Voriconazole 200mg tablets

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

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Active ingredient:
Voriconazole
Available from:
Accord Healthcare Ltd
ATC code:
J02AC03
INN (International Name):
Voriconazole
Dosage:
200mg
Pharmaceutical form:
Tablet
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 05020100; GTIN: 5055565725436

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Package Leaflet: Information for the user

Voriconazole Accord 50 mg film-coated tablets

Voriconazole Accord 200 mg film-coated tablets

voriconazole

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm

them, even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet

What Voriconazole Accord is and what it is used for

What you need to know before you take Voriconazole Accord

How to take Voriconazole Accord

Possible side effects

How to store Voriconazole Accord

Content of the pack and other information

1.

What Voriconazole Accord is and what it is used for

Voriconazole Accord contains the active substance voriconazole. Voriconazole Accord 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.

Fusarium sp

. (two different species

of fungi).

Voriconazole Accord 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.

2.

What you need to know before you take Voriconazole Accord

Do not take Voriconazole Accord

If you are allergic to voriconazole or any of the other ingredients of this medicine (listed in section 6).

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 Accord

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)

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)

Warnings and precautions

Talk to your doctor, pharmacist or nurse before taking Voriconazole Accord if:

you have had an allergic reaction to other azoles.

you are suffering from, or have ever suffered from liver disease. If you have liver disease, your

doctor may prescribe a lower dose of Voriconazole Accord. Your doctor should also monitor

your liver function while you are being treated with Voriconazole Accord by doing blood tests.

you are known to have cardiomyopathy, irregular heart beat, 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 Accord:

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 Accord

.

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

Children and adolescents

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

Other medicines and Voriconazole Accord

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 Accord, may affect the way

Voriconazole Accord works or Voriconazole Accord may affect the way they work.

Tell your doctor if you are taking the following medicine, as treatment with Voriconazole Accord at

the same time should be avoided if possible:

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

Tell your doctor if you are taking either of the following medicines, as treatment with Voriconazole

Accord 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 Accord 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 Accord 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 Accord 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)

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

Accord )

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)

Pregnancy and breast-feeding

Voriconazole Accord 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 Accord.

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 Accord 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 Accord contains lactose

If you have been told by your doctor that you have an intolerance to some sugars, tell your doctor

before taking Voriconazole Accord.

3.

How to take Voriconazole Accord

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 Dose)

400 mg every 12 hours

for the first 24 hours

200 mg every 12 hours

for the first 24 hours

Dose after the first 24 hours

(Maintenance Dose)

200 mg twice a day

100 mg 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

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

400 mg every 12 hours

for the first 24 hours

Dose after the first 24

hours

(Maintenance Dose)

9 mg/kg twice a day

(a maximum dose of 350 mg twice

daily)

200 mg 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 Accord for prevention of fungal infections, your doctor

may stop giving Voriconazole Accord if you or your child develop treatment related side effects.

If you take more Voriconazole Accord 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

Accord tablets with you. You may experience abnormal intolerance to light as a result of taking more

Voriconazole Accord than you should.

If you forget to take Voriconazole Accord

It is important to take your Voriconazole Accord 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 Accord

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 Accord correctly, as described above.

Continue taking Voriconazole Accord 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 Accord 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.

4.

Possible side effects

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 Accord 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 diarrhoea, 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 fibers 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 Accord 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 Accord 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.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side

effects not listed in this leaflet. You can also report side effects directly via the national reporting

Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcard

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Voriconazole Accord

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

Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the

last day of that month.

This medicine does not require any special storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Voriconazole Accord contains

The active substance is voriconazole. Each tablet contains either 50 mg voriconazole (for

Voriconazole Accord 50 mg film-coated tablets) or 200 mg voriconazole (for

VoriconazoleAccord 200 mg film-coated tablets).

The other ingredients are lactose monohydrate, pregelatinised starch, croscarmellose sodium,

povidone and magnesium stearate which make up the tablet core and hypromellose, titanium

dioxide (E171), lactose monohydrate and triacetin which make up the film-coat.

What Voriconazole Accord looks like and contents of the pack

Voriconazole Accord 50 mg film-coated tablets are supplied as white to off white, round, approximate

7.0mm in diameter, film-coated tablets, debossed with ‘V50’ on one side and plain on the other side.

Voriconazole Accord 200 mg film-coated tablets are supplied as white to off white, oval,

approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets, debossed with ‘V200’ on

one side and plain on the other side.

Voriconazole Accord 50 mg film-coated tablets and 200mg film-coated tablets are available as packs

of 2, 10, 14, 20, 28, 30, 50, 56 and 100 or unit dose blister packs (PVC / Aluminium) containing 10x1,

14x1, 28x1, 30x1, 56x1 or 100x1 film-coated tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow,

Middlesex, HA1 4HF,

United Kingdom

Manufacturer

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow, Middlesex, HA1 4HF,

United Kingdom

Pharmacare Premium Ltd

HHF 003, Hal Far Industrial Estate,

Birzebbugia, BBG 3000, Malta

This leaflet was last approved in 02/2018.

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu

Read the complete document

Object 1

Voriconazole Accord Film-coated Tablets

Summary of Product Characteristics Updated 17-Feb-2018 | Accord Healthcare Limited

1. Name of the medicinal product

Voriconazole Accord 50 mg film-coated tablets

Voriconazole Accord 200 mg film-coated tablets

2. Qualitative and quantitative composition

Voriconazole Accord 50 mg film-coated tablets

Each tablet contains 50 mg voriconazole.

Excipient with known effect

Each tablet contains 63 mg lactose (as monohydrate).

Voriconazole Accord 200 mg film-coated tablets

Each tablet contains 200 mg voriconazole.

Excipient with known effect

Each tablet contains 251 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Voriconazole Accord 50 mg film-coated tablets

White to off white, round, approximate 7.0 mm in diameter, film-coated tablets, debossed with 'V50' on

one side and plain on the other side.

Voriconazole Accord 200 mg film-coated tablets

White to off white, oval, approximately 15.6 mm in length and 7.8 mm in width, film-coated tablets,

debossed with 'V200' on one side and plain on the other side.

4. Clinical particulars

4.1 Therapeutic indications

Voriconazole Accord, 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 Accord 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.

4.2 Posology and method of administration

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).

Voriconazole may also be available as powder for solution for infusion, powder and solvent for solution

for infusion and powder for oral suspension, however not under this tradename.

Treatment

Adults

Therapy must be initiated with the specified loading dose regimen of either intravenous or oral

voriconazole 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 paediatricpatients

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).

Renal 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 Accord film-coated tablets are to be taken at least one hour before, or one hour following, a

meal.

4.3 Contraindications

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 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 with St John's Wort (see section 4.5).

4.4 Special warnings and precautions for use

Hypersensitivity

Caution should be used in prescribing Voriconazole Accord 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 Accord 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 Accord 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 Accord 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 Accord 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 Accord 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 has been reported in patients, some of whom have reported prior

phototoxic reactions. If phototoxic reactions occur multidisciplinary advice should be sought,

Voriconazole Accord discontinuation and use of alternative antifungal agents should be considered and

the patient should be referred to a dermatologist. If Voriconazole Accord is continued, however,

dermatologic evaluation should be performed on a systematic and regular basis, to allow early detection

and management of premalignant lesions. Voriconazole Accord should be discontinued if premalignant

skin lesions or squamous cell carcinoma are identified (see below the section under Long-term treatment).

Exfoliative cutaneous reactions

Reactions such as Stevens-Johnson syndrome developed during treatment with Voriconazole Accord. If a

patient develops a rash he should be monitored closely and Voriconazole Accord discontinued if lesions

progress.

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 Accord (see sections 4.2 and 5.1).

Squamous cell carcinoma of the skin (SCC) has been reported in relation with long-term Voriconazole

Accord 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 Accord 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

Accord 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-<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).

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 AUC

0-∞

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

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).

Voriconazole Accord tablets contain lactose and should not be given to patients with rare hereditary

problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.

4.5 Interaction with other medicinal products and other forms of interaction

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.

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), 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

, AUC

and AUC

0-∞

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 and

terfenadine

[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 C

↑ 38%

Efavirenz AUC

Voriconazole C

↓ 61%

Voriconazole AUC

Compared to efavirenz 600 mg

QD, Efavirenz C

Efavirenz AUC

Compared to voriconazole 200

mg BID,

Voriconazole C

↑23%

Voriconazole AUC

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)

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 C

↓ 69%

Voriconazole AUC

Compared to voriconazole 200

mg BID,

Voriconazole C

↓ 4%

Voriconazole AUC

Rifabutin C

↑195%

Rifabutin AUC

↑331%

Compared to voriconazole 200

mg BID,

Voriconazole C

↑ 104%

Voriconazole AUC

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 C

↓ 93%

Voriconazole AUC

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 C

and AUC

Voriconazole C

↓ 66%

Voriconazole AUC

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

Ritonavir C

↓ 25%

Ritonavir AUC

Voriconazole C

↓ 24%

Voriconazole AUC

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 AUC

0-∞

↓ 59%

Contraindicated (see section 4.3)

Everolimus

[CYP3A4 substrate, P-gp

substrate]

Although not studied,

voriconazole is likely to

significantly increase the plasma

concentrations of everolimus.

Coadministration of voriconazole with

everolimus is not recommended

because voriconazole is expected to

significantly increase everolimus

concentrations (see section 4.4).

Fluconazole (200 mg QD)

[CYP2C9, CYP2C19 and

CYP3A4 inhibitor]

Voriconazole C

↑ 57%

Voriconazole AUC

Fluconazole C

Fluconazole AUC

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

potentCYP450 inducer]

300 mg QD

300 mg QD (co-administered

with voriconazole 400 mg

BID)*

Voriconazole C

↓ 49%

Voriconazole AUC

Phenytoin C

↑ 67%

Phenytoin AUC

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 co-administered 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

Compared to voriconazole 200

mg BID,

Voriconazole C

↑ 34%

Voriconazole AUC

4.2).

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.

Benzodiazepines (e.g.,

midazolam, triazolam,

alprazolam)

[CYP3A4 substrates]

Although not studied clinically,

voriconazole is likely to increase

the plasma concentrations of

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)

Ciclosporin (in stable renal

transplant recipients receiving

chronic ciclosporin therapy)

Tacrolimus (0.1 mg/kg single

dose)

In an independent published

study,

Sirolimus C

↑ 6.6-fold

Sirolimus AUC

0-∞

↑11-fold

Ciclosporin C

↑ 13%

Ciclosporin AUC

Tacrolimus C

↑ 117%

Tacrolimus AUC

↑ 221%

Coadministration of voriconazole and

sirolimus is contraindicated (see

section 4.3).

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 C

↑ 1.7-fold

Oxycodone AUC

0-∞

↑ 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) C

R-methadone (active) AUC

↑ 47%

S-methadone C

↑ 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 C

↑ 20%

S-Ibuprofen AUC

0-∞

↑ 100%

Diclofenac C

↑ 114%

Diclofenac AUC

0-∞

↑ 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 C

↑116%

Omeprazole AUC

280%

Voriconazole C

↑15%

Voriconazole AUC

Other proton pump inhibitors

that are CYP2C19 substrates

may also be inhibited by

voriconazole and may result in

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.

increased plasma concentrations

of these medicinal products.

Oral Contraceptives*

[CYP3A4 substrate; CYP2C19

inhibitor]

Norethisterone/ethinylestradiol

(1 mg/0.035 mg QD)

Ethinylestradiol C

↑ 36%

Ethinylestradiol AUC

↑ 61%

Norethisterone C

↑ 15%

Norethisterone AUC

↑ 53%

Voriconazole C

↑ 14%

Voriconazole AUC

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 AUC

0-∞

↑ 6-

fold.

In an independent published

study,

Fentanyl AUC

0-∞

↑ 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.

Dose reduction of statins 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

Not studied clinically. In vitro

studies show that voriconazole

may inhibit the metabolism of

Careful monitoring for any occurrence

of drug toxicity and/or lack of efficacy,

and nelfinavir)*

[CYP3A4 substrates and

inhibitors]

HIV protease inhibitors and the

metabolism of voriconazole may

also be inhibited by HIV

protease inhibitors.

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.

Cimetidine (400 mg BID)

[non-specific CYP450 inhibitor

and increases gastric pH]

Voriconazole C

↑ 18%

Voriconazole AUC

No dose adjustment

Digoxin (0.25 mg QD)

[P-gp substrate]

Digoxin C

Digoxin AUC

No dose adjustment

Indinavir (800 mg TID)

[CYP3A4 inhibitor and

substrate]

Indinavir C

Indinavir AUC

Voriconazole C

Voriconazole AUC

No dose adjustment

Macrolide antibiotics

Erythromycin (1 g BID)

[CYP3A4 inhibitor]

Azithromycin (500 mg QD)

Voriconazole C

and AUC

Voriconazole C

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 C

Mycophenolic acid AUCt ↔

No dose adjustment

Prednisolone (60 mg single

dose)

[CYP3A4 substrate]

Prednisolone C

↑ 11%

Prednisolone AUC

0-∞

↑ 34%

No dose adjustment

Ranitidine (150 mg BID)

[increases gastric pH]

Voriconazole C

and AUC

No dose adjustment

4.6 Fertility, pregnancy and lactation

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 Accord 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 Accord.

Fertility

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

4.7 Effects on ability to drive and use machines

Voriconazole Accord 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.

4.8 Undesirable effects

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,

diarrhoea, 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, 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*

Blood and

lymphatic

system disorders

agranulocytosis

pancytopenia,

thrombocytopenia

, 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,

hypertonia

paraesthesia,

somnolence,

dizziness

brain oedema,

encephalopathy

extrapyramidal

disorder

neuropathy

peripheral, ataxia,

hypoaesthesia,

dysgeusia

hepatic

encephalopathy,

Guillain-Barre

syndrome,

nystagmus

Eye disorders

visual

impairment

retinal

haemorrhage

optic nerve

disorder

papilloedema

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

distress

acute respiratory

distress

syndrome,

pulmonary

oedema

Gastrointestinal

disorders

diarrhoea,

vomiting,

abdominal

cheilitis,

dyspepsia,

constipation,

peritonitis,

pancreatitis, swollen

tongue, duodenitis,

pain, nausea

gingivitis

gastroenteritis,

glossitis

Hepatobiliary

disorders

liver function

test abnormal

jaundice, jaundice

cholestatic,

hepatitis

hepatic failure,

hepatomegaly,

cholecystitis,

cholelithiasis

Skin and

subcutaneous

tissue disorders

rash

dermatitis

exfoliative,

alopecia, rash

maculo-papular,

pruritus, erythema

Stevens-Johnson

syndrome,

phototoxicity,

purpura, urticaria,

dermatitis allergic,

rash papular, rash

macular, eczema

toxic epidermal

necrolysis,

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

oedema

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.

Includes immune thrombocytopenic purpura.

Includes nuchal rigidity and tetany.

Includes hypoxic-ischaemic encephalopathy and metabolic encephalopathy.

Includes akathisia and parkinsonism.

See “Visual impairments” paragraph in section 4.8.

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

See section 4.4.

Includes dyspnoea and dyspnoea exertional.

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

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 serious

cutaneous reactions, including Stevens-Johnson syndrome (uncommon), toxic epidermal necrolysis (rare)

and erythema multiforme (rare) during treatment with voriconazole.

If a patient develops a rash they should be monitored closely and Voriconazole Accord 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 in patients treated with Voriconazole

Accord for long periods of time; the mechanism has not been established (see section 4.4).

Liver function tests

The overall incidence of transaminase increases>3xULN (not necessarily comprising an adverse event) in

the voriconazole clinical programme was 18.0% (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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows

continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are

asked to report any suspected adverse reactions via the national reporting system Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

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.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02A C03

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.

includingT. 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 andC. 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 species

MIC breakpoint (mg/L)

S (Susceptible)

>R (Resistant)

Candida albicans

1

0.125

0.125

Candida tropicalis

1

0.125

0.125

Candida parapsilosis

1

0.125

0.125

Candida glabrata

2

Insufficient evidence

Candida krusei

3

Insufficient evidence

Other Candida spp

.4

Insufficient evidence

Strains with MIC values above the Susceptible (S) breakpoint are rare, or not yet reported. The

identification and antimicrobial susceptibility tests on any such isolate must be repeated and if the result is

confirmed the isolate sent to a reference laboratory.

In clinical studies, response to voriconazole in patients with C glabrata infections was 21% lower

compared to C. albicans, C. parapsilosis and C. tropicalis. In vitro data showed a slight increase of

resistance of C. glabrata to voriconazole.

In clinical studies, response to voriconazole in C. krusei infections was similar to C. albicans, C.

parapsilosis and C. tropicalis. However, as there were only 9 cases available for EUCAST analysis, there

is currently insufficient evidence to set clinical breakpoints for C. krusei.

EUCAST has not determined non-species related breakpoints for voriconazole.

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 277immunocompromised 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 2-232days).

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 albicans species, a successful outcome was seen in3/3

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 180days 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

2 (0.9%)

4 (1.7%)

-0.8% (-2.8%, 1.3%)

0.4589

to day 100

Developed proven or probable IFI

while on study drug

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.

5.2 Pharmacokinetic properties

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 (C

) 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, C

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

radiolabeled 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, C

and AUC

for healthy young females were 83% and 113%

higher, respectively, than in healthy young males (18-45years). In the same study, no significant

differences in C

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 C

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

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 paediatric patients aged 2 to <12 years and 26

immunocompromised adolescent patients aged 12to <17 years. Multiple intravenous doses of 3, 4, 6, 7

and 8 mg/kg twice daily and multiple oral doses (using the powder for oral suspension) of 4 mg/kg, 6

mg/kg, and 200 mg twice daily were evaluated in 3 paediatric pharmacokinetic studies. Intravenous

loading doses of 6 mg/kg IV twice daily on day 1 followed by 4 mg/kg intravenous dose twice daily and

300 mg oral tablets twice daily were evaluated in one adolescent pharmacokinetic study. Larger inter-

subject variability was observed in paediatric patients compared to adults.

A comparison of the paediatric 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 paediatric patients relative to adults reflects the higher

elimination capacity in paediatric patients due to a greater liver mass to body mass ratio. Oral

bioavailability may, however, be limited in paediatric 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 (sees ection4.2).

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 < 20ml/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).

5.3 Preclinical safety data

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.

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Lactose monohydrate

Pregelatinized starch

Croscarmellose sodium

Povidone

Magnesium stearate

Film-coating

Hypromellose

Titanium dioxide (E171)

Lactose monohydrate

Triacetin

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC / Aluminium blister in cartons of 2, 10, 14, 20, 28, 30, 50, 56 or 100 film-coated tablets or unit dose

PVC / Aluminium blister in pack sizes of 10x1, 14x1, 28x1, 30x1, 56x1 or 100x1 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. Marketing authorisation holder

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow,

Middlesex, HA1 4HF,

United Kingdom.

8. Marketing authorisation number(s)

Voriconazole Accord 50 mg film-coated tablets

EU/1/13/835/001-009,

EU/1/13/835/019-024

Voriconazole Accord 200 mg film-coated tablets

EU/1/13/835/010-018,

EU/1/13/835/025-030

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 16 May 2013

Date of latest renewal: 9

February 2018

10. Date of revision of the text

09/02/2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency. http://www.ema.europa.eu

Company Contact Details

Accord Healthcare Limited

Address

Sage House, 319 Pinner Road, North Harrow, Middlesex, HA1 4HF, UK

Telephone

+44 (0)208 8631 427

Medical Information Direct Line

+44 (0)208 901 3370

Customer Care direct line

0800 373 573

http://www.accord-healthcare.eu

+44 (0)208 861 4867

Medical Information e-mail

[email

protected]

Medical Information Fax

+44 (0)208 861 4867

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