VORICONAZOLE NORMON 200 mg POWDER FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

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

1. What is Voriconazol Normon and what is it used for

Voriconazol Normon contains the active substance voriconazole. Voriconazol Normon 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 aged 2 years or older) with:

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

Voriconazole is used in patients with serious 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 Voriconazol Normon

Do not use Voriconazol Normon

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

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

During treatment with this medicine, you should 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 remedy).
• Naloxegol (used to treat constipation caused by opioid painkillers).
• Tolvaptan (used to treat low sodium levels in the blood or to slow the decline 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 this medicine if you:

• have had an allergic reaction to other azoles.
• 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.
• know that you have cardiomyopathy, irregular heartbeats, slow heart rate, or an abnormality in the electrocardiogram (ECG) called "QTc prolongation".

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 skin sensitivity to the sun's UV rays. These precautions also apply to children.

Tell your doctor immediately if you experience any of the following symptoms while being treated with this medicine:

• 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 may consider it essential to examine you regularly. There is a small chance that you may develop skin cancer with long-term use of voriconazole.

If you develop signs of "adrenal insufficiency" where 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" where the body produces too much cortisol hormone, which 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

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

Other medicines and Voriconazol Normon

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 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 whenever possible, and a dose adjustment of voriconazole may be necessary:

• Rifabutin (used for tuberculosis treatment). If you are already being treated with rifabutin, your doctor will need to monitor your blood count and the side effects of rifabutin.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin, your doctor will need to monitor the concentration of phenytoin in your blood during treatment with voriconazole and may need to adjust your dose.

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 effectively:

• Warfarin and other anticoagulants (e.g. phenprocoumon, acenocoumarol; used to reduce 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 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 voriconazole while taking 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 should NOT be taken at the same time as voriconazole).
• 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 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 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 breast-feeding

Do not use this medicine during pregnancy unless your doctor has told you to. Women of childbearing age using Voriconazol Normon should use effective contraception. Contact your doctor immediately if you become pregnant during treatment with this medicine.

If you are pregnant or breast-feeding, 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

Voriconazol Normon may cause blurred vision or discomfort due to increased sensitivity to light. If this happens, do not drive or operate tools or machines and inform your doctor.

Voriconazol Normon contains sodium

This medicine contains 35.38 mg of sodium (main component of cooking/table salt) per vial. This is equivalent to 1.76% of the maximum recommended daily intake of sodium for an adult.

Voriconazol Normon contains cyclodextrins

This medicine contains 3200 mg of hydroxypropylbetadex per vial, equivalent to 160 mg/ml in the reconstituted solution with 20 ml.

Do not use in children under 2 years of age unless your doctor has recommended it.

If you have kidney failure, consult your doctor before taking this medicine.

3. How to use Voriconazol Normon

Follow exactly the instructions of administration of this medicine given by your doctor or pharmacist. 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 liver 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 section 5 and 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 the medicine if you or your child experience treatment-related side effects.

If you forget to use Voriconazol Normon

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

If you stop treatment with Voriconazol Normon

Treatment with this medicine should be continued for as long as your doctor considers necessary, but the duration of treatment 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 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 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. Nevertheless, 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 Adverse Effects (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).
• Fever.
• Skin rash.
• Nausea, vomiting, and diarrhea.
• Headache.
• Swelling of the limbs.
• Stomach pain.
• Difficulty breathing.
• Elevated liver enzymes.

Common Adverse Effects (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.
• Allergic reaction or exaggerated immune response.
• 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.
• Ocular hemorrhage.
• Heart rhythm problems, including very rapid 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 bumps that converge, skin redness.
• Itching.
• Alopecia.
• Back pain.
• Kidney failure, presence of blood in urine, alterations in kidney function tests.

Uncommon Adverse Effects (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, serious eye diseases, such as eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage 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.
  • 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.
  • 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, sunburn or severe skin reaction after exposure to light or sun, skin redness and irritation, reddish or purplish skin color that may be caused by low platelet count, eczema.
  • Reaction in the perfusion area.

Rare Adverse Effects (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 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 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 plaques, sometimes thick and with tips or "horns".

Adverse Effects with Unknown Frequency:

• Pigmented spots and patches.

Other Important Adverse Effects whose Frequency is Unknown, but which must be Communicated to the Doctor Immediately:

• Skin cancer.
• Inflammation of the tissue surrounding the bone.
• Red, scaly skin patches or ring-shaped skin lesions that may be a symptom of an autoimmune disease called cutaneous lupus erythematosus.

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

Since it has been observed that voriconazole affects 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 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, report them to your doctor.

Reporting of 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 Medicines and Healthcare Products Agency (AEMPS) website: https://www.notificaRAM.es/. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Voriconazole Normon

Store below 25°C.

Keep this medicine out of sight and reach of children.

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

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

Medicines must not be thrown away through drains or into the trash. 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 Voriconazole Normon

• The active ingredient is voriconazole.
• The other components are hydroxypropylbetadex and sodium chloride.

Each vial contains 200 mg of voriconazole, 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

Voriconazole Normon is presented in the form of powder for solution for perfusion in single-dose glass vials.

Marketing Authorization Holder and Manufacturer

LABORATORIOS NORMON, S.A.

Ronda de Valdecarrizo, 6

28760, Tres Cantos – Madrid (Spain)

Date of the Last Revision of this Prospectus:May 2023

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

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

Information on Reconstitution and Dilution:

• Voriconazole Normon 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 transparent concentrate that contains 10 mg/ml of voriconazole.
• Discard the Voriconazole Normon 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 used.
• The required volume of reconstituted concentrate is then added to a compatible perfusion solution, including those listed below, to obtain a final Voriconazole Normon 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 transparent solutions without particles should be used.
• Do not inject as a bolus. Perfuse at a maximum speed of 3 mg/kg per hour.
• For information on storage, see section 5 "Storage of Voriconazole Normon".

Required Volumes of Voriconazole Normon Concentrate 10 mg/ml

This medicine 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°C and 8°C for a maximum period of 24 hours, unless the reconstitution has been carried out in controlled and validated aseptic conditions.

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 solutions 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:

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

Hemoderivatives must not be perfused simultaneously with the administration of Voriconazole Normon.

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

Voriconazole Normon must not be diluted with 4.2% sodium bicarbonate solution.