SPC-Cefprozil (Sun Pharma Canada, 250 mg, 500 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

SPC-Cefprozil (cefprozil) is indicated for the treatment of the following infections caused by susceptible strains of the designated microorganisms:

Upper Respiratory Tract

Pharyngitis / tonsillitis caused by group A ß-hemolytic (GABHS) Streptococcus pyogenes.

Substantial data establishing the efficacy of cefprozil in the subsequent prevention of rheumatic fever are not available at present, although no case was reported during its evaluation in over 978 pediatric and 831 adult patients in controlled clinical trials.

Otitis media caused by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella (Branhamella) catarrhalis.

Acute sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, (beta-lactamase positive and negative strains), and Moraxella (Branhamella) catarrhalis.

Skin And Skin Structure

Uncomplicated skin and skin-structure infections caused by Staphylococcus aureus (including penicillinase-producing strains) and Streptococcus pyogenes.

Urinary Tract

Uncomplicated urinary tract infections (including acute cystitis) caused by Escherichia coli,

Klebsiella pneumoniae, Proteus mirabilis.

Cultures and susceptibility studies should be performed when appropriate.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of SPC-Cefprozil and other antibacterial drugs, SPC-Cefprozil 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.

CONTRAINDICATIONS

SPC-Cefprozil (cefprozil) is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or to any component of the cefprozil preparations (see PHARMACEUTICAL INFORMATION, Composition).

WARNINGS AND PRECAUTIONS

Hypersensitivity

Serious Warnings and Precautions

Before therapy with SPC-Cefprozil (cefprozil) is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to cefprozil, cephalosporins, penicillins or other drugs. If this product is to be given to penicillin-sensitive patients, caution should be exercised because cross-sensitivity among beta-lactam antibiotics has been clearly documented and may occur in up to 10% of patients with a history of penicillin allergy.

If an allergic reaction to SPC-Cefprozil occurs, discontinue the drug. Serious acute hypersensitivity reactions may require treatment with epinephrine and other emergency measures, including oxygen, intravenous fluids, intravenous antihistamines, corticosteroids, pressor amines, and airway management, as clinically indicated.

General

Prolonged use of SPC-Cefprozil may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Positive direct Coombs tests have been reported during treatment with cephalosporin antibiotics.

Severe Cutaneous Adverse Reactions

Severe cutaneous adverse reactions (SCAR) such as acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) have been reported in association with beta-lactam treatment. When SCAR is suspected, SPC-Cefprozil should be discontinued and appropriate therapy and/or measures should be taken.

Gastrointestinal

Clostridium difficile-associated disease

Clostridium difficile-associated disease (CDAD) has been reported with use of many antibacterial agents, including SPC-Cefprozil (cefprozil). CDAD may range in severity from mild diarrhea to fatal colitis. It is important to consider this diagnosis in patients who present with diarrhea, or symptoms of colitis, pseudomembranous colitis, toxic megacolon, or perforation of colon subsequent to the administration of any antibacterial agent. CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

Treatment with antibacterial agents may alter the normal flora of the colon and may permit overgrowth of Clostridium difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. CDAD may cause significant morbidity and mortality. CDAD can be refractory to antimicrobial therapy.

If the diagnosis of CDAD is suspected or confirmed, appropriate therapeutic measures should be initiated. Mild cases of CDAD usually respond to discontinuation of antibacterial agents not directed against Clostridium difficile. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial agent clinically effective against Clostridium difficile. Surgical evaluation should be instituted as clinically indicated, as surgical intervention may be required in certain severe cases (see ADVERSE REACTIONS).

Hemolytic Anemia

SPC-CEFPROZIL SHOULD NOT BE USED IN PATIENTS WITH A HISTORY OF CEPHALOSPORIN ASSOCIATED HEMOLYTIC ANEMIA SINCE THE RECURRENCE OF HEMOLYSIS IS MUCH MORE SEVERE.

An immune mediated hemolytic anemia has been observed in patients receiving cephalosporin class antibacterials. Severe cases of hemolytic anemia, including fatalities, have been reported in both adults and children. If a patient develops anemia anytime during, or within 2 to 3 weeks subsequent to the administration of SPC-Cefprozil (cefprozil), the diagnosis of a cephalosporin-associated anemia should be considered and the drug discontinued until the etiology is determined.

Patients may benefit from periodic monitoring for signs and symptoms of hemolytic anemia, including measurement of hematological parameters or drug-induced antibody testing, where appropriate (see ADVERSE REACTIONS).

Renal

Evaluation of renal status before and during therapy is recommended, especially in seriously ill patients. In patients with known or suspected renal impairment (see DOSAGE AND ADMINISTRATION), careful clinical observation and appropriate laboratory studies should be done prior to and during therapy. The total daily dose of SPC-Cefprozil (cefprozil) should be reduced in patients with creatinine clearance values ≤30 mL/min because high and/or prolonged plasma antibiotic concentrations can occur from usual doses in such individuals. Cephalosporins, including SPC-Cefprozil, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function.

Prolonged use of SPC-Cefprozil may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Positive direct Coombs tests have been reported during treatment with cephalosporin antibiotics.

Cefprozil should be prescribed with caution in individuals with a history of gastrointestinal disease particularly colitis.

Special Populations

Use in Pregnancy

Reproduction studies have been performed in mice, rats, and rabbits at doses 14, 7 and 0.7 times the maximum human daily dose (1000 mg) based upon mg/m², and have revealed no evidence of harm to the fetus due to cefprozil. 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 the potential benefit justifies the potential risk.

Nursing Mothers

Less than 1.0% of a maternal dose is excreted in human milk. Caution should be exercised when cefprozil is administered to a nursing mother. Consideration should be given to temporary discontinuation of nursing and use of formula feeding.

Pediatric Use

The use of cefprozil in the treatment of acute sinusitis in these age groups is supported by evidence from adequate and well-controlled studies of cefprozil in adults and from pediatric pharmacokinetic studies.

Safety and effectiveness in children below the age of 6 months have not been established.

Accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.

Geriatric Use

Cefprozil has not been studied in the chronically ill or institutionalized elderly subjects. In these subjects, drug clearance by the kidney may be reduced even with normal serum creatinine clearance. Reduction of dose or of frequency of administration may be indicated.

ADVERSE REACTIONS

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The adverse reactions to cefprozil are similar to those observed with other orally administered cephalosporins. Cefprozil was usually well tolerated in controlled clinical trials. Approximately 2% of patients discontinued cefprozil therapy due to adverse events.

Most Common Clinical Trial Adverse Drug Reactions (> 1%)

Less Common Clinical Trial Adverse Drug Reactions (<1%)

Hepatobiliary: As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely.

Hypersensitivity: Erythema (0.1%), pruritus (0.3%) and urticaria (0.07%). Such reactions have been reported more frequently in children than in adults. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy.

Gastrointestinal: Abdominal pain (0.9%)

CNS: Dizziness, hyperactivity, headache, nervousness, insomnia, confusion, and drowsiness have been reported rarely (<1%) and causal relationship is uncertain. All were reversible.

Other: Genital pruritus (0.8%) and vaginitis (0.7%).

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory abnormalities

Transitory abnormalities in clinical laboratory test results of uncertain etiology have been reported during clinical trials as follows:

Hepatobiliary: Elevations of AST, ALT, alkaline phosphatase, and bilirubin.

Hematopoietic: Transiently decreased leukocyte count and eosinophilia.

Renal: Slight elevations in BUN and serum creatinine.

Post Market Adverse Drug Reactions

Adverse reactions reported from post-marketing experience and which were not seen in the clinical trials include anaphylaxis (see WARNINGS), angioedema, serum sickness, colitis including pseudomembraneous colitis (see WARNINGS), erythema multiforme, fever, Stevens-Johnson syndrome, thrombocytopenia and exfoliative dermatitis. Tooth discoloration has been reported during post-marketing surveillance. The association between these events and SPC-Cefprozil administration is unknown.

Hepatotoxicity, including hepatitis, has been reported during post-marketing surveillance, including cases in which a causal role of cefprozil could not be excluded.

In addition to the adverse reactions listed above which have been observed in patients treated with cefprozil, the following adverse reactions and altered laboratory tests have been reported for cephalosporin-class antibiotics. Toxic epidermal necrolysis, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia (see WARNINGS), hemorrhage, prolonged prothrombin time, positive Coombs's tests, elevated LDH, pancytopenia, neutropenia, agranulocytosis.

Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment, when the dosage was not reduced (See DOSAGE AND ADMINISTRATION and OVERDOSAGE). If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing SPC-Cefprozil in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug- resistant bacteria.

DRUG INTERACTIONS

Drug-Drug Interactions

Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the area under the curve for cefprozil.

If an aminoglycoside is used concurrently with cefprozil, especially if high dosages of the former are used or if therapy is prolonged, renal function should be monitored because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics.

Drug/Laboratory Interactions

Cephalosporin antibiotics may produce a false positive reaction for glucose in the urine with copper reduction tests (Benedict's or Fehling's solution or with Clinitest tablets), but not with enzyme-based tests (glucose oxidase) for glycosuria. A false negative reaction may occur in the ferricyanide test for blood glucose. The presence of cefprozil in the blood does not interfere with the assay of plasma or urine creatinine by the alkaline picrate method.

DOSAGE AND ADMINISTRATION

SPC-Cefprozil (cefprozil) is administered orally (with or without food), in the treatment of infections due to susceptible bacteria in the following doses:

Duration of Therapy

Duration of therapy in the majority of clinical trials was 10 to 15 days. The duration of treatment should be guided by the patient's clinical and bacteriological response. In the treatment of acute uncomplicated cystitis, a 7 day oral therapy is usually sufficient. In the treatment of infections due to Streptococcus pyogenes, a therapeutic dosage of cefprozil should be administered for at least 10 days.

Renal Impairment

Cefprozil may be administered to patients with impaired renal function. No dosage adjustment is necessary for patients with creatinine clearance values > 30 mL/min. For those with creatinine clearance values ≤ 30 mL/min, 50% of the standard dose should be given at the standard dosing interval. Cefprozil is in part removed by hemodialysis; therefore, cefprozil should be

administered after the completion of hemodialysis.

OVERDOSAGE

For the most recent information in the management of a suspected drug overdose, contact your regional poison control centre or Health Canada's toll-free number, 1-844 POISON-X (1-844-764-7669).

Since no case of overdosage has been reported to date, no specific information on symptoms or treatment of overdosage is available. In animal toxicology studies, single doses as high as 5000 mg/kg were without serious or lethal consequences.

Cefprozil is eliminated primarily by the kidneys. In case of severe overdosage, especially in patients with compromised renal function, hemodialysis will aid in the removal of cefprozil from the body.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Cefprozil is a semi synthetic broad spectrum cephalosporin antibiotic intended for oral administration. It has in vitro activity against a broad range of gram positive and gram negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis.

Pharmacokinetics

Cefprozil is well absorbed following oral administration in both fasting and non-fasting subjects. The oral bioavailability of cefprozil is about 90%. The pharmacokinetics of cefprozil are not altered when administered with meals, or when co-administered with antacid.

Average plasma concentrations after administration of cefprozil to fasting subjects are shown in the following table. Urinary recovery accounts for 60% of the administered dose.

* Data represent mean values from 12 healthy, young male volunteers.

During the first four-hour period after drug administration, the average urine concentrations following the 250 mg, 500 mg, and 1 g doses were approximately 170 mcg/mL, 450 mcg/mL and 600 mcg/mL, respectively.

The average plasma half-life in normal subjects is 1.3 hours. Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 mcg/mL to 20 mcg/mL. There is no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1 g every 8 hours for 10 days.

Special Populations and Conditions

Renal Insufficiency

In patients with reduced renal function, the plasma half-life prolongation is related to the degree of the renal dysfunction and may be prolonged up to 5.2 hours. In patients with complete absence of renal function, the plasma half-life of cefprozil averaged 5.9 hours. The half-life is shortened during hemodialysis to 2.1 hours. Excretion pathways in patients with markedly impaired renal function have not been determined. (See WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency

In patients with impaired hepatic function, no differences in pharmacokinetic parameters were observed, when compared to normal control subjects.

Geriatrics

Following administration of a single 1 g dose of cefprozil, the average AUC observed in healthy elderly subjects (≥65 years of age) was approximately 35-60% higher than that of healthy young adults and the average AUC in females was approximately 15-20% higher than in males. The magnitude of these age and gender-related variations in the pharmacokinetics of cefprozil are not sufficient to necessitate dosage adjustments.

Pediatrics

Comparable pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months - 12 years) and adults following oral administration. The maximum plasma concentrations are achieved at 1 - 2 hours after dosing. The plasma elimination half-life is approximately 1.5 hours. The AUC of cefprozil to pediatric patients after 7.5, 15 and 30 mg/kg doses is similar to that observed in normal adult subjects after 250, 500 and 1000 mg doses, respectively.

STORAGE AND STABILITY

Store at room temperature (15 to 30°C). Protect from light and excessive humidity.

DOSAGE FORMS, COMPOSITION AND PACKAGING

In addition to the active ingredient, cefprozil, each tablet also contains the non-medicinal ingredients hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, talc and titanium dioxide.

SPC-Cefprozil (cefprozil) tablets 250 mg are white to off-white oval, film coated tablets debossed with 'RB 41' on one side and plain on the other side.

SPC-Cefprozil tablets 500 mg are white to off-white oval, film coated tablets debossed with 'RB 42' on one side and plain on the other side.

SPC-Cefprozil 250 mg and 500 mg tablets are available in bottles of 100.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Cefprozil

Chemical Name: (6R,7R)-7-[(R)-2-amino-2-(p-hydroxyphenyl) acetamido]-8-oxo-3-propenyl-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Molecular formula (molecular mass): C₁₈H₁₉N₃0₅S•H₂O (407.45) g/mol

Structural Formula:

N

S

N

HO O

CH₃

H H

O

O

H

HO

H₂N H

H₂O.

Physicochemical properties: Cefprozil is a cis and trans isomeric mixture in a 9:1 ratio. It is a white to yellow colored crystalline powder with a melting point of 197°C. It is slightly soluble in water, practically insoluble in alcohol. Cefprozil has an apparent octanol / water partition coefficient of 0.01 at pH 6 and 22°C.

CLINICAL TRIALS

Comparative Bioavailability Studies

A blinded, randomized, single-dose, crossover comparative bioequivalence study was performed in 24 healthy male and female volunteers under fasting conditions for SPC-Cefprozil Tablets. The study compared the rate and extent of absorption of a single oral dose (1 x 500 mg) of SPC-Cefprozil tablets or Cefzil^® (cefprozil) (Bristol-Myers Squibb Canada Inc.) tablets. A summary of the pharmacokinetic parameters is given in the tables below:

^* SPC-Cefprozil Tablets 500 mg Sun Pharma Canada Inc. ^† Cefzil ^TM (cefprozil) Tablets 500 mg Bristol-Myers Squibb Canada Inc. ^§ Expressed as the arithmetic mean (CV%) only.

**Based on least square estimate.

MICROBIOLOGY

Cefprozil has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis. Cefprozil is more stable than cefaclor to beta lactamase hydrolysis by plasmid-encoded penicillinases including TEM and S. aureus enzymes as well as class Ia, Ib, Ic and Id enzymes.

The in vitro activity of cefprozil against clinical isolates is shown below:

Cefprozil is inactive against methicillin resistant Staphylococci, Enterococcus faecium, most strains of Acinetobacter, Enterobacter, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas and Serratia.

Susceptibility tests

Diffusion Techniques

Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. Interpretation involves correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for cefprozil.

The class disk for cephalosporin susceptibility testing (the cephalothin disk) is not appropriate

because of spectrum differences with cefprozil. The 30 mcg cefprozil disk should be used for all in vitro testing of isolates and should be interpreted according to the following criteria:

A report of "Susceptible" indicates that the pathogen is likely to be inhibited by generally achievable blood concentrations. A report of "Moderately Susceptible" indicates that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained. A report of "Resistant" indicates that the achievable concentration of the antibiotic is unlikely to be inhibitory.

Standardized procedures require the use of laboratory control organisms. The 30-mcg cefprozil disk should give the following zone diameters:

Dilution Techniques

Use a standardized dilution method (broth, agar, microdilution) or equivalent with cefprozil powder. The MIC values obtained should be interpreted according to the following criteria:

As with standard diffusion techniques, dilution techniques require the use of laboratory control organisms. Standard cefprozil powder should give the following MIC values:

TOXICOLOGY Acute Toxicity

Estimated

LD50 (mg/kg)

* CMC = Carboxymethyl cellulose

** Includes 5 neonates, 5 weanlings and 5 adults

No deaths occurred.

The only sign of toxicity in mice was a decreased body weight gain in males given cefprozil by oral gavage.

There were no signs of toxicity in neonatal (5 days of age), weanling (23 days of age) or adult (7 weeks) rats following administration of cefprozil 5000 mg/kg by oral gavage. Signs of toxicity in monkeys included soft or liquid stools and sporadically disturbed appetite.

Subacute Toxicity

*CMC = carboxymethylcelIulose

Chronic Toxicity

*CMC = carboxymethyl cellulose

Reproduction and Teratology

*Suspending vehicle: Sodium carboxymcthylcellulose 5%

Reproduction and Teratology (cont’d)

*Suspending vehicle: Sodium carboxymethylcellulose 0.5%

Special Studies

There were no testicular changes noted in special screening studies conducted with cefprozil.

No evidence of nephrotoxicity or systemic toxicity was apparent in rabbits given cefprozil by oral gavage with single doses up to 1000 mg/kg. Cefprozil administered orally at doses up to 500 mg/kg/day to neonatal male rats on postnatal days 6 through 11 resulted in neither testicular toxicity nor systemic toxicity.

In rats given either cefprozil (cis/trans isomers in a 9:1 ratio), the cis isomer or the trans isomer at 1500 mg/kg/day by oral gavage for one month, alopecia, salivation, reduced body weight in males, decreased litter weight and increased kidney weight were observed. No clinical pathology or gross or microscopic pathology was observed.

There were no remarkable differences in the toxicity of the cis isomer, the trans isomer, or cefprozil (the isomeric mixture) in rats given 1500 mg/kg/day by oral gavage for one month.

Mutagenicitv and Genotoxicity

Cefprozil (cis isomer) was not mutagenic in the Ames Microbial mutagen test with S. thyphimurium and the microbial reverse mutation assay using E. coli. Cefprozil (cis/trans isomers) was also not mutagenic in the forward gene mutation assay using Chinese Hamster ovary cells.

Unscheduled DNA synthesis in rat hepatocytes in vitro and clastogenecity in Chinese Hamster ovary cells in vitro or in rat bone marrow cells in vivo were unaffected by cefprozil (cis/trans isomers).

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