Voriconazole Ibisqus

Package leaflet: Information for the user

Voriconazole Ibisqus 200 mg powder for solution for infusion

Generic medicine
Please read all of this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again
• If you have any questions, ask your doctor, pharmacist or nurse
• This medicine has been prescribed for you only. Do not give it to other people, even if their symptoms are the same as yours, as it may be harmful
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4

Contents of this leaflet

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

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

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

• invasive aspergillosis (a type of fungal infection caused by species of Aspergillus)
• candidaemia (another type of fungal infection caused by species of Candida) in non-neutropenic patients (patients who do not have an unusually low white blood cell count)
• serious and invasive infections caused by species of Candida, when the fungus is resistant to fluconazole (another antifungal active substance)
• serious fungal infections caused by species of Scedosporium and Fusarium (two different species of fungi)

Voriconazole Ibisqus is indicated for patients with worsening fungal infections and potentially life-threatening conditions.
Prevention of fungal infections in high-risk bone marrow transplant patients.
This product should only be used under medical supervision.

2. What you should know before taking Voriconazole Ibisqus

Do not take Voriconazole Ibisqus:
if you are allergic to the active substance voriconazole or to sodium sulfobutylether beta-cyclodextrin (listed
in section 6).
It is very important that you inform your doctor or pharmacist if you are taking or have recently taken any
other medicines, including those without a prescription, or herbal medicines.
The medicines listed below must not be used during treatment with Voriconazole Ibisqus:

• Terfenadine (for allergies)
• Astemizole (for allergies)
• Cisapride (for stomach problems)
• Pimozide (for the treatment of mental illnesses)
• Quinidine (for irregular heartbeat)
• Ivabradine (for symptoms of chronic heart failure)
• Rifampicin (for the treatment of tuberculosis)
• Efavirenz (for the treatment of AIDS) at doses equal to or greater than 400 mg once daily
• Carbamazepine (for the treatment of seizures)
• Phenobarbital (for severe insomnia and seizures)
• Ergot alkaloids (e.g., ergotamine, dihydroergotamine; for migraine)
• Sirolimus (for transplant patients)
• Ritonavir (for the treatment of AIDS) at doses of 400 mg or more, twice daily
• St. John’s Wort (hypericum – herbal remedy)
• Naloxegol (for the treatment of constipation specifically caused by opioid pain medicines [e.g., morphine, oxycodone, fentanyl, tramadol, codeine])
• Tolvaptan (for the treatment of hyponatremia, i.e., low sodium levels in the blood, or to slow the decline in kidney function in patients with polycystic kidney disease)
• Lurasidone (for the treatment of depression)
• Venetoclax (for the treatment of patients with chronic lymphocytic leukemia - CLL)

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Voriconazole Ibisqus if:

• you have had an allergic reaction to other azoles
• you have or have had liver disease. If you have liver problems, your doctor may prescribe a lower dose of Voriconazole Ibisqus. Your doctor will need to monitor your liver function during treatment with Voriconazole Ibisqus through blood tests
• you know you have heart disease, irregular heartbeat, slow heart rate, or an electrocardiogram (ECG) abnormality called “long QTc syndrome”

You must avoid any exposure to sunlight and solar radiation during treatment. It is important to cover
exposed skin areas and use sunscreens with high sun protection factor (SPF), as increased sensitivity of the skin to UV radiation may occur. These precautions also apply to children.
During treatment with Voriconazole Ibisqus, inform your doctor immediately if you develop:

• sunburn
• severe skin reaction or blistering
• bone pain

If you develop any of the skin conditions described above, your doctor may refer you to a dermatologist, who after consultation may decide that regular follow-up visits are necessary. Long-term use of Voriconazole Ibisqus is associated with a small risk of developing skin carcinoma.
If you develop signs of “adrenal insufficiency”, in which the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol, which may cause symptoms such as chronic or persistent fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, inform your doctor.
Inform your doctor if you develop signs of “Cushing's syndrome”, in which the body produces excessive amounts of the hormone cortisol, which may cause symptoms such as weight gain, fat accumulation between the shoulders, rounded face, darkening of the skin on the abdomen, thinning of legs, breasts, and arms, thinning of the skin, easy bruising, increased blood sugar levels, excessive body hair growth, excessive sweating.
Your doctor will need to monitor liver and kidney function through blood tests.
Children and adolescents
Voriconazole Ibisqus must not be administered to children under 2 years of age.
Other medicines and Voriconazole Ibisqus
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine, including those without a prescription.
Some medicines, when taken together with Voriconazole Ibisqus, may alter the activity of Voriconazole Ibisqus or Voriconazole Ibisqus may alter the activity of these medicines.
Inform your doctor if you are taking the following medicine because, if possible, concomitant treatment with Voriconazole Ibisqus should be avoided:

• Ritonavir (for the treatment of AIDS) at doses of 100 mg twice daily
• Glasdegib (for the treatment of cancer): if you need to use both medicines, your doctor will frequently monitor your heart rhythm

Inform your doctor if you are taking one of the following medicines because, if possible, concomitant treatment with Voriconazole Ibisqus should be avoided and a dose adjustment of voriconazole may be necessary:

• Rifabutin (for the treatment of tuberculosis). If you are already being treated with rifabutin, blood cell counts and rifabutin-related side effects should be closely monitored.
• Phenytoin (for the treatment of epilepsy). If you are already being treated with phenytoin, blood levels of phenytoin should be monitored during treatment with Voriconazole Ibisqus and your dose may need to be adjusted.

Inform your doctor if you are taking any of the following medicines because dose adjustments or monitoring may be needed to ensure these medicines and/or Voriconazole Ibisqus remain effective:

• Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; to slow down the blood clotting process)
• Cyclosporine (for transplant patients)
• Tacrolimus (for transplant patients)
• Sulfonylureas (e.g., tolbutamide, glipizide, glyburide) (for diabetes)
• Statins (e.g., atorvastatin, simvastatin) (to reduce cholesterol)
• Benzodiazepines (e.g., midazolam, triazolam) (for severe insomnia and stress)
• Omeprazole (for the treatment of ulcers)
• Oral contraceptives (if you take Voriconazole Ibisqus while using oral contraceptives, side effects such as nausea and menstrual disturbances may occur)
• Vinca alkaloids (e.g., vincristine, vinblastine) (for cancer treatment)
• Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (for cancer treatment)
• Tretinoin (for the treatment of leukemia)
• Indinavir and other protease inhibitors for AIDS (for the treatment of AIDS)
• Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (for the treatment of AIDS) (some doses of efavirenz cannot be taken together with Voriconazole Ibisqus)
• Methadone (for the treatment of heroin dependence)
• Alfentanil and fentanyl and other short-acting opioids such as sufentanil (analgesics used in surgical procedures)
• Oxycodone and other long-acting opioids such as hydrocodone (used for the treatment of moderate to severe pain)
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (e.g., ibuprofen, diclofenac) (used for the treatment of pain and inflammation)
• Fluconazole (used to treat fungal infections)
• Everolimus (used for the treatment of advanced renal cell carcinoma and in transplant patients)
• Letermovir (used to prevent cytomegalovirus (CMV) disease following bone marrow transplantation)
• Ivacaftor: used for the treatment of cystic fibrosis
• Flucloxacillin (an antibiotic indicated for bacterial infections)

Pregnancy and breastfeeding
Voriconazole Ibisqus must not be taken during pregnancy unless specifically decided by your doctor. Women of childbearing potential must use an adequate contraceptive method. Contact your doctor immediately if you become pregnant during treatment with Voriconazole Ibisqus.
If you are pregnant or breastfeeding, or if you suspect you are pregnant or are planning to become pregnant, consult your doctor or pharmacist before taking this medicine.
Driving and using machines
Voriconazole Ibisqus may cause blurred vision or increased sensitivity to light. In this case, you must not drive and must not operate tools or machinery. In such cases, contact your doctor.
Voriconazole Ibisqus contains sodium
Each vial of this medicine contains 216–228 mg of sodium (a main component of table salt), equivalent to 10.8–11.4% of the maximum daily recommended dietary intake for an adult.
Voriconazole Ibisqus contains cyclodextrin
This medicine contains 3,200 mg of cyclodextrin per vial, equivalent to 160 mg/ml when reconstituted in 20 ml. If you have kidney problems, talk to your doctor before taking this medicine.

3. How to take Voriconazole Ibisqus

Take this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor.
Your doctor will determine the appropriate dose for you based on your body weight and the type of infection diagnosed.
Your doctor may adjust the dose according to your condition.
The recommended dose for adults (including elderly patients) is as follows:

Depending on the response to treatment, your doctor may reduce the dose to 3 mg/kg twice daily.
If you have mild to moderate cirrhosis, your doctor may decide to reduce the dose.
Use in children and adolescents
The recommended dose in children and adolescents is as follows:

Depending on the response to treatment, your doctor may increase or decrease the daily dose.
Voriconazole Ibisqus powder for concentrate for solution for infusion will be reconstituted and diluted by a pharmacist or nurse at the hospital to obtain the correct concentration. (For further information, see the final section of this leaflet.)
The medicine will be administered to you by intravenous infusion (into a vein) at a maximum infusion rate of 3 mg/kg/h over 1 to 3 hours.
If you or your child are taking Voriconazole Ibisqus to prevent fungal infections, your doctor may decide to discontinue treatment with Voriconazole Ibisqus if you or your child develop treatment-related side effects.

If you miss a dose of Voriconazole Ibisqus
Since this medicine will be administered under medical supervision, it is unlikely that a dose will be missed. However, if you think a dose has been missed, inform your doctor or pharmacist.

If you stop treatment with Voriconazole Ibisqus
Treatment with Voriconazole Ibisqus should continue for as long as your doctor decides; however, the duration of treatment with Voriconazole Ibisqus powder for concentrate for solution for infusion should not exceed 6 months. Patients with a weakened immune system or those with difficult-to-treat infections may require long-term treatment to prevent the infection from recurring. When your condition has improved, treatment may be switched from intravenous to tablets.
When treatment with Voriconazole Ibisqus is discontinued as directed by the doctor, no adverse effects should occur.

If you have any doubts about the use of this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
If side effects occur, most will probably be mild and temporary. However, some may be serious and require immediate medical attention.
Serious side effects – Stop taking Voriconazole Ibisqus and consult a doctor immediately

• Rash
• Jaundice, abnormal liver function tests
• Pancreatitis

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

• Visual impairment (visual disturbances including blurred vision, altered colour vision, abnormal light sensitivity, colour blindness, eye disorders, seeing halos, night blindness, fluctuating vision, seeing sparks, visual aura, reduced visual acuity, visual brightness, partial loss of visual field, spots in front of the eyes)
• Fever
• Skin rashes
• Nausea, vomiting, diarrhoea
• Headache
• Swelling of the extremities
• Stomach pain
• Difficulty breathing
• Elevated liver enzymes

Common: may affect 1 in 10 people

• Sinus inflammation, gum inflammation, chills, fatigue
• Reduction, sometimes severe, in the number of certain types of red blood cells (sometimes immune-mediated) and/or white blood cells (sometimes with fever), reduction in the number of blood cells (called platelets) that help blood clotting
• Low blood sugar levels, low blood potassium levels, low blood sodium levels
• Anxiety, depression, confusion, agitation, sleep disorders, hallucinations
• Seizures, tremor or uncontrolled muscle movements, tingling or abnormal skin sensations, increased muscle tone, drowsiness, dizziness
• Bleeding in the eye
• Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting
• Low blood pressure, inflammation of a vein (which may be associated with blood clot formation)
• Acute breathing difficulty, chest pain, facial swelling (mouth, lips and around the eyes), fluid accumulation in the lungs
• Constipation, indigestion, inflammation of the lips
• Jaundice, liver inflammation and liver damage
• Skin rash which may lead to severe blistering and peeling of the skin, characterised by flat red areas of skin with small merging bumps, skin redness
• Itching
• Hair loss
• Back pain
• Kidney failure, blood in urine, abnormal kidney function tests

Uncommon: may affect 1 in 100 people

• Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, gastrointestinal inflammation which may cause antibiotic-associated diarrhoea, inflammation of lymphatic vessels
• Inflammation of the thin tissue lining the abdominal wall and covering abdominal organs
• Swollen lymph nodes (sometimes painful), bone marrow failure, increased eosinophils
• Reduced adrenal gland function, reduced thyroid gland activity
• Changes in brain function, Parkinson-like symptoms, nerve damage leading to numbness, pain, tingling or burning in hands or feet
• Problems with balance and coordination
• Brain swelling
• Double vision, serious eye conditions including: eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage with visual impairment, swelling of the optic disc
• Reduced sensitivity to touch
• Altered taste
• Hearing disorders, ringing in the ears, vertigo
• Inflammation of certain internal organs, pancreas and duodenum, swelling and inflammation of the tongue
• Enlarged liver, liver failure, gallbladder diseases, gallstones
• Joint inflammation, inflammation of subcutaneous veins (which may be associated with blood clot formation)
• Kidney inflammation, presence of protein in urine, kidney damage
• Very rapid heartbeat or missed beats, sometimes with irregular electrical impulses
• Abnormal electrocardiogram (ECG)
• Increased cholesterol, increased blood urea
• Allergic skin reactions (sometimes severe), including a potentially life-threatening skin condition causing blisters and painful sores of the skin and mucous membranes, especially in the mouth, skin inflammation, urticaria, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, skin discolouration (red or purplish) which may be due to low platelet count, eczema
• Infusion site reaction
• Allergic reactions or exaggerated immune response

Rare: may affect 1 in 1,000 people

• Overactive thyroid gland
• Worsening of brain function as a serious complication of liver disease
• Loss of most of the optic nerve fibres, corneal opacity, involuntary eye movement
• Blistering photosensitivity
• Disorder in which the body's immune system attacks part of the peripheral nervous system
• Heart rhythm or conduction problems (sometimes fatal)
• Potentially life-threatening allergic reaction
• Disorders of the blood clotting system
• Allergic skin reactions (sometimes severe), including rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues, itchy or painful patches of thickened, red skin with silvery scales, skin and mucous membrane irritation, potentially life-threatening skin condition causing detachment of large areas of the epidermis (the outer layer of skin) from underlying skin layers
• Small patches of dry, scaly skin, sometimes thick with tips or 'horns'

Side effects with unknown frequency

• Freckles and pigmented spots

Other significant side effects, whose frequency is not known but which should be reported immediately to a doctor, are:

• Skin cancer
• Inflammation of tissues surrounding the bones
• Red, scaly patches or ring-shaped skin lesions which may be symptoms of an autoimmune disease called systemic lupus erythematosus

Reactions during infusion of Voriconazole Ibisqus (including skin redness, fever, sweating, increased heart rate and shortness of breath) are not common. If one or more of these reactions occur, your doctor may decide to stop the infusion.
Since Voriconazole Ibisqus has been observed to affect the liver and kidneys, your doctor will need to monitor liver and kidney function through blood tests. Inform your doctor if you have stomach pain or if your stools are different from normal.
Cases of skin carcinoma have been reported in patients treated with Voriconazole Ibisqus for prolonged periods.
Sunburn or severe skin reactions following exposure to light or sun have been reported more frequently in children. If you or your child develops skin disorders, your doctor may refer you to a dermatologist, who may decide whether regular follow-up visits with a dermatologist are necessary. Elevated liver enzymes have also been observed more frequently in children.
If any of these side effects persist or are bothersome, inform your doctor.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist or healthcare professional. You can also report side effects directly via the national reporting system at the website
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Voriconazole Ibisqus

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
After reconstitution, Voriconazole Ibisqus must be used immediately; however, if necessary, it may be stored for up to 24 hours at a temperature between 2°C and 8°C (in the refrigerator). The reconstituted Voriconazole Ibisqus solution must be diluted with a compatible diluent for intravenous infusion prior to administration. (For further information, see the concluding section of the package leaflet.)
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Voriconazolo Ibisqus contains
The active substance is voriconazole.
The other components are sulfobutylether beta-cyclodextrin sodium and sodium hydroxide (see section 2,
Voriconazolo Ibisqus 200 mg powder for solution for infusion contains cyclodextrin and sodium).
Each vial contains 200 mg of voriconazole, equivalent to a 10 mg/ml solution when reconstituted as recommended by the pharmacist or hospital nurse (see the information provided at the end of this leaflet).

Description of the appearance of Voriconazolo Ibisqus and contents of the pack
Voriconazolo Ibisqus is supplied in single-use glass vials containing a powder for solution for infusion.
Pack: 1 vial

Marketing Authorization Holder
Istituto Biochimico Italiano G. Lorenzini S.p.A.
Via Fossignano 2 - Aprilia (LT) – Italy
e-mail: [email protected]

Manufacturer
Istituto Biochimico Italiano G. Lorenzini S.p.A.
Via Fossignano 2 - Aprilia (LT) – Italy

The following information is intended exclusively for medical and healthcare professionals

Information on reconstitution and dilution

• Voriconazole Ibisqus powder for solution for infusion must initially be reconstituted with 19 ml of water for injections or with 19 ml of a 9 mg/ml (0.9%) Sodium Chloride infusion solution to obtain an extractable volume of 20 ml of a clear concentrate containing 10 mg/ml of voriconazole.
• Do not use the Voriconazole Ibisqus vial if the internal negative vacuum pressure does not draw the diluent into the vial.
• It is recommended to use a standard 20 ml syringe (non-automatic) to ensure accurate administration of the exact volume of water for injections (19.0 ml) or Sodium Chloride 9 mg/ml (0.9%) infusion solution.
• The required volume of reconstituted concentrate is then added to one of the compatible infusion solutions listed below to obtain a Voriconazole Ibisqus solution containing 0.5–5 mg/ml of voriconazole.
• This medicinal product is for single use only, and any unused solution must be discarded. Only clear solutions free from particles should be used.
• The product must not be administered as a bolus injection.
• For information on storage of the product, refer to Section 5 “How to store Voriconazole Ibisqus”.

Required volumes of reconstituted Voriconazole Ibisqus concentrate (10 mg/ml)
Volume of Voriconazole Ibisqus concentrate (10 mg/ml) required for
Body Weight Dose of 3 mg/kg Dose of 4 mg/kg Dose of 6 mg/kg Dose of 8 mg/kg Dose of 9 mg/kg
(kg) (number of (number of (number of (number of (number of
vials) vials) vials) vials) vials)
10 - 4.0 ml (1) - 8.0 ml (1) 9.0 ml (1)
15 - 6.0 ml (1) - 12.0 ml (1) 13.5 ml (1)
20 - 8.0 ml (1) - 16.0 ml (1) 18.0 ml (1)
25 - 10.0 ml (1) - 20.0 ml (1) 22.5 ml (2)
30 9.0 ml (1) 12.0 ml (1) 18.0 ml (1) 24.0 ml (2) 27.0 ml (2)
35 10.5 ml (1) 14.0 ml (1) 21.0 ml (2) 28.0 ml (2) 31.5 ml (2)
40 12.0 ml (1) 16.0 ml (1) 24.0 ml (2) 32.0 ml (2) 36.0 ml (2)
45 13.5 ml (1) 18.0 ml (1) 27.0 ml (2) 36.0 ml (2) 40.5 ml (3)
50 15.0 ml (1) 20.0 ml (1) 30.0 ml (2) 40.0 ml (2) 45.0 ml (3)
55 16.5 ml (1) 22.0 ml (2) 33.0 ml (2) 44.0 ml (3) 49.5 ml (3)
60 18.0 ml (1) 24.0 ml (2) 36.0 ml (2) 48.0 ml (3) 54.0 ml (3)
65 19.5 ml (1) 26.0 ml (2) 39.0 ml (2) 52.0 ml (3) 58.5 ml (3)
70 21.0 ml (2) 28.0 ml (2) 42.0 ml (3) - -
75 22.5 ml (2) 30.0 ml (2) 45.0 ml (3) - -
80 24.0 ml (2) 32.0 ml (2) 48.0 ml (3) - -
85 25.5 ml (2) 34.0 ml (2) 51.0 ml (3) - -
90 27.0 ml (2) 36.0 ml (2) 54.0 ml (3) - -
95 28.5 ml (2) 38.0 ml (2) 57.0 ml (3) - -
100 30.0 ml (2) 40.0 ml (2) 60.0 ml (3) - -

Voriconazole Ibisqus is a sterile, single-dose, lyophilized powder without preservatives. Therefore, from a microbiological standpoint, the reconstituted solution must be used immediately.
If not used immediately, the storage conditions before and after opening are the responsibility of the healthcare personnel. The product must not be used more than 24 hours after opening, if stored at 2–8°C, unless reconstitution has been carried out under controlled and validated aseptic conditions.

Compatible diluents
The reconstituted solution may be diluted with:

• Sodium Chloride 9 mg/ml (0.9%) Injection
• Sodium Lactate Compound for Intravenous Infusion
• Glucose 5% and Ringer Lactate for Intravenous Infusion
• Glucose 5% and Sodium Chloride 0.45% for Intravenous Infusion
• Glucose 5% for Intravenous Infusion
• Glucose 5% with 20 mEq Potassium Chloride for Intravenous Infusion
• Sodium Chloride 0.45% for Intravenous Infusion
• Glucose 5% and Sodium Chloride 0.9% for Intravenous Infusion

The compatibility of Voriconazole Ibisqus with diluents other than those listed above (or in the section “Incompatibilities”) is unknown.

Incompatibilities
Voriconazole Ibisqus must not be administered through the same line or cannula together with other intravenous infusion medicinal products, including parenteral nutrition (e.g., Aminofusin 10% Plus).
Transfusion of blood products must not be performed simultaneously with administration of Voriconazole Ibisqus.
Total parenteral nutrition may be administered concurrently with Voriconazole Ibisqus, but not through the same infusion route.
Voriconazole Ibisqus must not be diluted with Sodium Bicarbonate 4.2% Infusion.