safety of this medicine.

5. How to store Voriconazole Accordpharma

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and vial after "EXP". The expiry date refers to the last day of the stated month. The batch number on the packaging is indicated after the abbreviation "Lot".
Do not store above 30°C. Store in the original packaging to protect from light.
The concentrate obtained after reconstitution of Voriconazole Accordpharma should be used immediately; however, if necessary, it may be stored for up to 24 hours at 2º–8°C (in a refrigerator) or at room temperature (15º–25°C). Prior to administration, the concentrate of Voriconazole Accordpharma must be diluted with the recommended infusion solution (see information at the end of the leaflet).
After dilution, the solution may be stored for up to 48 hours at 2º–8°C (in a refrigerator) or up to 24 hours at 15º–25°C (room temperature).
From a microbiological point of view, the prepared solution should be used immediately.
Otherwise, the user is responsible for the storage conditions and duration prior to use. The storage time should not normally exceed 24 hours at 2°C to 8°C, provided that the solution preparation (reconstitution/dilution) was carried out under controlled and validated aseptic conditions.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Contents of the pack and other information

What Voriconazole Accordpharma contains

• The active substance is voriconazole.
• The other ingredients are: hydroxypropylbetadex, arginine hydrochloride, sodium hydroxide (for pH adjustment), concentrated hydrochloric acid (for pH adjustment) (see section 2. Voriconazole Accordpharma contains sodium and cyclodextrins).

Each vial contains 200 mg of voriconazole. After reconstitution according to instructions by a hospital pharmacist or nurse, the concentration of voriconazole is 10 mg/ml (see information provided at the end of the leaflet).

What Voriconazole Accordpharma looks like and contents of the pack
Voriconazole Accordpharma is a white or almost white powder for solution for infusion, supplied in single-use 30 ml glass vials.

Marketing Authorisation Holder and Manufacturer

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

Manufacturer
Actavis Italy S.p.A.
Via Pasteur 10
20014 Nerviano (MI)
Italy
S.C. Sindan-Pharma S.R.L.
11th Ion Mihalache Blvd.
011171 Bucharest 1
Romania
Accord Healthcare Polska Sp. z o.o.
Lutomierska Street 50
95-200 Pabianice

Information intended exclusively for professional medical personnel:

Information on dissolution (preparation of concentrate) and dilution:

• Voriconazole Accordpharma, powder for solution for infusion, should be dissolved in 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 Voriconazole Accordpharma vial should be discarded if, during the introduction of the solvent, it is not automatically drawn in due to the negative pressure 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, it is recommended to use standard 20 mL (non-automatic) syringes.
• 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).
• The medicinal product is intended for single use only, and any unused portions of the solution should be discarded. Only clear solutions free from particulate matter should be used.
• For intravenous use only.
• Information on storage conditions is provided in section 5, "How to store Voriconazole Accordpharma".

Required volumes of Voriconazole Accordpharma concentrate 10 mg/mL

Voriconazole Accordpharma 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 2–8°C (refrigerated), provided that reconstitution was performed under controlled and validated aseptic conditions.

Compatible infusion solutions:
The concentrate may be diluted with:

• 9 mg/ml (0.9%) sodium chloride injection solution
• 5% (50 mg/ml) glucose solution and sodium lactate Ringer's infusion solution for intravenous use
• 5% (50 mg/ml) glucose and 0.45% (4.5 mg/ml) sodium chloride infusion solution for intravenous use
• 5% (50 mg/ml) glucose infusion solution for intravenous use
• 5% (50 mg/ml) glucose and 20 mEq potassium chloride infusion solution for intravenous use
• 5% (50 mg/ml) glucose and 0.9% (9 mg/ml) sodium chloride infusion solution for intravenous use

Compatibility of Voriconazole Accordpharma with solutions other than those listed above (or listed under the section “Incompatibilities” below) is unknown.

Incompatibilities:
Voriconazole Accordpharma must not be administered together with other medicinal products in the same infusion line or intravenous access. This also applies to parenteral nutrition.
Voriconazole Accordpharma must not be administered simultaneously with any blood-derived products.
Intravenous infusion for parenteral nutrition may be administered concurrently with Voriconazole Accordpharma, but not through the same intravenous access or cannula.
4.2% (42 mg/ml) sodium bicarbonate infusion solution for intravenous use must not be used to dilute Voriconazole Accordpharma.
After reconstitution with water for injections, Voriconazole Accordpharma must not be used in combination with 0.45% (4.5 mg/ml) sodium chloride infusion solution or compound sodium lactate infusion solution for intravenous use due to their low osmolar concentration.