228.

5 mg/5 mL Powder for Suspension

457 mg/5 mL Powder for Suspension

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CLINICAL PHARMACOLOGY
PHARMACODYNAMICS
Amoxicillin (an aminopenicillin antibiotic) and potassium clavulanate (a β-lactamase
inhibitor) [Co-amoxiclav] is usually bactericidal in action. Concurrent administration
of clavulanic acid does not alter the mechanism of action of amoxicillin. However,
because clavulanic acid has a high affinity for and binds to certain β-lactamases
that generally inactivate amoxicillin by hydrolyzing its β-lactam ring, concurrent
administration of the drug with amoxicillin results in synergistic bactericidal effect
which expands amoxicillin's spectrum of activity against many strains of
β-lactamase-producing bacteria resistant to amoxicillin alone.

COMMONLY SUSCEPTIBLE SPECIES

Bacillus anthracis
Enterococcus faecalis
Listeria monocytogenes
Nocardia asteroides
Streptococcus pyogenes*†
Streptococcus agalactiae*†
Streptococcus spp. (other β-hemolytic)*†
Staphylococcus aureus
(methicillin susceptible)*
Staphylococcus saprophyticus (methicillin
susceptible)
Coagulase negative staphylococcus
(methicillin susceptible)
Bordetella pertussis
Haemophilus influenzae*
Haemophilus parainfluenzae
Helicobacter pylori
Moraxella catarrhalis*
Neisseria gonorrhoeae
Pasteurella multocida
Vibrio cholera
Borrelia burgdorferi
Other Microorganisms Leptospira ictterohaemorrhagiae
Treponema pallidum
Clostridium spp.
Peptocostreptoccus niger
Peptostreptococcus magnus
Peptostreptococcus spp.
Bacteroides fragilis
Bacteroides spp.
Capnocytophaga spp.
Eikenella corrodens
Fusobacterium nucleatum
Fusobacterium spp.
Porphyromonas spp.
Prevotella spp.
*where clinical efficacy of Co-amoxiclav has been demonstrated in clinical trials
†organisms that do not produce beta-lactamase. If an isolate is susceptible
to amoxicillin, it can be considered susceptible to Co-amoxiclav.
SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM
Corynebacterium spp.
Enterococcus faecium
Streptococcus pneumonia *†
Viridancs group streptococcus
Eschericia coli*
Klebsiella oxytoca
Klebsiella pneumoniae*
Klebsiella spp.
Proteus mirabilis
Proteus vulgaris
Proteus spp.
Salmonella spp.
Shigella spp.
*where clinical efficacy of Co-amoxiclav has been demonstrated in clinical trials
†organisms that do not produce beta-lactamase. If an isolate is susceptible
to amoxicillin, it can be considered susceptible to Co-amoxiclav.
INHERENTLY RESISTANT ORGANISMS
Acinetobacter spp.
Citrobacter freundii
Enterobacter spp.
Hafnia alvei
Legionella pneumophilia
Morganella morganii
Providencia spp.
Pseudomonas spp.
Serratia spp.
Stenotrophomas maltophilia
Yersinia enterolitica
Chlamydia pneumoniae
Chlamydia psittaci
Other Microorganisms Chlamydia spp.
Coxiella burnetti
Mycoplasma spp.

PHARMACOKINETICS
In a study in children 2 to 5 years old with urinary tract infections who received a single oral
dose of 125 mg of amoxicillin and 31.75 mg of clavulanic acid suspension, the Cmax of
amoxicillin were 9.4, 9.7, and 6.5 mcg/mL and of clavulanic acid were 2.1, 4.4, and 2.5
mcg/mL at 30, 60, and 90 minutes, respectively, after the dose.
In a study in fasting children who received a single amoxicillin dose of 35 mg/kg given as
Co-amoxiclav oral suspension, concentrations of amoxicillin and of clavulanic acid in
middle ear effusions averaged 3 and 0.5 mcg/mL, respectively, 2 hours after the dose.
When a single 5 mL oral dose of Co-amoxiclav 457 mg/5 mL suspension was administered
in healthy male and female subjects (fasted state), pharmacokinetic parameters reached
were: Cmax 5.789 mcg/mL, Tmax 1.164 hours, AUC0-t 12.21 mcg/mL•hr and AUC0-∞ 12.855
mcg/mL•hr for amoxicillin, and Cmax 1.379 mcg/mL, Tmax 1.039 hours, AUC0-t 2.492
mcg/mL•hr and AUC0-∞ 2.727 mcg/mL•hr for clavulanic acid.
Therapeutic concentrations of both amoxicillin and clavulanic acid have been found in the
gall bladder, abdominal tissue, skin, fat, and muscle tissues; the synovial and peritoneal
fluids, bile and pus. Animal studies show no evidence that either component may
accumulate in any organ.

Neither amoxicillin nor clavulanic acid is highly protein-bound; studies show that about
13% to 25% of total plasma drug concentration of each compound is protein-bound.
Both Co-amoxiclav components readily cross the placenta. Only small amounts of
amoxicillin and clavulanic acid are distributed in human milk.
Serum concentrations of amoxicillin and clavulanic acid both decline in a biphasic manner
and their t1/2 are similar. Approximately 50 to 73% of amoxicillin and 25 to 45% of
clavulanic acid are excreted unchanged in urine within 6 to 8 hours following oral
administration of a single dose of Co-amoxiclav in adults with normal renal function.
In a study in children 2 to 15 years old, the elimination t1/2 of amoxicillin and clavulanic acid
averaged 1.2 and 0.8 hours, respectively.

• Administer Co-amoxiclav at the start of a meal to minimize potential gastrointestinal

intolerance and to optimize absorption.
• Drink plenty of water to ensure proper state of hydration and adequate urinary output.
• Treatment should not exceed 14 days without first re-evaluating the patient.

Use the measuring spoon provided with the product.

Co-amoxiclav is dosed based on the amoxicillin component and is given in divided doses
every 12 hours.

• Known hypersensitivity to penicillin or any ingredient in this product

• History of severe immediate hypersensitivity reaction (e.g., anaphylaxis or
Stevens-Johnson syndrome) to another β-lactam antibiotic (e.g. a cephalosphorin,
carbapenem or monobactam)
• Patients with a previous history of cholestatic jaundice/hepatic impairment associated
with Co-amoxiclav or penicillin
• Patients with glandular fever or lymphatic lymphoma should not be given Co-amoxiclav
as the amoxicillin component is likely to cause a maculopapular rash
• Patients with infectious mononucleosis either suspected or confirmed

Decreased renal tubular secretion of amoxicillin resulting in

Probenecid increased and prolonged serum amoxicillin concentrations,
but not of clavulanic acid. Concomitant use is not
recommended.
Increased incidence of skin rashes, particularly in
Allopurinol hyperuricemic patients. It is not known whether this
potentiation of amoxicillin rashes is due to allopurinol or the
hyperuricemia in these patients.

Methotrexate Decreased renal clearance of methotrexate and subsequent

increase in methotrexate toxicity
Co-amoxiclav may reduce the efficacy of combined oral
Oral Contraceptives contraceptives by altering the gut flora and result in lower
estrogen absorption. It may also lead to increased
incidence of breakthrough bleeding or pregnancy on rare
occasions.
Oral Anticoagulants Abnormal prolongation of prothrombin time (increased
(Acenocoumarol or International Normalized Ratio [INR]) has been reported
Warfarin) in patients receiving amoxicillin and oral anticoagulants.
Appropriate monitoring should be undertaken when these
drugs should be used concomitantly. Adjustments in the
dose of oral anticoagulants may be necessary to maintain
the desired level of anticoagulation.
Co-amoxiclav should not be used in patients receiving
Disulfiram disulfiram (although there is no established
rationale/evidence to date that concomitant use would
result to a disulfiram-like reaction).
Reduction in pre-dose concentration of the active
metabolite mycophenolic acid (MPA) of approximately
Mycophenolate mofetil 50% has been reported following commencement of oral
Co-amoxiclav. The change in pre-dose level may not
accurately represent changes in overall MPA exposure.
Close monitoring should be performed during concomitant
administration of these drugs.

• High urine concentrations of ampicillin may result in false-positive reactions when testing for
urinary glucose using cupric sulfate (e.g., Clinitest®, Benedict’s Solution). Since this effect may
also occur with amoxicillin, glucose oxidase methods (e.g., Clinistix®) should be used when
urinary glucose determinations are indicated in patients receiving Co-amoxiclav.
• Although not reported to date with Co-amoxiclav, positive direct antiglobulin (Coombs’) test
results have been reported in patients who received ticarcillin and clavulanic acid and appear to
be caused by clavulanic acid. This reaction may interfere with hematologic studies or transfusion
cross-matching procedures and therefore should be considered in patients receiving
Co-amoxiclav.
• Following administration of amoxicillin to pregnant women, a transient decrease in plasma
concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol
has been noted.

Pregnancy: (Pregnancy Category B). There are no adequate or controlled studies in

pregnant women and safe use in pregnancy has not been definitely established. However, oral
Co-amoxiclav has been administered to pregnant women, particularly in the treatment of urinary
tract infections, without evidence of adverse effects to the fetus.
In a single study in women with preterm, premature rupture of the fetal membrane (pPROM), it
was reported t h a t prophylactic treatment with Co-amoxiclav may be associated with an
increased risk of necrotizing enterocolitis in neonates. As with all medicines, use should be
avoided in pregnancy unless considered essential by the physician.

Lactation: Co-amoxiclav is distributed in human milk and may cause diarrhea, fungal
infection of the mucous membrane and sensitization in the breastfed infant. Caution should be
exercised if Co-amoxiclav is to be administered to a nursing mother.
Use in children: Children weighing over 40 kg should be dosed based on recommended
dosing in adult patients.
Use in elderly patients: Since elderly patients have increased risk of renal impairment,
dose adjustment and renal function monitoring may be necessary.
Renal Impairment: Dosage adjustments are based on the maximum recommended level
of amoxicillin. No adjustment in dose is required in patients with creatinine clearance greater
than 30 mL/min.
Hepatic Impairment: Dose with caution; monitor hepatic function at regular intervals for
both adults and children.

Dermatologic and Hypersensitivity Reactions: acute generalized exanthematous

pustulosis (AGEP), anaphylaxis, angioedema, angioneurotic edema, bullous
exfoliative-dermatitis, edema, erythematous maculopapular rash, erythema multiforme,
exfoliative dermatitis (including toxic epidermal necrolysis), fever, hypersensitivity vasculitis,
pruritus, serum sickness-like syndrome (urticarial or skin rash accompanied by arthritis
arthralgia, myalgia, and frequently fever), skin rash, Stevens-Johnson syndrome and urticaria.
Gastrointestinal Effects: Abdominal cramps, abdominal discomfort, acid stomach,
anorexia, black “hairy” tongue, constipation, diarrhea/loose stools, Clostridium
difficile-associated diarrhea and colitis (antibiotic-associated hemorrhagic colitis and
pseudomembranous colitis), colic pain, dyspepsia, enterocolitis, flatulence, indigestion, intestinal
candidiasis, nausea, gastritis, glossitis, mucocutaneous candidiasis, stomatitis and vomiting.
Hematologic Effects: Anemia (including hemolytic anemia), basophilia, eosinophilia,
lymphocytopenia, prolonged bleeding time and prothrombin time, reversible agranulocytosis,
reversible leukopenia (including neutropenia), slight increase in platelets, thrombocytopenia,
thrombocytopenic purpura, and thrombocytosis.
Nervous System Effects: Agitation, aseptic meningitis, anxiety, behavioral changes,
confusion, dizziness, headache, insomnia, reversible hyperactivity and convulsions particularly
in patients with impaired renal functions or those receiving high doses
Hepatic Effects: A moderate rise in aspartate aminotransferase (AST) and/or alanine
aminotransferase (ALT), serum bilirubin and/or alkaline phosphatase, lactic dehydrogenase,
hepatic cholestasis, hepatitis, cholestatic jaundice, acute hepatic dysfunction
Renal and Genitourinary Effects: Acute interstitial nephritis, crystalluria, hematuria,
overgrowth of non-susceptible organisms and vaginitis
Other Effects: Bad taste, malaises and superficial tooth discoloration (brown, yellow, or gray
staining)

Clinical features of overdosage with Co-amoxiclav may include gastrointestinal symptoms, fluid
and electrolyte imbalance. Amoxicillin crystalluria, leading to renal failure, has also been
observed in some cases. Convulsions may occur in patients with impaired renal function or those
receiving high doses.
Children (Additional Statement)
A prospective study of 51 pediatric patients at a poison control 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.
Symptomatic treatment is recommended. Co-amoxiclav can be removed by hemodialysis.

• Store in a dry place at temperatures not exceeding 25°C.

• Keep the product out of sight and reach of children.

(DR-XY33485)

(DR-XY33488)

DATE OF FIRST AUTHORIZATION (DR-XY33485): April 2010

DATE OF FIRST AUTHORIZATION (DR-XY33488): April 2010
DATE OF REVISION OF PACKAGE INSERT: July 2015

ADVERSE DRUG REACTION REPORTING STATEMENT

For suspected adverse drug reaction,
seek medical attention immediately and
report to the FDA at www.fda.gov.ph
AND Unilab at (+632) 858-1000 or
[email protected]. By
reporting undesirable effects, you can
help provide more information on the
safety of this medicine.

Manufactured by Bilim Ilac Sanayii Ve Ticaret A.S.

Cerkezkoy Organize Sanayi Bolgesi
Karaagac Mahallesi 5. Sokak No: 6
Kapakli/Tekirdag-Turkey
Imported and Distributed by UNILAB, Inc.
No. 66 United Street, Mandaluyong City
Metro Manila, Philippines

PED152090IN03