Unasyn

Sultamicillin: Ampicillin, sulbactam.

Film-coated tablet: Sultamicillin is available as film-coated tablets containing the tosylate salt equivalent to 750 mg sultamicillin, yielding the equivalent of 294 mg sulbactam and 440 mg ampicillin.
Sultamicillin is a double ester in which ampicillin and the beta-lactamase inhibitor sulbactam are linked via a methylene group. Chemically, sultamicillin is the oxymethylpenicillinate sulfone ester of ampicillin and has a molecular weight of 594.7.
Powder for injection: Sulbactam sodium/ampicillin sodium IM/IV combination is available as a dry powder for reconstitution in vials containing the equivalent of 500 mg + 1,000 mg, 1,000 mg + 2,000 mg of sulbactam and ampicillin, respectively.
Sulbactam sodium is a derivative of the basic penicillin nucleus. Chemically it is sodium penicillanate sulfone and is an off-white crystalline powder highly soluble in water. The molecular weight is 255.22.
Ampicillin sodium is derived from the penicillin nucleus, 6-aminopenicillanic acid. Chemically, it is D(-)-α-aminobenzyl penicillin sodium salt and has a molecular weight of 371.39.
Sulbactam sodium/ampicillin sodium IM/IV contains sulbactam sodium and ampicillin sodium in a 1:2 ratio.
Excipients/Inactive Ingredients: Sultamicillin Tosylate Film-coated Tablets 750 mg: Lactose, maize starch, sodium starch glycolate, hydroxypropylcellulose, magnesium stearate.
Powder for injection: None.

Pharmacology: Pharmacodynamics: Biochemical studies with cell-free bacterial systems have shown sulbactam to be an irreversible inhibitor of most important beta-lactamases that occur in penicillin-resistant organisms. It possesses significant antibacterial activity only against Neisseriaceae, Acinetobacter calcoaceticus, Bacteroides spp, Branhamella catarrhalis and Pseudomonas cepacia. The potential for sulbactam sodium's preventing the destruction of penicillins and cephalosporins by resistant organisms was confirmed in whole-organism studies using resistant strains in which sulbactam sodium exhibited marked synergistic effects with penicillins and cephalosporins. Since sulbactam also binds to some penicillin-binding proteins, some sensitive strains are rendered more susceptible to the combination than to the β-lactam antibiotic alone.
The bactericidal component of this product is ampicillin which, like benzylpenicillin, acts against sensitive organisms during the stage of active multiplication by the inhibition of biosynthesis of cell wall mucopeptide.
Sultamicillin is effective against a wide range of gram-positive and gram-negative bacteria including Staphylococcus aureus and Staphylococcus epidermidis (including penicillin-resistant and some methicillin-resistant strains); Streptococcus pneumoniae, Streptococcus faecalis and other Streptococcus species; Haemophilus influenzae and Haemophilus parainfluenzae (both beta-lactamase-positive and -negative strains); Moraxella or Branhamella catarrhalis; anaerobes including Bacteroides fragilis and related species; Escherichia coli; Klebsiella species; Proteus species (both indole-positive and indole-negative); Enterobacter species; Morganella morganii; Citrobacter species; Neisseria meningitidis and Neisseria gonorrhoeae.
Pharmacokinetics: Film-coated tablet: Following oral administration in humans, sultamicillin is hydrolyzed during absorption to provide sulbactam and ampicillin in a 1:1 molar ratio in the systemic circulation. The bioavailability of an oral dose is 80% of an equal intravenous dose of sulbactam and ampicillin. Administration following food does not affect the systemic bioavailability of sultamicillin. Peak serum levels of ampicillin, following administration of sultamicillin, are approximately twice those of an equal dose of oral ampicillin.
Elimination half-lives are approximately 0.75 and 1 hour for sulbactam and ampicillin, respectively, in healthy volunteers, with 50%-75% of each agent being excreted unchanged in the urine. Elimination half-lives are increased in the elderly and in patients with renal dysfunction.
Probenecid decreases the renal tubular secretion of both ampicillin and sulbactam. Concurrent use of probenecid with sultamicillin results in increased and prolonged blood levels of ampicillin and sulbactam (see Interactions).
Powder for injection: Sulbactam sodium/ampicillin sodium IM/IV diffuses readily into most body tissues and fluids in the human. Penetration into brain and spinal fluid is low except when meninges are inflamed. High concentrations of sulbactam and ampicillin are achieved in the blood following intravenous or intramuscular administration and both components have a half-life of approximately 1 hour. Most of the sulbactam sodium/ampicillin sodium IM/IV is excreted unchanged in the urine.
Toxicology: Preclinical Safety Data: While reversible glycogenosis was observed in laboratory animals, this phenomenon was dose-and time-dependent and is not expected to develop at the therapeutic doses and corresponding plasma levels attained during the relatively short periods of combined ampicillin/sulbactam therapy in humans.
Long-term studies in animals have not been performed to evaluate the carcinogenic potential. The individual components of sultamicillin (ampicillin/sulbactam) tested negative for mutagenicity.
Reproduction studies have been performed in mice and rats with sultamicillin, an oral prodrug that hydrolyzes in vivo to release ampicillin and sulbactam, at doses in excess of the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to sultamicillin.

Film-coated tablet: Sultamicillin is indicated for infections caused by susceptible micro-organisms. Typical indications are upper respiratory tract infections including sinusitis, otitis media and tonsillitis; lower respiratory tract infections including bacterial pneumonias and bronchitis; urinary tract infections and pyelonephritis; skin and soft tissue infections and gonococcal infections.
Sultamicillin oral form may also be indicated in patients requiring sulbactam/ampicillin therapy following initial treatment with sulbactam/ampicillin IM/IV.
Powder for injection: Sulbactam sodium/ampicillin sodium IM/IV is indicated for infections caused by susceptible microorganisms. Typical indications are upper and lower respiratory tract infections including sinusitis, otitis media and epiglottitis; bacterial pneumonias; urinary tract infections and pyelonephritis; intra-abdominal infections including peritonitis, cholecystitis, endometritis and pelvic cellulitis; bacterial septicemia; skin, soft tissue, bone and joint infections and gonococcal infections.
Sulbactam sodium/ampicillin sodium IM/IV may also be administered peri-operatively to reduce the incidence of post-operative wound infections in patients undergoing abdominal or pelvic surgery, in which peritoneal contamination may be present. In termination of pregnancy or cesarean section, sulbactam sodium/ampicillin sodium IM/IV may be used prophylactically to reduce post-operative sepsis.

Film-coated tablet: The recommended dose of sultamicillin in adults (including elderly patients) is 375-750 mg twice daily.
In both adults and children, treatment is usually continued until 48 hours after pyrexia and other abnormal signs have resolved. Treatment is normally given for 5-14 days but the treatment period may be extended if necessary.
In the treatment of uncomplicated gonorrhoea, sultamicillin can be given as a single oral dose of 2.25 g (three 750 mg tablets). Concomitant probenecid 1.0 g should be administered in order to prolong plasma concentrations of sulbactam and ampicillin.
Cases of gonorrhea with a suspected lesion of syphilis should have dark field examinations before receiving sultamicillin and monthly serological tests for a minimum of four months.
It is recommended that there be at least 10 days treatment for any infection caused by hemolytic streptococci to prevent the occurrence of acute rheumatic fever or glomerulonephritis.
Use in Children and Infants: The dosage for most infections in children weighing less than 30 kg is sultamicillin 25-50 mg/kg/day orally in two divided doses, depending on the severity of the infection and the physician's judgment. For children weighing 30 kg or more, the usual adult dose should be given.
Use in Patients with Renal Impairment: In patients with severe impairment of renal function (creatinine clearance ≤30 ml/min), the elimination kinetics of sulbactam and ampicillin are similarly affected and hence the plasma ratio of one to the other will remain constant. The dose of sultamicillin in such patients should be administered less frequently in accordance with the usual practice for ampicillin.
Powder for injection: Sulbactam sodium/ampicillin sodium IM/IV can be administered by either intravenous or intramuscular routes. The following dilutions may be used: See Table 1.

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For intravenous administration, sulbactam sodium/ampicillin sodium IM/IV should be reconstituted with sterile water for injection or any compatible solution. (See Instructions for Use under Cautions for Usage.) To ensure complete dissolution, allow foaming to dissipate in order to visually inspect. The dose can be given by bolus injection over a minimum of 3 minutes or can be used in greater dilutions as an intravenous infusion over 15-30 minutes.
Pfizer sulbactam sodium/ampicillin sodium parenteral may also be administered by deep intramuscular injection; if pain is experienced, 0.5% sterile solution for injection of lignocaine hydrochloride anhydrous may be used for reconstitution of the powder.
Use in Adults: The usual dosage range of sulbactam sodium/ampicillin sodium IM/IV is 1.5 g to 12 g per day in divided doses every 6 or 8 hours up to a maximum daily dosage of sulbactam of 4 g. Less severe infections may be treated on an every 12-hours schedule. (See Table 2.)

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More or less frequent dosing may be indicated depending on the severity of the illness and the renal function of the patient. Treatment is usually continued until 48 hours after pyrexia and other abnormal signs have resolved. Treatment is normally given for 5 to 14 days, but the treatment period may be extended or additional ampicillin may be administered in severely ill cases.
In treating patients on restricted sodium intake, it should be noted that 1,500 mg of sulbactam sodium/ampicillin sodium IM/IV contains approximately 115 mg (5 mmol) of sodium.
For the prophylaxis of surgical infections, 1.5-3 g of sulbactam sodium/ampicillin sodium IM/IV should be given at induction of anesthesia, which allows sufficient time to achieve effective serum and tissue concentrations during the procedure. The dose may be repeated every 6-8 hours; administration is usually stopped 24 hours after the majority of surgical procedures, unless a therapeutic course of sulbactam sodium/ampicillin sodium IM/IV is indicated.
In the treatment of uncomplicated gonorrhea, sulbactam sodium/ampicillin sodium IM/IV can be given as a single dose of 1.5 g. Concomitant probenecid 1.0 g orally should be administered in order to prolong plasma concentrations of sulbactam and ampicillin.
Use in Children, Infants and Neonates: The dosage of sulbactam sodium/ampicillin sodium IM/IV for most infections in children, infants and neonates is 150 mg/kg/day (corresponding to sulbactam 50 mg/kg/day and ampicillin 100 mg/kg/day).
In children, infants and neonates, dosing is usually every 6 or 8 hours in accordance with the usual practice for ampicillin.
In neonates during the first week of life (especially pre-terms), the recommended dose is 75 mg/kg/day (corresponding to 25 mg/kg/day sulbactam and 50 mg/kg/day ampicillin) in divided doses every 12 hours.
Use in Patients with Renal Impairment: In patients with severe impairment of renal function (creatinine clearance ≤30 ml/min), the elimination kinetics of sulbactam and ampicillin are similarly affected and hence the plasma ratio of one to the other will remain constant. The dose of sulbactam sodium/ampicillin sodium IM/IV in such patients should be administered less frequently in accordance with the usual practice for ampicillin.

Limited information is available on the acute toxicity of ampicillin sodium and sulbactam sodium in humans. Overdosage of the drug would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. The fact that high cerebrospinal fluid (CSF) concentrations of β-lactam antibiotics may cause neurologic effects, including seizures, should be considered. Because ampicillin and sulbactam are both removed from the circulation by hemodialysis, these procedures may enhance elimination of the drug from the body if overdosage occurs in patients with impaired renal function.

The use of sultamicillin is contraindicated in individuals with a history of an allergic reaction to any of the penicillins.

Based on the Ministry of Public Health Announcement: 1. This medication is contraindicated in patients with known hypersensitivity to it.
2. This medication may cause sensitization and can be fatal.
3. In case of skin rash, irritation or swelling occurs, stop using this medication and consultation with the physician is recommended.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy including sultamicillin. These reactions are more apt to occur in individuals with a history of penicillin hypersensitivity and/or hypersensitivity reactions to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with a penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins and other allergens. If an allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted.
Serious anaphylactic reactions require immediate emergency treatment with adrenaline or epinephrine. Oxygen, intravenous steroids and airway management, including intubation, should be administered as indicated.
Severe skin reactions, such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), dermatitis exfoliative, erythema multiforme, and acute generalized exanthematous pustulosis [AGEP (for powder for injection)] have been reported in patients on ampicillin/sulbactam therapy. If a severe skin reaction occurs, ampicillin/sulbactam should be discontinued and appropriate therapy should be initiated (see Adverse Reactions).
As with any antibiotic preparation, constant observation for signs of overgrowth of non-susceptible organisms, including fungi, is essential. Should superinfection occur, the drug should be discontinued and/or appropriate therapy instituted.
Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including sultamicillin, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD.
Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.
Drug induced liver injury such as cholestatic hepatitis and jaundice have been associated with the use of ampicillin/sulbactam. Patients should be advised to contact their doctor if signs and symptoms of hepatic disease develop (see Adverse Reactions).
Since infectious mononucleosis is viral in origin, ampicillin (for film-coated tablet), or sulbactam sodium/ampicillin sodium IM/IV (for powder for injection) should not be used in the treatment. A high percentage of patients with mononucleosis who received ampicillin have developed a skin rash.
Film-coated tablet: It is advisable to check periodically for organ system dysfunction during prolonged therapy; this includes renal, hepatic and hematopoietic systems.
The principal route of excretion of sulbactam and ampicillin following oral administration of sultamicillin is via the urine. Because renal function is not fully developed in neonates, this should be considered when using sultamicillin in neonates.
Tablets: Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Powder for injection: As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy; this includes renal, hepatic and hematopoietic systems. This is particularly important in neonates, especially when premature, and other infants.
Effects on Ability to Drive and Use Machines: None known.

Use During Pregnancy/Fertility: Animal reproduction studies have revealed no evidence of impaired fertility or harm to the fetus due to sultamicillin. Sulbactam and ampicillin cross the placental barrier. However, safety for use in human pregnancy has not been established. Therefore, sultamicillin should be used during pregnancy only if the potential benefits outweigh the potential risk.
Use During Lactation: Film-coated tablet: The use of sultamicillin during lactation is not recommended. Low concentrations of ampicillin and sulbactam are excreted in the milk. This should be considered as the neonate may be exposed, particularly since renal function is not fully developed in neonates.
Powder for injection: Low concentrations of sulbactam (~0.13 up to 2.8 mg/L) and ampicillin (~0.11 up to 3 mg/L) are excreted in the milk. The use of sulbactam sodium/ampicillin sodium by a nursing mother may lead to adverse effects such as diarrhea in the child. Sulbactam sodium/ampicillin sodium can be used during lactation if the potential benefits outweigh the potential risks.

Film-coated tablet: Sultamicillin is generally well tolerated. The majority of side effects observed were of mild or moderate severity and were normally tolerated with continued treatment.
Infections and Infestations: Pseudomembranous colitis, Candida infection.
Blood and Lymphatic System Disorders: Thrombocytopenia.
Immune System Disorders: Anaphylactic shock, Anaphylactic reaction, Kounis syndrome, Hypersensitivity.
Nervous System Disorders: Dizziness, Somnolence, Sedation, Headache.
Respiratory, Thoracic and Mediastinal Disorders: Dyspnea.
Gastrointestinal Disorders: Enterocolitis, Melena, Diarrhea, Vomiting, Abdominal pain, Dyspepsia, Nausea, Stomatitis, Dysgeusia, Tongue discolouration.
Hepatobiliary Disorders: Jaundice, Hepatic function abnormal (see Precautions).
Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme (see Precautions), Angioedema, Urticaria, Dermatitis, Rash, Pruritus.
Musculoskeletal and Connective Tissue Disorders: Arthralgia.
General Disorders and Administration Site Conditions: Fatigue, Malaise.
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased (see Precautions).
Adverse reactions associated with the use of ampicillin alone and/or sulbactam/ampicillin IM/IV may be observed with sultamicillin. These include: Blood and Lymphatic System Disorders: Agranulocytosis, Hemolytic anemia, Thrombocytopenic purpura, Leukopenia, Neutropenia, Eosinophilia, Anemia.
Immune System Disorders: Anaphylactoid shock, Anaphylactoid reaction.
Nervous System Disorders: Convulsion.
Gastrointestinal Disorders: Glossitis.
Hepatobiliary Disorders: Hepatitis cholestatic, Cholestasis, Hyperbilirubinaemia (see Precautions).
Skin and Subcutaneous Tissue Disorders: Exfoliative dermatitis, Acute generalized exanthematous pustulosis (see Precautions).
Renal and Urinary Disorders: Tubulointerstitial nephritis.
Investigations: Platelet aggregation abnormal.
Powder for injection: Adverse reactions associated with the use of ampicillin alone may be observed with sulbactam sodium/ampicillin sodium IM/IV.
All ADRs listed in the CDS are presented by MedDRA SOC. Within each frequency category, the ADRs are presented in the order of seriousness. Seriousness of the ADRs was determined by clinical importance. (See Table 3.)

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Allopurinol: The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone.
Anticoagulants: Parenteral penicillins can produce alterations in platelet aggregation and coagulation tests. These effects may be additive with anticoagulants.
Bacteriostatic Drugs (Chloramphenicol, Erythromycin, Sulfonamides and Tetracyclines): Bacteriostatic drugs may interfere with the bactericidal effect of penicillins; it is best to avoid concurrent therapy.
Estrogen-Containing Oral Contraceptives: There have been case reports of reduced oral contraceptive effectiveness in women taking ampicillin, resulting in unplanned pregnancy. Although the association is weak, patients should be given the option to use an alternate or additional method of contraception while taking ampicillin.
Methotrexate: Concurrent use with penicillins has resulted in decreased clearance of methotrexate and a corresponding increase in methotrexate toxicity. Patients should be closely monitored. Leucovorin dosages may need to be increased and administered for longer periods of time.
Probenecid: Probenecid decreases renal tubular secretion of ampicillin and sulbactam when used concurrently; this effect results in increased and prolonged serum concentrations, prolonged elimination half-life and increased risk of toxicity.
Laboratory Test Interactions: False-positive glycosuria may be observed in urinalysis using Benedict's reagent, Fehling's reagent and Clinitest. Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol glucuronide, conjugated estrone and estradiol has been noted. This effect may also occur with sulbactam sodium/ampicillin sodium IM/IV.
Powder for injection: Aminoglycosides: Mixing ampicillin with aminoglycosides in vitro has resulted in substantial mutual inactivation; if these groups of antibacterials are to be administered concurrently, they should be administered at separate sites at least 1 hour apart (see Incompatibilities under Cautions for Usage).

Incompatibilities: Powder for injection: Sulbactam sodium/ampicillin sodium IM/IV and aminoglycosides should be reconstituted and administered separately, due to the in vitro inactivation of aminoglycosides by any of the aminopenicillins.
Instructions for Use: Powder for injection: Sulbactam sodium is compatible with most intravenous solutions, but ampicillin sodium and hence sulbactam sodium/ampicillin sodium IM/IV is less stable in solutions containing dextrose or other carbohydrates, and should not be mixed with blood products or protein hydrolysates. Ampicillin and hence sulbactam sodium/ampicillin sodium IM/IV is incompatible with aminoglycosides and should not be physically mixed in the same container (see Dosage & Administration). The concentrated solution for intramuscular administration should be used within 1 hour of reconstitution. Time periods for use with different diluents for intravenous infusion are as follows: See Table 4.

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Powder for injection: Store below 30°C.

Penicillins

J01CR01 - ampicillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.
J01CR04 - sultamicillin ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

FC tab: D; Powd for inj: S