Calamox (Co-amoxiclav)
Tablets/ Suspension U.S.P. Specs.

DESCRIPTION
CALAMOX (Co-amoxiclav) is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, Clavulanate potassium (the potassium salt of Clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O5 S•3H 2O. Chemically, amoxicillin is (2S,5R,6R)-6-[(R)(-)-2- Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dime-thyl-7-oxo-4-thia-1-a zabicyclo[ 3.2.0]heptane-2carboxylic acid trihydrate.

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C 8 H 8 KNO5. Chemically, Clavulanate potassium is potassium (Z) (2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate.

QUALITATIVE AND QUANTITATIVE COMPOSITION
CALAMOX (Co-amoxiclav) is available for oral administration as:

1. CALAMOX Tablets 375 mg
   Each Film-Coated Tablet Contains:
   Amoxicillin Trihydrate U.S.P. eq: to 250 mg Amoxicillin
   Clavulanate Potassium U.S.P. eq: to 125 mg Clavulanic acid
   (Product Specs.: U.S.P.)
2. CALAMOX Tablets 625 mg
   Each Film-Coated Tablet Contains:
   Amoxicillin Trihydrate U.S.P. eq: to 500 mg Amoxicillin
   Clavulanate Potassium U.S.P. eq: to 125 mg Clavulanic acid
   (Product Specs.: U.S.P.)
3. CALAMOX Tablets 1 G
   Each Film-Coated Tablet Contains:
   Amoxicillin Trihydrate U.S.P. eq: to 875 mg Amoxicillin
   Clavulanate Potassium U.S.P. eq: to 125 mg Clavulanic acid
   (Product Specs.: U.S.P.)
4. CALAMOX Suspension 156.25mg/5mL
   Each 5mL contains:
   Amoxicillin Trihydrate U.S.P. eq: to 125 mg Amoxicillin
   Clavulanate Potassium U.S.P. eq: to 31.25 mg Clavulanic acid
   (Product Specs.: U.S.P.)
5. CALAMOX-DS Suspension 312.5mg/5mL
   Each 5mL contains:
   Amoxicillin Trihydrate U.S.P. eq: to 250 mg Amoxicillin
   Clavulanate Potassium U.S.P. eq: to 62.5 mg Clavulanic acid
   (Product Specs.: U.S.P.)

CLINICAL PHARMACOLOGY
Mechanism of Action
Amoxicillin is a semisynthetic antibiotic with a broad spectrum of antibacterial activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by β-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes.

Clavulanic acid is a β-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of β-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance. It is generally less effective against chromosomally-mediated type 1 β-lactamases.

The formulation of amoxicillin and clavulanic acid in amoxicillin/clavulanate potassium protects amoxicillin from degradation by β-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin, other penicillins and cephalosporins. Thus, amoxicillin/clavulanate potassium possesses the distinctive properties of a broad-spectrum antibiotic and a β-lactamase inhibitor.

Microbiology
Co-amoxiclav is bactericidal to a wide range of organisms including:
Gram-Positive aerobes:
*Bacillus anthracis
Corynebacterium species
*Enterococcus faecalis
*Enterococcus faecium
*Staphylococcus aureus
*Coagulase negative staphylococci (including *Staphylococcus epidermidis)
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
Streptococcus species
Streptococcus viridians

Gram-Negative aerobes:
Bordetella pertussis
Brucella species
*Escherichia coli
Gardnerella vaginalis
*Haemophilus influenzae
*Klebsiella species
Legionella species
*Moraxella catarrhalis (Branhamella catarrhalis)
*Neisseria gonorrhoeae
*Neisseria meningitidis
Pasteurella multocida
*Proteus mirabilis
*Proteus vulgaris
*Yersinia enterocolitica
Gram-Positive anaerobes:
Clostridium species
Peptostreptococcus species
Gram-Negative anaerobes:
*Bacteroides species (including Bacteroides fragilis)
*Fusobacterium species

Others:
Chlamydiae
Leptospira icterohaemorrhagiae
*Some members of these species of bacteria produce beta-lactamase, rendering them insensitive to amoxicillin.
Pharmacokinetics

Absorption / Distribution:
Amoxicillin and clavulanic acid are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanate potassium is optimised when taken at the start of a meal. Neither amoxicillin nor clavulanic acid is highly protein bound.

Metabolism / Excretion:
Clavulanic acid is extensively metabolised to 2,5-dihydro-4-(2 hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxy -butane-2-one. The major route of elimination for amoxicillin is via the kidneys. It is partly excreted in the urine as penicilloic acid in quantities equivalent to 10-25% of the initial dose, whereas for clavulanate it is by both renal and non-renal mechanisms. Its metabolite is eliminated in rine and feces as carbon dioxide in expired air. Approximately 60-70% of the amoxicillin and approximately 40-65% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration amoxicillin / clavulanate potassium tablets.

THERAPEUTIC INDICATIONS
CALAMOX (Co-amoxiclav) is indicated for the short term treatment of bacterial infections such as:

• Acute bacterial sinusitis
• Acute otitis media
• Lower Respiratory Tract Infections e.g., acute exacerbations of chronic bronchitis, lobar and
• broncho-pneumonia.
• Genito-urinary Tract Infections e.g., cystitis, urethritis, pyelonephritis, female genital infections.
• Skin and Soft Tissue Infections e.g., boils, abscesses, cellulitis and wound infection.
• Bone and Joint Infections e.g., osteomyelitis.
• Other Infections e.g., septic abortion, puerperal sepsis, intra-abdominal sepsis, septicaemia, peritonitis, post-surgical infections.

CALAMOX (Co-amoxiclav) is also indicated for prophylaxis against infection which may be associated with major surgical procedures such as gastro-intestinal, pelvic, head and neck, cardiac, renal, joint replacement and biliary tract surgery.

DOSAGE AND ADMINISTRATION
Dosage depends on the age, weight and renal function of the patient and severity of the infection. CALAMOX (Co-amoxiclav) should be taken at the start of a meal to enhance the absorption of amoxicillin and to minimize the potential for gastrointestinal intolerance. Two CALAMOX 375mg tablets should not be substituted for one CALAMOX 625mg tablet since they are not equivalent.

Adults
Mild to moderate infections
1 CALAMOX 375mg tablet taken three times daily.
1 CALAMOX 625mg tablet taken two or three times daily.
1 CALAMOX 1g tablet taken twice daily.
Severe infections (Including chronic and recurrent urinary tract infections and those of the lower respiratory tract).
1 to 2 CALAMOX 625mg tablet given three times daily.
1 CALAMOX 1g tablet given two or three times daily.

Children up to 12 years
The usual oral recommended daily dosage is 25mg/kg/day in divided doses every eight hours.

Under 1 year:
25mg/kg/day (for e.g a 7.5kg child would require 2mL CALAMOX 156.25mg syrup three times daily)

1-6 Years (10-15kg):
5mL CALAMOX 156.25mg suspension three times a day.

Over 6 years (18-40kg):
5mL CALAMOX-DS 312.5mg suspension three times a day.
Children weighing 40kg and over should be dosed according to the adult recommendations.
The lower dose is recommended for infections such as skin and soft tissue and recurrent tonsillitis.
The higher dose is recommended for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections.

Renal Insufficiency
Adults
Creatinine Clearance greater than 30mL/min
No adjustment necessary
Creatinine Clearance 10 to 30mL/min
1 tablet of CALAMOX 625mg taken twice daily or 1 to 2 tablets of CALAMOX 375mg, depending upon severity of infection, taken twice daily.
Creatinine Clearance less than 10mL/min
1 tablet of CALAMOX 625mg given once daily or 1 to 2 tablets of CALAMOX 375mg , depending upon severity of infection, taken once daily.

Children
Creatinine Clearance greater than 30mL/min
No adjustment necessary

Creatinine Clearance 10 to 30mL/min
15mg/3.75mg/kg taken twice daily.

Creatinine Clearance less than 10ml/min
15mg/3.75mg/kg taken as a single daily dose.

Infants
Creatinine Clearance greater than 30mL/min:
No adjustment necessary.

Creatinine Clearance 10 to 30mL/min:
The recommended dose given twice daily instead of three times per day*.

Creatinine Clearance less than 10mL/min:
The recommended dose given once daily instead of three times per day*.
*In more serious cases this dose may be doubled.

Hemodialysis

Adults
1 tablet of CALAMOX 625mg or 2 tablets of CALAMOX 375mg taken every 24 hours, plus one dose during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased).
The CALAMOX 1g should only be used in patients with a creatinine clearance of more than 30mL/min.

Children
15mg/3.75mg/kg/day given as a single daily dose. Prior to haemodialysis one additional dose of  15mg/3.75mg/kg should be administered. In order to restore circulating drug levels, another dose of 15mg/3.75mg/kg should be administered after hemodialysis.

Hepatic Insufficiency
Caution should be taken while dosing and monitoring of hepatic function at regular interval is very necessary.

ADVERSE REACTIONS

Very Common: Diarrhea

Common: Mucocutaneous candidiasis, nausea, vomiting. Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking Co-amoxiclav at
the start of the meal.

Uncommon: Dizziness, headache, Skin rash, pruritus, urticaria.

Rare: Reversible Leucopenia (including neutropenia) and thrombocytopenia, Erythema multiforme.

Not Known: Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time, Angioneurotic oedema, anaphylaxis, serum sickness-like sydndrome, hypersensitivity
vasculitis. Antibiotic associated colitis (including pseudomembranous colitis and hemorrhagic colitis). Superficial tooth discoloration which can be removed usually by brushing. Hepatitis and cholestatic jaundice usually associated with prolonged treatment predominantly in males and elderly.
Steven-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (AGEP). Interstitial nephritis and crystalluria.

CONTRAINDICATIONS
Co-amoxiclav is contraindicated in patients with:

• History of hypersensitivity to beta-lactams, e.g., penicillins and cephalosporins.
• Previous history of amoxicillin-clavulanate-associated jaundice/hepatic dysfunction.

WARNINGS AND PRECAUTIONS

• Before initiating therapy with co-amoxiclav, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.
• If an allergic reaction occurs, co-amoxiclav therapy should be discontinued and appropriate alternative therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation may also be required.
• Co-amoxiclav should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.
• Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
• In general co-amoxiclav is well tolerated and possesses the characteristic low toxicity of the penicillin group of antibiotics. Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy.
• Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin-clavulanate 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.
• Co-amoxiclav should be used with caution in patients with evidence of hepatic dysfunction.
• In patients with renal insufficency, dosage should be adjusted according to the degree of impairment.
• In patients with reduced urine output crystalluria has been observed very rarely, predominantly with parenteral therapy. During 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.

Pregnancy
Co-amoxiclav should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation
Calamox has been showed to be excreted in human milk. Caution should be exercised when Calamox is administered to nursing mothers.

DRUG INTERACTIONS

• Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of Amoxicillin. Concomitant use with Co-amoxiclav may result in increased and prolonged blood levels of amoxicillin, but not of clavulanic acid.
• Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.
• In common with other antibiotics, Co-amoxiclav may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral contraceptives.
• Concomitant administration of amoxicillin and coumarin anticoagulants, such as warfarin, may increase the incidence of bleeding.

PRESENTATION:
Calamox Tablets 375mg: 1×6’s in Alu Alu Blister Pack.
Calamox Tablets 625mg: 1×6’s & 2×6’s in Alu Alu Blister Pack.
Calamox Tablets 1000mg: 1×6’s & 2×6’s in Alu Alu Blister Pack.
Calamox for oral Suspension: 156.25mg/5ml 60ml (after reconstitution) in 90ml Amber Glass Bottle.
Calamox for oral Suspension: 156.25mg/5ml 90ml (after reconstitution) in 120ml Amber Glass Bottle.
Calamox for oral Suspension: 312.5mg/5ml (DS) 60ml (after reconstitution) in 90ml Amber Glass Bottle.
Calamox for oral Suspension: 312.5mg/5ml (DS) 90ml (after reconstitution) in 120ml Amber Glass Bottle.

SHELF LIFE:
Calamox Tablets & Suspension has shelf life of two Years

Direction for reconstitution (for Suspension):
Add a little amount of previously boiled and cooled water. Invert bottle and shake until powder is dispersed. Then add more water upto the mark on the label.
The reconstituted suspension can be used within 7 days when stored in refrigerator. Do not freeze.

INSTRUCTIONS:

• Keep bottle tightly closed.
• Protect from heat, sunlight & moisture, store below 25°C.
• The Expiration date refers to the product correctly stored at required condition.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• Keep out of the reach of children.
• To be sold on prescription of a registered medical practitioner only.

Calamox Duo (Co-amoxiclav) For Oral Suspension

DESCRIPTION:
CALAMOX-DUO is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid).

Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16 H 19 N 3 O5 S•3H 2 O, and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(phydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate.

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. The clavulanate potassium molecular formula is C 8 H 8 KNO 5 , and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate.

COMPOSITION:
Each 5ml contains :
Amoxicillin Trihydrate U.S.P. eq. to 400mg Amoxicillin
Clavulanate Potassium U.S.P. eq. to 57mg Clavulanic acid.
(Product Specs.: U.S.P.)

CLINICAL PHARMACOLOGY:
Pharmacodynamic Properties:
Pharmacotherapeutic group: Antibacterials for systemic use; betalactam antibacterials, penicillins; combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

Mechanism Of Action:
Amoxicillin is a semisynthetic penicillin that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

Microbiology:
Gram-Positive Bacteria:

• Enterococcus faecalis
• Gardnerella vaginalis
• Staphylococcus aureus
• Coagulase-negative staphylococci
• Streptococcus agalactiae
• Streptococcus pneumoniae
• Streptococcus pyogenes and other beta-haemolytic streptococci
• Streptococcus viridans group
• Enterococcus faecium

Gram-Negative Bacteria:

• Capnocytophaga spp.
• Eikenella corrodens
• Haemophilus influenzae
• Moraxella catarrhalis
• Pasteurella multocida
• Escherichia coli
• Klebsiella oxytoca
• Klebsiella pneumoniae
• Proteus mirabilis
• Proteus vulgaris
• Acinetobacter sp.
• Citrobacter freundii
• Enterobacter sp.
• Legionella pneumophila
• Morganella morganii
• Providencia spp.
• Pseudomonas sp.
• Serratia sp.
• Stenotrophomonas maltophilia

Anaerobic Bacteria:

• Bacteroides fragilis
• Fusobacterium nucleatum
• Prevotella spp.

Other:

• Chlamydophila pneumoniae
• Chlamydophila psittaci
• Coxiella burnetti
• Mycoplasma pneumoniae

Pharmacokinetic Properties

Absorption:
Amoxicillin and clavulanic acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Absorption of amoxicillin/clavulanic acid is optimised when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (Tmax) in each case is approximately one hour.

Distribution:
About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 L/kg for amoxicillin and around 0.2 L/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.

Metabolism:
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic acid is extensively metabolized in man and eliminated in urine and faeces and as carbon dioxide in expired air.

Elimination:
The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 L/h. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine uring the first 6 h after administration of single Co-amoxiclav 457mg/5ml Powder for Oral Suspension. Urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.

Specific Populations
Renal Insufficiency
The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid.

Hepatic Insufficiency
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

Pediatrics:
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination.

Elderly:
Elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

THERAPEUTIC INDICATIONS:
Co-amoxiclav 457mg/5ml Powder for Oral Suspension is indicated for the treatment of the following infections in adults and children:

• Acute bacterial sinusitis
• Acute otitis media
• Acute exacerbations of chronic bronchitis
• Community acquired pneumonia
• Cystitis
• Pyelonephritis
• Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis.
• Bone and joint infections, in particular osteomyelitis.

DOSAGE AND ADMINISTRATION:

Adults and children ≥ 40 kg
Formulation of Co-amoxiclav 457mg/5ml Powder for Oral Suspension provides a total daily dose of 1750 mg amoxicillin/250 mg clavulanic acid with twice daily dosing and 2625 mg amoxicillin/375 mg clavulanic acid with three times daily dosing.

Recommended doses:

• Standard dose: (for all indications) 875 mg/125 mg two times a day.
• Higher dose – (particularly for infections such as otitis media, sinusitis, lower respiratory
  tract infections and urinary tract infections): 875 mg/125 mg three times a day.
  
  

Children < 40 kg

Formulation of Co-amoxiclav 457mg/5ml Powder for Oral Suspension provides a maximum daily dose of 1000-2800 mg amoxicillin/143-400 mg clavulanic acid. If it is considered that a higher daily dose of amoxicillin is required.

Recommended doses:

• 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day given as two divided doses.
• Up to 70 mg/10 mg/kg/day given as two divided doses may be considered for some infections (such as otitis media, sinusitis and lower respiratory tract infections).

It is recommended that another preparation of Co-amoxiclav 457mg/5ml Powder for Oral Suspension is selected in order to avoid administration of unnecessarily high daily doses of clavulanic acid.

No clinical data are available for Co-amoxiclav 457mg/5ml Powder for Oral Suspension 7:1 formulations regarding doses higher than 45 mg/6.4 mg/kg per day in children under 2 years.

There are no clinical data for Co-amoxiclav 457mg/5ml Powder for Oral Suspension 7:1 formulations for patients under 2 months of age. Dosing recommendations in this population therefore cannot be made.

Patients With Renal Impairment:
No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.
In patients with creatinine clearance less than 30 ml/min, the use of Co-amoxiclav 457mg/5ml Powder for Oral Suspension presentations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as no recommendations for dose adjustments are available.

Patients With Hepatic Impairment:
Dose with caution and monitor hepatic function at regular intervals

Method of Administration:
Co-amoxiclav 457mg/5ml Powder for Oral Suspension is for oral use and should be administered with a meal to minimise potential gastrointestinal intolerance. Shake to loosen powder, add water as directed, invert, and shake the bottle before each dose.

Preparation:
To make up to 70ml add small quantity of cool boiled water in the bottle and shake until all powder is dispersed, then slowly add more water upto the mark given on the label and shake vigorously.

CONTRAINDICATIONS:
Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a  cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid.

WARNINGS AND PRECAUTIONS:
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity or a history of sensitivity to multiple allergens. Before initiating therapy with CALAMOX-DUO, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, CALAMOX-DUO should be discontinued and appropriate therapy instituted.

Hepatic Dysfunction
Hepatic dysfunction, including hepatitis and cholestatic jaundice has been associated with the use of CALAMOX-DUO. Hepatic toxicity is usually reversible; however, deaths have been reported. Hepatic function should be monitored at regular intervals in patients with hepatic impairment.

Clostridium difficile Associated Diarrhea (CDAD)
Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including CALAMOX-DUO, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Skin Rash in Patients with Mononucleosis
A high percentage of patients with mononucleosis who receive amoxicillin develop an erythematous skin rash. Thus, CALAMOX-DUO should not be administered to patients with mononucleosis.

Potential for Microbial Overgrowth
The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxicillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

Development of Drug-Resistant Bacteria
Prescribing CALAMOX-DUO in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug-resistant bacteria.

DRUG INTERACTIONS:
Oral anticoagulants
Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported in patients receiving amoxicillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with CALAMOX-DUO. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.
Probenecid Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid. 

Methotrexate
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Allopurinol
The concurrent administration of allopurinol and amoxicillin increases the incidence of rashes in patients receiving both drugs as compared to patients receiving amoxicillin alone. It is not known whether this potentiation of amoxicillin rashes is due to allopurinol or the hyperuricemia present in these patients.

Oral Contraceptives
CALAMOX-DUO may affect intestinal flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives.

Mycophenolate mofetil
In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50% has been reported following commencement of oral amoxicillin plus clavulanic acid. Close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

Effects on Laboratory Tests
High urine concentrations of amoxicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST, Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with CALAMOX-DUO, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

ADVERSE EFFECTS:
Common: Mucocutaneous candidosis, diarrhoea, nausea, vomiting.

Uncommon: Dizziness, headache, indigestion, rises in ast and/or alt, skin rash, pruritus, urticaria.

Rare: Reversible leucopenia (including neutropenia), Thrombocytopenia, Erythema multiforme

Not Known: Overgrowth of non-susceptible organisms, reversible agranulocytosis, haemolytic anaemia, prolongation of bleeding time and prothrombin time, angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis, reversible hyperactivity, convulsions, aseptic meningitis, antibiotic-associated colitis, black hairy tongue, tooth discoloration, hepatitis, cholestatic jaundice, stevens-johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (agep), drug reaction with eosinophilia and systemic symptoms (dress), interstitial nephritis, crystalluria.

USE IN PREGNANCY AND LACTATION:
Pregnancy:
Pregnancy Category B
Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations.

Lactation:
Both substances are excreted into breast milk. Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility of sensitisation should be taken into account. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

OVERDOSE:
Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained. Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING:
After reconstitution the ready-for-use suspension is off-white.
This medicinal product should not be used if lumps of powder are visible in the bottle before reconstitution.
After reconstitution the product should not be used if the colour of the reconstituted product is different from the one described before.
SHELF LIFE:
2 years

INSTRUCTIONS & PRECAUTIONS:

• Before reconstitution protect from heat, sunlight & moisture, store below 25°C.
• Once reconstituted the suspension must be stored in refrigerator.
• Do not freeze and used within 7 days.
• Close the bottle properly after use.
• Keep out of the reach of children.
• The expiration date refer to the product correctly stored at the required condition.
• Patients and healthcare professionals can also report suspected adverse drug reaction at ade@bosch-pharma.com.
• To be sold on prescription of a registered medical practitioner only.

PRESENTATION:
Calamox DUO for oral suspension: 457mg per 5ml is available in 35ml & 70ml packaging.

Calamox Injection
(Co-amoxiclav for Injection B.P.)
0.3G, 0.6G & 1.2G Intravenous (Product Specs.: B.P.)

DESCRIPTION:
Calamox is a formulation of amoxicillin , a bactericidal broad spectrum penicillin and clavulanic acid, a progressive and irreversible inhibitor of ß-lactamase enzymes. The presence of clavulanic acid protects amoxicillin from destruction and subsequent loss of antibacterial activity by the ß-lactamase enzymes produced by many Gram-negative and Gram-positive bacteria. The spectrum of amoxicillin thus widened to include organisms normally resistant by virtue of their ability to produce ß-lactamase. Calamox will not only eliminate but also will not be inactivated by non-pathogenic ß-lactamase producing organisms at the site of infection.

FORMULATION:
CALAMOX 0.3g intravenous vial: Each containing 250mg amoxicillin and 50mg clavulanic acid
CALAMOX 0.6g intravenous vial: Each containing 500mg amoxicillin and 100mg clavulanic acid.
CALAMOX 1.2g intravenous vial: Each containing 1g amoxicillin and 200mg clavulanic acid.

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of penicillins, including beta-lactamase inhibitors;
ATC code: J01CR02.

Mechansim of action:
Calamox is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

MICROBIOLOGY:
Calamox is a semisynthetic antibiotic with in vitro bactericidal activity against Gram-positive and Gram-negative bacteria. Calamox is however, susceptible to degradation by beta-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a beta-lactam, structurally related to the penicillins, which possesses the ability to inactivate some beta-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated beta-lactamases frequently responsible for transferred drug resistance.
Aerobic Gram-positive micro-organism:
Staphylococcus aureus Enterococcus faecalis,Gardnerella vaginalis Staphylococcus aureus (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumonia, Streptococcus pyogenes and other beta-haemolytic Streptococci, Streptococcus viridans group.

Aerobic Gram-negative micro-organisms:
Actinobacillus actinomycetemcomitans, Capnocytophaga spp. Eikenella corrodens Haemophilus influenza, Moraxella catarrhalis,Neisseria gonorrhoeae, Pasteurella multocida.

Other micro-organism:
Chlamydia trachomatis,Chlamydophila pneumonia,Chlamydophila psittaci,Coxiella burnetti,Mycoplasma pneumoniae.

Pharmacokinetic Properties:
Absorption / Distribution:
About 25% of total plasma clavulanic acid and 18% of total plasma amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid.

Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid.Both amoxicillin and clavulanic acid have been shown to cross the placental barrier

Biotransformation
Amoxicillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of theinitial dose. Clavulanic acid is extensively metabolized in man, and eliminated in urine and faeces and as carbon dioxide in expired air.

Excretion:
The major route of elimination for amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms. Amoxicillin/clavulanic acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of a single 500/100 mg or a single 1000/200 mg bolus intravenous injection. Various studies have found the urinary excretion to be 50-85% for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.

Age
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Renal impairment
The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as
a higher proportion of amoxicillin is excreted via the renal route.

Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

CLINICAL PARTICULARS:
Therapeutic indications
CALAMOX is indicated for the treatment of the following infections in adults and children

• Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections, epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms)
• Acute exacerbations of chronic bronchitis
• Community acquired pneumonia
• Cystitis, Pyelonephritis
• Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis
• Bone and joint infections, in particular osteomyelitis
• Intra-abdominal infections, Female genital infections.

Prophylaxis against infections associated with major surgical procedures
in adults, such as those involving the:

• Gastrointestinal tract
• Pelvic cavity
• Head and neck
• Biliary tract surgery, joint replacement surgery.

Consideration should be given to official guidance on the appropriate use
of antibacterial agents.

DOSAGE AND ADMINISTRATION
Administration may be by intravenous injection or intermittent infusion.
Calamox is not suitable for intramuscular administration.

Adults and children ≥ 40 kg:

Children ≤ 40 kg

Recommended doses:

• Children aged 3 months and over: 25 mg/5 mg per kg every 8 hours.
• Children aged less than 3 months or weighing less than 4 kg: 25 mg/5 mg per kg every 12 hours.

Renal impairment:
Dosing adjustments are based on the maximum recommended level of amoxicillin.
No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

Adults and children ≥ 40 kg

Children ≤ 40 kg

Hepatic impairment:
Dose with caution; monitor hepatic function at regular intervals for both adults and children.

Method of administration
Calamox is for intravenous use.

Calamox may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. Calamox is not suitable for intramuscular administration.

Children aged less than 3 months should be administered Calamox by infusion only.

Treatment with Calamox may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient.

CONTRAINDICATION:
Calamox is contraindicated in patients with hypersensitivity to penicillin antibiotics.

History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam).

History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid.

WARNINGS AND PRECAUTIONS:
Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents Serious and
occasionally fatal hypersensitivity reactions have been reported in patients on penicillin therapy.

This presentation of amoxicillin/clavulanic acid may not be suitable for use when there is a high risk that  the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid.

Convulsions may occur in patients with impaired renal function or in those receiving high doses Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the
use of amoxicillin.

Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

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

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment Hepatic events have been reported predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occurduring or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased.

In patients with renal impairment, the dose should be adjusted according to the degree of impairment During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.

The presence of clavulanic acid in Calamox may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.
INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTION:

Oral anticoagulants
Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, in the literature there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral
anticoagulants may be necessary.

Methotrexate
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.

Probenecid
Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of
amoxicillin but not of clavulanic acid.

Mycophenolate mofetil
In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50% has been reported following commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure. Therefore, a change in the dose of mycophenolate mofetil should not normally be necessary in the absence of clinical evidence of graft dysfunction. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

USE IN PREGNANCY AND LACTATION:
Pregnancy:
The product has been used in human pregnancy in a limited number of cases, with no untoward effect; however, use in pregnancy is not recommended unless considered essential by the physician.

Lactation:
During lactation, trace quantities of penicillins can be detected in breast milk.  Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

ADVERSE EFFECTS:
The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and vomiting.
The following adverse effects have been observed with the amoxicillin/ clavulanic acid therapy.

Common:
Mucocutaneous candidiasis, Diarrhea, Uncommon: Dizziness, Headache, Rises in AST/ALT, Skin rash, Pruritus, Urticaria, Nausea, Vomiting, Indigestion.

Not known:
Overgrowth of non-susceptible organisms, Reversible agranulocytosis, Haemolytic anaemia, Prolongation of bleeding time and prothrombin time, Anaphylaxis, Serum sickness-like syndrome, Hypersensitivity vasculitis, Convulsion, Aseptic meningitis, Antibiotic-associated colitis, Hepatitis,Cholestatic jaundice,
Stevens-Johnson syndrome, Toxic epidermal necrolysis, Bullous exfoliative-dermatitis, Interstitial nephritis, Crystalluria

Rare: Reversible leucopenia, Thrombocytopenia, Erythema multiforme

OVERDOSAGE:
Symptoms and signs of overdose
Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed.

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

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained.

Treatment of intoxication
Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

PHARMACEUTICAL PARTICULARS
Stability and Compatibility:
Intravenous infusions of CALAMOX may be given in a range of different intravenous fluids. Satisfactory antibiotic concentrations are retained at 5°C and at room temperature (25°C) in the recommended volume of the following infusion fluids.

If reconstituted and maintained at room temperature, infusions should be completed within the times stated.

The stability of Calamox intravenous solutions is concentration dependent. In the event that the use of more concentrated solutions is required, the stability period should be adjusted accordingly.

For storage at 5°C, the reconstituted solution should be added to pre-refrigerated infusion bag which can be stored for upto 8 hrs. Thereafter, the infusion should be administered immediately after reaching room temperature.

Calamox is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solutions of Calamox may be injected into the drip tubing over a period of 3-4 minutes. Any residual antibiotic solution should be discarded.

Calamox vials are not suitable for multi-dose use.
Calamox should be administered within 20 minutes of reconstitution.

INCOMPATIBILITIES
CALAMOX Intravenous should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.

If CALAMOX is prescribed concurrently with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions.

Shelf Life:
The expiry is indicated on the packaging.

PRESENTATION:
CALAMOX I.V 0.3g vial: Each containing 250mg amoxycillin and 50mg clavulanic acid
CALAMOX I.V 0.6g vial: Each containing 500mg amoxycillin and 100mg clavulanic acid.
CALAMOX I.V 1.2g vial: Each containing 1g amoxycillin and 200mg clavulanic acid.

DIRECTIONS:

• Protect from light and moisture store at below 25°C.
• Use immediately after reconstitution.
• For single use only.
• Discard any unused solution.
• Keep out of the reach of children.
• For suspected adverse drug reaction for BOSCH products, report at ade@bosch-pharma.com

WARNING:
To be sold on the prescription of registered medical practitioner only.

Calamox Drops
(Co-amoxiclav)

DESCRIPTION:
CALAMOX is an oral antibacterial combination consisting of amoxicillin and the beta-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid).

Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C 16H 19N 3O5 S•3H 2 O, and the molecular weight is 419.46. Chemically, amoxicillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(phydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate.

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a beta-lactam structurally related to the penicillins and possesses the ability to inactivate some beta-lactamases by blocking the active sites of these enzymes. The clavulanate potassium molecular formula is C 8 H 8KNO 5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z)(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate.

COMPOSITION:
When reconstituted as directed each ml contains :
Amoxicillin Trihydrate U.S.P. eq. to 50mg Amoxicillin
Clavulanate Potassium U.S.P. eq. to 12.5mg Clavulanic acid
(Product Specs.: U.S.P.)

CLINICAL PHARMACOLOGY:
Pharmacodynamic Properties:
Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC
Code: J01CR02

Mechanism of Action:
Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the biosynthetic pathway of bacterial peptidoglycan, which is an integral structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which is usually followed by cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of amoxicillin alone does not include organisms which produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

Microbiology:
Gram-Positive Bacteria:
• Staphylococcus aureus
• Enterococcus faecalis
• Staphylococcus epidermidis
• Staphylococcus saprophyticus
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Viridans group Streptococcus

Gram-Negative Bacteria:
• Enterobacter species
• Escherichia coli
• Haemophilus influenzae
• Klebsiella species
• Moraxella catarrhalis
• Eikenella corrodens
• Proteus mirabilis

Anaerobic Bacteria:
• Bacteroides species
• Bacteroides fragilis
• Fusobacterium species
• Peptostreptococcus species

Pharmacokinetic Properties

Absorption:
Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While CALAMOX can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when CALAMOX was dosed at 30 and 150 minutes after the start of a high-fat breakfast.

Distribution:
Neither component in CALAMOX is highly protein-bound; clavulanic acid is approximately 25% bound to human serum and amoxicillin approximately 18% bound. Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. Two hours after oral administration of a single 35 mg/kg dose of suspension of CALAMOX to fasting children, average concentrations of 3 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

Metabolism and Excretion:
The half-life of amoxicillin after the oral administration of CALAMOX is 1.3 hours and that of clavulanic acid is 1 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250-mg or 500-mg tablet of CALAMOX.

SPECIFIC POPULATIONS
Renal Impairment
The total serum clearance of amoxicillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as a higher proportion of amoxicillin is excreted via the renal route. Doses in renal impairment must therefore prevent undue accumulation of amoxicillin while maintaining adequate levels of clavulanic acid.

Hepatic Impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

Pediatrics:
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. For very young children (including preterm newborns) in the first week of life the interval of administration should not exceed twice daily administration due to immaturity of the renal pathway of elimination.

Elderly:
Elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

THERAPEUTIC INDICATIONS:
CALAMOX infant drops are indicated for short-term treatment of bacterial infections at the following sites: Upper respiratory tract Infections (including ENT) e.g. recurrent tonsillitis, sinusitis, otitis media. Lower respiratory tract infections e.g. acute exacerbation of chronic bronchitis, lobar and bronchopneumonia. Genitourinary tract infections e.g. cystitis, urethritis, pyelonephritis. Skin and soft tissue infections, e.g. boils, abscesses, cellulitis, wound infections. Bone and joint infections e.g. osteomyelitis. Other infections e.g. intra abdominal sepsis. Infections caused by amoxicillin-susceptible organisms are amenable to CALAMOX treatment due to its amoxicillin content. Mixed infections caused by amoxicillin-susceptible organisms in conjunction with CALAMOX-susceptible β-lactamase producing organisms may therefore be treated with CALAMOX.

DOSAGE AND ADMINISTRATION:
The usual recommended daily dosage is 25 mg/kg/day in divided doses every eight hours. In more serious infections the dosage may be increased up to 50 mg/kg/day in divided doses every eight hours. Each 25 mg CALAMOX provides 20mg amoxicillin and 5 mg clavulanate. Calamox Drops should be administered by using the supplied dropper. The Dropper has marking according to the volume per drop providing convenience of dosing. For example at a marking of 1ml (equivalent to approx. 25 drops) should then be orally administered to the child.  A similar dose should be administered after 8 hours interval according to the weight of the child. The dosage chart of Calamox Drops which corresponds to the weight (Kg) and Age (months) are shown below:

* These doses may be doubled in cases of severe infection.

Dosage in renal impairment

* In more serious cases this dose may be doubled.

Dosage in hepatic impairment
Dose with caution; monitor hepatic function at regular intervals.

Administration:
To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of CALAMOX is optimised when taken at the start of a meal. Duration of therapy should be appropriate to the indication and should not be extended beyond 14 days without review.

CONTRAINDICATIONS:
Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients. History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid.

WARNINGS AND PRECAUTIONS:
Before initiating therapy with co-amoxiclav, careful enquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporin or other allergens. Serious and occasionally fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity. Co-amoxiclav should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. Prolongation of prothrombin time has been reported rarely in patients receiving Co-amoxiclav. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Changes in liver function tests have been observed in some patients receiving Co-amoxiclav. The clinical significance of these changes is uncertain but Co-amoxiclav should be used with caution in patients with evidence of hepatic dysfunction. Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for up to six weeks after treatment has ceased. In patients with renal impairment Co-amoxiclav dosage should be adjusted as recommended in the Dosage and Administration section. 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.

DRUG INTERACTIONS:
Use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use with CALAMOX may result in increased and prolonged blood levels of amoxicillin but not of clavulanate. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of Co-amoxiclav and allopurinol. In common with other antibiotics, Co-amoxiclav may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral contraceptives.

ADVERSE EFFECTS:
Common:
Mucocutaneous candidiasis, Blood and lymphatic system disorders, Diarrhoea, nausea, vomiting.

Uncommon:
Dizziness, headache, Indigestion, A moderate rise in AST and/or ALT, Skin rash, pruritus, urticaria.

Rare:
Reversible leucopenia (including neutropenia) and thrombocytopenia, Erythema multiforme.

Very Rare:
Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time, Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, hypersensitivity vasculitis, Reversible hyperactivity and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses, Antibiotic-associated colitis (including pseudomembranous colitis and  haemorrhagic colitis). Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing, Hepatitis and cholestatic jaundice. These events have been noted with other penicillins and cephalosporins, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthemous pustulosis (AGEP), Interstitial nephritis, crystalluria.

USE IN PREGNANCY AND LACTATION:
Pregnancy:
Teratogenic Effects: Pregnancy Category B
There are, however, no adequate and well controlled studies in pregnant women. This drug should be used during pregnancy only if clearly needed.

Lactation:
Both substances are excreted into breast milk. Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

OVERDOSE:
Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin/clavulanic acid can be removed from the circulation by haemodialysis.

SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING:
Add a small quantity of pre boiled cool water in the bottle and shake well, then add more water upto the mark given on the label and shake well to make suspension. Once reconstituted, the plastic dropper dosing device should then be used in place of the screw cap. The device is used to dose patients upto 6 months according to the schedule in the Dosage and Administration section.

NSTRUCTIONS:

• Do not take if seal is Broken.
• Before reconstitution protect from heat, sunlight & moisture, store below 25°C.
• Reconstituted suspension should be stored in a refrigerator (2°C-8°C) and used within seven
  Do not freeze.
• The Expiration date refer to the product correctly stored at required condition.
• Patients and healthcare professionals can also report suspected adverse drug reaction at
  ade@bosch-pharma.com.
• Keep out of the reach of children.
• To be sold on prescription of a registered medical practitioner only.

PRESENTATION:
Calamox Drops 62.5mg/ml: 20ml (after reconstitution) in 30ml Amber Glass Bottle.