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نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

Voriconazole MCP® contains the active substance voriconazole. Voriconazole MCP® is an antifungal medicine. It works by killing or stopping the growth of the fungi that cause infections. 

It is used for the treatment of patients (adults and children over the age of 2) with:

Invasive aspergillosis (a type of fungal infection due to Aspergillus sp).

Candidaemia (another type of fungal infection due to Candida sp) in non-neutropenic patients (patients without abnormally low white blood cells count).

Serious invasive Candida sp. infections when the fungus is resistant to fluconazole (another antifungal medicine).

Serious fungal infections caused by Scedosporium sp. or Fusarium sp. (two different species of fungi). 

Voriconazole MCP® is intended for patients with worsening, possibly life-threatening, fungal infections. 

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

This product should only be taken under the supervision of a doctor. 


Do not take Voriconazole MCP®:

If you are allergic to voriconazole or any of the other ingredients of this medicine.  

It is very important that you inform your doctor or pharmacist if you are taking or have taken any other medicines, even those that are obtained without a prescription, or herbal medicines.   

The medicines in the following list must not be taken during your course of Voriconazole MCP® treatment:  

Terfenadine (used for allergy).

Astemizole (used for allergy).

Cisapride (used for stomach problems).

Pimozide (used for treating mental illness).

Quinidine (used for irregular heart beat).

Ivabradine (used for symptoms of chronic heart failure).

Rifampicin (used for treating tuberculosis).

Efavirenz (used for treating HIV) in doses of 400 mg and above once daily.

Carbamazepine (used to treat seizures).

Phenobarbital (used for severe insomnia and seizures).

Ergot alkaloids (e.g., ergotamine, dihydroergotamine; used for migraine).

Sirolimus (used in transplant patients).

Ritonavir (used for treating HIV) in doses of 400 mg and more twice daily.

St. John’s Wort (herbal supplement). 

Naloxegol (used to treat constipation specifically caused by pain medicines, called opioids, (e.g., morphine, oxycodone, fentanyl, tramadol, codeine)).

Tolvaptan (used to treat hyponatremia (low levels of sodium in your blood) or to slow kidney function decline in patients with polycystic kidney disease).

Lurasidone (used to treat depression).

Venetoclax (used to treat patients with chronic lymphocytic leukaemia-CLL).

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Voriconazole MCP®

If you have had an allergic reaction to other azoles.

If youu are suffering from, or have ever suffered from liver disease. If you have liver disease, your doctor may prescribe a lower dose of Voriconazole MCP®. Your doctor should also monitor your liver function while you are being treated with Voriconazole MCP® by doing blood tests.

If you are known to have cardiomyopathy, irregular heartbeat, slow heart rate or an abnormality of electrocardiogram (ECG) called ‘long QTc syndrome’.  

You should avoid any sunlight and sun exposure while being treated.  It is important to cover sun exposed areas of skin and use sunscreen with high sun protection factor (SPF), as an increased sensitivity of skin to the sun’s UV rays can occur. These precautions are also applicable to children. 

While being treated with Voriconazole MCP®:

tell your doctor immediately if you develop: 

- 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 after consultation may decide that it is important for you to be seen on a regular basis. There is a small chance that skin cancer could develop with long-term use of Voriconazole MCP®.

If you develop signs of “adrenal insufficiency” where the adrenal glands do not produce adequate amounts of certain steroid hormones such as cortisol which may lead to symptoms such as: chronic, or long lasting fatigue, muscle weakness, loss of appetite, weight loss, abdominal pain, please tell your doctor.

If you develop signs of ‘Cushing’s syndrome’ where the body produces too much of the hormone cortisol which may lead to symptoms such as: weight gain, fatty hump between the shoulders, a rounded face, darkening of the skin on the stomach, thighs breasts, and arms, thinning skin, bruising easily, high blood sugar, excessive hair growth, excessive sweating, please tell your doctor.

Your doctor should monitor the function of your liver and kidney by doing blood tests.  

Children and adolescents

Voriconazole MCP® should not be given to children younger than 2 years of age.  

Other medicines and Voriconazole MCP®

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those that are obtained without a prescription.  

Some medicines, when taken at the same time as Voriconazole MCP®, may affect the way Voriconazole MCP® works or Voriconazole MCP® may affect the way they work.   

Tell your doctor if you are taking the following medicine, as treatment with Voriconazole MCP® at the same time should be avoided if possible:  

Ritonavir (used for treating HIV) in doses of 100 mg twice daily.

Glasdegib (used for treating cancer) – if you need to use both drugs your doctor will monitor your heart rhythm frequently. 

Tell your doctor if you are taking either of the following medicines, as treatment with Voriconazole MCP® at the same time should be avoided if possible, and a dose adjustment of voriconazole may be required:  

Rifabutin (used for treating tuberculosis). If you are already being treated with rifabutin your blood counts and side effects to rifabutin will need to be monitored.

Phenytoin (used to treat epilepsy). If you are already being treated with phenytoin your blood concentration of phenytoin will need to be monitored during your treatment with Voriconazole MCP® and your dose may be adjusted.  

Tell your doctor if you are taking any of the following medicines, as a dose adjustment or monitoring may be required to check that the medicines and/ or Voriconazole MCP® are still having the desired effect:  

Warfarin and other anticoagulants (e.g., phenprocoumon, acenocoumarol; used to slow down clotting of the blood).

Ciclosporin (used in transplant patients).

Tacrolimus (used in transplant patients).

Sulfonylureas (e.g., tolbutamide, glipizide, and glyburide) (used for diabetes).

Statins (e.g., atorvastatin, simvastatin) (used for lowering cholesterol).

Benzodiazepines (e.g midazolam, triazolam) (used for severe insomnia and stress).

Omeprazole (used for treating ulcers).

Oral contraceptives (if you take Voriconazole MCP® whilst using oral contraceptives, you may get side effects such as nausea and menstrual disorders).

Vinca alkaloids (e.g., vincristine and vinblastine) (used in treating cancer).

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib) (used for treating cancer).

Tretinoin (used to treat leukaemia).

Indinavir and other HIV protease inhibitors (used for treating HIV).

Non-nucleoside reverse transcriptase inhibitors (e.g., efavirenz, delavirdine, nevirapine) (used for treating HIV) (some doses of efavirenz can NOT be taken at the same time as Voriconazole MCP®).

Methadone (used to treat heroin addiction). 

Alfentanil and fentanyl and other short-acting opiates such as sufentanil (painkillers used for surgical procedures).

Oxycodone and other long-acting opiates such as hydrocodone (used for moderate to severe pain).

Non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac) (used for treating pain and inflammation).

Fluconazole (used for fungal infections).

Everolimus (used for treating advanced kidney cancer and in transplant patients). 

Letermovir (used for preventing cytomegalovirus (CMV) disease after bone marrow transplant).

Ivacaftor: used to treat cystic fibrosis. 

Pregnancy and breast-feeding 

Voriconazole MCP® must not be taken during pregnancy, unless indicated by your doctor. Effective contraception must be used in women of childbearing potential. Contact your doctor immediately if you become pregnant while taking Voriconazole MCP®.  

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

Driving and using machines

Voriconazole MCP® may cause blurring of vision or uncomfortable sensitivity to light. While affected, do not drive or operate any tools or machines. Contact your doctor if you experience this.   

Voriconazole MCP® contains lactose 

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor before taking Voriconazole MCP®.  


Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.  

Your doctor will determine your dose depending on your weight and the type of infection you have.  

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

 

 

Tablets

Patients 40 kg and above 

Patients less than 40 kg

Dose for the first 24 hours

(Loading Dos)

 400mg every 12 hours for the first 24 hours 

200mg every 12 hours for the first 24 hours 

Dose after the first 24 hours

(Maintenance Dose)

   200mg twice a day  

100mg twice a day    

 

 

Depending on your response to treatment, your doctor may increase the daily dose to 300 mg twice a day. 

The doctor may decide to decrease the dose if you have mild to moderate cirrhosis.  

 

Use in children and adolescents

The recommended dose for children and teenagers is as follows:

 

Tablets

 

Children aged 2 to less than 12 years and teenagers aged 12 to 14 years weighing less than 50 kg

Teenagers aged 12 to 14 years

weighing 50 kg or more; and all teenagers older than 14

Dose for the first 24 hours  (Loading Dose)

Your treatment will be started as an infusion

400mg every 12 hours for the first 24 hours

Dose after the first 24 hours  (Maintenance Dose)

9mg/kg twice a day 

(a maximum dose of 350 mg twice daily)

200mg twice a day

 

Depending on your response to treatment, your doctor may increase or decrease the daily dose. 

• Tablets must only be given if the child is able to swallow tablets.  

Take your tablet at least one hour before, or one hour after a meal. Swallow the tablet whole with some water.  If you or your child are taking Voriconazole MCP® for prevention of fungal infections, your doctor may stop giving Voriconazole MCP® if you or your child develop treatment related side effects.  

If you take more Voriconazole MCP® than you should

If you take more tablets than prescribed (or if someone else takes your tablets) you must seek medical advice or go to the nearest hospital casualty department immediately. Take your box of Voriconazole MCP® tablets with you. You may experience abnormal intolerance to light as a result of taking more Voriconazole MCP® than you should. 

If you forget to take Voriconazole MCP®

It is important to take your Voriconazole MCP® tablets regularly at the same time each day. If you forget to take one dose, take your next dose when it is due. Do not take a double dose to make up for a forgotten dose.  

If you stop taking Voriconazole MCP®

It has been shown that taking all doses at the appropriate times may greatly increase the effectiveness of your medicine. Therefore unless your doctor instructs you to stop treatment, it is important to keep taking Voriconazole MCP® correctly, as described above.  

Continue taking Voriconazole MCP® until your doctor tells you to stop. Do not stop treatment early because your infection may not be cured. Patients with a weakened immune system or those with difficult infections may require long-term treatment to prevent the infection from returning.  

When Voriconazole MCP® treatment is stopped by your doctor you should not experience any effects.  

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.  


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

If any side effects occur, most are likely to be minor and temporary. However, some may be serious and need medical attention.  

Serious side effects – Stop taking Voriconazole MCP® and see a doctor immediately

Rash.

Jaundice; Changes in blood tests of liver function.

Pancreatitis.

Other side effects 

Very common: may affect more than 1 in 10 people  

Visual impairment (change in vision including blurred vision, visual color alterations, abnormal intolerance to visual perception of light, colour blindness, eye disorder, halo vision, night blindness, swinging vision, seeing sparks, visual aura, visual acuity reduced, visual brightness, loss of part of the usual field of vision, spots before the eyes).

Fever.

Rash.

Nausea, vomiting, diarrhoea. 

Headache. 

Swelling of the extremities. 

Stomach pains.

Breathing difficulties.

Elevated liver enzymes. 

Common: may affect up to 1 in 10 people  

Inflammation of the sinuses, inflammation of the gums, chills, weakness.

Low numbers of some types, including severe, of red (sometimes immune-related) and/or white blood cells (sometimes with fever), low numbers of cells called platelets that help the blood to clot. 

Low blood sugar, low blood potassium, low sodium in the blood. 

Anxiety, depression, confusion, agitation, inability to sleep,  hallucinations.

Seizures, tremors or uncontrolled muscle movements, tingling or abnormal  skin sensations, increase in muscle tone, sleepiness, 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 the formation of a blood clot). 

Acute breathing difficulty, chest pain, swelling of the face (mouth, lips and around eyes), fluid accumulation in the lungs. 

Constipation, indigestion, inflammation of the lips.

Jaundice, inflammation of the liver and liver injury. 

Skin rashes which may lead to severe blistering and peeling of the skin characterized  by a flat, red area on the skin that is covered with small confluent bumps, redness of the skin.

Itchiness. 

Hair loss. 

Back pain.

Kidney failure, blood in the urine, changes in kidney function tests. 

Uncommon: may affect up to 1 in 100 people  

Flu-like symptoms, irritation and inflammation of the gastrointestinal tract, inflammation of the gastrointestinal tract causing antibiotic associated diarrhea, inflammation of the lymphatic vessels.

Inflammation of the thin tissue that lines the inner wall of the abdomen and covers the abdominal organ.

Enlarged lymph glands (sometimes painful), failure of blood marrow, increased eosinophil.

Depressed function of the adrenal gland, underactive thyroid gland.

Abnormal brain function, Parkinson-like symptoms, nerve injury resulting in  numbness, pain, tingling or burning in the hands or feet.

Problems with balance or coordination. 

Swelling of the brain.  

Double vision, serious conditions of the eye including: pain and inflammation of the eyes and eyelids, abnormal eye movement, damage to the optic nerve resulting in vision impairment, optic disc swelling. 

Decreased sensitivity to touch.

Abnormal sense of taste.

Hearing difficulties, ringing in the ears, vertigo. 

Inflammation of certain internal organs- pancreas and duodenum, swelling and  inflammation of the tongue. 

Enlarged 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). 

Inflammation of the kidney, proteins in the urine, damage to the kidney.    

Very fast heart rate or skipped heartbeats, sometimes with erratic electrical impulses.

Abnormal electrocardiogram (ECG). 

Blood cholesterol increased, blood urea increased.

Allergic skin reactions (sometimes severe), including life-threatening skin condition that causes painful blisters and sores of the skin and mucous membranes, especially in the mouth, inflammation of the skin, hives, sunburn or severe skin reaction following exposure to light or sun, skin redness and irritation, red or purple discoloration of the skin which may be caused by low platelet count, eczema.

Infusion site reaction.

Allergic reaction or exaggerated immune response.

Rare: may affect up to 1 in 1000 people

Overactive thyroid gland.

Deterioration of brain function that is a serious complication of liver disease.

Loss of most fibres in the optic nerve, clouding of the cornea, involuntary movement of the eye.

Bullous photosensitivity.

A disorder in which the body’s immune system attacks part of the peripheral nervous system.

Heart rhythm or conduction problems (sometimes  life threatening). 

Life threatening allergic reaction. 

Disorder of blood clotting system.

Allergic skin reactions (sometimes severe), including rapid swelling (oedema) of the dermis, subcutaneous tissue, mucosa and submucosal tissues, itchy or sore patches of thick, red skin with silvery scales of skin, irritation of the skin and mucous membranes, life-threatening skin condition that causes large portions of the epidermis, the skin’s outermost layer, to detach from the layers of skin below.

Small dry scaly skin patches, sometimes thick with spikes or ‘horns’. 

Side effects with frequency not known:

Freckles and pigmented spots. 

Other significant side effects whose frequency is not known, but should be reported to your 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.  

As Voriconazole MCP® has been known to affect the liver and the kidney, your doctor should monitor the function of your liver and kidney by doing blood tests. Please advise your doctor if you have any stomach pains or if your stools have a different consistency.

There have been reports of skin cancer in patients treated with voriconazole for long periods of time.  

Sunburn or severe skin reaction following exposure to light or sun was experienced more frequently in children. If you or your child develops 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 be seen on a regular basis. Elevated liver enzymes were also observed more frequently in children. 

If any of these side effects persist or are troublesome, please tell your doctor.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.


Keep out of the reach and sight of children.

Do not use Voriconazole MCP® after the expiry date (EXP) which is stated on the blister and the carton.

The expiry date refers to the last day of that month.

Voriconazole MCP® Tablets: Store below 30°C.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.


The active substance is Voriconazole.

The other ingredients are Lactose monohydrate, croscarmellose sodium, povidone K30, microcrystalline Cellulose,  magnesium stearate, Opadry OY-L White (Lactose monohydrate, HPMC, titanium dioxide and Macrogol), FD&C Yellow #6 lake, FD&C Blue #1 lake, Yellow iron oxide.


Voriconazole MCP® 200mg Film Coated Tablet, light green, oval deep biconvex film coated tablet engraved with H15 on one face, packed in Alu/PVC/PVDC blisters, intended for oral use. Pack size: 30 Film Coated Tablets (10 tablets in Alu/PVC/PVDC blister, 3 blisters/pack).

Med City Pharma-KSA.

Tel: 00966920003288

Fax: 00966126358138

Mobile: 00966555786968

P.O .Box: 42512 - Jeddah 21551

E-mail: MD.admin@Axantia.com


10/2023
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

يحتوي ڤوريكونازول إم سي بي® على المادة الفعالة ڤوريكونازول. ڤوريكونازول إم سي بي® هو عبارة عن دواء مضاد للفطريات. يعمل عن طريق القضاء أو تثبيط نمو الفطريات التي تسبب الالتهابات.

يستعمل لعلاج المرضى (البالغين والأطفال الذين تزيد أعمارهم عن سنتين) والذين يعانون من:

داء الرشاشيات الغازية (يحدث عندما يفشل الجهاز المناعي بسبب ضعفه في منع الرشاشيات من دخول مجرى الدم عبر الرئتين) (نوع من الالتهابات الفطرية تسببه أنواع الرشاشيات).

تسمم الدم بفطر الكانديدا (نوع آخر من الالتهابات الفطرية تسببه أنواع من الكانديدا) عند المرضى الذين لا يعانون من قلة العدلات (المرضى الذين لا يعانون من تعداد منخفض غير طبيعي لخلايا الدم البيضاء).

التهابات خطيرة غازية تسببها أنواع من الكانديدا عندما تكون الفطريات مقاومة لفلوكونازول (دواء آخر مضاد للفطريات).

التهابات فطرية خطيرة تسببها أنواع من زيدوسبوريوم أو أنواع من فيوزاريوم (نوعين مختلفين من الفطريات).

يستعمل ڤوريكونازول إم سي بي® للمرضى الذين يعانون من الالتهابات الفطرية، التي من المحتمل أن تكون مهددة للحياة، أو ازديادها سوءاً.

الوقاية من الالتهابات الفطرية عند المرضى المعرضين لخطر كبير للإصابة بها والذين خضعوا لعملية زراعة النخاع.

يجب تناول هذا المستحضر فقط تحت إشراف الطبيب.

يجب عدم تناول ڤوريكونازول إم سي بي® في الحالات التالية:

إذا كنت تعاني من تحسس لڤوريكونازول أو لأي من المكونات الأخرى في هذا الدواء.

من الضروري جدا إخبار طبيبك أو الصيدلي إذا كنت تتناول أو تناولت أي أدوية أخرى، بما في ذلك الأدوية التي يتم الحصول عليها بدون وصفة طبية، أو الأدوية العشبية.

يجب عدم تناول الأدوية التالية خلال فترة علاجك باستعمال ڤوريكونازول إم سي بي®:

تيرفينادين (يستعمل للحساسية).

أستميزول (يستعمل للحساسية).

سيسابريد (يستعمل لمشاكل المعدة).

بيموزايد (يستعمل لعلاج الأمراض العقلية).

كوينيدين (يستعمل لعلاج عدم انتظام نبضات القلب).

إيڤابرادين (يستعمل لعلاج أعراض قصور وظيفة عضلة القلب المزمنة).

ريفامبيسين (يستعمل لعلاج السل).

إيفاڤيرينز (تستعمل لعلاج ڤيروس نقص المناعة المكتسبة) بجرعات 400 ملغم و أكثر مرة واحدة يوميا.

كاربامازيبين (يستعمل لعلاج نوبات الصرع).

فينوباربيتال (يستعمل لعلاج الأرق الحاد و الصرع).

إيرجوت ألكالويد (مثل إيرجوتامين، دايهادروإيرجوتامين، يستعمل للشقيقة).

سايروليمس (يستعمل للمرضى الذين خضعوا لزراعة الأعضاء).

ريتوناڤير (يستعمل لعلاج ڤيروس نقص المناعة المكتسبة) بجرعات 400 ملغم و أكثر مرتين يوميا.

عشبة سانت جون (مكمل عشبي).

نالوكسيجول (يستعمل لعلاج الإمساك الذي ينتج عن الأدوية المسكنة للألم خصوصا المعروفة بالأفيونات (مثل المورفين، أوكسيكودون، فينتانيل، ترامادول، كوديين)).

تولڤابتان (يستعمل لعلاج نقص صوديوم الدم (انخفاض مستويات الصوديوم في الدم) أو لإبطاء قصور وظائف الكلى لدى المرضى الذين يعانون من مرض الكلى متعددة الكيسات).

لوراسيدون (يستعمل لعلاج الاكتئاب).

ڤينيتوكلاكس (يستعمل لعلاج المرضى الذين يعانون من سرطان الدم الليمفاوي المزمن).

الاحتياطات والمحاذير

قم باستشارة الطبيب، الصيدلي أو الممرض قبل تناول ڤوريكونازول إم سي بي® في الحالات التالية:

إذا عانيت في السابق من تفاعل تحسسي لأدوية أخرى من مجموعة الأزول.

إذا كنت تعاني أو عانيت في السابق من مرض في الكبد. إذا كنت تعاني من مرض في الكبد، قد يصف لك الطبيب جرعة أقل من ڤوريكونازول إم سي بي®. كما يجب على الطبيب أيضا مراقبة وظيفة الكبد لديك أثناء فترة علاجك باستعمال ڤوريكونازول إم سي بي® عن طريق عمل فحوصات للدم.

إذا كنت تعاني من اعتلال في عضلة القلب، عدم انتظام نبضات القلب، بطء معدل نبضات القلب أو تخطيط القلب الكهربائي غير طبيعي “متلازمة QT الطويلة”.

يجب أن تتجنب أشعة الشمس والتعرض لها أثناء فترة علاجك. من الضروري تغطية المناطق المعرضة للشمس واستعمال واقي شمسي ذو معامل حماية عالي، حيث يزداد تحسس الجلد لإشعاعات الشمس فوق البنفسجية. هذه الاحتياطات تنطبق أيضا على الأطفال.

أثناء فترة العلاج باستعمال ڤوريكونازول إم سي بي®:

أخبر طبيبك فورا إذا حصل لديك أي من الحالات التالية:

- حروق ناتجة عن التعرض لأشعة الشمس.

-  طفح جلدي حاد أو تنفطات.

- ألم في العظام.

إذا حصل لديك اضطرابات جلدية كما وصف في الأعلى، قد يطلب منك الطبيب استشارة طبيب الأمراض الجلدية، الذي من الممكن أن يقرر بعد الاستشارة أنه من الضروري زيارته بشكل منتظم. هناك فرصة قليلة لاحتمالية حصول سرطان الجلد عند الاستعمال طويل الأمد لڤوريكونازول إم سي بي®.

إذا ظهرت عليك علامات “قصور وظيفة الغدة الكظرية” حيث لا تقوم الغدة الكظرية بإنتاج كميات كافية من هرمونات ستيرويدية معينة مثل الكورتيزول الذي قد يسبب ظهور أعراض مثل: الشعور بالتعب المزمن أو المستمر، ضعف العضلات، فقدان الشهية، فقدان الوزن، ألم في البطن، الرجاء أخبر طبيبك.

اذا ظهرت عليك علامات “متلازمة كوشينج” حيث ينتج الجسم كمية أكبر من اللازم من هرمون الكورتيزول مما قد يؤدي إلى ظهور أعراض مثل: زيادة الوزن، ظهور كتلة دهنية بين الكتفين، استدارة الوجه، اسمرار الجلد في منطقة المعدة، الفخذين، الثديين و الذراعين، ترقق الجلد، سهولة ظهور الكدمات، ارتفاع مستوى سكر الدم، فرط نمو الشعر، فرط التعرق، الرجاء إخبار طبيبك.

يجب أن يراقب طبيبك وظائف الكبد والكلى عن طريق القيام بفحوصات الدم.

الأطفال والمراهقون

يجب عدم إعطاء ڤوريكونازول إم سي بي® للأطفال الأقل من سنتين.

تناول أدوية أخرى مع ڤوريكونازول إم سي بي®

الرجاء إخبار طبيبك أو الصيدلي إذا كنت تتناول، تناولت مؤخراً أي أدوية أخرى أو من الممكن أن تتناول أي أدوية أخرى، بما في ذلك الأدوية التي  يتم الحصول عليها بدون وصفة طبية.

بعض الأدوية عند تناولها بشكل متزامن مع ڤوريكونازول إم سي بي®، قد تؤثر على آلية عمله أو قد يؤثر ڤوريكونازول إم سي بي® على آلية عملها.

أخبر طبيبك إذا كنت تتناول أي من الأدوية التالية، حيث يجب تجنب العلاج المتزامن مع ڤوريكونازول إم سي بي® إذا كان ذلك ممكنا:

ريتوناڤير (يستعمل لعلاج ڤيروس نقص المناعة المكتسبة) بجرعات 100 ملغم مرتين يوميا.

جلاسديجيب (يستعمل لعلاج السرطان) – إذا احتجت إلى استعمال الدوائين، سيراقب طبيبك نظمية القلب بشكل متكرر.

أخبر طبيبك إذا كنت تتناول أي من الأدوية التالية، حيث يجب تجنب العلاج المتزامن مع ڤوريكونازول إم سي بي® إذا كان ذلك ممكنا، وقد يتطلب ذلك تعديل جرعة ڤوريكونازول:

ريفابيوتين (يستعمل لعلاج السل). إذا كنت تتعالج باستعمال ريفابيوتين، قد يتطلب ذلك مراقبة تعدادات الدم والآثار الجانبية لريفابيوتين.

فينيتوين (يستعمل لعلاج الصرع). إذا كنت تتعالج باستعمال فينيتوين، فإنه يجب مراقبة تركيزه في الدم خلال فترة علاجك باستعمال ڤوريكونازول إم سي بي® وقد يتم تعديل جرعتك من ڤوريكونازول إم سي بي®.

أخبر طبيبك إذا كنت تتناول أي من الأدوية التالية، قد يتم تعديل الجرعة أو مراقبتك للتأكد من أن الأدوية و/أو ڤوريكونازول إم سي بي® ما زال لديهم التأثير المطلوب:

وارفارين ومضادات التجلط الأخرى (مثل فينبروكومون، أسينوكومارول، تستعمل لإبطاء عملية تجلط الدم).

سايكلوسبورين (يستعمل للمرضى الذين خضعوا لزراعة الأعضاء).

تاكروليمس (يستعمل للمرضى الذين خضعوا لزراعة الأعضاء).

سلفونيل يوريا (مثل تولبيوتاميد، جليبيزايد، و جليبيرايد)(تستعمل لداء السكري).

الأدوية من مجموعة الستاتين (مثل أتورڤاستاتين، سيمڤاستاتين) (تستعمل لخفض مستوى الكوليستيرول).

الأدوية من مجموعة بينزوديازيبان (مثل ميدازولام، ترايازولام) (تستعمل للأرق الحاد والضغط).

أوميبرازول (يستعمل لعلاج التقرحات).

موانع الحمل التي يتم تناولها عن طريق الفم (إذا كنت تتناول ڤوريكونازول إم سي بي® أثناء فترة استعمالك لموانع الحمل التي يتم تناولها عن طريق الفم قد تعاني من آثار جانبية مثل الشعوور بالغثيان واضطرابات الدورة الشهرية).

ڤينكا ألكالويد (ڤينكريستين، فينبلاستين) (تستعمل لعلاج السرطان).

مثبطات تيروسين كاينيز (مثل، أكسيتينيب، بوسوتينيب، كابوزانتينيب، سيريتينيب، كوبيميتينيب، دابرافينيب، داساتينيب، نيلوتينيب، سونيتينيب، إيبروتينيب، ريبوسيكليب) (يستعمل لعلاج السرطان).

تريتينوين (يستعمل لعلاج سرطان الدم).

إنديناڤير ومثبطات بروتيز ڤيروس نقص المناعة المكتسبة (يستعمل لعلاج ڤيروس نقص المناعة المكتسبة).

مثبطات إنزيم الاستنساخ المنعكس غير النكليوسيد (مثل إيفاڤيرينز، ديلاڤيردين، نيڤيرابين) (تستعمل لعلاج ڤيروس نقص المناعة المكتسبة) (من غير الممكن تناول بعض الجرعات من إيفاڤيرينز بالتزامن مع ڤوريكونازول إم سي بي®).

ميثادون (يستعمل لعلاج الإدمان على الهيروين).

ألفينتانيل وفينتانيل والمستحضرات الأفيونية الأخرى قصيرة المفعول مثل سوفينتانيل (المسكنات التي تستعمل للعمليات الجراحية).

أوكسيكودون والمستحضرات الأفيونية الأخرى طويلة المفعول مثل هيدروكودون (تستعمل للألم المتوسط إلى الحاد).

مضادات الالتهاب غير الستيرويدية (مثل أيبوبروفين، ديكلوفيناك) (تستعمل لعلاج الألم والالتهاب).

فلوكونازول (يستعمل للالتهابات الفطرية).

إيڤيروليمس (يستعمل لعلاج سرطان الكلى المتقدم وللمرضى الذين خضعوا لزراعة الأعضاء).

ليترموڤير (يستعمل للوقاية من مرض الڤيروس المضخم للخلايا بعد زراعة نخاع العظم).

ايڤاكافتور: (يستعمل لعلاج التليف الكيسي).

الحمل و الرضاعة الطبيعية

الحمل

يجب عدم تناول ڤوريكونازول إم سي بي® خلال فترة الحمل، ما لم يوصف من قبل الطبيب. يجب استعمال وسائل منع الحمل الفعالة من قبل النساء القادرات على الإنجاب. استشيري طبيبك فورا عند حصول الحمل خلال فترة تناول ڤوريكونازول إم سي بي®.

إذا كنت حاملا أو مرضعة، تعتقدين أنك حاملا أو تخططين للحمل، استشيري الطبيب أو الصيدلي قبل تناول هذا الدواء.

القيادة و استخدام الآلات

قد يسبب ڤوريكونازول إم سي بي® ضبابية الرؤية أو تحسس غير مريح للضوء. أثناء فترة تعرضك لذلك، تجنب القيادة أو تشغيل أي أدوات أو آلات. اتصل مع الطبيب إذا حصل لديك ذلك.

يحتوي ڤوريكونازول إم سي بي® على اللاكتوز

إذا أخبرك طبيبك بأنك غير قادر على تحمل بعض السكريات، قم باستشارته قبل تناول ڤوريكونازول إم سي بي®.

https://localhost:44358/Dashboard

دائما تناول هذا الدواء تماما كما أخبرك طبيبك. تأكد من طبيبك أو الصيدلي إذا لم تكن متأكدا.

سيحدد الطبيب جرعتك بالاعتماد على وزنك ونوع الالتهاب الذي تعاني منه.

الجرعة الموصى بها للبالغين (بما في ذلك كبار السن) هي كالتالي:

 

الأقراص

المرضى الذين تبلغ أوزانهم 40 كغم فما فوق

المرضى الذين تقل أوزانهم عن  40 كغم

الجرعة لأول 24 ساعة (جرعة التحميل)

400 ملغم كل 12 ساعة لأول 24 ساعة

200 ملغم كل 12 ساعة لأول 24 ساعة

الجرعة بعد أول 24 ساعة (الجرعة المحافظة)

200 ملغم مرتين يوميا

100 ملغم مرتين يوميا

بناء على استجابتك للعلاج، قد يقوم طبيبك بزيادة الجرعة اليومية إلى 300 ملغم مرتين يوميا.

قد يقرر الطبيب تخفيض الجرعة إذا كنت تعاني من تشمع معتدل إلى متوسط في الكبد.

 

الاستعمال للأطفال والمراهقين

الجرعة الموصى بها للأطفال والمراهقين هي كالتالي:

 

الأقراص

الأطفال الذين تتراوح أعمارهم من سنتين إلى أقل من 12 سنة والمراهقون الذين تتراوح أعمارهم من 12 إلى 14 سنة وأوزانهم أقل من 50 كغم

المراهقون الذين تتراوح أعمارهم من 12 إلى 14 سنة وتبلغ أوزانهم 50 كغم أو أكثر، وجميع المراهقين الأكبر من 14 سنة.

الجرعة لأول 24 ساعة (جرعة التحميل)

سيبدأ علاجك على شكل حقن وريدي بطيء

400 ملغم كل 12 ساعة لأول 24 ساعة

الجرعة بعد أول 24 ساعة (الجرعة المحافظة)

9 ملغم/كغم مرتين يوميا (تبلغ الجرعة القصوى 350 ملغم مرتين يوميا)

200 ملغم مرتين يوميا

 

بناء على استجابتك للعلاج، قد يقوم طبيبك بزيادة أو تخفيض الجرعة اليومية.

يتم إعطاء الأقراص للطفل إذا كان قادراً على بلعها.

قم بتناول الأقراص قبل أو بعد ساعة واحدة على الأقل من تناول الطعام. تناول القرص كاملا مع شرب الماء. إذا كنت أنت أو طفلك تتناول ڤوريكونازول إم سي بي® للوقاية من الالتهابات الفطرية، قد يتوقف الطبيب عن إعطائك ڤوريكونازول إم سي بي® إذا حصل لديك أو لدى طفلك آثار جانبية متعلقة بالعلاج.

إذا تناولت ڤوريكونازول إم سي بي® أكثر مما يجب

إذا تناولت أقراص أكثر مما يجب (أو إذا تناول شخص آخر أقراصك) يجب أن تطلب النصيحة الطبية أو اذهب إلى قسم الطوارئ في أقرب مستشفى فوراً. اصطحب معك عبوة أقراص ڤوريكونازول إم سي بي®. قد يحصل لديك عدم تحمل غير طبيعي للضوء نتيجة لتناولك ڤوريكونازول إم سي بي® أكثر مما يجب.

إذا نسيت تناول ڤوريكونازول إم سي بي®

من المهم أن تتناول أقراصك من ڤوريكونازول إم سي بي® بانتظام في نفس الوقت يوميا. إذا نسيت تناول جرعة واحدة، تناول الجرعة التالية كالمعتاد. لا تتناول جرعة مضاعفة لتعويض الجرعة التي نسيتها.

إذا توقفت عن تناول ڤوريكونازول إم سي بي®

تبين أن تناول جميع الجرعات في الوقت المناسب قد يزيد بشكل كبير فعالية دوائك. لذلك ما لم يطلب منك الطبيب التوقف عن تناول العلاج، من الضروري الاستمرار بتناول ڤوريكونازول إم سي بي® بشكل صحيح، كما هو موصوف في الأعلى.

استمر بتناول ڤوريكونازول إم سي بي® حتى يخبرك الطبيب بالتوقف عن ذلك. لا تتوقف عن تناول العلاج مبكرا لأن الالتهاب لا يكون قد تم علاجه بالكامل. المرضى الذين يعانون من جهاز مناعة ضعيف أو الذين يعانون من التهابات صعبة قد يحتاجون إلى علاج طويل الأمد للوقاية من معاودة حدوث الالتهاب.

عند التوقف عن تناول ڤوريكونازول إم سي بي® بأمر من الطبيب يجب أن لا تعاني من أي تأثيرات.

إذا كان لديك أية أسئلة أخرى عن استعمال هذا الدواء، اسأل طبيبك، الصيدلي أو الممرض.

مثل جميع الأدوية، يمكن أن يتسبب هذا الدواء في آثار جانبية، على الرغم من أنها لا تحصل عند الجميع.

إذا حدثت أي من الآثار الجانبية، معظمها في الغالب تكون غير خطيرة ومؤقتة. لكن، بعضها قد تكون خطيرة وتحتاج إلى العناية الطبية.

آثار جانبية خطيرة - توقف عن تناول ڤوريكونازول إم سي بي® واذهب إلى الطبيب فورا

طفح.

يرقان، تغيرات في فحوصات الدم لوظيفة الكبد.

التهاب البنكرياس.

آثار جانبية أخرى

آثار جانبية شائعة جدا: قد تؤثر على أكثر من 1 من كل 10 أشخاص

ضعف الرؤية (تغيرات في الرؤية تتضمن ضبابية الرؤية، تغيرات في رؤية الألوان، عدم تحمل بشكل غير طبيعي لإدراك الضوء، عمى الألوان، اضطراب العين، رؤية هالة حول الضوء، عمى ليلي، تأرجح الرؤية، رؤية شرار، أورة بصرية، نقص حدة البصر، سطوع الرؤية، فقدان جزء من مجال الرؤية المعتاد، ظهور بقع أمام العين).

حمى.

طفح.

الشعور بالغثيان، قيء إسهال.

صداع.

تورم الأطراف.

آلام المعدة.

صعوبة التنفس

ارتفاع مستوى إنزيمات الكبد.

آثار جانبية شائعة: قد تؤثر على 1 من كل 10 أشخاص

التهاب الجيوب الأنفية، التهاب اللثة، قشعريرة، شعور بالضعف.

انخفاض عدد بعض أنواع خلايا الدم بما في ذلك انخفاض حاد في عدد خلايا الدم الحمراء (أحيانا تكون متعلقة باضطرابات الجهاز المناعي) و/أو خلايا الدم البيضاء (أحيانا يرافقها حمى)، انخفاض عدد خلايا تسمى الصفيحات الدموية التي تساعد الدم على التجلط.

انخفاض مستوى السكر، البوتاسيوم، الصوديوم في الدم.

قلق، اكتئاب، ارتباك، الشعور بالتهيج، عدم القدرة على النوم، هلوسات.

نوبات صرع، ارتعاش أو حركات غير مضبوطة في العضلات، الإحساس بوخز خفيف أو إحساس غير طبيعي في الجلد، زيادة توتر العضلات، شعور بالنعاس، الدوار.

نزيف في العين.

مشاكل نظمية القلب بما في ذلك نبضات القلب سريعة جدا، نبضات القلب بطيئة جدا الإغماء.

انخفاض ضغط الدم، التهاب الأوردة (الذي قد يرتبط بتشكل الجلطات الدموية).

صعوبة التنفس بشكل حاد، ألم الصدر، تورم الوجه (الفم، الشفاه و حول العيون)، تجمع السوائل في الرئة.

إمساك، عسر الهضم، التهاب الشفاه.

يرقان، التهاب الكبد و اصابة الكبد.

طفح جلدي، الذي قد يؤدي إلى تنفط حاد وتقشير الجلد الذي يتميز بظهور مناطق حمراء منبسطة على الجلد تغطى نتوءات صغيرة، احمرار الجلد.

حكة.

فقدان الشعر.

ألم في الظهر.

قصور وظائف الكلى، ظهور الدم في البول، تغيرات في نتائج فحوصات الدم لوظيفة الكلى.

آثار جانبية غير شائعة: قد تؤثر على 1 من كل 100 شخص

أعراض تشبه أعراض الانفلونزا، تهيج و التهاب الجهاز الهضمي، التهاب الجهاز الهضمي الذي يؤدي إلى الإصابة بإسهال مرتبط باستعمال المضادات الحيوية، التهاب الأوعية الليمفاوية.

التهاب الأنسجة الرقيقة المبطنة للجدار الداخلي في منطقة البطن وتغطي الأعضاء في منطقة البطن.

تضخم الغدد الليمفاوية (في بعض الأحيان تكون مؤلمة)، قصور وظيفة نخاع الدم، زيادة الحمضات.

تثبيط وظيفة الغدة الكظرية، قصور الغدة الدرقية.

وظيفة الدماغ غير طبيعية، أعراض مشابهة لباركنسون، إصابة العصب الذي ينتج عنه تنميل، ألم، الإحساس بوخز خفيف أو حرقة في اليدين أو القدمين.

اضطراب التوازن أو التناسق.

تورم الدماغ.

ازدواجية الرؤية، حالات خطيرة في العين تتضمن: ألم والتهاب في العيون والجفون، حركة غير طبيعية للعين، تلف العصب البصري مما يؤدي إلى ضعف الرؤية ، تورم القرص البصري.

انخفاض التحسس باللمس.

إحساس غير طبيعي في حاسة التذوق.

صعوبات في السمع، رنين في الأذنين، الشعور بالدوار.

التهاب أعضاء داخلية معينة - البنكرياس و الاثني عشر، تورم و التهاب اللسان.

تضخم الكبد، قصور وظيفة الكبد، مرض في المرارة، وتكون الحصى فيها.

التهاب المفاصل، التهاب الأوردة تحت الجلد (الذي قد يرتبط بتكون جلطات دموية).

التهاب الكلى، ظهور البروتينات في البول، تلف الكلى.

زيادة سرعة معدل نبضات القلب بشكل كبير أو خفقان، أحيانا يرافقها عدم انتظام الإشارات الكهربائية في القلب.

تخطيط القلب الكهربائي غير طبيعي.

زيادة مستوى الكوليستيرول، و اليوريا في الدم.

تفاعلات تحسسية في الجلد (أحيانا تكون حادة)، التي تتضمن حالات جلدية مهددة للحياة التي تسبب تنفط مؤلم و تقرحات في الجلد والأغشية المخاطية، بشكل خاص في الفم، التهاب الجلد، شرى، حروق ناتجة عن التعرض لأشعة الشمس أو تفاعلات جلدية حادة بعد التعرض للضوء أو أشعة الشمس، احمرار الجلد وتهيجه، تلون الجلد بلون أحمر أو أرجواني الذي قد يكون نتيجة انخفاض عدد الصفيحات الدموية، إكزيما.

تفاعل في مكان الحقن الوريدي البطيء.

تفاعل تحسسي أو استجابة مناعية عالية جدا.

آثار جانبية نادرة: قد تؤثر على 1 من كل 1000 شخص

فرط نشاط الغدة الدرقية.

ضعف وظيفة الدماغ التي تعد أحد المضاعفات الخطيرة لمرض الكبد.

فقدان أغلب الألياف في العصب البصري، تعتم القرنية، حركات غير إرادية في العين.

التحسس الضوئي الفقاعي.

اضطراب يقوم فيه الجهاز المناعي بالهجوم على جزء من نظام الأعصاب الطرفية.

مشاكل في نظمية القلب أو التوصيل (تكون أحيانا مهددة للحياة).

تفاعل تحسسي مهدد للحياة.

اضطراب نظام تجلط الدم.

تفاعلات تحسسية جلدية (أحيانا تكون حادة)، بما في ذلك تورم سريع (وذمة) في الأدمة، الأنسجة تحت الجلد، الأنسجة المخاطية وتحت المخاطية، بقع تسبب الحكة أو تقرح وتكون سميكة، احمرار الجلد مع ظهور قشور فضية اللون على الجلد، تهيج الجلد والأغشية المخاطية، حالة جلدية مهددة للحياة والتي تؤثر على أجزاء كبيرة من البشرة، حيث تنفصل طبقات الجلد الأبعد عن طبقات الجلد السفلى.

بقع صغيرة جافة و متقشرة على الجلد، أحيانا تكون سميكة مع بروزات.

آثار جانبية تكرار حدوثها غير معروف:

النمش وبقع مصبوغة.

آثار جانبية أخرى مهمة والتي تكرار حدوثها غير معروف، لكن يجب إخبار الطبيب على الفور عند حدوثها:

سرطان الجلد.

التهاب الأنسجة المحيطة بالعظام.

بقع حمراء متقشرة أو آفات جلدية على شكل حلقة والتي قد تكون أحد أعراض مرض مناعي ذاتي يعرف بالذأب الحمامي الجلدي.

لأنه من المعروف أن ڤوريكونازول إم سي بي® يؤثر على الكبد والكلى، يجب على طبيبك مراقبة وظيفة الكبد والكلى لديك عن طريق عمل فحوصات للدم. الرجاء إخبار الطبيب إذا كنت تعاني من أي آلام في المعدة أو إذا ظهر البراز بكثافة مختلفة.

هناك تقارير عن حدوث سرطان الجلد عند المرضى الذين استعملوا ڤوريكونازول لفترة طويلة.

إن تكرار حدوث حروق الشمس أو تفاعلات جلدية حادة بعد التعرض للضوء أو أشعة الشمس كان أكثر عند الأطفال. إذا حصل لديك أو لطفلك اضطرابات جلدية، قد يطلب منك الطبيب استشارة طبيب الأمراض الجلدية، الذي من الممكن أن يقرر بعد الاستشارة أنه من الضروري لك أو لطفلك زيارته بشكل منتظم.

تم ملاحظة  أيضا ارتفاع مستويات إنزيمات الكبد بتكرار أكبر عند الأطفال.

إذا استمرت أي من هذه الآثار الجانبية أو سببت لك الإزعاج، الرجاء إخبار الطبيب.

 

إذا ازدادت حدة أي من الآثار الجانبية أو إذا لاحظت حدوث أي آثار جانبية غير مذكورة في هذه النشرة، يرجى إخبار الطبيب أو الصيدلي.

يحفظ بعيدا عن متناول الأطفال و نظرهم.

لا تستعمل أقراص ڤوريكونازول إم سي بي® بعد تاريخ انتهاء الصلاحية المذكورعلى الشريط و العلبة الخارجية.

تاريخ الانتهاء يشير إلى اليوم الأخير من ذلك الشهر.

ڤوريكونازول إم سي بي® أقراص: يحفظ  بدرجة حرارة دون 30 °م.

يجب أن لا يتم التخلص من الأدوية عن طريق مياه الصرف الصحي أو النفايات المنزلية. اسأل الصيدلي عن كيفية التخلص من الأدوية التي لم تعد مطلوبة. وسوف تساعد هذه التدابير في حماية البيئة.

المادة الفعالة هي ڤوريكونازول.

المكونات الأخرى هي لاكتوز أحادي الهيدرات، ميكروكريستالين سيليلوز، بوفيدون ك 30،  كروسكارميلوز الصوديوم، ميكروكريستالين سيليلوز، ستيرات المغنيسيوم، مسحوق أوبادري أبيض (لاكتوز أحادي الهيدرات، هيدوكسي بروبيل سيليلوز، ثاني أكسيد التيتانيوم، ماكروجول)، لون أصفر#6، لون أزرق#1، أكسيد الحديد الأصفر.

حجم العبوة:

03 قرص مغلف (10 أقراص معبأة في ألومنيوم/بي ڤي سي/بي ڤي دي سي، 3 أشرطة/عبوة).

مدينة الدواء للصناعات الدوائية - المملكة العربية السعودية.

الهاتف: 00966920003288

فاكس: 00966126358138

جوال: 00966555786968

ص.ب: 42512 – جدة 21551

البريد الإلكتروني: MD.admin@axantia.com

10/2023
 Read this leaflet carefully before you start using this product as it contains important information for you

Voriconazole MCP® 200 mg film-coated tablets.

Voriconazole MCP® 200 mg film-coated tablets: Each film-coated tablet contains 200 mg voriconazole. For a full list of excipients, see section 6.1.

Voriconazole MCP® film-coated tablets. Voriconazole MCP® 200mg Film Coated Tablet light green, oval deep biconvex film coated tablet engraved with H15 on one face, packed in Alu/PVC/PVDC blisters, intended for oral use.

Voriconazole MCP® is a broad-spectrum, triazole antifungal agent and is indicated in adults and children aged 2 years and above as follows:

• Treatment of invasive aspergillosis.

• Treatment of candidaemia in non-neutropenic patients.

• Treatment of fluconazole-resistant serious invasive Candida infections (including C. krusei).

• Treatment of serious fungal infections caused by Scedosporium spp. and Fusarium spp.

Voriconazole MCP® should be administered primarily to patients with progressive, possibly life-threatening infections.

Prophylaxis of invasive fungal infections in high risk allogeneic hematopoietic stem cell transplant (HSCT) recipients.


Posology

Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.4).

Treatment

Adults

Therapy must be initiated with the specified loading dose regimen of either voriconazole intravenous or oral Voriconazole MCP® to achieve plasma concentrations on Day 1 that are close to steady state. On the basis of the high oral bioavailability (96%; see section 5.2), switching between intravenous and oral administration is appropriate when clinically indicated.

Detailed information on dosage recommendations is provided in the following table:

 

Intravenous

Oral

Patients 40 kg and above*

Patients less than 40 kg*

Loading dose regimen

(first 24 hours)

6 mg/kg every 12 hours

400 mg every 12 hours

200 mg every 12 hours

Maintenance dose

(after first 24 hours)

4 mg/kg twice daily

200 mg twice daily

100 mg twice daily

* This also applies to patients aged 15 years and older

Duration of treatment

Treatment duration should be as short as possible depending on the patient's clinical and mycological response. Long term exposure to voriconazole greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1).

Dosage adjustment (Adults)

If patient response to treatment is inadequate, the maintenance dose may be increased to 300 mg twice daily for oral administration. For patients less than 40 kg the oral dose may be increased to 150 mg twice daily.

If patient is unable to tolerate treatment at a higher dose, reduce the oral dose by 50 mg steps to the 200 mg twice daily (or 100 mg twice daily for patients less than 40 kg) maintenance dose.

In case of use as prophylaxis, refer below.

Children (2 to <12 years) and young adolescents with low body weight (12 to 14 years and <50 kg)

Voriconazole should be dosed as children as these young adolescents may metabolize voriconazole more similarly to children than to adults.

The recommended dosing regimen is as follows:

 

Intravenous

Oral

Loading Dose Regimen

(first 24 hours)

9 mg/kg every 12 hours

Not recommended

Maintenance Dose

(after first 24 hours)

8 mg/kg twice daily

9 mg/kg twice daily

(a maximum dose of 350 mg twice daily)

Note: Based on a population pharmacokinetic analysis in 112 immunocompromised paediatric patients aged 2 to <12 years and 26 immunocompromised adolescents aged 12 to <17 years.

It is recommended to initiate the therapy with intravenous regimen, and oral regimen should be considered only after there is a significant clinical improvement. It should be noted that an 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

These oral dose recommendations for children are based on studies in which voriconazole was administered as the powder for oral suspension. Bioequivalence between the powder for oral suspension and tablets has not been investigated in a paediatric population. Considering the assumed limited gastro-enteric transit time in paediatric patients, the absorption of tablets may be different in paediatric compared to adult patients. It is therefore recommended to use the oral suspension formulation in children aged 2 to <12.

All other adolescents (12 to 14 years and ≥50 kg; 15 to 17 years regardless of body weight)

Voriconazole should be dosed as adults.

Dosage adjustment (Children [2 to <12 years] and young adolescents with low body weight [12 to 14 years and <50 kg])

If patient response to treatment is inadequate, the dose may be increased by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially). If patient is unable to tolerate treatment, reduce the dose by 1 mg/kg steps (or by 50 mg steps if the maximum oral dose of 350 mg was used initially).

Use in paediatric patients aged 2 to <12 years with hepatic or renal insufficiency has not been studied (see sections 4.8 and 5.2).

Prophylaxis in Adults and Children

Prophylaxis should be initiated on the day of transplant and may be administered for up to 100 days. Prophylaxis should be as short as possible depending on the risk for developing invasive fungal infection (IFI) as defined by neutropenia or immunosuppression. It may only be continued up to 180 days after transplantation in case of continuing immunosuppression or graft versus host disease (GvHD) (see section 5.1).

Dosage

The recommended dosing regimen for prophylaxis is the same as for treatment in the respective age groups. Please refer to the treatment tables above.

Duration of prophylaxis

The safety and efficacy of voriconazole use for longer than 180 days has not been adequately studied in clinical trials.

Use of voriconazole in prophylaxis for greater than 180 days (6 months) requires careful assessment of the benefit-risk balance (see sections 4.4 and 5.1).

The following instructions apply to both Treatment and Prophylaxis

Dosage adjustment

For prophylaxis use, dose adjustments are not recommended in the case of lack of efficacy or treatment-related adverse events. In the case of treatment-related adverse events, discontinuation of voriconazole and use of alternative antifungal agents must be considered (see section 4.4 and 4.8)

Dosage adjustments in case of co-administration

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased from 200 mg to 400 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

The combination of voriconazole with rifabutin should, if possible be avoided. However, if the combination is strictly needed, the maintenance dose of voriconazole may be increased from 200 mg to 350 mg orally, twice daily (100 mg to 200 mg orally, twice daily in patients less than 40 kg), see sections 4.4 and 4.5.

Efavirenz may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 400 mg every 12 hours and the efavirenz dose is reduced by 50%, i.e. to 300 mg once daily. When treatment with voriconazole is stopped, the initial dosage of efavirenz should be restored (see sections 4.4 and 4.5).

Elderly

No dose adjustment is necessary for elderly patients (see section 5.2).

Rrenal impairment

The pharmacokinetics of orally administered voriconazole are not affected by renal impairment. Therefore, no adjustment is necessary for oral dosing for patients with mild to severe renal impairment (see section 5.2).

Voriconazole is haemodialysed with a clearance of 121 ml/min. A 4- hour haemodialysis session does not remove a sufficient amount of voriconazole to warrant dose adjustment.

Hepatic impairment

It is recommended that the standard loading dose regimens be used but that the maintenance dose be halved in patients with mild to moderate hepatic cirrhosis (Child-Pugh A and B) receiving voriconazole (see section 5.2).

Voriconazole has not been studied in patients with severe chronic hepatic cirrhosis (Child-Pugh C).

There is limited data on the safety of voriconazole in patients with abnormal Liver Function Tests (aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP], or total bilirubin >5 times the upper limit of normal).

Voriconazole has been associated with elevations in liver function tests and clinical signs of liver damage, such as jaundice, and must only be used in patients with severe hepatic impairment if the benefit outweighs the potential risk. Patients with severe hepatic impairment must be carefully monitored for drug toxicity (see section 4.8).

Paediatric population

The safety and efficacy of voriconazole in children below 2 years has not been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.

Method of administration

Voriconazole MCP® film-coated tablets are to be taken at least one hour before, or one hour following, a meal.


Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Coadministration with CYP3A4 substrates, terfenadine, astemizole, cisapride, pimozide or quinidine since increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes (see section 4.5). Coadministration with rifampicin, carbamazepine and phenobarbital and St John's Wort since these medicinal products are likely to decrease plasma voriconazole concentrations significantly (see section 4.5). Coadministration of standard doses of voriconazole with efavirenz doses of 400 mg once daily or higher is contraindicated, because efavirenz significantly decreases plasma voriconazole concentrations in healthy subjects at these doses. Voriconazole also significantly increases efavirenz plasma concentrations (see section 4.5, for lower doses see section 4.4). Coadministration with high-dose ritonavir (400 mg and above twice daily) because ritonavir significantly decreases plasma voriconazole concentrations in healthy subjects at this dose (see section 4.5, for lower doses see section 4.4). Coadministration with ergot alkaloids (ergotamine, dihydroergotamine), which are CYP3A4 substrates, since increased plasma concentrations of these medicinal products can lead to ergotism (see section 4.5). Coadministration with sirolimus since voriconazole is likely to increase plasma concentrations of sirolimus significantly (see section 4.5). Coadministration of voriconazole with naloxegol, a CYP3A4 substrate, since increased plasma concentrations of naloxegol can precipitate opioid withdrawal symptoms (see section 4.5). Coadministration of voriconazole with tolvaptan since strong CYP3A4 inhibitors such as voriconazole significantly increase plasma concentrations of tolvaptan (see section 4.5). Coadministration of voriconazole with lurasidone since significant increases in lurasidone exposure have the potential for serious adverse reactions (see section 4.5). Coadministration with venetoclax at initiation and during venetoclax dose titration phase since voriconazole is likely to significantly increase plasma concentrations of venetoclax and increase risk of tumour lysis syndrome (see section 4.5).

Hypersensitivity

Caution should be used in prescribing Voriconazole MCP® to patients with hypersensitivity to other azoles (see also section 4.8).

Cardiovascular

Voriconazole has been associated with QTc interval prolongation. There have been rare cases of torsades de pointes in patients taking voriconazole who had risk factors, such as history of cardiotoxic chemotherapy, cardiomyopathy, hypokalaemia and concomitant medicinal products that may have been contributory. Voriconazole should be administered with caution to patients with potentially proarrhythmic conditions, such as:

• Congenital or acquired QTc-prolongation.

• Cardiomyopathy, in particular when heart failure is present.

• Sinus bradycardia.

• Existing symptomatic arrhythmias.

•Concomitant medicinal product that is known to prolong QTc interval. Electrolyte disturbances such as hypokalaemia, hypomagnesaemia and hypocalcaemia should be monitored and corrected, if necessary, prior to initiation and during voriconazole therapy (see section 4.2). A study has been conducted in healthy volunteers which examined the effect on QTc interval of single doses of voriconazole up to 4 times the usual daily dose. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec (see section 5.1).

Hepatic toxicity

In clinical trials, there have been cases of serious hepatic reactions during treatment with voriconazole (including clinical hepatitis, cholestasis and fulminant hepatic failure, including fatalities). Instances of hepatic reactions were noted to occur primarily in patients with serious underlying medical conditions (predominantly haematological malignancy). Transient hepatic reactions, including hepatitis and jaundice, have occurred among patients with no other identifiable risk factors. Liver dysfunction has usually been reversible on discontinuation of therapy (see section 4.8).

Monitoring of hepatic function

Patients receiving Voriconazole MCP® must be carefully monitored for hepatic toxicity. Clinical management should include laboratory evaluation of hepatic function (specifically AST and ALT) at the initiation of treatment with Voriconazole MCP® and at least weekly for the first month of treatment. Treatment duration should be as short as possible; however, if based on the benefit-risk assessment the treatment is continued (see section 4.2), monitoring frequency can be reduced to monthly if there are no changes in the Liver Function Tests.

If the liver function tests become markedly elevated, Voriconazole MCP® should be discontinued, unless the medical judgment of the risk-benefit of the treatment for the patient justifies continued use.

Monitoring of hepatic function should be carried out in both children and adults.

Serious dermatological adverse reactions

• Phototoxicity

In addition voriconazole has been associated with phototoxicity including reactions such as ephelides, lentigo, actinic keratosis and pseudoporphyria. It is recommended that all patients, including children, avoid exposure to direct sunlight during Voriconazole MCP® treatment and use measures such as protective clothing and sunscreen with high sun protection factor (SPF).

• Squamous cell carcinoma of the skin (SCC)

Squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen's disease) has been reported in patients, some of whom have reported prior phototoxic reactions. If phototoxic reactions occur, multidisciplinary advice should be sought, Voriconazole MCP® discontinuation and use of alternative antifungal agents should be considered and the patient should be referred to a dermatologist. If Voriconazole MCP® is continued, however, dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection and management of premalignant lesions. Voriconazole MCP® should be discontinued if premalignant skin lesions or squamous cell carcinoma are identified (see below the section under Long-term treatment).

• Severe cutaneous adverse reactions

Severe cutaneous adverse reactions (SCARs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported with the use of voriconazole. If a patient develops a rash he should be monitored closely and Voriconazole MCP® discontinued if lesions progress.

Adrenal events

Adrenal insufficiency has been reported in patients receiving other azoles including voriconazole.

Adrenal insufficiency have been reported in patients receiving azoles with or without concomitant corticosteroids.

In patients receiving azoles without corticosteroids, adrenal insufficiency is related to direct inhibition of steroidogenesis by azoles. In patients taking corticosteroids, voriconazole associated CYP3A4 inhibition of their metabolism may lead to corticosteroid excess and adrenal suppression (see section 4.5). Cushing's syndrome with and without subsequent adrenal insufficiency has also been reported in patients receiving voriconazole concomitantly with corticosteroids.

Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued (see section 4.5). Patients should be instructed to seek immediate medical care if they develop signs and symptoms of Cushing's syndrome or adrenal insufficiency.

Long-term treatment

Long term exposure (treatment or prophylaxis) greater than 180 days (6 months) requires careful assessment of the benefit-risk balance and physicians should therefore consider the need to limit the exposure to Voriconazole MCP® (see sections 4.2 and 5.1).

Squamous cell carcinoma of the skin (SCC) (including cutaneous SCC in situ, or Bowen's disease) has been reported in relation with long-term voriconazole treatment.

Non-infectious periostitis with elevated fluoride and alkaline phosphatase levels has been reported in transplant patients. If a patient develops skeletal pain and radiologic findings compatible with periostitis Voriconazole MCP® discontinuation should be considered after multidisciplinary advice.

Visual adverse reactions

There have been reports of prolonged visual adverse reactions, including blurred vision, optic neuritis and papilloedema (see section 4.8).

Renal adverse reactions

Acute renal failure has been observed in severely ill patients undergoing treatment with voriconazole. Patients being treated with voriconazole are likely to be treated concomitantly with nephrotoxic medicinal products and have concurrent conditions that may result in decreased renal function (see section 4.8).

Monitoring of renal function

Patients should be monitored for the development of abnormal renal function. This should include laboratory evaluation, particularly serum creatinine.

Monitoring of pancreatic function

Patients, especially children, with risk factors for acute pancreatitis (e.g., recent chemotherapy, haematopoietic stem cell transplantation [HSCT]), should be monitored closely during Voriconazole MCP® treatment. Monitoring of serum amylase or lipase may be considered in this clinical situation.

Paediatric population

Safety and effectiveness in paediatric subjects below the age of two years has not been established (see sections 4.8 and 5.1). Voriconazole is indicated for paediatric patients aged two years or older. A higher frequency of liver enzyme elevations was observed in the paediatric population (see section 4.8). Hepatic function should be monitored in both children and adults. Oral bioavailability may be limited in paediatric patients aged 2 to <12 years with malabsorption and very low body weight for age. In that case, intravenous voriconazole administration is recommended.

• Serious dermatological adverse reactions (including SCC)

The frequency of phototoxicity reactions is higher in the paediatric population. As an evolution towards SCC has been reported, stringent measures for the photoprotection are warranted in this population of patients. In children experiencing photoaging injuries such as lentigines or ephelides, sun avoidance and dermatologic follow-up are recommended even after treatment discontinuation.

Prophylaxis

In case of treatment-related adverse events (hepatotoxicity, severe skin reactions including phototoxicity and SCC, severe or prolonged visual disorders and periostitis), discontinuation of voriconazole and use of alternative antifungal agents must be considered.

Phenytoin (CYP2C9 substrate and potent CYP450 inducer)

Careful monitoring of phenytoin levels is recommended when phenytoin is coadministered with voriconazole. Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk (see section 4.5).

Efavirenz (CYP450 inducer; CYP3A4 inhibitor and substrate)

When voriconazole is coadministered with efavirenz the dose of voriconazole should be increased to 400 mg every 12 hours and the dose of efavirenz should be decreased to 300 mg every 24 hours (see sections 4.2, 4.3 and 4.5).

Glasdegib (CYP3A4 substrate)

Coadministration of voriconazole is expected to increase glasdegib plasma concentrations and increase the risk of QTc prolongation (see section 4.5). If concomitant use cannot be avoided, frequent ECG monitoring is recommended.

Tyrosine kinase inhibitors (CYP3A4 substrate)

Coadministration of voriconazole with tyrosine kinase inhibitors metabolised by CYP3A4 is expected to increase tyrosine kinase inhibitor plasma concentrations and the risk of adverse reactions. If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor and close clinical monitoring is recommended (see section 4.5).

Rifabutin (Potent CYP450 inducer)

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended when rifabutin is coadministered with voriconazole. Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk (see section 4.5).

Ritonavir (potent CYP450 inducer; CYP3A4 inhibitor and substrate)

Coadministration of voriconazole and low-dose ritonavir (100 mg twice daily) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole (see sections 4.3 and 4.5).

Everolimus (CYP3A4 substrate, P-gp substrate)

Coadministration of voriconazole with everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations. Currently there are insufficient data to allow dosing recommendations in this situation (see section 4.5).

Methadone (CYP3A4 substrate)

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended when coadministered with voriconazole since methadone levels increased following coadministration of voriconazole. Dose reduction of methadone may be needed (see section 4.5).

Short-acting opiates (CYP3A4 substrate)

Reduction in the dose of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered when coadministered with voriconazole (see section 4.5). As the half-life of alfentanil is prolonged in a 4-fold manner when alfentanil is coadministered with voriconazole, and in an independent published study concomitant use of voriconazole with fentanyl resulted in an increase in the mean AUC0-∞ of fentanyl, frequent monitoring for opiate-associated adverse reactions (including a longer respiratory monitoring period) may be necessary.

Long-acting opiates (CYP3A4 substrate)

Reduction in the dose of oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered when coadministered with voriconazole. Frequent monitoring for opiate-associated adverse reactions may be necessary (see section 4.5).

Fluconazole (CYP2C9, CYP2C19 and CYP3A4 inhibitor)

Coadministration of oral voriconazole and oral fluconazole resulted in a significant increase in Cmax and AUC  of voriconazole in healthy subjects. The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole - associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole (see section 4.5).

Excipients

Lactose

This medicinal product contains lactose and should not be given to patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption.


Voriconazole is metabolised by, and inhibits the activity of, cytochrome P450 isoenzymes, CYP2C19, CYP2C9, and CYP3A4. Inhibitors or inducers of these isoenzymes may increase or decrease voriconazole plasma concentrations, respectively, and there is potential for voriconazole to increase the plasma concentrations of substances metabolised by these CYP450 isoenzymes, in particular for substances metabolised by CYP3A4 since voriconazole is a strong CYP3A4 inhibitor though the increase in AUC is substrate dependent (see Table below).

Unless otherwise specified, drug interaction studies have been performed in healthy adult male subjects using multiple dosing to steady state with oral voriconazole at 200 mg twice daily (BID). These results are relevant to other populations and routes of administration.

Voriconazole should be administered with caution in patients with concomitant medication that is known to prolong QTc interval. When there is also a potential for voriconazole to increase the plasma concentrations of substances metabolised by CYP3A4 isoenzymes (certain antihistamines, quinidine, cisapride, pimozide and ivabradine), coadministration is contraindicated (see below and section 4.3).

Interaction table

Interactions between voriconazole and other medicinal products are listed in the table below (once daily as “QD”, twice daily as “BID”, three times daily as “TID” and not determined as “ND”). The direction of the arrow for each pharmacokinetic parameter is based on the 90% confidence interval of the geometric mean ratio being within (↔), below (↓) or above (↑) the 80-125% range. The asterisk (*) indicates a two-way interaction. AUC , AUCt and AUC0-∞ represent area under the curve over a dosing interval, from time zero to the time with detectable measurement and from time zero to infinity, respectively.

The interactions in the table are presented in the following order: contraindications, those requiring dose adjustment and careful clinical and/or biological monitoring, and finally those that have no significant pharmacokinetic interaction but may be of clinical interest in this therapeutic field.

Medicinal product

[Mechanism of interaction]

Interaction

Geometric mean changes (%)

Recommendations concerning coadministration

Astemizole, cisapride, pimozide, quinidine, terfenadine and ivabradine

[CYP3A4 substrates]

Although not studied, increased plasma concentrations of these medicinal products can lead to QTc prolongation and rare occurrences of torsades de pointes.

Contraindicated (see section 4.3)

Carbamazepine and long-acting barbiturates (e.g., phenobarbital, mephobarbital)

[potent CYP450 inducers]

Although not studied, carbamazepine and long-acting barbiturates are likely to significantly decrease plasma voriconazole concentrations.

Contraindicated (see section 4.3)

Efavirenz (a non-nucleoside reverse transcriptase inhibitor) [CYP450 inducer; CYP3A4 inhibitor and substrate]

Efavirenz 400 mg QD, coadministered with voriconazole 200 mg BID* 

 

 

Efavirenz 300 mg QD, coadministered with voriconazole 400 mg BID*

 Efavirenz Cmax ↑ 38%

 

Efavirenz AUC   ↑ 44%

Voriconazole Cmax ↓ 61%

 

Voriconazole AUC  ↓ 77%

Compared to efavirenz 600 mg QD,

Efavirenz Cmax 

 

Efavirenz AUC   ↑ 17%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↑ 23%

 

Voriconazole AUC   ↓ 7%

Use of standard doses of voriconazole with efavirenz doses of 400 mg QD or higher is contraindicated (see section 4.3).

Voriconazole may be coadministered with efavirenz if the voriconazole maintenance dose is increased to 400 mg BID and the efavirenz dose is decreased to 300 mg QD. When voriconazole treatment is stopped, the initial dose of efavirenz should be restored (see section 4.2 and 4.4).

Ergot alkaloids (e.g., ergotamine and dihydroergotamine)

[CYP3A4 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of ergot alkaloids and lead to ergotism.

Contraindicated (see section 4.3)

Lurasidone

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of lurasidone.

Contraindicated (see section 4.3)

Naloxegol

[CYP3A4 substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of naloxegol.

Contraindicated (see section 4.3)

Rifabutin

[potent CYP450 inducer]

300 mg QD  

 

300 mg QD (coadministered with voriconazole 350 mg BID)*

 

300 mg QD (coadministered with voriconazole 400 mg BID)*

 Voriconazole Cmax ↓ 69%

 

 

Voriconazole AUC  ↓ 78%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↓ 4%

 

Voriconazole AUC  ↓ 32%

Rifabutin Cmax ↑ 195%

Rifabutin AUC  ↑ 331%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↑ 104%

 

Voriconazole AUC  ↑ 87%

Concomitant use of voriconazole and rifabutin should be avoided unless the benefit outweighs the risk.

The maintenance dose of voriconazole may be increased to 5 mg/kg intravenously BID or from 200 mg to 350 mg orally BID (100 mg to 200 mg orally BID in patients less than 40 kg) (see section 4.2).

Careful monitoring of full blood counts and adverse reactions to rifabutin (e.g., uveitis) is recommended when rifabutin is coadministered with voriconazole.

Rifampicin (600 mg QD)

[potent CYP450 inducer]

Voriconazole Cmax ↓ 93%

Voriconazole AUC  ↓ 96%

Contraindicated (see section 4.3)

Ritonavir (protease inhibitor)

[potent CYP450 inducer; CYP3A4 inhibitor and substrate]

High dose (400 mg BID)

 

 

Low dose (100 mg BID)*

 Ritonavir Cmax and AUC  ↔

Voriconazole Cmax ↓ 66%

 

Voriconazole AUC  ↓ 82%

Ritonavir Cmax ↓ 25%

 

 

Ritonavir AUC  ↓13%

Voriconazole Cmax ↓ 24%

 

Voriconazole AUC  ↓ 39%

Coadministration of voriconazole and high doses of ritonavir (400 mg and above BID) is contraindicated (see section 4.3).

Coadministration of voriconazole and low-dose ritonavir (100 mg BID) should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

St. John's Wort

[CYP450 inducer; P-gp inducer]

300 mg TID (coadministered with voriconazole 400 mg single dose)

 

In an independent published study,

Voriconazole AUC0-∞ ↓ 59%

 

Contraindicated (see section 4.3)

Tolvaptan

[CYP3A substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of tolvaptan.

Contraindicated (see section 4.3)

Venetoclax

[CYP3A substrate]

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of venetoclax.

Concomitant administration of voriconazole is contraindicated at initiation and during venetoclax dose titration phase (see section 4.3). Dose reduction of venetoclax is required as instructed in venetoclax prescribing information during steady daily dosing; close monitoring for signs of toxicity is recommended.

Fluconazole (200 mg QD)

[CYP2C9, CYP2C19 and CYP3A4 inhibitor]

Voriconazole Cmax ↑ 57%

 

Voriconazole AUC  ↑ 79%

Fluconazole Cmax ND

 

Fluconazole AUC  ND

The reduced dose and/or frequency of voriconazole and fluconazole that would eliminate this effect have not been established. Monitoring for voriconazole-associated adverse reactions is recommended if voriconazole is used sequentially after fluconazole.

Phenytoin

[CYP2C9 substrate and potent CYP450 inducer]

300 mg QD

 

 

300 mg QD (coadministered with voriconazole 400 mg BID)*

Voriconazole Cmax  ↓ 49%

 

Voriconazole AUC  ↓ 69%

 

Phenytoin Cmax ↑ 67%

 

Phenytoin AUC  ↑ 81%

Compared to voriconazole 200 mg BID,

Voriconazole Cmax ↑ 34%

 

Voriconazole AUC  ↑ 39%

Concomitant use of voriconazole and phenytoin should be avoided unless the benefit outweighs the risk. Careful monitoring of phenytoin plasma levels is recommended.

 

Phenytoin may be coadministered with voriconazole if the maintenance dose of voriconazole is increased to 5 mg/kg IV BID or from 200 mg to 400 mg oral BID (100 mg to 200 mg oral BID in patients less than 40 kg) (see section 4.2).

Letermovir

[CYP2C9 and CYP2C19 inducer]

Voriconazole Cmax ↓ 39%

Voriconazole AUC0-12 ↓ 44%

Voriconazole C12 ↓ 51%

If concomitant administration of voriconazole with letermovir cannot be avoided, monitor for loss of voriconazole effectiveness.

Glasdegib

[CYP3A4 substrate]

Although not studied, voriconazole is likely to increase the plasma concentrations of glasdegib and increase risk of QTc prolongation.

If concomitant use cannot be avoided, frequent ECG monitoring is recommended (see section 4.4).

Tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cabozantinib, ceritinib, cobimetinib, dabrafenib, dasatinib, nilotinib, sunitinib, ibrutinib, ribociclib)

[CYP3A4 substrates]

Although not studied, voriconazole may increase plasma concentrations of tyrosine kinase inhibitors metabolised by CYP3A4.

If concomitant use cannot be avoided, dose reduction of the tyrosine kinase inhibitor is recommended (see section 4.4).

Anticoagulants

Warfarin (30 mg single dose, co- administered with 300 mg BID voriconazole)

[CYP2C9 substrate]

Other oral coumarins

(e.g., phenprocoumon, acenocoumarol)

[CYP2C9 and CYP3A4 substrates]

 

Maximum increase in prothrombin time was approximately 2-fold. 

  

 

Although not studied, voriconazole may increase the plasma concentrations of coumarins that may cause an increase in prothrombin time.

 

Close monitoring of prothrombin time or other suitable anticoagulation tests is recommended, and the dose of anticoagulants should be adjusted accordingly.

Ivacaftor

[CYP3A4 substrate]

Although not studied, voriconazole is likely to increase the plasma concentrations of ivacaftor with risk of increased adverse reactions.

Dose reduction of ivacaftor is recommended.

Benzodiazepines [CYP3A4 substrates]

Midazolam (0.05 mg/kg IV single dose)

Midazolam (7.5 mg oral single dose)

Other benzodiazepines (e.g., triazolam, alprazolam)

In an independent published study,

Midazolam AUC0-∞ ↑ 3.7-fold

In an independent published study,

Midazolam Cmax ↑ 3.8-fold

Midazolam AUC0-∞ ↑ 10.3-fold

Although not studied, voriconazole is likely to increase the plasma concentrations of other benzodiazepines that are metabolised by CYP3A4 and lead to a prolonged sedative effect.

Dose reduction of benzodiazepines should be considered.

Immunosuppressants

[CYP3A4 substrates]

Sirolimus (2 mg single dose)

 

 

 

 

Everolimus

[also P-gP substrate]

 

Ciclosporin (in stable renal transplant recipients receiving chronic ciclosporin therapy)

 

Tacrolimus (0.1 mg/kg single dose)

 

In an independent published study, Sirolimus Cmax ↑ 6.6-fold

Sirolimus AUC0-∞ ↑ 11-fold

 

 

 

Although not studied, voriconazole is likely to significantly increase the plasma concentrations of everolimus.

 

 

Ciclosporin Cmax ↑ 13%

Ciclosporin AUC  ↑ 70%

 

 

Tacrolimus Cmax ↑ 117%

Tacrolimus AUCt ↑ 221%

Coadministration of voriconazole and sirolimus is contraindicated (see section 4.3).

Coadministration of voriconazole and everolimus is not recommended because voriconazole is expected to significantly increase everolimus concentrations (see section 4.4).

When initiating voriconazole in patients already on ciclosporin it is recommended that the ciclosporin dose be halved and ciclosporin level carefully monitored. Increased ciclosporin levels have been associated with nephrotoxicity. When voriconazole is discontinued, ciclosporin levels must be carefully monitored and the dose increased as necessary.

When initiating voriconazole in patients already on tacrolimus, it is recommended that the tacrolimus dose be reduced to a third of the original dose and tacrolimus level carefully monitored. Increased tacrolimus levels have been associated with nephrotoxicity. When voriconazole is discontinued, tacrolimus levels must be carefully monitored and the dose increased as necessary.

Long-Acting Opiates

[CYP3A4 substrates]

Oxycodone (10 mg single dose)

 

In an independent published study,

Oxycodone Cmax ↑ 1.7-fold

Oxycodone AUC0-∞ ↑ 3.6-fold

Dose reduction in oxycodone and other long-acting opiates metabolized by CYP3A4 (e.g., hydrocodone) should be considered. Frequent monitoring for opiate-associated adverse reactions may be necessary.

Methadone (32-100 mg QD)

[CYP3A4 substrate]

R-methadone (active) Cmax ↑ 31%

R-methadone (active) AUC  ↑ 47%

S-methadone Cmax ↑ 65%

S-methadone AUC  ↑ 103%

 

 

Frequent monitoring for adverse reactions and toxicity related to methadone, including QTc prolongation, is recommended. Dose reduction of methadone may be needed.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

[CYP2C9 substrates]

Ibuprofen (400 mg single dose)

 

Diclofenac (50 mg single dose)

 

 

 

S-Ibuprofen Cmax ↑ 20%

S-Ibuprofen AUC0-∞ ↑ 100%

Diclofenac Cmax ↑ 114%

Diclofenac AUC0-∞ ↑ 78%

 

Frequent monitoring for adverse reactions and toxicity related to NSAIDs is recommended. Dose reduction of NSAIDs may be needed.

 

 

 

Omeprazole (40 mg QD)*

[CYP2C19 inhibitor; CYP2C19 and CYP3A4 substrate]

Omeprazole Cmax ↑ 116%

Omeprazole AUC  ↑ 280%

Voriconazole Cmax ↑ 15%

 

Voriconazole AUC  ↑ 41%

Other proton pump inhibitors that are CYP2C19 substrates may also be inhibited by voriconazole and may result in increased plasma concentrations of these medicinal products.

No dose adjustment of voriconazole is recommended.

When initiating voriconazole in patients already receiving omeprazole doses of 40 mg or above, it is recommended that the omeprazole dose be halved.

 

 

Oral Contraceptives*

[CYP3A4 substrate; CYP2C19 inhibitor]

Norethisterone/ethinylestradiol (1 mg/0.035 mg QD)

Ethinylestradiol Cmax ↑ 36%

 

Ethinylestradiol AUC  ↑ 61%

Norethisterone Cmax ↑ 15%

 

Norethisterone AUC  ↑ 53%

Voriconazole Cmax ↑ 14%

 

Voriconazole AUC  ↑ 46%

Monitoring for adverse reactions related to oral contraceptives, in addition to those for voriconazole, is recommended.

Short-acting Opiates

[CYP3A4 substrates]

Alfentanil (20 μg/kg single dose, with concomitant naloxone)

Fentanyl (5 μg/kg single dose)

 

 

In an independent published study, Alfentanil AUC0-∞ ↑ 6-fold

In an independent published study, Fentanyl AUC0-∞ ↑ 1.34-fold

Dose reduction of alfentanil, fentanyl and other short-acting opiates similar in structure to alfentanil and metabolised by CYP3A4 (e.g., sufentanil) should be considered. Extended and frequent monitoring for respiratory depression and other opiate-associated adverse reactions is recommended.

 

Statins (e.g., lovastatin)

[CYP3A4 substrates]

Although not studied clinically, voriconazole is likely to increase the plasma concentrations of statins that are metabolised by CYP3A4 and could lead to rhabdomyolysis.

If concomitant administration of voriconazole with statins metabolised by CYP3A4 cannot be avoided, dose reduction of the statin should be considered.

Sulfonylureas (e.g., tolbutamide, glipizide, glyburide)

[CYP2C9 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of sulfonylureas and cause hypoglycaemia.

Careful monitoring of blood glucose is recommended. Dose reduction of sulfonylureas should be considered.

Vinca Alkaloids (e.g., vincristine and vinblastine)

[CYP3A4 substrates]

Although not studied, voriconazole is likely to increase the plasma concentrations of vinca alkaloids and lead to neurotoxicity.

Dose reduction of vinca alkaloids should be considered.

Other HIV Protease Inhibitors (e.g., saquinavir, amprenavir and nelfinavir)*

[CYP3A4 substrates and inhibitors]

Not studied clinically. In vitro studies show that voriconazole may inhibit the metabolism of HIV protease inhibitors and the metabolism of voriconazole may also be inhibited by HIV protease inhibitors.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Other Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) (e.g., delavirdine, nevirapine)*

[CYP3A4 substrates, inhibitors or CYP450 inducers]

Not studied clinically. In vitro studies show that the metabolism of voriconazole may be inhibited by NNRTIs and voriconazole may inhibit the metabolism of NNRTIs.

The findings of the effect of efavirenz on voriconazole suggest that the metabolism of voriconazole may be induced by an NNRTI.

Careful monitoring for any occurrence of drug toxicity and/or lack of efficacy, and dose adjustment may be needed.

Tretinoin

[CYP3A4 substrate]

Although not studied, voriconazole may increase tretinoin concentrations and increase risk of adverse reactions (pseudotumor cerebri, hypercalcaemia).

Dose adjustment of tretinoin is recommended during treatment with voriconazole and after its discontinuation.

Cimetidine (400 mg BID)

[non-specific CYP450 inhibitor and increases gastric pH]

Voriconazole Cmax ↑ 18%

 

Voriconazole AUC  ↑ 23%

No dose adjustment

Digoxin (0.25 mg QD)

[P-gp substrate]

Digoxin Cmax 

 

Digoxin AUC  ↔

No dose adjustment

 

Indinavir (800 mg TID)

[CYP3A4 inhibitor and substrate]

Indinavir Cmax 

 

Indinavir AUC  ↔

Voriconazole Cmax 

 

Voriconazole AUC  ↔

No dose adjustment

Macrolide antibiotics

Erythromycin (1 g BID)

[CYP3A4 inhibitor]

Azithromycin (500 mg QD)

Voriconazole Cmax and AUC  ↔

 

 

Voriconazole Cmax and AUC  ↔

The effect of voriconazole on either erythromycin or azithromycin is unknown.

No dose adjustment

Mycophenolic acid (1 g single dose)

[UDP-glucuronyl transferase substrate]

 

Mycophenolic acid Cmax 

Mycophenolic acid AUC

 

No dose adjustment

Corticosteroids

Prednisolone (60 mg single dose)

[CYP3A4 substrate]

Prednisolone Cmax ↑ 11%

Prednisolone AUC0-∞ ↑ 34%

No dose adjustment

Patients on long-term treatment with voriconazole and corticosteroids (including inhaled corticosteroids e.g., budesonide and intranasal corticosteroids) should be carefully monitored for adrenal cortex dysfunction both during treatment and when voriconazole is discontinued (see section 4.4).

Ranitidine (150 mg BID)

[increases gastric pH]

Voriconazole Cmax and AUC  ↔

No dose adjustment


Pregnancy

There are no adequate data on the use of voriconazole in pregnant women available.

Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Voriconazole MCP® must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus.

 

Women of child-bearing potential

Women of child-bearing potential must always use effective contraception during treatment.

 

Breast-feeding

The excretion of voriconazole into breast milk has not been investigated. Breast-feeding must be stopped on initiation of treatment with Voriconazole MCP®.

 

Fertility

In an animal study, no impairment of fertility was demonstrated in male and female rats (see section 5.3).


Voriconazole MCP® has moderate influence on the ability to drive and use machines. It may cause transient and reversible changes to vision, including blurring, altered/enhanced visual perception and/or photophobia. Patients must avoid potentially hazardous tasks, such as driving or operating machinery while experiencing these symptoms.

 


Summary of safety profile

The safety profile of voriconazole in adults is based on an integrated safety database of more than 2,000 subjects (including 1,603 adult patients in therapeutic trials) and an additional 270 adults in prophylaxis trials. This represents a heterogeneous population, containing patients with haematological malignancy, HIV- infected patients with oesophageal candidiasis and refractory fungal infections, non-neutropenic patients with candidaemia or aspergillosis and healthy volunteers.

The most commonly reported adverse reactions were visual impairment, pyrexia, rash, vomiting, nausea, diarrhea, headache, peripheral oedema, liver function test abnormal, respiratory distress and abdominal pain.

The severity of the adverse reactions was generally mild to moderate. No clinically significant differences were seen when the safety data were analysed by age, race, or gender.

 

Tabulated list of adverse reactions

In the table below, since the majority of the studies were of an open nature, all causality adverse reactions and their frequency categories in 1,873 adults from pooled therapeutic (1,603) and prophylaxis (270) studies, by system organ class and frequency, are listed.

Frequency categories are expressed as: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Undesirable effects reported in subjects receiving voriconazole:

System Organ Class

Very common

≥ 1/10

Common

≥ 1/100 to < 1/10

Uncommon

≥ 1/1,000 to < 1/100

Rare

≥ 1/10,000 to < 1/1,000

Frequency not known

(cannot be estimated from available data)

Infections and infestations

 

sinusitis

pseudomembranous colitis

 

 

Neoplasms benign, malignant and unspecified (including cysts and polyps)

 

 

 

 

squamous cell carcinoma (including cutaneous SCC in situ, or Bowen's disease)*

Blood and lymphatic system disorders

 

agranulocytosis1, pancytopenia, thrombocytopenia2, leukopenia, anaemia

bone marrow failure, lymphadenopathy, eosinophilia

disseminated intravascular coagulation

 

Immune system disorders

 

 

hypersensitivity

anaphylactoid reaction

 

Endocrine disorders

 

 

adrenal insufficiency, hypothyroidism

hyperthyroidism

 

Metabolism and nutrition disorders

oedema peripheral

hypoglycaemia, hypokalaemia, hyponatraemia

 

 

 

Psychiatric disorders

 

depression, hallucination, anxiety, insomnia, agitation, confusional state

 

 

 

Nervous system disorders

headache

convulsion, syncope, tremor, hypertonia3, paraesthesia, somnolence, dizziness

brain oedema, encephalopathy4, extrapyramidal disorder5, neuropathy peripheral, ataxia, hypoaesthesia, dysgeusia

hepatic encephalopathy, Guillain-Barre syndrome, nystagmus

 

Eye disorders

visual impairment6

retinal haemorrhage

optic nerve disorder7, papilloedema8, oculogyric crisis, diplopia, scleritis, blepharitis

optic atrophy, corneal opacity

 

Ear and labyrinth disorders

 

 

hypoacusis, vertigo, tinnitus

 

 

Cardiac disorders

 

arrhythmia supraventricular, tachycardia, bradycardia

ventricular fibrillation, ventricular extrasystoles, ventricular tachycardia, electrocardiogram QT prolonged, supraventricular tachycardia

torsades de pointes, atrioventricular block complete, bundle branch block, nodal rhythm

 

Vascular disorders

 

hypotension, phlebitis

thrombophlebitis, lymphangitis

 

 

Respiratory, thoracic and mediastinal disorders

respiratory distress9

acute respiratory distress syndrome, pulmonary oedema

 

 

 

Gastrointestinal disorders

diarrhea, vomiting, abdominal pain, nausea

cheilitis, dyspepsia, constipation, gingivitis

peritonitis, pancreatitis, swollen tongue, duodenitis, gastroenteritis, glossitis

 

 

Hepatobiliary disorders

liver function test abnormal

jaundice, jaundice cholestatic, hepatitis10

hepatic failure, hepatomegaly, cholecystitis, cholelithiasis

 

 

Skin and subcutaneous tissue disorders

rash

dermatitis exfoliative, alopecia, rash maculo-papular, pruritus, erythema

Stevens-Johnson syndrome8, phototoxicity, purpura, urticaria, dermatitis allergic, rash papular, rash macular, eczema

toxic epidermal necrolysis8, drug reaction with eosinophilia and systemic symptoms (DRESS)8, angioedema, actinic keratosis*, pseudoporphyria, erythema multiforme, psoriasis, drug eruption

cutaneous lupus erythematosus*, ephelides*, lentigo*

Musculoskeletal and connective tissue disorders

 

back pain

arthritis

 

periostitis*

Renal and urinary disorders

 

renal failure acute, haematuria

renal tubular necrosis, proteinuria, nephritis

 

 

General disorders and administration site conditions

pyrexia

chest pain, face oedema11, asthenia, chills

infusion site reaction, influenza like illness

 

 

Investigations

 

blood creatinine increased

blood urea increased, blood cholesterol increased

 

 

*ADR identified post-marketing

Includes febrile neutropenia and neutropenia.

2 Includes immune thrombocytopenic purpura.

3 Includes nuchal rigidity and tetany.

4 Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.

5 Includes akathisia and parkinsonism.

6 See “Visual impairments” paragraph in section 4.8.

7 Prolonged optic neuritis has been reported post-marketing. See section 4.4.

8 See section 4.4.

9 Includes dyspnoea and dyspnoea exertional.

10 Includes drug-induced liver injury, hepatitis toxic, hepatocellular injury and hepatotoxicity.

11 Includes periorbital oedema, lip oedema, and oedema mouth.

Description of selected adverse reactions

Visual impairments

In clinical trials, visual impairments (including blurred vision, photophobia, chloropsia, chromatopsia, colour blindness, cyanopsia, eye disorder, halo vision, night blindness, oscillopsia, photopsia, scintillating scotoma, visual acuity reduced, visual brightness, visual field defect, vitreous floaters, and xanthopsia) with voriconazole were very common. These visual impairments were transient and fully reversible, with the majority spontaneously resolving within 60 minutes and no clinically significant long-term visual effects were observed. There was evidence of attenuation with repeated doses of voriconazole. The visual impairments were generally mild, rarely resulted in discontinuation and were not associated with long-term sequelae. Visual impairments may be associated with higher plasma concentrations and/or doses.

The mechanism of action is unknown, although the site of action is most likely to be within the retina. In a study in healthy volunteers investigating the impact of voriconazole on retinal function, voriconazole caused a decrease in the electroretinogram (ERG) waveform amplitude. The ERG measures electrical currents in the retina. The ERG changes did not progress over 29 days of treatment and were fully reversible on withdrawal of voriconazole.

There have been post-marketing reports of prolonged visual adverse events (see section 4.4).

Dermatological reactions

Dermatological reactions were very common in patients treated with voriconazole in clinical trials, but these patients had serious underlying diseases and were receiving multiple concomitant medicinal products. The majority of rashes were of mild to moderate severity. Patients have developed severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) (uncommon), toxic epidermal necrolysis (TEN) (rare), drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) and erythema multiforme (rare) during treatment with Voriconazole MCP® (see section 4.4).

If a patient develops a rash they should be monitored closely and Voriconazole MCP® discontinued if lesions progress. Photosensitivity reactions such as ephelides, lentigo and actinic keratosis have been reported, especially during long-term therapy (see section 4.4).

There have been reports of squamous cell carcinoma of the skin (including cutaneous SCC in situ, or Bowen's disease) in patients treated with voriconazole for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests

The overall incidence of transaminase increases >3 xULN (not necessarily comprising an adverse event) in the voriconazole clinical programme was 18 % (319/1,768) in adults and 25.8% (73/283) in paediatric subjects who received voriconazole for pooled therapeutic and prophylaxis use. Liver function test abnormalities may be associated with higher plasma concentrations and/or doses. The majority of abnormal liver function tests either resolved during treatment without dose adjustment or following dose adjustment, including discontinuation of therapy.

Voriconazole has been associated with cases of serious hepatic toxicity in patients with other serious underlying conditions. This includes cases of jaundice, hepatitis and hepatic failure leading to death (see section 4.4).

Prophylaxis

In an open-label, comparative, multicenter study comparing voriconazole and itraconazole as primary prophylaxis in adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI, permanent discontinuation of voriconazole due to AEs was reported in 39.3% of subjects versus 39.6% of subjects in the itraconazole arm. Treatment-emergent hepatic AEs resulted in permanent discontinuation of study medication for 50 subjects (21.4%) treated with voriconazole and for 18 subjects (7.1%) treated with itraconazole.

Paediatric population

The safety of voriconazole was investigated in 288 paediatric patients aged 2 to <12 years (169) and 12 to <18 years (119) who received voriconazole for prophylaxis (183) and therapeutic use (105) in clinical trials. The safety of voriconazole was also investigated in 158 additional paediatric patients aged 2 to <12 years in compassionate use programs. Overall the safety profile of voriconazole in paediatric population was similar to that in adults. However, a trend towards a higher frequency of liver enzyme elevations, reported as adverse events in clinical trials was observed in paediatric patients as compared to adults (14.2% transaminases increased in paediatrics compared to 5.3% in adults). Post-marketing data suggest there might be a higher occurrence of skin reactions (especially erythema) in the paediatric population compared to adults. In the 22 patients less than 2 years old who received voriconazole in a compassionate use programme, the following adverse reactions (for which a relationship to voriconazole could not be excluded) were reported: photosensitivity reaction (1), arrhythmia (1), pancreatitis (1), blood bilirubin increased (1), hepatic enzymes increased (1), rash (1) and papilloedema (1). There have been post-marketing reports of pancreatitis in paediatric patients.


In clinical trials there were 3 cases of accidental overdose. All occurred in paediatric patients, who received up to five times the recommended intravenous dose of voriconazole. A single adverse reaction of photophobia of 10 minutes duration was reported.

There is no known antidote to voriconazole.

Voriconazole is haemodialysed with a clearance of 121 ml/min. In an overdose, haemodialysis may assist in the removal of voriconazole from the body.


Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02 AC03

Mode of action

Voriconazole is a triazole antifungal agent. The primary mode of action of voriconazole is the inhibition of fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, an essential step in fungal ergosterol biosynthesis. The accumulation of 14 alpha-methyl sterols correlates with the subsequent loss of ergosterol in the fungal cell membrane and may be responsible for the antifungal activity of voriconazole. Voriconazole has been shown to be more selective for fungal cytochrome P-450 enzymes than for various mammalian cytochrome P-450 enzyme systems.

Pharmacokinetic/pharmacodynamic relationship

In 10 therapeutic studies, the median for the average and maximum plasma concentrations in individual subjects across the studies was 2425 ng/ml (inter-quartile range 1193 to 4380 ng/ml) and 3742 ng/ml (inter-quartile range 2027 to 6302 ng/ml), respectively. A positive association between mean, maximum or minimum plasma voriconazole concentration and efficacy in therapeutic studies was not found and this relationship has not been explored in prophylaxis studies.

Pharmacokinetic-Pharmacodynamic analyses of clinical trial data identified positive associations between plasma voriconazole concentrations and both liver function test abnormalities and visual disturbances. Dose adjustments in prophylaxis studies have not been explored.

Clinical efficacy and safety

In vitro, voriconazole displays broad-spectrum antifungal activity with antifungal potency against Candida species (including fluconazole- resistant C. krusei and resistant strains of C. glabrata and C. albicans) and fungicidal activity against all Aspergillus species tested. In addition voriconazole shows in vitro fungicidal activity against emerging fungal pathogens, including those such as Scedosporium or Fusarium which have limited susceptibility to existing antifungal agents.

Clinical efficacy defined as partial or complete response, has been demonstrated for Aspergillus spp. including A. flavus, A. fumigatus, A. terreus, A. niger, A. nidulans; Candida spp.including C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis; and limited numbers of C. dubliniensis, C. inconspicua and C. guilliermondii, Scedosporium spp., including S. apiospermum, S. prolificans; and Fusarium spp.

Other treated fungal infections (often with either partial or complete response) included isolated cases of Alternaria spp.,Blastomyces dermatitidis, Blastoschizomyces capitatus, Cladosporium spp., Coccidioides immitis, Conidiobolus coronatus, Cryptococcus neoformans, Exserohilum rostratum, Exophiala spinifera, Fonsecaea pedrosoi, Madurella mycetomatis, Paecilomyces lilacinus, Penicillium spp. including P. marneffei, Phialophora richardsiae, Scopulariopsis brevicaulis and Trichosporon spp. including T. beigelii infections.

In vitro activity against clinical isolates has been observed for Acremonium spp., Alternaria spp., Bipolaris spp. Cladophialophora spp., and Histoplasma capsulatum, with most strains being inhibited by concentrations of voriconazole in the range 0.05 to 2 μg/ml.

In vitro activity against the following pathogens has been shown, but the clinical significance is unknown: Curvularia spp. and Sporothrix spp.

Breakpoints

Specimens for fungal culture and other relevant laboratory studies (serology, histopathology) should be obtained prior to therapy to isolate and identify causative organisms. Therapy may be instituted before the results of the cultures and other laboratory studies are known; however, once these results become available, anti-infective therapy should be adjusted accordingly.

The species most frequently involved in causing human infections include C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. krusei, all of which usually exhibit minimal inhibitory concentration (MICs) of less than 1 mg/L for voriconazole.

However, the in vitro activity of voriconazole against Candida species is not uniform. Specifically, for C. glabrata, the MICs of voriconazole for fluconazole-resistant isolates are proportionally higher than are those of fluconazole-susceptible isolates. Therefore, every attempt should be made to identify Candida to species level. If antifungal susceptibility testing is available, the MIC results may be interpreted using breakpoint criteria established by European Committee on Antimicrobial Susceptibility Testing (EUCAST).

 

EUCAST Breakpoints

Candida and Aspergillus species

Minimal Inhibitory Concentration (MIC) breakpoint (mg/L)

≤S (Susceptible)

>R (Resistant)

Candida albicans1

0.06

0.25

Candida dubliniensis1

0.06

0.25

Candida glabrata

Insufficient evidence (IE)

IE

Candida krusei

IE

IE

Candida parapsilosis1

0.125

0.25

Candida tropicalis1

0.125

0.25

Candida guilliermondii2

IE

IE

Non-species related breakpoints for Candida3

IE

IE

Aspergillus fumigatus4

1

1

Aspergillus nidulans4

1

1

Aspergillus flavus

IE5

IE5

Aspergillus niger

IE5

IE5

Aspergillus terreus

IE5

IE5

Non-species related breakpoints6

IE

IE

1 Strains with MIC values above the Susceptible/Intermediate (S/I) breakpoint are rare or not yet reported. The identification and antifungal susceptibility tests on any such isolate must be repeated and if the result is confirmed the isolate sent to a reference laboratory. Until there is evidence regarding clinical response for confirmed isolates with MIC above the current resistant breakpoint they should be reported resistant. A clinical response of 76% was achieved in infections caused by the species listed below when MICs were lower than or equal to the epidemiological cut-offs. Therefore, wild type populations of C. albicans, C. dubliniensis, C. parapsilosis and C. tropicalis are considered susceptible.

2 The epidemiological cut-off values (ECOFFs) for these species are in general higher than for C. albicans.

3 Non-species related breakpoints have been determined mainly on the basis of PK/PD data and are independent of MIC distributions of specific Candida species. They are for use only for organisms that do not have specific breakpoints.

4 Area of technical uncertainty (ATU) is 2. Report as R with the following comment: "In some clinical situations (non-invasive infections forms) voriconazole can be used provided sufficient exposure is ensured".

5 The ECOFFs for these species are in general one two-fold dilution higher than for A. fumigatus.

Non-species related breakpoints have not been determined.

Clinical experience

Successful outcome in this section is defined as complete or partial response.

Aspergillus infections – efficacy in aspergillosis patients with poor prognosis

Voriconazole has in vitro fungicidal activity against Aspergillus spp. The efficacy and survival benefit of voriconazole versus conventional amphotericin B in the primary treatment of acute invasive aspergillosis was demonstrated in an open, randomised, multicentre study in 277 immunocompromised patients treated for 12 weeks. Voriconazole was administered intravenously with a loading dose of 6 mg/kg every 12 hours for the first 24 hours followed by a maintenance dose of 4 mg/kg every 12 hours for a minimum of 7 days. Therapy could then be switched to the oral formulation at a dose of 200 mg every 12 hours. Median duration of IV voriconazole therapy was 10 days (range 2-85 days). After IV voriconazole therapy, the median duration of oral voriconazole therapy was 76 days (range 2-232 days).

A satisfactory global response (complete or partial resolution of all attributable symptoms, signs, radiographic/bronchoscopic abnormalities present at baseline) was seen in 53% of voriconazole-treated patients compared to 31% of patients treated with comparator. The 84-day survival rate for voriconazole was statistically significantly higher than that for the comparator and a clinically and statistically significant benefit was shown in favour of voriconazole for both time to death and time to discontinuation due to toxicity.

This study confirmed findings from an earlier, prospectively designed study where there was a positive outcome in subjects with risk factors for a poor prognosis, including graft versus host disease, and, in particular, cerebral infections (normally associated with almost 100% mortality).

The studies included cerebral, sinus, pulmonary and disseminated aspergillosis in patients with bone marrow and solid organ transplants, haematological malignancies, cancer and AIDS.

Candidaemia in non-neutropenic patients

The efficacy of voriconazole compared to the regimen of amphotericin B followed by fluconazole in the primary treatment of candidaemia was demonstrated in an open, comparative study. Three hundred and seventy non-neutropenic patients (above 12 years of age) with documented candidaemia were included in the study, of whom 248 were treated with voriconazole. Nine subjects in the voriconazole group and 5 in the amphotericin B followed by fluconazole group also had mycologically proven infection in deep tissue. Patients with renal failure were excluded from this study. The median treatment duration was 15 days in both treatment arms. In the primary analysis, successful response as assessed by a Data Review Committee (DRC) blinded to study medicinal product was defined as resolution/improvement in all clinical signs and symptoms of infection with eradication of Candida from blood and infected deep tissue sites 12 weeks after the end of therapy (EOT). Patients who did not have an assessment 12 weeks after EOT were counted as failures. In this analysis a successful response was seen in 41% of patients in both treatment arms.

In a secondary analysis, which utilised DRC assessments at the latest evaluable time point (EOT, or 2, 6, or 12 weeks after EOT) voriconazole and the regimen of amphotericin B followed by fluconazole had successful response rates of 65% and 71%, respectively. The Investigator's assessment of successful outcome at each of these time points is shown in the following table.

Timepoint

Voriconazole (N=248)

Amphotericin B → fluconazole (N=122)

EOT

178 (72%)

88 (72%)

2 weeks after EOT

125 (50%)

62 (51%)

6 weeks after EOT

104 (42%)

55 (45%)

12 weeks after EOT

104 (42%)

51 (42%)

Serious refractory Candida infections

The study comprised 55 patients with serious refractory systemic Candida infections (including candidaemia, disseminated and other invasive candidiasis) where prior antifungal treatment, particularly with fluconazole, had been ineffective. Successful response was seen in 24 patients (15 complete, 9 partial responses). In fluconazole-resistant non- albicansspecies, a successful outcome was seen in 3/3 C. krusei (complete responses) and 6/8 C. glabrata (5 complete, 1 partial response) infections. The clinical efficacy data were supported by limited susceptibility data.

Scedosporium and Fusarium infections

Voriconazole was shown to be effective against the following rare fungal pathogens:

Scedosporium spp.: Successful response to voriconazole therapy was seen in 16 (6 complete, 10 partial responses) of 28 patients with S. apiospermum and in 2 (both partial responses) of 7 patients with S. prolificans infection. In addition, a successful response was seen in 1 of 3 patients with infections caused by more than one organism including Scedosporium spp.

Fusarium spp.: Seven (3 complete, 4 partial responses) of 17 patients were successfully treated with voriconazole. Of these 7 patients, 3 had eye, 1 had sinus, and 3 had disseminated infection. Four additional patients with fusariosis had an infection caused by several organisms; 2 of them had a successful outcome.

The majority of patients receiving voriconazole treatment of the above mentioned rare infections were intolerant of, or refractory to, prior antifungal therapy.

Primary Prophylaxis of Invasive Fungal Infections – Efficacy in HSCT recipients without prior proven or probable IFI

Voriconazole was compared to itraconazole as primary prophylaxis in an open-label, comparative, multicenter study of adult and adolescent allogeneic HSCT recipients without prior proven or probable IFI. Success was defined as the ability to continue study drug prophylaxis for 100 days after HSCT (without stopping for >14 days) and survival with no proven or probable IFI for 180 days after HSCT. The modified intent-to-treat (MITT) group included 465 allogeneic HSCT recipients with 45% of patients having AML. From all patients 58% were subject to myeloablative conditions regimens. Prophylaxis with study drug was started immediately after HSCT: 224 received voriconazole and 241 received itraconazole. The median duration of study drug prophylaxis was 96 days for voriconazole and 68 days for itraconazole in the MITT group.

Success rates and other secondary endpoints are presented in the table below:

Study Endpoints

Voriconazole

N=224

Itraconazole

N=241

Difference in proportions and the 95% confidence interval (CI)

P-Value

Success at day 180*

109 (48.7%)

80 (33.2%)

16.4% (7.7%, 25.1%) **

0.0002**

Success at day 100

121 (54.0%)

96 (39.8%)

15.4% (6.6%, 24.2%) **

0.0006**

Completed at least 100 days of study drug prophylaxis

120 (53.6%)

94 (39.0%)

14.6% (5.6%, 23.5%)

0.0015

Survived to day 180

184 (82.1%)

197 (81.7%)

0.4% (-6.6%, 7.4%)

0.9107

Developed proven or probable IFI to day 180

3 (1.3%)

5 (2.1%)

-0.7% (-3.1%, 1.6%)

0.5390

Developed proven or probable IFI to day 100

2 (0.9%)

4 (1.7%)

-0.8% (-2.8%, 1.3%)

0.4589

Developed proven or probable IFI while on study drug

0

3 (1.2%)

-1.2% (-2.6%, 0.2%)

0.0813

* Primary endpoint of the study

** Difference in proportions, 95% CI and p-values obtained after adjustment for randomization

The breakthrough IFI rate to Day 180 and the primary endpoint of the study, which is Success at Day 180, for patients with AML and myeloablative conditioning regimens respectively, is presented in the table below:

AML

Study endpoints

Voriconazole

(N=98)

Itraconazole

(N=109)

Difference in proportions and the 95% confidence interval (CI)

Breakthrough IFI – Day 180

1 (1.0%)

2 (1.8%)

-0.8% (-4.0%, 2.4%) **

Success at Day 180*

55 (56.1%)

45 (41.3%)

14.7% (1.7%, 27.7%) ***

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

***Difference in proportions, 95% CI obtained after adjustment for randomization

 

Myeloablative conditioning regimens

Study endpoints

Voriconazole

(N=125)

Itraconazole

(N=143)

Difference in proportions and the 95% confidence interval (CI)

Breakthrough IFI – Day 180

2 (1.6%)

3 (2.1%)

-0.5% (-3.7%, 2.7%) **

Success at Day 180*

70 (56.0%)

53 (37.1%)

20.1% (8.5%, 31.7%)***

* Primary endpoint of study

** Using a margin of 5%, non inferiority is demonstrated

*** Difference in proportions, 95% CI obtained after adjustment for randomization

 

Secondary Prophylaxis of IFI – Efficacy in HSCT recipients with prior proven or probable IFI

Voriconazole was investigated as secondary prophylaxis in an open-label, non-comparative, multicenter study of adult allogeneic HSCT recipients with prior proven or probable IFI. The primary endpoint was the rate of occurrence of proven and probable IFI during the first year after HSCT. The MITT group included 40 patients with prior IFI, including 31 with aspergillosis, 5 with candidiasis, and 4 with other IFI. The median duration of study drug prophylaxis was 95.5 days in the MITT group.

Proven or probable IFIs developed in 7.5% (3/40) of patients during the first year after HSCT, including one candidemia, one scedosporiosis (both relapses of prior IFI), and one zygomycosis. The survival rate at Day 180 was 80.0% (32/40) and at 1 year was 70.0% (28/40).

Duration of treatment

In clinical trials, 705 patients received voriconazole therapy for greater than 12 weeks, with 164 patients receiving voriconazole for over 6 months.

Paediatric population

Fifty-three paediatric patients aged 2 to <18 years were treated with voriconazole in two prospective, open-label, non-comparative, multi-center clinical trials. One study enrolled 31 patients with possible, proven or probable invasive aspergillosis (IA), of whom 14 patients had proven or probable IA and were included in the MITT efficacy analyses. The second study enrolled 22 patients with invasive candidiasis including candidaemia (ICC), and esophageal candidiasis (EC) requiring either primary or salvage therapy, of whom 17 were included in the MITT efficacy analyses. For patients with IA the overall rates of global response at 6 weeks were 64.3% (9/14), the global response rate was 40% (2/5) for patients 2 to <12 years and 77.8% (7/9) for patients 12 to <18 years of age. For patients with ICC the global response rate at EOT was 85.7% (6/7) and for patients with EC the global response rate at EOT was 70% (7/10). The overall rate of response (ICC and EC combined) was 88.9% (8/9) for 2 to <12 years old and 62.5% (5/8) for 12 to <18 years old.

Clinical studies examining QTc interval

A placebo-controlled, randomized, single-dose, crossover study to evaluate the effect on the QTc interval of healthy volunteers was conducted with three oral doses of voriconazole and ketoconazole. The placebo-adjusted mean maximum increases in QTc from baseline after 800, 1200 and 1600 mg of voriconazole were 5.1, 4.8, and 8.2 msec, respectively and 7.0 msec for ketoconazole 800 mg. No subject in any group had an increase in QTc of ≥ 60 msec from baseline. No subject experienced an interval exceeding the potentially clinically-relevant threshold of 500 msec.


General pharmacokinetic characteristics

The pharmacokinetics of voriconazole have been characterised in healthy subjects, special populations and patients. During oral administration of 200 mg or 300 mg twice daily for 14 days in patients at risk of aspergillosis (mainly patients with malignant neoplasms of lymphatic or haematopoietic tissue), the observed pharmacokinetic characteristics of rapid and consistent absorption, accumulation and non-linear pharmacokinetics were in agreement with those observed in healthy subjects.

The pharmacokinetics of voriconazole are non-linear due to saturation of its metabolism. Greater than proportional increase in exposure is observed with increasing dose. It is estimated that, on average, increasing the oral dose from 200 mg twice daily to 300 mg twice daily leads to a 2.5-fold increase in exposure (AUC ). The oral maintenance dose of 200 mg (or 100 mg for patients less than 40 kg) achieves a voriconazole exposure similar to 3 mg/kg IV. A 300 mg (or 150 mg for patients less than 40 kg) oral maintenance dose achieves an exposure similar to 4 mg/kg IV. When the recommended intravenous or oral loading dose regimens are administered, plasma concentrations close to steady state are achieved within the first 24 hours of dosing. Without the loading dose, accumulation occurs during twice daily multiple dosing with steady-state plasma voriconazole concentrations being achieved by Day 6 in the majority of subjects.

Absorption

Voriconazole is rapidly and almost completely absorbed following oral administration, with maximum plasma concentrations (Cmax) achieved 1-2 hours after dosing. The absolute bioavailability of voriconazole after oral administration is estimated to be 96%. When multiple doses of voriconazole are administered with high fat meals, Cmax and AUC  are reduced by 34% and 24%, respectively. The absorption of voriconazole is not affected by changes in gastric pH.

Distribution

The volume of distribution at steady state for voriconazole is estimated to be 4.6 L/kg, suggesting extensive distribution into tissues. Plasma protein binding is estimated to be 58%. Cerebrospinal fluid samples from eight patients in a compassionate programme showed detectable voriconazole concentrations in all patients.

Biotransformation

In vitro studies showed that voriconazole is metabolised by the hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9 and CYP3A4.

The inter-individual variability of voriconazole pharmacokinetics is high.

In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolisers. For Caucasians and Blacks the prevalence of poor metabolisers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolisers have, on average, 4-fold higher voriconazole exposure (AUC ) than their homozygous extensive metaboliser counterparts. Subjects who are heterozygous extensive metabolisers have on average 2-fold higher voriconazole exposure than their homozygous extensive metaboliser counterparts.

The major metabolite of voriconazole is the N-oxide, which accounts for 72% of the circulating radiolabelled metabolites in plasma. This metabolite has minimal antifungal activity and does not contribute to the overall efficacy of voriconazole.

Elimination

Voriconazole is eliminated via hepatic metabolism with less than 2% of the dose excreted unchanged in the urine.

After administration of a radiolabelled dose of voriconazole, approximately 80% of the radioactivity is recovered in the urine after multiple intravenous dosing and 83% in the urine after multiple oral dosing. The majority (> 94%) of the total radioactivity is excreted in the first 96 hours after both oral and intravenous dosing.

The terminal half-life of voriconazole depends on dose and is approximately 6 hours at 200 mg (orally). Because of non-linear pharmacokinetics, the terminal half-life is not useful in the prediction of the accumulation or elimination of voriconazole.

Pharmacokinetics in special patient groups

Gender

In an oral multiple-dose study, Cmax and AUC  for healthy young females were 83% and 113% higher, respectively, than in healthy young males (18-45 years). In the same study, no significant differences in Cmax and AUC  were observed between healthy elderly males and healthy elderly females (≥ 65 years).

In the clinical programme, no dosage adjustment was made on the basis of gender. The safety profile and plasma concentrations observed in male and female patients were similar. Therefore, no dosage adjustment based on gender is necessary.

Elderly

In an oral multiple-dose study Cmax and AUC  in healthy elderly males (≥ 65 years) were 61% and 86% higher, respectively, than in healthy young males (18-45 years). No significant differences in Cmax and AUC  were observed between healthy elderly females (≥ 65 years) and healthy young females (18-45 years).

In the therapeutic studies no dosage adjustment was made on the basis of age. A relationship between plasma concentrations and age was observed. The safety profile of voriconazole in young and elderly patients was similar and, therefore, no dosage adjustment is necessary for the elderly (see section 4.2).

Paediatric population

The recommended doses in children and adolescent patients are based on a population pharmacokinetic analysis of data obtained from 112 immunocompromised pediatric patients aged 2 to <12 years and 26 immunocompromised adolescent patients aged 12 to <17 years.

A comparison of the pediatric and adult population pharmacokinetic data indicated that the predicted total exposure (AUC ) in children following administration of a 9 mg/kg IV loading dose was comparable to that in adults following a 6 mg/kg IV loading dose. The predicted total exposures in children following IV maintenance doses of 4 and 8 mg/kg twice daily were comparable to those in adults following 3 and 4 mg/kg IV twice daily, respectively. The predicted total exposure in children following an oral maintenance dose of 9 mg/kg (maximum of 350 mg) twice daily was comparable to that in adults following 200 mg oral twice daily. An 8 mg/kg intravenous dose will provide voriconazole exposure approximately 2-fold higher than a 9 mg/kg oral dose.

The higher intravenous maintenance dose in pediatric patients relative to adults reflects the higher elimination capacity in pediatric patients due to a greater liver mass to body mass ratio. Oral bioavailability may, however, be limited in pediatric patients with malabsorption and very low body weight for their age. In that case, intravenous voriconazole administration is recommended.

Voriconazole exposures in the majority of adolescent patients were comparable to those in adults receiving the same dosing regimens. However, lower voriconazole exposure was observed in some young adolescents with low body weight compared to adults. It is likely that these subjects may metabolize voriconazole more similarly to children than to adults. Based on the population pharmacokinetic analysis, 12- to 14-year-old adolescents weighing less than 50 kg should receive children's doses (see section 4.2).

Renal impairment

In an oral single-dose (200 mg) study in subjects with normal renal function and mild (creatinine clearance 41-60 ml/min) to severe (creatinine clearance < 20 ml/min) renal impairment, the pharmacokinetics of voriconazole were not significantly affected by renal impairment. The plasma protein binding of voriconazole was similar in subjects with different degrees of renal impairment. (see sections 4.2 and 4.4).

Hepatic impairment

After an oral single-dose (200 mg), AUC was 233% higher in subjects with mild to moderate hepatic cirrhosis (Child-Pugh A and B) compared with subjects with normal hepatic function. Protein binding of voriconazole was not affected by impaired hepatic function.

In an oral multiple-dose study, AUC  was similar in subjects with moderate hepatic cirrhosis (Child-Pugh B) given a maintenance dose of 100 mg twice daily and subjects with normal hepatic function given 200 mg twice daily. No pharmacokinetic data are available for patients with severe hepatic cirrhosis (Child-Pugh C) (see sections 4.2 and 4.4).


Repeated-dose toxicity studies with voriconazole indicated the liver to be the target organ. Hepatotoxicity occurred at plasma exposures similar to those obtained at therapeutic doses in humans, in common with other antifungal agents. In rats, mice and dogs, voriconazole also induced minimal adrenal changes. Conventional studies of safety pharmacology, genotoxicity or carcinogenic potential did not reveal a special hazard for humans.

In reproduction studies, voriconazole was shown to be teratogenic in rats and embryotoxic in rabbits at systemic exposures equal to those obtained in humans with therapeutic doses. In the pre- and post-natal development study in rats at exposures lower than those obtained in humans with therapeutic doses, voriconazole prolonged the duration of gestation and labour and produced dystocia with consequent maternal mortality and reduced perinatal survival of pups. The effects on parturition are probably mediated by species-specific mechanisms, involving reduction of oestradiol levels, and are consistent with those observed with other azole antifungal agents. Voriconazole administration induced no impairment of male or female fertility in rats at exposures similar to those obtained in humans at therapeutic doses.


The other ingredients are Lactose monohydrate, croscarmellose sodium, povidone K30, microcrystalline Cellulose, magnesium stearate, Opadry OY-L White (Lactose monohydrate, HPMC, titanium dioxide and Macrogol), FD&C Yellow #6 lake, FD&C Blue #1 lake, Yellow iron oxide.


Not applicable.


2 years.

Store below 30°C.


Voriconazole MCP® 200mg Film Coated Tablets Light green, oval deep biconvex film coated tablet engraved with H15 on one face, packed in Alu/PVC/PVDC blisters, intended for oral use.

Pack size:

30 Film Coated Tablets (10 tablets in Alu/PVC/PVDC blister, 3 blisters/pack).


No special requirements.


Med City Pharma-KSA. Tel: 00966920003288 Fax: 00966126358138 Mobile: 00966555786968 P.O .Box: 42512 - Jeddah 21551 E-mail: MD.admin@Axantia.com

10/2023
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