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NEGABAN 1G POWDER FOR SOLUTION FOR INJECTION/INFUSION

Active substance(s): TEMOCILLIN

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NEGABAN 1g,
powder for
(temocillin)

solution

4. POSSIBLE SIDE EFFECTS

for

injection/infusion

Read all of this leaflet carefully before you start using this
medicine.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you. Do not pass it on to others. It
may harm them, even if their symptoms are the same as yours.
- 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 pharmacist.
In this leaflet:
1. What Negaban is and what it is used for
2. Before you receive Negaban
3. How Negaban is given
4. Possible side effects
5. How to store Negaban
6. Further information
1. WHAT NEGABAN IS AND WHAT IT IS USED FOR
Negaban belongs to the penicillin group of antibiotics. It works by killing
some types of bacteria that may cause infections.

Like all medicines, Negaban can cause side effects, although not
everybody gets them.
Allergic reactions such as a rash, itching, breathing problems, swelling
of the tongue, lips, face and neck can occur occasionally. Some of these
reactions can be very severe, can occur very soon after having a dose of
Negaban or up to 48 hours later, and can happen after the first dose. In
these cases, discontinuance of treatment and urgent medical treatment
is needed: contact your doctor or nurse immediately.
Other side effects that have been reported with Negaban treatment
include diarrhoea (several loose bowel movements a day) and pain in the
muscles or in the joints at the injection site, inflammation of a vein with
or without formation of a clot. In case of persistent diarrhoea, treatment
must be discontinued immediately.
Bleeding manifestations and disorders of the nerves with muscular
contractions have been reported in patients suffering from severe
malfunction of the kidneys.
Tell a doctor or nurse immediately if you get any of these symptoms.
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 pharmacist.
5. HOW TO STORE NEGABAN

Negaban is used to treat:
• bacterial infections of the chest and lungs
• bacterial infections of the kidneys and bladder
• other types of infections when there are bacteria in the bloodstream

Keep out of the reach and sight of children.

2. BEFORE YOU RECEIVE NEGABAN

Since Negaban is usually given in hospitals, your doctor, nurse or
pharmacist will take care that it is stored in a refrigerator (2°C - 8°C) in the
original package and will check that it is not used after the expiry date.
They will also ensure that the powder is made into a solution immediately
before it is given to you.

Do not use Negaban
• if you ever had an allergic reaction to temocillin.
• if you ever had an allergic reaction to any antibiotic of the types called
penicillins, cephalosporins, carbapenems or monobactams.
If you are not sure, you should talk to your doctor, nurse or pharmacist
before you receive Negaban. This is especially important if you have ever
had an allergic reaction to any antibiotic but you are not sure what type
of antibiotic it was.
Take special care with Negaban
• if you have been told that your kidneys do not work normally.
• if you have been told that your potassium levels are low.
If any of the above applies to you, your doctor may still decide to give
you Negaban but may choose a lower dose than is usually given.
Using other medicines
You should continue to take all other medicines that you may be taking
on a regular basis on the advice of your doctor while you are receiving
Negaban.
Please tell your doctor or pharmacist if you are taking or have recently
taken any other medicines, including medicines obtained without a
prescription.

Do not use Negaban after the expiry date which is stated on the label and
carton after EXP. The expiry date refers to the last day of that month.

6. FURTHER INFORMATION
What Negaban contains
The active substance is temocillin.
There are no other ingredients.
What Negaban looks like and contents of the pack
Each vial of Negaban 1 g powder for solution for injection/infusion
contains 1 gram of the active ingredient temocillin.
Negaban 1 g powder for solution for injection/infusion is supplied in
packs that contain 1 vial.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Eumedica S.A. at Winston Churchill Avenue 67, BE-1180 Brussels,
Belgium.
Manufacturer
Eumedica S.A. at Chemin de Nauwelette 1, BE-7170 Manage, Belgium.

Using Negaban with food and drink
Negaban should not interfere with food and drink.

This leaflet was last approved in 08/2011.
------------------------------------------------------------------------------------------

Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.

TECHNICAL PACKAGE INSERT

• You should tell your doctor or nurse if you are pregnant or think you
may be pregnant before you receive Negaban because it should not
usually be given to pregnant women.
• You should tell your doctor or nurse if you are breastfeeding before
you receive Negaban. Small quantities of the active ingredient appear in
breast milk and can be passed on to your baby. Your doctor may decide
that you should not have Negaban or may advise you to have Negaban
but stop breast-feeding while you are being treated.
Driving and using machines
Negaban should not interfere with your ability to drive or operate
machinery.
3. HOW NEGABAN IS GIVEN
Method of administration
Always use Negaban exactly as your doctor has told you. You should
check with your doctor or pharmacist if you are not sure.
Negaban will first be dissolved in Water for Injection by your doctor,
nurse or pharmacist. This solution will then be given to you either by
injection into a vein or by injection into a muscle.
When Negaban is injected into a vein:
• It may be given in 3-4 minutes or it may be put into an infusion (drip)
and given over about 30 minutes or more.
• Your doctor or nurse will make sure that Negaban is not given into a
drip that also contains blood or blood products, other fluids that contain
proteins or fats, or antibiotics called aminoglycosides.
When Negaban is injected into a muscle:
• It may be dissolved in a weak solution of lidocaine so as to lessen the
local pain that is sometimes felt when it is given in this way.
• If your doctor decides to give Negaban with lidocaine,
- he/she will check with you that you are not allergic to lidocaine or to
any similar local anaesthetics,
- and your doctor or nurse will ensure that the injection is not accidentally
given into a blood vessel.
Usual doses
Your doctor will decide how much of this medicine you need each day
and how often the injections should be given. The usual doses used are:
Adults of all ages
1-2 grams twice a day.
Adults with kidneys that do not work normally
People whose kidneys do not work normally may need a lower daily dose
of Negaban. The dose may be reduced to no more than 1 gram per day or
even 1 gram every other day.
Because some temocillin is removed from the body during haemodialysis
treatments for very poor kidneys, a dose of Negaban is usually given after
completing a haemodialysis session.
Your doctor will tell you how much you should have if your kidneys do
not work normally.
Children
Insufficient data are available to recommend an appropriate dosage regime.
Your doctor will decide how long your treatment with Negaban will last.
If you use more Negaban than you should
Since Negaban is given by a doctor or nurse, it is very unlikely that you
will receive too much temocillin. If you think that you may have been
given too much, or an extra dose, tell your doctor or nurse.
If you forget to use Negaban
If you think that an injection has been missed, speak to your nurse,
doctor or pharmacist.
If you stop using Negaban
Not applicable.
If you have any further questions on the use of this product, ask your
doctor or pharmacist.

1. TRADE NAME OF THE MEDICINAL PRODUCT
Negaban 1 g, powder for solution for injection/infusion.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
1 g of temocillin as temocillin sodium.
3. PHARMACEUTICAL FORM
Powder for solution for injection/infusion.
Vial containing a white to pale yellow sterile solid.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Negaban is indicated for the treatment of septicaemia, urinary tract infection
and lower respiratory tract infection where susceptible gram-negative bacilli are
suspected or confirmed.
In mixed infections where gram-positive or anaerobic bacteria are also liable to be
implicated, co-administration with other appropriate antibacterial agents should
be considered.
Consideration should be given to official guidance on the appropriate use of
antibacterial agents.
4.2. Posology and method of administration
Adults (including the elderly): The usual dosage is 1-2 g every 12 hours.
Children: Insufficient data are available to recommend an appropriate dosage
regime.
Dosage in patients with impaired renal or hepatic functions (adults): Temocillin is
mainly excreted renally and unchanged. Excretion is reduced in renal impairment
and half-life is increased according to the severity of renal failure. In moderate
and severe renal failure, dose adjustments are necessary in accordance with the
following regimen:
Creatinine clearance
(ml/min)

Dosage per
administration

Interval between
administrations

More than 60

1 to 2 g

12 h

60 to 30

1g

12 h

30 to 10

1g

24 h

Less than 10

1 g or 500 mg

48 h or 24 h

In case of hemodialysis: as a rule, the I.M. route should be avoided, considering the
patient’s treatment with heparin. I.V. injection of Negaban is recommended, using
water for injection as solvent: 1 g (I.V.) every 48 hours, preferably at the end of the
hemodialysis. In case of daily hemodialysis: 500 mg (I.V.) after each hemodialysis.
In case of continuous peritoneal dialysis in ambulatory patients: 1 g Negaban I.M.
every 48 hours.
These data are based on studies where creatinine clearance was used to estimate the
degree of renal impairment.
Limited experience in patients with impaired hepatic function has not indicated a
need for a reduction in dosage.
Method of administration:
Negaban may be administered by intravenous injection, intermittent intravenous
infusion or intramuscular injection.
Intravenous solutions: See also Section 6.6. Negaban solutions should be administered
by slow injection into the vein (3-4 minutes) or as an intravenous infusion over a
period of 30-40 minutes.
Intramuscular injection: Negaban may be given intramuscularly after reconstitution
(see Section 6.6.). If pain is experienced at the site of I.M. injection, a sterile solution
of lidocaine hydrochloride 0.5-1% may be used in place of Water for Injections.
4.3. Contraindications
The use of Negaban is contraindicated in patients with a history of allergic reactions
to any of the penicillins or any other type of beta-lactam drug.
4.4. Special warnings and precautions for use
Serious and occasionally fatal anaphylactic reactions have been reported in patients
receiving therapy with penicillins. If an allergic reaction occurs during therapy with
Negaban, the drug must be discontinued.

Cross-allergy with cephalosporins is frequent (10 to 15%).
In patients with kidney failure, the posology must be adapted to the degree
of insufficiency, as recommended in Section 4.2. Posology and Method of
Administration.
Bleeding manifestations have occurr ed in some patients receiving beta-lactam
antibiotics. These reactions have sometimes been assessed with abnormalities
of coagulation tests and are more likely to occur in patients with renal failure.
If bleeding manifestations occur, the antibiotic should be discontinued and
appropriate therapy instituted.
As with any antibiotic, temocillin may be associated with induced
pseudomembranous colitis, although animal studies have never shown any
induction of Clostridium difficile infection. In case of severe, persistent diarrhoea,
caution is recommended,
Negaban must be discontinued and suitable therapy be initiated (eg oral
metronidazole or oral vancomycin). Preparations which inhibit peristalsis are
contra-indicated.
As with other antibiotics, the possibility of emergence of resistant organisms
which might cause superinfections should be kept in mind, particularly during
prolonged treatment. Microbiological follow-up may be required to detect any
important superinfection. If this occurs, appropriate measures should be taken.
As with other penicillins, patients may experience neuromuscular excitability or
convulsions if higher than recommended doses are given intravenously.
Periodic electrolyte determinations should be made in patients with low
potassium reserves and the possibility of hypokalaemia should be kept in mind
with patients who have potentially low potassium reserves and who are receiving
cytotoxic therapy or diuretics. Modest elevations of indices of liver function may
be observed.
1 vial of Negaban 1 g contains 5 mmol of sodium.
4.5. Interaction with other medicinal products and other forms of
interaction
None known.

Distribution: The protein serum binding rate is 85% in healthy volunteers.
Concentrations of temocillin in gall bladder bile at a mean of 2.4 hours after
I.V. injection of 1 g were variable. Temocillin was not detected in the bile of 2
out of 10 patients but in some cases concentrations were considerably higher
than those in serum. The mean concentration in gall bladder bile was 205 μg/ml.
Concentrations of temocillin in prostate homogenate between 1 and 3 hours
after I.M. injection of 1 g of temocillin ranged from 2.3-16 μg/ml (mean 8.25)
compared with a mean serum concentration of 12.5 μg/ml.
In a series of studies, the penetration of temocillin into tissues was investigated by
assaying either tissue fluid or homogenate for temocillin. Following I.V. injection
of 1 g of temocillin, concentrations in the fluid of cantharidine-induced skin
blisters reached a mean peak of 44.3 μg/ml at 3 hours. The mean half-life of
temocillin in blister fluid was 4.0 hours.
Temocillin concentrations in peripheral lymph after a 1 g I.V. injection were of a
similar order to those in blister fluid, reaching a mean peak of 30.6 μg/ml between
1.5 and 2 hours. The mean half-life of elimination from lymph was 4.4 hours. As
was found in skin blisters, concentrations of temocillin in lymph were above the
MIC of susceptible bacteria at 12 hours after administration.
Only a small proportion of temocillin passes into the cerebrospinal fluid.
Excretion: Temocillin is excreted unchanged mainly in the kidney. Excretion may
be delayed in cases of kidney failure so the dosage must be reduced, depending on
the degree of kidney failure shown by the creatinine clearance values.
Pharmacokinetic parameters in renal impairment:
creatinin
clearance
(ml/min)

No. of
Cmax
Dose (g)
subjects
(mg/L)
5
5
5
2
5
5

30-60
10-30
< 10

0.5
1
0.5
1
0.5
1

T½ß(h)

CLtot
(ml/min)

VDss
(L)

13.6
20.0
18.9
17.0
28.2
26.6

16.3
15.5
13.3
9.9
8.8
-

16.3
16.0
22.1
13.8
19.9
7.3

69.8
122.0
49.4
118.0
49.5
-

urine
excretion
(% in 24h)
51.6
40.2
23.1
17.0
8.3
-

- = Not determined
5.3. Preclinical safety data

4.6. Pregnancy and lactation
Animal studies with Negaban have shown no teratogenic effects. There is no
experience of Negaban in human pregnancy. Therefore, its use in pregnancy
cannot be recommended. Trace quantities of penicillins can be detected in the
milk of lactating mothers. Therefore, mothers should not breastfeed their infants
while receiving Negaban.

No information additional to that already contained in this Summary of Product
Characteristics.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
None.

4.7. Effects on ability to drive and use machines

6.2. Incompatibilities

None known.

Negaban should not be mixed with the following in the syringe, intravenous fluid
container or giving set:

Proteinaceous fluids (e.g. protein hydrolysates)

Blood products

Intravenous lipid emulsions

Aminoglycosides

4.8. Undesirable effects
Undesirable effects are typical of the injectable penicillins: they may include
diarrhoea, pain at the site of I.M. injection, occasionally rash, either urticarial or
erythematous.
Certain reactions such as fever, arthralgia or myalgia, sometimes develop more
than 48 hours after the start of the treatment. In any case, discontinuance of
treatment and recourse to another appropriate antibiotic therapy are essential.
In common with other ß-lactam antibiotics angioedema and anaphylaxis have
been reported.
There is also a risk of phlebitis and thrombophlebitis with intravenous
administration of ß-lactam antibiotics, although to a lesser extent in the case of
Negaban.
In patients suffering from renal failure, neurological disorders with convulsions
have been reported following the I.V. injection of high doses of penicillin.

This medicinal product must not be mixed with other products except those
mentioned in section 6.6.
6.3. Shelf life
Dry powder: 3 years
Shelf life after reconstitution: see Section 6.6. Special precautions for disposal and
other handling.
6.4. Special precautions for storage
Store in a refrigerator (2°C - 8°C). Store in the original package.

4.9. Overdose

6.5. Nature and contents of container

There have been no reported cases of overdosage. Dosages of up to 8 g daily have
been administered to volunteers without untoward effects.
Negaban may be removed from the circulation by haemodialysis.

Clear glass vial with butyl rubber stoppers and either aluminium seal or
aluminium plastic seal in packs of 1 vial or 5 vials.

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties

Negaban is not intended for multi-dose use, any part-used antibiotic solution
should be discarded. Solutions are normally a pale yellow colour.

Pharmacotherapeutic group: ß-lactam antibacterials - penicillins (ATC: J01CA17)

Intravenous injection

6.6. Special precautions for disposal and other handling

The product is an injectable antibiotic active in vitro against many aerobic
gram-negative bacteria, with the notable exception of Pseudomonas aeruginosa
and Acinetobacter spp.

Dose
1g

Recommended volume of Water for Injections
BP to be added for dissolution
10 ml

Mechanism of action:
ß-lactam antibiotics act by inhibiting the synthesis of the peptidoglycan layer
of bacterial cell walls. ß-lactam antibiotics irreversibly bind to the active site
of specific transpeptidases and carboxypeptidases known as Penicillin Binding
Proteins (PBP), preventing peptidoglycan production.

2g

20 ml

Mechanism of resistance:
Temocillin is stable to most types of ß-lactamases, including most AmpC and
Extended Spectrum ß-Lactamases. The only suspected mechanisms of resistance
to temocillin are outer membrane impermeabilisation or active efflux.
ß-lactamase producing Enterobacteriaceae resistant to 2nd or 3rd generation
cephalosporins may be sensitive to Negaban.
Breakpoints following the BSAC (British Society for Antimicrobial
Chemotherapy) method for Enterobacteriaceae:
Susceptible organisms: MIC ≤ 8 mg/L
Resistant organisms: MIC > 8 mg/L
Uncomplicated urinary tract infections:
Susceptible organisms: MIC ≤ 32 mg/L
Resistant organisms: MIC > 32 mg/L

Vial strength
1g

Recommended volume of Water for Injections
BP to be added for dissolution
2 ml

Final volume
2.7 ml

After addition of water to the vial, shake vigorously.
Inject I.M. solutions immediately after preparation.

If not used immediately, in-use storage times and conditions are the responsibility
of the user.
7. MARKETING AUTHORISATION HOLDER

Mean pharmacokinetic parameters of temocillin following administration of a
single dose:
ELDERLY
PATIENTS

HEALTHY SUBJECTS
I.V. BOLUS
1g
2g
4g
6
6
8
173.1 281.2 482.9
4.2
4.2
4.2
33.2
38.3
48.5
12.1

Intramuscular injection

From a microbiological point of view, unless the method of opening/reconstitution/
dilution precludes the risk of microbial contamination, the product should be
used immediately.

5.2. Pharmacokinetic properties

11.1

Intermittent intravenous infusion
Solutions should be prepared as described for intravenous injection and then
added to an intravenous infusion solution in a mini-bag or in-line burette and
administered over a period of 30-40 minutes. Alternatively, using a suitable
reconstitution device, the appropriate volume of intravenous fluid may be
transferred from the infusion bag into the vial and then drawn back into the bag
after dissolution.

Chemical and physical in-use stability has been demonstrated for 24 hours at
25°C for the following diluents:

Water for injection

5% Dextrose

Sodium lactate M/6

Sorbitol

Dextran

Inherently resistant organisms:
- Acinetobacter spp.
- Pseudomonas aeruginosa
- Gram positive organisms
- Anaerobic bacteria

VDss (L)

21.4 ml

Inject I.V. solutions in 3-4 minutes, within one hour following their preparation.

Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C
for the following diluents:

Physiological saline

10% Dextrose

Sodium chloride compound (Ringer)

Hartmann solution (sodium lactate + Ringer’s lactate)

Species for which acquired resistance may be a problem:
- Serratia marcescens
- Enterobacter spp.

Dose
No. of subjects
Cmax (mg/L)
T½ ß (h)
CLtot (ml/min)

10.7 ml

The solutions should preferably be used as soon as possible after their preparation
and, in any case, no later than the time indicated below if they are kept at a
temperature not exceeding 25°C:

Commonly susceptible organisms:
- Escherichia coli
- Klebsiella pneumoniae
- Citrobacter spp.
- Proteus mirabilis
- Proteus spp (indole +)
- Morganella morganii
- Pasteurella multocida
- Providencia stuartii
- Salmonella typhimurium
- Yersinia enterocolitica
- Moraxella catarrhalis
- Haemophilus influenzae
- Neisseria meningitides

MEAN
PARAMETER

Final volume

14.7

I.M.
1g
6
72.7
5.4
-

I.V.
1g
10
93.2+
11.7
11.2

-

10.9

RENALLY
IMPAIRED
PATIENTS*
I.V.
7.5 mg/kg
5
49.5
28.2
8.8
18.3
(VD AREA)

EUMEDICA S.A.
Winston Churchill Avenue 67
B-1180 Brussels
Belgium
8. MARKETING AUTHORISATION NUMBER(S)
PL 21772/0001
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
September 2003
10. DATE OF REVISION OF THE TEXT
August 2011

- = Not determined
* = CCR < 10 ml/min/1.73m2
+= Approx. 1 h post-dose
NEG.UK-1G-20110817

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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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