DAPTOMYCIN CLONMEL

Ireland - English - HPRA (Health Products Regulatory Authority)

Active ingredient:
DAPTOMYCIN
Available from:
Clonmel Healthcare Ltd
ATC code:
J01XX09
INN (International Name):
DAPTOMYCIN
Dosage:
500 Milligram
Pharmaceutical form:
Pdr for Soln Inj/Inf
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
daptomycin
Authorization status:
Not Marketed
Authorization number:
PA0126/286/002
Authorization date:
2017-07-14

Read the complete document

What is in this leaflet

1. What Daptomycin Clonmel is and what it is

used for

2. What you need to know before you are given

Daptomycin Clonmel

3. How Daptomycin Clonmel is given

4. Possible side effects

5. How to store Daptomycin Clonmel

6. Contents of the pack and other information

1. What Daptomycin Clonmel is and what it is

used for

active

substance

Daptomycin

Clonmel

powder

solution for injection or infusion is daptomycin. Daptomycin is

an antibiotic that can stop the growth of certain bacteria.

What is it used for?

Daptomycin Clonmel is used in adults and in children and

adolescents (age from 1 to 17 years) to treat infections of the

skin and the tissues below the skin. It is also used in adults to

treat infections in the tissues that line the inside of the heart

(including heart valves) which are caused by a bacterium called

Staphylococcus aureus and to treat infections in the blood

caused by the same bacterium when associated with skin or

heart infection.

Depending on the type

of infection(s)

that

have, your

doctor

also

prescribe

other

antibiotics

while

receiving treatment with Daptomycin Clonmel.

2. What you need to know before you are given

Daptomycin Clonmel

You must not be given Daptomycin Clonmel

if you are allergic to daptomycin or to sodium hydroxide or to

any of the other ingredients of this medicine (listed in section 6)

If this applies to you, tell your doctor or nurse. If you think you

may be allergic, ask your doctor or nurse for advice.

Warnings and precautions

Talk to your doctor or nurse before you are given Daptomycin

Clonmel:

if you have, or have previously had kidney problems. Your

doctor may need to change the dose of Daptomycin Clonmel

(see section 3 of this leaflet)

occasionally,

patients

receiving

Daptomycin

Clonmel

develop

tender

aching

muscles

muscle

weakness

(see section 4 of this leaflet for more information). If this

happens tell your doctor. Your doctor will make sure you have

a blood test and will advise whether or not to continue with

Daptomycin

Clonmel.

symptoms

generally

away

within a few days of stopping Daptomycin Clonmel

if you are very overweight. There is a possibility that your

blood levels of Daptomycin Clonmel could be higher than

those found in persons of average weight and you may need

careful monitoring in case of side effects

If any of these applies to you, tell your doctor or nurse before

you are given Daptomycin Clonmel.

Tell your doctor straight away if you develop any of the

following symptoms:

serious,

acute

allergic

reactions

have

been

observed

patients treated with nearly all antibacterial agents, includ-

ing daptomycin. Tell a doctor or a nurse straight away if you

experience symptoms suggestive of allergic reaction, such as

wheezing, difficulty breathing, swelling of the face, neck and

throat, rashes and hives, fever (see section 4 of this leaflet

for more information)

any unusual tingling or numbness of the hands or feet, loss

of feeling or difficulties with movements. If this happens, tell

your doctor who will decide whether you should continue the

treatment

diarrhoea, especially if you notice blood or mucus, or if diar-

rhoea becomes severe or persistent

new or worsening fever, cough or difficulty breathing. These

may be signs of a rare but serious lung disorder called

eosino philic pneumonia. Your doctor will check the condition

of your lungs and decide whether or not you should continue

Daptomycin Clonmel treatment

Blood tests

Daptomycin

Clonmel

interfere

with

laboratory

tests

that measure how well your blood is clotting. The results can

suggest poor blood clotting when, in fact, there is no problem.

Therefore it is important that your doctor takes into account

that you are receiving Daptomycin Clonmel. Please inform your

doctor that you are on treatment with Daptomycin Clonmel.

Your doctor will perform blood tests to monitor the health of

your muscles both before you start treatment and frequently

during treatment with Daptomycin Clonmel.

Children and adolescents

Daptomycin Clonmel should not be administered to children

below one year of age as studies in animals have indicated that

this age group may experience severe side effects.

Use in elderly

People over the age of 65 can be given the same dose as other

adults, provided their kidneys are working well.

Other medicines and Daptomycin Clonmel

Tell your doctor or nurse if you are taking, have recently taken

or might take any other medicines. It is particularly important

that you mention the following:

medicines called statins or fibrates (to lower cholesterol) or

ciclosporin (a medicinal product used in transplantation to

prevent organ rejection or for other conditions, e.g. rheu-

matoid arthritis or atopic dermatitis). It is possible that the

risk of side effects affecting the muscles may be higher

when any of these medicines (and some others that can

affect muscles) is taken during treatment with Daptomycin

Clonmel. Your doctor may decide not to give you Daptomycin

Clonmel or to stop the other medicine for a while

pain killing medicines called non-steroidal anti-inflammatory

drugs (NSAIDs) or COX-2 inhibitors (e.g. celecoxib). These

could interfere with the effects of Daptomycin Clonmel in the

kidney

oral anti-coagulants (e.g. warfarin), which are medicines that

prevent blood from clotting. It may be necessary for your

doctor to monitor your blood clotting times

Pregnancy and breast-feeding

Daptomycin Clonmel is not usually given to pregnant women. If

you are pregnant or breast-feeding, think you may be pregnant

or are planning to have a baby, ask your doctor or pharmacist

for advice before you are given this medicine.

Do not breast-feed if you are receiving Daptomycin Clonmel,

because it may pass into your breast milk and could affect the

baby.

Driving and using machines

Daptomycin Clonmel has no known effects on the ability to

drive or use machines.

Daptomycin Clonmel contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg)

per vial, i.e. essentially ‘sodium- free’.

3. How Daptomycin Clonmel is given

Daptomycin Clonmel will usually be given to you by a doctor or

a nurse.

Method of administration

In adult patients, it is given directly into your blood stream (into

a vein), either as an infusion lasting about 30 minutes or as an

injection lasting about 2 minutes.

Dosage

The dose will depend on how much you weigh and the type of

infection being treated. The usual dose for adults is:

4 mg for every kilogram (kg) of body weight once daily for

skin infections or

6 mg for every kg of body weight once daily for a heart infec-

tion or a blood infection associated with skin or heart infection

The same dose is recommended in people aged over 65 years

provided their kidneys are working well.

Children and adolescents (1 to 17 years of age)

The dose for children and adolescents (1 to 17 years of age)

being treated for skin infection will depend on the age of

patient. The recommended doses based on age are shown in

the table below:

Age group

Dosage

Duration of treatment

12 to 17 years

5 mg/kg once every

24 hours infused

over 30 minutes

Up to 14 days

7 to 11 years

7 mg/kg once every

24 hours infused

over 30 minutes

2 to 6 years

9 mg/kg once every

24 hours infused

over 60 minutes

1 to < 2 years

10 mg/kg once every

24 hours infused

over 60 minutes

If your kidneys do not work well, you may receive Daptomycin

Clonmel less often, e.g. once every other day. If you are receiv-

ing dialysis, and your next dose of Daptomycin Clonmel is due

on a dialysis day, you will be usually given Daptomycin Clonmel

after the dialysis session.

Duration of use

A course of treatment usually lasts for 1 to 2 weeks for skin

infections. For blood or heart infections and skin infections your

doctor will decide how long you should be treated.

Detailed instructions for use and handling are given at the end

of the leaflet.

4. Possible side effects

Like

medicines,

this

medicine

cause

side

effects,

although not everybody gets them.

The most serious side effects are described below:

Very rare serious side effects (may affect up to 1 in 10,000

people)

hypersensitivity

reaction

(serious

allergic

reaction

includ-

anaphylaxis,

angioedema,

drug

rash

with

eosinophilia

and systemic symptoms (DRESS)) has been reported in some

cases during administration of daptomycin. This serious allergic

reaction needs immediate medical attention. Tell your doctor

or nurse straight away if you experience any of the following

symptoms:

chest pain or tightness

rash with blistering, sometimes affecting the mouth and genitals

swelling around throat

rapid or weak pulse

wheezing

fever

shivering or trembling

hot flushes

dizziness

fainting

metallic taste

Tell your doctor straight away if you experience unexplained

muscle pain, tenderness, or weakness. In very rare cases

(reported in less than 1 in every 10,000 patients), muscle

problems can be serious, including muscle breakdown (rhabdo-

myolysis), which can result in kidney damage.

Serious side effects with frequency not known (frequency

cannot be estimated from the available data)

A rare but potentially serious lung disorder called eosinophilic

pneumonia has been reported in patients given daptomycin,

mostly after more than 2 weeks of treatment. The symptoms

include

difficulty

breathing,

worsening

cough,

or new or worsening fever. If you experience these symptoms,

tell your doctor or nurse straight away.

If you experience raised or fluid-filled skin spots over a large

area of your body, tell your doctor or nurse straight away.

The most frequently reported side effects are described below:

Common side effects (may affect up to 1 in 10 people)

fungal infections such as thrush

urinary tract infection

decreased number of red blood cells (anaemia)

dizziness, anxiety, difficulty in sleeping

headache

fever, weakness (asthenia)

high or low blood pressure

constipation, abdominal pain

diarrhoea, feeling sick (nausea) or being sick (vomiting)

flatulence

abdominal swelling or bloating

skin rash or itching

pain, itchiness or redness at the site of infusion

pain in arms or legs

blood testing showing higher levels of liver enzymes or creatine

phosphokinase (CPK)

Other

side

effects

which

occur

following

Daptomycin

Clonmel treatment are described below:

Uncommon side effects (may affect up to 1 in 100 people)

blood

disorders

(e.g.

increased

number

small

blood

particles called platelets, which may increase the tendency

Package leaflet: Information for the patient

Daptomycin Clonmel 500mg Powder

for Solution for Injection or Infusion

Daptomycin

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

information for you.

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

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

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their

signs of illness are the same as yours.

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this

leaflet. See section 4.

Daptomycin 500 mg PUD CHC IE

GI / PIL

XXXXXXX 1706

150 x 450 mm

8, 10, 16 pt

BLACK

2. Umlauf

07.06.2017

TYPE SERVICE

Daptomycin_500mg_PUD_CHC_IE_GI_150x450_XXXXXXX_1706.indd 1

07.06.17 09:43

for blood clotting, or higher levels of certain types of white

blood cells)

decreased appetite

tingling or numbness of the hands or feet, taste disturbance

trembling

changes in heart rhythm, flushes

indigestion (dyspepsia), inflammation of the tongue

itchy rash of skin

muscle

pain

weakness,

inflammation

muscles

(myositis), joint pain

kidney problems

inflammation and irritation of the vagina

general pain or weakness, tiredness (fatigue)

blood test showing increased levels of blood sugar, serum

creatinine,

myoglobin,

lactate

dehydrogenase

(LDH),

prolonged blood clotting time or imbalance of salts

Rare side effects (may affect up to 1 in 1,000 people)

yellowing of the skin and eyes

prothrombin time prolonged

Frequency not known (frequency cannot be estimated from

the available data)

Antibacterial-associated colitis, including pseudomembranous

colitis (severe or persistent diarrhoea containing blood and/or

mucus, associated with abdominal pain or fever).

Reporting of side effects

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

nurse. This includes any possible side effects not listed in this

leaflet. You can also report side effects directly via

HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2;

Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information

on the safety of this medicine.

5. How to store Daptomycin Clonmel

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

Do not use this medicine after the expiry date which is stated

on the carton and label after EXP. The expiry date refers to the

last day of that month.

Store in a refrigerator (2 °C – 8 °C).

After

reconstitution:

Chemical

physical

in-use

stability

of the reconstituted solution in the vial has been demonstrated

for 12 hours at 25 °C and up to 48 hours at 2 °C – 8 °C. Chemical

and physical stability of the diluted solution in infusion bags is

established as 12 hours at 25 °C or 24 hours at 2 °C – 8 °C.

For the 30-minute intravenous infusion, the combined storage

time (reconstituted solution in vial and diluted solution in infusion

bag at 25 °C must not exceed 12 hours (or 24 at 2 °C – 8 °C).

For the 2-minute intravenous injection, the storage time of

the reconstituted solution in the vial at 25°C must not exceed

12 hours (or 48 at 2 °C – 8 °C).

However, from a microbiological point of view the product

should be used immediately. No preservative or bacteriostatic

agent is present in this product. If not used immediately, in-use

storage times are the responsibility of the user and would not

normally be longer than 24 hours at 2 °C – 8 °C, unless recon-

stitution/dilution has taken place in controlled and validated

aseptic conditions.

Do not use this medicine if you notice visible signs of deterio-

ration.

Do not throw away any medicines via wastewater or household

waste. Ask your pharmacist how to throw away medicines you no

longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Daptomycin Clonmel contains

The active substance is daptomycin.

One vial of powder contains 500 mg daptomycin.

One ml provides 50 mg of daptomycin after reconstitution with

10 ml of sodium chloride 9 mg/ml (0.9%) solution.

The other ingredient is sodium hydroxide.

What Daptomycin Clonmel looks like and contents of the

pack

Daptomycin Clonmel powder for solution for injection or infu-

sion is supplied as a pale yellow to light brown cake or powder

in a glass vial. It is mixed with a solvent to form a liquid before

it is administered.

Daptomycin Clonmel is available in packs containing 1 vial or

5 vials.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder

Clonmel Healthcare Ltd

Waterford Road, Clonmel, Co. Tipperary, Ireland

Manufacturer

Dr Reddy’s Laboratories (UK) Ltd

6 Riverview Road, Beverley, East Yorkshire, HU17 0LD,

United Kingdom

STADA Arzneimittel AG

Stadastrasse 2–18, D-61118 Bad Vilbel, Germany

STADA Arzneimittel GmbH

Muthgasse 36, 1190 Wien, Austria

This medicinal product is authorised in the Member States

of the EEA under the following names:

Daptomycin STADA 500 mg Pulver zur Herstellung einer

Injektions-oder Infusionslösung

Daptomycin STADA 500 mg Pulver zur Herstellung einer

Injektions-/Infusionslösung

Daptomycin STADA 500 mg pulver til injektions-

og infusionsvæske, opløsning

Daptomycin STADA 500 mg injektio-

tai infuusionkuivaaine liuosta varten

Daptomycin Clonmel 500 mg powder for solution for

injection or infusion

Daptomycin STADA 500 mg pulver till injektions-/

infusionsvätska, lösning

Daptomicin STADA 500 mg prašek za raztopino

za injiciranje ali infundiranje

Daptomycin STADA Arzneimittel AG 500 mg powder for

solution for injection or infusion

This leaflet was last revised in March 2017.

following

information

intended

healthcare

professionals only

Important: Please refer to the Summary of Product Characteristics

before prescribing.

Instructions for use and handling

500 mg Powder for solution for injection or infusion

Daptomycin may be administered intravenously as an infusion

over 30 or 60 minutes or as an injection over 2 minutes. Prepa-

ration of the solution for infusion requires an additional dilution

step as detailed below.

Daptomycin Clonmel given as an intravenous infusion over

30 or 60 minutes

A 50 mg/ml concentration of Daptomycin Clonmel for infusion

can be achieved by reconstituting the lyophilised product with

10 ml of sodium chloride 9 mg/ml (0.9%) solution for injection.

lyophilised

product

takes

approximately

minutes

dissolve. The fully reconstituted product will appear clear and

may have a few small bubbles or foam around the edge of the

vial.

To prepare Daptomycin Clonmel for intravenous infusion, please

adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute

lyophilised Daptomycin Clonmel.

The polypropylene flip off seal should be removed to expose

the central portions of the rubber stopper. Wipe the top of

the rubber stopper with an alcohol swab or other antisep-

tic solution and allow to dry. After cleaning, do not touch

the rubber stopper or allow it to touch any other surface.

Draw 10 ml of sodium chloride 9 mg/ml (0.9%) solution for

injection into a syringe, using a sterile transfer needle that

is 21 gauge or smaller in diameter, or a needleless device,

then slowly inject through the centre of the rubber stopper

into the vial pointing the needle towards the wall of the vial.

vial

should

gently

rotated

ensure

complete

wetting of the product and then allowed to stand for 10

minutes.

Finally the vial should be gently rotated/swirled for a few

minutes as needed to obtain a clear reconstituted solution.

Vigorous shaking/agitation should be avoided to prevent

foaming of the product.

The reconstituted solution should be checked carefully to

ensure that the product is in solution and visually inspected

for the absence of particulates prior to use. Reconstituted

solutions of Daptomycin Clonmel range in colour from pale

yellow to light brown.

Slowly remove the reconstituted liquid (50 mg daptomycin/ml)

from the vial using a sterile needle that is 21 gauge or smaller

in diameter:

Invert the vial in order to allow the solution to drain towards

the stopper. Using the new syringe, insert the needle into

the inverted vial. Keeping the vial inverted, position the

needle tip at the very bottom of the solution in the vial when

drawing the solution into the syringe. Before removing the

needle from the vial, pull the plunger all the way back to

the end of the syringe barrel in order to remove all of the

solution from the inverted vial.

reconstituted

solution

should

then

diluted

with

sodium chloride 9 mg/ml (0.9%) (typical volume 50 ml).

Replace needle with a new needle for the intravenous infusion.

Expel air, large bubbles, and any excess solution in order to

obtain the required dose.

10. The

reconstituted

diluted

solution

should

then

infused intravenously over 30 or 60 minutes.

Daptomycin Clonmel is not physically or chemically compatible

with glucose-containing solutions.

The combined storage time (reconstituted solution in vial and

diluted solution in infusion bag) at 25 °C must not exceed

12 hours (24 hours if refrigerated).

Stability of the diluted solution in infusion bags is established

as 12 hours at 25 °C or 24 hours if stored under refrigeration

at 2 °C – 8 °C.

Daptomycin Clonmel given as 2-minute intravenous injection

(adult patients only)

Water should not be used for reconstitution of Daptomycin

Clonmel for intravenous injection. Daptomycin Clonmel should

only be reconstituted with sodium chloride 9 mg/ml (0.9%).

A 50 mg/ml concentration of Daptomycin Clonmel for injection

is obtained by reconstituting the lyophilised product with 10 ml

of sodium chloride 9 mg/ml (0.9%) solution for injection.

lyophilised

product

takes

approximately

minutes

dissolve. The fully reconstituted product will appear clear and

may have a few small bubbles or foam around the edge of the

vial.

prepare

Daptomycin

Clonmel

intravenous

injection,

please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute

lyophilised Daptomycin Clonmel.

The polypropylene flip off seal should be removed to expose

the central portions of the rubber stopper. Wipe the top of the

rubber stopper with an alcohol swab or other antiseptic solution

and allow to dry. After cleaning, do not touch the rubber stopper

or allow it to touch any other surface. Draw 10 ml of sodium

chloride 9 mg/ml (0.9%) solution for injection into a syringe

using a sterile transfer needle that is 21 gauge or smaller

diameter, or a needleless device, then slowly inject through the

centre of the rubber stopper into the vial pointing the needle

towards the wall of the vial.

2. The vial should be gently rotated to ensure complete wetting

of the product and then allowed to stand for 10 minutes.

3. Finally the vial should be gently rotated/swirled for a few

minutes as needed to obtain a clear reconstituted solution.

Vigorous

shaking/agitation

should

avoided

prevent

foaming of the product.

4. The reconstituted solution should be checked carefully to

ensure that the product is in solution and visually inspected

for the absence of particulates prior to use. Reconstituted

solutions of Daptomycin Clonmel range in colour from pale

yellow to light brown.

Slowly remove the reconstituted liquid (50 mg daptomycin/ml)

from the vial using a sterile needle that is 21 gauge or smaller

in diameter:

Invert the vial in order to allow the solution to drain towards

the stopper. Using a new syringe, insert the needle into the

inverted vial. Keeping the vial inverted, position the needle

tip at the very bottom of the solution in the vial when draw-

ing the solution into the syringe. Before removing the needle

from the vial, pull the plunger all the way back to the end

of the syringe barrel in order to remove all of the solution

from the inverted vial.

Replace needle with a new needle for the intravenous injection.

7. Expel air, large bubbles, and any excess solution in order to

obtain the required dose.

8. The reconstituted solution should then be injected intra-

venously slowly over 2 minutes.

Chemical and physical in-use stability on the reconstituted

solution in the vial has been demonstrated for 12 hours at 25 °C

and up to 48 hours if stored under refrigeration (2 °C – 8 °C).

However, from a microbiological point of view the product

should be used immediately. If not used immediately, in-use

storage times are the responsibility of the user and would

normally not be longer than 24 hours at 2 °C 8 °C unless recon-

stitution / dilution has taken place in controlled and validated

aseptic conditions.

Daptomycin Clonmel vials are for single-use only. Any unused

portion remaining in the vial should be discarded.

CLONMEL HEALTHCARE LTD

CLONMEL, IRELAND

1500xxxxx

XXXXXXX 1706 IE

Daptomycin_500mg_PUD_CHC_IE_GI_150x450_XXXXXXX_1706.indd 2

07.06.17 09:43

Read the complete document

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Daptomycin Clonmel 500 mg powder for solution for Injection or Infusion.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Daptomycin Clonmel 500 mg Powder for solution for infusion or injection: Each vial contains 500 mg daptomycin.

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium-free’.

One ml provides 50 mg of daptomycin after reconstitution with 10 ml of sodium chloride 9 mg/ml (0.9 %) solution.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder for solution for injection or infusion

A pale yellow to light brown lyophilised cake or powder.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Daptomycin Clonmel is indicated for the treatment of the following infections (see sections 4.4 and 5.1).

Adult and paediatric (2 to 17 years of age) patients with complicated skin and soft-tissue infections (cSSTI).

Adult patients with right-sided infective endocarditis (RIE) due to Staphylococcus aureus. It is recommended

that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and

should be based on expert advice. See sections 4.4 and 5.1.

Adult patients with Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI.

Daptomycin is active against Gram positive bacteria only (see section 5.1). In mixed infections where Gram negative

and/or certain types of anaerobic bacteria are suspected, Daptomycin Clonmel should be co-administered with

appropriate antibacterial agent(s).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2 Posology and method of administration

Clinical studies in patients employed infusion of daptomycin over 30 minutes. There is no clinical experience in

patients with the administration of daptomycin as an injection over 2 minutes. This mode of administration was only

studied in healthy subjects. However, when compared with the same doses given as intravenous infusions over

30 minutes there were no clinically important differences in the pharmacokinetics and safety profile of daptomycin (see

also sections 4.8 and 5.2).

Posology

Adults

cSSTI without concurrent Staphylococcus aureus bacteraemia: daptomycin 4 mg/kg is administered once every

24 hours for 7-14 days or until the infection is resolved (see section 5.1).

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cSSTI with concurrent Staphylococcus aureus bacteraemia: daptomycin 6 mg/kg is administered once every

24 hours. See below for dose adjustments in patients with renal impairment. The duration of therapy may need to

be longer than 14 days in accordance with the perceived risk of complications in the individual patient.

Known or suspected right-sided infective endocarditis due to Staphylococcus aureus: daptomycin 6 mg/kg is

administered once every 24 hours. See below for dose adjustments in patients with renal impairment. The

duration of therapy should be in accordance with available official recommendations.

Daptomycin Clonmel is administered intravenously in 0.9 % sodium chloride (see section 6.6).

Daptomycin Clonmel should not be used more frequently than once a day.

Renal impairment

Daptomycin is eliminated primarily by the kidney.

Due to limited clinical experience (see table and footnotes below) daptomycin should only be used in patients with any

degree of renal impairment (CrCl < 80 ml/min) when it is considered that the expected clinical benefit outweighs the

potential risk. The response to treatment, renal function and creatine phosphokinase (CPK) levels should be closely

monitored in all patients with any degree of renal impairment (see also sections 4.4 and 5.2).

Dose adjustments in patients with renal impairment by indication and creatinine clearance

The safety and efficacy of the dose interval adjustment have not been evaluated in controlled clinical trials and

the recommendation is based on pharmacokinetic studies and modelling results (see sections 4.4 and 5.2).

The same dose adjustments, which are based on pharmacokinetic data in volunteers including PK modelling

results, are recommended for patients on haemodialysis (HD) or continuous ambulatory peritoneal dialysis

(CAPD). Whenever possible, daptomycin should be administered following the completion of dialysis on

dialysis days (see section 5.2).

Hepatic impairment

No dose adjustment is necessary when administering daptomycin to patients with mild or moderate hepatic impairment

(Child-Pugh Class B) (see section 5.2). No data are available in patients with severe hepatic impairment (Child-Pugh

Class C). Therefore caution should be exercised if daptomycin is given to such patients.

Elderly patients

The recommended doses should be used in elderly patients except those with severe renal impairment (see above and

section 4.4).

Paediatric patients (2 to 17 years of age) with complicated skin and soft-tissue infections

The recommended dosage regimens based on age for paediatric patients with cSSTI are shown below.

Daptomycin Clonmel is administered intravenously in 0.9 % sodium chloride (see section 6.6).

Indication for use

Creatinine clearance

Dose recommendation

Comments

cSSTI without S.

aureus bacteraemia

30 ml/min

4 mg/kg once daily

See section 5.1

< 30 ml/min

4 mg/kg every 48 hours

(1, 2)

RIE or cSSTI

associated with S.

aureus bacteraemia

30 ml/min

6 mg/kg once daily

See section 5.1

< 30 ml/min

6 mg/kg every 48 hours

(1, 2)

Age group

Dosage

Duration of therapy

12 to 17 years

5 mg/kg once every 24 hours

Up to 14 days

7 to 11 years

7 mg/kg once every 24 hours

2 to 6 years

9 mg/kg once every 24 hours

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Daptomycin Clonmel should not be used more frequently than once a day.

Creatine phosphokinase (CPK) levels must be measured at baseline and at regular intervals (at least weekly) during

treatment (see section 4.4).

Paediatric patients below the age of one year should not be given daptomycin due to the risk of potential effects on

muscular, neuromuscular and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs

(see section 5.3).

The safety and efficacy of daptomycin in children and adolescents aged below 18 years with right-sided infective

endocarditis (RIE) due to Staphylococcus aureus or with Staphylococcus aureus bacteraemia (SAB) when associated

with RIE or with cSSTI have not been established. Currently available data are described in section 5.2 but no

recommendation on a posology can be made.

Method of administration

In adults, Daptomycin Clonmel is given by intravenous infusion (see section 6.6) and administered over a 30-minute

period or by intravenous injection (see section 6.6) and administered over a 2-minute period.

In paediatric patients aged 7 to 17 years, Daptomycin Clonmel is given by intravenous infusion over a 30-minute

period (see section 6.6). In paediatric patients aged 2 to 6 years, Daptomycin Clonmel is given by intravenous infusion

over a 60-minute period (see section 6.6).

For instructions on reconstitution/dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

General

If a focus of infection other than cSSTI or RIE is identified after initiation of daptomycin therapy consideration should

be given to instituting alternative antibacterial therapy that has been demonstrated to be efficacious in the treatment of

the specific type of infection(s) present.

Anaphylaxis/hypersensitivity reactions

Anaphylaxis/hypersensitivity reactions have been reported with daptomycin. If an allergic reaction to daptomycin

occurs, discontinue use and institute appropriate therapy.

Pneumonia

It has been demonstrated in clinical studies that daptomycin is not effective in the treatment of pneumonia. Daptomycin

is therefore not indicated for the treatment of pneumonia.

RIE due to Staphylococcus aureus

Clinical data on the use of daptomycin to treat RIE due to Staphylococcus aureus are limited to 19 patients (see

“Information from clinical trials” in section 5.1).

The efficacy of daptomycin in patients with prosthetic valve infections or with left-sided infective endocarditis due to

Staphylococcus aureus has not been demonstrated.

Deep-seated infections

Patients with deep-seated infections should receive any required surgical interventions (e.g. debridement, removal of

prosthetic devices, valve replacement surgery) without delay.

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Enterococcal infections

There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of daptomycin

against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. In addition, dose

regimens of daptomycin that might be appropriate for the treatment of enterococcal infections, with or without

bacteraemia, have not been identified. Failures with daptomycin in the treatment of enterococcal infections that were

mostly accompanied by bacteraemia have been reported. In some instances treatment failure has been associated with

the selection of organisms with reduced susceptibility or frank resistance to daptomycin (see section 5.1).

Non-susceptible micro-organisms

The use of antibacterials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs

during therapy, appropriate measures should be taken.

Clostridium difficile-associated diarrhoea

Clostridium difficile-associated diarrhoea (CDAD) has been reported with daptomycin (see section 4.8). If CDAD is

suspected or confirmed, daptomycin may need to be discontinued and appropriate treatment instituted as clinically

indicated.

Drug/laboratory test interactions

False prolongation of prothrombin time (PT) and elevation of international normalised ratio (INR) have been observed

when certain recombinant thromboplastin reagents are utilised for the assay (see also section 4.5).

Creatine phosphokinase and myopathy

Increases in plasma creatine phosphokinase (CPK; MM isoenzyme) levels associated with muscular pains and/or

weakness and cases of myositis, myoglobinaemia and rhabdomyolysis have been reported during therapy with

daptomycin (see also sections 4.5, 4.8 and 5.3). In clinical studies, marked increases in plasma CPK to > 5 x Upper

Limit of Normal (ULN) without muscle symptoms occurred more commonly in daptomycin-treated patients (1.9 %)

than in those that received comparators (0.5 %). Therefore, it is recommended that:

Plasma CPK should be measured at baseline and at regular intervals (at least once weekly) during therapy in all

patients.

CPK should be measured more frequently (e.g. every 2-3 days at least during the first two weeks of treatment) in

patients who are at higher risk of developing myopathy. For example, patients with any degree of renal

impairment (creatinine clearance < 80 ml/min; see also section 4.2), including those on haemodialysis or CAPD,

and patients taking other medicinal products known to be associated with myopathy (e.g. HMG-CoA reductase

inhibitors, fibrates and ciclosporin).

It cannot be ruled out that those patients with CPK greater than 5 times upper limit of normal at baseline may be

at increased risk of further increases during daptomycin therapy. This should be taken into account when

initiating daptomycin therapy and, if daptomycin is given, these patients should be monitored more frequently

than once weekly.

Daptomycin should not be administered to patients who are taking other medicinal products associated with

myopathy unless it is considered that the benefit to the patient outweighs the risk.

Patients should be reviewed regularly while on therapy for any signs or symptoms that might represent

myopathy.

Any patient that develops unexplained muscle pain, tenderness, weakness or cramps should have CPK levels

monitored every 2 days. Daptomycin should be discontinued in the presence of unexplained muscle symptoms if

the CPK level reaches greater than 5 times upper limit of normal.

Peripheral neuropathy

Patients who develop signs or symptoms that might represent a peripheral neuropathy during therapy with daptomycin

should be investigated and consideration should be given to discontinuation of daptomycin (see sections 4.8 and 5.3).

Paediatric population

Paediatric patients below the age of one year should not be given daptomycin due to the risk of potential effects on

muscular, neuromuscular, and/or nervous systems (either peripheral and/or central) that were observed in neonatal dogs

(see section 5.3).

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Eosinophilic pneumonia

Eosinophilic pneumonia has been reported in patients receiving daptomycin (see section 4.8). In most reported cases

associated with daptomycin, patients developed fever, dyspnoea with hypoxic respiratory insufficiency, and diffuse

pulmonary infiltrates. The majority of cases occurred after more than 2 weeks of treatment with daptomycin and

improved when daptomycin was discontinued and steroid therapy was initiated. Recurrence of eosinophilic pneumonia

upon re-exposure has been reported. Patients who develop these signs and symptoms while receiving daptomycin

should undergo prompt medical evaluation, including, if appropriate, bronchoalveolar lavage, to exclude other causes

(e.g. bacterial infection, fungal infection, parasites, other medicinal products). Daptomycin should be discontinued

immediately and treatment with systemic steroids should be initiated when appropriate.

Renal impairment

Renal impairment has been reported during treatment with daptomycin. Severe renal impairment may in itself also pre-

dispose to elevations in daptomycin levels which may increase the risk of development of myopathy (see above).

An adjustment of daptomycin dose interval is needed for patients whose creatinine clearance is < 30 ml/min (see

sections 4.2 and 5.2). The safety and efficacy of the dose interval adjustment have not been evaluated in controlled

clinical trials and the recommendation is mainly based on pharmacokinetic modelling data. Daptomycin should only be

used in such patients when it is considered that the expected clinical benefit outweighs the potential risk.

Caution is advised when administering daptomycin to patients who already have some degree of renal impairment

(creatinine clearance < 80 ml/min) before commencing therapy with daptomycin. Regular monitoring of renal function

is advised (see also section 5.2).

In addition, regular monitoring of renal function is advised during concomitant administration of potentially

nephrotoxic agents, regardless of the patient's pre-existing renal function (see also section 4.5).

Obesity

In obese subjects with Body Mass Index (BMI) > 40 kg/m2 but with creatinine clearance > 70 ml/min, the AUC0-

daptomycin was significantly increased (mean 42 % higher) compared with non-obese matched controls. There is

limited information on the safety and efficacy of daptomycin in the very obese and so caution is recommended.

However, there is currently no evidence that a dose reduction is required (see section 5.2).

Excipient

This medicinal product contains less than 1 mmol sodium (23 mg) per vial, i.e. essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

Daptomycin undergoes little to no Cytochrome P450 (CYP450)-mediated metabolism. It is unlikely that daptomycin

will inhibit or induce the metabolism of medicinal products metabolised by the P450 system.

Interaction studies for daptomycin were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin

had no effect on the pharmacokinetics of warfarin or probenecid, nor did these medicinal products alter the

pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam.

Although small changes in the pharmacokinetics of daptomycin and tobramycin were observed during coadministration

by intravenous infusion over a 30-minute period using a daptomycin dose of 2 mg/kg, the changes were not statistically

significant. The interaction between daptomycin and tobramycin with an approved dose of daptomycin is unknown.

Caution is warranted when daptomycin is co-administered with tobramycin.

Experience with the concomitant administration of daptomycin and warfarin is limited. Studies of daptomycin with

anticoagulants other than warfarin have not been conducted. Anticoagulant activity in patients receiving daptomycin

and warfarin should be monitored for the first several days after therapy with daptomycin is initiated.

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There is limited experience regarding concomitant administration of daptomycin with other medicinal products that

may trigger myopathy (e.g. HMG-CoA reductase inhibitors). However, some cases of marked rises in CPK levels and

cases of rhabdomyolysis occurred in patients taking one of these medicinal products at the same time as daptomycin. It

is recommended that other medicinal products associated with myopathy should if possible be temporarily discontinued

during treatment with daptomycin unless the benefits of concomitant administration outweigh the risk. If co-

administration cannot be avoided, CPK levels should be measured more frequently than once weekly and patients

should be closely monitored for any signs or symptoms that might represent myopathy. See sections 4.4, 4.8 and 5.3.

Daptomycin is primarily cleared by renal filtration and so plasma levels may be increased during co-administration

with medicinal products that reduce renal filtration (e.g. NSAIDs and COX-2 inhibitors). In addition, there is a

potential for a pharmacodynamic interaction to occur during co-administration due to additive renal effects. Therefore,

caution is advised when daptomycin is co-administered with any other medicinal product known to reduce renal

filtration.

During post–marketing surveillance, cases of interference between daptomycin and particular reagents used in some

assays of prothrombin time/international normalised ratio (PT/INR) have been reported. This interference led to a false

prolongation of PT and elevation of INR. If unexplained abnormalities of PT/INR are observed in patients taking

daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. The possibility of

erroneous results may be minimised by drawing samples for PT or INR testing near the time of trough plasma

concentrations of daptomycin (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

No clinical data on pregnancies are available for daptomycin. Animal studies do not indicate direct or indirect harmful

effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section

5.3).

Daptomycin should not be used during pregnancy unless clearly necessary i.e., only if the expected benefit outweighs

the possible risk.

Breastfeeding

In a single human case study, daptomycin was intravenously administered daily for 28 days to a nursing mother at a

dose of 500 mg/day, and samples of the patient's breast milk were collected over a 24-hour period on day 27. The

highest measured concentration of daptomycin in the breast milk was 0.045 mcg/ml, which is a low concentration.

Therefore, until more experience is gained, breast-feeding should be discontinued when daptomycin is administered to

nursing women.

Fertility

No clinical data on fertility are available for daptomycin. Animal studies do not indicate direct or indirect harmful

effects with respect to fertility (see section 5.3).

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.

On the basis of reported adverse drug reactions, daptomycin is presumed to be unlikely to produce an effect on the

ability to drive or use machinery.

4.8 Undesirable effects

Summary of the safety profile

In clinical studies, 2,011 subjects received daptomycin. Within these trials, 1,221 subjects received a daily dose of

4 mg/kg, of whom 1,108 were patients and 113 were healthy volunteers; 460 subjects received a daily dose of 6 mg/kg,

of whom 304 were patients and 156 were healthy volunteers.

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Adverse reactions (i.e. considered by the investigator to be possibly, probably, or definitely related to the medicinal

product) were reported at similar frequencies for daptomycin and comparator regimens.

The most frequently reported adverse reactions (frequency common (

1/100 to < 1/10)) are:

Fungal infections, urinary tract infection, candida infection, anaemia, anxiety, insomnia, dizziness, headache,

hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence,

bloating and distension, liver function tests abnormal (increased alanine aminotransferase (ALT), aspartate

aminotransferase (AST) or alkaline phosphatase (ALP)), rash, pruritus, limb pain, serum creatine phosphokinase (CPK)

increased, infusion site reactions, pyrexia, asthenia.

Less frequently reported, but more serious, adverse reactions include hypersensitivity reactions, eosinophilic

pneumonia, drug rash with eosinophilia and systemic symptoms (DRESS), angioedema and rhabdomyolysis.

Tabulated list of adverse reactions

The following adverse reactions were reported during therapy and during follow-up with frequencies corresponding to

very common (

1/10); common (

1/100 to < 1/10); uncommon (

1/1,000 to < 1/100); rare (

1/10,000 to < 1/1,000);

very rare (< 1/10,000); not known (cannot be estimated from the available data):

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1 Adverse reactions from clinical studies and post-marketing reports

System organ class

Frequency

Adverse reactions

Infections and infestations

Common

Fungal infections,

urinary tract infection,

candida infection

Uncommon

Fungaemia

Not known *

Clostridium difficile-associated diarrhoea **

Blood and lymphatic system

disorders

Common

Anaemia

Uncommon

Thrombocythaemia,

eosinophilia,

international normalised ratio (INR) increased

Rare

Prothrombin time (PT) prolonged

Immune system disorders

Not known *

Hypersensitivity **, manifested by isolated

spontaneous reports including, but not limited

to angioedema, drug rash with eosinophilia

and systemic symptoms (DRESS), pulmonary

eosinophilia, vesiculobullous rash with

mucous membrane involvement and sensation

of oropharyngeal swelling

Not known *

Anaphylaxis **

Not known *

Infusion reactions including the following

symptoms: tachycardia, wheezing, pyrexia,

rigors, systemic flushing, vertigo, syncope and

metallic taste

Metabolism and nutrition

disorders

Uncommon

Decreased appetite,

hyperglycaemia,

electrolyte imbalance

Psychiatric disorders

Common

Anxiety,

insomnia

Nervous system disorders

Common

Dizziness,

headache

Uncommon

Paraesthesia,

taste disorder,

tremor

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Based on post-marketing reports. Since these reactions are reported voluntarily from a population of uncertain size, it is not

possible to reliably estimate their frequency which is therefore categorised as not known.

** See section 4.4.

While the exact incidence of eosinophilic pneumonia associated with daptomycin is unknown, to date the

reporting rate of spontaneous reports is very low (< 1/10,000).

In some cases of myopathy involving raised CPK and muscle symptoms, the patients also presented with

elevated transaminases. These transaminase increases were likely to be related to the skeletal muscle effects.

The majority of transaminase elevations were of Grade 1-3 toxicity and resolved upon discontinuation of

treatment.

Not known *

Peripheral neuropathy **

Ear and labyrinth disorders

Uncommon

Vertigo

Cardiac disorders

Uncommon

Supraventricular tachycardia, extrasystole

Vascular disorders

Common

Hypertension,

hypotension

Uncommon

Flushes

Respiratory, thoracic and

mediastinal disorders

Not known *

Eosinophilic pneumonia 1,**,

cough

Gastrointestinal disorders

Common

Gastrointestinal and abdominal pain,

nausea,

vomiting,

constipation,

diarrhoea,

flatulence,

bloating and distension

Uncommon

Dyspepsia,

glossitis

Hepatobiliary disorders

Common

Liver function tests abnormal 2 (increased

alanine aminotransferase (ALT), aspartate

aminotransferase (AST) or alkaline

phosphatase (ALP))

Rare

Jaundice

Skin and subcutaneous tissue

disorders

Common

Rash,

pruritus

Uncommon

Urticaria

Not known*

Acute generalised exanthematous pustulosis

Musculoskeletal and

connective tissue disorders

Common

Limb pain,

serum creatine phosphokinase (CPK) 2

increased

Uncommon

Myositis,

increased myoglobin,

muscular weakness,

muscle pain,

arthralgia,

serum lactate dehydrogenase (LDH) increased

Not known *

Rhabdomyolysis 3,**

Renal and urinary disorders

Uncommon

Renal impairment, including renal failure and

renal insufficiency, serum creatinine increased

Reproductive system and

breast disorders

Uncommon

Vaginitis

General disorders and

administration site conditions

Common

Infusion site reactions,

pyrexia,

asthenia

Uncommon

Fatigue,

pain

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When clinical information on the patients was available to make a judgement, approximately 50 % of the cases

occurred in patients with pre-existing renal impairment, or in those receiving concomitant medicinal products

known to cause rhabdomyolysis.

The safety data for the administration of daptomycin via 2-minute intravenous injection are derived from two

pharmacokinetic studies in healthy volunteers. Based on these study results, both methods of daptomycin

administration, the 2-minute intravenous injection and the 30-minute intravenous infusion, had a similar safety and

tolerability profile. There was no relevant difference in local tolerability or in the nature and frequency of adverse

reactions.

Reporting of suspected adverse reactions

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

monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

In the event of overdose, supportive care is advised. Daptomycin is slowly cleared from the body by haemodialysis

(approximately 15 % of the administered dose is removed over 4 hours) or by peritoneal dialysis (approximately 11 %

of the administered dose is removed over 48 hours).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, Other antibacterials, ATC code: J01XX09

Mechanism of action

Daptomycin is a cyclic lipopeptide natural product that is active against Gram positive bacteria only.

The mechanism of action involves binding (in the presence of calcium ions) to bacterial membranes of both growing

and stationary phase cells causing depolarisation and leading to a rapid inhibition of protein, DNA, and RNA synthesis.

This results in bacterial cell death with negligible cell lysis.

PK/PD relationship

Daptomycin exhibits rapid, concentration dependent bactericidal activity against Gram positive organisms in vitro and

in in vivo animal models. In animal models AUC/MIC and Cmax/MIC correlate with efficacy and predicted bacterial

kill in vivo at single doses equivalent to human doses of 4 mg/kg and 6 mg/kg once daily.

Mechanisms of resistance

Strains with decreased susceptibility to daptomycin have been reported especially during the treatment of patients with

difficult-to-treat infections and/or following administration for prolonged periods. In particular, there have been reports

of treatment failures in patients infected with Staphylococcus aureus, Enterococcus faecalis or Enterococcus faecium,

including bacteraemic patients, that have been associated with the selection of organisms with reduced susceptibility or

frank resistance to daptomycin during therapy.

The mechanism(s) of daptomycin resistance is (are) not fully understood.

Breakpoints

Minimum inhibitory concentration (MIC) breakpoint established by the European Committee on Antimicrobial

Susceptibility Testing (EUCAST) for Staphylococci and Streptococci (except S. pneumoniae) are Susceptible

1 mg/l

and Resistant > 1 mg/l.

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Susceptibility

The prevalence of resistance may vary geographically and over 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.

* Denotes species against which it is considered that activity has been satisfactorily demonstrated in clinical studies.

Clinical efficacy and safety

In two clinical trials in complicated skin and soft tissues infections, 36 % of patients treated with daptomycin met the

criteria for systemic inflammatory response syndrome (SIRS). The most common type of infection treated was wound

infection (38 % of patients), while 21 % had major abscesses. These limitations of the patients population treated

should be taken into account when deciding to use daptomycin.

In a randomised controlled open-label study in 235 patients with Staphylococcus aureus bacteraemia (i.e., at least one

positive blood culture of Staphylococcus aureus prior to receiving the first dose) 19 of 120 patients treated with

daptomycin met the criteria for RIE. Of these 19 patients 11 were infected with methicillin-susceptible and 8 with

methicillin-resistant Staphylococcus aureus. The success rates in RIE patients are shown in the table below.

Failure of treatment due to persisting or relapsing Staphylococcus aureus infections was observed in 19/120 (15.8 %)

patients treated with daptomycin, 9/53 (16.7 %) patients treated with vancomycin and 2/62 (3.2 %) patients treated with

an anti-staphylococcal semi-synthetic penicillin. Among these failures six patients treated with daptomycin and one

patient treated with vancomycin were infected with Staphylococcus aureus that developed increasing MICs of

daptomycin on or following therapy (see “Mechanisms of resistance” above). Most patients who failed due to

persisting or relapsing Staphylococcus aureus infection had deep-seated infection and did not receive necessary

surgical intervention.

The safety and efficacy of daptomycin was evaluated in paediatric patients aged 1 to 17 years (Study DAP-PEDS-07-

03) with cSSTI caused by Gram positive pathogens. Patients were enrolled in a stepwise approach into well-defined

age groups and given age-dependent doses once daily for up to 14 days, as follows:

Age group 1 (n = 113): 12 to 17 years treated with daptomycin dosed at 5 mg/kg or standard-of-care (SOC);

Age group 2 (n = 113): 7 to 11 years treated with daptomycin dosed at 7 mg/kg or SOC;

Age group 3 (n = 125): 2 to 6 years treated with daptomycin dosed at 9 mg/kg or SOC;

Age group 4 (n = 45): 1 to < 2 years treated with daptomycin dosed at 10 mg/kg or SOC.

Commonly Susceptible Species

Staphylococcus aureus *

Staphylococcus haemolyticus

Coagulase negative staphylococci

Streptococcus agalactiae *

Streptococcus dysgalactiae subsp. equisimilis *

Streptococcus pyogenes *

Group G streptococci

Clostridium perfringens

Peptostreptococcus spp

Inherently resistant organisms

Gram negative organisms

Population

Daptomycin

Comparator

Differences in Success

n/N (%)

n/N (%)

Rates (95 % CI)

ITT (intention to treat) Population

8/19 (42.1 %)

7/16 (43.8 %)

-1.6 % (-34.6, 31.3)

PP (per protocol) Population

6/12 (50.0 %)

4/8 (50.0 %)

0.0 % (-44.7, 44.7)

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The primary objective of Study DAP-PEDS-07-03 was to assess the safety of treatment. Secondary objectives included

an assessment of efficacy of age-dependent doses of intravenous daptomycin in comparison with standard-of-care

therapy. The key efficacy endpoint was the sponsor-defined clinical outcome at test-of-cure (TOC), which was defined

by a blinded medical director.

A total of 389 subjects were treated in the study, including 256 subjects who received daptomycin and 133 subjects

who received standard-of-care. In all populations the clinical success rates were comparable between the daptomycin

and SOC treatment arms, supporting the primary efficacy analysis in the ITT population.

Summary of sponsor-defined clinical outcome at test-of-cure:

The overall therapeutic response rate also was similar for the daptomycin and SOC treatment arms for infections

caused by MRSA, MSSA and Streptococcus pyogenes (see table below; ME population); response rates were > 94 %

for both treatment arms across these common pathogens.

Summary of overall therapeutic response by type of baseline pathogen (ME population):

Subjects achieving clinical success (Clinical Response of “Cure” or “Improved”) and microbiological success

(pathogen–level response of “Eradicated” or “Presumed Eradicated”) are classified as overall therapeutic success.

5.2 Pharmacokinetic properties

Daptomycin pharmacokinetics are generally linear and time-independent at doses of 4 to 12 mg/kg administered as a

single daily dose by 30-minute intravenous infusion for up to 14 days in healthy volunteers. Steady-state concentrations

are achieved by the third daily dose.

Daptomycin administered as a 2-minute intravenous injection also exhibited dose proportional pharmacokinetics in the

approved therapeutic dose range of 4 to 6 mg/kg. Comparable exposure (AUC and Cmax) was demonstrated in healthy

subjects following administration of daptomycin as a 30-minute intravenous infusion or as a 2-minute intravenous

injection.

Animal studies showed that daptomycin is not absorbed to any significant extent after oral administration.

Distribution

The volume of distribution at steady state of daptomycin in healthy adult subjects was approximately 0.1 l/kg and was

independent of dose. Tissue distribution studies in rats showed that daptomycin appears to only minimally penetrate the

blood-brain barrier and the placental barrier following single and multiple doses.

Daptomycin is reversibly bound to human plasma proteins in a concentration independent manner. In healthy

volunteers and patients treated with daptomycin, protein binding averaged about 90 % including subjects with renal

impairment.

Clinical Success

DAP

n/N (%)

SOC

n/N (%)

% difference

Intent-to-treat

227/257 (88.3 %)

114/132 (86.4 %)

Modified intent-to-treat

186/210 (88.6 %)

92/105 (87.6 %)

Clinically evaluable

204/207 (98.6 %)

99/99 (100 %)

-1.5

Microbiologically evaluable (ME)

164/167 (98.2 %)

78/78 (100 %)

-1.8

Pathogen

Success a rate

n/N (%)

Daptomycin

Comparator

Methicillin-susceptible Staphylococcus aureus (MSSA)

68/69 (99 %)

28/29 (97 %)

Methicillin-resistant Staphylococcus aureus (MRSA)

63/66 (96 %)

34/34 (100 %)

Streptococcus pyogenes

17/18 (94 %)

5/5 (100 %)

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Biotransformation

In in vitro studies, daptomycin was not metabolised by human liver microsomes. In vitro studies with human

hepatocytes indicate that daptomycin does not inhibit or induce the activities of the following human cytochrome P450

isoforms: 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4. It is unlikely that daptomycin will inhibit or induce the

metabolism of medicinal products metabolised by the P450 system.

After infusion of 14C-daptomycin in healthy adults, the plasma radioactivity was similar to the concentration

determined by microbiological assay. Inactive metabolites were detected in urine, as determined by the difference in

total radioactive concentrations and microbiologically active concentrations. In a separate study, no metabolites were

observed in plasma, and minor amounts of three oxidative metabolites and one unidentified compound were detected in

urine. The site of metabolism has not been identified.

Elimination

Daptomycin is excreted primarily by the kidneys. Concomitant administration of probenecid and daptomycin has no

effect on daptomycin pharmacokinetics in humans suggesting minimal to no active tubular secretion of daptomycin.

Following intravenous administration, plasma clearance of daptomycin is approximately 7 to 9 ml/h/kg and its renal

clearance is 4 to 7 ml/h/kg.

In a mass balance study using radiolabelled material, 78 % of the administered dose was recovered from the urine

based on total radioactivity, whilst urinary recovery of unchanged daptomycin was approximately 50 % of the dose.

About 5 % of the administered radiolabel was excreted in the faeces.

Special populations

Elderly

Following administration of a single 4 mg/kg intravenous dose of daptomycin over a 30-minute period, the mean total

clearance of daptomycin was approximately 35 % lower and the mean AUC0-

was approximately 58 % higher in

elderly subjects (

75 years of age) compared with those in healthy young subjects (18 to 30 years of age). There were

no differences in Cmax. The differences noted are most likely due to the normal reduction in renal function observed in

the geriatric population.

No dose adjustment is necessary based on age alone. However, renal function should be assessed and the dose should

be reduced if there is evidence of severe renal impairment.

Children and adolescents (< 18 years of age)

The pharmacokinetics of daptomycin after a single 4 mg/kg dose of daptomycin were evaluated in three groups of

paediatric patients with proven or suspected Gram-positive infection (2 - 6 years, 7 - 11 years and 12 - 17 years). The

pharmacokinetics of daptomycin following a single 4 mg/kg dose in adolescents aged 12 - 17 years are generally

similar to those of healthy adult subjects with normal renal function with trends towards lower AUC and Cmax in

adolescents. In the younger age groups (2 - 6 years and 7 - 11 years), total clearance was higher compared with that in

adolescents, resulting in a lower level of exposure (AUC and Cmax) and elimination half-life. Efficacy was not

assessed in this study.

A separate study was conducted to evaluate the pharmacokinetics of daptomycin after a single 8 mg/kg or 10 mg/kg

dose of daptomycin as either a 1 or 2 hour infusion in paediatric subjects aged 2 to 6 years, inclusive, with proven or

suspected Gram-positive infection who were receiving standard antibacterial therapy.

The mean exposure (AUC0-

) was approximately 429 and 550 µg*hr/ml after the administration of 8 and 10 mg/kg

single doses, respectively, similar to the exposure seen in adults at the 4 mg/kg dose at steady state (495 µg*hr/ml). The

pharmacokinetics of daptomycin appears to be linear in the dose range studied. The half-life, clearance and volume of

distribution were similar at both dose levels.

A Phase 4 study was conducted to assess safety, efficacy, and pharmacokinetics of daptomycin in paediatric patients (1

to 17 years old, inclusive) with cSSTI caused by Gram-positive pathogens. Patients were enrolled into 4 groups (see

section 5.1).

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Intravenous daptomycin doses of 5 to 10 mg/kg were administered and 256 children received daptomycin, from which

pharmacokinetic sampling was performed on 45 children from across the age groups. Following the administration of

multiple doses, daptomycin AUC0-tau were 387, 438, 439 and 466 µg×hr/ml for 12 - 17 years, 7 - 11 years, 2 - 6 years

and 1 - < 2 years, respectively, indicating that the daptomycin exposure was similar across the different age groups

after dose adjustment based on body weight and age.

The mean Cmax ranged from 62.4 µg/ml to 81.9 µg/ml. The terminal t1/2 ranged from 3.8 to 5.3 hours across the

different age groups while the mean steady-state clearance ranged from 13.3 to 21.5 ml/hr/kg. The corresponding

clearance in patients in the lower age group was also higher, which is consistent with previous observations. Exposure

levels achieved with these doses were consistent with those achieved in the adult cSSTI study.

Obesity

Relative to non-obese subjects daptomycin systemic exposure measured by AUC was about 28 % higher in moderately

obese subjects (Body Mass Index of 25 - 40 kg/m2) and 42 % higher in extremely obese subjects (Body Mass Index of

> 40 kg/m2). However, no dose adjustment is considered to be necessary based on obesity alone.

Gender

No clinically significant gender-related differences in daptomycin pharmacokinetics have been observed.

Renal impairment

Following administration of a single 4 mg/kg or 6 mg/kg intravenous dose of daptomycin over a 30-minute period to

subjects with various degrees of renal impairment, total daptomycin clearance (CL) decreased and systemic exposure

(AUC) increased as renal function (creatinine clearance) decreased.

Based on pharmacokinetic data and modelling, the daptomycin AUC during the first day after administration of a

6 mg/kg dose to patients on HD or CAPD was 2-fold higher than that observed in patients with normal renal function

who received the same dose. On the second day after administration of a 6 mg/kg dose to HD and CAPD patients the

daptomycin AUC was approximately 1.3 -fold higher than that observed after a second 6 mg/kg dose in patients with

normal renal function. On this basis, it is recommended that patients on HD or CAPD receive daptomycin once every

48 hours at the dose recommended for the type of infection being treated (see section 4.2).

Hepatic impairment

The pharmacokinetics of daptomycin is not altered in subjects with moderate hepatic impairment (Child-Pugh B

classification of hepatic impairment) compared with healthy volunteers matched for gender, age and weight following a

single 4 mg/kg dose. No dosage adjustment is necessary when administering daptomycin in patients with moderate

hepatic impairment. The pharmacokinetics of daptomycin in patients with severe hepatic impairment (Child-Pugh C

classification) have not been evaluated.

5.3 Preclinical safety data

In studies of clinically-relevant duration (14-28 days), daptomycin administration was associated with minimal to mild

degenerative/regenerative changes in skeletal muscle in the rat and dog. Microscopic changes in skeletal muscle were

minimal (approximately 0.05 % of myofibres affected) and at the higher doses were accompanied by elevations in

CPK. No fibrosis or rhabdomyolysis was observed. Depending on the study duration, all muscle effects, including

microscopic changes, were fully reversible within 1-3 months following cessation of dosing. No functional or

pathological changes in smooth or cardiac muscle were observed.

The lowest observable effect level (LOEL) for myopathy in rats and dogs occurred at exposure levels of 0.8 to 2.3-fold

the human therapeutic levels at 6 mg/kg (30-minute intravenous infusion) for patients with normal renal function. As

the pharmacokinetics (see section 5.2) is comparable, the safety margins for both methods of administration are very

similar.

A study in dogs demonstrated that skeletal myopathy was reduced upon once daily administration as compared to

fractionated dosing at same total daily dose, suggesting that myopathic effects in animals were primarily related to time

between doses.

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Effects on peripheral nerves were observed at higher doses than those associated with skeletal muscle effects in adult

rats and dogs, and were primarily related to plasma Cmax. Peripheral nerve changes were characterised by minimal to

slight axonal degeneration and were frequently accompanied by functional changes. Reversal of both the microscopic

and functional effects was complete within 6 months post-dose. Safety margins for peripheral nerve effects in rats and

dogs are 8- and 6-fold, respectively, based on comparison of Cmax values at the No Observed Effect Level (NOEL)

with the Cmax achieved on dosing with 30-minute intravenous infusion of 6 mg/kg once daily in patients with normal

renal function.

The findings of in vitro and some in vivo studies designed to investigate the mechanism of daptomycin myotoxicity

indicate that the plasma membrane of differentiated spontaneously contracting muscle cells is the target of toxicity. The

specific cell surface component directly targeted has not been identified. Mitochondrial loss/damage was also observed;

however the role and significance of this finding in the overall pathology are unknown. This finding was not associated

with an effect on muscle contraction.

In contrast to adult dogs, juvenile dogs appeared to be more sensitive to peripheral nerve lesions as compared to

skeletal myopathy. Juvenile dogs developed peripheral and spinal nerve lesions at doses lower than those associated

with skeletal muscle toxicity.

In neonatal dogs, daptomycin caused marked clinical signs of twitching, muscle rigidity in the limbs, and impaired use

of limbs, which resulted in decreases in body weight and overall body condition at doses

50 mg/kg/day and

necessitated early discontinuation of treatment in these dose groups. At lower dose levels (25 mg/kg/day), mild and

reversible clinical signs of twitching and one incidence of muscle rigidity were observed without any effects on body

weight. There was no histopathological correlation in the peripheral and central nervous system tissue, or in the skeletal

muscle, at any dose level, and the mechanism and clinical relevance for the adverse clinical signs are therefore

unknown.

Reproductive toxicity testing showed no evidence of effects on fertility, embryofoetal, or postnatal development.

However, daptomycin can cross the placenta in pregnant rats (see section 5.2). Excretion of daptomycin into milk of

lactating animals has not been studied.

Long-term carcinogenicity studies in rodents were not conducted. Daptomycin was not mutagenic or clastogenic in a

battery of in vivo and in vitro genotoxicity tests.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydroxide

6.2 Incompatibilities

Daptomycin Clonmel is not physically or chemically compatible with glucose-containing solutions.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6

6.3 Shelf life

2 years

After reconstitution: Chemical and physical in-use stability of the reconstituted solution in the vial has been

demonstrated for 12 hours at 25 °C and up to 48 hours at 2 °C – 8 °C. Chemical and physical stability of the diluted

solution in infusion bags is established as 12 hours at 25 °C or 24 hours at 2 °C – 8 °C.

For the 30-minute intravenous infusion, the combined storage time (reconstituted solution in vial and diluted solution in

infusion bag; see section 6.6) at 25 °C must not exceed 12 hours (or 24 at 2 °C – 8 °C).

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For the 2-minute intravenous injection, the storage time of the reconstituted solution in the vial (see section 6.6) at 25°

C must not exceed 12 hours (or 48 at 2 °C – 8 °C).

However, from a microbiological point of view the product should be used immediately. No preservative or

bacteriostatic agent is present in this product. If not used immediately, in-use storage times are the responsibility of the

user and would not normally be longer than 24 hours at 2 °C – 8 °C, unless reconstitution/dilution has taken place in

controlled and validated aseptic conditions.

6.4 Special precautions for storage

Store in a refrigerator (2 °C – 8 °C).

For storage conditions after reconstitution and after reconstitution and dilution of the medicinal product see section 6.3.

6.5 Nature and contents of container

Single use 15 ml type I glass vials with bromobutyl rubber stoppers and sealed with 20 mm flip-off seal blue.

Available in packs containing 1 vial or 5 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Daptomycin may be administered intravenously as an infusion over 30 or 60 minutes or as an injection over 2 minutes

(see sections 4.2 and 5.2). Preparation of the solution for infusion requires an additional dilution step as detailed below.

Daptomycin Clonmel given as 30 or 60-minute intravenous infusion

A 50 mg/ml concentration of Daptomycin Clonmel for infusion is obtained by reconstituting the lyophilised product

with 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear

and may have a few small bubbles or foam around the edge of the vial.

To prepare Daptomycin Clonmel for intravenous infusion, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin Clonmel.

The polypropylene flip off seal should be removed to expose the central portions of the rubber stopper. Wipe the

top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do

not touch the rubber stopper or allow it to touch any other surface. Draw 10 ml of sodium chloride 9 mg/ml

(0.9 %) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter,

or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle

towards the wall of the vial.

The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for

10 minutes.

Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted

solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.

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The reconstituted solution should be checked carefully to ensure that the product is in solution and visually

inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin Clonmel range in

colour from pale yellow to light brown.Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the

vial using a sterile needle that is 21 gauge or smaller in diameter:Invert the vial in order to allow the solution to

drain towards the stopper. Using the new syringe, insert the needle into the inverted vial. Keeping the vial

inverted, position the needle tip at the very bottom of the solution in the vial when drawing the solution into the

syringe. Before removing the needle from the vial, pull the plunger all the way back to the end of the syringe

barrel in order to remove all of the solution from the inverted vial.

The reconstituted solution should then be diluted with sodium chloride 9 mg/ml (0.9 %) (typical volume 50 ml).

Replace needle with a new needle for the intravenous infusion.

Expel air, large bubbles, and any excess solution in order to obtain the required dose.

The reconstituted and diluted solution should then be infused intravenously over 30 or 60 minutes as directed in

section 4.2.

Daptomycin Clonmel given as 2 -minute intravenous injection

Water should not be used for reconstitution of Daptomycin Clonmel for intravenous injection. Daptomycin Clonmel

should only be reconstituted with sodium chloride 9 mg/ml (0.9 %).

A 50 mg/ml concentration of Daptomycin Clonmel for injection is obtained by reconstituting the lyophilised product

with 10 ml of sodium chloride 9 mg/ml (0.9 %) solution for injection.

The lyophilised product takes approximately 15 minutes to dissolve. The fully reconstituted product will appear clear

and may have a few small bubbles or foam around the edge of the vial.

To prepare Daptomycin Clonmel for intravenous injection, please adhere to the following instructions:

Aseptic technique should be used throughout to reconstitute lyophilised Daptomycin Clonmel.

The polypropylene flip off seal should be removed to expose the central portions of the rubber stopper. Wipe the

top of the rubber stopper with an alcohol swab or other antiseptic solution and allow to dry. After cleaning, do

not touch the rubber stopper or allow it to touch any other surface. Draw 10 ml of sodium chloride 9 mg/ml

(0.9 %) solution for injection into a syringe using a sterile transfer needle that is 21 gauge or smaller in diameter,

or a needleless device, then slowly inject through the centre of the rubber stopper into the vial pointing the needle

towards the wall of the vial.

The vial should be gently rotated to ensure complete wetting of the product and then allowed to stand for

10 minutes.

Finally the vial should be gently rotated/swirled for a few minutes as needed to obtain a clear reconstituted

solution. Vigorous shaking/agitation should be avoided to prevent foaming of the product.

The reconstituted solution should be checked carefully to ensure that the product is in solution and visually

inspected for the absence of particulates prior to use. Reconstituted solutions of Daptomycin Clonmel range in

colour from pale yellow to light brown.

Slowly remove the reconstituted liquid (50 mg daptomycin/ml) from the vial using a sterile needle that is

21 gauge or smaller in diameter:Invert the vial in order to allow the solution to drain towards the stopper. Using a

new syringe, insert the needle into the inverted vial. Keeping the vial inverted, position the needle tip at the very

bottom of the solution in the vial when drawing the solution into the syringe. Before removing the needle from

the vial, pull the plunger all the way back to the end of the syringe barrel in order to remove all of the solution

from the inverted vial.

Replace needle with a new needle for the intravenous injection.

Expel air, large bubbles, and any excess solution in order to obtain the required dose.

The reconstituted solution should then be injected intravenously slowly over 2 minutes as directed in section 4.2.

Daptomycin Clonmel vials are for single-use only.

From a microbiological point of view, the product should be used immediately after reconstitution (see section 6.3).

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

7 MARKETING AUTHORISATION HOLDER

Clonmel Healthcare Ltd

Waterford Road

Clonmel

Co. Tipperary

Ireland

8 MARKETING AUTHORISATION NUMBER

PA0126/286/002

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14

July 2017

10 DATE OF REVISION OF THE TEXT

September 2017

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