UNASYN 0.75 G.

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2018-0037393 ; 2018-0037821

UNASYN

®

1.5G

UNASYN

®

3G

(ampicillin sodium/sulbactam sodium)

To reduce the development of drug-resistant bacteria and maintain the effectiveness

of UNASYN

®

and other antibacterial drugs, UNASYN

®

should be used only to treat

infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

UNASYN

®

is an injectable antibacterial combination consisting of the semisynthetic

antibacterial ampicillin sodium and the beta-lactamase inhibitor sulbactam sodium for

intravenous and intramuscular administration.

Ampicillin sodium is derived from the penicillin nucleus, 6-aminopenicillanic acid.

Chemically, it is monosodium (2S, 5R, 6R)-6-[(R)-2-amino-2-phenylacetamido]-3,

3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate and has a molecular

weight of 371.39. Its chemical formula is C

S. The structural formula is:

COONa

Sulbactam sodium is a derivative of the basic penicillin nucleus. Chemically, sulbactam

sodium is sodium penicillinate sulfone; sodium (2S, 5R)-3,3-dimethyl-7-oxo-4-thia-

1-azabicyclo [3.2.0] heptane-2-carboxylate 4,4-dioxide. Its chemical formula is

NNaO

S with a molecular weight of 255.22. The structural formula is:

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COONa

UNASYN

®

, ampicillin sodium/sulbactam sodium parenteral combination, is available as

a white to off-white dry powder for reconstitution. UNASYN

®

dry powder is freely

soluble in aqueous diluents to yield pale yellow to yellow solutions containing ampicillin

sodium and sulbactam sodium equivalent to 250 mg ampicillin per mL and 125 mg

sulbactam per mL. The pH of the solutions is between 8.0 and 10.0.

Dilute solutions (up to 30 mg ampicillin and 15 mg sulbactam per mL) are essentially

colorless to pale yellow. The pH of dilute solutions remains the same.

1.5 g of UNASYN

®

(1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium

salt) parenteral contains approximately 115 mg (5 mEq) of sodium.

3 g of UNASYN

®

(2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium

salt) parenteral contains approximately 230 mg (10 mEq) of sodium.

INDICATIONS AND USAGE

UNASYN

®

is indicated for the treatment of infections due to susceptible strains of the

designated microorganisms in the conditions listed below.

Skin and Skin Structure Infections

caused by beta-lactamase producing strains of

Staphylococcus aureus

Escherichia coli

Klebsiella

spp.* (including

K. pneumoniae*

Proteus mirabilis

Bacteroides fragilis

Enterobacter

spp.,* and

Acinetobacter

calcoaceticus.*

NOTE: For information on use in pediatric patients see PRECAUTIONS–

Pediatric Use and

CLINICAL STUDIES

sections.

Intra-Abdominal Infections

caused by beta-lactamase producing strains of

Escherichia

coli

Klebsiella

spp. (including

K. pneumoniae*

Bacteroides

spp. (including

B. fragilis

Enterobacter

spp.*

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Gynecological Infections

caused by beta-lactamase producing strains of

Escherichia

coli,*

Bacteroides

spp.* (including

B. fragilis*

* Efficacy for this organism in this organ system was studied in fewer than 10 infections.

While UNASYN

®

is indicated only for the conditions listed above, infections caused by

ampicillin-susceptible organisms are also amenable to treatment with UNASYN

®

due to

its ampicillin content. Therefore, mixed infections caused by ampicillin-susceptible

organisms and beta-lactamase producing organisms susceptible to UNASYN

®

should not

require the addition of another antibacterial.

Appropriate culture and susceptibility tests should be performed before treatment in order

to isolate and identify the organisms causing infection and to determine their

susceptibility to UNASYN

®

Therapy may be instituted prior to obtaining the results from bacteriological and

susceptibility studies when there is reason to believe the infection may involve any of the

beta-lactamase producing organisms listed above in the indicated organ systems. Once

the results are known, therapy should be adjusted if appropriate.

To reduce the development of drug-resistant bacteria and maintain effectiveness of

UNASYN

®

and other antibacterial drugs, UNASYN

®

should be used only to treat

infections that are proven or strongly suspected to be caused by susceptible bacteria.

When culture and susceptibility information are available, they should be considered in

selecting or modifying antibacterial therapy. In the absence of such data, local

epidemiology and susceptibility patterns may contribute to the empiric selection of

therapy.

CLINICAL PHARMACOLOGY

General:

Immediately after completion of a 15-minute intravenous infusion of UNASYN

®

, peak

serum concentrations of ampicillin and sulbactam are attained. Ampicillin serum levels

are similar to those produced by the administration of equivalent amounts of ampicillin

alone. Peak ampicillin serum levels ranging from 109 to 150 mcg/mL are attained after

administration of 2000 mg of ampicillin plus 1000 mg sulbactam and 40 to 71 mcg/mL

after administration of 1000 mg ampicillin plus 500 mg sulbactam. The corresponding

mean peak serum levels for sulbactam range from 48 to 88 mcg/mL and 21 to

40 mcg/mL, respectively. After an intramuscular injection of 1000 mg ampicillin plus

500 mg sulbactam, peak ampicillin serum levels ranging from 8 to 37 mcg/mL and peak

sulbactam serum levels ranging from 6 to 24 mcg/mL are attained.

The mean serum half-life of both drugs is approximately 1 hour in healthy volunteers.

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Approximately 75 to 85% of both ampicillin and sulbactam are excreted unchanged in

the urine during the first 8 hours after administration of UNASYN

®

to individuals with

normal renal function. Somewhat higher and more prolonged serum levels of ampicillin

and sulbactam can be achieved with the concurrent administration of probenecid.

In patients with impaired 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 UNASYN

®

in such patients should be

administered less frequently in accordance with the usual practice for ampicillin (see

DOSAGE

ADMINISTRATION

section).

Ampicillin has been found to be approximately 28% reversibly bound to human serum

protein and sulbactam approximately 38% reversibly bound.

The following average levels of ampicillin and sulbactam were measured in the tissues

and fluids listed:

TABLE 1

Concentration of UNASYN

®

in Various Body Tissues and Fluids

Fluid or Tissue

Dose

(grams)

Ampicillin/Sulbactam

Concentration

(mcg/mL or mcg/g)

Ampicillin/Sulbactam

Peritoneal Fluid

0.5/0.5 IV

7/14

Blister Fluid (Cantharides)

0.5/0.5 IV

8/20

Tissue Fluid

1/0.5 IV

Intestinal Mucosa

0.5/0.5 IV

11/18

Appendix

2/1 IV

3/40

Penetration of both ampicillin and sulbactam into cerebrospinal fluid in the presence of

inflamed meninges has been demonstrated after IV administration of UNASYN

®

The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving

UNASYN

®

are similar to those observed in adults. Immediately after a 15-minute

infusion of 50 to 75 mg UNASYN

®

/kg body weight, peak serum and plasma

concentrations of 82 to 446 mcg ampicillin/mL and 44 to 203 mcg sulbactam/mL were

obtained. Mean half-life values were approximately 1 hour.

MICROBIOLOGY

Ampicillin is similar to benzyl penicillin in its bactericidal action against susceptible

organisms during the stage of active multiplication. It acts through the inhibition of cell

wall mucopeptide biosynthesis. Ampicillin has a broad spectrum of bactericidal activity

against many gram-positive and gram-negative aerobic and anaerobic bacteria.

(Ampicillin is, however, degraded by beta-lactamases and therefore the spectrum of

activity does not normally include organisms which produce these enzymes).

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A wide range of beta-lactamases found in microorganisms resistant to penicillins and

cephalosporins have been shown in biochemical studies with cell free bacterial systems to

be irreversibly inhibited by sulbactam. Although sulbactam alone possesses little useful

antibacterial activity except against the

Neisseriaceae

, whole organism studies have

shown that sulbactam restores ampicillin activity against beta-lactamase producing

strains. In particular, sulbactam has good inhibitory activity against the clinically

important plasmid mediated beta-lactamases most frequently responsible for transferred

drug resistance. Sulbactam has no effect on the activity of ampicillin against ampicillin

susceptible strains.

The presence of sulbactam in the UNASYN

®

formulation effectively extends the

antibacterial spectrum of ampicillin to include many bacteria normally resistant to it and

to other beta-lactam antibacterials. Thus, UNASYN

®

possesses the properties of a

broad-spectrum antibacterial and a beta-lactamase inhibitor.

While

in vitro

studies have demonstrated the susceptibility of most strains of the

following organisms, clinical efficacy for infections other than those included in the

INDICATIONS

and

USAGE

section has not been documented.

Gram-Positive Bacteria:

Staphylococcus aureus

(beta-lactamase and

non-beta-lactamase producing),

Staphylococcus epidermidis

(beta-lactamase and

non-beta-lactamase producing),

Staphylococcus saprophyticus

(beta-lactamase and

non-beta-lactamase producing),

Streptococcus faecalis

(Enterococcus),

Streptococcus

pneumoniae

(formerly

D. pneumoniae), Streptococcus pyogenes

Streptococcus

viridans

Gram-Negative Bacteria:

Hemophilus influenzae

(beta-lactamase and

non-beta-lactamase producing),

Moraxella (Branhamella) catarrhalis

(beta-lactamase

and non-beta-lactamase producing),

Escherichia coli

(beta-lactamase and

non-beta-lactamase producing),

Klebsiella

species (all known strains are beta-lactamase

producing),

Proteus mirabilis

(beta-lactamase and non-beta-lactamase producing),

Proteus vulgaris,

Providencia rettgeri

Providencia stuartii

Morganella morganii

, and

Neisseria gonorrhoeae

(beta-lactamase and non-beta-lactamase producing).

Anaerobes:

Clostridium

species,

Peptococcus

species,

Peptostreptococcus

species,

Bacteroides

species, including

B. fragilis

These are not beta-lactamase producing strains and, therefore, are susceptible to

ampicillin alone.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated

test methods and quality control standards recognized by FDA for this drug, please see:

https://www.fda.gov/STIC.

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CONTRAINDICATIONS

The use of UNASYN

®

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).

UNASYN

®

is contraindicated in patients with a previous history of cholestatic

jaundice/hepatic dysfunction associated with UNASYN

®

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, UNASYN

®

should be discontinued and the

appropriate therapy instituted.

Hepatotoxicity

Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with

the use of UNASYN

®

. 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

UNASYN

®

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 UNASYN

®

discontinued if lesions progress (see

CONTRAINDICATIONS

ADVERSE REACTIONS

sections).

Clostridium difficile-Associated Diarrhea

Clostridium difficile

associated diarrhea (CDAD) has been reported with use of nearly all

antibacterial agents, including UNASYN

®

, 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.

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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 antibacterial should not be administered to

patients with mononucleosis. In patients treated with UNASYN

®

the possibility of

superinfections with mycotic or bacterial pathogens should be kept in mind during

therapy. If superinfections occur (usually involving

Pseudomonas

Candida

), the drug

should be discontinued and/or appropriate therapy instituted.

Prescribing UNASYN

®

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

UNASYN

®

should only be used to treat bacterial infections. They do not treat viral

infections (e.g., the common cold). When UNASYN

®

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 UNASYN

®

or other antibacterial drugs in the future.

Diarrhea is a common problem caused by antibacterial which usually ends when the

antibacterial is discontinued. Sometimes after starting treatment with antibacterial,

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.

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Drug Interactions:

Probenecid decreases the renal tubular secretion of ampicillin and

sulbactam. Concurrent use of probenecid with UNASYN

®

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 UNASYN

®

and allopurinol administered

concurrently. UNASYN

®

and aminoglycosides should not be reconstituted together due

to the

in vitro

inactivation of aminoglycosides by the ampicillin component of

UNASYN

®

Drug/Laboratory Test Interactions:

Administration of UNASYN

®

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 UNASYN

®

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 UNASYN

®

. 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 UNASYN

®

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 UNASYN

®

is administered to a

nursing woman.

Pediatric Use:

The safety and effectiveness of UNASYN

®

have been established for

pediatric patients one year of age and older for skin and skin structure infections as

approved in adults. Use of UNASYN

®

in pediatric patients is supported by evidence from

adequate and well-controlled studies in adults with additional data from pediatric

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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,

CLINICAL STUDIES

sections).

The safety and effectiveness of UNASYN

®

have not been established for pediatric

patients for intra-abdominal infections.

ADVERSE REACTIONS

Adult Patients:

UNASYN

®

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 UNASYN

®

demonstrate a similar adverse events profile to those observed in adult patients.

Additionally, atypical lymphocytosis has been observed in one pediatric patient receiving

UNASYN

®

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

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identified during post-marketing use of ampicillin sodium/sulbactam sodium 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 sodium/sulbactam sodium.

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

UNASYN

®

, 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

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

WARNINGS

sections).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is

important. It allows continued monitoring of the benefit/risk balance of the medicinal

product.

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form

http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMe

dic@moh.gov.il

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

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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 UNASYN

®

for the treatment of skin and skin structure infections. Of

99 pediatric patients evaluable for clinical efficacy, 60 patients received a regimen

containing intravenous UNASYN

®

, 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 UNASYN

®

and cefuroxime-treated patients:

TABLE

Therapeutic Regimen

Clinical Success

Clinical Failure

UNASYN

®

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

UNASYN

®

may be administered by either the IV or the IM routes.

For IV administration, the dose can be given by slow intravenous injection over at least

10–15 minutes or can also be delivered in greater dilutions with 50–100 mL of a

compatible diluent as an intravenous infusion over 15–30 minutes.

UNASYN

®

may be administered by deep intramuscular injection (see

DIRECTIONS

FOR USE

Preparation for Intramuscular Injection

section).

The recommended adult dosage of UNASYN

®

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 UNASYN

®

, and corresponds to a range

of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of

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sulbactam should not exceed 4 grams per day.

Pediatric Patients 1 Year of Age or Older:

The recommended daily dose of

UNASYN

®

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 UNASYN

®

, and

corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. The safety and

efficacy of UNASYN

®

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 UNASYN

®

(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 UNASYN

®

in such patients should be

administered less frequently in accordance with the usual practice for ampicillin and

according to the following recommendations:

TABLE

UNASYN

®

Dosage Guide for Patients with Renal Impairment

Creatinine Clearance

(mL/min/1.73m

2

)

Ampicillin/Sulbactam

Half-Life (Hours)

Recommended

UNASYN

®

Dosage

1.5-3 g q 6h-q 8h

15-29

1.5-3 g q 12h

5-14

1.5-3g 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)

serum creatinine

Females

0.85

above value

COMPATIBILITY, RECONSTITUTION AND STABILITY

UNASYN

®

sterile powder is to be stored below 25°C prior to reconstitution.

The expiry date of the product is indicated on the packaging materials

When concomitant therapy with aminoglycosides is indicated, UNASYN

®

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aminoglycosides should be reconstituted and administered separately, due to the

in vitro

inactivation of aminoglycosides by any of the aminopenicillins.

DIRECTIONS FOR USE

General Dissolution Procedures:

UNASYN

®

sterile powder for intravenous and

intramuscular 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.

Preparation for Intravenous Use

1.5 g and 3.0 g Bottles: UNASYN

®

sterile powder in piggyback units may be

reconstituted directly to the desired concentrations using any of the following parenteral

diluents. Reconstitution of UNASYN

®

, at the specified concentrations, with these

diluents provide stable solutions for the time periods indicated in the following table:

(After the indicated time periods, any unused portions of solutions should be discarded).

TABLE

Diluent

Maximum Concentration

(mg/mL)

UNASYN

®

(Ampicillin/Sulbactam)

Use Periods

Sterile Water for Injection

45 (30/15)

45 (30/15)

30 (20/10)

8 hrs at 25°C

48 hrs at

4°C

72 hrs at

4°C

0.9% Sodium Chloride Injection

45 (30/15)

45 (30/15)

30 (20/10)

8 hrs at 25°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 25°C

4 hrs at

4°C

4 hrs at 25°C

Lactated Ringer’s Injection

45 (30/15)

45 (30/15)

8 hrs at 25°C

24 hrs at

4°C

M/6 Sodium Lactate Injection

45 (30/15)

45 (30/15)

8 hrs at 25°C

8 hrs at

4°C

5% Dextrose in 0.45% Saline

3 (2/1)

15 (10/5)

4 hrs at 25°C

4 hrs at

4°C

10% Invert Sugar

3 (2/1)

30 (20/10)

4 hrs at 25°C

3 hrs at

4°C

If piggyback bottles are unavailable, standard vials of UNASYN

®

sterile powder may be

used. Initially, the vials may be reconstituted with Sterile Water for Injection to yield

solutions containing 375 mg UNASYN

®

per mL (250 mg ampicillin/125 mg sulbactam

per mL). An appropriate volume should then be immediately diluted with a suitable

Unasyn LPD Israel CC 230518

2018-0037393 ; 2018-0037821

parenteral diluent to yield solutions containing 3 to 45 mg UNASYN

®

per mL (2 to

30 mg ampicillin/1 to 15 mg sulbactam/per mL).

Preparation for Intramuscular Injection

1.5 g and 3.0 g Standard Vials:

Vials for intramuscular use may be reconstituted with

Sterile Water for Injection USP, 0.5% Lidocaine Hydrochloride Injection USP or 2%

Lidocaine Hydrochloride Injection USP. Consult the following table for recommended

volumes to be added to obtain solutions containing 375 mg UNASYN

®

per mL (250 mg

ampicillin/125 mg sulbactam per mL). Note:

Use only freshly prepared solutions and

administer within one hour after preparation.

TABLE

UNASYN

®

Vial Size

Volume of Diluent

to be Added

Withdrawal

Volume*

1.5 g

3.2 mL

4.0 mL

3.0 g

6.4 mL

8.0 mL

There is sufficient excess present to allow withdrawal and administration of the stated volumes.

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

Unasyn

®

(ampicillin sodium/sulbactam sodium) 1.5G and 3G for IM/IV injection is

supplied in clear, colourless type III glass vials with grey siliconized, bromobutyl rubber

stoppers (natural rubber-free), aluminum caps, and colored flip-off over-caps (1 type III

glass vial in each pack).

MANUFACTURER:

Haupt Pharma Latina S.R.L., Latina, Italy.

LICENSE HOLDER:

Pfizer PFE Pharmaceuticals Israel Ltd., 9 Shenkar St., Herzliya Pituach, Israel 46725.

LICENSE NUMBER:

UNASYN

®

1.5G: 122-47-30258

UNASYN

®

3G: 122-48-30259

The content of this leaflet was approved by the Ministry of Health in October 2017 and

updated according to the guidelines of the Ministry of Health in June 2018