VORICONAZOLE TARBIS 200 mg POWDER FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Voriconazole Tarbis 200 mg powder for solution for infusion EFG

Read all of this leaflet carefully before you start 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 you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack

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

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

Voriconazole Tarbis contains the active substance voriconazole. Voriconazole is an antifungal medicine. It works by killing or preventing the growth of fungi that cause infections.

It is used for the treatment of patients (adults and children of 2 years or older) with:

• invasive aspergillosis (a type of fungal infection caused by Aspergillussp),
• candidemia (another type of fungal infection caused by Candidasp) in non-neutropenic patients (patients who do not have an abnormally low count of white blood cells),
• severe invasive infections caused by Candidasp, when the fungus is resistant to fluconazole (another antifungal medicine),
• severe fungal infections caused by Scedosporiumspor by Fusariumsp(two different species of fungi).

Voriconazole is used in patients with severe fungal infections that can be life-threatening.

Prevention of fungal infections in bone marrow transplant recipients with high risk.

This medicine should only be used under medical supervision.

2. What you need to know before you use Voriconazole Tarbis

Do not use Voriconazole Tarbis

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 remedies.

During treatment with voriconazole, 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 cardiac arrhythmias).
• Ivabradine (used for symptoms of chronic heart failure).
• Rifampicin (used for the treatment of tuberculosis).
• Efavirenz (used for the treatment of HIV) 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 the treatment of HIV) at doses of 400 mg and above twice daily. St. John's Wort (herbal remedy).
• Naloxegol (used to treat constipation caused by analgesics, called opioids [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 to use voriconazole if:

• you have had an allergic reaction to other azoles.
• you have or have ever had liver disease. If you have liver disease, your doctor may prescribe a lower dose of voriconazole. Your doctor should also monitor your liver function while you are being treated with voriconazole 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 even 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 you are being treated with voriconazole:

• tell your doctor immediately if you develop:
• 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 voriconazole.

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, tell 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, tell your doctor.

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

Children and adolescents

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

Other medicines and Voriconazole Tarbis

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.

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

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

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

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

• Rifabutin (used for the treatment of tuberculosis). 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 your treatment with voriconazole 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 voriconazole are still working as expected:

• Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to decrease blood clotting).
• Cyclosporine (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 the treatment of stomach ulcers).
• Oral contraceptives (if you use voriconazole 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).
• 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).
• Indinavir and other HIV protease inhibitors (used to treat HIV infection).
• Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, and nevirapine) (used to treat HIV infection) (some doses of efavirenz should NOT be taken at the same time as voriconazole).
• Methadone (used to treat heroin addiction).
• Alfentanil, fentanyl, and other short-acting opioids such as sufentanil (painkillers used for operations).
• Oxycodone and other long-acting opioids 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 voriconazole during pregnancy unless your doctor advises you to. Women of childbearing age using voriconazole should use effective contraception. Contact your doctor immediately if you become pregnant during treatment with voriconazole.

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

Voriconazole 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.

Voriconazole Tarbis contains sodium

This medicine contains 221.17 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.

Voriconazole Tarbis 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 Voriconazole Tarbis

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

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

Your doctor may change your 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.

This medicine 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 using this medicine to prevent fungal infections, your doctor may stop the administration of voriconazole if you or your child experience treatment-related side effects.

If you miss a dose of Voriconazole Tarbis

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

If you stop treatment with Voriconazole Tarbis

Treatment with voriconazole should be continued for as long as your doctor considers necessary, however, the duration of treatment with this medicine should not exceed 6 months.

Patient 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 oral tablets.

When your doctor stops treatment with voriconazole, you should not experience any effects from stopping 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 can be serious and require medical attention.

Severe Adverse Effects - Stop using this medicine and consult your doctor immediately

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

Other Adverse Effects

Very Common: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 disorders, 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.

Common:may affect up to 1 in 10 people

• Sinusitis, gum inflammation, chills, weakness.
• Low count, including severe, of certain types of red blood cells (sometimes of an immune nature) and/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 bleeding.
• Heart rhythm problems, including very fast or 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, 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 thin 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: pain and inflammation of the eyes and eyelids, abnormal eye movements, damage to the optic nerve that causes vision alteration, 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.
• Liver enlargement, 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 or extra heart rate, sometimes with erratic electrical impulses.
• Abnormal electrocardiogram (ECG).
• High cholesterol in the blood, high urea in the blood.
• Skin allergic reactions (sometimes severe), 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 in the perfusion area.
• 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.
• Deterioration 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 problems or conduction problems (sometimes potentially fatal).
• Potentially fatal allergic reaction.
• Alterations in blood coagulation.
• Skin allergic reactions (sometimes severe), such as rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa, and submucosal layers, itchy and painful thickened skin with silvery scales, skin 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 patches on the skin, sometimes thick and with tips or "horns".

Adverse Effects with Unknown Frequency:

• Freckles and pigmented spots.

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

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

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

Since it has been observed that voriconazole affects the liver and kidneys, your doctor should monitor liver and kidney function through blood tests. Inform your doctor if you have stomach pain or if the stools have a different consistency.

Cases of skin cancer have been reported in patients treated with this medicine 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, inform your doctor.

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is a possible adverse effect that does not appear 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 Voriconazol Tarbis

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date that appears on the label and box after "CAD". The expiration date is the last day of the month indicated.

This medicine does not require special storage conditions.

After reconstitution of the solution:

Once reconstituted, this medicine must be used immediately, but if necessary, it can be stored for up to 24 hours at a temperature between 2 °C and 8 °C (in the refrigerator). This reconstituted medicine must be diluted first with a compatible perfusion solution before its perfusion. (See the end of this prospectus for more information).

After dilution of the solution for perfusion:

The chemical and physical stability of the diluted perfusion solutions has been demonstrated for 3 hours at a temperature between 15 °C and 30 °C.

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

6. Package Contents and Additional Information

Composition of Voriconazol Tarbis

The active ingredient is voriconazole.

The other component is

Sulfobutyl ether beta-cyclodextrin sodium.

Each vial contains 200 mg of voriconazole, which is equivalent to a 10 mg/ml solution 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

Powder for solution for perfusion.

White or off-white lyophilized powder or compacted powder.

This medicine is presented in a single vial.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Tarbis Farma S.L.

Gran Vía Carlos III, 94

08028 Barcelona

Spain

Manufacturer

Amarox Pharma B.V.

Rouboslaan 32

Voorschoten, 2252TR

Netherlands

This medicine is authorized in the Member States of the European Economic Area with the following names:

Germany: Voriconazol Amarox 200 mg Pulver zur Herstellung einer Infusionslösung

Netherlands: Voriconazol Amarox 200 mg poeder voor oplossing voor infusie

Spain: Voriconazol Tarbis 200 mg polvo para solución para perfusión EFG

Date of the Last Revision of this Prospectus:August 2024

Detailed information about this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

……………………………………………………………………………………………..

This information is intended only for healthcare professionals:

Information on Reconstitution and Dilution

• Voriconazol Tarbis powder for solution for perfusion needs to be reconstituted with 19 ml of water for injectable preparations or 19 ml of sodium chloride 9 mg/ml (0.9%) for perfusion to obtain an extractable volume of 20 ml of clear concentrate that contains 10 mg/ml of voriconazole.
• Discard the Voriconazol Tarbis 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%) for perfusion is dispensed.
• The required volume of reconstituted concentrate is then added to a compatible perfusion solution, including those listed below, to obtain a final Voriconazol Tarbis solution that contains 0.5 to 5 mg/ml of voriconazole.
• This medicine is for single use and any unused solution must be discarded, and only clear solutions without particles should be used.
• It should not be administered as a bolus injection.
• Regarding information on storage, see section 5 "Storage of Voriconazol Tarbis".

Required Volumes of Voriconazol Tarbis Concentrate 10 mg/ml

Voriconazol Tarbis is a sterile lyophilized single-dose product without preservatives. From a microbiological point of view, the solution should 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 should 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.

After reconstitution:

Chemical and physical stability has been demonstrated for 24 hours between 2 °C and 8 °C.

After perfusion solution:

Chemical and physical stability of the diluted perfusion solutions has been demonstrated for 3 hours between 15°C and 30°C.

Compatible Perfusion Solutions:

The reconstituted solution can be diluted with:

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

Compound sodium lactate intravenous infusion

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

5% glucose solution 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 solution 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:

Voriconazole should not be perfused in the same vein or cannula simultaneously with other drug perfusions, including parenteral nutrition (e.g., Aminofusin 10% Plus).

Hemoderivatives should not be perfused simultaneously with the administration of this medicine.

Total parenteral nutrition can be perfused simultaneously with the administration of this medicine, but not in the same vein or cannula.

This medicine should not be diluted with 4.2% sodium bicarbonate solution.