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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Ampicillin 2 g powder for solution for injection/infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One vial contains 2126 mg of ampicillin sodium (equivalent to 2000 mg ampicillin). For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Powder for solution for injection/infusion White to off white crystalline powder

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Ampicillin powder for solution for injection/infusion is indicated in the treatment of infections caused by ampicillin- sensitive organisms (see section 4.4 and 5.1). As needed, ampicillin should be administered after initial broad spectrum coverage with a third generation cephalosporin.

•    Complicated acute bacterial sinusitis

•    Endocarditis

•    Pyelonephritis

•    Cystitis (see section 4.4)

•    Intra-abdominal infections

•    Female genital infections

•    Listeria Meningitis when used in conjunction with an aminoglycoside

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

4.2 Posology and method of administration

Posology

The dose level of ampicillin is dependent on the patient’s age, weight and renal function, the severity and site of infection and the presumed or identified etiologic agents.

10 ml of the reconstituted 10 % solution for intramuscular and intravenous injection or infusion contains 1.063 g of ampicillin sodium (equivalent to 1,0 g ampicillin and

65.8 mg or 2.86 mmol sodium).

Intravenous or intra-muscular injection

Adults and adolescents

500mg every 4 to 6 hours (the daily dose can be rised up to 6 g in case of severe infection)

Intravenous injection or infusion

Child 1 month - 12 years

25-50mg/kg (max 1g) every 6 hours (the dose can be doubled in case of severe infection)

Neonate 21 - 28days

30mg/kg every 6 hours (the dose can be doubled in case of severe infection)

Neonate 7 - 21 days

30mg/kg every 8 hours (the dose can be doubled in case of severe infection)

Neonate under 7 days

30mg/kg every 12 hours (the dose can be doubled in case of severe infection)

Special dosage and use recommendations

Impaired renal function

No dose adjustment is required in patients with creatinine clearance (CrCl) greater than

30 ml/min.

For severely impaired renal function with a glomerular filtration rate of 30 ml/min and less, a reduction in the dose is recommended, since an accumulation of ampicillin is to be expected:

-    at a creatinine clearance of 20 to 30 ml/min, the normal dose should be reduced to

²4

-    at a creatinine clearance below 20 ml/min, the normal dose should be reduced to Vi

As a general rule, a dose of 1 g ampicillin in 8 hours should not be exceeded in patients with severe renal insufficiency.

For intramuscular administration, the usual limit of the injection volume must be complied with.

Duration of use

The duration of use depends on the course of the disease. As a general rule, ampicillin is used for 7 to 10 days, but for at least another 2 to 3 days after the signs of disease have subsided.

For the treatment of infections with beta-hemolytic streptococci, for safety reasons it is recommended to extend the treatment to at least 10 days to prevent late complications (e.g. rheumatic fever, glomerulonephritis).

4.3 Contraindications

Hypersensitivity to the active substance, 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).

History ofjaundice/hepatic impairment due to ampicillin.

4.4 Special warnings and precautions for use

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

Ampicillin has a limited spectrum of antibacterial activity. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with ampicillin. This particularly applies when considering the treatment of patients with intraabdominal infections, female genital infections and endocarditis.

Serious 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 hypersensitivity and in atopic individuals. If an allergic reaction occurs, ampicillin/sulbactam therapy must be discontinued and appropriate alternative therapy instituted.

Ampicillin should be avoided if infectious mononucleosis is suspected or the patient suffers from cytomegalovirus infection or Lymphoid leukaemia 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.

Ampicillin should be used in the treatment of cystitis only when susceptibility is documented.

Concomitant use of allopurinol during treatment with ampicillin can increase the likelihood of allergic skin reactions.

Prolonged use may occasionally result in overgrowth of non-susceptible organisms. Prolongation of prothrombin time has been reported rarely in patients receiving

ampicillin. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2)

During treatment with Ampicillin, 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 non-hormonal 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 Strides should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic drugs are contra-indicated in this situation.

20 ml of the reconstituted 10 % injection solution contain 5.72 mmol (131.6 mg) sodium. This should be taken into account in persons on a sodium-restricted (low-sodium/salt) diet.

4.5 Interaction with other medicinal products and other forms of interaction

Probenecid

The coadministration of probenecid inhibits the tubular secretion of ampicillin and leads to higher and longer persisting ampicillin concentrations in serum and bile.

Allopurinol

The simultaneous use of allopurinol during treatment with ampicillin can promote the development of allergic skin reactions.

Anticoagulants

Coadministration of anticoagulants of the coumarin type can increase the tendency to bleeding.

Digoxin

An increase in the absorption of coadministered digoxin is possible during ampicillin therapy.

Methotrexate

Ampicillin can inhibit the excretion of methotrexate and thereby intensify undesirable effects of methotrexate. The methotrexate levels in the blood should be monitored.

Hormonal contraceptives

In rare cases the efficacy of hormonal contraceptives may be impaired during ampicillin therapy. The additional use of non-hormonal methods of contraception is therefore recommended.

4.6 Fertility, Pregnancy and lactation

Pregnancy

Data from a limited number of exposed pregnancies do not suggest that ampicillin has any adverse effects on pregnancy or the health of the foetus/newborn. No other relevant epidemiological data are available to date. Animal studies have produced no evidence of direct or indirect harmful effects on pregnancy, embryonic/foetal development,

childbirth or postnatal development (see section 5.3). Use of ampicillin during pregnancy should be approached with caution

Breastfeeding

Ampicillin is excreted in breast milk. Breast fed infants may therefore suffer diarrhoea and mucosal yeast colonisation, which in some cases may necessitate the discontinuation of breast feeding. The possibility of sensitisation should be considered. Ampicillin may be used during lactation after a suitable benefit-risk analysis.

Fertility

In animal studies, ampicillin had no effect on 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. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

4.8 Undesirable effects

The most commonly reported undesirable effects are skin reactions (pruritis, rash, exanthema, itching), abdominal pain, meteorism, soft stools, diarrhoea, nausea and vomiting.

The undesirable effects derived from clinical studies and post-marketing surveillance, sorted by MedDRA System Organ Class are listed below.

The following terminologies have been used in order to classify the occurrence of undesirable effects:

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)

System/Organ	Very	Common	Uncommon	Rare	Very Rare
Class	Common

Infections and infestations			Infection with fungi or resistant bacteria especially during prolonged and/or
Blood and lymphatic system disorders					Myelosuppressio n and haematocyto- logical changes (granulocyto penia, thrombocytopenia, anaemia, pancytopenia); Prolongation of bleeding and prothrombin timel.
Immune system disorders2,8	Skin reactions (pruritus, rash, exanthema, itching)3	Morbilliform rash4. Exanthem and enanthem in the oral region5.	More serious allergic reactions such as serum sickness, drug fever, angioneurotic oedema, laryngeal oedema, haemolytic anaemia, allergic vasculitis or nephritis, severe allergic, sometimes vesiculating skin reactions (exfoliative dermatitis, Lyell’s syndrome, exudative erythema multiforme, Stevens-Johnson syndrome).		Life-threatening anaphylactic shock6.

Nervous system disorders9				Dizziness, headache, myoclonus and seizures (in renal insufficiency or at very high intravenous doses).
Gastro intestinal disorders	Abdominal pain, nausea, vomiting, meteorism, soft stools, diarrhoea7.				Pseudomembranous colitis8 (in most cases caused by Clostridium difficile).
Hepatobiliary disorders			Transaminase elevation.
Renal and urinary disorders			Crystalluria on high-dose intravenous administration, acute interstitial nephritis		Acute renal failure with excretion of urine crystals.
General disorders and administration site conditions		Swelling and pain; Localised phlebitis.

4.9 Overdose

Symptoms of overdose

Typical signs of intoxication following the administration of larger amounts of

ampicillin have not been observed to date. Long-term therapy is also not associated with specific toxic adverse reactions. The symptoms of overdosage essentially correspond to the profile of undesirable effects (see section 4.8).

The single administration of a larger amount of ampicillin is not acutely poisonous (toxic).

The administration of very high doses can lead to oliguric renal failure and may have effects on nerve cells, for example in the form of central nervous excitation, impairments of muscular function and seizures. The risk of these undesirable effects is increased in patients with severely impaired renal function.

In individual cases, however, these effects were only observed after intravenous administration.

Treatment of overdose

There is no specific antidote in the event of overdose. Treatment comprises symptomatic measures with particular attention to maintaining the water/electrolyte balance.

Ampicillin can be removed from the body by hemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:

Ampicillin is a semi-synthetic, non-beta-lactamase resistant aminopenicillin, ATC code: J01CA01.

Mechanism of action

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.

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 can be due to the following mechanisms:

-    Inactivation by beta-lactamases: ampicillin has only low beta-lactamase stability and is therefore not active against beta-lactamase forming bacteria. Almost all strains of

some bacterial species form beta-lactamases. These species are therefore naturally resistant to ampicillin (e.g. Enterobacter cloacae, Klebsiella pneumoniae).

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

-    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 exists with amoxicillin and to some extent with other penicillins and cephalosporins.

Breakpoints

MIC breakpoints for Ampicillin are those of the European Committee on Antimicrobial

Susceptibility Testing (EUCAST).

Microorganism	Susceptible <	Resistant >
Enterobacteriaceae	< 8 mg/l	> 8 mg/l
Enterococcus spp.1 Haemophilus influenzae Staphlococcus spp2	<    4 mg/l <    1 mg/l <    0.12 mg/l	>    8 mg/l >    1 mg/l >    0.12 mg/l
Streptococcus A. B. C G2	< 0.25 mg/l	> 0.25 mg/l
Streptococcus pneumoniae	< 0.5 mg/l	> 2 mg/l
Other streptococcil	< 0.5 mg/l	> 2 mg/l
Neisseria meningitidis	< 0.12 mg/l	> 1 mg/l
Gram-negative anaerobes	< 0.5 mg/l	> 2 mg/l
Gram-positive anaerobes	< 4 mg/l	> 8 mg/l
Non species-specific limit values	< 2 mg/l	> 8 mg/l
Listeria monocytogenes	< 1 mg/l	> 1 mg/l

¹ In endocarditis, refer to national or international endocarditis guidelines for breakpoints.

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

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%.

³ The resistance rate is <10% in the outpatient setting.

5.2 Pharmacokinetic properties

Distribution

Ampicillin is extensively distributed to tissues, crosses the placental barrier and diffuses into breast milk. Only 5 % of the ampicillin concentration in plasma diffuses into cerebrospinal fluid (CSF) with intact meninges. With inflamed meninges, the ampicillin concentration in CSF can increase to 50 % of the ampicillin concentration in plasma.

The serum protein binding is 17-20 %. The apparent volume of distribution is about 15 l.

Serum level

After oral administration of 1000 mg ampicillin, peak plasma levels of about 5 mg/l are reached after 90 to 120 min. After intramuscular injection, peak plasma levels are reached after 30 to 60 min.

Metabolism

Ampicillin is partly metabolised to microbiologically inactive penicilloates.

Elimination

Ampicillin is eliminated intact mainly by the renal route, but also through bile and faeces. After oral administration, about 40 % of a dose is recovered unchanged in the urine. After parenteral administration, about 73 +/- 10 % of an administered dose is excreted as unchanged substance in the 0- to 12-hour urine. Up to 10 % of a dose is eliminated in the form of biotransformation products. The elimination half-life is about

50 to 60 min. In oliguria, the half-life may be prolonged to 8 to 20 hours. The half-life is also prolonged in newborns (2 to 4 hours). The renal clearance of ampicillin is about

194 ml/min after intravenous administration.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional repeated- dose toxicity studies and studies to investigate genotoxic potential.

Following intravenous administration no teratogenic potential or pre-natal effects were observed in the rat or rabbit. Repeated administration for up to 13 weeks in the rat and dog (2 mg/kg/day) showed no histological effects on the ovary; however, reversible impairment of spermatogenesis was observed in the dog at 200 mg/day. In animal studies at doses higher than those used in humans, ampicillin did not have any adverse effects on fertility.

6 PHARMACEUTICAL PARTICULARS

List of excipients

None

6.2 Incompatibilities

Ampicillin solutions should always be administered separately, unless compatibility with other infusion solutions or medicines has been established.

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

Ampicillin solutions should not be mixed with aminoglycosides, metronidazole and injectable tetracycline derivatives such as oxytetracycline, rolitetracycline and doxycycline. Visual signs of incompatibility are precipitation, clouding and discoloration.

6.3 Shelf life

2 years

Shelf-life after preparation of the ready-to-use solution Reconstituted/diluted solution should be used immediately.

6.4 Special precautions for storage

Do not store above 25°C.

Use only freshly prepared solutions.

6.5 Nature and contents of container

Pack with 1 glass vial with dark grey bromobutyl rubber stopper and brown flip off aluminium seal containing 2126 mg powder for solution for injection/infusion.

6.6 Special precautions for disposal

Ampicillin solutions are compatible with 0.9% (9 mg/ml) sodium chloride solution, 5% (50mg/ml) glucose solution and Ringer solution.

The 10 % injection/infusion solution is prepared by dissolving 2.12 g powder in 20 ml water for injections.

The solutions should always be prepared freshly before use and checked for clarity. Use only clear solutions for injection or infusion! Do not use solutions with cloudiness or precipitation.

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

7 MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL, UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1528

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/10/2012

10 DATE OF REVISION OF THE TEXT

14/11/2014