VORICONAZOL HIKMA 200 mg POWDER FOR SOLUTION FOR INFUSION

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

Do not use Voriconazole Hikma

• if you are allergic to voriconazole or to sulfobutylether beta-cyclodextrin sodium (included 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 medicines.

During treatment with Voriconazole Hikma, 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 or higher 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 or higher twice daily.
• St. John's Wort (hypericum, herbal medicine).
• 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 deterioration of kidney function in patients with polycystic kidney disease).
• Lurasidone (used to treat depression).
• Venetoclax (used to treat patients with chronic lymphocytic leukemia [CLL]).

Warnings and precautions

Consult your doctor, pharmacist or nurse before starting Voriconazole 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 Voriconazole Hikma. Your doctor should also monitor your liver function while you are being treated with Voriconazole Hikma by performing blood tests.
• you know that you have cardiomyopathy, irregular heartbeats, slow heart rate or an abnormality in the electrocardiogram (ECG) called "QTc prolonged syndrome".

You should avoid any exposure to the sun and sunlight during treatment. It is important that you cover exposed areas and use a sunscreen with a high sun protection factor (SPF), as you may experience increased skin sensitivity to the sun's UV rays. These precautions also apply to children.

While being treated with Voriconazole Hikma:

• tell 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 Hikma.

If you develop signs of "adrenal insufficiency" in which the adrenal glands do not produce sufficient amounts of certain steroid hormones, such as cortisol, which can cause symptoms such as: chronic or prolonged fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, inform your doctor.

If you present signs of "Cushing's syndrome" in which the body produces too much cortisol hormone that can cause symptoms such as: weight gain, hump of fat between the shoulders, rounded face, darkening of the skin of the abdomen, thighs, breasts and arms, thin skin, easy bruising, high blood sugar levels, excessive hair growth or excessive sweating, inform your doctor.

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

Children and adolescents

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

Using Voriconazole Hikma 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 Hikma, can affect the action of Voriconazole Hikma or Voriconazole Hikma may affect the action of other medicines.

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

• 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 Hikma 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 Hikma are still working as expected:

• Warfarin and other anticoagulants (e.g. phenprocoumon, acenocoumarol; used to decrease 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 Hikma while using oral contraceptives, you may experience side effects such as nausea and menstrual disorders).
• Vinca alkaloids (e.g. vincristine and vinblastine) (used to treat cancer).
• Tyrosine kinase inhibitors (e.g. axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used to treat cancer).
• Tretinoin (used to treat leukemia).
• Indinavir and other HIV protease inhibitors (used to treat HIV infection).
• Non-nucleoside reverse transcriptase inhibitors (e.g. efavirenz, delavirdine and nevirapine) (used to treat HIV infection) (some doses of efavirenz should NOT be taken at the same time as Voriconazole Hikma).
• 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.

Pregnancy and breastfeeding

Do not use Voriconazole Hikma during pregnancy unless your doctor advises you to. Women of childbearing age using Voriconazole Hikma should use effective contraception. Contact your doctor immediately if you become pregnant during treatment with Voriconazole Hikma.

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.

Driving and using machines

Voriconazole Hikma 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 Hikma contains sodium

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

Voriconazole Hikma contains cyclodextrins

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

3. How to use Voriconazole Hikma

Follow exactly the instructions of administration of this medicine given by your doctor. If you are not sure, 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 the 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 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 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 Hikma to prevent fungal infections, your doctor may stop the administration of Voriconazole Hikma if you or your child experience treatment-related side effects.

If you miss a dose of Voriconazole Hikma

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 Hikma

Treatment with Voriconazole Hikma should be continued for as long as your doctor considers necessary, however, the duration of treatment with voriconazole 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 Hikma, 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 Voriconazol Hikma 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 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.
• Ocular hemorrhage.
• Heart rhythm problems, including very fast or very slow heartbeat, fainting.
• Hypotension, inflammation of the veins (which may be associated with the formation of blood clots).
• Acute difficulty breathing, chest pain, swelling of the face (mouth, lips, and around the eyes), fluid retention in the lungs.
• Constipation, indigestion, lip inflammation.
• Jaundice (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 protrusions that converge, skin redness.
• Itching.
• Alopecia.
• Back pain.
• Kidney failure, presence of blood in urine, alterations in kidney function tests.

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 the lymph nodes, bone marrow failure, increased eosinophils.
• Decreased function of the adrenal gland, underactive thyroid gland.
• Abnormal brain function, symptoms similar to Parkinson's disease, nerve damage causing numbness, pain, tingling, or burning in the hands or feet.
• Problems with balance or coordination.
• Brain swelling.
• Double vision, serious eye diseases, such as: pain and inflammation of the eyes and eyelids, abnormal eye movements, damage to the optic nerve that causes vision alteration, inflammation of the optic papilla.
• Decreased sensitivity to touch.
• Alteration of the sense of taste.
• Difficulty hearing, ringing in the ears, vertigo.
• Inflammation of certain internal organs, pancreas, and duodenum, swelling and inflammation of the tongue.
• 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 blood, high urea in blood.
• Severe allergic skin reactions (including potentially life-threatening conditions), such as a potentially life-threatening 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 at the infusion site.
• Allergic reaction or exaggerated immune response.

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

• Overactive thyroid gland.
• Worsening of brain activity as a serious complication of liver disease.
• Loss of most of the optic nerve fibers, corneal opacity, involuntary eye movement.
• Blisters due to photosensitivity.
• Disorder in which the immune system attacks part of the peripheral nervous system.
• Heart rhythm problems or conduction problems (sometimes potentially fatal).
• Potentially fatal allergic reaction.
• Alterations in blood coagulation.
• Severe allergic skin reactions (including potentially life-threatening conditions), 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 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:

• Pigmented spots and patches.

Other important adverse effects whose frequency is unknown, 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 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 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 is not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Storage of Voriconazol Hikma

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

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

This medicine does not require any special temperature conditions for storage. Keep it in the original packaging to protect it from light.

Medicines should not be disposed of through wastewater or household waste. Ask your pharmacist how to dispose of the packaging and medicines you no longer need. This will help protect the environment.

6. Package Contents and Additional Information

Composition of Voriconazol Hikma

• The active ingredient is voriconazole.
• The other component is sulfobutyl ether beta-cyclodextrin sodium.
• Each vial contains 200 mg of voriconazole, which is equivalent to a 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 leaflet).

Appearance of the Product and Package Contents

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

Voriconazol Hikma is available in packages of 1 or 5 vials of powder for solution for infusion.

Only some package 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

Manufacturer

Hikma Italia S.p.A.

Viale Certosa, 10

27100 Pavia

Italy

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

Date of the Last Revision of this Leaflet:

Detailed information about this medicine is available on the European Medicines Agency website http://www.ema.europa.eu.

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

Information on Reconstitution and Dilution

Voriconazol Hikma powder for solution for infusion needs to be reconstituted with 19 ml of water for injectable preparations or 19 ml of sodium chloride 9 mg/ml (0.9%) for infusion to obtain an extractable volume of 20 ml of clear concentrate that contains 10 mg/ml of voriconazole.

It is recommended to use a standard 20 ml syringe (not automatic) to ensure that the exact amount (19.0 ml) of water for injectable preparations or sodium chloride 9 mg/ml (0.9%) for infusion is dispensed.

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

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

This specialty is for single use, and any unused solution should be discarded, and only clear solutions without particles should be used.

It should not be administered as a bolus.

This medicine does not require special temperature conditions before use. Keep it in the original packaging to protect it from light.

Required Volumes of Voriconazol Hikma Concentrate 10 mg/ml

Voriconazol Hikma is a sterile lyophilized single-dose product.

Stability after reconstitution:

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

Stability after dilution:

Chemical and physical stability in use of the diluted solution has been demonstrated for 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 once reconstituted. If not used immediately, the time and conditions of storage before use are the responsibility of the user, and it should be kept between 2°C and 8°C (in a refrigerator) for a maximum period of 24 hours, unless the reconstitution was 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

Compound sodium lactate intravenous infusion

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

5% glucose solution and 0.45% sodium chloride solution for intravenous infusion

5% glucose solution for intravenous infusion

5% glucose solution with 20 mEq of potassium chloride for intravenous infusion

0.45% sodium chloride solution for intravenous infusion

5% glucose solution and 0.9% sodium chloride solution for intravenous infusion

The compatibility of Voriconazol Hikma with other diluents, other than those specifically mentioned above (or those mentioned below in "Incompatibilities"), is unknown.

Incompatibilities:

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

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

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

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