Informations for option: Ampicillin / Sulbactam 2 G/1 G Powder For Solution For Injection Or Infusion, show other option

Select option:

1. Ampicillin / Sulbactam 2 G/1 G Powder For Solution For Injection Or Infusion
2. Ampicillin / Sulbactam 2 G/1 G Powder For Solution For Injection Or Infusion

Document: document 1 change

• document 0
• document 1

---

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ampicillin / Sulbactam 2 g/1 g Powder for solution for injection or infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substances: sulbactam sodium, ampicillin sodium Ampicillin / Sulbactam 2 g/1 g:

Each vial with 3220 mg powder contains 1094 mg sulbactam sodium, equivalent to 1 g sulbactam, and 2126 mg ampicillin sodium, equivalent to 2 g ampicillin.

Excipient: 10 mmol (230 mg) of sodium/vial of powder for solution for injection or infusion.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Powder for solution for injection or infusion White to off-white powder

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ampicillin / Sulbactam is indicated in the treatment of the following

-    community acquired pneumonia

-    upper urinary tract infection

-    intra-abdominal infections

-    gynaecological infections (see section 5.1)

-    skin and soft tissues infections

-    Prophylaxis against infections associated with abdominal surgery.

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

4.2    Posology and method of administration

Posology

The recommended dose for adults is 3 to 12 g Ampicillin / Sulbactam depending on the severity of the infection divided into equal single doses every 6 to 8 hours.

Paediatric patients:

For children over 2 years the recommended dose is 150 mg/kg/day (ampicillin 100 mg/kg/day + sulbactam 50 mg/kg/day). The therapeutic dosage should be given in three or four divided doses.

The intramuscular application should not be given in newborn infants, infants and toddlers (below 2 years). Ampicillin / Sulbactam should be given exclusively by intravenous use according to the following indications:

-    For newborn infants above the second living week, infants and toddlers till 2 years the recommended dose is 150 mg/kg/day (ampicillin 100 mg/kg/day + sulbactam 50 mg/kg/day). The therapeutic dosage should be given in three or four divided doses.

-    For newborn infants in the first living-week the recommended dose is 75 mg/kg /day (equivalent to ampicillin 50 mg/kg/day plus sulbactam 25 mg/kg/day). The therapeutic dosage should be given in two divided doses.

Use in the Elderly: Ampicillin / Sulbactam injection may be administered in the elderly in the usual dosages with no special precautions.

Prophylaxis of surgical infections: l.5 - 3g of Ampicillin / Sulbactam injection should be given at induction of anaesthesia, which allows time to achieve effective serum and tissue concentrations during the procedure. In case of long-term surgery another dose in 3-4 hours may be administered. Administration of Ampicillin / Sulbactam is usually stopped 24 hours after the majority of surgical procedures unless a therapeutic course of is indicated.

Use in patients with renal impairment:

In patients with severe renal impairment (creatinine clearance < 30ml/min) the elimination kinetics of sulbactam and ampicillin are similarly affected and hence the plasma ratio of one to the other will remain constant whatever the renal function is. The dose of Ampicillin / Sulbactam in such patients should be administered less frequently in accordance with the usual practice for ampicillin.

Recommended dosages for patients with impaired renal function:

Creatinine clearance (ml / min)	Dose interval
>30	6 to 8 hours
15 to 30	12 hours
5 to 14	24 hours
<5	48 hours

Sulbactam and ampicillin are both eliminated from the blood stream to an equal extent by hemodialysis treatment. Ampicillin / Sulbactam should therefore be administered immediately after dialysis and then at 48 hour intervals until the following dialysis treatment.

Use in patients with hepatic impairment: Usual recommended doses.

Method of administration

Please refer to section 6.6.

Duration of use

The duration of treatment depends on the course of the illness. The duration of treatment is generally 5 to 14 days depending on the severity of the infection. In severe cases, treatment may be continued for a prolonged period. The treatment should be continued for another 48 hours after the fever and other symptoms of the disease have subsided.

4.3 Contraindications

Hypersensitivity to the active substances, (ampicillin and sulbactam); to any other penicillin or to any of the excipients listed in section 6.1.

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

4.4 Special warnings and precautions for use

Before initiating therapy with ampicillin/sulbactam, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta- lactam agents.

Severe and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin or cephalosporins hypersensitivity and in atopic individuals. If an allergic reaction occurs, ampicillin/sulbactam therapy must be discontinued and appropriate alternative therapy instituted.

Serious anaphylactic reactions require an emergency treatment with adrenalin. Oxygen, intravenous steroids and airway management, including intubation, should also be administered when required.

Before starting a treatment with a penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other drugs.

Ampicillin/sulbactam should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy (more than 14 days). The monitoring is very important in neonates, and in the other paediatric patients.

As with every antibiotic therapy, the physician should be alert to signs of overgrowth of nonsensitive organisms (including fungi). As soon as an infection with these organisms occurs, the product should be discontinued and / or suitable treatment instituted.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms.

During treatment with Ampicillin / Sulbactam, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.

Administration of ampicillin may reduce the efficacy of oral contraceptives. Supplemental nonhormonal contraceptive measures may be required.

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including ampicillin / sulbactam and may range in severity from mild to life threatening (see section

4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of any antibiotics. Should antibiotic- associated colitis occur, Ampicillin / Sulbactam should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are

contra-indicated in this situation.

Ampicillin / Sulbactam 2 g/1 g: This medicinal product contains 10 mmol (230 mg) of sodium/vial of powder for solution for injection or infusion.

To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Effects of other medicinal products:

Acetylsalicylic acid, indometacin and phenylbutazone decrease excretion of penicillins.

Other antibiotics or chemotherapeutic agents

Ampicillin / sulbactam should not be combined with bacteriostatic chemotherapeutics or antibiotics such as tetracyclines, erythromycin, sulphonamides or chloramphenicol due to the possibility of reduced effectiveness.

Aminoglycosides are inactivated in vitro by ampicillin: therefore the mixing of aminoglycosides with ampicillin and sulbactam must be avoided in the solution for infusion. If concomitant treatment is necessary the two substances should be administered at different sites at a time interval of at least one hour. (see section 6.2)

Allopurinol

In gout patients being treated with allopurinol, simultaneous treatment with ampicillin /sulbactam increases the likelihood of cutaneous reactions.

Anticoagulants

The changes in platelet aggregation and prothrombin time observed with parenterally administered penicillins may be increased on simultaneous administration of anticoagulants.

Methotrexate

The concurrent administration of methotrexate and penicillins resulted in reduced methotrexate clearance and consequentially in methotrexate toxicity. These patients should be closely monitored and the increased and prolonged administration of Leucovorin should be considered.

Probenecid

The concomitant administration of probenecid leads to higher and more persisting ampicillin and sulbactam concentrations in serum and ampicillin concentrations in the bile due to inhibition of renal elimination (tubular secretion).

Hormonal contraceptives

During treatment with aminopenicillins, the reliability of the contraceptive effect of hormonal contraceptives (”the pill”) may be compromised in rare cases. It is therefore recommended to additionally use non-hormonal methods of contraception.

Influence of laboratory tests

A high concentration of ampicillin in urines may result in false positive values of glucosuria. The use of glucose tests based on enzymatic glucose oxydase reactions is recommended.

4.6 Fertility, pregnancy and lactation

Fertility

In animal studies, ampicillin and sulbactam had no effect on fertility (see section 5.3).

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effects of Ampicillin and Sulbactam on pregnancy or on the health of the foetus/newborn child. However, data on first trimester exposure are lacking. In animal studies with ampicillin and sulbactam no teratogenicity was observed (see section 5.3). Ampicillin /Sulbactam should not be used during pregnancy unless clearly necessary.

Lactation

Ampicillin and sulbactam are excreted into human breast-milk. Although excretion of both drugs is low, diarrhoea and fungus infection of the mucous membranes and allergic sensitization could occur in the breast-fed infant. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Ampicillin /Sulbactam should be made taking into account the benefit of breast-feeding to the child and the benefit of Ampicillin / Sulbactam therapy to the woman.

4.7 Effects on ability to drive and use machines

No studies on the ability to drive and use machines under influence of ampicillin and sulbactam have been carried out. However, patients should be made aware that due to undesirable effects (see section 4.8) the reactivity may be decreased.

4.8 Undesirable effects

The following undesirable effects have been observed and reported during treatment with ampicillin / sulbactam with the following frequencies: 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 form the available data)

The most common undesirable effects are pain at the injection site, phlebitis, nausea, vomiting, meteorism and diarrhea. For severe and persistent diarrhea, the possibility of potentially fatal antibiotic-associated pseudomembranous colitis should be considered. In these cases, Ampicillin / Sulbactam should therefore be discontinued immediately and a suitable therapy (e.g. oral vancomycin 4 x 250 mg daily) instituted. Drugs that inhibit peristalsis are contraindicated.

System Organ Class	Frequency	Undesirable effects
Infections and infestations	Not known	Overgrowth of nonsensitive organisms
Blood and lymphatic system disorders	Very rare	Hematocytological changes such as reversible and haemolytical anemia, thrombocytopenia, eosinophilia and leucopenia. Impairment of blood coagulation.
Immune system disorders	Rare	Hypersensitivity reactions like urticaria, fever, maculopapular eruptions are possible. If such symptoms occur, the drug should be discontinued and the doctor consulted. An immediate reaction in the form of urticaria generally indicates a true penicillin allergy and requires discontinuation of the treatment.

		Severe acute hypersensitivity reactions can appear such as: facial oedema, swelling of the tongue, swelling of the larynx narrowing of the airways, severe skin reactions such as erythema exsudativum multiforme, Stevens-Johnson syndrome or toxic epidermal necrolysis (Leyell syndrome), tachycardia, dyspnoea, drug fever, eosinophilia, serum sickness, haemolytic anaemia, allergic vasculitis and nephritis, hypotension, anaphylactoid reaction, anaphylactic shock. On occurrence of these signs, immediate medical assistance may be necessary. Skin fungi and penicillin can share antigenic properties, so that hypersensitivity reactions as seen after a second contact may occur even on the first administration of a penicillin in a person currently or previously suffering from a fungal skin infection.
Nervous system disorders	Uncommon	Vertigo and headache. Neurotoxic reactions (cramps) in events of meningitis or epilepsy, particularly after administration of high doses and impaired renal function respectively.
Gastrointestinal disorders	Common	Nausea,vomiting, meteorism and diarrhoea can occur. If severe and persistent diarrhoea occurs, the possibility of antibiotic-related pseudomembranous

		colitis should be considered, which can be life-treating. Therefore in these cases Ampicillin/Sulbactam should be discontinued immediately and a suitable therapy (e.g. oral vancomycin 250 mg four times daily) instituted. Peristaltis-inhibiting drugs are contraindicated.
Hepatobiliary disorders	Very rare	Transient and reversible increase in transaminases (SGOT[ALT], SGPT [AST], bilirubinaemia, abnormal liver function tests, jaundice
Skin and subcutaneous tissue disorders	Uncommon	Rash, pruritus and other cutaneous reactions. The typical, meales-like ampicillin rash (ampicillin-associated exanthema) that occurs 5 to 11 days after the start of the treatment, does not necessarily preclude subsequent treatment with penicillin derivates.
Musculoskeletal an d connective tissue disorders	Very rare	Transient and minor increase of creatinephosphokinase (CPK)
Renal and urinary disorders	Rare	Interstitial Nephritis, crystalluria by high intravenous dosage.
General disorders and administration site conditions	Very common	Intramuscular injection may be followed by pain at the injection site.
	Common	Intravenous administration may be followed by phlebitis or pain at the injection site. Diarrhoea

4.9 Overdose

Only limited experience is available for the acute toxicity of ampicillin / sulbactam. Overdose may induce symptoms corresponding to the undesirable effect profile (see Section 4.8) of Ampicillin / Sulbactam. In such cases, these described undesirable effects may possibly be observed more frequently and in a more severe form. In very high doses, beta- lactam antibiotics can induce cerebral (epileptic) seizures. Since ampicillin and sulbactam can be removed by hemodialysis, in the event of overdose, higher elimination can be achieved by hemodialysis in patients with renal impairment.

Treatment

Sedation with diazepam for seizures resulting from overdose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors, ATC code: J01CR01

Mechanism of action

Ampicillin is a semi-synthetic, non beta-lactamase-resistant aminopenicillin. Sulbactam is a beta-lactamase inhibitor with a structure similar to that of ampicillin and other penicillins.

The mechanism of action of ampicillin is based on inhibition of bacterial wall synthesis (in the growth phase) via blockade of the penicillin-binding proteins (PBPs) such as the transpeptidases. This results in a bactericidal action.

In combination with sulbactam, the inactivation of ampicillin by certain beta-lactamases is inhibited. Sulbactam protects ampicillin from degradation by most beta-lactamases of staphylococci and several plasmid-encoded beta-lactamases (e.g. TEM, OXA) and certain chromosomally encoded beta-lactamases of gram-negative bacteria. These beta-lactamases are present in, for example, Escherichia coli, Klebsiella spp., Proteus mirabilis and Haemophilus influenzae. The antibacterial spectrum of action of ampicillin is broadened to include bacteria whose beta-lactamases are inhibited by sulbactam.

PK/PD Relationship

The efficacy depends mainly on the time period for which the active substance level of ampicillin remains above the minimal inhibitory concentration (MIC) of the microorganism.

Mechanisms of resistance

Resistance to ampicillin/sulbactam can be due to the following mechanisms:

-    Inactivation by beta-lactamases: ampicillin/sulbactam does not have sufficient activity against beta-lactamase-producing bacteria whose beta-lactamases are not inhibited by sulbactam.

-    Reduced affinity of PBPs for ampicillin: the acquired resistance of pneumococci and other streptococci against ampicillin/sulbactam is due to the modification of existing PBPs as the result of a mutation. Methicillin (oxacillin)-resistant staphylococci are resistant due to the formation of an additional PBP with reduced affinity for ampicillin and all other beta-lactam antibiotics.

-    Insufficient penetration of ampicillin through the outer cell wall of gram-negative bacteria can result in inadequate inhibition of the PBPs.

-    Ampicillin can be actively extruded from the cell by efflux pumps.

Partial or complete cross-resistance of ampicilllin/sulbactam exists with penicillins, cephalosporins and other beta-lactam/beta-lactamase inhibitor combinations.

Breakpoints

MIC breakpoints for Ampicillin / Sulbactam are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Microorganism	Susceptible	Resistant
Enterobacteriaceae	-	> 8 mg/l
Enterococcus spp.	< 4 mg/l	> 8 mg/l
Haemophilus influenzae1	< 1 mg/l	> 1 mg/l
Moraxella catarrhalis12	< 1 mg/l	> 1 mg/l
Staphylococcus spp	< 0.12	> 0.12
Streptococcus A, B, C G3	< 0.25	> 0.25
Streptococcus pneumoniae3	< 0.06	> 2
Gram-negative anaerobes	< 4 mg/l	> 8 mg/l
Gram-positive anaerobes	< 4 mg/l	> 8 mg/l

Non species-specific limit values *    < 2 mg/l    > 8 mg/l

'For susceptibility testing purposes, the concentration of sulbactam is fixed at 4mg/L

²    Susceptibility is inferred from amoxicillin-clavunate

³    breakpoints values are based on benzylpenicillin breakpoints Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infection is questionable.

Organism susceptibility to ampicillin/sulbactam observed in the European clinical studies conducted in adults or children with various infections have been summarized in the following table.

It must be noted that this information gives only an approximate guidance on the probability that a microorganism will be susceptible to Ampicillin / Sulbactam.

Commonly susceptible species_

Aerobic gram-positive microorganisms

Enterococcus faecalis

Staphylococcus aureus (methicillin-sensitive)

Streptococcus agalactiae

Streptococcus pneumoniae (incl. penicillin-intermediate strains)

Streptococcus pyogenes Streptococci of the ”Viridans group ^A

Aerobic gram-negative microorganisms

Haemophilus influenzae Moraxella catarrhalis°

Neisseria gonorrhoeae°

Anaerobic microorganisms

Bacteroides fragilis°

Fusobacterium nucleatum°

Prevotella spp.

Other microorganisms

Gardnerella vaginalis⁰

Inherently resistant organisms Aerobic

gram-positive microorganisms

Staphylococcus aureus (methicillin-resistant)

Aerobic gram-negative microorganisms

Acinetobacter baumannii Citrobacter freundii Enterobacter cloacae Morganella morganii Pseudomonas aeruginosa Serratia marcescens Stenotrophomonas maltophilia

Other microorganisms

Chlamydia spp.

Chlamydophila spp.

Legionella pneumophila Mycoplasma spp.

Ureaplasma urealyticum_

° No current data were available when the table was published. Sensitivity is assumed in the primary literature, standard works and therapy recommendations.

+ The resistance rate is above 50% in at least one region.

^A Collective name for a heterogeneous group of Streptococcus species. Resistance rate can vary depending on the Streptococcus species concerned.

⁰⁰ No recent data available; in studies (older than 5 years) the proportion of resistant strains is reported as >10%.

The resistance rate is <10% in the outpatient setting.

5.2 Pharmacokinetic properties

High serum levels are reached both after intravenous and intramuscular administration of ampicillin / sulbactam. The results of pharmacokinetic studies in volunteers show the serum concentrations listed in below table in dependence on time, dose and route of administration:

30 min	1 h	2 h	4 h	6 h	8 h
7	6	3	1	0.3	0.1
12	12	6	2	0.4	0.2
11	12	8	3	1	0.4
16	17	13	4	1	0.6
15	9	4	1	0.4	0.1
28	14	6	1	0.4	0.2
37	21	9	2	0.7	0.3
65	33	12	3	1	0.4

Higher peak serum levels are achieved with intravenous administration than with

intramuscular administration of ampicillin / sulbactam; the bioavailability of ampicillin / sulbactam is practically complete after intramuscular administration.

Ampicillin and sulbactam are also rapidly distributed to a large number of tissues, body fluids and secretions.

The half-life both of sulbactam and ampicillin is about 1 hour in young adults and about 2 hours in elderly subjects. About 80 % of both substances is excreted renally 8 hours after administration of a single dose of ampicillin / sulbactam. The simultaneous administration of sulbactam and ampicillin causes no clinically relevant deviations in the kinetic parameters of the two substances when administered individually.

5.3 Preclinical safety data

Pre-clinical data reveal no special hazard for humans based on conventional studies of repeated-dose toxicity and genotoxicity. Long-term studies to evaluate the carcinogenic potential have not been performed. In studies performed on rats and rabbits at doses up to ten times the human dose, the combination of ampicillin and sulbactam was not teratogenic and did not have any adverse effects on fertility (rat).

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

None.

6.2 Incompatibilities

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

The following active substances or solutions for reconstitution/dilution should not be administered simultaneously:

•    Ampicillin / Sulbactam should not be mixed together with blood constituents or protein-containing solutions.

•    Because of a chemical incompatibility between penicillins and aminoglycosides, which causes inactivation of aminoglycosides, Ampicillin / Sulbactam should not be mixed with aminoglycosides in a syringe or infusion solution. The two substances should be administered at different sites at a time interval of at least one hour.

•    Another antibiotic (e.g. aminoglycosides).

•    The following are also incompatible and should therefore be administered separately: metronidazole; injectable tetracycline derivatives such as oxytetracycline, rolitetracycline and doxycycline; also thiopental sodium; prednisolone; procaine 2 %; suxamethonium chloride and noradrenaline. Visible signs of incompatibility are precipitation, turbidity or discoloration.

6.3 Shelf life

Unopened vial

2 years.

After opening

The content of the vial should be used immediately after the first breakage of vial. Reconstituted/Diluted solution

The solution for intramuscular or intravenous injection/infusion must be used immediately after reconstitution.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Unopened vial: Do not store above 25°C.

For storage conditions after reconstitution/dilution of the medicinal product, see Section 6.3.

6.5 Nature and contents of container

20 ml vial with clear, colourless Type I glass with dark grey bromobutyl rubber stopper. Ampicillin / Sulbactam 2 g/1 g(vial with 3220 mg powder): Hospital pack with 1 vial.

6.6 Special precautions for disposal

If an injection or infusion solution is to be prepared, this should be performed by trained healthcare personnel under aseptic conditions in a designated aseptic area.

Intramuscular injection

Dissolve the contents of one vial of Ampicillin / Sulbactam 2 g/1 g in 6.4 ml water for injections. To prevent pain during the injection, the solution can be prepared using 5 mg/ml (0.5%) lidocaine hydrochloride solution.

Intravenous injection

For intravenous injection, the contents of one vial of Ampicillin / Sulbactam 2 g/1 g can be prepared with at least 6.4 ml of water for injections and injected intravenously over at least 3 minutes after the substance has completely dissolved.

Short intravenous infusion

As for the intravenous injection, dissolve the contents of one vial of Ampicillin / Sulbactam 2 g/1 g in water for injections and then dilute further with 100 ml of one of the following infusion solutions: 9mg/ml (0,9%) Sodium Chloride Injection, 50mg/ml (5%) Glucose Injection, Lactated Ringer’s Solution, 50mg/ml (5%) Glucose in 0.45% NaCl,

100mg/ml (10%) Invert Sugar. Infuse the finished solution intravenously over 15 to 30 minutes.

The reconstitution/dilution is to be made under aseptic conditions. The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solutions is clear and free form particles.

For single use only. Discard any unused solution.

MARKETING AUTHORISATION HOLDER

Strides Arcolab International Limited Unit 4, Metro Centre,

Tolpits Lane, Watford,

Herts,WD 18 9SS United Kingdom

02/07/2012