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SPORANOX I.V. 10 MG/ML CONCENTRATE AND SOLVENT FOR SOLUTION FOR INFUSION

Active substance(s): ITRACONAZOLE

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PACKAGE LEAFLET: INFORMATION FOR THE USER

Sporanox ® I.V. 10 mg/ml
concentrate and solvent for solution for infusion
itraconazole
Read all of this leaflet carefully
before you are given this
medicine:
• Keep this leaflet. You may need to
read it again.
• If you have any further questions, ask
your doctor or nurse.
• If any of the side effects gets serious,
or if you notice any side effects not
listed in this leaflet, please tell your
doctor or nurse.

In this leaflet:
1 What Sporanox I.V. is and what it

is used for

2 Before you are given Sporanox I.V.
3 How you will be given

Sporanox I.V.

4 Possible side effects
5 How Sporanox I.V. is stored
6 Further information

1 What Sporanox I.V. is and what it is used for
Sporanox I.V. is one of a group of
medicines called “antifungals”. These
medicines are used to treat infections
caused by fungi including yeasts.

Sporanox I.V. is used to:

• Treat fungal infections of the internal
organs.

2 Before you are given Sporanox I.V.
You should not be given
Sporanox I.V. if:

• You are allergic (hypersensitive) to any
of the ingredients in Sporanox I.V.
(listed in section 6 further information)
• You are pregnant, think you might be
pregnant or are trying to become
pregnant, (see the section on
Pregnancy)
• Your kidney function is seriously
reduced
• You cannot have sodium chloride by
injection.
• You are taking any of the following
medicines:
- terfenadine, astemizole or mizolastine
(antihistamine for allergies)
- bepridil-used to treat angina
(crushing chest pain)
- nisoldipine (used for high blood
pressure)
- cisapride (used for stomach upsets)
- midazolam by mouth or triazolam
(used to help you sleep or for anxiety)
- lovastatin, simvastatin or atorvastatin
(used to lower cholesterol)
- pimozide and sertindole (for
conditions affecting thoughts,
feelings and/or behaviour)
- levacetylmethadol - for treatment of
drug abuse (opioid-dependency)
- dihydroergotamine, ergotamine and
eletriptan (for migraine headaches)
- ergometrine (ergonovine) and
methylergometrine
(methylergonovine) used after giving
birth
- quinidine and dofetilide (for irregular
heart beat rhythms)

Take special care with
Sporanox I.V.

Tell your doctor immediately: If you
have any unusual feelings of tingling,
numbness or weakness in your hands
or feet whilst taking Sporanox I.V..
If you experience any hearing loss
symptoms. In very rare cases patients
taking Sporanox have reported
temporary or permanent hearing loss.
You must tell your doctor before you are
given Sporanox I.V. if you suffer from or
have suffered in the past from any of
the following:
• Any liver problems or jaundice
(yellowing of the skin). If your doctor
decides to give you Sporanox I.V. the
dose may have to be changed. Your
doctor may give you instructions on
symptoms to watch out for and ask
you to have your blood checked.
• An allergic reaction to any other
antifungal medicine.
• Heart problems, including heart failure
(also called congestive heart failure or
CHF), Sporanox I.V. could make it
worse. If your doctor decides to give
you Sporanox I.V. you should be told
about the symptoms listed below to
watch out for. If you get any of the
following stop taking Sporanox I.V. and
tell your doctor straight away. These
may be signs of heart failure:
- shortness of breath
- unexpected weight gain
- swelling of your legs or stomach
- feel unusually tired
- wake up short of breath at night
• Are on a low salt diet.
• A kidney disorder, you may be
monitored more closely or your dose
of Sporanox I.V. may have to be
changed.

Taking other medicines

There are some medicines that you
should not take whilst being given
Sporanox IV. These are listed under the
heading “You should not be given
Sporanox I.V. if:”.

Tell your doctor if you are using the
following as they may stop Sporanox I.V.
from working properly:
• rifampicin, rifabutin and isoniazid
(antibiotics used to treat tuberculosis)
• phenytoin, carbamazepine and
phenobarbital (anti-epileptics)
• St John’s Wort (a herbal medicine)
Do not use Sporanox I.V. within 2 weeks
of taking these medicines.
Tell your doctor before taking any of
the following medicines as the dose of
Sporanox I.V. or other treatments may
need to be altered:
• clarithromycin or erythromycin
(anitibiotics for infections)
• medicines that act on the heart and
blood vessels (digoxin, disopyramide
and calcium channel blockers such as
dihydropyridines, verapamil and
cilostazol)
• drugs that slow down blood clotting or
thin the blood, such as warfarin
• methylprednisolone, budesonide,
fluticasone and dexamethasone drugs
given by mouth and injection for
inflammation, asthma and allergies
• cyclosporin, tacrolimus, rapamycin
(also known as sirolimus), which are
usually given after an organ transplant
• medicines used in HIV-infected
patients, such as ritonavir, indinavir
and saquinavir
• medicines for cancer (such as
busulphan, docetaxel, trimetrexate
and a group of medicines known as
vinca alkaloids)
• alfentanil and fentanyl (for pain)
• buspirone, alprazolam, brotizolam and
midazolam when given by injection into
a vein (for anxiety or to help you sleep)
• reboxetine (for depression)
• an antihistamine containing ebastine
• halofantrine (for malaria)
• repaglinide (for diabetes)
• cerivastatin (for lowering levels of
cholesterol)
Please tell your doctor or pharmacist if
you are taking or have recently taken
any other medicines, including
medicines obtained without a
prescription or herbal medicines.

Children and the elderly

Sporanox I.V. is not normally given to
children or the elderly. Your doctor may
prescribe it in special cases.

Pregnancy

Do not take Sporanox I.V. if you are
pregnant, unless your doctor has told
you to. If you are of child bearing age
and could become pregnant, you
should use contraceptives to make sure
that you do not become pregnant while
you are receiving your medicine. As
Sporanox I.V. remains in the body for
some time after you stop receiving it,
you should continue to use some form
of contraception until your next period
after your treatment with Sporanox I.V.
has finished.
If you do find that you are pregnant after
receiving a course of Sporanox I.V., tell
your doctor straight away.
Before taking any medicine - always tell
your doctor if you are pregnant, think
you might be pregnant or are trying to
become pregnant.

Breast feeding

You should stop breast-feeding before
you are given Sporanox, as small
amounts of the medicine could be
present in your breast milk.

Driving and using machines
Sporanox I.V. can sometimes cause
dizziness, blurred/double vision or
hearing loss. If you have these
symptoms, do not drive or use
machines.

3 How you will be given Sporanox I.V.
Your medicine will be given to you by
your doctor or nurse. Sporanox I.V.
concentrate is mixed with the sodium
chloride solution in the bag and is then
given by slow injection into a vein.
This is called an intravenous (I.V.)
infusion and will usually take about an
hour. For the first two days, you will be
given two infusions each day. From Day
three onwards you will be given one
infusion each day.

How much you will be given

Children:
Not recommended.
Elderly:
Not recommended.

If a dose is missed or you are
given too much Sporanox l.V

Since this medicine will be given to you
by a doctor or nurse, it is unlikely that
you will be given too much or that a
dose will be missed. However, if you are
worried, tell your doctor or nurse.

The recommended dosage is as follows:
Adults:
Day 1 and Day 2 of the treatment:
Two 1-hour infusions of 200 mg
Sporanox I.V. will be given each day
as a 60 ml infusion.
From Day 3 onwards:
One 1-hour infusion of 200 mg
Sporanox I.V. will be given each day as
a 60 ml infusion.

4 Possible side effects
Like all medicines, Sporanox I.V. can
cause side effects, although not
everybody gets them.
Medicines can cause serious allergic
reactions.
Stop taking Sporanox I.V. and contact
your doctor immediately if you have:
• any sudden wheeziness, difficulty in
breathing, swelling of the face, rash,
itching (especially affecting the whole
body) or a severe skin disorder
(widespread rashes with peeling skin
and blisters in the mouth, eyes and
genitals, or rashes with small pustules
or blisters).
• severe lack of appetite, feeling sick,
being sick, unusual tiredness,
abdominal (stomach) pain, unusually
dark urine, or pale stools. These may
be symptoms of severe liver problems.
You should also let your doctor know
immediately if you have any of the side
effects below:
• Symptoms that resemble heart failure
such as shortness of breath,
unexpected weight gain, swelling of
the legs, unusual fatigue (tiredness),
repeated waking at night.
• A tingling sensation, sensitivity to light,
numbness or weakness in the limbs.
• Blurred vision/double vision, ringing in
your ears, lose the ability to control
your urine or increased need to urinate
(pass water)
• If you experience any symptoms of
hearing loss
Other side effects include:
Very common side effects (occur in
more than 1 in 10 patients)
• feeling sick (nausea)

Common side effects (occur in less
than 1 in 10 patients) are:
• muscle weakness (possible symptom
of low blood levels of potassium)
• headache, dizziness
• stomach ache, being sick (vomiting),
diarrhoea, constipation
• increases in specific liver function
tests (hepatic enzyme increased),
inflammation of the liver (hepatitis),
yellowing of the skin (jaundice)
• rash, itching
• general swelling
• fever or high temperature
• shortness of breath
Uncommon side effects (occur in less
than 1 in 100 patients) are:
• high blood sugar levels
• unpleasant taste
• muscle pain
The following side effects have been
reported in patients taking Sporanox I.V.
with unknown frequency:
• certain blood disorders which may
increase the risk of bleeding, bruising
or infections
• excess of triglycerides in the blood
• high blood pressure
• indigestion
• hair loss
• painful joints
• menstrual disorders
• erectile dysfunction
• severe upper stomach pain, often with
nausea and vomiting due to
inflammation of the pancreas
(pancreatitis)
If any of these side effects gets
serious, or if you notice any side
effects not listed in this leaflet,
please tell your doctor or pharmacist.

5 How to store Sporanox I.V.
Keep out of the reach and sight of
children.
Sporanox I.V. will be kept in the hospital
pharmacy.
The product should not be used after
the expiry date printed on the inner and
outer packaging. The expiry date refers
to the last day of that month.
Do not store Sporanox I.V. concentrate
above 25°C.

Store in the original container.
Do not store the bag containing Sodium
Chloride above 25°C. Do not freeze.
Protect the mixed solution from direct
sunlight. Once mixed, the product
should be used immediately.

6 Further Information
What Sporanox I.V. contains:

• The active ingredient in Sporanox I.V.
is itraconazole (10mg of itraconazole
per ml).
• The other ingredients are
hydroxypropyl--cyclodextrin,
propylene glycol, hydrochloric acid
concentrated, sodium hydroxide and
water for injections.

What 0.9% Sodium Chloride
Injection contains:

• Sodium Chloride, water for injections.

What Sporanox I.V. looks like
and the contents of the pack

It is a kit containing a clear, colourless
concentrated solution for intravenous
(I.V.) infusion, which means the solution
needs to be diluted before use.
Sporanox I.V. comes in a 25 millilitre
(ml) ampoule, together with a bag
containing a clear, colourless Sodium
Chloride solution and an extension line.
These two solutions will be mixed
together to give a clear, colourless
solution before they are given directly
into your veins.
One ml of Sporanox I.V. concentrate
contains 10 milligrams (mg) of
itraconazole. When the Sporanox I.V.
concentrate is added to the bag
containing sodium chloride solution,
each ml of the mixed solution contains
3.33 mg itraconazole.
The Sodium Chloride bag is a plastic
polypropylene infusion bag, which
contains 50 ml of Sodium Chloride
solution. One ml of solution contains
9 mg sodium chloride. It is used to
dilute the Sporanox I.V. concentrate
making it easier to be given.

Marketing Authorisation Holder:
Janssen-Cilag Ltd, 50-100 Holmers
Farm Way, High Wycombe,
Buckinghamshire HP12 4EG, UK
Manufacturer:
Sporanox I.V. 10mg/ml concentrate and
solvent for solution for infusion are
manufactured by:
Lusomedicamenta
Sociedade Técnica Farmacêutica S.A.
Estrada Consiglieri Pedroso, 69-B
Queluz
2730-055 Barcarena
Portugal
This medicinal product is authorised
in the member states of the EEA
under the following names:
Germany: SEMPERA®
Spain: SPORANOX®
Ireland: SPORANOX®
Italy: SPORANOX®
Portugal: SPORANOX®
Greece: SPORANOX®
U.K: SPORANOX®
®

Registered trademark

For information in large
print, tape, CD or
Braille, phone 0800 731
8450 (UK) or 1800
709122 (IRE)
This leaflet was last approved in
08/2012

I.V.
TECHNICAL INFORMATION
Summary of Product Characteristics
1. Name of the Medicinal Product
Sporanox® I.V. 10 mg/ml concentrate and solvent for
solution for infusion.
2. Qualitative and Quantitative Composition
Each ml of the Sporanox IV concentrate contains 10 mg
itraconazole.
One ampoule with 25 ml contains 250 mg itraconazole
(itraconazole trihydrochloride salt formed in situ).
Each ml of the admixed solution contains 3.33 mg
itraconazole.
One single dose of 200 mg itraconazole corresponds to 60 ml
of the admixed solution.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Concentrate and solvent for solution for infusion.
Sporanox IV 10 mg/ml concentrate and solvent (0.9%
Sodium Chloride Injection) for solution for infusion is
presented in a procedure pack consisting of:
(a) 25 ml of Sporanox IV 10 mg/ml concentrate for infusion,
a colourless solution presented in a glass ampoule.
(b) 50 ml of 0.9 % Sodium Chloride Injection solvent for
solution for infusion, a colourless solution presented in
a polypropylene bag.
(c) Extension line with 2-way stopcock and in-line filter.
4. Clinical Particulars
4.1. Therapeutic Indications
Sporanox I.V. is indicated for the treatment of histoplasmosis.
Sporanox I.V. is indicated in the following systemic fungal
conditions when first-line systemic anti-fungal therapy is
inappropriate or has proved ineŮective. (This may be due to
underlying pathology, insensitivity of the pathogen or drug
toxicity).
Treatment of aspergillosis, candidosis and cryptococcosis
(including
cryptococcal
meningitis):
in
immunocompromised patients with cryptococcosis and in
all patients with cryptococcosis of the central nervous
system.
Consideration should be given to national and/or local
guidance regarding the appropriate use of antifungal
agents.
4.2. Posology and Method of Administration
This product is supplied with an extension line with a 2-way
stopcock and 0.2 ǹm in-line filter. The dedicated extension
line including the in-line filter must be used to ensure the
correct administration of the product (see section 6.6).
Sporanox I.V. is given on the first two days in a loading
dose twice daily, followed by once daily dosing.
Day 1 and 2 of the treatment: 1-hour infusion of 200 mg
(60 ml of the admixed solution) Sporanox I.V. twice daily.
(See section 6.6).
From day 3 on: one 1-hour infusion of 200 mg (60 ml of the
admixed solution) Sporanox I.V. each day. Safety for
periods longer than 14 days has not been established.
Use in children: Since clinical data on the use of Sporanox
I.V. in paediatric patients are unavailable, Sporanox I.V.
should not be used in children unless the potential benefit
outweighs the potential risk. (See section 4.4).
Use in elderly: Since clinical data of the use of Sporanox
I.V. in elderly patients are limited, it is advised to use
Sporanox I.V. in these patients only if the potential benefit
outweighs the potential risk. (See section 4.4).
Use in patients with renal impairment: Limited data are
available on the use of intravenous itraconazole in patients
with renal impairment.
Hydroxypropyl-E-cyclodextrin, a required component of
Sporanox intravenous formulation, is eliminated through
glomerular filtration. Therefore, in patients with severe renal
impairment defined as creatinine clearance below
30 ml/min the use of Sporanox IV is contraindicated. (See
section 4.3).
In patients with mild and moderate renal impairment,
Sporanox IV should be used with caution. Serum creatinine
levels should be closely monitored and, if renal toxicity is
suspected, consideration should be given to changing to
the oral capsule formulation. (See sections 4.4 and 5.2).
Use in patients with hepatic impairment: Limited data are
available on the use of itraconazole in patients with hepatic
impairment. Caution should be exercised when this drug is
administered in this patient population. (See section 5.2).
4.3. Contraindications
̋ Sporanox I.V. is contraindicated in patients with
a known hypersensitivity to itraconazole or to any of the
excipients.
̋ Sporanox I.V. cannot be used when administration of
Sodium Chloride Injection is contraindicated.
̋ The excipient hydroxypropyl-E-cyclodextrin is eliminated
through glomerular filtration. Therefore, Sporanox I.V. is
contraindicated in patients with severe renal impairment
defined as creatinine clearance below 30 ml/min. (See
sections 4.4 and 5.2).
̋ Coadministration of the following drugs is
contraindicated with Sporanox I.V. (See section 4.5):
• CYP3A4 metabolised substrates that can prolong the
QT-interval e.g., terfenadine, astemizole, bepridil,
mizolastine, cisapride, dofetilide, levacetylmethadol
(levomethadyl), quinidine, sertindole or pimozide
coadministration may result in increased plasma levels
of these substrates which can lead to QTc
prolongation and rare occurrences of torsades de
pointes.
• CYP3A4 metabolised HMG-CoA reductase inhibitors
such as simvastatin, lovastatin and atorvastatin
• Triazolam and oral midazolam
• Ergot alkaloids such as dihydroergotamine,
ergometrine (ergonovine), ergotamine and
methylergometrine (methylergonovine).
• Eletriptan
• Nisoldipine
̋ Sporanox I.V. must not be used during pregnancy for non
life-threatening indications (see section 4.6).
4.4. Special Warning and Precautions for Use
Cross hypersensitivity
There is no information regarding cross hypersensitivity
between itraconazole and other azole antifungal agents.
Caution should be used in prescribing Sporanox IV to
patients with hypersensitivity to other azoles
Cardiac eŮects
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. A similar investigation was not performed in the
target patient population.
Itraconazole has been shown to have a negative inotropic
eŮect 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 the benefit clearly outweighs the risk.
Physicians should carefully review the risks and benefits of
Sporanox therapy for patients with known risk factors for
congestive heart failure. These risk factors include cardiac
disease, such as ischaemic 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.
Caution should be exercised when co-administering
itraconazole and calcium channel blockers (see section 4.5).
Hepatic eŮects
Very rare cases of serious hepatotoxicity, including some
cases of fatal acute liver failure, have occurred with the use
of Sporanox. Some of these cases involved patients with no
pre-existing liver disease. Some of these cases have been
observed within the first month of treatment, 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 or
dark urine. In these patients treatment should be stopped
immediately and liver function testing should be conducted.
Most cases of serious hepatotoxicity 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. In patients with raised
liver enzymes or active liver disease, or who have
experienced liver toxicity with other drugs, treatment should
not be started unless the expected benefit exceeds the risk
of hepatic injury. In patients with impaired hepatic function
liver enzyme should be carefully monitored when taking
itraconazole.
Use in children
Since clinical data on the use of Sporanox IV in paediatric
patients are unavailable, Sporanox IV should not be used in
children unless the potential benefit outweighs the potential
risk.
Use in elderly
Since clinical data of the use of Sporanox IV in elderly
patients are limited, it is advised to use Sporanox IV in
these patients only if the potential benefit outweighs the
potential risk.
Hepatic impairment
Studies have not been conducted with intravenous
itraconazole 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
the drug is administered to this patient population (see
sections 4.2 and 5.2).
Renal impairment
Hydroxypropyl-E-cyclodextrin,
when
administered
intravenously, is eliminated through glomerular filtration.
Therefore, in patients with renal impairment defined as
creatinine clearance below 30 ml/min Sporanox IV is
contraindicated (see sections 4.3 and 5.2).
Sporanox IV should be used with caution in patients with
a lesser degree of renal failure. In patients with mild and
moderate renal impairment, serum creatinine levels should
be closely monitored and, if renal toxicity is suspected,
consideration should be given to changing to the oral
capsule formulation (see section 4.4).
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 and
4.5). The hearing loss usually resolves when treatment is
stopped, but can persist in some patients.
Neuropathy
If neuropathy occurs that may be attributable to Sporanox
IV, the treatment should be discontinued.
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 their sensitivity
should be tested before the start of itraconazole therapy.
Interaction potential
Sporanox has a potential for clinically important drug
interactions (see section 4.5).

Itraconazole should not be used within 2 weeks after
discontinuation of treatment with CYP 3A4 inducing agents
(rifampicin, rifabutin, phenobarbital, phenytoin,
carbamazepine, Hypericum perforatum (St. John´s wort).
The use of itraconazole with these drugs may lead to
subtherapeutic plasma levels of itraconazole and thus
treatment failure.
4.5. Interactions with Other Medicinal Products and
Other Forms of Interaction
1. Drugs aŮecting the metabolism of itraconazole:
Itraconazole is mainly metabolised through the cytochrome
CYP3A4. Interaction studies have been performed with
rifampicin, rifabutin and phenytoin, which are potent
enzyme inducers of CYP3A4. Since the bioavailability of
itraconazole and hydroxy-itraconazole was decreased in
these studies to such an extent that eůcacy may be largely
reduced, the combination of itraconazole with these potent
enzyme inducers is not recommended. No formal study
data are available for other enzyme inducers, such as
carbamazepine, Hypericum perforatum (St John’s Wort),
phenobarbital and isoniazid but similar eŮects should be
anticipated.
Potent inhibitors of CYP3A4 such as ritonavir, indinavir,
clarithromycin and erythromycin may increase the
bioavailability of itraconazole.
2. EŮect of itraconazole on the metabolism of other
drugs:
Itraconazole can inhibit the metabolism of drugs
metabolised by the cytochrome 3A family. This can result in
an increase and/or a prolongation of their eŮects, including
side eŮects. When using concomitant medication, the
corresponding label should be consulted for information on
the route of metabolism. After stopping treatment,
itraconazole plasma concentrations decline gradually,
depending on the dose and duration of treatment (See
section 5.2.). This should be taken into account when the
inhibitory eŮect of itraconazole on co-medicated drugs is
considered.
Drugs which are contraindicated with itraconazole:
• Terfenadine, astemizole, bepridil, mizolastine,
levacetylmethadol (levomethadyl), cisapride, dofetilide,
quinidine, sertindole or pimozide are contraindicated with
Sporanox I.V. since coadministration may result in
increased plasma levels of these substrates which can
lead to QTc prolongation and rare occurrences of
torsades de pointes (see section 4.3).
• CYP3A4 metabolised HMG-CoA reductase inhibitors
such as simvastatin, lovastatin, and atorvastatin.
• Triazolam and oral midazolam.
• Ergot alkaloids such as dihydroergotamine, ergometrine
(ergonovine), ergotamine and methylergometrine
(methylergonovine).
• Eletriptan.
• Nisoldipine
Caution should be exercised when co-administering
itraconazole with calcium channel blockers due to an
increased risk of congestive heart failure. In addition to
possible pharmacokinetic interactions involving the drug
metabolising enzyme CYP3A4, calcium channel blockers
can have negative inotropic eŮects which may be additive
to those of itraconazole.
The following drugs should be used with caution
and their plasma concentrations, eŮects or side eŮects
should be monitored. Their dosage, if co-administered with
itraconazole, should be reduced if necessary.
̋ Oral anticoagulants;
̋ HIV Protease Inhibitors such as ritonavir, indinavir,
saquinavir;
̋ Certain antineoplastic agents such as vinca alkaloids,
busulfan, docetaxel and trimetrexate;
̋ CYP3A4 metabolised calcium channel blockers such as
dihydropyridines and verapamil;
̋ Certain CYP3A4 metabolised HMG-CoA reductase
inhibitors such as cerivastatin (see also drugs which are
contraindicated with itraconazole);
̋ Certain immunosuppressive agents: cyclosporine,
tacrolimus, rapamycin (also known as sirolimus);
̋ Certain glucocorticosteroids such as budesonide,
dexamethasone, fluticasone and methylprednisolone;
̋ Digoxin: (via inhibition of P-glycoprotein)
̋ Others: carbamazepine, cilostazol, buspirone, alfentanil,
alprazolam, brotizolam, midazolam I.V., rifabutin,
disopyramide, ebastine, fentanyl, halofantrine,
repaglinide and reboxetine. The importance of the
concentration increase and clinical relevance of these
changes during co-administration with itraconazole
remain to be established.
No interaction of itraconazole with zidovudine (AZT) and
fluvastatine has been observed.
No inducing eŮects of itraconazole on the metabolism of
ethinyloestradiol and norethisterone were observed.
3. EŮect on protein binding:
In vitro studies have shown that there are no interactions on
the plasma protein binding between itraconazole and
imipramine, propranolol, diazepam, cimetidine,
indometacin, tolbutamide and sulfamethazine.
4.6. Pregnancy and Lactation
Pregnancy
Sporanox IV must not be used during pregnancy except for
life-threatening cases where the potential benefit to the
mother outweighs the potential harm to the foetus (See
section 4.3).
In animal studies itraconazole shows reproduction toxicity
(See section 5.3).
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 receiving Sporanox IV
should use contraceptive precautions. EŮective
contraception should be continued until the next menstrual
period following the end of Sporanox IV therapy.
Lactation
A very small amount of itraconazole is excreted in human
milk and must not be administered to lactating women.
Breast-feeding is to be discontinued prior to taking
itraconazole.
4.7. EŮects on Ability to Drive and Use Machines
No studies on the eŮects on the ability to drive and use
machines have been performed. When driving vehicles and
operating machinery the possibility of adverse reactions
such as dizziness, visual disturbances and hearing loss
(see section 4.8), which may occur in some instances,
must be taken into account.
4.8. Undesirable EŮects
In clinical trials with intravenous itraconazole, the most
frequently reported adverse experiences were of
gastrointestinal, metabolic and nutritional, and hepatobiliary
origin.
The table below presents adverse drug reactions by
System Organ Class. Within each System Organ Class, the
adverse drug reactions are presented by incidence, using
the following convention:
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).
Adverse Drug Reactions
Blood and lymphatic system disorders
Not Known
Leukopenia, neutropenia,
thrombocytopenia
Immune system disorders
Not Known
Serum Sickness, Angioneurotic
Oedema, Anaphylactic Reaction,
Anaphylactoid Reaction,
Hypersensitivity*
Metabolism and nutrition disorders
Common
Hypokalemia
Uncommon
Hyperglycaemia
Not Known
Hypertriglyceridemia
Nervous system disorders
Common
Headache, Dizziness
Uncommon
Hypoaesthesia
Not Known
Peripheral Neuropathy*, Paraesthesia
Eye disorders
Uncommon
Visual Disorders, including Vision
Blurred and Diplopia
Ear and labyrinth disorder
Uncommon
Transient or permanent hearing loss*
Not Known
Tinnitus
Cardiac disorders
Not Known
Congestive Heart Failure*,
Hypertension
Respiratory, thoracic and mediastinal disorders
Common
Dyspnoea
Uncommon
Pulmonary Oedema
Gastrointestinal disorders
Very Common Nausea
Common
Abdominal Pain, Vomiting, Diarrhoea,
Constipation
Uncommon
Dysgeusia
Not Known
Pancreatitis, Dyspepsia
Hepato-biliary disorders
Common
Hepatitis, Jaundice,
Hyperbilirubinaemia, Hepatic Enzymes
Increased
Not Known
Hepatotoxicity*, Acute Hepatic Failure*
Skin and subcutaneous tissue disorders
Common
Rash, Pruritus
Not Known
Toxic Epidermal Necrolysis, StevensJohnson Syndrome, Acute generalised
exanthematous pustulosis, Erythema
Multiforme, Exfoliative Dermatitis,
Leukocytoclastic Vasculitis, Urticaria,
Alopecia, Photosensitivity
Musculoskeletal and connective tissue disorders
Uncommon
Myalgia
Not Known
Arthralgia
Renal and urinary disorders
Not Known
Pollakiuria, urinary incontinence
Reproductive system and breast disorders
Not Known
Menstrual Disorders, Erectile
Dysfunction
General disorders and administration site
conditions
Common
Oedema, Pyrexia
* see section 4.4
4.9. Overdose
In the event of overdose, supportive measures should be
employed. Itraconazole cannot be removed by
haemodialysis. No specific antidote is available.
5. Pharmacological Properties
5.1. Pharmacodynamic Properties
Pharmacotherapeutic group: Antimycotic for systemic use,
triazole derivatives
ATC code: J02A C02
Mode of action
Itraconazole inhibits fungal 14D-demethylase, resulting in
a depletion of ergosterol and disruption of membrane
synthesis by fungi.
PK/PD relationship
The PK/PD relationship for itraconazole, and for triazoles in
general, is poorly understood and is complicated by limited
understanding of antifungal pharmacokinetics.
Mechanism(s) of resistance
Resistance of fungi to azoles appears to develop slowly
and is often the result of several genetic mutations.

Mechanisms that have been described are:
• Over-expression of ERG11, the gene that encodes
14-alpha-demethylase (the target enzyme)
• Point mutations in ERG11 that lead to decreased aůnity
of 14-alpha-demethylase for itraconazole
• Drug-transporter over-expression resulting in increased
eűux of itraconazole from fungal cells (i.e., removal of
itraconazole from its target)
• Cross-resistance. Cross-resistance amongst members of
the azole class of drugs has been observed within
Candida species though resistance to one member of
the class does not necessarily confer resistance to other
azoles.
Breakpoints
Breakpoints for itraconazole have not yet been established
for fungi using EUCAST methods.
Using CLSI methods, breakpoints for itraconazole have
only been established for Candida species from superficial
mycotic infections. The CLSI breakpoints are: susceptible
̞0.125 mg/L and resistant ̟1 mg/L.
The prevalence of acquired resistance may
vary geographically and with time for selected species, and
local information on resistance is desirable, particularly
when treating severe infections. As necessary, expert
advice should be sought when the local prevalence of
resistance is such that the utility of the agent in at least
some types of infections is questionable.
The in vitro susceptibility of fungi to itraconazole depends on
the inoculum size, incubation temperature, growth phase of
the fungi, and the culture medium used. For these reasons,
the minimum inhibitory concentration of itraconazole may
vary widely. Susceptibility in the table below is based on
MIC90 < 1 mg itraconazole/L. There is no correlation between
in vitro susceptibility and clinical eůcacy.

6.3. Shelf Life
Sporanox I.V.:
Shelf life as packaged:
2 years
0.9% Sodium Chloride Injection:
3 years
Admixed Solution:
24 hours.

Commonly susceptible species
Aspergillus spp.2
Blastomyces dermatitidis1
Candida albicans
Candida parapsilosis
Cladosporium spp.
Coccidioides immitis1
Cryptococcus neoformans
Epidermophyton floccosum
Fonsecaea spp. 1
Geotrichum spp.
Histoplasma spp.
Malassezia (formerly Pityrosporum) spp.
Microsporum spp.
Paracoccidioides brasiliensis1
Penicillium marneŮei1
Pseudallescheria boydii
Sporothrix schenckii
Trichophyton spp.
Trichosporon spp.
Species for which acquired resistance may be a problem
Candida glabrata3
Candida krusei
Candida tropicalis3
Inherently resistant organisms
Absidia spp.
Fusarium spp.
Mucor spp.
Rhizomucor spp.
Rhizopus spp.
Scedosporium proliferans
Scopulariopsis spp.
1 These organisms may be encountered in patients who
have returned from travel outside Europe.
2 Itraconazole-resistant strains of Aspergillus fumigatus
have been reported.
3 Natural intermediate susceptibility.

6.6. Instruction for Use/Handling
Sporanox I.V.:

5.2.
Pharmacokinetic Properties
General pharmacokinetic characteristics
The pharmacokinetics of intravenously administered
itraconazole has been investigated in healthy subjects, and
patients after single and multiple dosing and in special
populations after single doses.
Peak plasma concentrations of itraconazole are reached at
the end of the intravenous infusion, declining thereafter.
Peak plasma concentrations of hydroxyl-itraconazole (see
Biotransformation below) are reached within 3 hours of
beginning of a one-hour infusion, declining thereafter.
Each 200 mg intravenous dose of itraconazole contains 8 g
hydroxypropyl-E-cyclodextrin to increase the solubility of
itraconazole. The pharmacokinetic profiles of each are
described below. (See Itraconazole; see Special populationsRenal Impairment, Hydroxypropyl-E-cyclodextrin.)
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
aůnity 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
its 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. Brain to
plasma ratios were about 1 as measured in beagle dogs.
Biotransformation
Itraconazole is extensively metabolised by the liver into a
large number of metabolites. One of the main metabolites is
hydroxy-itraconazole, which has in vitro antifungal activity
comparable to itraconazole. Trough plasma concentrations
of the hydroxy-metabolite are about twice those of
itraconazole.
As shown in in-vitro studies, CYP3A4 is the major enzyme
that is involved in the metabolism of itraconazole.
Elimination
Itraconazole total plasma clearance following intravenous
administration is on average 381 ml/min. Itraconazole is
excreted as inactive metabolites to about 35% in urine
within one week and about 54% with feces. Renal excretion
of the itraconazole and the active metabolite hydroxyitraconazole account for less than 1% of an intravenous
dose. Based on an oral dose, fecal excretion of unchanged
drug ranges from 3% to 18% of the dose. Itraconazole is
excreted mainly as inactive metabolites in urine (35%) and
in feces (54%) within one week of an oral dose.
Linearity/non-linearity
As a consequence of non-linear pharmacokinetics,
itraconazole accumulates in plasma during multiple dosing.
In a multiple-dose pharmacokinetic study, itraconazole IV
was administered as a 1-hour infusion of 200 mg
itraconazole twice daily on days 1 and 2 of treatment,
followed by a 1-hour infusion of 200 mg once daily from day
3 to 7. Steady-state concentrations were reached after the
fourth dose of itraconazole IV and by the seventh dose for
hydroxy-itraconazole. Mean Cmax and Cmin values after
4 doses of 200 mg itraconazole IV in healthy subjects were
3055 ng/ml and 687 ng/ml respectively, while mean values
for hydroxy-itraconazole at the same time points were
1058 ng/ml and 1263 ng/ml respectively. Itraconazole mean
total plasma clearance following intravenous administration
is 278 ml/min. The mean elimination half-life of itraconazole
is about 32.5 hours after repeated dosing.
Special Populations
Hepatic Impairment
Studies have not been conducted with intravenous
itraconazole in patients with hepatic impairment.
Itraconazole is predominantly metabolised in the liver.
A single oral dose (100 mg capsule) was administered to
12 patients with cirrhosis and six healthy control subjects;
Cmax, AUC and terminal half-life of itraconazole were
measured and compared between groups. Mean
itraconazole Cmax was reduced significantly (by 47%) in
patients with cirrhosis. Mean elimination half-life was
prolonged compared to that found in subjects without
hepatic impairment (37 vs. 16 hours, respectively). Data are
not available in cirrhotic patients during long-term use of
itraconazole.
Renal Impairment
A small fraction (<1%) of an intravenous dose of
itraconazole is excreted unchanged in urine.
After a single intravenous dose, the mean terminal half-lives
of itraconazole in patients with mild (CrCl 50-79 ml/min),
moderate (CrCl 20-49 ml/min), and severe renal impairment
(CrCl <20 ml/min) were similar to that in healthy subjects,
(range of means 42-49 hr vs 48 hr 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 eŮect on the
half-life or clearance of itraconazole or hydroxy-itraconazole.
Hydroxypropyl-ß-Cyclodextrin
In patients with normal renal function, the pharmacokinetic
profile of hydroxypropyl- E –cyclodextrin, an ingredient of
Sporanox intravenous formulation, has a short half-life of 1 to
2 hours, and demonstrates no accumulation following
successive daily doses. In healthy subjects and in patients
with mild to severe renal insuůciency, the majority of
an 8 g dose of hydroxypropyl-E-cyclodextrin is eliminated in
the urine. Following a single intravenous dose of itraconazole
200 mg, clearance of hydroxypropyl-E-cyclodextrin was
reduced in subjects with renal impairment, resulting in higher
exposure to hydroxypropyl-E-cyclodextrin. In subjects with
mild, moderate, and severe renal impairment, half-life
values were increased over normal values by approximately
two-, four-, and six-fold, respectively. In these patients,
successive infusions may result in accumulation of
hydroxypropyl-E-cyclodextrin until steady state is reached.
Hydroxypropyl- E-cyclodextrin is removed by hemodialysis.
5.3. Preclinical Safety Data
Nonclinical data on itraconazole revealed no indications for
gene toxicity, primary carcinogenicity or impairment of
fertility. At high doses, eŮects were observed in the adrenal
cortex, liver and the mononuclear phagocyte system but
appear to have a low relevance for the proposed clinical
use. Itraconazole was found to cause a dose-related
increase in maternal toxicity, embryotoxicity and
teratogenicity in rats and mice at high doses. A global lower
bone mineral density was observed in juvenile dogs after
chronic itraconazole administration, and in rats,
a decreased bone plate activity, thinning of the zona
compacta of the large bones, and an increased bone
fragility was observed.
6. Pharmaceutical Particulars
6.1. List of Excipients
Sporanox I.V.:
Hydroxypropyl-E-cyclodextrin
propylene glycol
hydrochloric acid concentrated
sodium hydroxide
(for pH adjustment)
water for injections.
0.9% Sodium
Chloride Injection: Sodium Chloride
water for Injections
6.2. Incompatibilities
Itraconazole has the potential to precipitate when Sporanox I.V.
is diluted in solutions other than the 50 ml 0.9% sodium
chloride injection supplied.

6.4. Special Precautions for Storage
Sporanox I.V.:
Do not store above 25°C. Store in the original container.
0.9% Sodium Chloride Injection:
Do not store above 25°C. Do not freeze.
Admixed solution:
Protect from direct sunlight.
From a microbiological point of view, the product should be
used immediately. If not used immediately, in-use storage
times and conditions prior to use are the responsibility of
the user and would normally not be longer than 24 hours at
2 to 8°C, unless the dilution of the admixture has taken
place in controlled and validated aseptic conditions.
6.5. Nature and Contents of Container
Sporanox I.V.:
25 ml siliconised type I colourless glass ampoule with 25 ml
containing 250 mg itraconazole.
0.9% Sodium Chloride:
Flexible 75 ml polypropylene infusion bag, equipped with a
flexible inlet and outlet port, and containing 52 to 56 ml of
0.9% Sodium Chloride Injection.
Extension Line:
Polyvinylchloride tubing with 2-way stopcock and
in-line filter.

Itraconazole has the potential to precipitate when 25 ml of
Sporanox I.V. concentrate are diluted in solutions other
than 50 ml 0.9% Sodium Chloride Injection. The full
amount of 25 ml of Sporanox I.V. concentrate from the
ampoule must be diluted into the Sodium Chloride Infusion
Bag, which is intended to be used exclusively in
combination with Sporanox I.V. concentrate. Only the
components of unit sales pack (eg, saline bag, an
extension line with a 2-way stopcock and 0.2 ǹm in-line
filter, and Sporanox IV ampoule) must be used. Sporanox
I.V. cannot be co-administered with other drugs or fluids.
(See section 6.2).
Prior to starting the admixing process, the Sporanox IV
concentrate and the solvent (Sodium Chloride) must be
visually inspected. Only clear solutions free from foreign
particles should be used for the preparation of the
admixture.
The full amount of Sporanox IV concentrate must be
injected into the Sodium Chloride bag in a slow single
action (up to 60 seconds). During the admixing process
opalescence may appear but will clear after gently mixing.
When visually inspecting the bag after admixing and prior
to administration, product intrinsic aggregates may be
observed. These aggregates do not aŮect the quality of
the product. The dedicated extension line with the 0.2 ǹm
in-line filter must be used to prevent aggregates from
reaching the recipient’s circulation.
Sporanox I.V. should be prepared for administration
according to the following instructions:
Opening ampoule:
̋ Break the ampoule as shown:

Opening sodium chloride bag:
Tear outer wrap at notch and remove infusion bag.
Flush procedure before the infusion
Before the infusion, the catheter should be flushed to avoid
compatibility problems between residual amounts of other
drugs and itraconazole.
̋ Fill the extension line provided with the kit containing the
0.2 micrometer in-line filter with sterile 0.9% sodium
chloride solution and connect directly to the indwelling
intravenous catheter.
̋ Flush the extension line provided with the kit and
indwelling intravenous catheter with sterile 0.9% sodium
chloride solution.
Admixing Sporanox I.V. Concentrate and 0.9% Sodium
Chloride Injection:
̋ Each component must be at room temperature.
̋ Admix only in the infusion bag provided.
̋ Using aseptic technique and an additive delivery needle
of appropriate length (not supplied with the kit), draw up
all the concentrate from the ampoule and subsequently
add the Sporanox I.V. concentrate to the infusion bag by
puncturing the resealable additive port and inject.
̋ Add the entire volume (25 ml) of Sporanox IV
concentrate to the bag in a slow single action (up to 60
seconds). During the admixing process some
opalescence may appear. This is a normal phenomenon
for the product and will disappear after the full content of
the 25 ml of Sporanox IV has been diluted into the
Sodium Chloride infusion bag and after gentle mixing.
Withdraw needle after injecting the Sporanox IV
concentrate into the bag.
̋ Gently mix the content of the bag once the Sporanox IV
concentrate is completely transferred to the bag. The
admixture will become clear but product intrinsic
aggregates (described as fibrous to flake-like, noncrystalline, white particles) may be observed. These
aggregates do not aŮect the quality of the product.
The admixture should be used immediately and should be
protected from direct sunlight. During administration,
exposure to normal room light is acceptable: (See sections
6.3 and 6.4).
Infusion:
̋ The admixed solution is intended for single-dose infusion
only. No administration should occur if the solution is a
milky white colour that does not disappear after gentle
mixing, or contains foreign matter, or if the infusion bag is
damaged.
̋ The infusion bag should now contain 25 ml Sporanox IV
concentrate and 50 ml 0.9% Sodium Chloride Injection.
̋ Note: An infusion line with drip chamber is not supplied
with the kit. Close the flow control device (e.g., rotary
clamp) on the infusion line. Remove the breakable part of
the outlet port. Using aseptic technique, push the pin of
the infusion line in the flexible port of the infusion bag.
̋ Slowly release the flow control device and fill the drip
chamber to half full by squeezing (pumping) it.
̋ Open the flow control device until all air has been
expelled from the infusion line.
̋ Connect the infusion line to the two-way stopcock of the
extension line.
̋ The Sporanox infusion is now ready for intravenous
infusion to the patient.
̋ Adjust the infusion rate to 1 ml/min (approximately
25 drops/min) by means of a flow control device
(e.g. rotary clamp or infusion pump).
̋ Administer 60 ml of the solution to the patient over
approximately one hour.
̋ Stop the infusion when 60 ml is administered.
̋ Note that 200 mg of itraconazole has been administered.
̋ Flush the line as per the flushing procedure described
below.
Flush procedure after the infusion:
̋ After the infusion a complete flush procedure must be
started to clean the catheter. This is done to avoid
compatibility problems between residual amounts of
itraconazole and other drugs which later could be
administered through the same catheter.
̋ Flush the extension line and catheter with 15 – 20 ml of
sterile 0.9% sodium chloride solution at the level of the
2-way stop cock, just before the 0.2 micrometer in-line
filter.
̋ Perform the flush in a continuous run of 30 seconds to
15 minutes.
̋ After flushing, disconnect and discard the bag, the
infusion line and the extension line.
̋ Do not re-sterilise or re-use the Sporanox infusion set.
To avoid precipitation, other medication should only be
administered via the catheter after flushing.
If using a multi-lumen catheter, other medication may not
be administered until the Sporanox I.V. infusion has been
completed and the catheter has been flushed.

1.
2.
3.
4. & 5.

Sodium chloride infusion bag
Sporanox IV ampoule
Infusion line with drip chamber (not provided)
Extension line with 2-way stopcock and in-line filter.

Administrative Data
7. Marketing Authorisation Holder
Janssen-Cilag Ltd
50-100 Holmers Farm Way,
High Wycombe,
Bucks,
HP12 4EG,
UK
8. Marketing Authorisation Number
PL 00242/0344
PA 748/9/4
9. Date of First Authorisation/Renewal of Authorisation
UK:
22 July 1999 / 21 July 2009
Ireland:
22 August 2003 / 21 July 2009
10. Date of (Partial) Revision of the Text
On
approval
08/2012

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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