QUALITATIVE AND QUANTITATIVE COMPOSITION

Supramox 250mg Capsules
Each capsule contains:
Amoxicillin Trihydrate eq. to 250mg Amoxicillin USP
(Product Specs.: USP)

Supramox 500mg Capsules
Each capsule contains:
Amoxicillin Trihydrate eq. to 500mg Amoxicillin USP
(Product Specs.: USP)

Supramox Suspension 125mg/5mL
Each 5mL contains:
Amoxicillin Trihydrate eq. to 125mg Amoxicillin USP
(Product Specs.: USP)

Supramox Suspension 250mg/5mL
Each 5mL contains:
Amoxicillin Trihydrate eq. to 250mg Amoxicillin USP
(Product Specs.: USP)

PHARMACEUTICAL FORM
Capsules and Powder for Oral suspension

CLINICAL PARTICULARS

Therapeutic indications
Supramox capsules and suspension are indicated for the treatment of the following infections in adults and children.

• Acute bacterial sinusitis
• Acute streptococcal tonsillitis and pharyngitis
• Acute exacerbations of chronic bronchitis
• Community acquired pneumonia
• Acute otitis media
• Acute cystitis and acute pyelonephritis.
• Asymptomatic Bacteriuria in pregnancy
• Typhoid and paratyphoid fevers
• Dental abscess with spreading cellulitis
• Prosthetic joint infections
• Helicobacter pylori eradication
• Lyme disease
• Prophylaxis of endocarditis

Posology and method of administration

Posology
The dose of Amoxicillin that is selected to treat an individual infection should take into account: The expected pathogens and their likely susceptibility to antibacterial agents, the severity and the site of infection, the age, weight and renal function of the patient; as shown below The duration of therapy should be determined by the type of infection and the response of the patient, and should generally be as short as possible. Some infections require longer periods of treatment.

Adults and children ≥40 kg

Indication	Dose
Acute bacterial sinusitis	250mg to 500mg every 8 hours or 750mg to 1g every 12 hours For severe infections 750mg to 1g every 8 hours Acute cystitis may be treated with 3g twice daily for one day
Asymptomatic bacteriuria in pregnancy
Acute pyelonephritis
Dental abscess with spreading cellulitis
Acute cystitis
Acute otitis media	500mg every 8 hours, 750mg to 1g every 12 hours For severe infections 750mg to 1g every 8 hours for 10 days
Acute streptococcal tonsillitis and pharyngitis
Acute exacerbations of chronic bronchitis
Community acquired pneumonia	500mg to 1g every 8 hours
Typhoid and paratyphoid fever	500mg to 2g every 8 hours
Prosthetic joint infections	500mg to 1g every 8 hours
Prophylaxis of endocarditis	2g orally, single dose 30 to 60 minutes before procedure
Helicobacter pylori eradication	750mg to 1g twice daily in combination with a proton pump inhibitor (e.g., omeprazole, lansoprazole) and another antibiotic (e.g., clarithromycin, metronidazole) for 7 days
Lyme disease	Early stage: 500mg to 1g every 8 hours up to a maximum of 4 g/day in divided doses for 14 days (10 to 21 days) Late stage (systemic involvement): 500mg to 2g every 8 hours up to a maximum of 6g/day in divided doses for 10 to 30 days

Children <40 kg

Children may be treated with Amoxicillin capsules, dispersible tablets, suspensions or sachets. Amoxicillin Paediatric Suspension is recommended for children under six months of age. Children weighing 40kg or more should be prescribed the adult dosage.

Indication	Dose
Acute bacterial sinusitis	20 to 90mg/kg/day in divided doses
Acute otitis media
Community acquired pneumonia
Acute cystitis
Acute pyelonephritis
Dental abscess with spreading cellulitis
Acute streptococcal tonsillitis and pharyngitis	40 to 90mg/kg/day in divided doses
Typhoid and paratyphoid fever	100mg/kg/day in three divided doses
Prophylaxis of endocarditis	50mg/kg orally, single dose 30 to 60 minutes before procedure
Lyme disease	Early stage: 25 to 50mg/kg/day in three divided doses for 10 to 21 days. Late stage (systemic involvement): 100mg/kg/day in three divided doses for 10 to 30 days

Elderly: No dose adjustment is considered necessary.

Renal impairment

GFR (mL/min)	Adults and children ≥ 40kg	Children < 40 kg
greater than 30	No adjustment necessary	No adjustment necessary
10 to 30	Maximum 500mg twice daily	15mg/kg given twice daily (maximum 500mg twice daily)
less than 10	Maximum 500mg/day	15mg/kg given as a single dose (maximum 500mg)

Hepatic impairment: Dose with caution and monitor hepatic function at regular intervals

Method of administration
Amoxicillin is for oral use. Absorption of amoxicillin is unimpaired by food.
Therapy can be started parenterally according to the dosing recommendations of the intravenous formulation and continued with an oral preparation.
Swallow with water without opening capsule.

Contraindications

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

Special Warnings and Precautions For Use

Hypersensitivity reactions
Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other betalactam agents. If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapy instituted.

Non susceptible microorganisms: Amoxicillin is not suitable for the treatment of some types of infection unless the pathogen is already documented and known to be susceptible or there is a very high likelihood that the pathogen would be suitable for treatment with amoxicillin . This particularly applies when considering the treatment of patients with urinary tract infections and severe infections of the ear, nose and throat.

Convulsions: May occur in patients with impaired renal function or in those receiving high doses or in patients with predisposing factors (e.g., history of seizures, treated epilepsy or meningeal disorders.

Renal impairment: In patients with renal impairment, the dose should be adjusted according to the degree of impairment.

Skin reactions: The occurrence at the treatment initiation of a feverish generalized erythema associated with pustula may be a symptom of acute generalized exanthemous pustulosis. This reaction requires amoxicillin discontinuation and contra-indicates any subsequent administration.

Jarisch-Herxheimer reaction: Amoxicillin’s bactericidal activity acts against Lyme disease bacteria, Borrelia burgdorferi. Patients should be reassured that this is a common and usually self-limiting consequence of antibiotic treatment of Lyme disease.

Overgrowth of non-susceptible microorganisms: Prolonged use of may occasionally result in overgrowth of non-susceptible organisms (superinfection).

Prolonged therapy: Periodic assessment of organ system functions including renal, hepatic and hematopoietic function is advisable during prolonged therapy. Elevated liver enzymes and changes in blood counts have been reported.

Crystalluria: In patients with reduced urine output, crystalluria (including acute renal injury) 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. In patients with bladder catheters, a regular check of patency should be maintained.

Interference with diagnostic tests: Elevated serum and urinary levels of amoxicillin are likely to affect certain laboratory tests. Due to high urinary concentrations of amoxicillin, false positive readings are common with chemical methods.

It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. The presence of amoxicillin may distort assay results for oestriol in pregnant women.

Interaction with other medicinal products and other forms of interaction
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

Allopurinol: Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

Tetracyclines: Tetracyclines and other bacteriostatic drugs may interfere with the bactericidal effects of amoxicillin.

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

Oral anticoagulants: Oral anticoagulants and penicillin antibiotics have been widely used without reports of interaction. If co-administering, monitor prothrombin time and adjust oral anticoagulant dose if necessary.

Fertility, Pregnancy and lactation
Pregnancy: Amoxicillin may be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

Lactation: Amoxicillin is excreted into breast milk in small quantities with the possible risk of sensitization. Amoxicillin should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

Fertility: No data Available

Effects on ability to drive and use machines
Undesirable effects may occur (e.g., allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines.

Undesirable Effects
The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and skin rash. The following terminologies have been used in order to classify the occurance of undesirable effects: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Not known

Infecons and infestaons
Very rare	Mucocutaneous candidiasis
Blood and lymphac system disorders
Very rare	Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolyc anaemia. Prolongaon of bleeding me and prothrombin me
Immune system disorders
Very rare	Severe allergic reacons, including angioneuroc oedema, anaphylaxis, serum sickness and hypersensivity vasculis
Not known	Jarisch-Herxheimer reacon
Nervous system disorders
Very rare	Hyperkinesia, dizziness, convulsions
Not known	Asepc meningis
Gastrointesnal disorders
Common	Diarrhoea and nausea
Uncommon	Voming
Hepatobiliary disorders
Very rare	Hepas and cholestac jaundice. A moderate rise in AST and/or ALT.
Skin and subcutaneous ssue disorders
Common	Skin rash
Uncommon	Urcaria and pruritus
Renal and urinary tract disorders
Very rare	Intersal nephris
Not known	Crystalluria (including acute renal injury)
Cardiac disorders
Not known	Kounis syndrome

Overdose
Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. Amoxicillin can be removed from the circulation by hemodialysis. Amoxicillin crystalluria, in some cases leading to renal failure, has been observed.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties
Pharmacotherapeutic group: penicillins with extended spectrum;
ATC code: J01CA04

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 bactericidal 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.

Pharmacokinetic/ pharmacodynamic relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for amoxicillin.

Mechanisms of resistance
The main mechanisms of resistance to amoxicillin are:

• Inactivation by bacterial beta-lactamases
• Alteration of PBPs, which reduce the affinity of the antibacterial agent for the target.

Impermeability of bacteria or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints
MIC breakpoints for amoxicillin are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST).

Organism	MIC breakpoint (mg/L)
	Susceptible ≤	Resistant >
Enterobacteriaceae	81	8
Staphylococcus spp.	Note2	Note2
Enterococcus spp.3	4	8
Streptococcus groups A, B, C and G	Note4	Note4
Streptococcus pneumoniae	Note5	Note5
Viridans group steprococci	0.5	2
Haemophilus influenzae	26	26
Moraxella catarrhalis	Note7	Note7
Neisseria meningitidis	0.125	1
Gram positive anaerobes except Clostridium difficile8	4	8
Gram negative anaerobes8	0.5	2
Helicobacter pylori	0.1259	0.1259
Pasteurella multocida	1	1
Non-species related breakpoints10	2	8
1Wild type Enterobacteriaceae are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild type isolates of E. coli and P. mirabilis as intermediate. When this is the case, use the MIC breakpoint S≤ 0.5 mg/L 2Most staphylococci are penicillinase producers, w hich are resistant to amoxicillin. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents. 3Susceptibility to amoxicillin can be inferred from ampicillin 4The susceptibility of streptococcus groups A, B, C and G to pen icillins is inferred from the benzylpenicillin susceptibility 5Breakpoints relate only to non-meningitis isolates. For isolates categorised as intermediate to ampicillin avoid oral treatment with amoxicillin. Susceptibility inferred from the MIC of ampicillin 6Breakpoints are based on intravenous administration. Beta -lactamase positive isolates should be reported resistant 7Beta lactamase producers should be reported resistant 8Susceptibility to amoxicillin can be inferred from benzylpenicillin. 9The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility. 10The non-species related breakpoints are based on doses of at least 0.5g x 3 or 4 doses daily (1.5 to 2 g/day).

Pharmacokinetic properties
Absorption
Amoxicillin fully dissociates in aqueous solution at physiological pH. It is rapidly and well absorbed by the oral route of administration. Following oral administration, amoxicillin is approximately 70% bioavailable. The time to peak plasma concentration (Tmax) is approximately one hour.

Distribution
About 18% of total plasma amoxicillin is bound to protein and the apparent volume of distribution is around 0.3 to 0.41/kg.
Following intravenous administration, amoxicillin has been found in gall bladder, abdominal tissue, skin, fat, muscle tissue, synovial and peritoneal fluids, bile and pus. Amoxicillin does not adequately distribute into the cerebrospinal fluid. Amoxicillin, like most penicillin, can be detected in breast milk. Amoxicillin has 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 the initial dose.

Elimination
The major route of elimination for amoxicillin is via the kidney. Amoxicillin has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25L/hour in healthy subjects. Approximately 60 to 70% of an orally administered dose is excreted unchanged in the urine during the first 6 hours after administration of a single 250mg or 500mg dose of amoxicillin. Concomitant use of probenecid delays amoxicillin excretion.

Age
The elimination half-life of amoxicillin is similar for children aged around 3 months to 2 years and older children and adults. The 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.

Gender
Gender has no significant impact on the pharmacokinetics of amoxicillin.

Renal impairment
The total serum clearance of amoxicillin decreases proportionately with decreasing renal function.

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

PHARMACEUTICAL PROPERTIES
Incompatibilities
Not applicable

Shelf life: 03 years

Direction for Reconstitution:
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.

Special precautions for storage and Instruction
Protect from heat, sunlight & moisture, store below 25°C.
The expiration date refers to the product correctly stored at the required condition.
Keep out of the reach of children.
Precautions: Once reconstituted the suspension must be used within 14 days when stored in a refrigerator or within 7 days at room temperature.
Close the cap properly after use.
To be sold on the prescription of a registered medical practitioner only.

Nature and contents of container / Presentation
Capsules:
Supramox 250mg Capsules: Blister pack of 20 and 100 Capsules.
Supramox 500mg Capsules: Blister pack of 20 and 100 Capsules.

Suspensions:
Supramox Suspension 125mg/5mL: 60mL (after reconstitution) in 90mL amber glass bottle.
Supramox Suspension 125mg/5mL: 90mL (after reconstitution) in 120mL amber glass bottle
Supramox Suspension 250mg/5mL: 60mL (after reconstitution) in 90mL amber glass bottle
Supramox Suspension 250mg/5mL: 90mL (after reconstitution) in 120mL amber glass bottle

REGISTRATION HOLDER / MARKETING AUTHORIZATION HOLDER
Head office:
Bosch Pharmaceuticals (Pvt.) Ltd.,
8, Modern Society, Tipu Sultan Road, Karachi-Pakistan

Manufacturer:
Bosch Pharmaceuticals (Pvt.) Ltd.
221-223, Sector 23, Korangi Industrial Area, Karachi-Pakistan.

REGISTRATION / MARKETING AUTHORIZATION NUMBER
Supramox 250mg Capsules:015926
Supramox 500mg Capsules:015921
Supramox Suspension 125mg/5mL:016050
Supramox Suspension 250mg/5mL:015927

DATE FROM WHICH MARKETING IS AUTHORIZED/RENEWAL OF THE AUTHORIZATION
08-11-1994/07-11-2019

DATE OF REVISION OF THE TEXT
04-07-2024