JAMP AMOXI CLAV TABLET

Canada - English - Health Canada

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Active ingredient:
AMOXICILLIN (AMOXICILLIN TRIHYDRATE); CLAVULANIC ACID (CLAVULANATE POTASSIUM)
Available from:
JAMP PHARMA CORPORATION
ATC code:
J01CR02
INN (International Name):
AMOXICILLIN AND BETA-LACTAMASE INHIBITOR
Dosage:
250MG; 125MG
Pharmaceutical form:
TABLET
Composition:
AMOXICILLIN (AMOXICILLIN TRIHYDRATE) 250MG; CLAVULANIC ACID (CLAVULANATE POTASSIUM) 125MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
AMINOPENICILLINS
Product summary:
Active ingredient group (AIG) number: 0234720008; AHFS: 08:12.16.08
Authorization status:
APPROVED
Authorization number:
02508249
Authorization date:
2020-11-20

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Page 1 of 39

Product Monograph

including Patient Medication Information

Pr

JAMP Amoxi Clav

amoxicillin / clavulanate potassium tablets

House Standard

JAMP Amoxi Clav -250 tablets

250 mg amoxicillin (as trihydrate) and 125 mg clavulanic acid (as clavulanate potassium)

JAMP Amoxi Clav -500F tablets

500 mg amoxicillin (as trihydrate) and 125 mg clavulanic acid (as clavulanate potassium)

JAMP Amoxi Clav -875 tablets

875 mg amoxicillin (as trihydrate) and 125 mg clavulanic acid (as clavulanate potassium)

Combinations of penicillins, including beta-lactamase inhibitors

ATC code: J01CR02

JAMP Pharma Corporation

1310 rue Nobel

Boucherville, Québec

J4B 5H3.

Date of Approval:

November 19, 2020.

Submission Control No: 233779

Page 2 of 39

Product Monograph

Pr

JAMP Amoxi Clav

amoxicillin / clavulanate potassium tablets

Antibiotic and β-Lactamase Inhibitor

ACTION

Amoxicillin exerts a bactericidal action against sensitive organisms during the stage of active

multiplication through the inhibition of the biosynthesis of bacterial cell wall mucopeptides.

Clavulanic acid inhibits specific β-lactamases of some microorganisms and allows amoxicillin to

inhibit amoxicillin (ampicillin) resistant organisms which produce clavulanic acid sensitive β-

lactamases

Indications and Clinical Use

JAMP Amoxi Clav (amoxicillin / clavulanate potassium) is indicated for the treatment of the following

infections when caused by JAMP Amoxi Clav-susceptible strains of the designated bacteria.

Sinusitis when caused by β-lactamase producing strains of

H. influenzae or Moraxella (Branhamella) catarrhalis.

Otitis Media when caused by β-lactamase producing strains of

H. influenzae or Moraxella (Branhamella) catarrhalis.

Lower Respiratory Tract Infections when caused by β-lactamase producing strains of H.

influenzae, K. pneumoniae, S. aureus or Moraxella (Branhamella) catarrhalis.

Skin and Soft Tissue Infections when caused by β-lactamase producing strains of S.

aureus.

Urinary Tract Infections when caused by β-lactamase producing strains of

E. coli.

Page 3 of 39

While JAMP Amoxi Clav is indicated only for the conditions listed above, infections caused by

ampicillin (amoxicillin) susceptible organisms are also amenable to JAMP Amoxi Clav treatment

due to its amoxicillin content. Furthermore, mixed infections caused by organisms susceptible

ampicillin (amoxicillin) and β-lactamase producing organisms susceptible to JAMP Amoxi

Clav should

not require the addition of another antibiotic.

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

JAMP

Amoxi Clav and other antibacterial drugs, JAMP Amoxi Clav 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 data,

susceptibility

patterns, and local official antibiotic prescribing guidelines, may contribute to the

empiric

selection of therapy.

Contraindications

The use of JAMP Amoxi Clav is contraindicated in patients with a history of hypersensitivity to

penicillin, or cephalosporin group of β-lactams, or to any ingredients contained in the

preparation or component of the container. For a complete listing, see COMPOSITION and

AVAILABILITY OF DOSAGE FORMS.

JAMP Amoxi Clav is contraindicated in patients where infectious mononucleosis is either

suspected or

confirmed.

JAMP Amoxi Clav is contraindicated in patients with a previous history of amoxicillin and

clavulanate potassium-associated

jaundice/hepatic dysfunction.

Warnings

Serious and occasionally fatal hypersensitivity reactions, including angioedema,

anaphylactic/anaphylactoid and severe cutaneous adverse reactions (SCAR) (e.g., acute

generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS), toxic

epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms

(DRESS)) have been reported in patients on penicillin therapy, including amoxicillin and

clavulanate potassium

(see ADVERSE REACTIONS). Although these reactions

are more

frequent following parenteral therapy, they have occurred in patients receiving

penicillins orally.

Page 4 of 39

These reactions are more apt to occur in individuals with a history of

sensitivity to multiple

allergens. There have been reports of individuals with a history of

cephalosporin hypersensitivity

who have experienced severe reactions when treated with penicillins. Before initiating therapy

with JAMP Amoxi Clav, careful inquiry should be made concerning

previous hypersensitivity

reactions to penicillins, cephalosporins, or other allergens (see CONTRAINDICATIONS).

If an allergic reaction occurs, the administration of JAMP Amoxi Clav should be discontinued and

appropriate alternative therapy should be instituted. Serious anaphylactic/anaphylactoid

reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous

steroids and airway management, including intubation should also be used as indicated.

Abnormal prolongation of prothrombin time (increased international normalized ratio (INR)) has

been reported in patients receiving amoxicillin and clavulanate potassium and oral

anticoagulants. Appropriate monitoring

should be undertaken when anticoagulants are

prescribed concurrently. Adjustments in the

dose of oral anticoagulants may be necessary to

maintain the desired level of anticoagulation.

JAMP Amoxi Clav should be used with caution in patients with evidence of hepatic dysfunction.

Hepatic toxicity associated with the use of JAMP Amoxi Clav is usually reversible. On rare

occasions,

deaths have been reported (less than 1 death reported per estimated 4 million

prescriptions

worldwide). These have generally been cases associated with serious underlying

diseases or

concomitant medications (see CONTRAINDICATIONS and ADVERSE REACTIONS

- Liver).

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly

with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to

maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin

crystalluria (see OVERDOSAGE).

Susceptibility/Resistance

Development of Drug Resistant Bacteria

Prescribing JAMP Amoxi Clav 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.

Page 5 of 39

Precautions

General

Periodic assessment of renal, hepatic, and hematopoietic function should be made during

prolonged therapy with JAMP Amoxi Clav.

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind

during therapy with JAMP Amoxi Clav. If superinfection should occur (usually involving

Aerobacter,

Pseudomonas or Candida), the administration of JAMP Amoxi Clav should be

discontinued and

appropriate therapy instituted.

The occurrence of a morbilliform rash following the use of ampicillin in patients with infectious

mononucleosis is well documented

. This reaction has also been reported following the use of

amoxicillin

. A similar reaction would also be expected with amoxicillin and clavulanate

potassium.

Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.

Clostridium difficile-associated disease

Clostridium difficile -associated disease (CDAD) has been reported with the use of many

antibacterial agents, including amoxicillin and clavulanate potassium. 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. Clostridium 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

Page 6 of 39

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).

Renal

JAMP Amoxi Clav is excreted mostly by the kidney. In renal impairment, dosage adjustments

should

be made based on the maximum recommended level of amoxicillin (see DOSAGE

ADMINISTRATION).

Pregnancy

In a single study in women with preterm, premature rupture of the fetal membranes (pPROM), it

was reported that prophylactic treatment with amoxicillin and clavulanate potassium may be

associated with an increased

risk of necrotising enterocolitis in neonates. Use should be

avoided in pregnancy, unless

considered essential by the physician.

Nursing Mothers

Penicillins (including ampicillin) have been shown to be excreted in human breast milk. It is not

known whether clavulanic acid is excreted in breast milk. Caution should be exercised if

JAMP

Amoxi Clav is to be administered to a nursing mother.

Drug Interactions

In common with other broad spectrum antibiotics, amoxicillin-clavulanate may reduce the

efficacy of combined oral contraceptives by altering the gut-flora to result in lower estrogen

reabsorption. Concomitant use of probenecid is not recommended, and may result in increased

and prolonged blood levels of amoxicillin, but not of clavulanic acid.

Increases in prothrombin time, INR or bleeding have been reported in patients maintained on

coumarin anticoagulants, such as acenocoumarol and warfarin and then coadministered

amoxicillin or amoxicillin and clavulanate potassium. If coadministration is necessary, the

prothrombin time or INR should

be carefully monitored upon antibiotic addition or withdrawal.

Reduction in the median pre-dose concentration of the mycophenolic acid (MPA), the active

metabolite of mycophenolate mofetil, of approximately 54% has been reported in renal

transplant recipients in the days immediately following the commencement of oral amoxicillin-

Page 7 of 39

clavulanic acid.

These reductions in pre-dose MPA concentrations from baseline (mycophenolate mofetil alone)

tended to diminish with continued antibiotic use and cease after discontinuation. The change in

pre-dose level may not accurately represent changes in overall MPA exposure; therefore,

clinical relevance of these observations is unclear.

Adverse Reactions

The following adverse reactions have been observed during therapy with amoxicillin and

clavulanate potassium:

Gastrointestinal

Diarrhea has been reported very commonly in adults and commonly in children. Nausea and

vomiting have been reported commonly in adults and children. Mucocutaneous candidiasis

has been reported commonly. Abdominal cramps, flatulence,

constipation, anorexia, colic

pain, acid stomach, intestinal candidiasis, antibiotic-associated

colitis (including

pseudomembranous colitis and haemorrhagic colitis) have been reported

rarely. If

gastrointestinal reactions

are evident, they may be reduced by taking amoxicillin and

clavulanate potassium at the start of the meal.

A U.S./Canadian clinical trial compared a 10-day amoxicillin and clavulanate potassium b.i.d.

regimen (45/6.4 mg/kg/day

q12h) with a 10-day amoxicillin and clavulanate potassium t.i.d.

regimen (40/10 mg/kg/day q8h) in 575 patients with acute

otitis media, aged 2 months to 12

years. The incidence of diarrhea was significantly lower in

patients who received the b.i.d.

regimen compared to patients who received the t.i.d. regimen

(9.6% vs. 26.7%; p<0.001).

Significantly fewer patients who received the b.i.d. regimen

withdrew due to diarrhea compared

to patients receiving the t.i.d. regimen (2.8% vs. 7.6%;

p=0.009). The incidence of

related/possibly related diaper rash was also lower in patients who

received the b.i.d. regimen

compared to patients who received the t.i.d. regimen (3.1% vs. 6.6%; p =0.054).

Data from two pivotal studies in 1,191 patients treated for either lower respiratory tract infections

or complicated urinary tract infections compared a regimen of 875 mg amoxicillin / 125 mg

clavulanate potassium tablets q12h

with 500 mg amoxicillin / 125 mg clavulanate potassium

tablets dosed q8h. The most frequently reported adverse event was diarrhea; incidence rates

were similar (14.9%

and 14.3% respectively) for the 875 mg q12h and 500 mg q8h dosing

Page 8 of 39

regimens. However,

there was a statistically significant difference in rates of moderate/severe

diarrhea between the

regimens: 3.4% for 875 mg q12h dosing versus 5.9% for the 500 mg q8h

dosing.

Black hairy tongue has been reported very rarely. Tooth discolouration has been reported very

rarely in children and adults. Good oral hygiene may help to prevent tooth discolouration as it

can often be removed by brushing.

Hypersensitivity Reactions

Erythematous macropapular rash, urticaria, anaphylaxis, hypersensitivity vasculitis and pruritus.

A morbilliform rash in patients with mononucleosis. Rarely erythema multiforme and Stevens-

Johnson syndrome (SJS) have been reported. Other reactions including angioedema, toxic

epidermal necrolysis (TEN), bullous exfoliative dermatitis, and acute generalised exanthematous

pustulosis (AGEP) as in the case of other β-lactam antibiotics, have been seen rarely.

Interstitial nephritis can occur rarely. Drug reaction with eosinophilia and systemic symptoms

(DRESS) has also been reported (see WARNINGS).

Note

If any hypersensitivity dermatitis reaction occurs, treatment with JAMP Amoxi Clav should be

discontinued.

Liver

Transient hepatitis and cholestatic jaundice have been reported rarely. These events have

been noted with other penicillins and cephalosporins. The hepatic events associated with

amoxicillin and clavulanate potassium may be severe, and occur predominantly in males and

elderly patients and may be

associated with prolonged treatment. These events have been

very rarely reported in children.

Signs and symptoms usually occur during or shortly after

treatment, but in some cases may not

become apparent until several weeks after treatment has

ceased. The hepatic events are

usually reversible. However, in extremely rare circumstances,

deaths have been reported.

These have almost always been cases associated with serious underlying disease or

concomitant medications. Moderate rises in AST (SGOT), alkaline phosphatase, lactic

dehydrogenase, and/or ALT (SGPT) have been noted in patients treated with ampicillin class

antibiotics. The significance of these findings is unknown.

Page 9 of 39

Hemic and Lymphatic Systems

As with other β-lactams, anemia, hemolytic anemia, thrombocytopenia, thrombocytopenic

purpura, eosinophilia, leukopenia, lymphocytopenia, basophilia, slight increase in platelets,

neutropenia and agranulocytosis have been reported rarely during therapy with the penicillins.

These reactions are usually reversible on discontinuation of therapy and are believed to be

hypersensitivity phenomena. Prolongation of bleeding time and prolongation of prothrombin

time have also been reported.

CNS Effects

Aseptic meningitis.

Convulsions may occur with impaired renal function or in those receiving high doses.

Renal and Urinary Tract Disorders

Very rare: crystalluria and interstitial nephritis (see SYMPTOMS and TREATMENT OF

OVERDOSAGE).

Other

Vaginitis, headache, bad taste, dizziness, malaise, glossitis, and stomatitis.

Symptoms and Treatment of Overdosage

Activated charcoal may be administered to aid in the removal of unabsorbed drug. General

supported measures are also recommended.

Many patients have been asymptomatic following overdosage or have experienced primarily

gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash,

hyperactivity, or drowsiness have also been observed in a small number of patients. Amoxicillin

crystalluria, in some cases leading to renal failure, has been observed (see WARNINGS for

use).

In the case of overdosage, discontinue JAMP Amoxi Clav, treat symptomatically, and institute

supportive measures as required. If gastrointestinal symptoms and disturbance of the fluid

electrolyte balances are evident, they may be treated symptomatically. JAMP Amoxi Clav

For management of a suspected drug overdose, contact your regional Poison Control Centre.

Page 10 of 39

can be

removed from the circulation by haemodialysis. A prospective study of 51 pediatric

patients at

a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin

are not

associated with significant clinical symptoms and do not require gastric emptying.

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of

patients after overdosage with amoxicillin. Renal impairment appears to be reversible

with

cessation of drug administration. High blood levels may occur more readily in patients with

impaired renal function because of decreased renal clearance of both amoxicillin and

clavulanate.

Both amoxicillin and clavulanate are removed from the circulation by hemodialysis

Dosage and Administration

While JAMP Amoxi Clav can be given without regard to meals, absorption of clavulanic acid

when

taken with food is greater relative to the fasted state. Dosing in the fasted or fed state

minimal effect on the pharmacokinetics of amoxicillin. The safety and efficacy of

amoxicillin and clavulanate potassium

have been established in clinical trials where

amoxicillin and clavulanate potassium was taken without regard to meals.

To minimize potential gastrointestinal intolerance, administer at the start of a meal.

Dosage adjustment in renal impairment is based on the maximum recommended level of

amoxicillin. JAMP Amoxi Clav presentations with a 7:1 ratio of amoxicillin:clavulanate (i.e. the

JAMP Amoxi Clav -875 tablets) should be used

only in patients with a creatinine clearance of

more than 30 ml/min (see Renal Impairment and

Hemodialysis).

Adults

N.B. Since both the JAMP Amoxi Clav 250/125 mg and JAMP Amoxi Clav 500/125 mg tablets

contain the same amount of clavulanic acid (125 mg as the potassium salt), two JAMP Amoxi

Clav 250/125 mg tablets are not equivalent to one JAMP Amoxi Clav 500/125 mg tablet.

Therefore, two JAMP Amoxi Clav 250/125 mg tablets should not be substituted for one JAMP

Amoxi Clav 500/125 mg tablet.

For mild to moderate infections, the usual adult dose is 1 JAMP Amoxi Clav 500/125 mg tablet

every 12 hours or 1 JAMP Amoxi Clav 250/125 mg tablet every 8 hours. For more severe

infections (including chronic and recurrent urinary tract infections

and infections of the lower

Page 11 of 39

respiratory tract), the dose should be 1 JAMP Amoxi Clav 875/125 mg tablet

every 12 hours or 1

JAMP Amoxi Clav 500/125 mg tablet every 8 hours.

The tablets should not be split or divided.

Children weighing more

than 38 kg should be dosed according to the adult

recommendations.

Renal Impairment

Adults

Creatinine clearance greater than

30 ml/min

No adjustment necessary.

Creatinine clearance 10 to

30 ml/min

1 times 500/125 mg given twice daily.

Creatinine clearance less than

10 ml/min

1 times 500/125 mg given once daily.

Haemodialysis

Adults

One 500F (500/125 mg) tablet every 24 h, PLUS 1 500F tablet during dialysis, to be repeated at

the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are

decreased).

875 (875/125 mg) tablets (7:1 ratio amoxicillin:clavanulate) should only be used in patients with

a creatinine clearance of more than 30 ml/min.

Page 12 of 39

Pharmaceutical Information

Drug Substance

Proper Name:

amoxicillin / clavulanate potassium

Amoxicillin

Chemical Name:

Trihydrate of 6-[(-)-α-amino-4-hydroxy-

phenylacetamido]-penicillanic acid

Structural Formula:

Molecular Formula:

S.3H

Molecular Weight:

419.47 g/mol (trihydrate)

365.41 g/mol (anhydrous)

Description:

Amoxicillin trihydrate is a white or slightly off-white highly

hygroscopic powder.

Clavulanate Potassium

Chemical Name:

Potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7- oxo-4-oxa-1-

azabicyclo[3,2,0]-heptane-2-carboxylate

Structural Formula:

Page 13 of 39

Molecular Formula:

Molecular Weight:

199.16 g/mol (free acid)

237.25 g/mol (potassium salt)

Description:

A white to pale yellow powder.

Composition

JAMP Amoxi Clav tablets contain amoxicillin as the trihydrate and

clavulanic acid as the

potassium salt in a ratio of 2:1 for the JAMP Amoxi Clav -250 tablet, a ratio of 4:1 for the JAMP

Amoxi Clav -500F tablet and a ratio of 7:1 for the JAMP Amoxi Clav -875 tablet.

JAMP Amoxi Clav -250 mg tablets:

Each debossed white to off white oval film-coated tablet contains 250 mg amoxicillin as

trihydrate and 125 mg of clavulanic acid as the potassium salt (in a ratio of 2:1) and the

following non-medicinal ingredients: microcrystalline cellulose, croscarmellose sodium, colloidal

anhydrous silica, magnesium stearate, ethyl cellulose, hypromellose, propylene glycol, SDA 3A

Alcohol 27 CFR, titanium dioxide and hydroxypropyl cellulose.

JAMP Amoxi Clav -500F tablets:

Each scored, debossed white to off white oval film-coated tablet contains 500 mg amoxicillin as

the trihydrate and 125 mg of clavulanic acid as the potassium salt (in a ratio of 4:1) and the

following non-medicinal ingredients: microcrystalline cellulose, croscarmellose sodium, colloidal

anhydrous silica, magnesium stearate, ethyl cellulose, hypromellose, propylene glycol, SDA 3A

Alcohol 27 CFR, titanium dioxide and hydroxypropyl cellulose.

JAMP Amoxi Clav -875 tablets:

Each scored, debossed white to off white capsule-shaped tablet contains 875 mg amoxicillin as

the trihydrate and 125 mg of clavulanic acid as the potassium salt (in a ratio of 7:1) and the

Page 14 of 39

following non-medicinal ingredients: microcrystalline cellulose, croscarmellose sodium, colloidal

anhydrous silica, magnesium stearate, ethyl cellulose, hypromellose, propylene glycol, SDA 3A

Alcohol 27 CFR, titanium dioxide and hydroxypropyl cellulose.

Stability and Storage Recommendations

Store in a dry place at room temperature (15°C – 25°C). Store in the original container. Do not

remove desiccant.

Availability of Dosage Forms

JAMP Amoxi Clav is available in tablets.

JAMP Amoxi Clav -250 tablets:

Amoxicillin and Clavulanate Potassium Tablets 250/125 mg are immediate-release, White to off

white colored, oval shaped film coated tablets, debossed with 'AC 250' on one side and plain on

other side. Available in bottles of 100 tablets.

JAMP Amoxi Clav -500 tablets:

Amoxicillin and Clavulanate Potassium Tablets 500/125 mg are immediate-release, White to off

white colored, oval shaped film coated tablets, debossed with 'AC 500' with score line in between

'AC' and '500' on one side and plain on other side. Available in bottles of 100 tablets.

JAMP Amoxi Clav -875 tablets:

Amoxicillin and Clavulanate Potassium Tablets 875/125 mg are immediate-release, White to off

white colored, capsule shaped film coated tablets, debossed with 'AC 875' with score line in

between 'AC' and '875' on one side and plain on other side. Available in bottles of 100 tablets.

Page 15 of 39

CLINICAL TRIALS

Comparative Bioavailability Study

A double blinded, balanced, randomized, two-treatment, two-sequence, four-period, full replicate,

cross-over, single-dose, oral bioequivalence study of Amoxicillin and Clavulanate Potassium Tablets

500/125 mg (JAMP Pharma Corporation) and

CLAVULIN

- 500F (amoxicillin and clavulanate

potassium) Tablets (GlaxoSmithKline Inc.) was conducted in 44 healthy, adult, male human subjects

under fasting conditions.

A summary of the comparative bioavailability data from the 44 male subjects is presented in following

table

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Amoxicillin

(1 x 500/125 mg)

From measured data

uncorrected for potency

Geometric Mean**

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

90% Confidence

Interval

(hr. ng/mL)

27879.32

29353.50 (29.4)

28022.56

29476.10 (29.3)

99.5

94.7 - 104.5

(hr. ng/mL)

28180.17

29668.59 (29.4)

28319.86

29788.84 (29.3)

99.5

94.8 - 104.5

(ng/mL)

7699.04

8095.46 (30.2)

7979.26

8440.25 (31.6)

96.5

90.8 - 102.5

2.67 (1.25-5.00)

2.33 (1.00-5.00)

1.60 (16.4)

1.59 (14.9)

Expressed as Geometric Least Squares Means.

Amoxicillin and Clavulanate Potassium Tablets 500/125 mg (JAMP Pharma Corporation, Canada).

† Pr

CLAVULIN

- 500F (amoxicillin and clavulanate potassium) Tablets (GlaxoSmithKline Inc.) and

purchased in Canada.

Expressed as the median (range)

Expressed as the arithmetic mean (CV%) only

Page 16 of 39

Clavulanic acid

(1 x 500/125 mg)

From measured data

uncorrected for potency

Geometric Mean**

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

90% Confidence

Interval

(hr. ng/mL)

5924.50

6429.124 (39.2)

6269.52

6782.690 (36.9)

94.5

88.3 - 101.2

(hr. ng/mL)

5939.51

6445.470 (39.2)

6286.34

6800.750 (36.9)

94.5

88.2 - 101.2

(ng/mL)

2164.00

2374.85 (42.1)

2287.21

2512.83 (42.4)

94.6

87.4 - 102.4

1.50

(0.75-3.00)

1.50

(0.75-3.50)

1.26 (13.5)

1.25 (14.2)

Expressed as Geometric Least Squares Means.

Amoxicillin and Clavulanate Potassium Tablets 500/125 mg (JAMP Pharma Corporation, Canada).

† Pr

CLAVULIN

- 500F (amoxicillin and clavulanate potassium) Tablets (GlaxoSmithKline Inc.) and

purchased in Canada.

Expressed as the median (range)

Expressed as the arithmetic mean (CV%) only

Comparative Bioavailability Study

A double blinded, balanced, randomized, two-treatment, two-sequence, four-period, full replicate,

cross-over, single-dose, oral bioequivalence study of Amoxicillin and Clavulanate Potassium Tablets

875/125 mg (JAMP Pharma Corporation) and

CLAVULIN

- 875 (amoxicillin and clavulanate

potassium) Tablets (GlaxoSmithKline Inc.) was conducted in 44 healthy, adult, human male subjects

under fasting conditions.

A summary of the comparative bioavailability data from the 43 male subjects is presented in following

table.

Page 17 of 39

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

Amoxicillin

(1 x 875/125 mg)

From measured data

uncorrected for potency

Geometric Mean**

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

90% Confidence

Interval

(hr. ng/mL)

48091.47

49764.76 (26.1)

50318.85

51385.69 (22.6)

95.6

90.4 - 101.0

(hr. ng/mL)

48611.05

50323.10 (26.3)

50838.07

51921.39 (22.7)

95.6

90.4 - 101.1

(ng/mL)

13250.77

13790.28 (29.3)

13983.95

14384.61 (23.4)

94.8

90.2 - 99.5

2.67 (1.00 - 5.00)

2.33 (1.00 - 5.00)

1.58 (16.2)

1.60 (15.4)

Expressed as Geometric Least Squares Means.

Amoxicillin and Clavulanate Potassium Tablets 875/125 mg (JAMP Pharma Corporation, Canada).

† Pr

CLAVULIN

- 875 (amoxicillin and clavulanate potassium) Tablets (GlaxoSmithKline Inc.) and

purchased in Canada.

Expressed as the median (range)

Expressed as the arithmetic mean (CV%) only

Page 18 of 39

Clavulanic acid

(1 x 875/125 mg)

From measured data

uncorrected for potency

Geometric Mean**

Arithmetic Mean (CV %)

Parameter

Test

Reference

% Ratio of

Geometric

Means

90% Confidence

Interval

(hr. ng/mL)

7170.65

7951.22 (40.6)

7158.67

8110.86 (40.0)

100.2

91.4 - 109.8

(hr. ng/mL)

7185.27

7966.78 (40.6)

7173.41

8125.48 (40.0)

100.2

91.4 - 109.8

(ng/mL)

2766.35

3232.99 (50.0)

2753.42

3281.74 (48.5)

100.5

89.4 - 112.8

1.50 (0.75 - 4.00)

1.50 (0.75 - 3.00)

1.19 (10.2)

1.21 (11.6)

Expressed as Geometric Least Squares Means.

Amoxicillin and Clavulanate Potassium Tablets 875/125 mg (JAMP Pharma Corporation, Canada).

† Pr

CLAVULIN

- 875 (amoxicillin and clavulanate potassium) Tablets (GlaxoSmithKline Inc.) and

purchased in Canada.

Expressed as the median (range)

Expressed as the arithmetic mean (CV%) only

Page 19 of 39

Microbiology

In the list below, organisms are categorised according to their in vitro susceptibility to

amoxicillin-clavulanate based mainly on studies published during 2001-2011.

Table 1

In vitro susceptibility of micro-organisms to amoxicillin-clavulanate

Where clinical efficacy of amoxicillin-clavulanate has been demonstrated in

clinical trials this is indicated with an asterisk (*).

Organisms that do not produce beta-lactamase are identified (with

). If an

isolate is susceptible to amoxicillin, it can be considered susceptible to

amoxicillin-clavulanate.

Commonly susceptible species

Gram-positive aerobes:

Enterococcus faecalis

Streptococcus bovis

Streptococcus pyogenes

Streptococcus agalactiae

Streptococcus spp. (other β-hemolytic)

Staphylococcus aureus (methicillin susceptible)*

Staphylococcus saprophyticus (methicillin susceptible)

Coagulase negative staphylococcus (methicillin susceptible)

Gram-negative aerobes:

Haemophilus influenzae*

Haemophilus parainfluenzae

Moraxella catarrhalis*

Pasteurella multocida

Proteus mirabilis

Gram positive anaerobes:

Clostridium spp.

Peptostreptococcus spp.

Gram-negative anaerobes:

Eikenella corrodens

Fusobacterium spp.

Porphyromonas spp.

Prevotella spp.

Page 20 of 39

Species for which acquired resistance may be a problem

Gram-positive aerobes:

Streptococcus pneumoniae

Viridans group streptococcus

Gram-negative aerobes:

Escherichia coli*

Klebsiella oxytoca

Klebsiella pneumoniae*

Klebsiella spp.

Proteus vulgaris

Salmonella spp.

Shigella spp.

Gram-negative anaerobes:

Bacteroides fragilis

Bacteroides spp.

Bacteroides thetiotamicron

Inherently resistant organisms

Gram-positive aerobes:

Enterococcus faecium

Gram-negative aerobes:

Acinetobacter spp.

Aeromonas spp.

Citrobacter spp.

Enterobacter spp.

Hafnia alvei

Morganella morganii

Providencia rettgeri

Providencia stuartii

Pseudomonas spp.

Serratia marcescens

Page 21 of 39

Susceptibility Testing

Interpretive Criteria for Dilution and Disk Diffusion Testing

MIC and disk diffusion results should be interpreted according to Table 2 and are based on

CLSI

methodologies (CLSI M7-A9

and M2-A10

11

). The recommended dilution pattern utilizes

constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of

amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of

clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The disk procedure

uses

paper disks impregnated with 30 mcg amoxicillin/clavulanate potassium (20 mcg

amoxicillin plus

10 mcg clavulanate potassium).

A report of S (“Susceptible”) indicates that the antimicrobial is likely to inhibit growth of the

pathogen if the antimicrobial compound in the blood reaches the concentration usually

achievable.

A report of I (“Intermediate”) indicates that the result should be considered equivocal, and, if the

microorganism is not fully susceptible to alternative, clinically feasible antimicrobials, the test

should be repeated. This category implies possible clinical applicability in body sites where the

drug is physiologically concentrated or in situations where high doses of

antimicrobial can be

used. This category also provides a buffer zone that prevents small

uncontrolled technical factors

from causing major discrepancies in interpretation. A report of R

(“Resistant”) indicates that the

antimicrobial is not likely to inhibit growth of the pathogen if the

antimicrobial compound in the

blood reaches the concentration usually achievable; other therapy should be selected.

Page 22 of 39

Table 2

Susceptibility Test Result Interpretive Criteria for

Amoxicillin/Clavulanate Potassium

Pathogen

Minimum Inhibitory

Concentration (mcg/mL)

Disk Diffusion (Zone Diameter in

mm)

S

I

R

S

I

R

Haemophilus

influenzae

(Note 1)

≤ 4/2

applicable

(NA)

≥ 8/4

≥ 20

≤ 19

Enterobacteriaceae

≤ 8/4

16/8

≥ 32/16

≥ 18

14 to 17

≤ 13

Staphylococcus

aureus

(Note 2)

≤ 4/2

≥ 8/4

≥ 20

≤ 19

Streptococcus

pneumoniae

(nonmeningitis

isolates)

≤ 2/1

≥ 8/4

(Note 3)

Note 1: β-lactamase–negative, ampicillin-resistant H. influenzae isolates must be considered resistant to

amoxicillin/clavulanate potassium

Note 2: Staphylococci which are susceptible to amoxicillin/clavulanate potassium but resistant to

methicillin or oxacillin must be considered as resistant

Note 3: Susceptibility of S. pneumoniae should be determined using a 1-mcg oxacillin disk. Isolates with oxacillin

zone sizes of ≥ 20 mm are susceptible to amoxicillin/clavulanate potassium. An amoxicillin/clavulanate potassium

MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of ≤ 19 mm.

Quality Control Reference Ranges

Standardized susceptibility test procedures require the use of quality control microorganisms to

determine the performance of the test procedures. The expected quality control results based

on CLSI MIC and disk diffusion methods are shown in Table 3 (CLSI M100-S21

Table 3

Acceptable Quality Control Ranges for Amoxicillin/Clavulanate Potassium

Quality Control Organism

Minimum Inhibitory

Concentration Range

(mcg/mL)

Disk Diffusion (Zone

Diameter Range in

mm)

Escherichia coli ATCC 35218

[H. influenzae quality control (Note 1)]

4/2 to 16/8

17 to 22

Escherichia coli ATCC 25922

2/1 to 8/4

18 to 24

Haemophilus influenzae ATCC 49247

2/1 to 16/8

15 to 23

Staphylococcus aureus ATCC 29213

0.12/0.06 to 0.5/0.25

Not applicable (NA)

Staphylococcus aureus ATCC 25923

28 to 36

Streptococcus pneumoniae ATCC 49619

0.03/0.015 to 0.12/0.06

ATCC is a trademark of the American Type Culture Collection.

Note 1: When using Haemophilus Test Medium (HTM)

Page 23 of 39

PHARMACOLOGY

There is no significant difference between the absorptions of amoxicillin and clavulanic acid,

whether administered separately or as a combination in amoxicillin and clavulanate potassium

tablets.

Adults

Serum profiles of amoxicillin and clavulanic acid following single oral doses of amoxicillin

and clavulanate potassium

250 tablets (250 mg of amoxicillin and 125 mg of clavulanic

acid; a 2:1 ratio preparation) or

amoxicillin and clavulanate potassium -500 tablets (500 mg

of amoxicillin and 125 mg of clavulanic acid; a 4:1 ratio

preparation) are shown in Figures 1

and 2 below.

Some pharmacokinetic parameters and the urinary excretion for these two preparations are

given in Table 4 and 5.

Table 4

Pharmacokinetic Parameters

Parameter*

Amoxicillin and clavulanate

potassium -250 Tablets

Amoxicillin and clavulanate

potassium -500 Tablets

Amoxicillin

Clavulanic acid

Amoxicillin

Clavulanic acid

(mcg/mL)

4.45 ± 0.91

2.27 ± 0.76

7.66 ± 1.65

2.33 ± 0.73

1.39 ± 40.65

1.08 ± 0.32

1.35 ± 0.31

1.22 ± 0.40

AUC (mcg/ml.h)

11.39 ± 1.60

4.73 ± 1.67

20.15 ± 3.31

5.24 ± 1.63

* C

- maximum serum concentration ± SD

- time to reach the maximum serum concentration ± SD

AUC - area under the curve ± SD

Page 24 of 39

Table 5

Urinary Excretion of Amoxicillin (mg) and of

Clavulanic Acid (mg)

Collection

Period

Amoxicillin and clavulanate

potassium -250 Tablets

Amoxicillin and clavulanate

potassium -500 Tablets

Amoxicillin

Clavulanic acid

Amoxicillin

Clavulanic Acid

0 to 2 hours

77.72 ± 44.69

19.71 ± 15.00

228.84 ± 141.87

18.07 ± 8.47

2 to 4 hours

65.00 ± 40.65

11.22 ± 7.77

131.41 ± 63.93

11.76 ± 5.99

4 to 6 hours

15.80 ± 11.82

2.24 ± 1.40

40.17 ± 22.81

4.19 ± 3.75

Total Excreted

158.72 ± 54.48

33.18 ± 16.61

391.30 ± 194.01

33.27 ± 13.68

% Excreted

63.5%

26.5%

78.3%

26.6%

N.B. Excretion is in terms of active drug.

The 24-hour pharmacokinetic profile of amoxicillin and clavulanic acid following a dosing

regimen of amoxicillin and clavulanate potassium -875 tablets every 12 hours, amoxicillin and

clavulanate potassium tablets -500 mg every 8 hours, amoxicillin and clavulanate potassium

tablets -500 mg every 12 hours and amoxicillin and clavulanate potassium tablets -250 mg

every 8 hours, with a light meal was compared in

healthy volunteers. Some pharmacokinetic

parameters for these preparations are provided in

Table 6.

Table 6

Amoxicillin and Clavulanic Acid Plasma Concentrations

Dose* and Regimen

AUC

0-24 hr

(mcg/mL.hr.) ± SD

Mean † Maximum Plasma

Concentration (mcg/mL) ± SD

(amoxicillin/clavulanic acid)

Amoxicillin

clavulanic acid

amoxicillin

clavulanic acid

250/125 mg t.i.d.

26.77 ± 4.56

12.63 ± 3.25

3.32 ± 1.12

1.47 ± 0.70

500/125 mg b.i.d.

33.43 ± 6.76

8.60 ± 1.95

6.51 ± 1.41

1.75 ± 0.61

500/125 mg t.i.d.

53.35 ± 8.87

15.72 ± 3.86

7.19 ± 2.26

2.40 ± 0.83

875/125 mg b.i.d.

53.52 ± 12.31

10.16 ± 3.04

11.64 ± 2.78

2.18 ± 0.99

* Administered at the start of a light meal.

† Mean values of 16 normal volunteers. Peak concentrations occurred approximately 1.5 hours after the dose.

The AUC (0-24h) for amoxicillin was comparable between the amoxicillin and clavulanate

potassium -875 b.i.d. and

Amoxicillin and clavulanate potassium -500 mg t.i.d. regimens and

between the Amoxicillin and clavulanate potassium -500 mg b.i.d. and Amoxicillin and

clavulanate potassium -250 mg t.i.d. regimens. Although the T

values (time above MIC of

1 mcg/mL) were slightly reduced

for the b.i.d. regimen, no differences were observed for half-

life or C

after normalization for

doses of amoxicillin and clavulanic acid.

Page 25 of 39

The half-life of amoxicillin when given alone is 1.2 hours and 1.3 hours when given in the

form

of amoxicillin and clavulanate potassium tablets. The half-life of clavulanic acid alone

is 1.0 hour. Time above the minimum

inhibitory concentration of 1.0 mcg/mL for

amoxicillin has been shown to be similar after corresponding b.i.d. and t.i.d. dosing

regimens of

amoxicillin and clavulanate potassium in adults and children.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay

renal

excretion of clavulanic acid.

Neither component of amoxicillin and clavulanate potassium tablets is highly protein-

bound; clavulanic acid has been found to be

approximately 30% bound to human serum

protein and amoxicillin approximately 20% bound.

TOXICOLOGY

Acute Toxicology

The acute toxicity of amoxicillin trihydrate and potassium clavulanate, formulated in a 2:1 and

4:1 ratio, was determined in mice and rats dosed orally and intravenously. LD

50's

are shown in

Table 7.

Table 7

Acute Toxicity

Species

Route

Sex

Drug Ratio

LD

50

(mg/kg)**

Rats

Oral

>5000

Mice

Oral

>5000

>5000

>5000

Rats

Oral

>5000

>5000

i.v.

1850

1960

>5000

Mice

Oral

>5000

i.v.

1715-2450*

1715-2450*

* estimated

** calculated in terms of amoxicillin and clavulanic acid.

All animals were observed for 14 days. Soft faeces which were observed in rats at the

beginning

Page 26 of 39

of the observation period regained good general condition by the end of the

observation period.

All mice showed a slight dose-related loss of condition for up to 72 hours

after dosing, thereafter

remaining in good condition for the duration of the study. Animals,

dosed by the intravenous

route, which survived were observed to have mild convulsions and abnormal gait 2-3 minutes after

dosing. Those, which did not survive, convulsed immediately

on dosing and died within 1 minute.

The LD

of clavulanate potassium administered orally to 4 day old rats was determined to be

1,360 mg/kg. This compares with an oral LD

of greater than 10,000 mg/kg for adult rats. In

these neonates, weight loss, diarrhea and abdominal distension were frequently observed

following dosing.

Subacute Toxicity

Rats:

moxicillin trihydrate and clavulanate potassium formulated in a 2:1 ratio were administered

orally by gavage to 3 groups of rats each comprising 10 males and 10 females at doses of

20/10, 60/30 or 180/90 mg/kg/day for 4 weeks. A fourth group served as a control. Clinical

condition and laboratory determinations were monitored and post-mortem and histopathologic

determinations were carried out. There were no deaths during the study. Apart from the

passage of slightly soft faeces in all treated groups, there were no adverse clinical signs. Body

weight gain and food intake were comparable with controls. Water intake was increased in the

male high dose group (8%, 16.3%, 16.8% and 12.2% for weeks 1, 2, 3 and 4, respectively).

Female rats showed an overall increase in water consumption of 22%, 11% and 13% for low,

intermediate and high dose groups, respectively. Hematology and blood chemistry parameters

were comparable to controls and within accepted normal limits. There was a statistically

significant increase in urine output in the low and high dose male groups compared to controls.

Macroscopic examination revealed an increased incidence of caecal enlargement in all treated

groups and was marginally greatest at the high dose level. There was a statistically significant

decrease in relative liver weights in both sexes (-9%, -14% and -9% for high, intermediate and

low dose male groups, respectively and -12%, -16% and -6% for equivalent female groups).

The mean relative thymus weight in the high dose male group was also significantly decreased

by 21% and the relative heart weight in the intermediate dose female group was significantly

reduced by 12% compared with control. Histological examination of the kidneys revealed

minimal chronic inflammatory cell infiltration in a proportion of animals from all groups and was

associated with occasional distended tubules and tubules characterized by basophilic staining

Page 27 of 39

of the cells of the epithelium.

Dogs:

Amoxicillin trihydrate and clavulanate potassium formulated in a 2:1 ratio were administered

orally

by gavage to 3 groups of beagle dogs, each comprising 2 males and 2 females, at doses

20/10, 60/30 or 180/90 mg/kg/day for 28 days. A fourth group served as a control. Clinical

condition and laboratory determinations were monitored and post-mortem and histopathologic

determinations were carried out. There were no deaths during the study. The high dose

animals

showed immediate signs of excessive salivation and severe vomiting was seen up to 2-

1/2 hours

after dosing. Vomiting was present but less severe in the female intermediate dose

group. Body

weight gain, food and water consumption and hematology were unaffected by

treatment. The

blood glucose level of the 60/30 mg/kg dosed male dogs was raised 25% on day 13 and 11% on

day 27. These two dogs also showed increases in mean BUN (70%), total

protein (5%) and

albumin (10%) concentrations at the terminal bleed. The high dose group had

reduced total

protein (11%) and albumin (10%) levels on day 27. Female dogs dosed at 180/90 mg/kg had

total protein levels reduced by 4% and total albumin levels reduced by 12% and 10% at interim

and terminal bleeds.

All dose groups had SGOT activity slightly reduced on days 13 and 27. A pronounced

enzymuria and minor proteinuria was seen in one male dog of the low dose group. All dosed

groups had slight elevation in osmolality and electrolyte excretion. The low dose female group

had a slight elevation in urinary alkaline phosphatase (UAP) activity while the urine

concentration

capacity of test animals was marginally raised. Macroscopic post-mortem

examinations did not

reveal any treatment-related changes. Histological examination revealed

that in the colon of two

female dogs in the high dose group, distended glands were prominent

and were associated with

chronic inflammatory changes both in the colon and in the mucosa of

the duodenum in one

instance. No other changes were observed that would be considered to

be related to the

administration of the test compound.

Page 28 of 39

Chronic Toxicity

Rats:

Amoxicillin trihydrate and clavulanate potassium formulated in a 2:1 ratio were administered

orally by gavage to four groups of Sprague-Dawley rats, each comprising 15 males and

15 females, at doses of 20/10, 40/20, 100/50 or 800/400 mg/kg/day for 26 weeks. A fifth group

served as a control. Five male and 5 female rats were added to each of the high dose and

control groups to determine the effect of drug withdrawal. At the end of the treatment period,

these two groups were left undosed for a period of four weeks before sacrificing. Clinical

condition and laboratory determinations were monitored and post-mortem and histopathologic

determinations were carried out.

There were 4 deaths during the treatment period: one male and two females in the

20/10 mg/kg/day group and one female in the 40/20 mg/kg/day group. There were no deaths

during the withdrawal period. Salivation immediately after dosing was noted in both male and

female high dose groups. For males receiving 800/400 mg/kg/day, 21% lower body weight

gains were recorded from week 3 onwards and 10% lower body weight gains were recorded in

the 100/50 mg/kg/day group. Females receiving 800/400 mg/kg/day had lower body weight

gains of 62% recorded from week 13.

Decreased urine volumes (males - 30%, females - 54%) were recorded in the

800/400 mg/kg/day group. A statistically significant increase in osmolality was noted in the

female high dose group compared to controls.

There was an increase in total white blood cell count associated with an increase in lymphocytes

in male rats from the high dose group. This group also had shorter APTT (Activated Partial

Thromboplastin Time) while a non-dose related shortened PT (Prothrombin Time) was observed

for males receiving 800/400, 100/50, or 40/20 mg/kg at various intervals during treatment, and

for all treated males after 24 weeks. At the end of the withdrawal period, values for all

parameters were similar to controls. Blood chemistry investigations revealed lower serum

albumin (5 to 16%) and higher globulin levels (16 to 30%) during weeks 12 and 24 for male

animals receiving 800/400 mg/kg, with an associated decrease in A/G ratios.

A similar effect was seen at week 24 for males receiving 100/50 mg/kg. High dose female rats

had globulin levels and A/G ratios similar to controls. However, total protein levels were lower

than controls, with an associated decrease in serum albumin levels. At the end of the

Page 29 of 39

withdrawal period the only difference from controls was a reduction in total serum protein in

females.

At post-mortem examination, a prominent limiting ridge was seen in the stomachs of nearly all

the high dose group rats and 1 male dosed at 100/50 mg/kg. Distension of the caecum was

seen at all dose levels in a dose-related fashion. At the end of the withdrawal period these

findings were no longer observed. Significantly increased liver weights (males - 40%; females

- 22%), spleen weights (females - 23%) and kidney weights (males - 10%) were recorded

for the high dose group. There was an increase of 30% in liver weights in high dose females

and an increase of 26% in kidney weights of high dose males at the end of the withdrawal

period. Treatment related microscopic effects were seen in high dose rats of both sexes.

These were hepatocyte enlargement in centrilobular and mid-zonal areas of the liver,

hyperplasia of the non-glandular epithelium of the stomach in the region of the limiting ridge and

distension of the lumen of the caecum. The only persistent change present after the withdrawal

period was hepatocyte enlargement in all previously dosed males.

A study of similar design was carried out in which identical doses of only the clavulanic acid

component of the combination described above were administered. In general, the results were

similar to those reported above for the combination.

Dogs:

Amoxicillin trihydrate and clavulanate potassium formulated in a 2:1 ratio were administered

orally by gavage to four groups of Beagle dogs, each comprising 4 females and 4 males, at

doses of 10/5, 20/10, 40/20 or 100/50 mg/kg/day for 26 weeks. A fifth group served as a control.

Three male and 3 female dogs were added to each of the high dose and control groups to

determine the effect of drug withdrawal. At the end of the treatment period, these two groups

were left undosed for a period of 30 days before sacrificing. Clinical condition and laboratory

determinations were monitored and post-mortem and histopathologic determinations were

carried out.

There were no deaths during the study. Salivation and emesis including the occasional

presence of blood streaks (1 mL) in the vomitus were observed in the high dose groups. A low

incidence of fecal occult blood was observed in both treated and control animals but the highest

incidence occurred in the high dose group after 3 months of treatment. Abnormal granulations

in segmented neutrophils were observed most frequently in animals from the high dose group.

Page 30 of 39

Serum glucose levels in males from all treated groups and females from the low and high dose

groups were found to be 8 - 29% greater than in controls on some of the assessment occasions

during treatment. Similarly, high dose males and females had decreased total protein levels of 9

- 13% on various occasions during treatment. In both cases the absolute magnitude of the

change was small with the observed values not falling outside of normal ranges for Beagle dogs.

Focal reddening and petechiation of the mucosa of the pyloric antrum, the presence of white

patchy areas in the liver and the presence of white streaks along the cortico-medullary junctions

of the kidneys were recorded more frequently for animals of the treated groups than for

control animals. At the end of the recovery period kidney changes and some GI effects

remained. Histopathological studies revealed hepatic and renal changes in the form of

cytoplasmic glycogen diminution or disappearance and tubular vacuolization. The kidney and

liver changes identified in dogs killed after 6 months of treatment were not observed in dogs of

the regression group. Histopathological examination of the GI tract revealed capillary

congestion and some extravasation of erythrocytes in the superficial mucosa of the fundus and

pylorus in both treated and control dogs.

A study of similar design was carried out in which identical doses of only the clavulanic acid

component of the combination described above were administered. In general, the results were

similar to those reported above for the combination.

Reproductive Studies

Fertility and General Reproductive Performance

Amoxicillin trihydrate and clavulanate potassium in a 2:1 ratio were administered orally by

gavage to 3 groups of rats, each comprising 24 males and 24 females, at doses of 20/10,

100/50 or 800/400 mg/kg/day. A fourth group served as a control. Male rats were dosed daily

for a minimum of 63 days prior to mating and continuing until weaning of offspring on day 21.

Female rats were treated for 15 days prior to mating until weaning or until selected for

caesarean section at the end of gestation. On gestation day 20, 10 females/group were

sacrificed, a caesarean section was carried out and the remaining 14 females/group were

allowed to litter normally. Two high dose males died, one each during study week 11 and 15.

Necropsy indicated impaction of the caecal content for one while the other showed pulmonary

hemorrhage. Treatment related effects in the high dose males included a slight increase in

wheezing and hair loss, decrease in mean body weight gain (21%) and a moderate increase in

soft stools.

Page 31 of 39

A slight increase in hair loss was noted in the 100/50 and 800/400 mg/kg/day females. Fertility

and general reproductive performance was not affected by treatment as assessed by pregnancy

rate and duration of gestation. Male and female mean pup body weights were statistically

significantly higher in the 100/50 mg/kg/day group when compared to control. Although not

statistically significant, a decrease, which tended to be dose related, was observed with respect

to viable fetuses, total implantations and corpora lutea per dam. Two F

fetuses, from the

800/400 mg/kg dose group, had malformations (one had a malformed scapula and the other a

thread-like tail and small anus). Litter size, foetal loss and development and behaviour of pups

were not adversely affected by treatment.

A study of similar design was carried out in which identical doses of only the clavulanic acid

component of the combination described above were administered. The results were generally

similar to those reported above for the combination with the addition that 2 fetuses from the 400

mg/kg/day dose group exhibited scoliosis.

Teratology

Three groups of 30 female rats were mated and amoxicillin trihydrate and clavulanate potassium

in a 2:1 ratio were then administered from day 6 to day 15 of gestation at doses of 20/10,

100/50 or 800/400 mg/kg/day. A fourth group served as a control. On day 20 of gestation,

20 females/group were sacrificed and a caesarean section was carried out while the remaining

10/group were allowed to litter normally. One dam in the 100/50 mg/kg/day group died;

however, the dam was normal internally. Maternal observations revealed a dose related loss

of hair, a reduction (11 to 23%) in mean maternal body weight gain for gestation days 6 to 20

and a decrease in food consumption. Slight increases in post-implantation losses were seen in

the treated groups, but these were neither dose-related nor statistically significant.

Pregnancy rate, litter size, foetal loss and mean pup weights were not affected by the treatment.

The incidence of bent ribs was dose-related and scoliosis was observed in three offspring of

dams dosed at 100/50 and 800/400 mg/kg/day. Other offspring abnormalities included extra

sternebrae (1 pup), numerous petechiae on the stomach and misplace sternebrae (1 pup) and

cleft lip with several skeletal anomalies involving the vertebrae, ribs, skull and sternum (1 pup).

A study of similar design was carried out in which identical doses of only the clavulanic acid

component of the combination described above were administered. The results were generally

Page 32 of 39

similar to those reported above for the combination with the addition that a dose related

reduction in ossification and a statistically significant decrease in mean pup body weight were

also observed.

Perinatal and Postnatal Studies

Amoxicillin trihydrate and clavulanate potassium in a ratio of 2:1 were administered orally by

gavage to 3 groups, each comprising 20 pregnant rats, at doses of 20/10, 100/50 or

800/400 mg/kg/day from day 15 of gestation, through lactation to 21 days post-partum. A fourth

group served as a control. Among parent animals, no deaths were observed but there was a

slight decrease (17%) of mean body weight in the 800/400 mg/kg/day group on gestation days

15 to 20 and lactation days 0 to 4. Among the litters, 6 deaths were observed; 5 in the

100/50 mg/kg/day group and 1 in the 800/400 mg/kg/day group. A statistically significant

decrease in mean number of viable pups per litter in the high dose group was observed. There

was a statistically significant decrease in pup survival in the 100/50 mg/kg/day dose group on

lactation days 4, 8, 12 and 21 and a small statistically insignificant decrease in the

800/400 mg/kg/day group. In the F

generation animals, which were mated, a statistically

significant decrease in total implantations per dam and corpora lutea was observed for animals

in dams of the 800/400 mg/kg/day group compared to control. The F

generation parameters

revealed no other biologically meaningful differences or dose-related trends in litter

observations, behavioural and developmental indices, neuropharmacological responses or

reproductive capability of any treatment group when compared with control.

A study of similar design was carried out in which identical doses of only the clavulanic acid

component of the combination described above were administered. The maternal effects

observed were, in general, similar to those reported above for the combination preparation. In

the F

generation, 1 pup from each of the 50 and 400 mg/kg dosage groups had bilateral

rudimentary ribs and 1 pup from the 400 mg/kg dosage group had hydrocephaly in addition to

bilateral rudimentary ribs.

Page 33 of 39

References or Selected Bibliography

Brogden RN, Carmine A, Heel RC, Morley PA, Speight TM, Avery GS.

Amoxycillin/clavulanic acid: a review of its antibacterial activity, pharmacokinetics and

therapeutic use. Drugs 1981; 22(5):337-362.

Cole M. Inhibitors of bacterial beta-lactamases. Drugs Future 1981; 6(11):697-727.

Leigh DA, Marriner JM, Freeth M, Bradnock K, Nisbet D. Antibacterial Activity of

Augmentin and Treatment of Tissue Infections. Excerpta Med Int Cong Ser 1980;222-

230.

Mulroy R. Amoxycillin rash in infectious mononucleosis. Br Med J 1973; 1(5852):554.

Pullen H. Infectious mononucleosis. Br Med J 1973; 2(5862):350-352.

Rolinson GN. The History and Background of Augmentin. Proc First Symp Augmentin

1980;4-7.

Rolinson GN. The History and Background of Augmentin. Proc Eur Symp Augmentin

Scheveningen 1982; 4:5-10.

Slocombe B. Inhibition of beta-lactamases in Branhamella catarrhalis. Drugs 1986; 31

Suppl 3:79-81.

Swanson-Biearman B, Dean BS, Lopez G, Krenzelok EP. The effects of penicillin and

cephalosporin ingestions in children less than six years of age. Vet Hum Toxicol 1988;

30(1):66-67.

Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial

Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – 8th ed.

CLSI Document M07-A9. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for

Antimicrobial Disk Susceptibility Test; Approved Standard – 10th ed. CLSI Document

M02-A10. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2009.

Clinical and Laboratory Standards Institute (CLSI). Performance Standards for

Antimicrobial Susceptibility Testing – 21st Informational Supplement. CSLI Document

M100-S21. CLSI, 940 West Valley Rd., Suite 1400, Wayne, PA 19087, 2011.

CLAVULIN

Product Monograph, GlaxoSmithKline Inc., Submission Control No: 232771.

Date of Revision: January 28, 2020.

Page 34 of 39

IMPORTANT: PLEASE READ

READ THIS FOR SAFE AND EFFECTIVE USE OF YOUR MEDICINE

PATIENT MEDICATION INFORMATION

Pr

JAMP Amoxi Clav

amoxicillin / clavulanate potassium tablets

Read this carefully before you start taking JAMP Amoxi Clav (amoxicillin / clavulanate potassium) and

each time you get a refill. This leaflet is a summary and will not tell you everything about this drug. Talk to

your healthcare professional about your medical condition and treatment and ask if there is any new

information about JAMP Amoxi Clav.

What is JAMP Amoxi Clav used for?

JAMP Amoxi Clav is an antibiotic used to treat bacterial infections.

How does JAMP Amoxi Clav work?

JAMP Amoxi Clav’s ingredients work in 2 ways. Amoxicillin causes bacterial death. Clavulanic acid helps

amoxicillin kill bacteria.

What are the ingredients in JAMP Amoxi Clav?

Medicinal ingredients: amoxicillin (as trihydrate) and clavulanic acid (as clavulanate potassium).

Non-medicinal ingredients:

Tablets:

microcrystalline cellulose, croscarmellose sodium, colloidal anhydrous silica, magnesium stearate, ethyl

cellulose, hypromellose, propylene glycol, SDA 3A Alcohol 27 CFR, titanium dioxide and hydroxypropyl

cellulose.

JAMP Amoxi Clav comes in the following dosage forms:

JAMP Amoxi Clav Tablets: 250/125mg, 500/125mg and 875/125mg of amoxicillin / clavulanic acid.

Do not use if:

you or your child are allergic to:

amoxicillin.

beta-lactam antibiotics (such as penicillins and cephalosporins).

any of the other ingredients of JAMP Amoxi Clav. See What are the ingredients in JAMP

Amoxi Clav.

you or your child have had a history of:

jaundice (yellowing of the skin and/or eyes) or liver disease, after taking JAMP Amoxi Clav.

you have mononucleosis.

To help avoid side effects and ensure proper use, talk to your healthcare professional before you take

JAMP Amoxi Clav. Talk about any health conditions or problems you may have, including if you or

your child:

Page 35 of 39

IMPORTANT: PLEASE READ

have had an allergic reaction (such as a rash) when taking an antibiotic.

start to have a skin rash while taking JAMP Amoxi Clav then:

stop taking JAMP Amoxi Clav.

tell your healthcare professional right away.

have mononucleosis.

have liver or kidney problems.

are pregnant or planning to become pregnant.

are breastfeeding or planning to breastfeed:

The amoxicillin in JAMP Amoxi Clav is passed into human breast milk. Talk about this

with your healthcare professional.

are taking a birth control pill. Birth control pills may not work as well if you take JAMP Amoxi Clav.

Other warnings you should know about:

JAMP Amoxi Clav treats only bacterial infections, not viral infections like the common cold.

Although you may feel better early in treatment, use JAMP Amoxi Clav exactly as directed.

Using too much JAMP Amoxi Clav or using it in the wrong way may cause:

more bacteria to grow

bacteria that will not be killed (resistance).

it not to work for you in the future (resistance).

Do not share your medicine.

Tell your healthcare professional about all the medicines you or your child are taking, including any

drugs, vitamins, minerals, natural supplements or alternative medicines.

The following may interact with JAMP Amoxi Clav:

allopurinol or probenecid (for treatment of gout)

anticoagulants (used to prevent blood clots) such as warfarin

mycophenolate mofetil (suppressed the immune system)

How to take JAMP Amoxi Clav:

You must use the medicine as instructed by your healthcare professional. Your healthcare professional will

decide how much medicine you or your child need each day, and how many days you should take it for.

Treatment normally lasts 7 to 10 days. Your healthcare professional may ask you to take JAMP Amoxi Clav

for 48 to 72 hours more depending on how it works for you.

It is better to take JAMP Amoxi Clav at the same time as a meal, but it still works without food.

If there is anything you do not understand please ask your healthcare professional.

Usual dose:

Adults:

Page 36 of 39

IMPORTANT: PLEASE READ

The usual adult dose is 1 JAMP Amoxi Clav 500/125 mg tablet every 12 hours or 1 JAMP Amoxi Clav

250/125 mg tablet every 8 hours. For more severe infections and infections of the lower respiratory tract,

your healthcare professional may prescribe 1 JAMP Amoxi Clav 875/125 mg tablet every 12 hours or 1

JAMP Amoxi Clav 500/125 mg tablet every 8 hours.

N.B. Since both the JAMP Amoxi Clav 250/125 mg and JAMP Amoxi Clav 500/125 mg tablets contain the

same amount of clavulanic acid (125 mg as the potassium salt), two JAMP Amoxi Clav 250/125 mg tablets are

not equivalent to one JAMP Amoxi Clav 500/125 mg tablet. Therefore, two JAMP Amoxi Clav 250/125 mg

tablets should not be substituted for one JAMP Amoxi Clav 500/125 mg tablet.

The tablets should not be split or divided.

Children weighing more than 38 kg should be dosed according to the adult recommendations.

Patients with kidney problems:

If you have kidney problems, your doctor may adjust your dose.

Overdose:

Missed Dose:

If you or your child miss a dose of JAMP Amoxi Clav, take it as soon as you remember. However, if it is

almost time for the next dose, do not take the missed dose. Instead, continue with your next scheduled dose.

Do not try to make up for the missed dose by taking double the dose next time.

What are possible side effects from using JAMP Amoxi Clav?

Using JAMP Amoxi Clav may cause side effects:

that are not all listed here. If not listed here, contact your healthcare professional. Side effects may

also be explained in Warnings and Precautions, or if they are serious they will be listed in the Serious

Side Effects Table below.

While taking JAMP Amoxi Clav, a very common side effect in adults can be diarrhea (loose, or watery

bowel movements).

While taking JAMP Amoxi Clav, common side effects can be:

a yeast infection of the nails, skin, mouth, vagina, stomach or urinary tract.

nausea (feeling sick) or vomiting.

diarrhea (loose, or watery bowel movements) in children.

While taking JAMP Amoxi Clav, uncommon side effects can be:

indigestion and headache

mild skin rash or itching

While taking JAMP Amoxi Clav, very rare side effects can be:

your tongue may change colour to yellow, brown or black or look “hairy”.

your teeth may discolour.

If you think you have taken too much JAMP Amoxi Clav, contact your healthcare

professional, hospital emergency department or regional Poison Control Centre immediately,

even if there are no symptoms.

Page 37 of 39

IMPORTANT: PLEASE READ

to reduce or prevent discolouring, brush your teeth thoroughly.

talk to your dentist or doctor if this does not go away.

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare professional

Stop taking drug

and get immediate

medical help

Only if severe

In all cases

RARE

Erythema multiforme (allergic

skin reaction): skin reaction

which results in itchy reddish

purple patches especially on the

palms of the hands or soles of

the feet

Blood problems, with

symptoms such as bleeding, or

bruising, more easily than usual

VERY RARE

Allergic reactions: difficulty

breathing, fever, hives (itchy

and red bumps on skin), itching,

rash, swelling of your tongue or

throat

Drug reaction with

eosinophilia and systemic

symptoms (DRESS) (severe

life-threatening reaction): flu-

like symptoms with fever, rash,

swelling of the face or glands

Vasculitis (blood vessel

inflammation): red or purple

raised spots on the skin, fatigue,

fever, numbness or weakness

Page 38 of 39

IMPORTANT: PLEASE READ

Serious side effects and what to do about them

Symptom / effect

Talk to your healthcare professional

Stop taking drug

and get immediate

medical help

Only if severe

In all cases

Severe skin reactions:

(Steven-Johnson syndrome

and toxic epidermal necrolysis)

blisters and peeling skin,

particularly around the mouth,

nose, eyes, and genitals; or more

severely, blisters and peeling

skin on a lot of the body; body

aches or fever

(bullous exfoliative dermatitis)

red itchy scaly rash with blisters

and bumps under the skin

(exanthemous pustulosis)

widespread red skin rash with

small blisters containing pus

Central Nervous System

(fits or seizures)

problems such as convulsions

(aseptic meningitis)

inflammation of the

protective membrane

surrounding the brain

Liver problems with symptoms

such as yellowing of the skin

and/or eyes, or dark coloured

urine, nausea, vomiting,

abdominal pain, fever or

unusual tiredness

Kidney problems with

symptoms such as blood in the

urine which may be associated

with a rash, fever, joint pain, or

a reduction in passing water

(urination)

Clostridium difficile colitis

(bowel inflammation): with

symptoms such as severe

diarrhea (bloody or watery) with

or without fever, abdominal

pain, or tenderness

Page 39 of 39

IMPORTANT: PLEASE READ

If you have a troublesome symptom or side effect that is not listed here or becomes bad enough to interfere

with your daily activities, talk to your healthcare professional.

Storage:

Store in a dry place at room temperature (15ºC - 25ºC). Store in the original container. Do not

remove desiccant.

Keep out of reach and sight of children.

If you want more information about JAMP Amoxi Clav:

Talk to your healthcare professional

Find the full product monograph that is prepared for healthcare professionals and includes the latest

available Patient Medication Information by visiting the Health Canada website (https://health-

products.canada.ca/dpd-bdpp/index-eng.jsp); or by calling 1-866-399-9091.

This leaflet was prepared by JAMP Pharma Corporation

1310, rue Nobel

Boucherville, Qu

J4B 5H3

Last Approved: November 19, 2020

Reporting Side Effects

You can report any suspected side effects associated with the use of health products to

Health Canada by:

Visiting the Web page on Adverse Reaction Reporting

(https://www.canada.ca/en/health-canada/services/drugs-health-products/medeffect-

canada/adverse-reaction-reporting.html) for information on how to report online,

mail or by fax; or

Calling toll-free at 1-866-234-2345.

NOTE: Contact your health professional if you need information about how to manage

your

side effects. The Canada Vigilance Program does not provide medical advice.

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