Epicocillin vial is indicated in the treatment of infections caused by ampicillin- sensitive organisms. As needed, ampicillin should be administered after initial broad spectrum coverage with a third generation cephalosporin.
• Complicated acute bacterial sinusitis
• Endocarditis
• Pyelonephritis
• Cystitis
• 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.

Posology
The dose level of Epicocillin vial 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) greaterthan 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 ampicillins to be expected:
- at a creatinine clearance of 20 to 30 ml/min, the normal dose should be reduced to⅔,
- at a creatinine clearance below 20 ml/min, the normal dose should be reduced to ⅓.As a general rule, a dose of 1 g Epicocillin vial in 8 hours should not be exceeded inpatients 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, Epicocillin vial 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 itis recommended to extend the treatment to at least 10 days to prevent late complications (e.g. rheumatic fever, glomerulonephritis).

Hypersensitivity to the active substance, to any other penicillin or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to Epicocillin vial.

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

Epicocillin vial 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 Epicocillin vial. This particularly applies when considering the treatment of patients with intra abdominal 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.
Epicocillin vial should be avoided if infectious mononucleosis is suspected or the patient suffers from cytomegalovirus infection or Lymphoid leukaemia since the occurrence of a morbilli form 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.
Epicocillin vial should be used in the treatment of cystitis only when susceptibility is documented.
Concomitant use of allopurinol during treatment with Epicocillin vial 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 Epicocillin vial. 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.
In patients with renal impairment, the dose should be adjusted according to the degree of impairment.
During treatment with Epicocillin vial, 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 Epicocillin vial 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. Therefore, it is important to consider this diagnosis inpatients 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.

Probenecid
The co-administration 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
Co-administration of anticoagulants of the coumarin type can increase the tendency to bleeding.
Digoxin
An increase in the absorption of co-administered digoxin is possible during Epicocillin vial 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 Epicocillin vial therapy. The additional use of non-hormonal methods of contraception is therefore recommended.

Pregnancy
Data from a limited number of exposed pregnancies do not suggest that Epicocillin vial 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. Use of Epicocillin vial 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 iscontinuation of breast feeding. The possibility of sensitisation should be considered. Epicocillin vial may be used during lactation after a suitable benefit-risk analysis.
Fertility
In animal studies, Epicocillin vial had no effect on fertility.

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.

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 Class	Very Common	Common	Uncommon	Rare	Very Rare
Infections and infestations			Infection with fungi or resistant bacteria especially during prolonged and/or repeated use.
Blood and lymphatic system disorders					Myelosuppressio n and haematocytological changes (granulocytopenia, thrombocytopenia, anaemia, pancytopenia); Prolongation of bleeding and prothrombin time1.
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).
Gastrointestinal 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.

To report any side effect﴾s﴿:
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre ﴾NPC﴿
Fax: +966‐11‐205‐7662
Call NPC at +966‐11‐2038222, Exts 2317‐2356‐2353‐2354‐2334‐2340.
Toll free phone: 8002490000
E‐mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
Or Other GCC States:
Please contact the relevant competent authority.

Symptoms of overdose
Typical signs of intoxication following the administration of larger amounts of Epicocillin vial have not been observed to date. Long-term therapy is also not associated with specific toxic adverse reactions. The symptoms of over-dosage essentially correspond to the profile of undesirable effects (see section 4.8).
The single administration of a larger amount of Epicocillin vial 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.
Epicocillin vial can be removed from the body by hemodialysis.

Pharmaco-therapeutic group:
Ampicillin is a semi-synthetic, non-beta-lactamase resistant amino-penicillin.
Mechanism of action
The mechanism of action of Epicocillin vial 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 andother streptococci is due to the modification of existing PBPs as the result of amutation. Methicillin (oxacillin)-resistant staphylococci, however, are resistant due tothe 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 ampicillin exists with amoxicillin and to some extent with other penicillins and cephalosporins.
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.
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 ^

Anaerobic microorganisms
Bacteroidesfragilis°
Fusobacteriumnucleatum°
Other microorganisms
Gardnerellavaginalis°
Species for which acquired resistance may be a problem
Aerobicgram-positive microorganisms
Enterococcus faecium+
Staphylococcus aureus з
Staphylococcus epidermidis+
Staphylococcus haemolyticus+
Staphylococcus hominis+
Aerobic gram-negative microorganisms
Escherichia coli
Haemophilusinfluenzae
Klebsiellaoxytoca
Moraxella catarrhalis ∞
Neisseria gonorrhoeae
Proteus mirabilis
Proteus vulgaris
Anaerobic microorganisms
Prevotella spp.
Inherently resistant organisms
Aerobic gram-positive microorganisms
Staphylococcus aureus (methicillin-resistant)
Aerobic gram-negative microorganisms
Acinetobacterbaumannii
Citrobacterfreundii
Enterobacter cloacae

Klebsiellapneumoniae
Morganellamorganii
Pseudomonas aeruginosa
Serratiamarcescens
Stenotrophomonasmaltophilia
Anaerobic microorganisms
Bacteroides spp.
Other microorganisms
Chlamydia spp.
Chlamydophila spp.
Legionella pneumophila
Mycoplasma spp.
Ureaplasmaurealyticum
° 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.
^ Collective name for a heterogeneous group of Streptococcus species. Resistance rate can vary depending on the Streptococcus species concerned.
∞ No recent data available; in studies (older than 5 years) the proportion of resistant strains is reported as ≥10%.
з The resistance rate is <10% in the outpatient setting.

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 in to 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 15l.

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 isabout50 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 isabout194 ml/min after intravenous administration.

None stated.

None.

Epicocillin vial 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.
Epicocillin vial 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.

3 years.

Should be stored in a dry place away from light at a temperature not exceeding 30°C.

Epicocillin 500 mg Vials: Boxes of 1 or 50 vial each.

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 0.26g, 0.53g, 1.06 g powder in 2.5, 5, 10 ml water for injections respectively.
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.