AMPICILLIN SODIUM AND SULBACTAM SODIUM injection, powder, for solution

ampicillin sodium and sulbactam sodium by

Drug Labeling and Warnings

ampicillin sodium and sulbactam sodium by is a Prescription medication manufactured, distributed, or labeled by Mylan Institutional LLC. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • CONTRAINDICATIONS

    The use of ampicillin and sulbactam for injection is contraindicated in individuals with a history of serious hypersensitivity reactions (e.g., anaphylaxis or Stevens-Johnson syndrome) to ampicillin, sulbactam or to other beta-lactam antibacterial drugs (e.g., penicillins and cephalosporins).

    Ampicillin and sulbactam for injection is contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with ampicillin and sulbactam for injection.

  • WARNINGS

    Hypersensitivity

    Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. 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, ampicillin and sulbactam for injection should be discontinued and the appropriate therapy instituted.

    Hepatotoxicity

    Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of ampicillin and sulbactam for injection. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

    Severe Cutaneous Adverse Reactions

    Ampicillin and sulbactam for injection may cause severe skin reactions, such as toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), dermatitis exfoliative, erythema multiforme, and Acute generalized exanthematous pustulosis (AGEP). If patients develop a skin rash they should be monitored closely and ampicillin and sulbactam for injection discontinued if lesions progress (see CONTRAINDICATIONS and ADVERSE REACTIONS sections).

    Clostridium difficile-Associated Diarrhea

    Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ampicillin and sulbactam for injection, 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 antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

    If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

  • PRECAUTIONS

    General

    A high percentage of patients with mononucleosis who receive ampicillin develop a skin rash. Thus, ampicillin class antibacterials should not be administered to patients with mononucleosis. In patients treated with ampicillin and sulbactam for injection the possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted.

    Prescribing ampicillin and sulbactam for injection in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

    Information for Patients

    Patients should be counseled that antibacterial drugs including ampicillin and sulbactam for injection should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ampicillin and sulbactam for injection is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ampicillin and sulbactam for injection or other antibacterial drugs in the future.

    Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.

    Drug Interactions

    Probenecid decreases the renal tubular secretion of ampicillin and sulbactam. Concurrent use of probenecid with ampicillin and sulbactam for injection may result in increased and prolonged blood levels of ampicillin and sulbactam. 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. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients. There are no data with ampicillin and sulbactam for injection and allopurinol administered concurrently. Ampicillin and sulbactam for injection and aminoglycosides should not be reconstituted together due to the in vitro inactivation of aminoglycosides by the ampicillin component of ampicillin and sulbactam for injection.

    Drug/Laboratory Test Interactions

    Administration of ampicillin and sulbactam for injection will result in high urine concentration of ampicillin. High urine concentrations of ampicillin may result in false positive reactions when testing for the presence of glucose in urine using Clinitest™, Benedict's Solution or Fehling's Solution. It is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix™ or Testape™) be used. 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 ampicillin and sulbactam for injection.

    Carcinogenesis, Mutagenesis, Impairment of Fertility

    Long-term studies in animals have not been performed to evaluate carcinogenic or mutagenic potential.

    Pregnancy

    Reproduction studies have been performed in mice, rats, and rabbits at doses up to ten (10) times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to ampicillin and sulbactam for injection. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. (see –PRECAUTIONS-Drug/Laboratory Test Interactions section).

    Labor and Delivery

    Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of ampicillin and sulbactam for injection in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary.

    Nursing Mothers

    Low concentrations of ampicillin and sulbactam are excreted in the milk; therefore, caution should be exercised when ampicillin and sulbactam for injection is administered to a nursing woman.

    Pediatric Use

    The safety and effectiveness of ampicillin and sulbactam for injection have been established for pediatric patients one year of age and older for skin and skin structure infections as approved in adults. Use of ampicillin and sulbactam for injection in pediatric patients is supported by evidence from adequate and well-controlled studies in adults with additional data from pediatric pharmacokinetic studies, a controlled clinical trial conducted in pediatric patients and post-marketing adverse events surveillance. (see CLINICAL PHARMACOLOGY, INDICATIONS AND USAGE, ADVERSE REACTIONS, DOSAGE AND ADMINISTRATION, and CLINICAL STUDIES sections).

    The safety and effectiveness of ampicillin and sulbactam for injection have not been established for pediatric patients for intra-abdominal infections.

  • ADVERSE REACTIONS

    Adult Patients

    Ampicillin and sulbactam for injection is generally well tolerated. The following adverse reactions have been reported in clinical trials.

    Local Adverse Reactions

    Pain at IM injection site – 16%

    Pain at IV injection site – 3%

    Thrombophlebitis – 3%

    Phlebitis – 1.2%

    Systemic Adverse Reactions

    The most frequently reported adverse reactions were diarrhea in 3% of the patients and rash in less than 2% of the patients.

    Additional systemic reactions reported in less than 1% of the patients were: itching, nausea, vomiting, candidiasis, fatigue, malaise, headache, chest pain, flatulence, abdominal distension, glossitis, urine retention, dysuria, edema, facial swelling, erythema, chills, tightness in throat, substernal pain, epistaxis and mucosal bleeding.

    Pediatric Patients

    Available safety data for pediatric patients treated with ampicillin and sulbactam for injection demonstrate a similar adverse events profile to those observed in adult patients. Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving ampicillin and sulbactam for injection.

    Adverse Laboratory Changes

    Adverse laboratory changes without regard to drug relationship that were reported during clinical trials were:

    Hepatic: Increased AST (SGOT), ALT (SGPT), alkaline phosphatase, and LDH.

    Hematologic: Decreased hemoglobin, hematocrit, RBC, WBC, neutrophils, lymphocytes, platelets and increased lymphocytes, monocytes, basophils, eosinophils, and platelets.

    Blood Chemistry: Decreased serum albumin and total proteins.

    Renal: Increased BUN and creatinine.

    Urinalysis: Presence of RBC's and hyaline casts in urine.

    Postmarketing Experience

    In addition to adverse reactions reported from clinical trials, the following have been identified during post-marketing use of ampicillin and sulbactam for injection or other products containing ampicillin. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency, or potential causal connection to ampicillin and sulbactam for injection.

    Blood and Lymphatic System Disorders: Hemolytic anemia, thrombocytopenic purpura, and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Some individuals have developed positive direct Coombs Tests during treatment with ampicillin and sulbactam for injection, as with other beta-lactam antibacterials.

    Gastrointestinal Disorders:Abdominal pain, cholestatic hepatitis, cholestasis, hyperbilirubinemia, jaundice, abnormal hepatic function, melena, gastritis, stomatitis, dyspepsia, black “hairy” tongue, and Clostridium difficile associated diarrhea (see CONTRAINDICATIONS and WARNINGS sections).

    General Disorders and Administration Site Conditions: Injection site reaction

    Immune System Disorders: Serious and fatal hypersensitivity (anaphylactic) reactions (See WARNINGS section).

    Nervous System Disorders: Convulsion and dizziness

    Renal and Urinary Disorders: Tubulointerstitial nephritis

    Respiratory, Thoracic and Mediastinal Disorders: Dyspnea

    Skin and Subcutaneous Tissue Disorders: Toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, Acute generalized exanthematous pustulosis (AGEP), erythema multiforme, exfoliative dermatitis, and urticaria (see CONTRAINDICATIONS and WARNINGS sections).

    To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch for voluntary reporting of adverse reactions.

  • OVERDOSAGE

    Neurological adverse reactions, including convulsions, may occur with the attainment of high CSF levels of beta-lactams. Ampicillin may be removed from circulation by hemodialysis. The molecular weight, degree of protein binding and pharmacokinetics profile of sulbactam suggest that this compound may also be removed by hemodialysis.

  • CLINICAL STUDIES

    Skin and Skin Structure Infections in Pediatric Patients

    Data from a controlled clinical trial conducted in pediatric patients provided evidence supporting the safety and efficacy of ampicillin and sulbactam for injection for the treatment of skin and skin structure infections. Of 99 pediatric patients evaluable for clinical efficacy, 60 patients received a regimen containing intravenous ampicillin and sulbactam for injection, and 39 patients received a regimen containing intravenous cefuroxime. This trial demonstrated similar outcomes (assessed at an appropriate interval after discontinuation of all antimicrobial therapy) for ampicillin and sulbactam for injection - and cefuroxime-treated patients:

    TABLE 4
    Therapeutic Regimen
    		Clinical Success
    		Clinical Failure

    Ampicillin and Sulbactam

    51/60 (85%)

    9/60 (15%)

    Cefuroxime

    34/39 (87%)

    5/39 (13%)

    Most patients received a course of oral antimicrobials following initial treatment with intravenous administration of parenteral antimicrobials. The study protocol required that the following three criteria be met prior to transition from intravenous to oral antimicrobial therapy: (1) receipt of a minimum of 72 hours of intravenous therapy; (2) no documented fever for prior 24 hours; and (3) improvement or resolution of the signs and symptoms of infection.

    The choice of oral antimicrobial agent used in this trial was determined by susceptibility testing of the original pathogen, if isolated, to oral agents available. The course of oral antimicrobial therapy should not routinely exceed 14 days.

  • DOSAGE AND ADMINISTRATION

    The pharmacy bulk package is for preparation of solutions for IV infusion only. Ampicillin and sulbactam should be administered by slow intravenous injection over at least 10 to 15 minutes or can also be delivered in greater dilutions with 50 to 100 mL of a compatible diluent as an intravenous infusion over 15 to 30 minutes.

    The recommended adult dosage of ampicillin and sulbactam for injection is 1.5 g (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of ampicillin and sulbactam for injection, and corresponds to a range of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of sulbactam should not exceed 4 grams per day.

    Pediatric Patients 1 Year of Age or Older

    The recommended daily dose of ampicillin and sulbactam for injection in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours. This 300 mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of ampicillin and sulbactam for injection, and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. The safety and efficacy of ampicillin and sulbactam for injection administered via intramuscular injection in pediatric patients have not been established. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous ampicillin and sulbactam for injection (see CLINICAL STUDIES section).

    Impaired Renal Function

    In patients with impairment of renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of ampicillin and sulbactam for injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations:

    TABLE 5

    Ampicillin and Sulbactam for Injection Dosage Guide for Patients with Renal Impairment

    •   Creatinine Clearance

    (mL/min/1.73m2)

    •   Ampicillin/Sulbactam
    •   Half-Life (Hours)

    Recommended

    Ampicillin and Sulbactam for Injection Dosage

    ≥30

    1

    1.5 to 3 g q 6h to q 8h

    15 to 29

    5

    1.5 to 3 g q 12h

    5 to 14

    9

    1.5 to 3 g q 24h

    When only serum creatinine is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady-state of renal function.

    Males weight (kg) × (140 – age)

    72 × serum creatinine

    Females 0.85 × above value

  • COMPATIBILITY, RECONSTITUTION AND STABILITY

    When concomitant therapy with aminoglycosides is indicated, ampicillin and sulbactam for injection and aminoglycosides should be reconstituted and administered separately, due to the in vitro inactivation of aminoglycosides by any of the aminopenicillins.

    DIRECTIONS FOR USE 

  • Intravenous Administration

    Directions for Proper Use of Pharmacy Bulk Package

    Ampicillin and sulbactam for injection sterile powder for intravenous use may be reconstituted with any of the compatible diluents described in this insert. Solutions should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for complete solubilization. Ampicillin and sulbactam concentrations between 3 and 45 mg (2 to 30 mg ampicillin/1 to 15 mg sulbactam/mL) are recommended for intravenous use.

    The 15 gram bottle may be reconstituted with either 92 mL Sterile Water for Injection or 0.9% Sodium Chloride Injection. The diluent should be added in two separate aliquots in a suitable work area, such as a laminar flow hood. Add 50 mL of solution, shake to dissolve. Then add an additional 42 mL and shake. The solution should be allowed to stand after dissolution to allow any foaming to dissipate in order to permit visual inspection for complete solubilization. The resultant solution will have a final concentration of approximately 100 mg/mL ampicillin and 50 mg/mL sulbactam. The closure may be penetrated only one time after reconstitution, if needed, using a suitable sterile transfer device or dispensing set that allows for measured dispensing of the contents.

    After reconstitution, use within two hours if stored at room temperature, or within four hours if stored under refrigeration.

    Reconstituted Bulk Solution Should Not be Used For Direct Infusion

    If the reconstituted bulk solution is stored for less than one hour at room temperature (20°C/68°F) prior to further dilution, the use periods indicated in Table 6 apply for the diluted solutions.

    If the bulk solution is stored for one to two hours at room temperature (20°C/68°F) and then diluted with Sterile Water for Injection or 0.9% Sodium Chloride Injection to the following concentrations, the use periods indicated in Table 7 apply.

    Any unused portions of solution that remain after the indicated time periods should be discarded.

    Table 6
    DiluentMaximum Concentration
    (mg/mL)
    Ampicillin and Sulbactam for Injection (Ampicillin/Sulbactam)    		Use Periods

    Sterile Water for Injection

    45 (30/15)
    45 (30/15)
    30 (20/10)

      8 hrs at 21°C
    48 hrs at   4°C
    72 hrs at 4°C

    0.9% Sodium Chloride Injection, (USP)

    45 (30/15)
    45 (30/15)
    30 (20/10)

      8 hrs at 21°C
    48 hrs at   4°C
    72 hrs at   4°C

    5% Dextrose Injection

    30 (20/10)
    30 (20/10)
    3 (2/1)

      2 hrs at 21°C
      4 hrs at   4°C
      2 hrs at 21°C

    Lactated Ringer's Injection

    45 (30/15)
    45 (30/15)

      8 hrs at 21°C
    24 hrs at   4°C

    M/6 Sodium Lactate Injection

    45 (30/15)
    45 (30/15)

      8 hrs at 21°C
    12 hrs at   4°C

    5% Dextrose in 0.45% Saline

      3 (2/1)
    15 (10/5)

      4 hrs at 21°C
      4 hrs at   4°C

    10% Invert Sugar

      3 (2/1)
    30 (20/10)

      4 hrs at 21°C
      3 hrs at   4°C

    Table 7

    IV Solution

    Maximum Concentration (mg/mL)

    Ampicillin and Sulbactam for Injection (Ampicillin/Sulbactam)

    Use Period

    Sterile Water for Injection, USP

    45 (30/15)

    4 hrs at 21°C

    45 (30/15)

    24 hrs at 4°C

    0.9% Sodium Chloride Injection, USP

    45 (30/15)

    4 hrs at 21°C

    45 (30/15)

    24 hrs at 4°C

    Animal Pharmacology

    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 man.

  • HOW SUPPLIED

    Ampicillin and Sulbactam for Injection, USP, a sterile white to off-white dry powder, is available in Pharmacy Package bottle containing ampicillin sodium and sulbactam sodium equivalent to 10 g ampicillin and 5 g sulbactam × 1 (NDC: 67457-649-10).

    Ampicillin and Sulbactam for Injection, USP sterile powder is to be stored at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]prior to reconstitution.

  • SPL UNCLASSIFIED SECTION

    Clinitest™ is a registered trademark of Miles, Inc.

    Clinistix™ is a registered trademark of Bayer Corporation.

    Testape™ is a registered trademark of Eli Lilly Company.

    Rx only

    Manufactured for:

    Mylan Institutional LLC

    Rockford, IL 61103 U.S.A.

    Manufactured by:

    MITIM S.r.l.

    Via Cacciamali n°34-36-38 25125 Brescia, ITALY (premises)

    Via Rodi n° 27 Brescia, ITALY (headquarters)

    JUNE 2018

  • Package/Label Display Panel

    NDC: 67457-649-10

    Ampicillin and Sulbactam for Injection, USP

    15 g* per Pharmacy Bulk Package

    PHARMACY BULK PACKAGE - NOT FOR DIRECT INFUSION

    Sterile

    For Intravenous Use

    Rx only

    One Pharmacy Bulk Package Bottle

    Carton 15 g
  • INGREDIENTS AND APPEARANCE
    AMPICILLIN SODIUM AND SULBACTAM SODIUM 
    ampicillin sodium and sulbactam sodium injection, powder, for solution
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 67457-649
    Route of AdministrationINTRAMUSCULAR, INTRAVENOUS
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    AMPICILLIN SODIUM (UNII: JFN36L5S8K) (AMPICILLIN - UNII:7C782967RD) AMPICILLIN100 mg  in 1 mL
    SULBACTAM SODIUM (UNII: DKQ4T82YE6) (SULBACTAM - UNII:S4TF6I2330) SULBACTAM50 mg  in 1 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 67457-649-101 in 1 CARTON04/08/2014
    192 mL in 1 VIAL, PHARMACY BULK PACKAGE; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    ANDAANDA20219704/08/2014
    Labeler - Mylan Institutional LLC (790384502)
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