VORICONAZOL KERN PHARMA 200 mg POWDER FOR SOLUTION FOR INFUSION

Introduction

Package Leaflet: Information for the User

Voriconazole Kern Pharma 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 or pharmacist.
• 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 or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack and other information

1. What Voriconazole Kern Pharma is and what it is used for
2. What you need to know before you use Voriconazole Kern Pharma
3. How to use Voriconazole Kern Pharma
4. Possible side effects

5 Storage of Voriconazole Kern Pharma

1. Contents of the pack and further information

1. What Voriconazole Kern Pharma is and what it is used for

Voriconazole Kern Pharma 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 aged 2 years or older) with:

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

Voriconazole Kern Pharma is used in patients with serious fungal infections that may 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 Kern Pharma

Do not use Voriconazole Kern Pharma

• 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 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).
• Astemizol (used for allergy).
• Cisapride (used for digestive problems).
• Pimozide (used for mental disorders).
• Quinidine (used for heart rhythm disorders).
• 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 (hypericum, herbal remedy).

Warnings and precautions

Consult your doctor 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) known as "QTc prolonged syndrome".

You should avoid 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 have increased skin sensitivity to the sun's UV rays. These precautions also apply to children.

While you are being treated with voriconazole, inform 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 voriconazole.

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

Children and adolescents

This medicine must not be given to children under 2 years of age.

Using Voriconazole Kern Pharma with other medicines

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 Kern Pharma, may 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.

Tell your doctor if you are using any of the following medicines, as it should be avoided as far as possible to take them at the same time as voriconazole, 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 should be monitored.
• Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin, your phenytoin blood levels should 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 producing the desired effect:

• 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).
• Sulphonylureas (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).
• 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 MUST 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).
• Flucloxacillin (an antibiotic used against bacterial infections).

Pregnancy and breast-feeding

Do not use voriconazole during pregnancy unless your doctor has told 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 breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before using this medicine.

Driving and using machines

This medicine may cause blurred vision or sensitivity to light. If this happens, do not drive or use tools or machines and tell your doctor.

Voriconazole Kern Pharma contains sodium

Patients on low sodium diets should be aware that this medicine contains 88.74 mg (3.86 mmol) of sodium per vial.

3. How to use Voriconazole Kern Pharma

Follow exactly the instructions of your doctor. If you are not sure, ask your doctor or pharmacist again.

Your doctor will determine the dose depending 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.

Voriconazole powder for solution for infusion must be reconstituted and diluted to the correct concentration by hospital pharmacy or nursing staff (for further 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 voriconazole for the prevention of 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 Kern Pharma

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 using Voriconazole Kern Pharma

Treatment with voriconazole should be continued for as long as your doctor considers necessary, however, the duration of treatment with voriconazole 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 oral tablets.

When your doctor stops your 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 or pharmacist.

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 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 certain 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.
• Eye hemorrhage.
• Heart rhythm problems that include 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 protuberances that converge, skin redness.
• Itching.
• Alopecia.
• Back pain.
• Kidney failure, presence of blood in urine, alterations in blood tests to control kidney function.

Uncommon (may affect up to 1 in 100 people):

• Flu-like symptoms, irritation, and inflammation of the gastrointestinal tract, inflammation of the gastrointestinal tract 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.
• Coordination problems.
• 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 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 skin disease, potentially life-threatening 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 (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 plates of thickened and reddened skin with silvery skin scales, skin and mucous membrane irritation, potentially life-threatening 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:

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

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

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 the 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 of Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist, even if it is an 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. Conservation of Voriconazol Kern Pharma

Keep this medicine out of sight and reach of children.

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

Once reconstituted, this medicine 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 Voriconazol Kern Pharma must be diluted first with a compatible perfusion diluent before being perfused. (For more information, see the end of this prospectus).

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

6. Package Contents and Additional Information

Composition of Voriconazol Kern Pharma

• The active principle is voriconazole.
• The other components are hydroxypropyl-beta-cyclodextrin, sodium chloride, and hydrochloric acid.

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

Voriconazol Kern Pharma is presented in the form of a lyophilized powder for solution for perfusion in 25 ml single-use glass vials type I with a rubber stopper and aluminum cap with a plastic seal.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

Kern Pharma, S.L.

Venus, 72 - Pol. Ind. Colón II

08228 Terrassa - Barcelona

Spain

Manufacturer

Anfarm Hellas S.A.

Schimatari Viotias

320 09

Greece

or

Pharmathen S.A.

Dervenakion 6

15351 Pallini

Attikis - Greece

or

Pharmathen International S.A.

Sapes Industrial Park, Block 5

69300 Rodopi - Greece

Date of the Last Revision of this Prospectus: June 2023.

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

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This information is intended only for doctors or healthcare professionals:

Information on Reconstitution and Dilution

• Voriconazol Kern Pharma 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 Voriconazol Kern Pharma 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 perfusion solution, including those listed below, to obtain a final Voriconazol Kern Pharma 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 transparent solutions without particles should be used.
• It should not be administered as a bolus.
• Regarding information on conservation, see section 5 "Conservation of Voriconazol Kern Pharma".

Required Volumes of Voriconazol Kern Pharma Concentrate 10 mg/ml

Voriconazol Kern Pharma is a sterile lyophilized single-dose product. From a microbiological point of view, the solution should be used immediately once reconstituted. If not used immediately, the time and conditions of conservation before use are the responsibility of the user, and it should be kept between 2 and 8°C (in the refrigerator) 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 perfusion.
• 5% glucose and lactated Ringer's solution for intravenous perfusion.
• 5% glucose and 0.45% sodium chloride solution for intravenous perfusion.
• 5% glucose solution for intravenous perfusion.
• 5% glucose solution with 20 mEq of potassium chloride for intravenous perfusion.
• 0.45% sodium chloride solution for intravenous perfusion.
• 5% glucose and 0.9% sodium chloride solution for intravenous perfusion.

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

Incompatibilities:

Voriconazol Kern Pharma 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 Voriconazol Kern Pharma.

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

Voriconazol Kern Pharma should not be diluted with 4.2% sodium bicarbonate solution.