Apo-Cefprozil (Apotex, 125 mg, 250 mg) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

APO-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 β-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 APO-

CEFPROZIL and other antibacterial drugs, APO-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

APO-CEFPROZIL (cefprozil) is contraindicated in patients with known allergy to the cephalosporin class of antibiotics or to any component of the cefprozil preparations.

WARNINGS AND PRECAUTIONS

General

Prolonged use of APO-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, APO-CEFPROZIL should be discontinued and appropriate therapy and/or measures should be taken.

Gastrointestinal

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of “antibiotic-associated colitis”. Pseudomembranous colitis is associated with the use of broad spectrum antibiotics (including macrolides, semisynthetic penicillins and cephalosporins) and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an oral antibacterial drug effective against C. difficile (e.g., metronidazole).

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 APO-CEFRPOZIL (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 APO-CEFPROZIL, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function.

Special Populations

Pregnant Women

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 Women

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.

Pediatrics

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.

Geriatrics

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 Trail 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: Confusion, dizziness, drowsiness, headache, hyperactivity, insomnia and nervousness. Causal relationship is uncertain and 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 serum sickness, pseudomembraneous colitis, Stevens-Johnson syndrome and exfoliative dermatitis. The association between these events and cefprozil administration is unknown.

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. Anaphylaxis, erythema multiforme, toxic epidermal necrolysis, fever, renal dysfunction, toxic nephropathy, aplastic anemia, hemolytic anemia, hemorrhage, prolonged prothrombin time, positive Coombs’s tests, elevated LDH, pancytopenia, neutropenia, agranulocytosis, thrombocytopenia.

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 APO-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

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

Adults (13 years and older)

Upper respiratory tract (Pharyngitis / Tonsillitis) 500 mg q24h Acute sinusitis 250 mg or 500 mg q12h

Skin & skin structure 250 mg ql2h or 500 mg q24h Uncomplicated urinary tract 500 mg q24h

Children (2 years - 12 years)

Skin & skin structure 20 mg/kg q24h

* Ages given are a useful guide only. Correct dosage should be determined by weight.

Infants and children (6 months - 12 years)

Otis media 15 mg/kg ql2h

Upper respiratory tract (pharyngitis / tonsillitis) 7.5 mg/kg ql2h

• * Ages given are a useful guide only. Correct dosage should be determined by weight.

Acute sinusitis 7.5 mg/kg q12h or 15 mg/kg q12h

Follow dosing instructions as for otitis media and upper respiratory tract presented above.

The maximum pediatric daily dose should not exceed the maximum daily dose recommended for adults (i.e. 1 g per day).

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

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 µg/mL, 450 µg/mL and 600 µg/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 µg/mL to 20 µg/mL. There is no evidence of accumulation of cefbrozil 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 ADMINSTRATION).

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

APO-CEFPROZIL powder for oral suspension should be stored at room temperature (15°C – 30°C).

RECONSTITUTION

Prior to dispensing, the pharmacist must constitute the dry powder with water as follows:

STORAGE OF RECONSTITUTED SUSPENSION

The reconstituted APO-CEFPROZIL oral suspension must be stored in the refrigerator (2ºC - 8ºC) for up to 14 days. Keep container tightly closed. Discard unused portion after 14 days.

DOSAGE FORMS, COMPOSITION AND PACKAGING

In addition to the active ingredient, cefprozil, the powder for oral suspension also contains the non-medicinal ingredients xanthan gum, FD&C red #40, artificial tutti frutti flavour, saccharin sodium and sucrose.

APO-CEFPROZIL 125 mg/5 mL Oral Suspension: Off-white powder which forms pink opaque suspension with a fruity odour, containing 125 mg of cefprozil (on anhydrous basis) per 5 mL dose. Powder for oral suspension available in bottles of 50 mL, 75 mL and 100 mL.

APO-CEFPROZIL 250 mg/5 mL Oral Suspension: Off-white powder which forms pink opaque suspension with a fruity odour, containing 250 mg of cefprozil (on anhydrous basis) per 5 mL dose. Powder for oral suspension available in bottles of 50 mL, 75 mL and 100 mL.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Cefprozil

Chemical Name: 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 7-[[amino(4-hydroxyphenyl)acetyl]amino]-8- oxo-3-(1-propenyl)-, monohydrate, [6R- [6α,7β(R*)]]-

(6R, 7R)-7-[(R)-2-Amino-2-(p-

hydroxyphenyl)acetamido]-8-oxo-3-propenyl-5- thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Molecular formula and molecular weight: C₁₈H₁₉N₃0₅S·H₂O, anhydrous: 389.43,

monohydrate: 407.44

Structural Formula:

Physicochemical properties: Cefprozil is a Z and E isomeric mixture in a 9:1 ratio. It is a white to light yellow coloured crystalline powder with a melting point of 197°C. It is soluble in 1 N Hydrochloric acid and very slightly soluble in water. It is poorly soluble (<1 mg/mL) in acetone, chloroform, ethanol and isopropanol and has an approximate solubility of 11 mg/mL in methanol and

1.6 mg/mL in demethyl sulfoxide. Cefprozil has an apparent octanol/water partition coefficient of 0.01 at pH 6 and 22°C. It has a pH between 3.5 and 6.5, in a solution containing 5 mg per mL and pKa of 2.92 ± 0.50 and 6.93 ± 0.31 for pK_a1 and pK_a2 respectively. UV absorption bands (of a 0.015% solution in methanol) at λ_max = 205.36 nm (0.8326 ABS), 231.55 nm (0.6429 ABS) and 282.53 nm (0.5190 ABS). Maximum was observed at 205.36 nm.

CLINICAL TRIALS

Comparative Bioavailability Studies

A double blinded, randomized, two-way, single dose crossover comparative bioavailability study was performed on 15 healthy male and female volunteers under fasting conditions. The rate and extent of absorption of cefprozil was measured and compared following a single oral dose of APO-CEFPROZIL (Cefprozil) or CEFZIL oral suspension. The results from measured data are summarized in the following table.

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 µg 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-µg 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

• * 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 = Carboxymethylcellulose

Chronic Toxicity

• * CMC = Carboxymethylcellulose

Reproduction and Teratology

• * Suspending vehicle: Sodium carboxymethylcellulose 0.5%

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 cefrozil (the isomeric mixture) in rats given 1500 mg/kg/day by oral gavage for one month.

Mutagenicity 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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