SPORANOX ORAL SOLUTION

- certain medicines to treat irritated urinary bladder:

fesoterodine, imidafenacin, solifenacin, tolterodine.

- certain medicines to treat erectile dysfunction: sildenafil,

tadalafil.

- praziquantel, a medicine to treat worms.

- ebastine, to treat allergies.

- reboxetine, to treat depression.

- meloxicam, a medicine to treat joint inflammation and

pain.

- cinacalcet, a medicine to treat an overactive thyroid.

- certain medicines to treat low blood sodium levels:

mozavaptan, tolvaptan.

- alitretinoin (oral formulation), to treat eczema.

- eletriptan, to treat migraines.

- loperamide (to treat diarrhea).

- medicines which slow blood coagulation or thin the blood,

such as warfarin.

Use of the medicine and food

It is recommended to abstain from eating grapefruit or drinking

grapefruit juice during the course of treatment.

Always take the medicine without food, since the absorption

of the medicine will be better. Do not eat or drink for a full

hour after taking this medicine.

Pregnancy and breastfeeding

Do not take Sporanox Oral Solution if you are pregnant

(unless a life-threatening situation is at hand and the doctor

has instructed otherwise).

If you are of child-bearing age and could become pregnant,

use effective contraceptives to make sure that you do not

become pregnant while taking this medicine. Since the

preparation remains in the body for some time after you stop

taking it, continue to use contraception until your second

menstrual period after stopping treatment with this medicine

occurs.

If you are breastfeeding, do not take Sporanox Oral Solution;

consult with the doctor before commencing treatment with

Sporanox Oral Solution; very small quantities of Sporanox

Oral Solution may pass into the breast milk.

Driving and using machines

Sporanox Oral Solution can sometimes cause dizziness,

blurred vision/double vision or hearing loss. If you have

any of these symptoms, do not drive and do not operate

machinery.

Important information regarding some of the ingredients

of the medicine

Each ml contains 0.6 mg sodium saccharin and 190 microliter

sorbitol 70% solution.

Inform the doctor if you suffer from an intolerance to fructose

(a type of sugar) that is found in sorbitol, which is one of the

ingredients of the Sporanox Oral Solution preparation.

3. HOW SHOULD THE MEDICINE bE USED?

Always use according to the doctor's instructions.

Check with the doctor or pharmacist if you are uncertain.

The dosage and treatment regimen will be determined by

the doctor only.

Do not exceed the recommended dose.

This medicine is not usually intended for children or the elderly,

unless the doctor has explicitly instructed otherwise.

Always take the medicine without food, since the absorption

of the medicine will be better. Do not eat or drink for a full

hour after taking this medicine.

For treatment of fungal infection of the mouth, throat or

esophagus, gargle with the solution in your mouth for 20

seconds before swallowing. Avoid rinsing your mouth after

taking the medicine. Do not eat or drink for an hour after

using this medicine.

Instructions for opening the bottle:

The bottle comes with a safety cap that prevents children from

randomly opening it. Open the bottle by pressing down on

the cap (1), while turning it counterclockwise (2).

Instructions for using the measuring cup:

A. The solution comes with a clear plastic

measuring cup on top of the bottle

cap.

B. Remove the measuring cup from the

bottle.

C. Measurement should be done by

filling the concave, upper part of the

measuring cup with the solution. See

markings on the attached sketch.

D. The concave, upper part of the

measuring cup has “ring” markings

of 2.5 ml, 5 ml and 10 ml.

E. The bottom part of the measuring cup

has three holes on both sides meant

only for gripping the measuring cup.

Do not use this part for measuring the

amount of solution.

F. The amount of solution measured will

be according to the dosage determined

by the doctor.

If you accidentally take too high a dosage or if a child has

accidentally swallowed the medicine, immediately refer to a

doctor or proceed to a hospital emergency room and bring the

package of the medicine with you. The doctor will consider

administering active charcoal.

If you forget to take the medicine, take the next dose as usual.

Do not take a double dose.

How can you contribute to the success of the treatment?

Complete the treatment regimen as recommended by the

doctor.

Even if there is an improvement in your health, do not

discontinue treatment with the medicine without consulting

with the doctor.

Do not take medicines in the dark! Check the label and the

dose each time you take medicine. Wear glasses if you need

them.

If you have further questions regarding use of the medicine,

consult a doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of Sporanox Oral Solution may

cause side effects in some users. Do not be alarmed when

reading the list of side effects. You may not suffer from any

of them.

The following symptoms may occur:

Abdominal pain and irritable bowel syndrome, nausea,

vomiting, diarrhea, constipation, excess gas in the stomach,

shortness of breath, cough, fluid in the lungs, altered voice,

inflammation of the sinuses, inflammation of the nose,

upper respiratory tract inflammation, headache, menstrual

cycle disorders, erectile dysfunction, dizziness, confusion,

tremor, sleepiness, fatigue, chills, muscle weakness or

pain, painful joints, pain, chest pain, swelling, generalized

swelling, inflammation of the pancreas, unpleasant taste,

fever, excessive sweating or hair loss, rash, certain blood

problems that may increase the chance of bleeding, bruising

or infections, inflammation of the liver (hepatitis), yellowing of

the skin (jaundice), itching.

In addition, an increase in heart rate, an increase in blood

pressure, a decrease in blood pressure, or heart failure may

occur.

Changes in laboratory tests results may occur such as

decrease in granulocytes, decrease in white blood cells,

decrease in platelets, decrease in blood magnesium level,

decrease in blood potassium level, increase in blood

potassium level, increase in blood sugar level, increase in

blood creatine phosphokinase level, increase in liver enzymes,

increase in blood bilirubin level, increase in blood triglycerides,

or increase in blood urea.

Effects which require special attention:

Inform your doctor immediately if you experience any of the

effects below:

- Hypersensitivity to Sporanox Oral Solution, manifested, for

example, by skin rash, itching, redness of the skin (hives),

shortness of breath or difficulty breathing, swollen face or

a severe skin problem (widespread rash with peeling skin

and blisters in the mouth, eyes and genitals, or rash with

pustules or small blisters on the skin) - stop treatment with

Sporanox Oral Solution immediately.

- One or more of the following symptoms that can occur

may be related to a severe liver problem: lack of appetite,

nausea, vomiting, abnormal tiredness, abdominal pain,

very dark urine or light-colored stools - stop treatment with

Sporanox Oral Solution immediately.

- Reduced sensation in the limbs, tingling sensation in the

limbs or other nerve problems in the arms or legs.

- Hypersensitivity to sunlight.

- One of more of the following symptoms which may be

related to heart failure: shortness of breath, unexpected

weight gain, swelling of the legs, unusual fatigue, or you

begin to wake up at night.

- Blurry or double vision, ringing in the ears, loss of control

of urination or urinating much more often than usual,

symptoms of hearing loss. Temporary or permanent hearing

loss may occur.

In any event that you experience side effects not mentioned

in this leaflet, or if there is a change in your general health,

consult with the doctor immediately.

5. HOW SHOULD THE MEDICINE bE STORED?

Avoid poisoning! This medicine and any other medicine must

be kept in a safe place out of the reach of children and/or

infants to avoid poisoning. Do not induce vomiting unless

explicitly instructed to do so by the doctor.

Do not use the medicine after the expiry date (exp. Date) that

appears on the package. The expiry date refers to the last

day of that month.

Store at or below 25°C.

Sporanox Oral Solution can only be used for one month after

first opening the bottle.

6. FURTHER INFORMATION

In addition to the active ingredient, this medicine also

contains:

Hydroxypropyl-

-cyclodextrin, sorbitol liquid non-crystallising,

propylene glycol, concentrated hydrochloric acid, cherry

flavor 1, cherry flavor 2, caramel, sodium saccharin, sodium

hydroxide, purified water.

What does the medicine look like and what are the contents

of the package:

Sporanox Oral Solution is provided in a 150 ml bottle with

a measuring cup.

The solution is clear, colored yellow to yellowish-brown and

has a cherry odor.

Registration Holder and address: J-C Health Care Ltd.,

Kibbutz Shefayim, 6099000, Israel.

Manufacturer: Janssen Pharmaceutica, Beerse, Belgium.

This leaflet was checked and approved by the Ministry of

Health in July 2013.

Registration number of the medicine in the National Drug

Registry of the Ministry of Health: 141 49 29632 01

PATIENT PACKAGE INSERT IN ACCORDANCE

WITH THE PHARMACISTS’ REGULATIONS

(PREPARATIONS) - 1986

The medicine is dispensed with a doctor's prescription only

Sporanox Oral Solution

®

Each ml contains 10 mg itraconazole

Inactive ingredients and allergens in the preparation - see

section 6 "Further Information".

Read this leaflet carefully in its entirety before using the

medicine. This leaflet contains concise information about the

medicine. If you have further questions, refer to the doctor

or pharmacist.

This medicine has been prescribed to treat you. Do not pass

it on to others. It may harm them even if it seems to you that

their medical condition is similar.

This medicine is not usually intended for children or the elderly,

unless the doctor has explicitly instructed otherwise.

1. WHAT IS THE MEDICINE INTENDED FOR?

Sporanox Oral Solution is a medicine from the triazole group

for treatment of fungal infections of: the mouth, throat and

esophagus and for prevention of fungal infections during

neutropenia in patients suffering from impaired function of

the immune system.

Therapeutic group: Triazole antifungals.

2. bEFORE USING THE MEDICINE

Do not use the medicine if:

- You are sensitive (allergic) to the active ingredient or to

any of the other ingredients contained in the medicine,

listed in section 6 "Further Information".

- You are pregnant.

- You are of child-bearing age. Use effective contraceptives

in order to ensure that you do not become pregnant while

under treatment with this medicine. Since the preparation

remains in the body for a certain period of time after you

have stopped using it, continue using contraception until

your second menstrual period after stopping treatment

with the medicine.

You are suffering from heart failure, since the preparation

may aggravate your condition. If the doctor decided to

prescribe the preparation for you, despite the fact that

you suffer from heart failure, refer for medical attention

immediately if you experience shortness of breath, sudden,

unexpected weight gain, swelling of the legs or abdomen,

unusual fatigue or if you start to wake up at night.

- In addition, do not use certain medicines if you are under

treatment with this medicine. There are many medicines

which interact with Sporanox Oral Solution. Please see

the list of medicines further in this leaflet.

Special warnings regarding use of the medicine:

before treatment with Sporanox Oral Solution, tell the

doctor:

- If you are taking other medicines concomitantly to taking

Sporanox Oral Solution, since taking certain medicines

together can cause harm.

- If you are suffering from impaired function of the liver, such

as jaundice, there may be a need to adjust the dosage.

If you have to take Sporanox Oral Solution continuously for

more than one month, the doctor may want to check your

liver by performing blood tests.

- Stop taking Sporanox Oral Solution and refer to your doctor

immediately if you experience the following symptoms

of severe liver problems that occur during the course of

treatment: lack of appetite, nausea, vomiting, tiredness,

abdominal pain, yellow skin or eyes, light-colored stools or

very dark urine. In order to rule out liver disorders (which

may occur in rare cases), the doctor may ask that you

perform periodic blood tests during the course of treatment

with the medicine.

- You are suffering from impaired function of the heart.

Immediately refer to your doctor or bring to his attention if

you develop shortness of breath, unexpected weight gain,

swelling of the legs, unusual fatigue or if you begin to wake

up at night with shortness of breath, since these can be

symptoms of heart failure.

- If you are suffering from kidney function problems. There

may be a need to change the dosage.

- Tell the doctor or get medical assistance immediately if

you develop a severe allergic reaction (characterized by

significant skin rash, itching, hives, difficulty breathing

and/or swollen face) during the course of treatment with

Sporanox Oral Solution.

- Stop taking Sporanox Oral Solution and tell your doctor

immediately if you develop hypersensitivity to sunlight.

- Stop taking Sporanox Oral Solution and tell your doctor

immediately if you develop a severe skin reaction such

as widespread rash with skin peeling and blisters in the

mouth, eyes and genitals, or a rash with small pustules or

blisters.

- Stop taking Sporanox Oral Solution and tell your doctor

immediately if you develop a tingling sensation, diminished

sensation or weakness in the limbs, or other nerve problems

in the arms or legs.

- Inform your doctor if you have suffered from an allergic

reaction in the past to other antifungals.

- If you suffer from cystic fibrosis (C.F.), your doctor may

discontinue treatment, at his discretion, if you are not

responding to therapy.

- Tell your doctor if your vision gets blurry or you see double, if

you hear ringing in your ears, if you lost the ability to control

urination or if you urinate much more than usual.

- Stop taking Sporanox Oral Solution and inform the doctor

immediately if you notice any decrease in hearing or any

symptoms of hearing loss. In very rare cases, patients who

took Sporanox reported temporary or permanent decrease/

loss of hearing.

- Do not switch Sporanox Oral Solution with Sporanox

Capsules.

If you are taking, or have recently taken, other medicines,

including non-prescription medicines and nutritional

supplements, tell the doctor or pharmacist. It is particularly

important to inform the doctor or pharmacist if you are

taking:

Medicines that must never be taken concomitantly with

Sporanox Oral Solution

- certain medicines for allergy: terfenadine, astemizole,

mizolastine.

- certain medicines used to treat angina (crushing chest pain)

or high blood pressure: bepridil, felodipine, nisoldipine,

lercanidipine, ivabradine, ranolazine, eplerenone.

- cisapride, a medicine to treat certain digestive problems.

- certain medicines to lower cholesterol: simvastatin,

lovastatin, atorvastatin.

- sleeping pills midazolam (oral), and triazolam.

- certain medicines to treat arrhythmias: disopyramide,

dronedarone, quinidine, dofetilide.

- certain medicines to treat psychotic disorders: lurasidone,

pimozide, sertindole.

- colchicine, a medicine to treat gout, when administered to

patients with impaired function of the kidneys or the liver.

- certain medicines to treat severe pain or to manage

addiction: levacetylmethadol (levomethadyl), methadone.

- halofantrine, a medicine to treat malaria.

- irinotecan, an anti-cancer drug.

- preparations from the ergot group: dihydroergotamine,

eletriptan or ergotamine, used to treat migraines.

- preparations from the ergot group, such as ergometrine

(ergonovine) or methylergometrine (methylergonovine).

Wait at least 2 weeks after stopping treatment with Sporanox

Oral Solution before taking these medicines.

Medicines that can decrease the effect of Sporanox Oral

Solution, such as

- medicines to treat epilepsy: carbamazepine, phenytoin,

phenobarbital.

- medicines to treat tuberculosis: rifampicin, rifabutin,

isoniazid.

- medicines to treat HIV/AIDS: efavirenz, nevirapine.

- St. John's wort.

Inform the doctor if you are taking these medicines.

Wait at least two weeks after stopping treatment with these

medicines before commencing treatment with Sporanox Oral

Solution.

Medicines that are not recommended unless your doctor

decides that they are essential

- certain medicines to treat cancer, especially dasatinib,

nilotinib, trabectedin.

- aliskiren, a medicine to treat hypertension.

- rifabutin, a medicine to treat tuberculosis.

- carbamazepine, a medicine to treat epilepsy.

- colchicine, a medicine to treat gout.

everolimus, a medicine given after an organ transplantation.

- fentanyl, a strong medicine to treat pain.

- rivaroxaban, a medicine that slows down blood clotting.

- salmeterol, a medicine to improve breathing.

- tamsulosin, a medicine to treat male urinary incontinence.

- vardenafil, a medicine to treat erectile dysfunction.

Wait at least two weeks after stopping treatment with

Sporanox Oral Solution before starting these medicines,

unless the doctor feels it is necessary to take them.

Medicines that may require a dosage change (for either

Sporanox Oral Solution or the other medicine), such as

- certain antibiotics: ciprofloxacin, clarithromycin,

erythromycin.

- certain medicines that act on the heart or blood vessels:

digoxin, nadolol, certain calcium-channel blockers such as

verapamil, dihydropyridines, and cilostazol.

- medicines that slow down blood clotting: coumarins,

cilostazol, dabigatran.

- methylprednisolone, budesonide, ciclesonide, fluticasone

or dexamethasone (which are given by mouth, injection or

inhalation) to treat inflammations, asthma, and allergies.

- cyclosporine, tacrolimus, temsirolimus or rapamycin (also

known as sirolimus), which are usually given after an organ

transplantation.

- certain medicines to treat HIV/AIDS: maraviroc, and protease

inhibitors: indinavir, ritonavir, darunavir, fosamprenavir,

saquinavir.

- certain medicines to treat cancer: bortezomib, busulfan,

docetaxel, erlotinib, ixabepilone, lapatinib, trimetrexate,

vinca alkaloids.

- certain medicines given for sedation or hypnosis, such as

buspirone, alprazolam, brotizolam, perospirone, ramelteon,

intravenous midazolam.

- certain strong medicines to treat pain: alfentanil, fentanyl,

buprenorphine, oxycodone.

- certain medicines to treat diabetes: repaglinide,

saxagliptin.

- certain medicines to treat psychosis: aripiprazole,

haloperidol, quetiapine, risperidone.

- certain medicines to treat nausea and vomiting: aprepitant,

domperidone.

Sporanox oral sol PI _approved_July_13

"

ע עבקנ הז ןולע טמרופ

"

ודי לע רשואו קדבנ ונכותו תואירבה דרשמ י

"

1. TRADE NAME OF THE MEDICINAL PRODUCT

SPORANOX ORAL SOLUTION

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml SPORANOX oral solution contains 10 mg itraconazole. For excipients, see Section 6.1.

3. PHARMACEUTICAL FORM

Oral solution.

SPORANOX oral solution is clear.

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

SPORANOX

oral solution is indicated for the treatmemt of :

1. Oropharyngeal and esophageal candidiasis,

2. Prevention of fungal infection during neutropenia in immunodeficient patients.

4.2. Posology and method of administration

For optimal absorption, SPORANOX oral solution should be taken without food (patients are

advised to refrain from eating or drinking for at least 1 hour after intake).

For the treatment of oral and/or esophageal candidosis, the oral solution should be swished

around the oral cavity (approx. 20 seconds) and swallowed. There should be no rinsing after

swallowing.

Treatment of oral and/or esophageal candidosis

200 mg (2 measuring cups) per day in two intakes, or alternatively in one intake, for 1 week. If

there is no response after 1 week, treatment should be continued for another week.

Treatment of fluconazole resistant oral and/or esophageal candidosis

100 to 200 mg (1-2

measuring cups) twice daily for 2 weeks. If there is no response after 2 weeks, treatment should

Sporanox oral sol PI _approved_July_13

be continued for another 2 weeks. The 400 mg daily dose should not be used for longer than 14

days if there are no signs of improvement.

Prophylaxis of fungal infections

5 mg/kg per day administered in two intakes. In clinical trials, prophylaxis treatment was

started immediately prior to the cytostatic treatment and generally one week before transplant

procedure. Treatment was continued until recovery of neutrophils (i.e. > 1000 cells/µl).

Empiric therapy of febrile neutropenic patients with suspected systemic mycoses

Treatment should be started with SPORANOX IV. The recommended dose of SPORANOX IV

is 200 mg b.i.d. for four doses, followed by 200 mg once daily for up to 14 days. Each

intravenous

dose

should

infused

over

hour.

Treatment

should

continued

with

SPORANOX oral solution 200 mg (20 ml) b.i.d. until resolution of clinically significant

neutropenia. The safety and efficacy of SPORANOX use exceeding 28 days in empiric therapy

of febrile patients with suspected systemic mycoses is not known.

Use in

pediatric patients

Clinical data on the use of SPORANOX oral solution in pediatric patients are limited. The use

of SPORANOX oral solution in pediatric patients is not recommended unless it is determined

that the potential benefit outweighs the potential risks. See section 4.4 Special warnings and

special precautions for use.

Prophylaxis of fungal infections: there are no efficacy data available in neutropenic children.

Limited safety experience is available with a dose of 5 mg/kg per day administered in two

intakes. The incidence of adverse events such as diarrhea, abdominal pain, vomiting, fever, rash

and mucositis was higher than in adults. However, it is not clear to what extent this is

attributable to SPORANOX oral solution or the chemotherapy.

Use in elderly

Clinical data on the use of SPORANOX oral solution in elderly patients are limited, it is

advised to use SPORANOX oral solution in these patients only if it is determined that the

potential benefits outweighs the potential risks. In general, it is recommended that the dose

selection for an elderly patient should be taken into consideration, reflecting the greater

frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other

drug therapy.See Section 4.4 Special warnings and special precautions for use.

Sporanox oral sol PI _approved_July_13

Use in patients with hepatic impairment

Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Caution should be exercised when this drug is administered in this patient population. (See

Section 5.2 Pharmacokinetic properties, Special populations, Hepatic impairment)

Use in patients with renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The

exposure of itraconazole may be lower in some patients with renal insufficiency. Caution

should be exercised when this drug is administered in this patient population and adjusting the

dose may be considered.

4.3. Contraindications

-SPORANOX oral solution is contraindicated in patients with known hypersensitivity to

itraconazole or to any of the excipients.

-Co-administration of the following drugs is contraindicated with Sporanox Oral Solution (see also

4.5 Interaction with other medicinal products and other forms of interaction):

- CYP3A4 metabolised substrates that can prolong the QT-interval e.g., astemizole, bepridil,

cisapride, dofetilide, levacetylmethadol (levomethadyl), mizolastine, pimozide, quinidine, sertindole

and terfenadine are contraindicated with Sporanox oral solution. Co-administration may result in

increased plasma concentrations of these substrates, which can lead to QT prolongation and rare

occurrences of

torsade de pointes.

- CYP3A4 metabolized HMG-CoA reductase inhibitors such as atorvastatin, lovastatin and

simvastatin

- Triazolam and oral midazolam

- Ergot alkaloids such as dihydroergotamine, ergometrine (ergonovine), ergotamine and

methylergometrine (methylergonovine).

- Eletriptan

- Nisoldipine

-Sporanox oral solution should not be administered to patients with evidence of ventricular

dysfunction such as congestive heart failure (CHF) or a history of CHF except for the

treatment of life-threatening or other serious infections. See Section 4.4 Special warnings and

special precautions for use.

Sporanox oral sol PI _approved_July_13

-SPORANOX oral solution must not be used during pregnancy (except for life-threatening

cases). See Section 4.6 Pregnancy and lactation and Fertility.

Women of childbearing potential taking SPORANOX oral solution should use contraceptive

precautions. Effective contraception should be continued until the menstrual period following

the end of SPORANOX oral solution therapy.

4.4. Special warnings and special precautions for use

Cardiac effects

In a healthy volunteer study with SPORANOX IV, a transient asymptomatic decrease of the

left ventricular ejection fraction was observed; this resolved before the next infusion. The

clinical relevance of these findings to the oral formulations is unknown.

Itraconazole has been shown to have a negative inotropic effect and SPORANOX has been

associated with reports of congestive heart failure. Heart failure was more frequently reported

among spontaneous reports of 400 mg total daily dose than among those of lower total daily

doses, suggesting that the risk of heart failure might increase with the total daily dose of

itraconazole.

SPORANOX should not be used in patients with congestive heart failure or with a history of

congestive

heart

failure

unless

benefit

clearly

outweighs

risk.

This

individual

benefit/risk assessment should take into consideration factors such as the severity of the

indication, the dosing regimen, (e.g., total daily dose), and individual risk factors for congestive

heart failure. These risk factors include cardiac disease, such as ischemic and valvular disease;

significant pulmonary disease, such as chronic obstructive pulmonary disease; and renal failure

and other edematous disorders. Such patients should be informed of the signs and symptoms of

congestive heart failure, should be treated with caution, and should be monitored for signs and

symptoms of congestive heart failure during treatment; if such signs or symptoms do occur

during treatment, SPORANOX should be discontinued.

Calcium channel blockers can have negative inotropic effects which may be additive to those of

itraconazole. In addition itraconazole can inhibit the metabolism of calcium channel blockers.

Therefore, caution should be used when co-administering itraconazole and calcium channel

blockers due to an increased risk of CHF.

Sporanox oral sol PI _approved_July_13

Interaction potential

Coadministration of specific drugs with itraconazole may result in changes in efficacy of

itraconazole and/or the coadministered drug, life-threatening effects and/or sudden death.

Drugs that are contraindicated, not recommended or recommended for use with caution in

combination with itraconazole are listed in ( Section 4.5: Interaction with other medicinal

products and other forms of interaction).

Cystic fibrosis

In cystic fibrosis patients, variability in therapeutic levels of itraconazole was observed with

steady state dosing of oral solution using 2.5 mg/kg bid. Steady state concentrations of >

250 ng/mL were achieved in approximately 50% of subjects greater than 16 years of age, but in

none of the patients less than 16 years of age. If a patient does not respond to SPORANOX oral

solution, consideration should be given to switching to SPORANOX IV or to alternative

therapy.

Use in

pediatric patients

Clinical data on the use of SPORANOX oral solution in pediatric patients are limited. The use

of SPORANOX oral solution in pediatric patients is not recommended unless it is determined

that the potential benefit outweighs the potential risks.

Use in elderly

Clinical data on the use of SPORANOX oral solution in elderly patients are limited. It is

advised to use SPORANOX oral solution in these patients only if it is determined that the

potential benefit outweighs the potential risks. In general, it is recommended that the dose

selection for an elderly patient should be taken into consideration, reflecting the greater

frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other

drug therapy.

Hepatic effects

Very rare cases of serious hepatotoxicity, including some cases of fatal acute liver failure, have

occurred with the use of SPORANOX. Most of these cases involved patients who, had pre-

existing liver disease, were treated for systemic indications, had significant other medical

conditions and/or were taking other hepatotoxic drugs. Some patients had no obvious risk

factors for liver disease. Some of these cases were observed within the first month of treatment,

Sporanox oral sol PI _approved_July_13

including some within the first week. Liver function monitoring should be considered in

patients receiving SPORANOX treatment. Patients should be instructed to promptly report to

their physician signs and symptoms suggestive of hepatitis such as anorexia, nausea, vomiting,

fatigue,

abdominal

pain

dark

urine.

these

patients

treatment

should

stopped

immediately and liver function testing should be conducted.

Limited data are available on the use of oral itraconazole in patients with hepatic impairment.

Caution should be exercised when the drug is administered in this patient population. It is

recommended that patients with impaired hepatic function be carefully monitored when

taking itraconazole. It is recommended that the prolonged elimination half-life of itraconazole

observed in the single oral dose clinical trial with itraconazole capsules in cirrhotic patients

be considered when deciding to initiate therapy with other medications metabolized by

CYP3A4.

In patients with elevated or abnormal liver enzymes or active liver disease, or who have

experienced liver toxicity with other drugs, treatment with SPORANOX oral solution is

strongly discouraged unless there is a serious or life threatening situation where the expected

benefit exceeds the risk. It is recommended that liver function monitoring should be done in

patients with pre-existing hepatic function abnormalities or those who have experienced liver

toxicity with other medications.

(See Pharmacokinetic Properties - Special Populations, Hepatic impairment.)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment. The

exposure of itraconazole may be lower in some patients with renal insufficiency. Caution

should be exercised when this drug is administered in this patient population and adjusting the

dose may be considered

Treatment of severely neutropenic patients

SPORANOX

oral

solution

treatment

oral

and/or

esophageal

candidosis

investigated in severely neutropenic patients. Due to the pharmacokinetic properties (See

Section 5.2.), SPORANOX oral solution is not recommended for initiation of treatment in

patients at immediate risk of systemic candidosis.

Cross-hypersensitivity

Sporanox oral sol PI _approved_July_13

There is no information regarding cross-hypersensitivity between itraconazole and other azole

antifungal agents. Caution should be used in prescribing SPORANOX oral solution to patients

with hypersensitivity to other azoles.

Neuropathy

If neuropathy occurs that may be attributable to SPORANOX oral solution, the treatment

should be discontinued.

Hearing Loss

Transient or permanent hearing loss has been reported in patients receiving treatment with

itraconazole. Several of these reports included concurrent administration of quinidine which is

contraindicated (See Sections 4.3 Contraindications and 4.5 Interaction with other medicinal

products and other forms of interaction, 2. Effect of itraconazole on the metabolism of other

drugs). The hearing loss usually resolves when treatment is stopped, but can persist in some

patients.

Cross-resistance

In systemic candidosis, if fluconazole-resistant strains of Candida species are suspected, it

cannot be assumed that these are sensitive to itraconazole, hence it is recommended to have

their sensitivity tested before the start of itraconazole therapy.

Interchangeability

It is not recommended that SPORANOX capsules and SPORANOX oral solution be used

interchangeably. This is because drug exposure is greater with the oral solution than with the

capsules when the same dose of drug is given.

Sporanox Oral Solution contains sorbitol and should not be given to patients with rare

hereditary problems of fructose intolerance.

4.5. Interaction with other medicinal products and other forms of interaction

Itraconazole is mainly metabolized through CYP3A4. Other substances that either share this

metabolic pathway or modify CYP3A4 activity may influence the pharmacokinetics of

itraconazole. Similarly, itraconazole may modify the pharmacokinetics of other substances

that share this metabolic pathway. Itraconazole is a potent CYP3A4 inhibitor and a P-

glycoprotein inhibitor. When using concomitant medication, it is recommended that the

Sporanox oral sol PI _approved_July_13

corresponding label be consulted for information on the route of metabolism and the

possible need to adjust dosages.

Drugs that may decrease itraconazole plasma concentrations

Coadministration of itraconaozle with potent enzyme inducers of CYP3A4 may decrease

the bioavailability of itraconazole and hydroxy-itraconazole to such an extent that efficacy

may be largely reduced. Examples include:

Antibacterials: isoniazid, rifabutin (see also under Drugs that may have their plasma

concentrations increased by itraconazole), rifampicin.

Anticonvulsants: carbamazepine, (see also under Drugs that may have their plasma

concentrations increased by itraconazole), phenobarbital, phenytoin.

Antivirals: efavirenz, nevirapine.

Hypericum perforatum (St. John’s wort).

Therefore, administration of potent enzyme inducers of CYP3A4 with itraconazole is not

recommended. It is recommended that the use of these drugs be avoided from 2 weeks

before and during treatment with itraconazole, unless the benefits outweigh the risk of

potentially reduced itraconazole efficacy. Upon coadministration, it is recommended that

the antifungal activity be monitored and the itraconazole dose increased as deemed

necessary.

Drugs that may increase itraconazole plasma concentrations

Potent inhibitors of CYP3A4 may increase the bioavailability of itraconazole. Examples

include:

Antibacterials:ciprofloxacin, clarithromycin, erythromycin;

Antivirals: ritonavir-boosted darunavir, ritonavir-boosted fosamprenavir, indinavir

(see also under Drugs that may have their plasma concentrations increased by

itraconazole),

ritonavir

(see

also

under

Drugs

that

have

their

plasma

concentrations increased by itraconazole),

recommended

that

these

drugs

used

with

caution

when

coadministered

with

itraconazole

oral

solution.

recommended

that

patients

must

take

itraconazole

Sporanox oral sol PI _approved_July_13

concomitantly with potent inhibitors of CYP3A4 be monitored closely for signs or symptoms

of increased or prolonged pharmacologic effects of itraconazole, and the itraconazole dose be

decreased as deemed necessary. When appropriate, it is recommended that itraconazole plasma

concentrations be measured.

Drugs that may have their plasma concentrations increased by itraconazole

Itraconazole and its major metabolite, hydroxy-itraconazole, can inhibit the metabolism of

drugs metabolized by CYP3A4 and can inhibit the drug transport by P-glycoprotein, which

may result in increased plasma concentrations of these drugs and/or their active metabolite(s)

when they are administered with itraconazole. These elevated plasma concentrations may

increase or prolong both therapeutic and adverse effects of these drugs. CYP3A4-metabolized

drugs known to prolong the QT interval may be contraindicated with itraconazole, since the

combination may lead to ventricular tachyarrhythmias including occurrences of torsade de

pointes, a potentially fatal arrhythmia. Once treatment is stopped, itraconazole plasma

concentrations decrease to an almost undetectable concentration within 7 to 14 days, depending

on the dose and duration of treatment. In patients with hepatic cirrhosis or in subjects receiving

CYP3A4 inhibitors, the decline in plasma concentrations may be even more gradual. This is

particularly important when initiating therapy with drugs whose metabolism is affected by

itraconazole.

The interacting drugs are categorized as follows:

-‘Contraindicated’: Under no circumstances is the drug to be coadministered with

itraconazole, and up to two weeks after discontinuation of treatment with itraconazole.

-‘Not recommended’: It is recommended that the use of the drug be avoided during

and up to two weeks after discontinuation of treatment with itraconazole, unless the

benefits outweigh the potentially increased risks of side effects. If coadministration

cannot

avoided,

clinical

monitoring

signs

symptoms

increased

prolonged effects or side effects of the interacting drug is recommended, and its

dosage be reduced or interrupted as deemed necessary. When appropriate, it is

recommended that plasma concentrations be measured.

-‘Use

with

caution’:

Careful

monitoring

recommended

when

drug

coadministered with itraconazole. Upon coadministration, it is recommended that

patients be monitored closely for signs or symptoms of increased or prolonged effects

or side effects of the interacting drug, and its dosage be reduced as deemed necessary.

When appropriate, it is recommended that plasma concentrations be measured.

Examples

drugs

that

have

their

plasma

concentrations

increased

itraconazole presented by drug class with advice regarding coadministration with

itraconazole:

Sporanox oral sol PI _approved_July_13

Drug Class

Contraindicated

Not Recommended

Use with Caution

Alpha Blockers

tamsulosin

Analgesics

levacetylmethadol

(levomethadyl),

methadone

Fentanyl

alfentanil,

buprenorphine

sublingual,

oxycodone

Antiarrhythmics

disopyramide,

dofetilide,

dronedarone,

quinidine

digoxin

Antibacterials

rifabutin

Anticoagulants

Antiplatelet Drugs

rivaroxaban

coumarins,

cilostazol,

dabigatran

Anticonvulsants

carbamazepine

Antidiabetics

repaglinide,

saxagliptin

Antihelmintics

Antiprotozoals

Halofantrine

Praziquantel

Antihistamines

astemizole,

mizolastine,

terfenadine

ebastine

Antimigraine Drugs

ergot alkaloids, such

Sporanox oral sol PI _approved_July_13

Drug Class

Contraindicated

Not Recommended

Use with Caution

dihydroergotamine,

ergometrine

(ergonovine),

ergotamine,

methylergometrine

(methylergonovine)

eletriptan

Antineoplastics

irinotecan

dasatinib,

nilotinib,

trabectedin

bortezomib,

busulphan,

docetaxel,

erlotinib,

ixabepilone,

lapatinib,

trimetrexate,

vinca alkaloids

Antipsychotics,

Anxiolytics

Hypnotics

lurasidone,

oral midazolam,

pimozide,

sertindole,

triazolam

alprazolam,

aripiprazole,

brotizolam,

buspirone,

haloperidol,

midazolam IV,

perospirone,

quetiapine,

ramelteon,

Sporanox oral sol PI _approved_July_13

Drug Class

Contraindicated

Not Recommended

Use with Caution

risperidone

Antivirals

maraviroc,

indinavir

ritonavir

saquinavir

Beta Blockers

nadolol

Calcium

Channel

Blockers

bepridil,

felodipine,

lercanidipine,

nisoldipine

other dihydropyridines,

including verapamil

Cardiovascular Drugs,

Miscellaneous

ivabradine,

ranolazine

aliskiren

Diuretics

eplerenone

Gastrointestinal Drugs

cisapride,

aprepitant,

domperidone

Immunosuppressants

everolimus

budesonide,

ciclesonide,

cyclosporine,

dexamethasone,

fluticasone,

methylprednisolone,

rapamycin (also known

as sirolimus),

tacrolimus,

Sporanox oral sol PI _approved_July_13

Drug Class

Contraindicated

Not Recommended

Use with Caution

temsirolimus

Lipid

Regulating

Drugs

lovastatin,

simvastatin,

atrovastatin

Respiratory Drugs

salmeterol

SSRIs, Tricyclics and

Related

Antidepressants

reboxetine

Urological Drugs

vardenafil

fesoterodine.

imidafenacin,

sildenafil,

solifenacin,

tadalafil,

tolterodine

Other

colchicine, in

subjects with renal

or hepatic

impairment

colchicine

alitretinoin

(oral

formulation),

cinacalcet,

mozavaptan,

tolvaptan

loperamide

See also under Drugs that may decrease itraconazole plasma concentrations

See also under Drugs that may increase itraconazole plasma concentrations

Drugs that may have their plasma concentrations decreased by itraconazole

Sporanox oral sol PI _approved_July_13

Coadministration of itraconazole with the NSAID meloxicam may decrease the plasma

concentration of meloxicam. It is recommended that meloxicam be used with caution when

coadministered with itraconazole, and its effects or side effects be monitored. It is

recommended that the dosage of meloxicam, if coadministered with itraconazole, be adapted if

necessary.

Pediatric Population

Interaction studies have only been performed in adults.

4.6. Pregnancy, lactation

and Fertility

Pregnancy

SPORANOX must not be used during pregnancy except for life-threatening cases where the

potential benefit to the mother outweighs the potential harm to the fetus (See Section 4.3

Contraindications).

In animal studies itraconazole has shown reproduction toxicity (See Section 5.3 Preclinical

safety data).

There is limited information on the use of SPORANOX during pregnancy. During post-

marketing experience, cases of congenital abnormalities have been reported. These cases

included skeletal, genitourinary tract, cardiovascular and ophthalmic malformations as well as

chromosomal and multiple malformations. A causal relationship with SPORANOX has not

been established.

Epidemiological data on exposure to SPORANOX during the first trimester of pregnancy –

mostly in patients receiving short-term treatment for vulvovaginal candidosis – did not show an

increased risk for malformations as compared to control subjects not exposed to any known

teratogens.

Women of childbearing potential

Women of childbearing potential taking SPORANOX oral solution should use contraceptive

precautions. Effective contraception should be continued until the menstrual period following

the end of SPORANOX therapy.

Lactation

Sporanox oral sol PI _approved_July_13

A very small amount of itraconazole is excreted in human milk. The expected benefits of

treatment with SPORANOX oral solution should therefore be weighed against the potential

risk of breast-feeding. In case of doubt, the patient should not breast-feed.

Fertility

Refer to

Non-Clinical Information

in animal

fertility information relevant to itraconazole

and hydroxypropyl-β-cyclodextrin.

4.7. Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. When

driving

vehicles

operating

machinery

possibility

adverse

reactions

such

dizziness, visual disturbances and hearing loss (See Adverse Reactions.), which may occur in

some instances, must be taken into account.

4.8. Undesirable effects

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events

that were considered to be reasonably associated with the use of itraconazole based on the

comprehensive assessment of the available adverse event information. A causal relationship with

itraconazole cannot be reliably established in individual cases. Further, because clinical trials are

conducted under widely varying conditions, adverse reaction rates observed in the clinical trials

of a drug cannot be directly compared to rates in the clinical trials of another drug and may not

reflect the rates observed in clinical practice.

Clinical Trial Data

The safety of SPORANOX oral solution was evaluated in 889 patients who participated in six

double-blind and four open-label clinical trials. Of the 889 patients treated with SPORANOX oral

solution, 624 patients were treated with SPORANOX oral solution during the double-blind trials.

All 889 patients received at least one dose of SPORANOX oral solution for the treatment of

oropharyngeal and esophageal candidiasis and provided safety data. Adverse drug reactions

(ADRs) reported for ≥1% of patients treated with SPORANOX oral solution in these clinical

trials are shown in Table 1.

Sporanox oral sol PI _approved_July_13

Table 1:

Adverse Drug Reactions Reported by ≥1% of

Patients Treated with SPORANOX Oral Solution

in 10 Clinical Trials

System Organ Class

Adverse Drug Reaction

TRADENAME

Oral Solution

(N=889)

Nervous System Disorders

Headache

Dysgeusia

Dizziness

Respiratory, Thoracic and Mediastinal

Disorders

Cough

Gastrointestinal Disorders

Diarrhea

Nausea

Vomiting

Abdominal pain

Dyspepsia

Skin and Subcutaneous Tissue Disorders

Rash

General Disorders and Administration Site

Conditions

Pyrexia

Adverse drug reactions that occurred in <1% of patients treated with SPORANOX oral solution

in these clinical trials are listed in Table 2.

Table 2:

Adverse Drug Reactions Reported by <1% of

Patients Treated with SPORANOX Oral

Solution in 10 Clinical Trials

System Organ Class

Adverse Drug Reaction

Blood and Lymphatic System Disorders

Leukopenia

Thrombocytopenia

Immune System Disorders

Hypersensitivity

Metabolism and Nutrition Disorders

Hypokalemia

Nervous System Disorders

Hypoesthesia

Neuropathy peripheral

Sporanox oral sol PI _approved_July_13

Paresthesia

Ear and Labyrinth Disorders

Tinnitus

Cardiac Disorders

Cardiac failure

Gastrointestinal Disorders

Constipation

Hepatobiliary Disorders

Hepatic failure

Hyperbilirubinemia

Skin and Subcutaneous Tissue Disorders

Pruritus

Urticaria

Musculoskeletal and Connective Tissue Disorders

Arthralgia

Myalgia

Reproductive System and Breast Disorders

Menstrual disorder

General Disorders and Administration Site Conditions

Edema

The following is a list of additional ADRs associated with itraconazole that have been reported in

clinical trials of SPORANOX capsules and SPORANOX IV, excluding the ADR term “Injection

site inflammation” which is specific to the injection route of administration.

Infections and Infestations:

Sinusitis, Upper respiratory tract infection, Rhinitis

Blood and Lymphatic System Disorders:

Granulocytopenia

Immune System Disorders:

Anaphylactoid reaction

Metabolism and Nutrition Disorders:

Hyperglycemia, Hyperkalemia, Hypomagnesemia

Psychiatric Disorders:

Confusional state

Nervous System Disorders:

Somnolence, Tremor

Cardiac Disorders:

Left ventricular failure, Tachycardia

Vascular Disorders:

Hypertension, Hypotension

Respiratory, Thoracic and Mediastinal Disorders:

Pulmonary edema, Dysphonia

Gastrointestinal Disorders

: Gastrointestinal disorder, Flatulence

Hepatobiliary Disorders:

Hepatitis, Jaundice, Hepatic function abnormal

Sporanox oral sol PI _approved_July_13

Skin and Subcutaneous Tissue Disorders:

Rash erythematous, Hyperhidrosis

Renal and Urinary Disorders:

Renal impairment, Pollakiuria, Urinary incontinence

Reproductive System and Breast Disorders:

Erectile dysfunction

General Disorders and Administration Site Conditions:

Generalized edema, Face edema,

Chest pain, Pain, Fatigue, Chills

Investigations:

Alanine aminotransferase increased, Aspartate aminotransferase increased, Blood

alkaline phosphatase increased, Blood lactate dehydrogenase increased, Blood urea increased,

Gamma-glutamyltransferase increased, Hepatic enzyme increased, Urine analysis abnormal

Pediatrics

The safety of SPORANOX oral solution was evaluated in 250 pediatric patients aged 6 months to

14 years who participated in five open-label clinical trials. These patients received at least one

dose of SPORANOX oral solution for prophylaxis of fungal infections or for treatment of oral

thrush or systemic fungal infections and provided safety data.

Based on pooled safety data from these clinical trials, the very common reported ADRs in

pediatric

patients

were

Vomiting

(36.0%),

Pyrexia

(30.8%),

Diarrhea

(28.4%),

Mucosal

inflammation (23.2%), Rash (22.8%), Abdominal pain (17.2%), Nausea (15.6%), Hypertension

(14.0%), and Cough (11.2%). The nature of ADRs in pediatric patients is similar to that observed

in adult subjects, but the incidence is higher in the pediatric patients.

Post marketing Experience

Adverse drug reactions first identified during post-marketing experience with SPORANOX (all

formulations) are included in Table 3 . The frequencies are provided according to the following

convention:

Very common

≥1/10

Common

≥1/100 and <1/10

Uncommon

≥1/1000 and <1/100

Rare

≥1/10,000 and <1/1000

Very rare

<1/10,000, including isolated reports.

In Table 3, ADRs are presented by frequency category based on spontaneous reporting rates.

Sporanox oral sol PI _approved_July_13

Table 3:

Adverse Drug Reactions Identified During Post-

Marketing Experience with SPORANOX by

Frequency Category Estimated from Spontaneous

Reporting Rates

Immune System Disorders

Very rare

Serum sickness, Angioneurotic edema,

Anaphylactic reaction

Metabolism and Nutrition Disorders

Very rare

Hypertriglyceridemia

Eye Disorders

Very rare

Visual disturbances (including diplopia and

vision blurred)

Ear and Labyrinth Disorders

Very rare

Transient or permanent hearing loss

Cardiac Disorders

Very rare

Congestive heart failure

Respiratory, Thoracic and Mediastinal Disorders

Common

Dyspnea

Gastrointestinal Disorders

Very rare

Pancreatitis

Hepatobiliary Disorders

Very rare

Serious hepatotoxicity (including some cases of

fatal acute liver failure)

Common

Hepatic enzyme increased

Skin and Subcutaneous Tissue Disorders

Very rare

Toxic epidermal necrolysis, Stevens-Johnson

syndrome, Acute generalized exanthematous

pustulosis, Erythema multiforme, Exfoliative

dermatitis, Leukocytoclastic vasculitis, Alopecia,

Photosensitivity

Investigations

Very rare

Blood creatine phosphokinase increased

4.9. Overdose

Symptoms and signs

In general, adverse events reported with overdose have been consistent with those reported for

itraconazole use. (See Adverse Reactions.)

Sporanox oral sol PI _approved_July_13

Treatment

In the event of an overdose, supportive measures should be employed. Activated charcoal may

be given if considered appropriate. Itraconazole cannot be removed by hemodialysis.

No specific antidote is available.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic classification

Antimycotic for systemic use, triazole derivatives

ATC code: J02A C02

Mechanism of action

In vitro

studies have demonstrated that itraconazole impairs the synthesis of ergosterol in

fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its

synthesis ultimately results in an antifungal effect.

Pharmacodynamic effects

Microbiology

Itraconazole, a triazole derivative, has a broad spectrum of activity.

For itraconazole, breakpoints have only been established for

Candida

spp. from superficial

mycotic

infections

(CLSI

M27-A2,

breakpoints

have

been

established

EUCAST

methodology). The CLSI breakpoints are as follows: susceptible ≤0.125; susceptible, dose-

dependent 0.25-0.5 and resistant ≥1 µg/mL. Interpretive breakpoints have not been established

for the filamentous fungi.

In vitro

studies demonstrate that itraconazole inhibits the growth of a broad range of fungi

pathogenic for humans at concentrations usually ≤1 µg/ml. These include:

dermatophytes (

Trichophyton spp.

Microsporum spp.

Epidermophyton floccosum

); yeasts

Candida

spp.

including

C.

albicans,

C.

tropicalis

C.

parapsilosis

C.

krusei

Cryptococcus neoformans, Malassezia spp.

Trichosporon spp.

Geotrichum spp.

Aspergillus

spp.

Histoplasma spp.

; ., including

H. capsulatum Paracoccidioides brasiliensis

Sporothrix

Sporanox oral sol PI _approved_July_13

schenckii

Fonsecaea spp.

Cladosporium spp.

Blastomyces dermatitidis

Coccidiodes immitis

Pseudallescheria boydii

Penicillium marneffei

; and various other yeasts and fungi.

Candida krusei, Candida glabrata

Candida tropicalis

are generally the least susceptible

Candida

species, with some isolates showing unequivocal resistance to itraconazole

in vitro

The principal fungus types that are not inhibited by itraconazole are

Zygomycetes

(e.g.

Rhizopus spp.

Rhizomucor spp.

Mucor spp.

Absidia spp.

Fusarium spp.

Scedosporium

spp.

Scopulariopsis spp.

Azole resistance appears to develop slowly and is often the result of several genetic mutations.

Mechanisms that have been described are overexpression of ERG11, which encodes the target

enzyme 14α-demethylase, point mutations in ERG11 that lead to decreased target affinity

and/or

transporter

overexpression

resuling

increased

efflux.

Cross-resistance

between

members of the azole class has been observed within

Candida

spp., although resistance to one

member of the class does not necessarily confer resistance to other azoles. Itraconazole-

resistant strains of

Aspergillus fumigatus

have been reported.

5.2. Pharmacokinetic properties

Itraconazole

General pharmacokinetic characteristics

Peak plasma concentrations are reached within 2.5 hours following administration of the oral

solution. As a consequence of non-linear pharmacokinetics, itraconazole accumulates in plasma

during multiple dosing. Steady-state concentrations are generally reached within about 15 days,

with C

and AUC values 4 to 7-fold higher than those seen after a single dose. Steady-state

values of about 2 µg/ml are reached after oral administration of 200 mg once daily. The

terminal half-life of itraconazole generally ranges from 16 to 28 hours after single dose and

increases to 34 to 42 hours with repeated dosing. Once treatment is stopped, itraconazole

plasma concentrations decrease to an almost undetectable concentration within 7 to 14 days,

depending on the dose and duration of treatment. Itraconazole mean total plasma clearance

following intravenous administration is 278 ml/min. Itraconazole clearance decreases at higher

doses due to saturable hepatic metabolism.

Absorption

Itraconazole

rapidly

absorbed

after

administration

oral

solution.

Peak

plasma

concentrations of itraconazole are reached within 2.5 hours following administration of the oral

Sporanox oral sol PI _approved_July_13

solution under fasting conditions. The observed absolute bioavailability of itraconazole under

fed conditions is about 55% and increases by 30% when the oral solution is taken in fasting

conditions.

Itraconazole exposure is greater with the oral solution than with the capsule formulation when

the same dose of drug is given. (See

Warnings and Precautions

Distribution

Most of the itraconazole in plasma is bound to protein (99.8%) with albumin being the main

binding component (99.6% for the hydroxy- metabolite). It has also a marked affinity for lipids.

Only 0.2% of the itraconazole in plasma is present as free drug. Itraconazole is distributed in a

large apparent volume in the body (> 700 L), suggesting extensive distribution into tissues:

Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be two

to three times higher than corresponding concentrations in plasma, and the uptake into

keratinous tissues, skin in particular, up to four times higher.

Concentrations in the cerebrospinal fluid are much lower than in plasama, but efficacy has been

demonstrated against infections present in the cerebrospinal fluid.

Metabolism

Itraconazole is extensively metabolized by the liver into a large number of metabolites.

In vitro

studies have shown that CYP3A4 is the major enzyme involved in the metabolism of

itraconazole.

main

metabolite is hydroxy-itraconazole

which has

in

vitro

antifungal

activity comparable to itraconazole: trough plasma concentrations of this metabolite are about

twice those of itraconazole.

Excretion

Itraconazole is excreted mainly as inactive metabolites in urine (35%) and in feces (54%)

within one week of an oral solution dose. Renal excretion of itraconazole and the active

metabolite hydroxy-itraconazole account for less than 1% of an intravenous dose. Based on an

oral radiolabeled dose, fecal excretion of unchanged drug ranges from 3% to 18% of the dose.

As re-distribution of itraconazole from keratinous tissues appears to be negligible, elimination

of itraconazole from these tissues is related to epidermal regeneration. Contrary to plasma, the

concentration in skin persists for 2 to 4 weeks after discontinuation of a 4-week treatment and

in nail keratin – where itraconazole can be detected as early as 1 week after start of treatment –

for at least six months after the end of a 3-month treatment period.

Sporanox oral sol PI _approved_July_13

Special Populations

Hepatic impairment

Itraconazole

predominantly

metabolized

liver.

pharmacokinetic

study

conducted in 6 healthy and 12 cirrhotic subjects who were administered a single 100-mg dose

of itraconazole as a capsule. A statistically significant reduction in mean C

(47%) and a

twofold increase in the elimination half-life (37 ± 17 hours vs. 16 ± 5 hours) of itraconazole

were noted in cirrhotic subjects compared with healthy subjects.

However overall exposure to itraconazole, based on AUC was similar in cirrhotic patients and

in healthy subjects. Data are not available in cirrhotic patients during long-term use of

itraconazole. (See Sections 4.2 Posology and method of administration, and 4.4 Special

warnings and special precautions for use.)

Renal impairment

Limited data are available on the use of oral itraconazole in patients with renal impairment.

A pharmacokinetic study using a single 200-mg dose of itraconazole (four 50-mg capsules) was

conducted in three groups of patients with renal impairment (uremia: n=7; hemodialysis: n=7;

and continuous ambulatory peritoneal dialysis: n=5). In uremic subjects with a mean creatinine

clearance of 13 ml/min. × 1.73 m

, the exposure, based on AUC, was slightly reduced

compared with normal population parameters. This study did not demonstrate any significant

effect of hemodialysis or continuous ambulatory peritoneal dialysis on the pharmacokinetics of

itraconazole (T

, and AUC

0-8h

). Plasma concentration-versus-time profiles showed wide

intersubject variation in all three groups.

After a single intravenous dose, the mean terminal half-lives of itraconazole in patients with

mild (defined in this study as CrCl 50-79 ml/min), moderate (defined in this study as CrCl 20-

49 ml/min), and severe renal impairment (defined in this study as CrCl <20 ml/min) were

similar to that in healthy subjects, (range of means 42-49 hours vs 48 hours in renally impaired

patients and healthy subjects, respectively.) Overall exposure to itraconazole, based on AUC,

was decreased in patients with moderate and severe renal impairment by approximately 30%

and 40%, respectively, as compared with subjects with normal renal function.

Data are not available in renally impaired patients during long-term use of itraconazole.

Dialysis has no effect on the half-life or clearance of itraconazole or hydroxy-itraconazole. (See

also

Dosage and

Administration

Warnings and

Precautions

Sporanox oral sol PI _approved_July_13

Pediatrics

Limited

pharmacokinetic

data

available

itraconazole

pediatric

population. Clinical pharmacokinetic studies in children and adolescents aged between 5

months and 17 years were performed with itraconazole capsules, oral solution or intravenous

formulation Individual doses with the capsule and oral solution formulation ranged from 1.5 to

12.5 mg/kg/day, given as once-daily or twice-daily administration. The intravenous formulation

was given either as a 2.5 mg/kg single infusion, or a 2.5 mg/kg infusion given once daily or

twice daily. For the same daily dose, twice daily dosing compared to single daily dosing

yielded peak and trough concentrations comparable to adult single daily dosing. No significant

age dependence was observed for itraconazole AUC and total body clearance, while weak

associations between age and itraconazole distribution volume, C

and terminal elimination

rate were noted. Itraconazole apparent clearance and distribution volume seemed to be related

to weight.

Hydroxypropyl­ß­Cyclodextrin

The oral bioavailability of hydroxypropyl-β-cyclodextrin given as a solubilizer of itraconazole

in oral solution is on average lower than 0.5% and is similar to that of hydroxypropyl-β-

cyclodextrin

alone.

This

oral

bioavailability

hydroxypropyl-β-cyclodextrin

modified by the presence of food and is similar after single and repeated administrations.

5.3. NON CLINICAL INFORMATION

Itraconazole

Itraconazole has been tested in a standard battery of non-clinical safety studies.

Acute toxicity studies with itraconazole in mice, rats, guinea pigs and dogs indicate a wide

safety margin. Sub (chronic) oral toxicity studies in rats and dogs revealed several target organs

or tissues: adrenal cortex, liver and mononuclear phagocyte system as well as disorders of the

lipid metabolism presenting as xanthoma cells in various organs.

At high doses, histological investigations of adrenal cortex showed a reversible swelling with

cellular hypertrophy of the zona reticularis and fasciculata, which was sometimes associated

with a thinning of the zona glomerulosa. Reversible hepatic changes were found at high doses.

Slight changes were observed in the sinusoidal cells and vacuolation of the hepatocytes, the

latter indicating cellular dysfunction, but without visible hepatitis or hepatocellular necrosis.

Sporanox oral sol PI _approved_July_13

Histological

changes

mononuclear

phagosystem

were

mainly

characterized

macrophages with increased proteinaceous material in various parenchymal tissues.

A global lower bone mineral density was observed in juvenile dogs after chronic itraconazole

administration.

In three toxicology studies using rats, itraconazole induced bone defects. The induced defects

included reduced bone plate activity, thinning of the zona compacta of the large bones, and

increased bone fragility.

Carcinogenicity and Mutagenicity

Itraconazole is not a primary carcinogen in rats or mice. In male rats, however, there was a

higher incidence of soft-tissue sarcoma, which is attributed to the increase in non-neoplastic,

chronic inflammatory reactions of the connective tissue as a consequence of raised cholesterol

levels and cholesterosis in connective tissue.

There are no indications of a mutagenic potential of itraconazole.

Reproductive Toxicology

Itraconazole was found to cause a dose-related increase in maternal toxicity, embryotoxicity,

and teratogenicity in rats and mice at high doses. In rats, the teratogenicity consisted of major

skeletal defects; in mice, it consisted of encephaloceles and macroglossia.

Fertility

There is no evidence of a primary influence on fertility under treatment with itraconazole.

Hydroxypropyl-β-cyclodextrin (HP-β-CD)

Single and repeated dose toxicity studies in mice, rats and dogs indicate a wide safety margin

after oral and intravenous administration of HP-β-CD. Most effects were adaptive in nature

(histological changes in the urinary tract, softening of feces related to the osmotic water

retention in the large intestine, activation of the mononuclear phagocyte system) and showed

good reversibility.

Slight liver changes occurred at doses of about 30 times the proposed human dose of HP-β-CD.

Sporanox oral sol PI _approved_July_13

Oral treatment of juvenile Beagle dogs with HP-β-CD at 1200 mg/kg for a period of up to 13

weeks with a 4-week recovery period was clinically well tolerated with no effects noted when

compared to control animals at laboratory or histopathology examination.

Carcinogenicity and Mutagenicity

No primary carcinogenicity activity was evidenced in the mouse carcinogenicity study.

In the rat carcinogenicity study, an increased incidence of neoplasms in the large intestine (at

5000 mg/kg/day) and in the exocrine pancreas (from 500 mg/kg/day) were seen.

Based

human

equivalent

dose

calculation

normalized

body

surface

area,

recommended clinical dose of TRADENAME oral solution contains approximately 1.7 times

the amount of HP-β-CD as was in the 500 mg/kg/day dose administered in rats in this

carcinogenicity study.

The slightly higher incidence of adenocarcinomas in the large intestines was linked to the

hypertrophic/hyperplastic and inflammatory changes in the colonic mucosa brought about by

HP-β-CD-induced increased osmotic forces and is considered to be of low clinical relevance.

Development of the pancreatic tumors is related to the mitogenic action of cholecystokinin in

rats. This finding was not observed in the mouse carcinogenicity study, nor in a 12-month

toxicity study in dogs or in a 2-year toxicity study in female cynomolgus monkeys. There is no

evidence that cholecystokinin has a mitogenic action in man. However, the clinical relevance of

these findings is not applicable.

HP-β-CD is not mutagenic.

The chemical structure of HP-β-CD does not raise suspicion for genotoxic activity. Tests on

DNA-damage, gene mutations and chromosome aberrations

in vitro

in vivo

did not reveal

any genotoxic activity.

Reproductive Toxicology

HP-β-CD has no direct embryotoxic and no teratogenic effect,

Fertility

HP-β-CD has no antifertile effect.

Sporanox oral sol PI _approved_July_13

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Hydroxypropyl-β-cyclodextrin, sorbitol liquid non-crystallising, propylene glycol, concentrated

hydrochloric

acid,

cherry

flavor

cherry

flavor

caramel,

sodium

saccharin,

sodium

hydroxide, purified water.

6.2. Incompatibilities

None known.

6.3. Shelf life

24 months as packaged for sale.

See expiry date on the outer pack.

6.4. Special precautions for storage

Store at 25°C or below.

6.5. Nature and contents of container

150 ml amber glass bottle, with child-resistant polypropylene screw cap and LDPE liner ring.

6.6. Instructions for use/handling

SPORANOX oral solution is supplied in bottles with a childproof cap, and should be opened as

follows: push the plastic screw cap down while turning it counter clockwise.

A measuring cup is supplied with the SPORANOX oral solution. Use the measuring cup just

as it sits on the bottle. Make sure that the side with the graduations (the side that holds less) is

uppermost; that is the side you have to fill. When the arrow on the side points up, the correct

side is uppermost.

MANUFACTURER

Janssen Pharmaceutica, Beerse, Belgium

REGISTRATION HOLDER

J-C Health care Ltd., Kibbutz Shefayim, 60990