VFEND 200 mg POWDER FOR SOLUTION FOR INFUSION

2. What you need to know before you use VFEND

Do not use VFEND

if you are allergic to voriconazole or to sodium sulfobutylether beta-cyclodextrin (included in section 6).

It is very important that you inform your doctor or pharmacist if you are using or have recently used other medicines, including those obtained without a prescription, or herbal medicines.

During treatment with VFEND, you must not take the following medicines:

• Terfenadine (used for allergy).
• Astemizole (used for allergy).
• Cisapride (used for digestive problems).
• Pimozide (used for mental disorders).
• Quinidine (used for heart rhythm disorders).
• Ivabradine (used for symptoms of chronic heart failure).
• Rifampicin (used for tuberculosis treatment).
• Efavirenz (used for HIV treatment) at doses of 400 mg and above once daily.
• Carbamazepine (used to treat seizures).
• Phenobarbital (used for severe insomnia and seizures).
• Ergot alkaloids (e.g. ergotamine, dihydroergotamine; used for migraine).
• Sirolimus (used in patients who have received a transplant).
• Ritonavir (used for HIV treatment) at doses of 400 mg and above twice daily.
• St. John's Wort (hypericum, herbal medicine).
• Naloxegol (used to treat constipation caused by opioid analgesics [e.g. morphine, oxycodone, fentanyl, tramadol, codeine]).
• Tolvaptan (used to treat hyponatremia [low sodium levels in the blood] or to slow the deterioration of kidney function in patients with polycystic kidney disease).
• Lurasidone (used to treat depression),
• Venetoclax (used to treat patients with chronic lymphocytic leukemia [CLL]).

Warnings and precautions

Consult your doctor, pharmacist or nurse before starting treatment with VFEND if:

• you have had an allergic reaction to other azoles.
• you have or have had liver disease. If you have liver disease, your doctor may prescribe a lower dose of VFEND. Your doctor should also monitor your liver function while you are being treated with VFEND by performing blood tests.
• you know that you have cardiomyopathy, irregular heartbeats, slow heart rate or an abnormality in the electrocardiogram (ECG) called "QTc prolonged syndrome".

You should avoid any exposure to the sun and sunlight during treatment. It is important that you cover exposed areas and use a sunscreen with a high sun protection factor (SPF), as you may experience increased sensitivity of the skin to the sun's UV rays. This may be increased further by the use of other medicines that make the skin more sensitive to sunlight, such as methotrexate. These precautions also apply to children.

While being treated with VFEND:

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

If you develop skin disorders such as those described above, your doctor may refer you to a dermatologist, who after consultation may consider it important to examine you regularly. There is a small probability that you may develop skin cancer with long-term use of VFEND.

If you develop signs of "adrenal insufficiency" in which the adrenal glands do not produce sufficient amounts of certain steroid hormones, such as cortisol, which can cause symptoms such as: chronic or prolonged fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, inform your doctor.

If you present signs of "Cushing's syndrome" in which the body produces too much cortisol hormone that can cause symptoms such as: weight gain, hump of fat between the shoulders, rounded face, darkening of the skin of the abdomen, thighs, breasts and arms, thin skin, easy bruising, high blood sugar levels, excessive hair growth or excessive sweating, inform your doctor.

Your doctor should monitor your liver and kidney function by performing blood tests.

Children and adolescents

VFEND should not be given to children under 2 years of age.

Other medicines and VFEND

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

• Some medicines, when used at the same time as VFEND, can affect the action of VFEND or VFEND may affect the action of other medicines.

Tell your doctor if you are using the following medicines, as concurrent treatment with VFEND should be avoided if possible:

• Ritonavir (used for HIV treatment) at doses of 100 mg twice daily.
• Glasdegib (used for cancer treatment); if you need to use both medicines, your doctor will frequently monitor your heart rate.

Tell your doctor if you are using any of the following medicines, as concurrent treatment with VFEND should be avoided as much as possible, and a dose adjustment of voriconazole may be required:

• Rifabutin (used for tuberculosis treatment). If you are already being treated with rifabutin, your blood count and rifabutin side effects will need to be monitored.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin, your phenytoin blood levels will need to be monitored during treatment with VFEND and your dose may need to be adjusted.

Tell your doctor if you are taking any of the following medicines, as you may need a dose adjustment or monitoring to check that these medicines and/or VFEND are still working as expected:

• Warfarin and other anticoagulants (e.g. phenprocoumon, acenocoumarol; used to decrease blood clotting).
• Ciclosporin (used in patients who have received a transplant).
• Tacrolimus (used in patients who have received a transplant).
• Sulfonylureas (e.g. tolbutamide, glipizide and gliburide) (used for diabetes).
• Statins (e.g. atorvastatin, simvastatin) (used to reduce cholesterol levels).
• Benzodiazepines (e.g. midazolam, triazolam) (used for severe insomnia and stress).
• Omeprazole (used for stomach ulcer treatment).
• Oral contraceptives (if you use VFEND while using oral contraceptives, you may experience side effects such as nausea and menstrual disorders).
• Vinca alkaloids (e.g. vincristine and vinblastine) (used to treat cancer).
• Indinavir and other HIV protease inhibitors (used to treat HIV infection).
• Tyrosine kinase inhibitors (e.g. axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used to treat cancer).
• Tretinoin (used to treat leukemia).
• Non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz, delavirdine and nevirapine) (used to treat HIV infection) (some doses of efavirenz MUST NOT be taken at the same time as VFEND).
• Methadone (used to treat heroin addiction).
• Alfentanil, fentanyl and other short-acting opiates such as sufentanil (painkillers used for operations).
• Oxycodone and other long-acting opiates such as hydrocodone (used to treat moderate to severe pain).
• Non-steroidal anti-inflammatory medicines (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 patients who have received a transplant).
• Letermovir (used to prevent cytomegalovirus (CMV) infection after bone marrow transplantation).
• Ivacaftor: used to treat cystic fibrosis.
• Flucloxacillin (antibiotic used against bacterial infections).

Pregnancy and breastfeeding

do not use VFEND during pregnancy unless your doctor tells you to. Women of childbearing age using VFEND should use effective contraception. Contact your doctor immediately if you become pregnant during treatment with VFEND.

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Driving and using machines

VFEND may cause blurred vision or discomfort due to increased sensitivity to light. If this happens, do not drive or use tools or machines and tell your doctor.

VFEND contains sodium

This medicine contains 221 mg of sodium (main component of cooking/table salt) per vial. This is equivalent to 11% of the maximum recommended daily intake of sodium for an adult.

VFEND contains cyclodextrin

This medicine contains 3,200 mg of cyclodextrin in each vial, equivalent to 160 mg/ml when reconstituted in 20 ml. If you have kidney problems, consult your doctor before taking this medicine.

3. How to use VFEND

Follow exactly the instructions for administration of this medicine given by your doctor. If you are unsure, consult your doctor or pharmacist again.

Your doctor will determine the dose based on your weight and the type of infection you have.

Your doctor may change the dose depending on your situation.

The recommended dose in adults (including elderly patients) is as follows:

Depending on your response to treatment, your doctor may reduce the dose to 3 mg/kg twice daily.

Your doctor may decide to reduce the dose if you have mild to moderate cirrhosis.

Use in children and adolescents

The recommended dose in children and adolescents is as follows:

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

VFEND powder for solution for infusion must be reconstituted and diluted to the correct concentration by hospital pharmacy or nursing staff (for more information, see the end of this leaflet).

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

If you or your child are taking VFEND to prevent fungal infections, your doctor may stop VFEND administration if you or your child experience treatment-related side effects.

If you miss a dose of VFEND

Given that you will receive this medicine under close medical supervision, it is unlikely that you will miss a dose. However, tell your doctor or pharmacist if you think you have missed a dose.

If you stop treatment with VFEND

Treatment with VFEND should be continued for as long as your doctor considers necessary, however, the duration of treatment with VFEND powder for solution for infusion should not exceed 6 months.

Patients with compromised immune systems or those with complicated infections may require longer treatment to prevent the infection from coming back. Once your condition improves, intravenous infusion may be replaced by taking tablets.

When your doctor stops treatment with VFEND, you should not experience any effects from stopping the treatment.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them. If any appear, it is most likely to be mild and transient. However, some may be serious and require medical attention.

Severe Adverse Effects - Stop Using VFEND and Consult a Doctor Immediately

• Skin rash.
• Jaundice, alterations in blood tests to control liver function.
• Pancreatitis.

Other Adverse Effects

Very frequent: may affect more than 1 in 10 people

• Visual disturbance (change in vision, such as blurred vision, visual disturbances of colors, abnormal intolerance to visual perception of light, color blindness, eye disorder, visual halo, night blindness, oscillating vision, spark vision, visual aura, decreased visual acuity, visual clarity, partial loss of usual visual field, spots in the visual field).
• Fever.
• Skin rash.
• Nausea, vomiting, and diarrhea.
• Headache.
• Swelling of the limbs.
• Stomach pain.
• Difficulty breathing.
• Elevated liver enzymes.

Frequent: may affect up to 1 in 10 people

• Sinusitis, gum inflammation, chills, weakness.
• Low count, including severe, of some types of red blood cells (sometimes of an immune nature) or white blood cells (sometimes accompanied by fever) in the blood, low platelet count that helps blood clot.
• Low blood sugar levels, low potassium levels in the blood, low sodium levels in the blood.
• Anxiety, depression, confusion, agitation, insomnia, hallucinations.
• Seizures, tremors or uncontrolled muscle movements, tingling or abnormal sensations in the skin, increased muscle tone, somnolence, dizziness.
• Eye hemorrhage.
• Heart rhythm problems, including very fast heartbeat, very slow heartbeat, fainting.
• Hypotension, inflammation of the veins (which may be associated with the formation of blood clots).
• Acute difficulty breathing, chest pain, swelling of the face (mouth, lips, and around the eyes), fluid retention in the lungs.
• Constipation, indigestion, lip inflammation.
• Jaundice (yellowish skin color), liver inflammation, and liver damage.
• Skin eruptions, which can be severe, with blisters and peeling, characterized by a flat and reddened area, covered with small protrusions that converge, skin redness.
• Itching.
• Alopecia.
• Back pain.
• Kidney failure, presence of blood in urine, alterations in kidney function tests.
• Sunburn or severe skin reaction after exposure to light or sun.
• Skin cancer.

Uncommon: may affect up to 1 in 100 people

• Flu-like symptoms, irritation, and inflammation of the gastrointestinal tract, gastrointestinal tract inflammation that causes antibiotic-associated diarrhea, inflammation of the lymphatic vessels.
• Inflammation of the tissue that lines the inner wall of the abdomen and covers the abdominal organs.
• Enlargement (sometimes painful) of the lymph nodes, bone marrow failure, increased eosinophils.
• Decreased function of the adrenal gland, underactive thyroid gland.
• Abnormal brain function, symptoms similar to Parkinson's disease, nerve damage causing numbness, pain, tingling, or burning in the hands or feet.
• Problems with balance or coordination.
• Brain swelling.
• Double vision, serious eye diseases, such as: eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage that affects vision, inflammation of the optic papilla.
• Decreased sensitivity to touch.
• Alteration of the sense of taste.
• Difficulty hearing, ringing in the ears, vertigo.
• Inflammation of certain internal organs, pancreas, and duodenum, swelling, and inflammation of the tongue.
• Enlargement of the liver, liver failure, gallbladder disease, gallstones.
• Joint inflammation, inflammation of the veins under the skin (which may be associated with the formation of a blood clot).
• Kidney inflammation, protein in the urine, kidney damage.
• Very high heart rate or extrasystoles, sometimes with erratic electrical impulses.
• Abnormal electrocardiogram (ECG).
• High cholesterol in the blood, high urea in the blood.
• Severe allergic skin reactions (sometimes life-threatening), such as a potentially fatal skin disease that causes blisters and painful sores on the skin and mucous membranes, especially in the mouth, skin inflammation, hives, skin redness and irritation, reddish or purplish skin color that may be caused by low platelet count, eczema.
• Reaction at the infusion site.
• Allergic reaction or exaggerated immune response.
• Inflammation of the tissue surrounding the bone.

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

• Overactive thyroid gland.
• Worsening of brain activity as a serious complication of liver disease.
• Loss of most of the optic nerve fibers, corneal opacity, involuntary eye movement.
• Blisters due to photosensitivity.
• Disorder in which the immune system attacks part of the peripheral nervous system.
• Heart rhythm or conduction problems (sometimes potentially fatal).
• Potentially fatal allergic reaction.
• Alterations in blood coagulation.
• Severe allergic skin reactions (sometimes life-threatening), such as rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa, and submucosal layers, itchy and painful skin plaques with silvery scales, skin irritation, and mucous membrane irritation, potentially fatal skin disease that causes large portions of the epidermis, the outermost layer of the skin, to peel off from the underlying skin layers.
• Small, scaly, and dry skin patches, sometimes thick and with tips or "horns".

Adverse effects with unknown frequency:

• Pigmented spots and patches.

Other important adverse effects whose frequency is not known, but which should be reported to the doctor immediately:

• Red, scaly skin patches or ring-shaped lesions that may be a symptom of an autoimmune disease called cutaneous lupus erythematosus.

During infusion, there have been infrequent reactions with VFEND (including facial redness, fever, sweating, increased heart rate, and difficulty breathing). The doctor may interrupt the infusion if this occurs.

Since VFEND has been shown to affect the liver and kidneys, your doctor should monitor liver and kidney function through blood tests. Warn your doctor if you have stomach pain or if your stools have a different consistency.

Cases of skin cancer have been reported in patients treated with Vfend for long periods.

The frequency of sunburn or severe skin reactions after exposure to light or sun was higher in children. If you or your child have skin disorders, your doctor may refer you to a dermatologist who, after consultation, may decide that it is important for you or your child to undergo regular follow-up. Elevated liver enzymes were also observed more frequently in children.

If any of these adverse effects persist or are bothersome, report them to your doctor.

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of VFEND

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date shown on the label. The expiration date is the last day of the month indicated.

Once reconstituted, VFEND must be used immediately, although, if necessary, it can be stored for up to 24 hours between 2°C - 8°C (in the refrigerator). Reconstituted VFEND must be diluted first with a compatible infusion diluent before being infused. (For more information, see the end of this prospectus).

Medicines should not be thrown away through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of VFEND

• The active ingredient is voriconazole.
• The other component is sulfobutylether beta-cyclodextrin sodium (see section 2, VFEND 200 mg powder for solution for infusion contains cyclodextrin and sodium).

Each vial contains 200 mg of voriconazole, which is equivalent to a concentrated solution of 10 mg/ml once reconstituted following the instructions indicated by the hospital pharmacy or nursing staff (see the information at the end of this prospectus).

Appearance of the Product and Package Contents

VFEND is presented in the form of powder for solution for infusion in single-use glass vials.

Marketing Authorization Holder and Manufacturer

Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

Manufacturer

Fareva Amboise, Zone Industrielle, 29 route des Industries, 37530 Pocé-sur-Cisse, France.

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of Last Approval of this Prospectus:09/2023.

Detailed information about this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

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The following information is intended only for doctors and healthcare professionals:

Information on Reconstitution and Dilution

• VFEND powder for solution for infusion needs to be reconstituted with 19 ml of water for injectable preparations or 19 ml of sodium chloride 9 mg/ml (0.9%) for infusion to obtain an extractable volume of 20 ml of clear concentrate that contains 10 mg/ml of voriconazole.
• Discard the VFEND vial if the vacuum does not allow the solvent to be introduced into the vial.
• The use of a standard 20 ml syringe (not automatic) is recommended to ensure that the exact amount (19.0 ml) of water for injectable preparations or sodium chloride 9 mg/ml (0.9%) is dispensed.
• The required volume of reconstituted concentrate is then added to a compatible infusion solution, including those listed below, to obtain a final VFEND solution that contains 0.5 to 5 mg/ml of voriconazole.
• This specialty is for single use, and any unused solution must be discarded, and only clear solutions without particles should be used.
• It must not be administered as a bolus.
• Regarding storage information, see section 5 "Storage of VFEND".

Required volumes of VFEND concentrate 10 mg/ml

VFEND is a sterile lyophilized product without preservatives for single use. From a microbiological point of view, the solution must be used immediately once reconstituted. If not used immediately, the time and conditions of storage before use are the responsibility of the user, and it must be kept between 2 and 8°C for a maximum period of 24 hours, unless the reconstitution has been carried out in controlled and validated aseptic conditions.

Compatible Infusion Solutions:

The reconstituted solution can be diluted with:

Sodium chloride 9 mg/ml (0.9%) injection solution

Compound sodium lactate intravenous infusion

5% glucose and lactated Ringer's solution for intravenous infusion

5% glucose and 0.45% sodium chloride solution for intravenous infusion

5% glucose solution for intravenous infusion

5% glucose solution with 20 mEq of potassium chloride for intravenous infusion

0.45% sodium chloride solution for intravenous infusion

5% glucose and 0.9% sodium chloride solution for intravenous infusion

The compatibility of voriconazole with other diluents different from those specifically mentioned above (or those mentioned below in "Incompatibilities") is unknown.

Incompatibilities:

VFEND must not be infused in the same line or cannula simultaneously with other drug infusions, including parenteral nutrition (e.g., Aminofusin 10% Plus).

Hemoderivatives must not be infused simultaneously with the administration of VFEND.

Total parenteral nutrition can be infused simultaneously with the administration of VFEND, but not in the same line or cannula.

VFEND must not be diluted with 4.2% sodium bicarbonate solution.