VORICONAZOLE AUROVITAS SPAIN 200 mg POWDER FOR SOLUTION FOR INFUSION

2. What you need to know before you use Voriconazole Aurovitas Spain

Do not use Voriconazole Aurovitas Spain

If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

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 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 transplant patients).
• Ritonavir (used for HIV treatment) at doses of 400 mg and above twice daily.
• St. John's Wort (Hypericum, medicinal plant).
• 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 decline in 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

Tell your doctor, pharmacist, or nurse before starting to use this medicine 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 essential 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 can 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 being treated with voriconazole:

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

If you develop skin disorders like those described above, your doctor may refer you to a dermatologist, who may consider it essential to examine you regularly after the consultation. 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 like: 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, which can cause symptoms like: 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 old.

Other medicines and Voriconazole Aurovitas Spain

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 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 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 voriconazole should be avoided as much as possible, and a dose adjustment of voriconazole may be necessary:

• 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 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 transplant patients).
• Tacrolimus (used in transplant patients).
• Sulfonylureas (e.g., tolbutamide, glipizide, and gliburide) (used for diabetes).
• Statins (e.g., atorvastatin, simvastatin) (used to lower cholesterol levels).
• Benzodiazepines (e.g., midazolam, triazolam) (used for severe insomnia and stress).
• Omeprazole (used for stomach ulcer treatment).
• Oral contraceptives (if you use this medicine while using oral contraceptives, you may experience side effects like 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 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 transplant patients).
• 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

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.

You should not use voriconazole during pregnancy unless your doctor considers it essential. Women of childbearing age using voriconazole should use effective contraception. Contact your doctor immediately if you become pregnant during treatment with voriconazole.

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 Aurovitas Spain contains sodium

This medicine contains approximately 88.74 mg of sodium (main component of cooking/table salt) per vial. This is equivalent to 4.44% of the maximum recommended daily intake of sodium for an adult.

Consult your doctor or pharmacist if you need to take 5 or more vials daily for an extended period, especially if you have been advised to follow a low-salt diet.

Voriconazole Aurovitas Spain contains hydroxypropyl-beta-cyclodextrin

If you have kidney problems, consult your doctor before using this medicine.

3. How to use Voriconazole Aurovitas Spain

Follow the instructions for administration of this medicine exactly as told 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 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.

Voriconazole Aurovitas Spain 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 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 forget to use Voriconazole Aurovitas Spain

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 Voriconazole Aurovitas Spain

Treatment with voriconazole should be continued for as long as your doctor considers necessary; however, the duration of treatment with Voriconazole Aurovitas Spain powder for solution for infusion 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 the treatment.

If you have any further questions on the use of this product, 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. Nevertheless, some can be serious and require medical attention.

Severe Adverse Effects

Stop using voriconazole and go to the doctor immediately if you experience:

• 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, including 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 (sometimes immune-related) or white blood cells (sometimes accompanied by fever) in the blood, low platelet count that helps blood clot.
• Low blood sugar levels, low blood potassium levels, low blood sodium levels.
• 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, vein inflammation (which may be associated with blood clot formation).
• 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, red area covered with small bumps that merge, skin redness.
• Itching.
• Alopecia.
• Back pain.
• Kidney failure, blood in urine, alterations in kidney function tests.
• Sunburn or severe skin reaction after exposure to light or sun.
• Skin cancer.

Infrequent: 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, lymphatic vessel inflammation.
• Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal organs.
• Enlargement (sometimes painful) of 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, severe eye diseases, such as eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage that causes vision changes, optic papilla inflammation.
• 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, tongue swelling and inflammation.
• Liver enlargement, liver failure, gallbladder disease, gallstones.
• Joint inflammation, vein inflammation under the skin (which may be associated with blood clot formation).
• Kidney inflammation, protein in urine, kidney damage.
• Very high heart rate or extrasystoles, sometimes with erratic electrical impulses.
• Abnormal electrocardiogram (ECG).
• High cholesterol in blood, high urea in blood.
• Severe skin allergic reactions (sometimes life-threatening), such as a skin disease that causes painful blisters and ulcers 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.
• Deterioration of brain activity as a severe 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.
• Severe skin allergic reactions (sometimes life-threatening), such as rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa, and submucosal layers, itchy, and painful thickened and reddened skin plaques with silvery skin scales, skin and mucous membrane irritation, potentially life-threatening skin disease that causes large portions of the epidermis, the outermost skin layer, 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 (cannot be estimated from available data):

• Pigmented spots and patches.

Other important adverse effects whose frequency is unknown, but which should be reported to the doctor immediately:

• Red, scaly skin plaques 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 voriconazole (including facial redness, fever, sweating, increased heart rate, and difficulty breathing). The doctor may interrupt the infusion if this occurs.

Since voriconazole has been shown to affect 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 your stools have a different consistency.

Cases of skin cancer have been reported in patients treated with voriconazole 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 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 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 Voriconazole Aurovitas Spain

Keep this medicine out of sight and reach of children.

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

This medicine does not require special storage conditions before opening.

Chemical and physical stability has been demonstrated for 72 hours at 25°C and 2-8°C.

From a microbiological point of view, once reconstituted, the medicine should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should not normally exceed 24 hours at 2-8°C (in the refrigerator), unless reconstitution was performed under controlled and validated aseptic conditions. The reconstituted medicine 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 that are no longer needed. This will help protect the environment.

6. Container contents and additional information

Composition of Voriconazol Aurovitas Spain

• The active ingredient is voriconazole. Each vial contains 200 mg of voriconazole. After reconstitution, each ml of solution contains 10 mg of voriconazole.
• The other components are hydroxypropyl-beta-cyclodextrin, sodium chloride, hydrochloric acid (for pH adjustment).

Appearance of the product and container contents

Each container contains a vial. Voriconazol Aurovitas Spain is presented as a white or almost white lyophilized powder for solution for infusion in a 25 ml type I glass vial with a gray chlorobutyl rubber stopper and a metal capsule with a red plastic flip-off closure.

Marketing authorization holder

Eugia Pharma (Malta) Limited

Vault 14, Level 2, Valletta Waterfront

Floriana, FRN 1914

Malta

Manufacturer

Pharmathen International S.A.

Sapes Industrial Park, Block 5

69300 Rodopi

Greece

or

Pharmathen S.A.

Dervenakion 6

15351 Pallini

Attikis

Greece

or

Anfarm Hellas S.A

Schimatari Viotias

320 09

Greece

Further information on this medicinal product can be obtained from the local representative of the marketing authorization holder:

Aurovitas Spain, S.A.U.

Avda. de Burgos, 16-D

28036 Madrid

Spain

This medicinal product is authorized in the Member States of the European Economic Areaand in the United Kingdom (Northern Ireland)under the following names:

Date of last revision of this leaflet: February 2024

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

The following information is intended only for healthcare professionals:

Information on reconstitution and dilution

• Voriconazol Aurovitas Spain powder for solution for infusion needs to be reconstituted first with 19 ml of water for injectable preparations or 19 ml of sodium chloride 9 mg/ml (0.9%) injectable solution to obtain an extractable volume of 20 ml of clear concentrate containing 10 mg/ml of voriconazole.
• Discard the Voriconazol Aurovitas Spain 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%) injectable solution is dispensed.
• The required volume of reconstituted concentrate is then added to a compatible infusion solution, including those listed below, to obtain a final solution of Voriconazol Aurovitas Spain containing 0.5 to 5 mg/ml of voriconazole.
• This medicinal product 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 rapid intravenous injection.
• Regarding information on storage, see section 5 "Storage of Voriconazol Aurovitas Spain".

Volumes of Voriconazol Aurovitas Spain 10 mg/ml concentrate required

Voriconazol Aurovitas Spain is a sterile, preservative-free, single-dose lyophilized powder. From a microbiological point of view, the reconstituted solution should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should not normally exceed 24 hours at 2-8°C (in a refrigerator), unless the reconstitution has been performed in controlled and validated aseptic conditions. Voriconazol Aurovitas Spain needs to be diluted first with a compatible solution before being infused.

Compatible infusion solutions

The reconstituted solution can be diluted with:

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

Compound sodium lactate intravenous infusion solution

5% glucose and lactated Ringer's intravenous infusion solution

5% glucose and 0.45% sodium chloride intravenous infusion solution

5% glucose intravenous infusion solution

5% glucose in 20 mEq of potassium chloride intravenous infusion solution

0.45% sodium chloride intravenous infusion solution

5% glucose and sodium chloride 9 mg/ml (0.9%) injection solution

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

Incompatibilities

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

Hemoderivatives should not be infused simultaneously with the administration of Voriconazol Aurovitas Spain.

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

Voriconazol Aurovitas Spain should not be diluted with 4.2% sodium bicarbonate solution.