Voriconazole Hikma

Package leaflet: Information for the user

Voriconazole Hikma 200 mg powder for solution for infusion

voriconazole
Please read all of this leaflet carefully before taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist, or nurse.
• This medicine has been prescribed for you only. Do not give it to other people, even if they have the same symptoms as yours, because it may be harmful.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse (see section 4).

Contents of this leaflet:

1. What Voriconazole Hikma is and what it is used for
2. What you need to know before taking Voriconazole Hikma
3. How to use Voriconazole Hikma
4. Possible side effects
5. How to store Voriconazole Hikma
6. Contents of the pack and other information

1. What Voriconazole Hikma is and what it is used for

Voriconazole Hikma contains the active substance voriconazole. Voriconazole Hikma is an antifungal medicine. It works by stopping the growth or killing the fungi that cause infections.
It is used to treat patients (adults and children over 2 years of age) with:

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

Voriconazole Hikma is indicated for patients with worsening fungal infections and potentially life-threatening conditions.
Prevention of fungal infections in high-risk patients undergoing bone marrow transplantation.
This medicine should only be used under medical supervision.

2. What you need to know before taking Voriconazole Hikma

Do not take Voriconazole Hikma:

• If you are allergic to the active substance voriconazole or to sodium sulfobutylether beta cyclodextrin (listed in section 6).

It is very important that you inform your doctor or pharmacist if you are taking or have recently taken any other medicines, including those without a prescription, or herbal preparations.
The following medicines must not be used during treatment with Voriconazole Hikma:

• Terfenadine (for allergies)
• Astemizole (for allergies)
• Cisapride (for stomach problems)
• Pimozide (for the treatment of mental illnesses)
• Quinidine (for irregular heartbeat)
• Ivabradine (for symptoms of chronic heart failure)
• Rifampicin (for the treatment of tuberculosis)
• Efavirenz (for the treatment of AIDS) at doses equal to or greater than 400 mg once daily
• Carbamazepine (for the treatment of seizures)
• Phenobarbital (for severe insomnia and seizures)
• Ergot alkaloids (e.g., ergotamine, dihydroergotamine; for migraine)
• Sirolimus (for transplant patients)
• Ritonavir (for the treatment of AIDS) at doses of 400 mg or more twice daily
• St. John’s Wort (Hypericum - herbal supplement)
• Naloxegol (for the treatment of constipation specifically caused by opioid pain medicines [e.g., morphine, oxycodone, fentanyl, tramadol, codeine])
• Tolvaptan (for the treatment of hyponatremia, i.e., low sodium levels in the blood, or to slow the decline in kidney function in patients with polycystic kidney disease)
• Lurasidone (for the treatment of depression)
• Finerenone (for the treatment of chronic kidney disease)
• Venetoclax (for the treatment of patients with chronic lymphocytic leukemia - CLL)

Warnings and precautions
Talk to your doctor, pharmacist, or nurse before taking Voriconazole Hikma if:

• you have had an allergic reaction to other azole antifungals.
• you have or have had liver disease. If you have liver problems, your doctor may prescribe a lower dose of Voriconazole Hikma. Your doctor will need to monitor your liver function during treatment with Voriconazole Hikma by performing blood tests.
• you know you have heart disease, irregular heartbeat, slow heartbeat, or an abnormality on electrocardiogram (ECG) called “long QTc syndrome”.

You must avoid any exposure to sunlight and UV light during treatment. It is important to cover exposed skin areas and use sunscreens with high protection factor (SPF), as increased sensitivity of the skin to UV radiation may occur. This sensitivity may be further increased by other medicines that make the skin more sensitive to sunlight, such as methotrexate. These precautions also apply to children.
During treatment with Voriconazole Hikma:

• inform your doctor immediately if you develop
  • sunburn
  • severe skin reaction or blistering
  • bone pain

If you develop any of the skin conditions described above, your doctor may refer you to a dermatologist, who after evaluation may decide that regular follow-up visits are necessary. With prolonged use of Voriconazole Hikma, there is a small risk of developing skin carcinoma.
If you develop signs of “adrenal insufficiency”, in which the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol, which may cause symptoms such as: chronic or persistent fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, inform your doctor.
Inform your doctor if you develop signs of “Cushing's syndrome”, in which the body produces excessive amounts of the hormone cortisol, which may cause symptoms such as weight gain, fat accumulation between the shoulders, rounded face, darkening of the skin on the abdomen, thinning of legs, breasts, and arms, thinning of the skin, easy bruising, increased blood sugar levels, excessive body hair growth, and excessive sweating.
Your doctor will need to monitor your liver and kidney function through blood tests.

Children and adolescents
Voriconazole Hikma must not be administered to children under 2 years of age.

Other medicines and Voriconazole Hikma:
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those without a prescription.

Some medicines, when taken together with Voriconazole Hikma, may alter the activity of Voriconazole Hikma, or Voriconazole Hikma may alter the activity of these medicines.

Inform your doctor if you are taking the following medicine because, if possible, concomitant treatment with Voriconazole Hikma should be avoided:

• Ritonavir (for the treatment of AIDS) at doses of 100 mg twice daily
• Glasdegib (for the treatment of cancer): if you need to use both medicines, your doctor will frequently monitor your heart rhythm

Inform your doctor if you are taking any of the following medicines because, if possible, concomitant treatment with Voriconazole Hikma should be avoided and a dose adjustment of voriconazole may be necessary:

• Rifabutin (for the treatment of tuberculosis). If you are already being treated with rifabutin, blood cell counts and rifabutin-related side effects should be closely monitored.
• Phenytoin (for the treatment of epilepsy). If you are already being treated with phenytoin, blood levels of phenytoin should be monitored during treatment with Voriconazole Hikma, and your dose may need to be adjusted.

Inform your doctor if you are taking any of the following medicines, as dose adjustments or monitoring may be needed to ensure these medicines and/or Voriconazole Hikma continue to have the desired effect:

• Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; to slow down blood clotting)
• Cyclosporine (for transplant patients)
• Tacrolimus (for transplant patients)
• Sulfonylureas (e.g., tolbutamide, glipizide, glyburide) (for diabetes)
• Statins (e.g., atorvastatin, simvastatin) (to reduce cholesterol)
• Benzodiazepines (e.g., midazolam, triazolam) (for severe insomnia and anxiety)
• Omeprazole (for the treatment of ulcers)
• Oral contraceptives (if you take Voriconazole Hikma while using oral contraceptives, side effects such as nausea and menstrual disturbances may occur)
• Vinca alkaloids (e.g., vincristine, vinblastine) (for cancer treatment)
• Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (for cancer treatment)
• Tretinoin (for the treatment of leukemia)
• Indinavir and other protease inhibitors for AIDS (for the treatment of AIDS)
• Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (for the treatment of AIDS) (some doses of efavirenz must NOT be taken together with Voriconazole Hikma)
• Methadone (for heroin addiction treatment)
• Alfentanil and fentanyl and other short-acting opioids such as sufentanil (analgesics used in surgical procedures)
• Oxycodone and other long-acting opioids such as hydrocodone (used for moderate to severe pain)
• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) (e.g., ibuprofen, diclofenac) (used for pain and inflammation)
• Fluconazole (used for fungal infections)
• Everolimus (used for advanced kidney cancer and in transplant patients)
• Letermovir (used to prevent cytomegalovirus (CMV) disease after bone marrow transplantation)
• Ivacaftor (used for the treatment of cystic fibrosis)
• Flucloxacillin (an antibiotic indicated for bacterial infections)

Pregnancy and breastfeeding
Voriconazole Hikma must not be used during pregnancy unless specifically decided by your doctor. Women of childbearing potential must use an effective method of contraception. Contact your doctor immediately if you become pregnant during treatment with Voriconazole Hikma.
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.

Driving and using machines
Voriconazole Hikma may cause blurred vision or increased sensitivity to light. In such cases, you should not drive or operate tools or machinery. In these cases, contact your doctor.

Voriconazole Hikma contains sodium
This medicine contains 217.6 mg of sodium (the main component of table salt) per vial. This corresponds to 10.9% of the maximum daily dietary intake recommended for an adult.

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

3. How to take Voriconazole Hikma

Take this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor.
Your doctor will determine the appropriate dose for you based on your body weight and the type of infection diagnosed.
Your doctor may adjust the dose according to your condition.
The recommended dose for adults (including elderly patients) is as follows:

Depending on the response to treatment, your doctor may reduce the dose to 3 mg/kg twice daily.
If you have mild to moderate cirrhosis, your doctor may decide to reduce the dose.
Use in children and adolescents
The recommended dose in children and adolescents is as follows:

Depending on the response to treatment, your doctor may increase or decrease the daily dose.
Voriconazole Hikma powder for solution for intravenous infusion will be reconstituted and diluted by a pharmacist or hospital nurse to obtain the correct concentration. (For further information, see the final section of the package leaflet).
The medicine will be administered to you by intravenous infusion (into a vein) at a maximum infusion rate of 3 mg/kg/h over 1 to 3 hours.
If you or your child is taking Voriconazole Hikma to prevent fungal infections, your doctor may decide to discontinue treatment if you or your child develops treatment-related adverse effects.

If you miss a dose of Voriconazole Hikma:
Since this medicine is administered under medical supervision, it is unlikely that a dose will be missed. However, if you think a dose has been missed, inform your doctor or pharmacist.

If you stop treatment with Voriconazole Hikma:
Treatment with Voriconazole Hikma must continue for as long as your doctor decides; however, the duration of treatment with Voriconazole Hikma powder for solution for intravenous infusion must not exceed 6 months.
Patients with a weakened immune system or those with difficult-to-treat infections may require long-term treatment to prevent the infection from recurring. Once your condition has improved, treatment may be switched from intravenous to tablets.
When treatment with Voriconazole Hikma is discontinued as directed by the doctor, no adverse effects should occur.

If you have any doubts about using this medicine, consult your doctor, pharmacist, or nurse.

4. Possible side effects

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

If side effects occur, most will probably be minor and temporary. However, some can be serious and require immediate medical attention.

Serious side effects – Stop taking Voriconazole Hikma and consult a doctor immediately

• Rash
• Jaundice, changes in liver function tests
• Pancreatitis

Other side effects

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

• Visual disturbances (including blurred vision, altered colour vision, abnormal tolerance to light, colour blindness, eye disorders, seeing halos, night blindness, fluctuating vision, seeing sparks, visual aura, reduced visual acuity, visual brightness, partial loss of visual field, spots in front of the eyes)
• Fever
• Skin rashes
• Nausea, vomiting, diarrhoea
• Headache
• Swelling of the extremities
• Stomach pain
• Difficulty breathing
• Elevated liver enzymes

Common (may affect up to 1 in 10 people):

• Sinus inflammation, gum inflammation, chills, fatigue
• Reduction, sometimes severe, in the number of certain types of red blood cells (sometimes immune-mediated) and/or white blood cells (sometimes with fever), reduction in the number of blood cells (called platelets) that help blood clotting
• Low blood sugar levels, low blood potassium levels, low blood sodium levels
• Anxiety, depression, confusion, agitation, sleep disorders, hallucinations
• Seizures, tremor or uncontrolled muscle movements, tingling or abnormal skin sensations, increased muscle tone, drowsiness, dizziness
• Bleeding in the eye
• Heart rhythm problems including very fast heartbeat, very slow heartbeat, fainting
• Low blood pressure, inflammation of a vein (which may be associated with blood clot formation)
• Acute breathing difficulty, chest pain, facial swelling (mouth, lips and around the eyes), fluid accumulation in the lungs
• Constipation, indigestion, inflammation of the lips
• Jaundice, liver inflammation and liver injury
• Skin rash which may lead to severe blistering and peeling of the skin, characterised by a flat, red area of skin with small merging bumps, skin redness
• Itching
• Hair loss
• Back pain
• Kidney failure, blood in the urine, changes in kidney function tests
• Sunburn or severe skin reaction following exposure to light or sun
• Skin cancer

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

• Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, gastrointestinal inflammation which may cause antibiotic-associated diarrhoea, inflammation of the lymphatic vessels
• Inflammation of the thin tissue lining the inner abdominal wall and covering abdominal organs
• Enlarged lymph nodes (sometimes painful), bone marrow failure, increased eosinophils
• Reduced adrenal gland function, reduced thyroid gland activity
• Changes in brain function, Parkinson-like symptoms, nerve damage leading to numbness, pain, tingling or burning in hands or feet
• Problems with balance and coordination
• Brain oedema
• Double vision, serious eye conditions including: eye and eyelid pain and inflammation, abnormal eye movements, optic nerve damage with visual impairment, swelling of the optic disc
• Reduced sensitivity to touch
• Altered taste
• Hearing disorders, ringing in the ears, vertigo
• Inflammation of certain internal organs – pancreas and duodenum, swelling and inflammation of the tongue
• Enlarged liver, liver failure, gallbladder diseases, gallstones
• Joint inflammation, inflammation of subcutaneous veins (which may be associated with blood clots)
• Kidney inflammation, presence of protein in the urine, kidney damage
• Very rapid heartbeat or missed beats, sometimes with irregular electrical impulses
• Abnormal electrocardiogram (ECG)
• Increased cholesterol, increased blood urea
• Allergic skin reactions (sometimes severe), including a potentially life-threatening skin condition causing blisters and painful sores of the skin and mucous membranes, especially in the mouth, skin inflammation, urticaria, redness and irritation of the skin, skin colour changes, red or purplish, which could be due to low platelet count, eczema
• Infusion site reaction
• Allergic reactions or exaggerated immune response
• Inflammation of tissues surrounding the bones

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

• Overactive thyroid gland
• Deterioration in brain function, severe complication of liver disease
• Loss of most of the fibres of the optic nerve, corneal opacity, involuntary eye movement
• Bullous photosensitivity
• Disorder in which the body's immune system attacks part of the peripheral nervous system
• Heart conduction rhythm problems (sometimes fatal)
• Potentially life-threatening allergic reaction
• Coagulation disorders
• Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues, itchy or painful patches of thickened, red skin with silvery scales, skin and mucous membrane irritation, potentially life-threatening skin condition causing detachment of large portions of the epidermis (the outer skin layer) from the underlying skin layers
• Small dry, scaly skin patches, sometimes thick with tips or 'horns'

Side effects with unknown frequency:

• Freckles and pigmented spots

Other significant side effects, whose frequency is unknown but which should be reported immediately to a doctor, include:

• Red, scaly or ring-shaped skin lesions which could be symptoms of an autoimmune disease called systemic lupus erythematosus

Infusion-related reactions (including skin redness, fever, sweating, increased heart rate and shortness of breath) during Voriconazole Hikma infusion are not common. If any of these reactions occur, your doctor may decide to stop the infusion.

Since Voriconazole Hikma has been observed to affect the liver and kidneys, your doctor will need to monitor liver and kidney function through blood tests. Inform your doctor if you have stomach pain or if your stools are different from normal.

Cases of skin carcinoma have been reported in patients treated with voriconazole for prolonged periods. Sunburn or a severe skin reaction following exposure to light or sun has been reported more frequently in children. If you or your child develops skin problems, your doctor may refer you to a dermatologist, who may decide whether it is important for you or your child to continue regular visits with a dermatologist. Elevated liver enzymes have also been observed more frequently in children.

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

Reporting of side effects

If you experience any side effect, including those not listed in this leaflet, talk to your doctor. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Voriconazole Hikma

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage temperature. Store in the original packaging to protect the medicine from light.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Voriconazolo Hikma contains

• The active substance is voriconazole. Each vial contains 200 mg of voriconazole, equivalent to a 10 mg/ml solution when reconstituted as recommended by the pharmacist or hospital nurse.
• The other component is sodium sulfobutylether beta cyclodextrin.

Description of the appearance of Voriconazolo Hikma and contents of the pack
Voriconazolo Hikma is a white to almost white, pasty powder.
Voriconazolo Hikma is available in packs of 1 or 5 glass vials as a powder for solution for infusion. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Hikma Farmacêutica (Portugal), S.A.
Estrada do Rio da Mó n.º 8, 8A and 8B, Fervença
2705-906 Terrugem SNT
Portugal
Manufacturers
Hikma Italia S.p.A.
Viale Certosa, 10
27100 Pavia
Italy
For further information on this medicinal product, contact the local representative of the Marketing Authorisation Holder:
AT / BE / DE / NL IT
Hikma Pharma GmbH Hikma Italia S.p.A.
Tel: +49 89-45450-302 Tel: +39 0382 1751801
BG / CY / CZ / DK / EE / EL / FI / HR / HU / UK
IE / IS / LI / LT / LU / LV / MT / NO / PL / PT Consilient Health Ltd
/ RO / SE / SI / SK Tel.: +44(0)203 751 1888
Hikma Farmacêutica (Portugal), S.A.
Tel.: +351 219 608 410
FR ES
Hikma France HIKMA ESPAÑA, S.L.U.
Tel.: +33(0) 1 87 69 98 43 Tel: +34 910075141
More detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/.

The following information is intended exclusively for medical and healthcare professionals:
Information on reconstitution and dilution
Voriconazolo Hikma powder for solution for infusion must be reconstituted with either 19 ml of water for injections or with 19 ml of 9 mg/ml (0.9%) sodium chloride infusion solution to obtain an extractable volume of 20 ml of a clear concentrate containing 10 mg/ml of voriconazole.
It is recommended to use a standard 20 ml syringe (non-automatic) to ensure the exact amount of water for injections (19.0 ml) or 9 mg/ml (0.9%) sodium chloride injection solution is withdrawn.
After reconstitution with 19 ml of water for injections or 0.9% sodium chloride injection solution, a clear, colourless solution is obtained.
For administration, the required volume of the reconstituted concentrate is added to a compatible infusion solution (detailed below) to achieve a final Voriconazolo Hikma solution containing 0.5–5 mg/ml.
This medicinal product is for single use only; any unused solution must be discarded, and only solutions free from visible particles should be used.
The product must not be administered as an intravenous bolus.
Prior to use, this medicinal product does not require special storage conditions. Store in the original packaging to protect from light.
Required volumes of Voriconazolo Hikma Concentrate 10 mg/ml

Voriconazole Hikma is a sterile, lyophilized, single-dose powder without preservatives.
Stability after reconstitution:
Chemical and physical in-use stability has been demonstrated for 36 hours between 2°C and 8°C for the reconstituted solution.
Stability after dilution:
Chemical and physical stability of the diluted solution for infusion has been demonstrated for 36 hours at a temperature between 2°C and 8°C, followed by 3 hours at room temperature.
From a microbiological standpoint, after reconstitution, the medicinal product should be used immediately. If not used immediately, the times and conditions of storage of the reconstituted vial prior to use are the responsibility of the user and normally should not exceed 24 hours between 2°C and 8°C (in the refrigerator), unless reconstitution has been carried out under controlled and validated aseptic conditions.
Compatible Infusion Solutions:
The reconstituted solution may be diluted in:
Sodium chloride 9 mg/ml (0.9%) injection solution
Sodium lactate intravenous infusion
5% glucose and Ringer lactate intravenous infusion
5% glucose and 0.45% sodium chloride intravenous infusion
5% glucose intravenous infusion
5% glucose intravenous infusion with 20 mEq potassium chloride
0.45% sodium chloride intravenous infusion
5% glucose and 0.9% sodium chloride intravenous infusion
The compatibility of Voriconazole Hikma with solvents other than those detailed above (or listed below in the section 'Incompatibilities') is unknown.
Incompatibilities:
Voriconazole Hikma must not be infused simultaneously with other intravenous medicinal products through the same infusion line or cannula, including parenteral nutrition (e.g., Aminofusin 10% Plus).
Transfusion of blood products must not occur simultaneously with Voriconazole Hikma.
Total parenteral nutrition may be administered at the same time as Voriconazole Hikma, but not through the same line or the same cannula.
Voriconazole Hikma must not be diluted with Sodium Bicarbonate 4.2% Solution.