NOXAFIL SUSPENSION

PATIENT PACKAGE INSERT IN ACCORDANCE WITH

THE PHARMACISTS' REGULATIONS (PREPARATIONS) - 1986

This medicine is marketed upon physician’s prescription only

NOXAFIL

®

Suspension

40 mg/mL

Oral Suspension

Each mL of suspension contains:

Posaconazole 40 mg

For a list of inactive ingredients please refer to section 6.

Read all of this leaflet carefully before you start using this medicine.

This leaflet contains consice information about NOXAFIL. If you have any further

questions, ask your doctor or pharmacist.

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

them, even if their medical condition seems similar to yours.

NOXAFIL suspension is intended for use in adults (18 years of age and older).

1. WHAT NOXAFIL IS INTENDED FOR?

NOXAFIL is used to prevent and treat different types of fungal infections.

NOXAFIL is used to treat the following types of fungal infections in adults when other

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

Infections caused by fungi of the Aspergillus family and are resistant to treatment with

amphotericin B or itraconazole or when the patient cannot receive these medicines;

Infections caused by fungi of the Fusarium family and are resistant to treatment with

amphotericin B or when the patient cannot receive this medicine;

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

and “mycetoma” and are resistant to treatment with itraconazole or when the patient

cannot receive this medicine;

Infections caused by a fungus called Coccidioides that are resistant to treatment with

amphotericin B, itraconazole or fluconazole or when the patient cannot receive these

medicines;

Infections in the mouth or throat area (known as “thrush”) caused by fungi called

Candida, which were not previously treated.

Fungal infection called Zygomycosis, in patients intolerant of or with disease that is

refractory to alternative therapy.

NOXAFIL can also be used to prevent fungal infections in adults who are at high risk of

getting a fungul infection, such as:

patients whose immune system may be weakened due to chemotherapy for “acute

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

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

transplant” (HSCT).

Therapeutic group:

Posaconazole belongs to a group of medicines called “antifungals”.

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

cause infections.

2. BEFORE YOU TAKE NOXAFIL

2.1 Do not take NOXAFIL if:

You are allergic (hypersensitive) to posaconazole or any of the other ingredients

of this medicine (listed in section 6).

you are taking: terfenadine, astemizole, cisapride, pimozide, halofantrine,

quinidine, any medicines that contain “ergot alkaloids” such as ergotamine or

dihydroergotamine, or a medicine from the statin family such as simvastatin,

atorvastatin or lovastatin.

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

doctor or pharmacist before taking NOXAFIL.

See section 2.3 “Interactions with other medicines” below for more information including

information on other medicines which may interact with NOXAFIL.

2.2 Special warnings concerning use of NOXAFIL

Before taking NOXAFIL, tell your doctor if:

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

fluconazole, itraconazole or voriconazole.

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

are taking this medicine.

develop

severe

diarrhoea

vomiting,

these

conditions

limit

effectiveness of this medicine.

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

QTc interval

you have a weakness of the heart muscle or heart failure

you have a very slow heartbeat

you have heart rhythm disturbance

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

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 or the pharmacist

before taking NOXAFIL.

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

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

section 4 for more information.

2.3 Interactions with other medicines

If you are taking, have recently taken

or might take other medicines, including non-

prescription medicines and nutritional supplements, you should inform the attending

doctor or pharmacist.

Do not take NOXAFIL if you are taking any of the following medicines:

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).

NOXAFIL 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. NOXAFIL 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 medicine of the statin family such as simvastatin, atorvastatin or lovastatin used to

treat high levels of cholesterol.

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

doctor or pharmacist before taking this medicine.

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 NOXAFIL. 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 caused by NOXAFIL due to

increasing the amount of NOXAFIL in the blood.

The following medicines may decrease the effectiveness of NOXAFIL by decreasing the

amount of NOXAFIL in the blood:

rifabutin and rifampicin (used to treat certain infections). If you are 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, such as: phenytoin, carbamazepine,

phenobarbital or primidone.

efavirenz and fosamprenavir used to treat HIV infection.

medicines

used

decrease

stomach

acid

such

cimetidine

ranitidine

omeprazole and similar medicines that are called proton pump inhibitors.

NOXAFIL 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 among others to prevent transplant rejection)

tacrolimus and sirolimus (used to prevent transplant rejection)

rifabutin (used to treat certain infections)

medicines

used

treat

called

protease

inhibitors

(including

lopinavir

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 NOXAFIL.

2.4 Taking NOXAFIL with food and drink

To improve absorption of posaconazole, whenever possible it should be taken during or

immediately

after

food

nutritional

drink

(see

section

“How

should

you

use

NOXAFIL?”). There is no information on the effect of alcohol on posaconazole.

2.5 Pregnancy and breast-feeding

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

Do not take NOXAFIL 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 NOXAFIL, contact your doctor straight away.

Do not breast-feed while taking NOXAFIL. This is because small amounts of NOXAFIL

may pass into breast milk.

2.6 Driving and using machines

You may feel dizzy, sleepy, or have blurred vision while taking NOXAFIL. These may affect

your ability to drive or use tools or machines. If you suffer from these side effects, do not

drive or use any tools or machines and contact your doctor.

2.7 Important information about some of the ingredients of NOXAFIL

NOXAFIL contains approximately 1.75 g of glucose per 5 mL of suspension (350 mg/mL).

You should not take this medicine if you have a condition called glucose-galactose

malabsorption and should take note of this amount of glucose if you need to watch your

sugar intake for any reason.

3. HOW SHOULD YOU USE NOXAFIL?

Do not switch between taking NOXAFIL tablets and NOXAFIL 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 has told you. You should check with your

doctor or pharmacist if you are not sure.

Your doctor will monitor your response and condition

to determine how long NOXAFIL

needs to be given and whether any change is needed to your daily dose.

The table below shows the recommended dose and length of treatment which 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, without consulting the attending doctor.

Whenever possible you should take posaconazole during or immediately after food or a

nutritional drink.

Shake well before use.

You should always use the measuring spoon to measure the correct amount of the

medicine. If a measuring spoon or some other measuring device is not provided with the

package, consult the pharmacist. Do not use a household spoon to measure the amount of

medicine. Household spoons differ in their size and you may not get the correct dose of the

medicine.

Child resistant caps significantly lowered the number of poisonings that are caused by

medicines every year. However, if you are having difficulties opening the package, you can

ask the pharmacist to remove the safety mechanism of the cap and turn it to a regular and

easy-to-open cap.

Indication

Recommended dose and length of treatment

Treatment of refractory Fungal

Infections (Invasive aspergillosis,

Fusariosis, zygomycosis,

Chromoblastomycosis/Mycetoma,

Coccidioidomycosis)

recommended

dose

200 mg

(one

5 mL

spoonful) taken four times daily.

Alternatively, if recommended by your doctor, you

may take 400 mg (two 5 mL spoonfuls) twice a day

provided that you are able to take both doses during

or after food or a nutritional drink.

First time treatment of Thrush

On the first day of treatment take 200 mg (one 5 mL

spoonful)

once.

After

first

day,

take

100 mg

(2.5 mL) once a day.

Prevention of serious Fungal

Infections

Take 200 mg (one 5 mL spoonful) three times a day.

Do not exceed the recommended dose.

If you have accidentally taken a higher dose than you should

If you have taken an overdose of NOXAFIL, or if a child has accidentally swallowed the

medicine, proceed immediately to a doctor or to a hospital emergency room and bring the

package of the medicine with you.

If you forget to take NOXAFIL

If you have missed a dose, take it as soon as you remember and then carry on as before.

However, if it is almost time for your next dose, take your dose when it is due. Do not take a

double dose to make up for a forgotten dose.

Complete the full course of treatment as instructed by the doctor.

Even if there is an improvement in your health, do not discontinue use of this medicine

before consulting your doctor or pharmacist.

Do not take medicines in the dark! Check the label and the dose each time you take your

medicine. Wear glasses if you need them.

have

further

questions

of this medicine,

your

doctor

pharmacist.

4. SIDE EFFECTS

Like all medicines, NOXAFIL can cause side effects, in some users.

Do not be alarmed by reading the list of side effects, you may not suffer from any of them.

Serious side effects

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

Common side effects: 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) – that can be shown

up in blood tests. This can make you more likely to get infections

fever

feeling weak, dizzy, tired or sleepy

rash

itching

constipation

rectal discomfort

Uncommon side effects: 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

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 side effects: 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 the 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

Side effects with unknown frequency: frequency cannot be estimated from the available

data

pseudoaldosteronism, which results in high blood pressure with a low potassium level

(shown in blood test)

some patients have also reported feeling confused after taking NOXAFIL.

If a side effect appears, if any of the side effects gets serious or if you notice side effects

not mentioned in this leaflet, consult your doctor.

Side effects can be reported to the Ministry of Health by using the online form for adverse

events reporting which is on the Ministry of Health Homepage: (www.health.gov.il

or by following the link:

https://sideeffects.health.gov.il/

5. HOW TO STORE NOXAFIL?

Avoid poisoning! This medicine, and all other medicines, must be stored in a safe

place out of the sight and reach of children and/or infants, in order to avoid poisoning.

Do not induce vomiting unless explicitly instructed to do so by a doctor.

Do not use NOXAFIL after the expiry date (exp. date) which is stated on the pack. The

expiry date refers to the last day of the indicated month.

Storage conditions: Store below 25˚C. Do not freeze. If you have any suspension left

in a bottle more than four weeks after it was first opened, you should not use this

medicine.

Please

return

bottle

containing

leftover

suspension

your

pharmacist.

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. FURTHER INFORMATION

6.1 In addition to the active ingredient the medicine also contains the following inactive

ingredients: liquid glucose (corn syrup), glycerol, polysorbate 80, artificial cherry flavour

#13174,

titanium

dioxide,

simethicone,

xanthan

gum,

sodium

benzoate,

citric

acid

monohydrate, sodium citrate dihydrate, and purified water.

Each mL of suspension contains: Liquid glucose 350 mg and sodium.

6.2 What NOXAFIL looks like and contents of the pack

NOXAFIL is a white, cherry flavoured, 105 mL oral suspension packaged in amber glass

bottles. A measuring spoon is provided with each bottle for measuring 2.5 and 5 mL doses

of the oral suspension.

Marketing Authorization Holder:

Merck Sharp & Dohme (Israel-1996) Company Ltd., P.O.B 7121, Petah-Tikva 49170.

Manufacturer:

Merck Sharp & Dohme Corp., New-Jersey, USA.

Drug registration no. listed in the official registry of the Ministry of Health:

138.37.31627

Revised in August 2020.

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Noxafil

40 mg/mL oral suspension

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each mL of oral suspension contains 40 mg of posaconazole.

Excipient with known effect:

This medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Oral suspension

White suspension

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Noxafil oral suspension 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;

Oropharyngeal candidiasis: as first-line therapy in patients who have severe disease or

are immunocompromised, in whom response to topical therapy is expected to be poor.

Zygomycosis, in patients intolerant of, or with disease that is refractory to, alternative

therapy.

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

.

Noxafil oral suspension 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 Noxafil Tablets and Noxafil 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. Substitution of the tablets for the oral suspension, or vice versa,

can result in inadvertent overdosing or underdosing and adverse drug reactions. 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

Noxafil is also available as 100 mg gastro-resistant tablet. Noxafil tablets are the preferred

formulation to optimize plasma concentrations and generally provide higher plasma drug

exposures than Noxafil 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

200 mg (5 mL) four times a day. Alternatively, patients who

can tolerate food or a nutritional supplement may take 400 mg

(10 mL) twice a day during or immediately following a meal

or nutritional supplement

Duration of therapy should be based on the severity of the

underlying disease, recovery from immunosuppression, and

clinical response.

Oropharyngeal candidiasis

Loading dose of 200 mg (5 mL) once a day on the first day,

then 100 mg (2.5 mL) once a day for 13 days.

Each dose of Noxafil should be administered during or

immediately after

a meal, or a nutritional supplement in

patients who cannot tolerate food to enhance the oral

absorption and to ensure adequate exposure.

Prophylaxis of invasive

fungal infections

200 mg (5 mL) three times a day.

Each dose of Noxafil should

be administered during or immediately after a meal, or a

nutritional supplement in patients who cannot tolerate food to

enhance the oral absorption and to ensure adequate exposure.

The duration of therapy is based on recovery from neutropenia

or immunosuppression. For patients with acute myelogenous

leukemia or myelodysplastic syndromes, prophylaxis with

Noxafil should start several days before the anticipated onset

of neutropenia and continue for 7 days after the neutrophil

count rises above 500 cells per mm

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 Noxafil in children aged below 18 years have not been established.

Method of administration

For oral use

The oral suspension must be shaken well before use.

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 Noxafil 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 Noxafil 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 Noxafil 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. Noxafil 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). Noxafil 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), efavirenz and cimetidine

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).

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 medicinal product contains approximately 1.75 g of glucose per 5 mL of suspension.

Patients with glucose-galactose malabsorption should not take this medicine.

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 C

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 1

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

Posaconazole plasma concentrations (C

and AUC) were reduced by 39 % when

posaconazole was administered with cimetidine (400 mg twice a day) due to reduced

absorption possibly secondary to a decrease in gastric acid production. Co-administration of

posaconazole with H

receptor antagonists should be avoided if possible.

Similarly, administration of 400 mg posaconazole with esomeprazole (40 mg daily) decreased

mean C

and AUC by 46 % and 32 %, respectively, compared to dosing with 400 mg

posaconazole alone.

Co-administration of posaconazole with proton pump inhibitors should be avoided if possible.

Food

The absorption of posaconazole is significantly increased by food (see sections 4.2 and 5.2).

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, unless posaconazole is administered in a strictly standardised way

with food, given the large food effect on posaconazole exposure (see section 5.2).

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

.

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 C

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 (1.7 times the

400-mg twice daily regimen based on steady-state plasma concentrations in healthy

volunteers) or female rats at a dose up to 45 mg/kg (2.2 times the 400-mg twice daily

regimen). 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

Summary of the safety profile

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 (cannot be estimated from the available data).

Table 2.

Adverse reactions by body system and frequency reported in clinical trials and/or

post-marketing use*

Blood and lymphatic system

disorders

Common:

Uncommon:

Rare:

neutropenia

thrombocytopenia, leukopenia, anaemia, eosinophilia,

lymphadenopathy, splenic infarction

haemolytic uraemic syndrome, thrombotic

thrombocytopenic purpura , pancytopenia, coagulopathy,

haemorrhage

Immune system disorders

Uncommon:

Rare:

allergic reaction

hypersensitivity reaction

Endocrine disorders

Rare:

Not known:

adrenal insufficiency, blood gonadotropin decreased

pseudoaldosteronism

Metabolism and nutrition

disorders

Common:

Uncommon:

electrolyte imbalance, anorexia, decreased appetite,

hypokalaemia, hypomagnesaemia

hyperglycaemia, hypoglycaemia

Psychiatric disorders

Uncommon:

Rare:

abnormal dreams, confusional state, sleep disorder

psychotic disorder, depression

Nervous system disorders

Common:

Uncommon:

Rare:

paresthesia, dizziness, somnolence, headache, dysgeusia

convulsions, neuropathy, hypoaesthesia, tremor, aphasia,

insomnia

cerebrovascular accident, encephalopathy, peripheral

neuropathy, syncope

Eye disorders

Uncommon:

Rare:

blurred vision, photophobia, visual acuity reduced

diplopia, scotoma

Ear and labyrinth disorder

Rare:

hearing impairment

Cardiac disorders

Uncommon:

Rare:

long QT syndrome

, electrocardiogram abnormal

palpitations, bradycardia, supraventricular extrasystoles,

tachycardia

torsades de pointes, sudden death, ventricular tachycardia,

cardio-respiratory arrest, cardiac failure, myocardial

infarction

Vascular disorders

Common:

Uncommon:

Rare:

hypertension

hypotension, vasculitis

pulmonary embolism, deep vein thrombosis

Respiratory, thoracic and

mediastinal disorders

Uncommon:

Rare:

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

tachypnoea

pulmonary hypertension, interstitial pneumonia, pneumonitis

Gastrointestinal disorders

Very common:

Common:

Uncommon:

Rare:

nausea

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

flatulence, constipation, anorectal discomfort

pancreatitis, abdominal distension, enteritis, epigastric

discomfort, eructation, gastrooesophageal reflux disease,

oedema mouth

gastrointestinal haemorrhage, ileus

Hepatobiliary disorders

Common:

Uncommon:

Rare:

liver function tests raised (ALT increased, AST increased,

bilirubin increased, alkaline phosphatase increased, GGT

increased)

hepatocellular damage, hepatitis, jaundice, hepatomegaly

cholestasis, hepatic toxicity, hepatic function abnormal

hepatic failure, hepatitis cholestatic, hepatosplenomegaly,

liver tenderness, asterixis

Skin and subcutaneous tissue

disorders

Common:

Uncommon:

Rare:

rash, pruritis

mouth ulceration, alopecia, dermatitis, erythema, petechiae

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:

Rare:

acute renal failure, renal failure, blood creatinine increased

renal tubular acidosis, interstitial nephritis

Reproductive system and breast

disorders

Uncommon:

Rare:

menstrual disorder

breast pain

General disorders and

administration site

conditions

Common:

Uncommon:

Rare:

pyrexia (fever), asthenia, fatigue

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

intolerance, feeling jittery, mucosal inflammation

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 suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the

National Regulation by using an online form

https://sideeffects.health.gov.il

4.9

Overdose

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

species of

Fusarium,

Rhizomucor

Mucor

, and

Rhizopus.

The microbiological data suggest that posaconazole is

active against

organisms not previously regarded

as susceptible to azoles such as the

zygomycetes (e.g. species of Absidia, Mucor, Rhizopus and Rhizomucor)

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.

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

and the effects of food on absorption).

Clinical experience

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 3, 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 3

. 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

(60 %)

(29 %)

Zygomycosis:

Successful responses to posaconazole therapy were noted in 7/13 (54%) of

patients with zygomycete infections. Sites of infection included the sinuses, lung, and skin.

Organisms included Rhizopus, Mucor and Rhizomucor. Most of the patients had underlying

haematological malignancies, half of which required a bone marrow transplant. Half of the

patients were enrolled with intolerance to previous therapy and the other half as a result of

disease that was refractory to prior therapy. Three patients were noted to have disseminated

disease, one of which had a successful outcome after failing amphotericin B therapy.

Fusarium

.

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

Includes other less common species or species unknown

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.

Treatment of azole-susceptible Oropharyngeal Candidiasis (OPC)

A randomised, evaluator-blind, controlled study was completed in HIV-infected patients with

azole-susceptible oropharyngeal candidiasis (most patients studied had C. albicans isolated at

baseline). The primary efficacy variable was the clinical success rate (defined as cure or

improvement) after 14 days of treatment. Patients were treated with posaconazole or

fluconazole oral suspension (both posaconazole and fluconazole were given as follows:

100 mg twice a day for 1 day followed by 100 mg once a day for 13 days).

The clinical response rates from the above study are shown in the Table 4 below.

Posaconazole was shown to be non-inferior to fluconazole for clinical success rates at Day 14

as well as 4 weeks after the end of treatment.

Table 4.

Clinical success rates in Oropharyngeal Candidiasis

Endpoint

Posaconazole

Fluconazole

Clinical success rate at Day 14

91.7 % (155/169)

92.5 % (148/160)

Clinical success rate 4 weeks after end of treatment

68.5 % (98/143)

61.8 % (84/136)

Clinical success rate was defined as the number of cases assessed as having a clinical response (cure or

improvement) divided by the total number of cases eligible for analysis.

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-

randomisation 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-randomisation. 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

b

1899

d

7/304 (2)

25/298 (8)

0.0009

e

7/291 (2)

22/288 (8)

0.0038

Fixed-time period

c

1899

d

14/304 (5)

33/298 (11)

0.0031

d

16/301 (5)

27/299 (9)

0.0740

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

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

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

from the baseline day to 111 days post-baseline.

All randomised

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

b

1899

d

2/304 (1)

20/298 (7)

e

3/291 (1)

17/288 (6)

Fixed-time period

c

1899

d

4/304 (1)

26/298 (9)

d

7/301 (2)

21/299 (7)

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

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

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

from the baseline day to 111 days post-baseline.

All randomised

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 randomisation, 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

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

Absorption

Posaconazole is absorbed with a median t

of 3 hours (fed patients). The pharmacokinetics

of posaconazole are linear following single and multiple dose administration of up to 800 mg

when taken with a high fat meal. No further increases in exposure were observed when doses

above 800 mg daily were administered to patients and healthy volunteers. In the fasting state,

AUC increased less than in proportion to dose above 200 mg. In healthy volunteers under

fasting conditions, dividing the total daily dose (800 mg) into 200 mg four times daily

compared to 400 mg twice daily, was shown to increase posaconazole exposure by 2.6-fold.

Effect of food on oral absorption in healthy volunteers

The absorption of posaconazole was significantly increased when posaconazole 400 mg (once

daily) was administered during and immediately after the consumption of a high fat meal

(~ 50 grams fat) compared to administration before a meal, with C

and AUC increasing by

approximately 330 % and 360 %, respectively. The AUC of posaconazole is: 4 times greater

when administered with a high-fat meal (~ 50 grams fat) and about 2.6 times greater when

administered during a non-fat meal or nutritional supplement (14 grams fat) relative to the

fasted state (see sections 4.2 and 4.5).

Distribution

Posaconazole is slowly absorbed and slowly eliminated with a large apparent volume of

distribution (1,774 litres) and 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 is slowly eliminated with a mean half-life (t

) of 35 hours (range 20 to

66 hours). 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 is attained following 7 to 10 days of multiple-dose

administration.

Pharmacokinetics in special populations

Children (< 18 years)

Pharmacokinetics in paediatric patients below the age of 18 years have not been established.

Gender

The pharmacokinetics of posaconazole are comparable in men and women.

Elderly (≥ 65 years)

An increase in C

(26 %) and AUC (29 %) was observed in elderly subjects (24 subjects

65 years of age) relative to younger subjects (24 subjects 18 - 45 years of age). However, in

clinical efficacy trials, the safety profile of posaconazole between the young and elderly

patients was similar.

Race

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 modelling 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 with 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, Cl

< 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.

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.

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 systemic exposures 4.6-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 1.4-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 1.4-fold and 4.6-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

Liquid glucose (corn syrup)

Glycerol

Polysorbate 80

Artificial cherry flavour #13174

Titanium dioxide

Simeticone

Xanthan gum

Sodium benzoate

Citric acid monohydrate

Sodium citrate dihydrate

Purified water

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

Unopened container: The expiry date of the product is indicated on the packaging materials

After first opening the container: 4 weeks.

6.4

Special precautions for storage

Store below 25˚C. Do not freeze.

6.5

Nature and contents of container

105 mL of oral suspension in a 123 ml bottle (glass amber type IV) closed with a plastic

child-resistant cap (polypropylene) and a measuring spoon (polystyrene) with 2 graduations:

2.5 mL and 5 mL.

6.6

Special precautions for disposal

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

local requirements.

7.

MARKETING AUTHORISATION HOLDER

Merck Sharp & Dohme (Israel- 1996) Company Ltd.,

P.O.Box 7121, Petah-Tikva 49170.

8.

MANUFACTURER:

Merck Sharp & Dohme Corp., New-Jersey, USA

9. MARKETING AUTHORISATION NUMBER

138 37 31627

Revised in August 2020.