Posaconazole Accord

European Union - English - EMA (European Medicines Agency)

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Active ingredient:
posaconazole
Available from:
Accord Healthcare S.L.U.
ATC code:
J02AC04
INN (International Name):
posaconazole
Therapeutic group:
Antimycotics for systemic use
Therapeutic area:
Mycoses
Therapeutic indications:
Posaconazole Accord is indicated for use in the treatment of the following fungal infections in adults:Invasive aspergillosis in patients with disease that is refractory to amphotericin B or itraconazole or in patients who are intolerant of these medicinal products;Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are intolerant of amphotericin B;Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole or in patients who are intolerant of itraconazole;Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or fluconazole or in patients who are intolerant of these medicinal products.Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days of prior therapeutic doses of effective antifungal therapy.Posaconazole Accord is also indicated for prophylaxis of invasive fungal infections in the following patients: Patients receiving remission-induction chemoth
Authorization status:
Authorised
Authorization number:
EMEA/H/C/005005
Authorization date:
2019-07-25
EMEA code:
EMEA/H/C/005005

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B. PACKAGE LEAFLET

Package leaflet: Information for the user

Posaconazole Accord 100 mg gastro-resistant tablets

posaconazole

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 or 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 or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What Posaconazole Accord is and what it is used for

What you need to know before you take Posaconazole Accord

How to take Posaconazole Accord

Possible side effects

How to store Posaconazole Accord

Contents of the pack and other information

1.

What Posaconazole Accord is and what it is used for

Posaconazole Accord contains a medicine called posaconazole. This belongs to a group of medicines

called “antifungals”. It is used to prevent and treat many different fungal infections.

This medicine works by killing or stopping the growth of some types of fungi that can cause

infections.

Posaconazole Accord can be used in adults to treat the following types of fungal infections when other

antifungal medicines have not worked or you have had to stop taking them:

infections caused by fungi of the

Aspergillus

family that have not improved during treatment

with the anti-fungal medicines amphotericin B or itraconazole or when these medicines have

had to be stopped;

infections caused by fungi of the

Fusarium

family that have not improved during treatment with

amphotericin B or when amphotericin B has had to be stopped;

infections caused by fungi that cause the conditions known as “chromoblastomycosis” and

“mycetoma” that have not improved during treatment with itraconazole or when itraconazole

has had to be stopped;

infections caused by a fungus called

Coccidioides

that have not improved during treatment with

one or more of amphotericin B, itraconazole or fluconazole or when these medicines have had

to be stopped.

This medicine can also be used to prevent fungal infections in adults who are at high risk of getting a

fungal infection, such as:

patients who have a weak immune system due to having chemotherapy for “acute myelogenous

leukemia” (AML) or “myelodysplastic syndromes” (MDS)

patients having “high- dose immunosuppressive therapy” after “hematopoietic stem cell

transplant” (HSCT).

2.

What you need to know before you take Posaconazole Accord

Do not take Posaconazole Accord

if you are allergic to posaconazole or any of the other ingredients of this medicine (listed in

section 6).

if you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, any

medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine, or a “statin”

such as simvastatin, atorvastatin or lovastatin

Do not take Posaconazole Accord if any of the above apply to you. If you are not sure, talk to your

doctor or pharmacist before taking Posaconazole Accord.

See “Other medicines and Posaconazole Accord” below for more information including information

on other medicines which may interact with Posaconazole Accord.

Warnings and precautions

Talk to your doctor or pharmacist before taking Posaconazole Accord

if you have had an allergic reaction to another antifungal medicine such as ketoconazole,

fluconazole, itraconazole or voriconazole.

if you have or have ever had liver problems. You may need to have blood tests while you are

taking this medicine.

if you develop severe diarrhoea or vomiting, as these conditions may limit the effectiveness of

this medicine.

if you have an abnormal heart rhythm tracing (ECG) that shows a problem called long QTc

interval

if you have a weakness of the heart muscle or heart failure

if you have a very slow heartbeat

if you have heart rhythm disturbance

if you have any problem with potassium, magnesium or calcium levels in your blood

if you are taking vincristine, vinblastine and other “vinca alkaloids” (medicines used to treat

cancer).

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before

taking Posaconazole Accord.

If you develop severe diarrhoea or vomiting (being sick) while taking Posaconazole Accord, talk to

your doctor, pharmacist or nurse straight away, as this may stop it from working properly. See Section

4 for more information

Children

Posaconazole Accord should not be used in children (17 years of age and younger).

Other medicines and Posaconazole Accord

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines.

Do not take Posaconazole Accord if you are taking any of the following:

terfenadine (used to treat allergies)

astemizole (used to treat allergies)

cisapride (used to treat stomach problems)

pimozide (used to treat symptoms of Tourette's and mental illness)

halofantrine (used to treat malaria)

quinidine (used to treat abnormal heart rhythms).

Posaconazole Accord can increase the amount of these medicines in the blood which may lead to very

serious changes to your heart rhythm:

any medicines that contain “ergot alkaloids” such as ergotamine or dihydroergotamine used to

treat migraines. Posaconazole Accord can increase the amount of these medicines in the blood

which may lead to a severe decrease in blood flow to your fingers or toes and could cause

damage to them.

a “statin” such as simvastatin, atorvastatin or lovastatin used to treat high cholesterol.

Do not take Posaconazole Accord if any of the above apply to you. If you are not sure, talk to your

doctor or pharmacist before taking this medicine.

Other medicines

Look at the list of medicines given above that must not be taken while you are taking Posaconazole

Accord. In addition to the medicines named above there are other medicines that carry a risk of rhythm

problems that may be greater when they are taken with Posaconazole Accord. Please make sure you

tell your doctor about all the medicines you are taking (prescribed or non-prescribed).

Certain medicines may increase the risk of side effects of Posaconazole Accord by increasing the

amount of Posaconazole Accord in the blood.

The following medicines may decrease the effectiveness of Posaconazole Accord by decreasing the

amount of Posaconazole Accord in the blood:

rifabutin and rifampicin (used to treat certain infections). If you are already taking rifabutin, you

will need a blood test and you will need to look out for some possible side effects of rifabutin.

some medicines used to treat or prevent fits including; phenytoin, carbamazepine, phenobarbital

or primidone).

efavirenz and fosamprenavir used to treat HIV infection.

Posaconazole Accord may possibly increase the risk of side effects of some other medicines by

increasing the amount of these medicines in the blood. These medicines include:

vincristine, vinblastine and other “vinca alkaloids” (used to treat cancer)

ciclosporin (used during or after transplant surgery)

tacrolimus and sirolimus (used during or after transplant surgery)

rifabutin (used to treat certain infections)

medicines used to treat HIV called protease inhibitors (including lopinavir and atazanavir,

which are given with ritonavir)

midazolam, triazolam, alprazolam or other “benzodiazepines” (used as sedatives or muscle

relaxants)

diltiazem, verapamil, nifedipine, nisoldipine or other “calcium channel blockers” (used to treat

high blood pressure)

digoxin (used to treat heart failure)

Glipizide or other “sulfonylureas” (used to treat high blood sugar).

If any of the above apply to you (or you are not sure), talk to your doctor or pharmacist before taking

Posaconazole Accord.

Pregnancy and breast-feeding

Tell your doctor if you are or think you are pregnant before you start to take Posaconazole Accord.

Do not take Posaconazole Accord if you are pregnant unless you are told to by your doctor.

If you are a woman who could become pregnant you should use effective contraception while you are

taking this medicine. If you become pregnant while you are taking Posaconazole Accord, contact your

doctor straight away.

Do not breast-feed while taking Posaconazole Accord. This is because small amounts may pass into

breast milk.

Driving and using machines

You may feel dizzy, sleepy, or have blurred vision while taking Posaconazole Accord, which may

affect your ability to drive or use tools or machines. If this happens, do not drive or use any tools or

machines and contact your doctor.

Posaconazole Accord contain sodium

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-

free’.

3.

How to take Posaconazole Accord

Do not switch between taking Posaconazole Accord tablets and posaconazole oral suspension without

talking to your doctor or pharmacist because it may result in a lack of efficacy or an increased risk of

adverse reactions.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor

or pharmacist if you are not sure.

How much to take

The usual dose is 300 mg (three 100 mg tablets) twice a day on the first day, then 300 mg (three

100 mg tablets) once a day, thereafter.

The length of treatment may depend on the type of infection that you have and may be individually

adapted for you by your doctor. Do not adapt your dose yourself before consulting your doctor or

change your treatment regimen.

Taking this medicine

Swallow the tablet whole with some water.

Do not crush, chew, break or dissolve the tablet.

Tablets may be taken with or without food.

If you take more Posaconazole Accord than you should

If you think that you may have taken too much Posaconazole Accord, talk to a doctor or go to the

hospital straight away.

If you forget to take Posaconazole Accord

If you forget a dose, take it as soon as you remember it.

However, if it is almost time for your next dose, skip the missed dose and go back to your

regular schedule.

Do not take a double dose to make up for a forgotten dose.

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.

Serious side effects

Tell your doctor or pharmacist or nurse straight away if you notice any of the following serious

side effects – you may need urgent medical treatment:

nausea or vomit (feeling or being sick), diarrhoea

signs of liver problems - these include yellowing of your skin or whites of the eyes, unusually

dark urine or pale faeces, feeling sick for no reason, stomach problems, loss of appetite or

unusual tiredness or weakness, an increase in liver enzymes shown up in blood tests

allergic reaction.

Other side effects

Tell your doctor, pharmacist or nurse if you notice any of the following side effects:

Common: the following may affect up to 1 in 10 people

a change in the salt level in your blood shown in blood tests - signs include feeling confused or

weak

abnormal skin sensations, such as numbness, tingling, itching, creeping, pricking or burning

headache

low potassium levels – shown up in blood tests

low magnesium levels – shown up in blood tests

high blood pressure

loss of appetite, stomach pain or upset stomach, passing wind, dry mouth, changes in your taste

heartburn (a burning sensation in the chest rising up to the throat)

low levels of “neutrophils” a type of white blood cell (neutropenia) –this can make you more

likely to get infections and be shown up in blood tests

fever

feeling weak, dizzy, tired or sleepy

rash

itching

constipation

rectal discomfort

Uncommon: the following may affect up to 1 in 100 people

anaemia - signs include headaches, feeling tired or dizzy, being short of breath or looking pale

and a low level of haemoglobin shown up in blood tests

low level of platelets (thrombocytopenia) shown in blood tests – this may lead to bleeding

low level of “leukocytes” a type of white blood cell (leukopenia) shown in blood tests – this can

make you more likely to get infections

high level of “eosinophils” a type of white blood cell (eosinophilia) – this can happen if you

have inflammation

inflammation of the blood vessels

heart rhythm problems

fits (convulsions)

nerve damage (neuropathy)

abnormal heart rhythm – shown up on a heart trace (ECG), palpitations, slow or fast heartbeat,

high or low blood pressure

low blood pressure

inflammation of the pancreas (pancreatitis) – this may cause severe stomach pain

oxygen supply to the spleen is interrupted (splenic infarction) - this may cause severe stomach

pain

severe kidney problems – signs include passing more or less urine, that is a different colour than

usual

high blood levels of creatinine – shown in blood tests

cough, hiccups

nose bleeds

severe sharp chest pain when breathing in (pleurritic pain)

swelling of lymph glands (lymphadenopathy)

reduced feeling of sensitivity especially on the skin

tremor

high or low blood sugar levels

blurred vision, sensitivity to light

hair loss (alopecia)

mouth ulcers

shivering, feeling generally unwell

pain, back or neck pain, pain in arms or legs

water retention (oedema)

menstrual problems (abnormal vaginal bleeding)

inability to sleep (insomnia)

being completely or partially unable to talk

swelling of the mouth

abnormal dreams, or difficulty sleeping

problems with co-ordination or balance

mucosal inflammation

stuffy nose

difficulty breathing

chest discomfort

feeling bloated

mild to severe nausea, vomiting, cramps and diarrhoea, usually caused by a virus, stomach pain

belching

feeling jittery

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

pneumonia – signs include feeling short of breath and producing discoloured phlegm

high blood pressure in the blood vessels in the lungs (pulmonary hypertension) this can cause

serious damage to your lungs and heart

blood problems such as unusual blood clotting or prolonged bleeding

severe allergic reactions, including widespread blistering rash and skin peeling

mental problems such as hearing voices or seeing things that are not there

fainting

having problems thinking or talking, having jerking movements, especially in your hands that

you cannot control

stroke – signs include pain, weakness, numbness, or tingling in the limbs

having a blind or dark spot in your field of vision

heart failure or heart attack which could lead to the heart stopping beating and death, heart

rhythm problems, with sudden death

blood clots in your legs (deep vein thrombosis) – signs include intense pain or swelling of the

legs

blood clots in your lungs (pulmonary embolism) – signs include feeling short of breath or pain

while breathing

bleeding into your stomach or gut – signs include vomiting blood or passing blood in your stool

a blockage in your gut (intestinal obstruction) especially in the “ileum”. The blockage will

prevent the contents of your intestine from passing through to the lower bowel signs include

feeling bloated, vomiting, severe constipation, loss of appetite, and cramps

“haemolytic uraemic syndrome” when red blood cells breakup (hemolysis) which may happen

with or without kidney failure

“pancytopenia” low level of all blood cells (red and white blood cells and platelets) shown in

blood tests

large purple discolourations on the skin (thrombotic thrombocytopenic purpura)

swelling of the face or tongue

depression

double vision

breast pain

adrenal glands not working properly – this may cause weakness, tiredness, loss of appetite, skin

discolouration

pituitary gland not working properly – this may cause low blood levels of some hormones that

affect the function of the male or female sex organs

hearing problems

Some patients have also reported feeling confused after taking Posaconazole Accord, the frequency of

this is not known.

Tell your doctor, pharmacist or nurse if you notice any of the side effects listed above.

Reporting of side effects

If you get any side effects, talk to your doctor or 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

system listed in Appendix V By reporting side effects you can help provide more information on the

safety of this medicine.

5.

How to store Posaconazole 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 blister or carton after EXP. That

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 Posaconazole Accord contains

The active substance is posaconazole. Each tablet contains 100 mg of posaconazole.

The other ingredients are: Methacrylic acid-ethyl acrylate copolymer (1:1), triethyl citrate (E1505),

xylitol (E967), hydroxypropyl cellulose (E463), propyl gallate (E310), cellulose microcrystalline

(E460), silica colloidal anhydrous, croscarmellose sodium, sodium stearyl fumarate, polyvinyl alcohol,

titanium dioxide (E171), macrogol, talc (E553b), iron oxide yellow (E172).

What Posaconazole Accord looks like and contents of the pack

Posaconazole Accord gastro-resistant tablets are yellow coated, capsule shaped tablet of approximate

17.5 mm length and 6.7 mm width, debossed with “100P” on one side and plain on the other side,

packaged in a blister or in perforated unit dose blister in cartons of 24 or 96 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6

planta, Barcelona,

08039 Barcelona, Spain

Manufacturer

Accord Healthcare Limited

Sage House, 319 Pinner Road

North Harrow, Middlesex, HA1 4HF

United Kingdom

Delorbis Pharmaceuticals Limited

Ergates Industrial Area

Athinon 17 V, Ergates

Nicosia, 2643

Cyprus

Laboratori Fundacio Dau

C/ C, 12-14 Pol. Ind. Zona Franca,

Barcelona, 08040, Spain

Wessling Hungary Kft.

Anonymus ut 6.

Budapest, 1045,

Hungary

Pharmadox Healthcare Ltd.

KW20A Kordin Industrial Park

Paola, PLA 3000

Malta

This leaflet was last revised in

MM/YYYY

Other sources of information

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

http://www.ema.europa.eu

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Posaconazole Accord 100 mg gastro-resistant tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each gastro-resistant tablet contains 100 mg of posaconazole.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Gastro-resistant tablet

Yellow coated, capsule shaped tablet of approximate 17.5 mm length and 6.7 mm width, debossed

with “100P” on one side and plain on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Posaconazole Accord is indicated for use in the treatment of the following fungal infections in adults

(see section 5.1):

Invasive aspergillosis in patients with disease that is refractory to amphotericin B or

itraconazole or in patients who are intolerant of these medicinal products;

Fusariosis in patients with disease that is refractory to amphotericin B or in patients who are

intolerant of amphotericin B;

Chromoblastomycosis and mycetoma in patients with disease that is refractory to itraconazole

or in patients who are intolerant of itraconazole;

Coccidioidomycosis in patients with disease that is refractory to amphotericin B, itraconazole or

fluconazole or in patients who are intolerant of these medicinal products.

Refractoriness is defined as progression of infection or failure to improve after a minimum of 7 days

of prior therapeutic doses of effective antifungal therapy.

Posaconazole Accord is also indicated for prophylaxis of invasive fungal infections in the following

patients:

Patients receiving remission-induction chemotherapy for acute myelogenous leukemia (AML)

or myelodysplastic syndromes (MDS) expected to result in prolonged neutropenia and who are

at high risk of developing invasive fungal infections;

Hematopoietic stem cell transplant (HSCT) recipients who are undergoing high-dose

immunosuppressive therapy for graft versus host disease and who are at high risk of developing

invasive fungal infections.

4.2

Posology and method of administration

Non-Interchangeability between Posaconazole Accord tablets and posaconazole oral suspension

The tablet and oral suspension are not to be used interchangeably due to the differences between these

two formulations in frequency of dosing, administration with food and plasma drug concentration

achieved. Therefore, follow the specific dosage recommendations for each formulation.

Treatment should be initiated by a physician experienced in the management of fungal infections or in

the supportive care in the high risk patients for which posaconazole is indicated as prophylaxis.

Posology

Posaconazole is also available as 40 mg/mL oral suspension and 300 mg concentrate for solution for

infusion. Posaconazole tablets are the preferred formulation to optimize plasma concentrations and

generally provide higher plasma drug exposures than posaconazole oral suspension.

Recommended dose is shown in Table 1.

Table 1.

Recommended dose according to indication.

Indication

Dose and duration of therapy

(See section 5.2)

Refractory invasive fungal infections

(IFI)/patients with IFI intolerant to 1

line therapy

Loading dose of 300 mg (three 100 mg tablets) twice a day

on the first day, then 300 mg (three 100 mg tablets) once a

day thereafter. Each dose may be taken without regard to

food intake. Duration of therapy should be based on the

severity of the underlying disease, recovery from

immunosuppression, and clinical response.

Prophylaxis of invasive fungal

infections

Loading dose of 300 mg (three 100 mg tablets) twice a day

on the first day, then 300 mg (three 100 mg tablets) once a

day thereafter. Each dose may be taken without regard to

food intake. Duration of therapy is based on recovery from

neutropenia or immunosuppression. For patients with acute

myelogenous leukemia or myelodysplastic syndromes,

prophylaxis with Posaconazole Accord should start several

days before the anticipated onset of neutropenia and continue

for 7 days after the neutrophil count rises above 500 cells per

Special populations

Renal impairment

An effect of renal impairment on the pharmacokinetics of posaconazole is not expected and no dose

adjustment is recommended (see section 5.2).

Hepatic impairment

Limited data on the effect of hepatic impairment (including Child-Pugh C classification of chronic

liver disease) on the pharmacokinetics of posaconazole demonstrate an increase in plasma exposure

compared to subjects with normal hepatic function, but do not suggest that dose adjustment is

necessary (see sections 4.4 and 5.2). It is recommended to exercise caution due to the potential for

higher plasma exposure.

Paediatric population

The safety and efficacy of posaconazole in children aged below 18 years have not been established.

Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology

can be made.

No data are available for the tablet formulation.

Method of administration

For oral use.

Posaconazole Accord may be taken with or without food (see section 5.2). The tablets should be

swallowed whole with water and should not be crushed, chewed, or broken.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Co-administration with ergot alkaloids (see section 4.5).

Co-administration with the CYP3A4 substrates terfenadine, astemizole, cisapride, pimozide,

halofantrine or quinidine since this may result in increased plasma concentrations of these medicinal

products, leading to QTc prolongation and rare occurrences of torsades de pointes (see sections 4.4

and 4.5).

Co-administration with the HMG-CoA reductase inhibitors simvastatin, lovastatin and atorvastatin

(see section 4.5).

4.4

Special warnings and precautions for use

Hypersensitivity

There is no information regarding cross-sensitivity between posaconazole and other azole antifungal

agents. Caution should be used when prescribing Posaconazole Accord to patients with

hypersensitivity to other azoles.

Hepatic toxicity

Hepatic reactions (e.g. mild to moderate elevations in ALT, AST, alkaline phosphatase, total bilirubin

and/or clinical hepatitis) have been reported during treatment with posaconazole. Elevated liver

function tests were generally reversible on discontinuation of therapy and in some instances these tests

normalised without interruption of therapy. Rarely, more severe hepatic reactions with fatal outcomes

have been reported.

Posaconazole should be used with caution in patients with hepatic impairment due to limited clinical

experience and the possibility that posaconazole plasma levels may be higher in these patients (see

sections 4.2 and 5.2).

Monitoring of hepatic function

Liver function tests should be evaluated at the start of and during the course of posaconazole therapy.

Patients who develop abnormal liver function tests during Posaconazole Accord therapy must be

routinely monitored for the development of more severe hepatic injury. Patient management should

include laboratory evaluation of hepatic function (particularly liver function tests and bilirubin).

Discontinuation of Posaconazole Accord should be considered if clinical signs and symptoms are

consistent with development of liver disease.

QTc prolongation

Some azoles have been associated with prolongation of the QTc interval. Posaconazole Accord must

not be administered with medicinal products that are substrates for CYP3A4 and are known to prolong

the QTc interval (see sections 4.3 and 4.5). Posaconazole Accord should be administered with caution

to patients with pro-arrhythmic conditions such as:

Congenital or acquired QTc prolongation

Cardiomyopathy, especially in the presence of cardiac failure

Sinus bradycardia

Existing symptomatic arrhythmias

Concomitant use with medicinal products known to prolong the QTc interval (other than those

mentioned in section 4.3).

Electrolyte disturbances, especially those involving potassium, magnesium or calcium levels, should

be monitored and corrected as necessary before and during posaconazole therapy.

Drug interactions

Posaconazole is an inhibitor of CYP3A4 and should only be used under specific circumstances during

treatment with other medicinal products that are metabolised by CYP3A4 (see section 4.5).

Midazolam and other benzodiazepines

Due to the risk of prolonged sedation and possible respiratory depression co-administration of

posaconazole with any benzodiazepines metabolised by CYP3A4 (e.g. midazolam, triazolam,

alprazolam) should only be considered if clearly necessary. Dose adjustment of benzodiazepines

metabolised by CYP3A4 should be considered (see section 4.5).

Vincristine toxicity

Concomitant administration of azole antifungals, including posaconazole, with vincristine has been

associated with neurotoxicity and other serious adverse reactions, including seizures, peripheral

neuropathy, syndrome of inappropriate antidiuretic hormone secretion, and paralytic ileus. Reserve

azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including

vincristine, who have no alternative antifungal treatment options (see section 4.5).

Rifamycin antibacterials (rifampicin, rifabutin), certain anticonvulsants (phenytoin, carbamazepine,

phenobarbital, primidone), and efavirenz

Posaconazole concentrations may be significantly lowered in combination; therefore, concomitant use

with posaconazole should be avoided unless the benefit to the patient outweighs the risk (see

section 4.5).

Plasma exposure

Posaconazole plasma concentrations following administration of posaconazole tablets are generally

higher than those obtained with posaconazole oral suspension. Posaconazole plasma concentrations

following administration of posaconazole tablets may increase over time in some patients (see

section 5.2). Safety data at higher exposure levels achieved with posaconazole tablets are at present

limited.

Gastrointestinal dysfunction

There are limited pharmacokinetic data in patients with severe gastrointestinal dysfunction (such as

severe diarrhoea). Patients who have severe diarrhoea or vomiting should be monitored closely for

breakthrough fungal infections.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially

‘sodium-free’.

4.5

Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products on posaconazole

Posaconazole is metabolised via UDP glucuronidation (phase 2 enzymes) and is a substrate for p-

glycoprotein (P-gp) efflux in vitro. Therefore, inhibitors (e.g. verapamil, ciclosporin, quinidine,

clarithromycin, erythromycin, etc.) or inducers (e.g. rifampicin, rifabutin, certain anticonvulsants, etc.)

of these clearance pathways may increase or decrease posaconazole plasma concentrations,

respectively.

Rifabutin

Rifabutin (300 mg once a day) decreased the C

(maximum plasma concentration) and AUC (area

under the plasma concentration time curve) of posaconazole to 57% and 51%, respectively.

Concomitant use of posaconazole and rifabutin and similar inducers (e.g. rifampicin) should be

avoided unless the benefit to the patient outweighs the risk. See also below regarding the effect of

posaconazole on rifabutin plasma levels.

Efavirenz

Efavirenz (400 mg once a day) decreased the Cmax and AUC of posaconazole by 45% and 50%,

respectively. Concomitant use of posaconazole and efavirenz should be avoided unless the benefit to

the patient outweighs the risk.

Fosamprenavir

Combining fosamprenavir with posaconazole may lead to decreased posaconazole plasma

concentrations. If concomitant administration is required, close monitoring for breakthrough fungal

infections is recommended. Repeat dose administration of fosamprenavir (700 mg twice daily x

10 days) decreased the C

and AUC of posaconazole oral suspension (200 mg once daily on the

day, 200 mg twice daily on the 2

day, then 400 mg twice daily x 8 Days) by 21% and 23%,

respectively. The effect of posaconazole on fosamprenavir levels when fosamprenavir is given with

ritonavir is unknown.

Phenytoin

Phenytoin (200 mg once a day) decreased the C

and AUC of posaconazole by 41% and 50%,

respectively. Concomitant use of posaconazole and phenytoin and similar inducers (e.g.

carbamazepine, phenobarbital, primidone) should be avoided unless the benefit to the patient

outweighs the risk.

H

2

receptor antagonists and proton pump inhibitors

No clinically relevant effects were observed when posaconazole tablets are concomitantly used with

antacids, H

-receptor antagonists and proton pump inhibitors. No dosage adjustment of posaconazole

tablets is required when posaconazole tablets are concomitantly used with antacids, H

-receptor

antagonists and proton pump inhibitors.

Effects of posaconazole on other medicinal products

Posaconazole is a potent inhibitor of CYP3A4. Co-administration of posaconazole with CYP3A4

substrates may result in large increases in exposure to CYP3A4 substrates as exemplified by the

effects on tacrolimus, sirolimus, atazanavir and midazolam below. Caution is advised during co-

administration of posaconazole with CYP3A4 substrates administered intravenously and the dose of

the CYP3A4 substrate may need to be reduced. If posaconazole is used concomitantly with CYP3A4

substrates that are administered orally, and for which an increase in plasma concentrations may be

associated with unacceptable adverse reactions, plasma concentrations of the CYP3A4 substrate

and/or adverse reactions should be closely monitored and the dose adjusted as needed. Several of the

interaction studies were conducted in healthy volunteers in whom a higher exposure to posaconazole

occurs compared to patients administered the same dose. The effect of posaconazole on CYP3A4

substrates in patients might be somewhat lower than that observed in healthy volunteers, and is

expected to be variable between patients due to the variable posaconazole exposure in patients. The

effect of co-administration with posaconazole on plasma levels of CYP3A4 substrates may also be

variable within a patient.

Terfenadine, astemizole, cisapride, pimozide, halofantrine and quinidine (CYP3A4 substrates)

Co-administration of posaconazole and terfenadine, astemizole, cisapride, pimozide, halofantrine or

quinidine is contraindicated. Co-administration may result in increased plasma concentrations of these

medicinal products, leading to QTc prolongation and rare occurrences of torsades de pointes (see

section 4.3).

Ergot alkaloids

Posaconazole may increase the plasma concentration of ergot alkaloids (ergotamine and

dihydroergotamine), which may lead to ergotism. Co-administration of posaconazole and ergot

alkaloids is contraindicated (see section 4.3).

HMG-CoA reductase inhibitors metabolised through CYP3A4 (e.g. simvastatin, lovastatin, and

atorvastatin)

Posaconazole may substantially increase plasma levels of HMG-CoA reductase inhibitors that are

metabolised by CYP3A4. Treatment with these HMG-CoA reductase inhibitors should be

discontinued during treatment with posaconazole as increased levels have been associated with

rhabdomyolysis (see section 4.3).

Vinca alkaloids

Most of the vinca alkaloids (e.g., vincristine and vinblastine) are substrates of CYP3A4. Concomitant

administration of azole antifungals, including posaconazole, with vincristine has been associated with

serious adverse reactions (see section 4.4). Posaconazole may increase the plasma concentrations of

vinca alkaloids which may lead to neurotoxicity and other serious adverse reactions. Therefore,

reserve azole antifungals, including posaconazole, for patients receiving a vinca alkaloid, including

vincristine, who have no alternative antifungal treatment options.

Rifabutin

Posaconazole increased the C

and AUC of rifabutin by 31% and 72%, respectively. Concomitant

use of posaconazole and rifabutin should be avoided unless the benefit to the patient outweighs the

risk (see also above regarding the effect of rifabutin on plasma levels of posaconazole). If these

medicinal products are co-administered, careful monitoring of full blood counts and adverse reactions

related to increased rifabutin levels (e.g. uveitis) is recommended.

Sirolimus

Repeat dose administration of posaconazole oral suspension (400 mg twice daily for 16 days)

increased the C

and AUC of sirolimus (2 mg single dose) an average of 6.7-fold and 8.9-fold (range

3.1 to 17.5-fold), respectively, in healthy subjects. The effect of posaconazole on sirolimus in patients

is unknown, but is expected to be variable due to the variable posaconazole exposure in patients.

Co-administration of posaconazole with sirolimus is not recommended and should be avoided

whenever possible. If it is considered that co-administration is unavoidable, then it is recommended

that the dose of sirolimus should be greatly reduced at the time of initiation of posaconazole therapy

and that there should be very frequent monitoring of trough concentrations of sirolimus in whole

blood. Sirolimus concentrations should be measured upon initiation, during co-administration, and at

discontinuation of posaconazole treatment, with sirolimus doses adjusted accordingly. It should be

noted that the relationship between sirolimus trough concentration and AUC is changed during

co-administration with posaconazole. As a result, sirolimus trough concentrations that fall within the

usual therapeutic range may result in sub-therapeutic levels. Therefore, trough concentrations that fall

in the upper part of the usual therapeutic range should be targeted and careful attention should be paid

to clinical signs and symptoms, laboratory parameters and tissue biopsies.

Ciclosporin

In heart transplant patients on stable doses of ciclosporin, posaconazole oral suspension 200 mg once

daily increased ciclosporin concentrations requiring dose reductions. Cases of elevated ciclosporin

levels resulting in serious adverse reactions, including nephrotoxicity and one fatal case of

leukoencephalopathy, were reported in clinical efficacy studies. When initiating treatment with

posaconazole in patients already receiving ciclosporin, the dose of ciclosporin should be reduced (e.g.

to about three quarters of the current dose). Thereafter blood levels of ciclosporin should be monitored

carefully during co-administration, and upon discontinuation of posaconazole treatment, and the dose

of ciclosporin should be adjusted as necessary.

Tacrolimus

Posaconazole increased C

and AUC of tacrolimus (0.05 mg/kg body weight single dose) by 121%

and 358%, respectively. Clinically significant interactions resulting in hospitalisation and/or

posaconazole discontinuation were reported in clinical efficacy studies. When initiating posaconazole

treatment in patients already receiving tacrolimus, the dose of tacrolimus should be reduced (e.g. to

about one third of the current dose). Thereafter blood levels of tacrolimus should be monitored

carefully during co-administration, and upon discontinuation of posaconazole, and the dose of

tacrolimus should be adjusted as necessary.

HIV Protease inhibitors

As HIV protease inhibitors are CYP3A4 substrates, it is expected that posaconazole will increase

plasma levels of these antiretroviral agents. Following co-administration of posaconazole oral

suspension (400 mg twice daily) with atazanavir (300 mg once daily) for 7 days in healthy subjects

and AUC of atazanavir increased by an average of 2.6-fold and 3.7-fold (range 1.2 to 26-fold

respectively. Following co-administration of posaconazole oral suspension (400 mg twice daily) with

atazanavir and ritonavir (300/100 mg once daily) for 7 days in healthy subjects C

and AUC of

atazanavir increased by an average of 1.5-fold and 2.5-fold (range 0.9 to 4.1-fold), respectively. The

addition of posaconazole to therapy with atazanavir or with atazanavir plus ritonavir was associated

with increases in plasma bilirubin levels. Frequent monitoring for adverse reactions and toxicity

related to antiretroviral agents that are substrates of CYP3A4 is recommended during co-

administration with posaconazole.

Midazolam and other benzodiazepines metabolised by CYP3A4

In a study in healthy volunteers posaconazole oral suspension (200 mg once daily for 10 days)

increased the exposure (AUC) of intravenous midazolam (0.05 mg/kg) by 83%. In another study in

healthy volunteers, repeat dose administration of posaconazole oral suspension (200 mg twice daily

for 7 days) increased the C

and AUC of intravenous midazolam (0.4 mg single dose) by an average

of 1.3- and 4.6-fold (range 1.7 to 6.4-fold), respectively; Posaconazole oral suspension 400 mg twice

daily for 7 days increased the intravenous midazolam C

and AUC by 1.6 and 6.2-fold (range 1.6 to

7.6-fold), respectively. Both doses of posaconazole increased C

and AUC of oral midazolam (2 mg

single oral dose) by 2.2 and 4.5-fold, respectively. In addition, posaconazole oral suspension (200 mg

or 400 mg) prolonged the mean terminal half-life of midazolam from approximately 3-4 hours to

8-10 hours during co-administration.

Due to the risk of prolonged sedation it is recommended that dose adjustments should be considered

when posaconazole is administered concomitantly with any benzodiazepine that is metabolised by

CYP3A4 (e.g. midazolam, triazolam, alprazolam) (see section 4.4).

Calcium channel blockers metabolised through CYP3A4 (e.g. diltiazem, verapamil, nifedipine,

nisoldipine)

Frequent monitoring for adverse reactions and toxicity related to calcium channel blockers is

recommended during co-administration with posaconazole. Dose adjustment of calcium channel

blockers may be required.

Digoxin

Administration of other azoles has been associated with increases in digoxin levels. Therefore,

posaconazole may increase plasma concentration of digoxin and digoxin levels need to be monitored

when initiating or discontinuing posaconazole treatment.

Sulfonylureas

Glucose concentrations decreased in some healthy volunteers when glipizide was co-administered

with posaconazole. Monitoring of glucose concentrations is recommended in diabetic patients.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Pregnancy

There is insufficient information on the use of posaconazole in pregnant women. Studies in animals

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

Women of childbearing potential have to use effective contraception during treatment. Posaconazole

must not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk

to the foetus.

Breast-feeding

Posaconazole is excreted into the milk of lactating rats (see section 5.3). The excretion of

posaconazole in human breast milk has not been investigated. Breast-feeding must be stopped on

initiation of treatment with posaconazole.

Fertility

Posaconazole had no effect on fertility of male rats at doses up to 180 mg/kg (3.4 times the 300 mg

tablet based on steady-state plasma concentrations in patients) or female rats at a dose up to 45 mg/kg

(2.6 times the 300 mg tablet based on steady-state plasma concentrations in patients). There is no

clinical experience assessing the impact of posaconazole on fertility in humans.

4.7

Effects on ability to drive and use machines

Since certain adverse reactions (e.g. dizziness, somnolence, etc.) have been reported with

posaconazole use, which potentially may affect driving/operating machinery, caution needs to be used.

4.8

Undesirable effects

Safety data mainly derive from studies with the oral suspension.

The tablet formulation was investigated in AML and MDS patients and those after HSCT with or at

risk for Graft versus Host Disease (GvHD) only. Maximum duration of exposure to the tablet

formulation was shorter than with the oral suspension. Plasma exposure resulting from the tablet

formulation was higher than observed with the oral suspension. A higher incidence of adverse

reactions cannot be ruled out.

Summary of the safety profile

Posaconazole tablets

The safety of posaconazole tablets has been assessed in 230 patients enrolled in the pivotal clinical

study. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of posaconazole

tablets when given as antifungal prophylaxis. Patients were immunocompromised with underlying

conditions including haematological malignancy, neutropenia post-chemotherapy, GVHD, and post

HSCT. Posaconazole therapy was given for a median duration of 28 days. Twenty patients received

200 mg daily dose and 210 patients received 300 mg daily dose (following twice daily dosing on

Day 1 in each cohort).

Posaconazole tablet and oral suspension safety

The safety of posaconazole oral suspension has been assessed in > 2,400 patients and healthy

volunteers enrolled in clinical trials and from post-marketing experience. The most frequently reported

serious related adverse reactions included nausea, vomiting, diarrhoea, pyrexia, and increased

bilirubin.

The safety of posaconazole tablet has been assessed in 336 patients and healthy volunteers enrolled in

clinical trials. The safety profile of tablets was similar to that of the oral suspension.

Tabulated list of adverse reactions

Within the organ system classes, adverse reactions are listed under headings of frequency using the

following categories: 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.

Table 2.

Adverse reactions by body system and frequency*

Blood and lymphatic system disorders

Common:

Neutropenia

Uncommon:

thrombocytopenia, leukopenia, anaemia, eosinophilia,

lymphadenopathy, splenic infarction

Rare:

haemolytic uraemic syndrome, thrombotic

thrombocytopenic purpura, pancytopenia, coagulopathy,

haemorrhage

Immune system disorders

Uncommon:

allergic reaction

Rare:

hypersensitivity reaction

Endocrine disorders

Rare:

adrenal insufficiency, blood gonadotropin decreased

Metabolism and nutrition disorders

Common:

electrolyte imbalance, anorexia, decreased appetite,

hypokalaemia, hypomagnesaemia

Uncommon:

hyperglycaemia, hypoglycaemia

Psychiatric disorders

Uncommon:

abnormal dreams, confusional state, sleep disorder

Rare:

psychotic disorder, depression

Nervous system disorders

Common:

paresthesia, dizziness, somnolence, headache, dysgeusia

Uncommon:

convulsions, neuropathy, hypoaesthesia, tremor, aphasia,

insomnia

Rare:

cerebrovascular accident, encephalopathy, peripheral

neuropathy, syncope

Eye disorders

Uncommon:

blurred vision, photophobia, visual acuity reduced

Rare:

diplopia, scotoma

Ear and labyrinth disorder

Rare:

hearing impairment

Cardiac disorders

Uncommon:

long QT syndrome

, electrocardiogram abnormal

palpitations, bradycardia, supraventricular extrasystoles,

tachycardia

Rare:

torsade de pointes, sudden death, ventricular tachycardia,

cardio-respiratory arrest, cardiac failure, myocardial

infarction

Vascular disorders

Common:

hypertension

Uncommon:

hypotension, vasculitis

Rare:

pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and mediastinal disorders

Uncommon:

cough, epistaxis, hiccups, nasal congestion, pleuritic pain,

tachypnoea

Rare:

pulmonary hypertension, interstitial pneumonia,

pneumonitis

Gastrointestinal disorders

Very Common:

nausea

Common:

vomiting, abdominal pain, diarrhoea, dyspepsia, dry mouth,

flatulence, constipation, anorectal discomfort

Uncommon:

pancreatitis, abdominal distension, enteritis, epigastric

discomfort, eructation, gastrooesophageal reflux disease,

oedema mouth

Rare:

gastrointestinal haemorrhage, ileus

Hepatobiliary disorders

Common:

liver function tests raised (ALT increased, AST increased,

bilirubin increased, alkaline phosphatase increased, GGT

increased)

Uncommon:

hepatocellular damage, hepatitis, jaundice, hepatomegaly,

cholestasis, hepatic toxicity, hepatic function abnormal

Rare:

hepatic failure, hepatitis cholestatic, hepatosplenomegaly,

liver tenderness, asterixis

Skin and subcutaneous tissue disorders

Common:

rash, pruritis

Uncommon:

mouth ulceration, alopecia, dermatitis, erythema, petechiae

Rare:

Stevens Johnson syndrome, vesicular rash

Musculoskeletal and connective tissue disorders

Uncommon:

back pain, neck pain, musculoskeletal pain, pain in

extremity

Renal and urinary disorders

Uncommon:

acute renal failure, renal failure, blood creatinine increased

Rare:

renal tubular acidosis, interstitial nephritis

Reproductive system and breast disorders

Uncommon:

menstrual disorder

Rare:

breast pain

General disorders and administration site conditions

Common:

pyrexia (fever), asthenia, fatigue

Uncommon:

oedema, pain, chills, malaise, chest discomfort, drug

intolerance, feeling jittery, mucosal inflammation

Rare:

tongue oedema, face oedema

Investigations

Uncommon:

altered medicine levels, blood phosphorus decreased, chest

x-ray abnormal

Based on adverse reactions observed with the oral suspension, gastro-resistant tablets, and

concentrate for solution for infusion.

See section 4.4.

Description of selected adverse reactions

Hepatobiliary disorders

During post-marketing surveillance of posaconazole oral suspension, severe hepatic injury with fatal

outcome has been reported (see section 4.4).

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

listed in Appendix V.

4.9

Overdose

There is no experience with overdose of posaconazole tablets.

During clinical trials, patients who received posaconazole oral suspension doses up to 1,600 mg/day

experienced no different adverse reactions from those reported with patients at the lower doses.

Accidental overdose was noted in one patient who took posaconazole oral suspension 1,200 mg twice

a day for 3 days. No adverse reactions were noted by the investigator.

Posaconazole is not removed by haemodialysis. There is no special treatment available in the case of

overdose with posaconazole. Supportive care may be considered.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Antimycotics for systemic use, triazole derivatives, ATC code: J02AC04

Mechanism of action

Posaconazole inhibits the enzyme lanosterol 14α-demethylase (CYP51), which catalyses an essential

step in ergosterol biosynthesis.

Microbiology

Posaconazole has been shown in vitro to be active against the following microorganisms:

Aspergillus

species (

Aspergillus fumigatus, A. flavus, A. terreus, A. nidulans, A. niger, A. ustus), Candida species

(Candida albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, C. dubliniensis, C. famata, C.

inconspicua, C. lipolytica, C. norvegensis, C. pseudotropicalis), Coccidioides immitis, Fonsecaea

pedrosoi, and species of Fusarium, Rhizomucor, Mucor, and Rhizopus

. The microbiological data

suggest that posaconazole is active against

Rhizomucor, Mucor,

Rhizopus;

however the clinical

data are currently too limited to assess the efficacy of posaconazole against these causative agents.

Resistance

Clinical isolates with decreased susceptibility to posaconazole have been identified. The principle

mechanism of resistance is the acquisition of substitutions in the target protein, CYP51.

Epidemiological Cut-off (ECOFF) Values for

Aspergillus spp

The ECOFF values for posaconazole, which distinguish the wild type population from isolates with

acquired resistance, have been determined by EUCAST methodology.

EUCAST ECOFF values:

-

Aspergillus flavus:

0.5 mg/L

-

Aspergillus fumigatus:

0.25 mg/L

-

Aspergillus nidulans:

0.5 mg/L

-

Aspergillus niger:

0.5 mg/L

-

Aspergillus terreus:

0.25 mg/L

There are currently insufficient data to set clinical breakpoints for Aspergillus spp. ECOFF values do

not equate to clinical breakpoints.

Breakpoints

EUCAST MIC breakpoints for posaconazole [susceptible (S); resistant (R)]:

-

Candida albicans:

S ≤0.06 mg/L, R >0.06 mg/L

-

Candida tropicalis:

S ≤0.06 mg/L, R >0.06 mg/L

-

Candida parapsilosis:

S ≤0.06 mg/L, R >0.06 mg/L

There are currently insufficient data to set clinical breakpoints for other Candida species.

Combination with other antifungal agents

The use of combination antifungal therapies should not decrease the efficacy of either posaconazole or

the other therapies; however, there is currently no clinical evidence that combination therapy will

provide an added benefit.

Clinical experience

Summary of posaconazole tablet bridging study

Study 5615 was a non-comparative multi-center study performed to evaluate the pharmacokinetic

properties, safety, and tolerability of posaconazole tablet. Study 5615 was conducted in a similar

patient population to that previously studied in the pivotal posaconazole oral suspension clinical

program. The pharmacokinetics and safety data from Study 5615 were bridged to the existing data

(including efficacy data) with the oral suspension.

The subject population included: 1) patients with AML or MDS who had recently received

chemotherapy and had developed or were anticipated to develop significant neutropenia, or 2) patients

who had undergone a HSCT and were receiving immunosuppressive therapy for prevention or

treatment of GVHD. Two different dosing groups were evaluated: 200 mg twice daily on Day 1,

followed by 200 mg once daily thereafter (Part IA) and 300 mg twice daily on Day 1, followed by

300 mg once daily thereafter (Part 1B and Part 2).

Serial PK samples were collected on Day 1 and at steady-state on Day 8 for all Part 1 subjects and a

subset of Part 2 subjects. Moreover, sparse PK samples were collected at several days during steady

state before the next dose (C

) for a larger subject population. Based on average C

concentrations,

a predicted average concentration (Cav) could be calculated for 186 subjects dosed with 300 mg. PK

analysis in patients of Cav found that 81% of the subjects treated with the 300 mg once daily dose

attained steady state predicted Cav between 500-2,500 ng/mL. One subject (<1%) had a predicted Cav

below 500 ng/mL and 19% of the subjects had a predicted Cav above 2,500 ng/mL. Subjects achieved

a mean predicted Cav at steady state of 1,970 ng/mL.

In Table 3 a comparison is shown of exposure (Cav) after administration of posaconazole tablet and

posaconazole oral suspension at therapeutic doses in patients depicted as quartile analysis. Exposures

after tablet administration are generally higher than, but overlapping with, exposures after

administration of posaconazole oral suspension.

Table 3.

Cav quartile analyses of pivotal patient studies with posaconazole tablet and oral suspension

Posaconazole

tablet

Posaconazole oral suspension

Prophylaxis in

AML and HSCT

Study 5615

Prophylaxis

in

GVHD

Study 316

Prophylaxis in

Neutropenia

Study 1899

Treatment -

Invasive

Aspergillosis

Study 0041

300 mg once

daily (Day 1 300

mg twice daily)*

200 mg three

times daily

200 mg three

times daily

200 mg four times

daily

(hospitalized) then

400 mg twice daily

Quartile

pCav Range

(ng/mL)

Cav Range

(ng/mL)

Cav Range

(ng/mL)

Cav Range

(ng/mL)

Q1

442 – 1,223

22-557

90-322

55-277

Q2

1,240 – 1,710

557-915

322-490

290-544

Q3

1,719 – 2,291

915-1563

490-734

550-861

Q4

2,304 – 9,523

1563-3650

734-2200

877-2010

pCav: predicted Cav

Cav = the average concentration when measured at steady state

*20 patients received 200 mg once daily (Day 1 200 mg twice daily)

Summary of posaconazole oral suspension studies

Invasive aspergillosis

Oral posaconazole suspension 800 mg/day in divided doses was evaluated for the treatment of

invasive aspergillosis in patients with disease refractory to amphotericin B (including liposomal

formulations) or itraconazole or in patients who were intolerant of these medicinal products in a non-

comparative salvage therapy trial (Study 0041). Clinical outcomes were compared with those in an

external control group derived from a retrospective review of medical records. The external control

group included 86 patients treated with available therapy (as above) mostly at the same time and at the

same sites as the patients treated with posaconazole. Most of the cases of aspergillosis were considered

to be refractory to prior therapy in both the posaconazole group (88%) and in the external control

group (79%).

As shown in Table 4, a successful response (complete or partial resolution) at the end of treatment was

seen in 42% of posaconazole-treated patients compared to 26% of the external group. However, this

was not a prospective, randomised controlled study and so all comparisons with the external control

group should be viewed with caution.

Table 4.

Overall efficacy of posaconazole oral suspension at the end of treatment for invasive

aspergillosis in comparison to an external control group

Posaconazole oral suspension

External control group

Overall Response

45/107 (42%)

22/86 (26%)

Success by Species

All mycologically confirmed

Aspergillus

spp.

34/76 (45%)

19/74 (26%)

A. fumigatus

12/29 (41%)

12/34 (35%)

A. flavus

10/19 (53%)

3/16 (19%)

A. terreus

4/14 (29%)

2/13 (15%)

A. niger

3/5 (60%)

2/7 (29%)

Includes other less common species or species unknown

Fusarium spp.

11 of 24 patients who had proven or probable fusariosis were successfully treated with posaconazole

oral suspension 800 mg/day in divided doses for a median of 124 days and up to 212 days. Among

eighteen patients who were intolerant or had infections refractory to amphotericin B or itraconazole,

seven patients were classed as responders.

Chromoblastomycosis/Mycetoma

9 of 11 patients were successfully treated with posaconazole oral suspension 800 mg/day in divided

doses for a median of 268 days and up to 377 days. Five of these patients had chromoblastomycosis

due to Fonsecaea pedrosoi and 4 had mycetoma, mostly due to Madurella species.

Coccidioidomycosis

11 of 16 patients were successfully treated (at the end of treatment complete or partial resolution of

signs and symptoms present at baseline) with posaconazole oral suspension 800 mg/day in divided

doses for a median of 296 days and up to 460 days.

Prophylaxis of Invasive Fungal Infections (IFIs) (Studies 316 and 1899)

Two randomised, controlled prophylaxis studies were conducted among patients at high risk for

developing invasive fungal infections.

Study 316 was a randomised, double-blind trial of posaconazole oral suspension (200 mg three times a

day) versus fluconazole capsules (400 mg once daily) in allogeneic hematopoietic stem cell transplant

recipients with graft-versus-host disease (GVHD). The primary efficacy endpoint was the incidence of

proven/probable IFIs at 16 weeks post-randomization as determined by an independent, blinded

external expert panel. A key secondary endpoint was the incidence of proven/probable IFIs during the

on-treatment period (first dose to last dose of study medicinal product + 7 days). The majority

(377/600, [63%]) of patients included had Acute Grade 2 or 3 or chronic extensive (195/600, [32.5%])

GVHD at study start. The mean duration of therapy was 80 days for posaconazole and 77 days for

fluconazole.

Study 1899 was a randomised, evaluator-blinded study of posaconazole oral suspension (200 mg three

times a day) versus fluconazole suspension (400 mg once daily) or itraconazole oral solution (200 mg

twice a day) in neutropenic patients who were receiving cytotoxic chemotherapy for acute

myelogenous leukaemia or myelodysplastic syndromes. The primary efficacy endpoint was the

incidence of proven/probable IFIs as determined by an independent, blinded external expert panel

during the on-treatment period. A key secondary endpoint was the incidence of proven/probable IFIs

at 100 days post-randomization. New diagnosis of acute myelogenous leukaemia was the most

common underlying condition (435/602, [72%]). The mean duration of therapy was 29 days for

posaconazole and 25 days for fluconazole/itraconazole.

In both prophylaxis studies, aspergillosis was the most common breakthrough infection. See Table 5

and 6 for results from both studies. There were fewer breakthrough

Aspergillus

infections in patients

receiving posaconazole prophylaxis when compared to control patients.

Table 5

. Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study

Posaconazole oral

suspension

Control

a

P-Value

Proportion (%) of patients with proven/probable IFIs

On-treatment period

1899

7/304 (2)

25/298 (8)

0.0009

7/291 (2)

22/288 (8)

0.0038

Fixed-time period

1899

14/304 (5)

33/298 (11)

0.0031

16/301 (5)

27/299 (9)

0.0740

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.

a: FLU/ITZ (1899); FLU (316).

In 1899 this was the period from randomization to last dose of study medicinal product plus 7 days; in 316

it was the period from first dose to last dose of study medicinal product plus 7 days.

In 1899, this was the period from randomization to 100 days post-randomization; in 316 it was the period

from the baseline day to 111 days post-baseline.

d: All randomized

e: All treated

Table 6.

Results from clinical studies in prophylaxis of Invasive Fungal Infections

Study

Posaconazole oral

suspension

Control

a

Proportion (%) of patients with proven/probable Aspergillosis

On-treatment period

1899

2/304 (1)

20/298 (7)

3/291 (1)

17/288 (6)

Fixed-time period

1899

4/304(1)

26/298 (9)

7/301 (2)

21/299 (7)

FLU = fluconazole; ITZ = itraconazole; POS = posaconazole.

a: FLU/ITZ (1899); FLU (316).

In 1899 this was the period from randomization to last dose of study medicinal product plus 7 days; in 316

it was the period from first dose to last dose of study medicinal product plus 7 days.

In 1899, this was the period from randomization to 100 days post-randomization; in 316 it was the period

from the baseline day to 111 days post-baseline.

d: All randomized

e: All treated

In Study 1899, a significant decrease in all cause mortality in favour of posaconazole was observed

[POS 49/304 (16%) vs. FLU/ITZ 67/298 (22%) p= 0.048]. Based on Kaplan-Meier estimates, the

probability of survival up to day 100 after randomization, was significantly higher for posaconazole

recipients; this survival benefit was demonstrated when the analysis considered all causes of death

(P=0.0354) as well as IFI-related deaths (P = 0.0209).

In Study 316, overall mortality was similar (POS, 25%; FLU, 28%); however, the proportion of

IFI- related deaths was significantly lower in the POS group (4/301) compared with the FLU group

(12/299; P= 0.0413).

Paediatric population

There is no paediatric experience for posaconazole tablets.

Sixteen patients 8-17 years of age were treated with posaconazole oral suspension 800 mg/day in a

study for invasive fungal infections. Based on the available data in 16 of these paediatric patients, the

safety profile appears to be similar to patients ≥ 18 years of age.

Additionally, twelve patients 13-17 years of age received posaconazole oral suspension 600 mg/day

for prophylaxis of invasive fungal infections (Studies 316 and 1899). The safety profile in these

patients < 18 years of age appears similar to the safety profile observed in adults. Based on

pharmacokinetic data in 10 of these paediatric patients, the pharmacokinetic profile appears to be

similar to patients ≥ 18 years of age.

Safety and efficacy in paediatric patients below the age of 18 years have not been established.

Electrocardiogram evaluation

Multiple, time-matched ECGs collected over a 12 hour period were obtained before and during

administration of posaconazole oral suspension (400 mg twice daily with high fat meals) from

173 healthy male and female volunteers aged 18 to 85 years. No clinically relevant changes in the

mean QTc (Fridericia) interval from baseline were observed.

5.2

Pharmacokinetic properties

Pharmacokinetic / Pharmacodynamic relationships

A correlation between total medicinal product exposure divided by MIC (AUC/MIC) and clinical

outcome was observed. The critical ratio for subjects with

Aspergillus

infections was ~200. It is

particularly important to try to ensure that maximal plasma levels are achieved in patients infected

with

Aspergillus

(see sections 4.2 and 5.2 on recommended dose regimens).

Absorption

Posaconazole tablets are absorbed with a median T

of 4 to 5 hours and exhibits dose proportional

pharmacokinetics after single and multiple dosing up to 300 mg.

Following a single dose administration of 300 mg posaconazole tablets after a high fat meal to healthy

volunteers, the AUC

0-72 hours

and C

were higher compared to administration under fasted condition

(51% and 16% for AUC

0-72 hours

and C

respectively).

Posaconazole plasma concentrations following administration of posaconazole tablets may increase

over time in some patients. The reason for this time-dependency is not completely understood.

Distribution

Posaconazole, after administration of the tablet, has a mean apparent volume of distribution of 394 L

(42%), ranging between 294-583 L among the studies in healthy volunteers.

Posaconazole is highly protein bound (> 98%), predominantly to serum albumin.

Biotransformation

Posaconazole does not have any major circulating metabolites and its concentrations are unlikely to be

altered by inhibitors of CYP450 enzymes. Of the circulating metabolites, the majority are glucuronide

conjugates of posaconazole with only minor amounts of oxidative (CYP450 mediated) metabolites

observed. The excreted metabolites in urine and faeces account for approximately 17% of the

administered radiolabelled dose.

Elimination

Posaconazole after administration of the tablets, is slowly eliminated with a mean half-life (t

) of

29 hours (range 26 to 31 hours) and a mean apparent clearance ranging from 7.5 to 11 L/hr. After

administration of

C-posaconazole, radioactivity was predominantly recovered in the faeces (77% of

the radiolabelled dose) with the major component being parent compound (66% of the radiolabelled

dose). Renal clearance is a minor elimination pathway, with 14% of the radiolabelled dose excreted in

urine (< 0.2% of the radiolabelled dose is parent compound). Steady-state plasma concentrations are

attained by Day 6 at the 300 mg dose (once daily after twice daily loading dose at Day 1).

Pharmacokinetics in special populations

Children (< 18 years)

There is no paediatric experience with posaconazole tablets.

The pharmacokinetics of posaconazole oral suspension have been evaluated in paediatric patients.

Following administration of 800 mg per day of posaconazole oral suspension as a divided dose for

treatment of invasive fungal infections, mean trough plasma concentrations from 12 patients

8-17 years of age (776 ng/mL) were similar to concentrations from 194 patients 18-64 years of age

(817 ng/mL). No pharmacokinetic data are available from paediatric patients less than 8 years of age.

Similarly, in the prophylaxis studies, the mean steady-state posaconazole average concentration (Cav)

was comparable among ten adolescents (13-17 years of age) to Cav achieved in adults (≥ 18 years of

age).

Gender

The pharmacokinetics of posaconazole tablets are comparable in men and women.

Elderly

The pharmacokinetics of posaconazole tablets are comparable in young and elderly subjects. No

overall differences in safety were observed between the geriatric patients and younger patients;

therefore, no dosage adjustment is recommended for geriatric patients.

Race

There is insufficient data among different races with posaconazole tablets.

There was a slight decrease (16%) in the AUC and C

of posaconazole oral suspension in Black

subjects relative to Caucasian subjects. However, the safety profile of posaconazole between the Black

and Caucasian subjects was similar.

Weight

Pharmacokinetic modeling with an oral tablet formulation suggests that patients weighing greater than

120 kg may have lower posaconazole exposure. It is, therefore, suggested to closely monitor for

breakthrough fungal infections in patients weighing more than 120 kg.

Patients, in particular those receiving posaconazole after HSCT, who have a low body weight

(< 60 kg) are more likely to experience higher plasma concentrations of posaconazole and should be

closely monitored for adverse events.

Renal impairment

Following single-dose administration of posaconazole oral suspension, there was no effect of mild and

moderate renal impairment (n=18, Cl

≥ 20 mL/min/1.73 m

) on posaconazole pharmacokinetics;

therefore, no dose adjustment is required. In subjects with severe renal impairment (n=6,

< 20 mL/min/1.73 m

), the AUC of posaconazole was highly variable [> 96% CV (coefficient of

variance)] compared to other renal groups [< 40% CV]. However, as posaconazole is not significantly

renally eliminated, an effect of severe renal impairment on the pharmacokinetics of posaconazole is

not expected and no dose adjustment is recommended. Posaconazole is not removed by haemodialysis.

Similar recommendations apply to posaconazole tablets; however, a specific study has not been

conducted with the posaconazole tablets.

Hepatic impairment

After a single oral dose of 400 mg posaconazole oral suspension to patients with mild (Child-Pugh

Class A), moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment (six per

group), the mean AUC was 1.3 to 1.6-fold higher compared to that for matched control subjects with

normal hepatic function. Unbound concentrations were not determined and it cannot be excluded that

there is a larger increase in unbound posaconazole exposure than the observed 60% increase in total

AUC. The elimination half-life (t

) was prolonged from approximately 27 hours up to ~43 hours in

respective groups. No dose adjustment is recommended for patients with mild to severe hepatic

impairment but caution is advised due to the potential for higher plasma exposure.

Similar recommendations apply to posaconazole tablets; however, a specific study has not been

conducted with the posaconazole tablets.

5.3

Preclinical safety data

As observed with other azole antifungal agents, effects related to inhibition of steroid hormone

synthesis were seen in repeated-dose toxicity studies with posaconazole. Adrenal suppressive effects

were observed in toxicity studies in rats and dogs at exposures equal to or greater than those obtained

at therapeutic doses in humans.

Neuronal phospholipidosis occurred in dogs dosed for ≥ 3 months at lower systemic exposures than

those obtained at therapeutic doses in humans. This finding was not seen in monkeys dosed for one

year. In twelve-month neurotoxicity studies in dogs and monkeys, no functional effects were observed

on the central or peripheral nervous systems at systemic exposures greater than those achieved

therapeutically.

Pulmonary phospholipidosis resulting in dilatation and obstruction of the alveoli was observed in the

2-year study in rats. These findings are not necessarily indicative of a potential for functional changes

in humans.

No effects on electrocardiograms, including QT and QTc intervals, were seen in a repeat dose safety

pharmacology study in monkeys at maximal plasma concentrations 8.5-fold greater than the

concentrations obtained at therapeutic doses in humans. Echocardiography revealed no indication of

cardiac decompensation in a repeat dose safety pharmacology study in rats at a systemic exposure

2.1-fold greater than that achieved therapeutically. Increased systolic and arterial blood pressures (up

to 29 mm-Hg) were seen in rats and monkeys at systemic exposures 2.1-fold and 8.5-fold greater,

respectively, than those achieved with the human therapeutic doses.

Reproduction, peri- and postnatal development studies were conducted in rats. At exposures lower

than those obtained at therapeutic doses in humans, posaconazole caused skeletal variations and

malformations, dystocia, increased length of gestation, reduced mean litter size and postnatal viability.

In rabbits, posaconazole was embryotoxic at exposures greater than those obtained at therapeutic

doses. As observed with other azole antifungal agents, these effects on reproduction were considered

to be due to a treatment-related effect on steroidogenesis.

Posaconazole was not genotoxic in

in vitro

in vivo

studies. Carcinogenicity studies did not reveal

special hazards for humans.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Methacrylic acid-Ethyl acrylate copolymer (1:1)

Triethyl citrate (E1505)

Xylitol (E967)

Hydroxypropyl cellulose (E463)

Propyl gallate (E310)

Cellulose, microcrystalline (E460)

Silica, colloidal anhydrous

Croscarmellose sodium

Sodium stearyl fumarate

Tablet coating

Polyvinyl alcohol-part hydrolyzed

Titanium dioxide (E171)

Macrogol

Talc (E553b)

Iron oxide yellow (E172)

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container

Triplex (PVC/PE/PVdC) white opaque-aluminium blister or perforated unit dose blister in cartons of

24 or 96 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Accord Healthcare S.L.U.

World Trade Center, Moll de Barcelona s/n,

Edifici Est, 6

planta, Barcelona,

08039 Barcelona, Spain

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/19/1379/001-004

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

10.

DATE OF REVISION OF THE TEXT

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

http://www.ema.europa.eu

Official address

Domenico Scarlattilaan 6

1083 HS Amsterdam

The Netherlands

An agency of the European Union

Address for visits and deliveries

Refer to www.ema.europa.eu/how-to-find-us

Send us a question

Go to www.ema.europa.eu/contact

Telephone

+31 (0)88 781 6000

© European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged.

EMA/320670/2019

EMEA/H/C/005005

Posaconazole Accord (posaconazole)

An overview of Posaconazole Accord and why it is authorised in the EU

What is Posaconazole Accord and what is it used for?

Posaconazole Accord is an antifungal medicine used to treat adults with the following fungal diseases,

when treatments with other antifungal medicines (amphotericin B, itraconazole or fluconazole) cannot

be tolerated or have failed:

invasive aspergillosis (fungal infection caused by Aspergillus),

fusariosis (fungal infection caused by Fusarium),

chromoblastomycosis and mycetoma (long-term fungal infections of the skin or the tissue just

below the skin, usually caused by fungal spores infecting wounds due to thorns or splinters),

coccidioidomycosis (fungal infection of the lungs caused by breathing in spores).

Posaconazole Accord is also used to prevent invasive fungal infections in patients whose immune

system is weakened because of treatments they are receiving for blood or bone marrow cancers or

medicines used in haematopoietic stem cell transplantation (a procedure where the patient’s bone

marrow is replaced by stem cells from a donor to form new bone marrow).

Posaconazole Accord contains the active substance posaconazole and is a ‘generic medicine’. This

means that Posaconazole Accord contains the same active substance and works in the same way as a

‘reference medicine’ already authorised in the EU called Noxafil. For more information on generic

medicines, see the question-and-answer document here.

How is Posaconazole Accord used?

Posaconazole Accord can only be obtained with a prescription and treatment should be started by a

doctor who has experience in managing fungal infections or in treating patients at high risk of invasive

fungal infections.

Posaconazole Accord is available as gastro-resistant tablets (100 mg). Gastro-resistant means that the

tablets pass through the stomach without being broken down until they reach the intestine.

The recommended dose is 300 mg twice a day on the first day followed by 300 mg once a day

thereafter; the duration of treatment depends on the severity of the disease and the patient’s

response.

Posaconazole Accord (posaconazole)

EMA/320670/2019

Page 2/2

For more information about using Posaconazole Accord, see the package leaflet or contact your doctor

or pharmacist.

How does Posaconazole Accord work?

The active substance in Posaconazole Accord, posaconazole, is an antifungal medicine that belongs to

the triazole group. It works by preventing the formation of ergosterol, which is an important part of

fungal cell walls. Without ergosterol, the fungus dies or is prevented from spreading. The list of fungi

Posaconazole Accord is active against can be found in the summary of product characteristics.

How has Posaconazole Accord been studied?

Studies on the benefits and risks of the active substance in the authorised uses have already been

carried out with the reference medicine, Noxafil, and do not need to be repeated for Posaconazole

Accord.

As for every medicine, the company provided studies on the quality of Posaconazole Accord. The

company also carried out studies that showed that it is ‘bioequivalent’ to the reference medicine. Two

medicines are bioequivalent when they produce the same levels of the active substance in the body

and are therefore expected to have the same effect.

What are the benefits and risks of Posaconazole Accord?

Because Posaconazole Accord is a generic medicine and is bioequivalent to the reference medicine, its

benefits and risks are taken as being the same as the reference medicine’s.

Why is Posaconazole Accord authorised in the EU?

The European Medicines Agency concluded that, in accordance with EU requirements, Posaconazole

Accord has been shown to have comparable quality and to be bioequivalent to Noxafil. Therefore, the

Agency’s view was that, as for Noxafil, the benefit of Posaconazole Accord outweighs the identified risk

and it can be authorised for use in the EU.

What measures are being taken to ensure the safe and effective use of

Posaconazole Accord?

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Posaconazole Accord have been included in the summary of product characteristics

and the package leaflet.

As for all medicines, data on the use of Posaconazole Accord are continuously monitored. Side effects

reported with Posaconazole Accord are carefully evaluated and any necessary action taken to protect

patients.

Other information about Posaconazole Accord

Posaconazole Accord received a marketing authorisation valid throughout the EU on 25 July 2019.

Further information on Posaconazole Accord can be found on the Agency’s website:

ema.europa.eu/medicines/human/EPAR/posaconazole-accord.

Information on the reference medicine can also be found on the Agency’s website.

This overview was last updated in 08-2019.

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