Label: Information for the User

Voriconazole Hikma 200 mg Powder for Solution for Infusion EFG

voriconazole

Read the entire label carefully before starting to use the medication, as it contains important information for you.

• Keep this label, as you may need to refer to it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• This medication has been prescribed only for you, and you should not give it to others who may have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor, pharmacist, or nurse, even if they are not listed in this label (See section 4).

Voriconazol Hikma contains the active ingredient voriconazol. Voriconazol is an antifungal medication. It acts by eliminating 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 produced byAspergillus sp).
• candidemia (another type of fungal infection produced byCandida sp) in non-neutropenic patients (patients who do not have an abnormally low white blood cell count).
• serious invasive infections produced byCandida sp, when the fungus is resistant to fluconazol (another antifungal medication).
• serious fungal infections produced byScedosporium spor byFusarium sp(two different species of fungi).

Voriconazol Hikma is used in patients with serious fungal infections that can put their lives at risk.

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

This medication must be used only under medical supervision.

No use Voriconazol Hikma

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

It is very important to inform your doctor or pharmacist if you are using or have recently used other medications, including those purchased without a prescription, or herbal remedies.

Do not take the following medications during treatment with Voriconazol Hikma:

• Terfenadine (used for allergies).
• Astemizol (used for allergies).
• Cisapride (used for digestive problems).
• Pimozide (used for mental disorders).
• Quinidine (used for arrhythmias).
• 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 a day.
• Carbamazepine (used to treat seizures).
• Phenobarbital (used for severe insomnia and seizures).
• Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraines).
• Sirolimus (used in patients who have received a transplant).
• Ritonavir (used for HIV treatment) at doses of 400 mg and above twice a day.
• St. John's Wort (hypericum, herbal remedy).
• Naloxegol (used to treat constipation caused specifically by 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 renal function in patients with polycystic kidney disease).
• Lurasidone (used to treat depression).
• Venetoclax (used for the treatment of patients with chronic lymphocytic leukemia [CLL]).

Warnings and precautions

Consult your doctor, pharmacist, or nurse before starting to use Voriconazol Hikma if:

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

Avoid any exposure to the sun and sunlight during treatment. It is essential to cover exposed areas and use a high-factor sunscreen, as you may experience increased skin sensitivity to UV rays from the sun. These precautions also apply to children.

While on treatment with Voriconazol Hikma:

• Inform your doctor if you experience:

• sunburn
• severe skin rash or blisters
• bone pain

If you develop skin disorders as described above, your doctor may refer you to a dermatologist, who may consider regular examinations. There is a small probability of developing skin cancer with long-term use of this Voriconazol Hikma.

If you develop signs of "adrenal insufficiency" where the adrenal glands do not produce sufficient amounts of certain steroid hormones, such as cortisol, which may cause symptoms like:

• chronic or prolonged fatigue
• muscle weakness
• loss of appetite
• weight loss
• abdominal pain

Inform your doctor.

If you present signs of the "Cushing's syndrome" where the body produces too much cortisol hormone, which may cause symptoms like:

• weight gain
• hump of fat between the shoulders
• rounded face
• darkening of the skin on the abdomen, thighs, breasts, and arms
• thin skin
• easily bruising
• high blood sugar levels
• excessive hair growth
• excessive sweating

Inform your doctor.

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

Children and adolescents

Voriconazol Hikma should not be administered to children under 2 years old.

Use of Voriconazol Hikma with other medications

Inform your doctor or pharmacist if you are taking, have recently taken, or may need to take any other medication.

Some medications, when used at the same time as Voriconazol Hikma, may affect the action of Voriconazol Hikma or Voriconazol Hikma may affect the action of other medications.

Inform your doctor if you are using the following medications, as simultaneous treatment with Voriconazol Hikma should be avoided if possible:

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

Inform your doctor if you are using any of the following medications, as simultaneous treatment with Voriconazol Hikma should be avoided as much as possible, and may require an adjustment of the voriconazole dose:

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

Inform your doctor if you are taking any of the following medications, as you may need to adjust your dose or have your medications monitored to ensure they continue to produce 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).
• Sulfonylureas (e.g., tolbutamide, glipizide, and glibenclamide) (used for diabetes).
• Statins (e.g., atorvastatin, simvastatin) (used to reduce cholesterol levels).
• Benzodiazepines (e.g., midazolam, triazolam) (used for severe insomnia and stress).
• Omeprazole (used for stomach ulcer treatment).
• Oral contraceptives (if you use Voriconazol Hikma while using oral contraceptives, you may experience side effects such as nausea and menstrual disorders).
• Vincristine and vinblastine alkaloids (used to treat cancer).
• Inhibitors of tyrosine kinase (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).
• Nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, and nevirapine) (used to treat HIV infection) (some efavirenz doses cannot be taken at the same time as Voriconazol Hikma).
• Methadone (used to treat heroin addiction).
• Alfentanil, fentanyl, and other short-acting opioids (e.g., sufentanil) (used for surgical procedures).
• Oxycodone and other long-acting opioids (e.g., hydrocodone) (used to treat moderate to severe pain).
• Nonsteroidal 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 a bone marrow transplant).
• Ivacaftor: used to treat cystic fibrosis.

Pregnancy and breastfeeding

Do not use Voriconazol Hikma during pregnancy unless your doctor indicates it. Women of childbearing age on Voriconazol treatment should use effective contraception. Contact your doctor immediately if you become pregnant during treatment with Voriconazol Hikma.

If you are pregnant or breastfeeding, or think you may be pregnant, consult your doctor or pharmacist before using this medication.

Driving and operating machines

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

Voriconazol Hikma contains sodium

This medication contains 217.6 mg of sodium (main component of table salt/for cooking) in each vial. This is equivalent to 10.9% of the recommended daily maximum sodium intake for an adult.

Voriconazol Hikma contains cyclodextrins

This medication contains 3200 mg of cyclodextrins in each vial, equivalent to 160 mg/ml when reconstituted in 20ml. If you have renal insufficiency, consult your doctor before taking this medication.

Follow exactly the administration instructions of this medication as indicated by your doctor. In case of doubt, 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 based on your situation.

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

Your doctor may reduce the dose to 3 mg/kg twice a day depending on your response to treatment.

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:

Your doctor may increase or decrease the daily dose depending on your response to treatment.

Voriconazole Hikma 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 via intravenous infusion (in vein) at a maximum rate of 3 mg/kg per hour for 1 to 3 hours.

If you or your child are taking Voriconazole Hikma for the prevention of fungal infections, your doctor may stop the administration of Voriconazole Hikma if you or your child experience treatment-related adverse effects.

If you forgot a dose of Voriconazole Hikma

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

If you interrupt treatment with Voriconazole Hikma

Treatment with Voriconazole Hikma should be continued for as long as your doctor considers necessary, although the duration of treatment with voriconazole should not exceed 6 months.

Patients with compromised immune systems or those with complicated infections may require longer treatments to prevent the infection from recurring. Once your condition improves, you may substitute intravenous infusion with oral tablets.

When your doctor stops treatment with Voriconazole Hikma, you should not experience any effects related to the interruption.

If you have any other questions about the use of this medication, ask your doctor, pharmacist, or nurse.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

If any occur, they are likely to be mild and temporary. However, some may be serious and require medical attention.

Severe side effects - Stop using Voriconazol Hikma and seek medical attention immediately

• Skin rash.
• Jaundice, liver function test abnormalities.
• Pancreatitis.

Other side effects

Very common: may affect more than 1 in 10 people:

• Visual disturbance (change in vision, such as blurred vision, visual colour changes, abnormal light perception intolerance, colour blindness, eye disorder, halo vision, night blindness, oscillating vision, spark vision, visual aura, decreased visual acuity, visual clarity, partial loss of usual visual field, visual field spots).
• Fever.
• Skin rash.
• Nausea, vomiting, and diarrhea.
• Headache.
• Swelling of the extremities.
• Abdominal 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 some types of red or white blood cells in the blood, low platelet count that helps blood to clot.
• Low blood sugar, low potassium in the blood, low sodium in the blood.
• Anxiety, depression, confusion, agitation, insomnia, hallucinations.
• Convulsions, tremors, or uncontrolled muscle movements, tingling or abnormal sensations in the skin, increased muscle tone, drowsiness, dizziness.
• Eye hemorrhage.
• Cardiac rhythm problems that include very fast heart rate, very slow heart rate, fainting.
• Hypotension, vein inflammation (which may be associated with blood clot formation).
• Acute difficulty breathing, chest pain, facial swelling (mouth, lips, and around the eyes), fluid retention in the lungs.
• Constipation, indigestion, lip inflammation.
• Jaundice (yellow skin colour), liver inflammation, and liver damage.
• Skin eruptions, which may be severe, with blisters and peeling, characterized by a flat, red area covered with small protuberances that converge, skin redness.
• Itching.
• Alopecia.
• Back pain.
• Renal failure, blood in urine, renal function test abnormalities.

Uncommon: may affect up to 1 in 100 people

• Flu-like symptoms, gastrointestinal tract irritation, gastrointestinal tract inflammation that causes diarrhea associated with antibiotics, lymphatic vessel inflammation.
• Peritoneal inflammation, which is the thin tissue that lines the abdominal wall and covers the abdominal organs.
• Enlargement (sometimes painful) of lymph nodes, bone marrow insufficiency, eosinophil increase.
• Adrenal gland dysfunction, hypothyroidism.
• Abnormal brain function, Parkinson's disease-like symptoms, nerve damage causing numbness, pain, tingling, or burning in the hands or feet.
• Balance or coordination problems.
• Brain swelling.
• Dual vision, severe eye diseases, such as: eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage that causes vision changes, papillary optic inflammation.
• Decreased sensitivity to touch.
• Altered sense of taste.
• Difficulty hearing, tinnitus, vertigo.
• Inflammation of certain internal organs, pancreas and duodenum, swelling and inflammation of the tongue.
• Enlarged liver, liver failure, gallbladder disease, gallstones.
• Joint inflammation, vein inflammation under the skin (which may be associated with blood clot formation).
• Renal inflammation, protein in urine, renal damage.
• Very high or extrasystolic heart rate, sometimes with erratic electrical impulses.
• Abnormal electrocardiogram (ECG).
• Elevated blood cholesterol, elevated blood urea.
• Severe skin reactions, such as skin disease, potentially fatal 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 the sun, skin redness and irritation, skin redness or purpura that may be caused by low platelet count, eczema.
• Reaction in the perfusion area.
• Severe allergic reaction or excessive immune response.

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

• Hyperactive thyroid gland.
• Cerebral activity deterioration as a severe complication of liver disease.
• Optic nerve fibre loss, corneal opacity, involuntary eye movement.
• Photosensitivity blister formation.
• Disease in which the immune system attacks part of the peripheral nervous system.
• Cardiac rhythm problems or conduction problems (sometimes potentially fatal.
• Potentially fatal allergic reaction.
• Blood coagulation abnormalities.
• Severe skin reactions, such as hives, rapid swelling (edema) of the dermis, subcutaneous tissue, mucosa, and submucosal layers, pruritic and painful skin plaques with scaly, thickened, and red skin, skin irritation and mucous membrane irritation, potentially fatal skin disease that causes large areas of the epidermis, the skin's outermost layer, to peel off from the layers of skin beneath it.
• Small, scaly, and dry skin plaques, sometimes thick and with points or "horns".

Unknown frequency side effects:

• Moles and pigmented spots

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

• Skin cancer.
• Periosteal inflammation.
• Red, scaly, or ring-shaped skin lesions that may be a symptom of an autoimmune disease called 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 happens.

Since voriconazole has been observed to affect the liver and kidneys, your doctor should monitor liver and renal function through blood tests. Inform your doctor if you have abdominal pain or if your stools have a different consistency.

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

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

If any of these side effects persist or are bothersome, inform your doctor.

Reporting side effects

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

Keep this medication out of the sight and reach of children.

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

This medication does not require any special temperature conditions for its conservation. Store it in the original packaging to protect it from light.

Medications should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This will help protect the environment.

Voriconazole Hikma Composition

• The active ingredient is voriconazole.
• The other component is sodium sulfobutyl ether beta-cyclodextrin.
• Each vial contains 200 mg of voriconazole, which is equivalent to a concentrated solution of 10 mg/ml after reconstitution following the instructions provided by the pharmacy or nursing staff of the hospital (see the information at the end of this leaflet)

Appearance of the product and contents of the pack

Voriconazole Hikma is a white or off-white compact powder.

Voriconazole Hikma is available in packs of 1 or 5 vials of powder for solution for infusion.

Only some pack sizes may be marketed.

Marketing Authorization Holder

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó n.º 8, 8A e 8B, Fervença

2705-906 Terrugem SNT

Portugal

Responsible Person

Hikma Italia S.p.A.

Viale Certosa, 10

27100 Pavia

Italy

For further information about this medicinal product, please consult the representative of the marketing authorisation holder in your country:

Last update of the leaflet:

The detailed information on this medicinal product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu

The following information is intended only for healthcare professionals:

Information on reconstitution and dilution

Voriconazole Hikma powder for solution for infusion must be reconstituted with 19 ml of water for injection or 19 ml of sodium chloride 9 mg/ml (0.9%) for infusion to obtain a volume of 20 ml of a concentrated solution containing 10 mg/ml of voriconazole.

It is recommended to use a standard 20 ml syringe (non-automatic) to ensure that the exact amount (19.0 ml) of water for injection or sodium chloride 9 mg/ml (0.9%) is dispensed.

After reconstitution with 19 ml of water for injection or sodium chloride 9 mg/ml (0.9%), a transparent injection solution is obtained.

The required volume of reconstituted concentrate is then added to a compatible infusion solution listed below to obtain a final voriconazole solution containing 0.5 to 5 mg/ml of voriconazole.

This product is for single use only and any unused solution must be discarded and only transparent solutions without particles should be used.

It should not be administered as a bolus.

This medicinal product does not require special temperature conditions before use. Store in the original packaging to protect it from light.

Volumes required of Voriconazole Hikma Concentrate 10 mg/ml

Voriconazole Hikma is a sterile, preservative-free, single-dose lyophilisate.

Stability after reconstitution:

It has been demonstrated that the chemical and physical stability in use is 36 hours between 2°C and 8°C for the reconstituted solution.

Stability after dilution:

It has been demonstrated that the chemical and physical stability in use of the diluted solution is 36 hours between 2°C and 8°C followed by 3 hours at room temperature.

Therefore, from a microbiological point of view, the solution should be used immediately after reconstitution. If not used immediately, the time and conditions of storage before use are the responsibility of the user, and it should be stored between 2°C and 8°C (in a refrigerator) for a maximum period of 24 hours unless the reconstitution has been performed in controlled and validated aseptic conditions.

Compatible infusion solutions:

The reconstituted solution can be diluted with:

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

Lactate Ringer's solution for intravenous infusion

Glucose 5% solution for intravenous infusion

Glucose 5% solution with sodium chloride 0.45% for intravenous infusion

Glucose 5% solution with potassium chloride 20 mEq for intravenous infusion

Sodium chloride 0.45% solution for intravenous infusion

Glucose 5% solution with sodium chloride 0.9% for intravenous infusion

The compatibility of Voriconazole Hikma with other diluents other than those specifically mentioned above (or mentioned below in “Incompatibilities”) is unknown.

Incompatibilities:

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

Simultaneous infusion of blood derivatives should not be performed with the administration of Voriconazole Hikma.

Parenteral nutrition can be administered simultaneously with Voriconazole Hikma but not in the same vein or cannula.

Voriconazole Hikma should not be diluted with sodium bicarbonate 4.2% solution.