Sulmacefta

Description
White or almost white powder with a yellowish tinge.

Pharmacotherapeutic Group: Semi-synthetic antibiotic penicillin + beta- lactamase inhibitor.

ATC Code: J01CR01.

Pharmacological Properties
Pharmacodynamics
Ampicillin+Sulbactam is a combination medicinal product with antimicrobial broad-spectrum.

Ampicillin-antibiotic from the semi-synthetic antibiotic penicillin group is an antimicrobial constituent; its bactericidal effect is connected with protein synthesis inhibition of bacteria cell walls. Sulbactam is an irreversible inhibitor of beta-lactamases; it expands the spectrum of activity of Ampicillin against resistant strains, the resistance of which develops under the influence of beta-lactamases; it does not change the activity of Ampicillin against sensitive strains; it binds to some penicillin-binding proteins of bacteria and exhibits synergism when administered simultaneously with beta-lactam antibiotics. It is stable in aqueous solution, has independent antibacterial activity against Neisseria gonorrhoeae and Acinetobacter spp. and is resistant to the action of most plasmid beta-lactamases.

Ampicillin+Sulbactam combination is active against the following bacteria (including strains producing beta-lactamases):
Aerobic Gram-Positive Bacteria: Staphylococcus aureus (producing and not producing beta-lactamase strains), Staphylococcus epidermidis (producing and not producing beta-lactamase strains), Staphylococcus saprophyticus (producing and not producing beta-lactamase strains), Streptococcus pyogenes, Streptococcus pneumoniae (including strains resistant to penicillin), Streptococcus spp. of viridans group, Enterococcus faecalis, Listeria monocytogenes.
Aerobic Gram-Negative Bacteria: Escherichia coli, Proteus mirabilis, Proteus vulgaris, Klebsiella spp., Neisseria gonorrhoeae (producing and not producing beta-lactamase strains), Moraxella catarrhalis (producing and not producing beta-lactamase strain), Morganella morganii, Haemophilus influenza (including strains resistant to Ampicillin), Providencia rettgeri, Providencia stuartii.

Anaerobic Micronychia: Bacteroides spp., including Bacteroides fragilis, Clostridium spp. (with the exception of Clostridium difficile), Peptococcus spp., Peptostreptococcus spp.
Resistant to: Methicillin-Resistant Staphylococcus spp., Citrobacter spp., the majority of strains Enterobacter spp., Pseudomonas aeruginosa, Mycobacterium spp., Clostridium difficile, Chlamydia pneumoniae, Mycoplasma pneumoniae.

Pharmacokinetics
Maximum serum concentrations (Cmax) of Ampicillin and Sulbactam after intravenous (I.V.) injection of 1.5 g and 3.0 g of the drug is 40-71 µg/mL and 109-150 µg/mL for Ampicillin; and 21-40 µg/mL and 48-88 µg/mL for Sulbactam accordingly. After intramuscular (I.M.)r injection of 1.5 g of Ampicillin+Sulbactam, Cmax of Ampicillin varies from 8 µg/mL to 37 µg/mL; Cmax of Sulbactam-from 6 µg/mL to 24 µg/mL. Plasma protein binding level is 28% for Ampicillin and 38% -for Sulbactam.

Ampicillin and Sulbactam are properly distributed in various tissues and fluids.

Therapeutic concentrations after I.V. and I.M. injections are generated in peritoneal and pleural fluids, interstitial fluid, gut walls, 2 pelvic organs, skin and subcutaneous tissue. They poorly penetrate through a hematoencephalic barrier, in case of piitis, penetrance into cerebrospinal fluid increases. Elimination half-life (Т1/2) of Ampicillin and Sulbactam is in average about 1 hour. Both drug constituents are directly excreted by kidneys. 75-85 % of Ampicillin and Sulbactam dose injected is eliminated out of the body by kidneys within the first 8 hours. Patients with various extent of kidney function impairment, Т1/2 of the drug constituents increases, thus requiring dose adjustment and dose schedule correction.

Indications for Use
Infectious and inflammatory diseases caused by strains sensitive to Ampicillin+Sulbactam combination:
–    Infection of Ear Nose Throat (ENT) organs (including sinusitis, otitis media, tonsillitis)
–    Respiratory organs infections (acute bronchitis and flare-up of a chronic bronchitis, pneumonia, lung abscess, empyema)
–    -Infective endocarditis
–    -Bacterial meningitis
–    Sepsis
–    Uncomplicated and complicated infections of abdominal cavity organs (cholecystitis, cholangitis, peritonitis, abdominal cavity abscess)
–    Urinary tract infections (acute pyelonephritis and flare-up of a chronic pyelonephritis, pyelitis) Pelvic inflammatory infections (salpingitis, salpingo-oothecitis, tubo-ovarian abscess, endometritis, pelvioperitonitis)
–    Diplococcus infection
–    Skin and soft tissue infections (    erysipelas, abscess, phlegmon, wound fever, postoperative infection)
–    Bone and joint infections.
Prevention of postoperative complications after surgery operations of abdominal and pelvic organs.

Contraindications
Hypersensitivity to any of the drug constituents and other beta- lactam antibiotics (penicillins, cephalosporins, carbapenemase), glandular fever (including morbilliform rash signs), lymphatic leukemia.

Ampicillin+Sulbactam combination safe use for patients with End Stage Renal Failure (with creatinine clearance (CLCR) i less than 5 mL/min) is unknown.
If lidocaine is used as a solvent there is hypersensitivity to amide-type local anesthetics, severe shock, intracardiac conduction block, massive cardiac decompensation. Prior to I.M. injection of the drug with the use of lidocaine or procaine contraindications available to lidocaine or procaine should be excluded. Contraindications to lidocaine or procaine use are specified in the Instructions for medical use of lidocaine and procaine.

With caution
Bronchial asthma, hay catarrh and other allergic reactions, renal insufficiency,  chronic gastric diseases shown in medical history; prior colitis connected with the administration of antimicrobial drugs, compromised kidney function, elderly age

Use During Pregnancy and Breastfeeding
Administration during pregnancy is possible only if the potential benefit for the mother outweighs the potential risk to the fetus. Ampicillin and Sulbactam inpour into breast milk in low concentrations. If administration of the drug during lactation is necessary, breastfeeding should be terminated.

Administration and Dosage
Intravenously/I.V. (bolus and dropwise) or intramuscularly (I.M.)
Mode of administration depends on the infection severity and dosage selected.
Total doses of Ampicillin and Sulbactam (in 2:1 ratio) are shown below.
For adults and children over the age of 12 whose body weight (bwt) exceeds 40 kg the drug should be injected I.V. or I.M. per 1.5 g every 6 hours to treat moderate severe infections. To treat severe infections –  3 g of the drug should be injected every 6 hours.
Maximum daily dose of Sulbactam should not exceed 4 g.
Treatment should be continued for at least another 2-3 days after the disappearance of clinical symptoms of the disease. Length of treatment should be 5-14 days, however, for severe cases this period may be extended or additional Ampicillin may be prescribed.
In case on uncomplicated gonorrhea -1.5 g     on a once-only basis.
To prevention postoperative infections -1.5-3 g during anaesthesis; then the same dosage in every 6-8 hours during 24 hours after the operation.
For newborn infants over the age of 1 month and to 12 years old (or whose body bwt exceeds 40 kg) the drug should be injected at a dose of 150 mg/kg per day; this dose should be divided into 3-4 injections. The dose may be increased to 300 mg/kg/day in case of severe disease. Length of therapy treatment should not exceed 14 days.
For immature and newborn infants of the first lifetime week a daily dose should be 75 mg/kg; the latter should be divided into two injections.
For newborn infants over the age of 7 days to 28 days a daily dose should be 150 mg/kg; the latter should be divided into 3 I.V. injections.
For patients with impaired renal function, the dosing schedule should be corrected depending on creatinine clearance (CLCR) values.

For children with renal insufficiency (CLCR-less than 30 mL/min), common single doses (50-75 mg/kg) should be provided for, in this case intervals between doses should be extended, as prescribed for adults.

Preparation of Solutions
To prepare solution for I.M. injections, sterile injection grade water or 0.5 % lidocaine solution or 0.5 % procaine solution should be used. The following minimum amounts of solvent should be added directly to the vial with antibiotic powder:
To the vial containing 3 g of the drug – 6.5 mL of the solvent;
To the vial containing 1.5 g of the drug- 4.0 mL of the solvent;
To the vial containing 0.75 g of the drug -2.0 mL of the solvent;
To the vial containing 0.375 g of the drug -1.0 mL of the solvent.

The solution obtained should be injected I.M. deeply in body areas with obvious muscle layers (upper transdermal clunis square or lateral hip surface).

It is recommended to conduct an aspiration test to prevent adverse injection of the solution into a blood vessel.

It is prohibited to inject intravenous (I.V.) the drug solution prepared with the use of lidocaine or procaine solutions.

To prepare solutions for intravenous bolus injections either sterile injection grade water or 0.9 % sodium chloride solution should be used as solvents.

The following minimum amounts of solvent should be added directly to the vial with antibiotic powder:
To the vial containing 3 g of the drug -20 mL of the solvent
To the vial containing 1.5 g of the drug -15-20 mL of the solvent
To the vial containing 0.75 g of the drug -10 mL of the solvent
To the vial containing 0.375 g of the drug -10 mL of the solvent.
The solution obtained should be injected intravenous slowly within 3-5 minutes.

Ampicillin+Sulbactam solution may be injected directly to a     vein or a infusion system tube if a patient receives infusion treatment.

For intravenous (I.V.) dropwise injections, the solution (prepared as indicated above) should be added to the vial containing 100-200 mL of 0.9 % sodium chloride solution and 5% dextroglucose solution and it should be injected at a rate of 60-80 drops per minute.

Adverse Effects
Allergic Reactions: urticaria, dermahemia, skin itch, Quincke’s edema, rhinitis, conjunctivitis, febrilily, arthralgia, anaphylactic shock, Stevens- Johnson syndrome (SJS), multiform erythema, toxic epidermal necrolysis. Digestive System Disorders: vomiting sickness, bdelygmla, decreased appetite, diarrhea, gaseous distention, glossitis, pseudomembranous colitis, increment in activity of “liver” transaminases.

Hematopoietic System Disorders: hemolytic anemia, deficiency of blood, thrombocytopenia, eosinophilia, leukopenia, neutropenia, lymphopenia, lymphocytosis, thrombocytosis, monocytosis.

Nervous System Disorders: drowsiness, headache. Convulsions were reported.

Laboratory parameters: azotemia, urea elevated concentrations in blood plasma, hypercreatininemia, decrease in serum protein content, leukocyturia, cylindruria, temporary increment in activity of alanine transaminase (ALT) and aspartate aminotransferase (AST), false-positive Coombs’ test.

Local Reactions: in case of I.M. injection- pain at the injection site; in case of I.V. injection-phlebitis, thrombophlebitis.

Others: discomfort, chest pain, sore throat, dysuria, hydrops, bleeding sickness; in case of long term treatment-superinfection (candidiasis) caused by bacteria resistant to the drug; rare cases of interstitial nephritis.

Overdosage
Symptoms: neurological disorders to the extent of convulsions (especially for patients with compromised liver function), vomiting sickness, bdelygmla, diarrhea, water and electrolyte imbalance (due to bdelygmla, diarrhea).

Treatment: to be symptomatic; for severe cases haemodialysis is effective.

Interactions with Other Drugs
When administered concurrently with indirect anticoagulants, Ampicillin+Sulbactam combination intensifies their effect, reduces the effectiveness of oral contraceptives, medicinal products in the course of metabolic process of which p-aminobenzoic acid and ethinyl estradiol are generated (risk of bleeding events “breakthroughs”).

When administered concurrently with Aminoglycosides, synergism of bactericidal effect against gram-positive and gram-negative bacteria is observed.

The drug is pharmaceutically incompatible with blood products or hydrolyzed proteins and Aminoglycosides. When the drug is administered concurrently with Aminoglycosides, it is not allowed to mix medicinal products in one syringe or one infusion system; in case of I.M. injections the drug should be introduced into different body areas; in case of I.V. injections the drug should be introduced separately while following specific sequence with as much time intervals as possible or separate intravenous catheters should be used.

Probenecid, allopurinol, phenylbutazone, non-steroidal anti-inflammatory drugs decrease tubular secretion of Ampicillin and Sulbactam and increase their elimination half-life. Diuretics decrease penicillin clearance.

Antibacterial antibiotics (including cephalosporins, cycloserine, vancomycin, rifampicin, Aminoglycosides) have a synergistic effect; bacteriostatic antibiotics (including macrolides, chloramphenicol, lincosamides, tetracyclines) have an antagonistic effect.

Simultaneous administration of Ampicillin and allopurinol increases the risk of developing skin rashes.

Special instructions
Prior to commencement of therapy a comprehensive medical history should be prepared in terms of previous allergic reactions to beta-lactam antibiotics. If an allergic reaction develops,the drug administration should be discontinued.

With prolonged administration of the drug, it is necessary to exercise periodic control over kidneys/liver functions; and complete blood cell count should be provided for.

Both during the drug administration and in 2-3 weeks after the treatment cessation and even a few months later upon termination of antibiotic administration, Clostridium difficile-associated diarrhea may likely develop; the progress of the disease may be either mild as a rapid temporary diarrhea or as pseudomembranous colitis-serious illness accompanied by common symptoms (fever, anhydration symptoms, water-electrolytic imbalance; including tachycardia, arterial hypotonia, ventilation-perfusion imbalance, high leukocytosis), loose stool, sometimes with blood admixtures in the excrements, abdominal pains. Clostridium difficile-associated diarrhea cases were recorded a fewer weeks later or even a fewer months later after termination of antibiotics administration. At suspicion on or proven case of pseudomembranous colitis, administration of Ampicillin+Sulbactam should be discontinued and relevant treatment should be prescribed (metronidazole, vancomycin per os (orally), gastrointestinal adsorbents, infusion therapy). In such cases, administration of medicinal products suppressing intestinal motility is prohibited. For mild diseases it is sufficient to withhold the drug and prescribe relevant treatment (metronidazole, vancomycin ingested gastrointestinal adsorbents, infusion therapy). Administration of medicinal products suppressing (inhibiting) intestinal motility is prohibited.

During protracted treatment it is necessary to exercise control over hematopoietic system/liver and kidneys potential.

If Ampicillin+Sulbactam combination (or any other antibiotics) is administered, superinfection may develop due to growth of microflora insensitive to the drug; in this case the drug administration should be discontinued and relevant treatment should be prescribed.

Direct false-positive Coombs’ test and a false-positive reaction to urinary glucose are made possible (by the use of Benedict’s or Fehling’s methods).

For patients suffering from sepsis there a possibility to develop bacteriolysis reactions (Jarisch-Herxheimer type reactions).

For treatment of patients kept on diet with low sodium content, it is necessary to consider that 3,000 mg of the drug contain about 230 mg (10 mmol) of sodium.

Effects on the Ability to Drive and Use Machines
There is no data on the negative effect of the drug in recommended doses on the ability to drive and use mechanisms.

However, given the likelihood of central nervous system disorders, care should be taken when engaging in potentially hazardous activities that require increased     mental alertness and rate of psychomotor actions.

Dispensing Form
Powder for preparation of solutions for intravenous and intramuscular injections, 250 mg + 125 mg, 500 mg + 250 mg, 1,000 mg + 500 mg, 2,000 mg + 1,000 mg.
The drug quantity containing 250 mg + 125 mg, 500 mg + 250 mg of the active substances should be placed in vials made of transparent glass of the 1st hydrolytic class with a capacity of 10 or 20 ml, hermetically sealed with medical rubber stoppers, crimped with aluminum caps or combined caps (aluminum caps with safety plastic caps).

The drug quantity containing 1,000 mg + 500 mg, 2,000 mg + 1,000 mg of active substances should be placed in vials made of transparent glass of the 1st hydrolytic class with a capacity of 20 mL, hermetically sealed with medical rubber stoppers, crimped with aluminum caps or combined caps (aluminum caps with safety plastic caps).
1 vial with the drug and instructions for medical use should be placed in an outer carton.

For in-patient facilities: 10-50 vials with the drug and equal quantity of instructions for medical use should be placed in a carton box.

Storage Conditions
In places protected from the light at a temperature not exceeding 25 °C.
Keep out of the reach of children.

Expiry Date
3 years.

Do not use after expiration date.

Drug Dispensing Terms
Dispensed as medical prescription.

Manufacturer
Ruzpharma, LLC, Russia
143132, Moscow Oblast Ruzsky District, Tuchkovo work settlement, ul. Komsomolskya, d.12, str.1.

Marketing Authorization Holder
AlPharma, LLC, Russia
127238, Moscow, 3 Nizhnelikhoborsky proezd,dom 1A, etazh 4, pom. X, kom. 12.

Company Receiving Consumers’ Complaints
PHARMCOMPLIANCE PHARMACOVIGILANCE AGENCY, Limited Lability Company
117186, Moscow, ul. Nagornaya, d.15-8, pom. I, office 61.
Tel: +7 495 142 24 87
Cell phone: +7 901 369 45 95
e-mail: pv@farmakonadzor.com

Director General

S.M. Sidorov