Voriconazole Noridem

Package leaflet: Information for the user

Voriconazole Noridem 200 mg powder for solution for infusion

voriconazole
Generic medicine
Please read this leaflet carefully before using 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 their symptoms are the same as yours, as it may be harmful.
• If you experience any adverse reaction, including those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

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

1. What Voriconazolo Noridem is and what it is used for

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

• 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 species and Fusarium species (two different types of fungi).

Voriconazolo Noridem is indicated for patients with worsening fungal infections and who are at high risk of bone marrow transplantation.
Prevention of fungal infections in patients undergoing high-risk bone marrow transplantation.
This product should only be used under medical supervision.

2. What you should know before taking Voriconazole Noridem

Do not take Voriconazole Noridem

• 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 medicines.
The following medicines must not be used during treatment with Voriconazole Noridem:

• 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 perforatum – 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)
• Venetoclax (for the treatment of patients with chronic lymphocytic leukemia-CLL)

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

• you have had an allergic reaction to other azoles.
• you suffer or have suffered from liver disease. If you have liver problems, your doctor may prescribe a lower dose of Voriconazole Noridem. Your doctor will need to monitor your liver function during treatment with Voriconazole Noridem by performing blood tests.
• you know you have heart disease, an irregular heartbeat, a slow heartbeat, or an abnormality on the 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 high-protection sunscreens (SPF), as increased sensitivity of the skin to UV light 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 Noridem:

• 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 consultation may decide that regular check-ups are necessary. With long-term use of Voriconazole Noridem, 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, or 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 liver and kidney function through blood tests.
Children and adolescents
Voriconazole Noridem must not be administered to children under 2 years of age.
Other medicines and Voriconazole Noridem
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 Noridem, may alter the activity of Voriconazole Noridem, or Voriconazole Noridem may alter the activity of these medicines.
Inform your doctor if you are taking the following medicine, because concomitant treatment with Voriconazole Noridem should be avoided if possible:

• 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 concomitant treatment with Voriconazole Noridem should be avoided if possible, 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 Noridem, and your dose may need to be adjusted.

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

• Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; to slow blood clotting)
• Cyclosporine (for transplant patients)
• Tacrolimus (for transplant patients)
• Sulfonylureas (e.g., tolbutamide, glipizide, glibenclamide; for diabetes)
• Statins (e.g., atorvastatin, simvastatin; to reduce cholesterol)
• Benzodiazepines (e.g., midazolam, triazolam; for severe insomnia and stress)
• Omeprazole (for the treatment of ulcers)
• Oral contraceptives (if you take Voriconazole Noridem while using oral contraceptives, side effects such as nausea and menstrual disturbances may occur)
• Vinca alkaloids (e.g., vincristine and 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 cannot be taken together with Voriconazole Noridem)
• Methadone (for the treatment of heroin addiction)
• 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 (e.g., ibuprofen, diclofenac) (used for pain and inflammation)
• Fluconazole (used to treat fungal infections)
• Everolimus (used for the treatment of advanced renal cell carcinoma and in transplant patients)
• Letermovir (used to prevent cytomegalovirus (CMV) disease following allogeneic hematopoietic stem cell transplantation)
• Ivacaftor: used for the treatment of cystic fibrosis
• Flucloxacillin (an antibiotic indicated for bacterial infections)

Pregnancy and breastfeeding
Voriconazole NORIDEM must not be used during pregnancy unless specifically decided by your doctor. Women of childbearing potential must use an adequate contraceptive method. Contact your doctor immediately if you become pregnant during treatment with Voriconazole Noridem.
If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Driving and using machines
Voriconazole Noridem may cause blurred vision or increased sensitivity to light. In such cases, you must not drive and must not operate tools or machinery. In these cases, contact your doctor.
Voriconazole Noridem contains sodium
This medicine contains 217.6 mg of sodium (a main component of table salt) per vial. This corresponds to 10.8% of the maximum daily dietary intake recommended for an adult.
Voriconazole Noridem contains cyclodextrin
This medicine contains 3,200 mg of cyclodextrin(s) per vial, equivalent to 106.6 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 Noridem

Take this medicine exactly as directed 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 Noridem 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, please refer to 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/hr over 1 to 3 hours.
If you or your child are taking Voriconazole Noridem to prevent fungal infections, your doctor may decide to discontinue treatment if you or your child develop treatment-related adverse effects.

If you have missed a dose of Voriconazole Noridem
Since this medicine will be 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 Noridem
Treatment with Voriconazole Noridem must continue for as long as your doctor decides; however, the duration of treatment with Voriconazole Noridem 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. When your condition has improved, treatment may be switched from intravenous to tablets.
When treatment with Voriconazole Noridem is discontinued at the doctor's discretion, no effects are expected to occur.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
If side effects occur, most will probably be mild and temporary. However, some may be serious and require immediate medical attention.
Serious side effects – Stop taking Voriconazole Noridem and contact a doctor immediately

• Rash
• Jaundice, abnormal liver function tests
• Pancreatitis

Other side effects
Very common: may affect more than 1 in 10 people

• Visual disturbances (including blurred vision, altered vision, abnormal sensitivity to light, colour blindness, eye disorders, seeing halos, night blindness, fluctuating vision, seeing sparks, visual aura, reduced visual acuity, increased 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 rapid 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 damage
• Skin rash which may lead to severe blistering and peeling of the skin, characterised by flat, red skin areas with small merging bumps, skin redness
• Itching
• Hair loss
• Back pain
• Kidney failure, blood in urine, abnormal kidney function tests

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 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 causing 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 leading to visual impairment, swelling of the optic disc
• Reduced sensitivity to touch
• Altered taste
• Hearing disorders, ringing in the ears, vertigo
• Inflammation of internal organs, pancreas and duodenum, swelling and inflammation of the tongue
• Liver enlargement, liver failure, gallbladder diseases, gallstones
• Joint inflammation, inflammation of subcutaneous veins (which may be associated with blood clot formation)
• Kidney inflammation, protein in urine, kidney damage
• Very rapid heart rate or missed beats, sometimes with irregular electrical impulses
• Abnormal electrocardiogram (ECG)
• Increased cholesterol, increased blood urea
• Allergic skin reactions (sometimes severe), including potentially life-threatening skin condition causing blisters and painful sores of the skin and mucous membranes, especially in the mouth, skin inflammation, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, skin colour changes which may be due to low platelet count, eczema
• Infusion site reaction
• Allergic reactions or exaggerated immune response

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

• Overactive thyroid gland
• Worsening of brain function, severe complication of liver disease
• Significant loss of optic nerve fibres, corneal opacity, involuntary eye movement
• Bullous photosensitivity
• Disorder in which the body's immune system attacks part of the peripheral nervous system
• Heart rhythm or conduction 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, scaly skin with silvery scales, skin and mucous membrane irritation, potentially life-threatening skin condition causing detachment of large areas of the epidermis (the outer layer of skin) from underlying skin layers
• Small patches of dry, scaly skin, sometimes thickened, 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:

• Skin cancer
• Inflammation of tissues surrounding the bones
• Red, scaly or ring-shaped skin lesions which could be symptoms of an autoimmune disease called systemic lupus erythematosus

The occurrence of reactions (including skin redness, fever, sweating, increased heart rate and shortness of breath) during infusion of Voriconazole Noridem is not common. If one or more of these reactions occur, your doctor may decide to stop the infusion.
Since Voriconazole Noridem 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 Noridem for prolonged periods.
Sunburn or 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, pharmacist or nurse. You can also report side effects directly via the national reporting system at:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Voriconazole Noridem

Store below 30°C.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label. The expiry date refers to the last day of that month.
After reconstitution, Voriconazole Noridem must be used immediately; however, if necessary, it may be stored for up to 24 hours at a temperature between 2°C and 8°C (in the refrigerator). The reconstituted Voriconazole Noridem solution must be diluted with a compatible intravenous infusion diluent prior to administration. (For further information, see the concluding section of the package leaflet).
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 Noridem contains

• The active substance is voriconazole.
• The other component is sulfobutylether beta cyclodextrin sodium (see section 2, Voriconazolo Noridem contains cyclodextrin and sodium). Each vial contains 200 mg of voriconazole, equivalent to a solution of 10 mg/mL, when reconstituted as recommended by the pharmacist or hospital nurse (see information provided at the end of this leaflet).

Description of the appearance of Voriconazolo Noridem and contents of the pack
Voriconazolo Noridem is supplied in single-use glass vials containing a powder for solution for intravenous infusion. Packs of 1, 10 or 50 vials.

Marketing Authorization Holder and Manufacturer
Noridem Enterprises Limited
Evagorou & Makariou
Mitsi Building 3, Office 115
1065 Nicosia, Cyprus

Manufacturer:
DEMO S.A. INDUSTRIA FARMACEUTICA
21st Km National Road Athens–Lamia,
14568 Krioneri, Attiki, Greece

This medicinal product is authorized in the European Economic Area countries under the following names:
Portugal: Voriconazol Bradex
Greece: Voriconazole BRADEX 200 mg Κόνις για διάλυμα προς έγχυση
Austria: Voriconazol Noridem 200 mg Pulver zur Herstellung einer Infusionslösung
Germany: Voriconazol Noridem 200 mg Pulver zur Herstellung einer Infusionslösung
Czech Republic: Voriconazole Noridem
Slovak Republic: Voriconazole Noridem 200 mg prášok na infúzny roztok
France: VORICONAZOLE NORIDEM 200 mg, poudre pour solution pour perfusion
Italy: Voriconazolo Noridem
Ireland: Voriconazole 200mg powder for solution for infusion
Netherlands: Voriconazol Noridem 200 mg poeder voor oplossing voor infusie
Spain: Voriconazol Noridem 200 mg polvo para solución para perfusión EFG
Poland: Voriconazole Noridem
Romania: Voriconazol Noridem 200 mg pulbere pentru soluţie perfuzabilă
<------------------------------------------------------------------------------------------------------------------------->

The following information is intended for healthcare professionals only:

Reconstitution and Dilution Instructions

• Voriconazole Noridem powder for solution for intravenous infusion must initially be reconstituted with 19 mL of Water for Injections or with 19 mL of a 9 mg/mL (0.9%) Sodium Chloride infusion solution to obtain a total extractable volume of 20 mL of a clear concentrate containing 10 mg/mL of voriconazole.
• Do not use the Voriconazole Noridem vial if the internal negative vacuum pressure does not draw the diluent into the vial.
• It is recommended to use a standard 20 mL syringe (non-automatic) to ensure accurate administration of the required volume of Water for Injections (19.0 mL) or Sodium Chloride 9 mg/mL (0.9%) infusion solution.
• The required volume of the reconstituted concentrate is then added to one of the compatible infusion solutions listed below to obtain a Voriconazole Noridem solution containing 0.5–5 mg/mL of voriconazole.
• This medicinal product is for single use only; any unused solution must be discarded, and only clear, particle-free solutions should be used.
• The product must not be administered as an intravenous bolus.
• For information on storage of the product, refer to Section 5 “How to store Voriconazole Noridem”.

Required volumes of Voriconazole Noridem concentrate at 10 mg/mL

Voriconazole Noridem is a sterile, lyophilized single-dose powder without preservatives. Therefore, from a microbiological standpoint, the reconstituted solution must be used immediately.
If not used immediately, the storage conditions before and after opening the container are the responsibility of healthcare personnel, and the product must not be used more than 24 hours after opening, if stored at 2–8°C, unless reconstitution has been carried out under controlled and validated aseptic conditions.

Compatible diluents:
The reconstituted solution may be diluted with:
Sodium Chloride 9 mg/mL (0.9%) Injection
Sodium Lactate Compound for Intravenous Infusion
Glucose 5% and Lactated Ringer’s for Intravenous Infusion
Glucose 5% and Sodium Chloride 0.45% for Intravenous Infusion
Glucose 5% for Intravenous Infusion
Glucose 5% with 20 mEq Potassium Chloride for Intravenous Infusion
Sodium Chloride 0.45% for Intravenous Infusion
Glucose 5% and Sodium Chloride 0.9% for Intravenous Infusion

The compatibility of Voriconazole Noridem with diluents other than those listed above (or listed in the section “Incompatibilities”) is unknown.

Incompatibilities:
Voriconazole Noridem must not be administered through the same line or cannula together with other intravenous infusion drugs, including parenteral nutrition (e.g., Aminofusina 10% Plus).
Transfusion of blood products must not be performed simultaneously with the administration of Voriconazole Noridem.
Total parenteral nutrition infusion may be administered simultaneously with Voriconazole Noridem, but not through the same infusion route.
Voriconazole Noridem must not be diluted with Sodium Bicarbonate 4.2% Infusion.