Geramox 250mg & 500mg Capsules

1. NAME OF THE MEDICINAL PRODUCT

Geramox 250 mg Capsules, Hard
Geramox 500 mg Capsules, Hhard

4.2 Posology and method of administration

Indication*	Dose*
Acute bacterial sinusitis	250 mg to 500 mg every 8 hours or 750 mg to 1 g every 12 hours   For severe infections 750 mg to 1 g every 8 hours   Acute cystitis may be treated with 3 g twice daily for one day
Asymptomatic bacteriuria in pregnancy
Acute pyelonephritis
Dental abscess with spreading cellulitis
Acute cystitis
Acute otitis media	500 mg every 8 hours, 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours for 10 days
Acute streptococcal tonsillitis and pharyngitis
Acute exacerbations of chronic bronchitis
Community acquired pneumonia	500 mg to 1 g every 8 hours
Typhoid and paratyphoid fever	500 mg to 2 g every 8 hours
Prosthetic joint infections	500 mg to 1 g every 8 hours
Prophylaxis of endocarditis	2 g orally, single dose 30 to 60 minutes before procedure
Helicobacter pylori eradication	750 mg to 1 g 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 (see section 4.4)	Early stage: 500 mg to 1 g 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): 500 mg to 2 g every 8 hours up to a maximum of 6 g/day in divided doses for 10 to 30 days
* Consideration should be given to the official treatment guidelines for each indication

* Consideration should be given to the official treatment guidelines for each indication

 

Children weighing < 40 kg

 

Children may be treated with amoxicillin capsules, dispersible tablets, suspensions or sachets.

 

Children weighing 40 kg or more should be prescribed the adult dosage.

 

Appropriate paediatric formulation, e.g. Geramox Powder for Oral suspension is recommended for children under six months of age.

 

Recommended doses:

Indication+	Dose+
Acute bacterial sinusitis	20 to 90 mg/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 90 mg/kg/day in divided doses*
Typhoid and paratyphoid fever	100 mg/kg/day in three divided doses
Prophylaxis of endocarditis	50 mg/kg orally, single dose 30 to 60 minutes before procedure
Lyme disease (see section 4.4)	Early stage: 25 to 50 mg/kg/day in three divided doses for 10 to 21 days Late stage (systemic involvement): 100 mg/kg/day in three divided doses for 10 to 30 days
* Twice daily dosing regimens should only be considered when the dose is in the upper range
+Consideration should be given to the official treatment guidelines for each indication.

 

                    +Consideration should be given to the official treatment guidelines for each indication.

 

Renal impairment

 

GFR (ml/min)	Adults and children ≥ 40 kg	Children < 40 kg *
Greater than > 30	nNo adjustment necessary	nNo adjustment necessary
10 to- 30	mMaximum 500 mg twice daily	15 mg/kg given twice daily (maximum 500 mg twice daily)
less than < 10	mMaximum 500 mg/day	15 mg/kg given as a single dose (maximum 500 mg)
*In the majority of cases, parenteral therapy is preferred.

*In the majority of cases, parenteral therapy is preferred.

Amoxicillin may be removed from the circulation by haemodialysis.

 

	Haemodialysis
Adults and children over  >40 kg	500 mg every 24 h   Prior to haemodialysis one additional dose of 500 mg should be administered. In order to restore circulating drug levels, another dose of 500 mg should be administered after haemodialysis.
Adults and cChildren under 40 kg	15 mg/kg/day given as a single daily dose (maximum 500 mg). Prior to haemodialysis one additional dose of 15 mg/kg should be administered. In order to restore circulating drug levels, another dose of 15 mg/kg should be administered after haemodialysis.

4.8 Undesirable effects

System Organ Class (SOC)	Frequency
	Very common	Common	Uncommon	Rare	Very rare	Not known

Renal and urinary tract disorders					Interstitial nephritis, Crystalluria (see sections 4.4 and 4.9 Overdose)
*The incidence of these adverse effects was derived from clinical studies involving a total of approximately 6,000 adults and paediatric patients taking amoxicillin.   # Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it usually be removed by brushing.

4.9     Overdose

 

Treatment of intoxication

             Gastrointestinal symptoms should be treated symptomatically, with attention to the water/electrolyte balance. More specific measures may be necessary in patients with impaired renal function: the antibiotic is removed by haemodialysis.

 

Amoxicillin can be removed from the circulation by haemodialysis.

 

10.     DATE OF REVISION OF THE TEXT

 

SeptemberOctober 2017

4. CLINICAL PARTICULARS

4.4 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 beta-lactam agents (see section 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse reactionsanaphylaxis) haves been reported in patients onreceiving penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin therapy must be discontinued and appropriate alternative therapy instituted.

4.8 Undesirable effects

Skin and subcutaneous tissue disorders

*Clinical Trial Data: Skin rash

*Clinical Trial Data: Urticaria and pruritus

Post-marketing Data: Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (see section 4.4) and drug reaction with eosinophilia and systemic symptoms (DRESS).

10. DATE OF REVISION OF THE TEXT

September November 20176

4.2 Posology and method of administration

Posology

The dose of Geramox that is selected to treat an individual infection should take into account:

The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)
The severity and the site of the 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 period of treatment (see section 4.4 regarding prolonged therapy).

Adults and children ≥ 40 kg

Indication*	Dose*
Acute bacterial sinusitis	250 mg to 500 mg every 8 hours or 750 mg to 1 g every 12 hours   For severe infections 750 mg to 1 g every 8 hours   Acute cystitis may be treated with 3 g twice daily for one day
Asymptomatic bacteriuria in pregnancy
Acute pyelonephritis
Dental abscess with spreading cellulitis
Acute cystitis
Acute otitis media	500 mg every 8 hours, 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours for 10 days
Acute streptococcal tonsillitis and pharyngitis
Acute exacerbations of chronic bronchitis
Community acquired pneumonia	500 mg to 1 g every 8 hours
Typhoid and paratyphoid fever	500 mg to 2 g every 8 hours
Prosthetic joint infections	500 mg to 1 g every 8 hours
Prophylaxis of endocarditis	2 g orally, single dose 30 to 60 minutes before procedure
Helicobacter pylori eradication	750 mg to 1 g 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 (see section 4.4)	Early stage: 500 mg to 1 g 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): 500 mg to 2 g every 8 hours up to a maximum of 6 g/day in divided doses for 10 to 30 days

* Consideration should be given to the official treatment guidelines for each indication

Paediatric population

Children weighing < 40 kg

Children may be treated with amoxicillin capsules, dispersible tablets or, suspensions or sachets.

Children weighing 40 kg or more should be prescribed the adult dosage.

Appropriate paediatric formulation, e.g. Geramox Powder for Oral suspension is recommended for children under six months of age.

Recommended doses

Indication+	Dose+
Acute bacterial sinusitis	20 to 90 mg/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 90 mg/kg/day in divided doses*
Typhoid and paratyphoid fever	100 mg/kg/day in three divided doses
Prophylaxis of endocarditis	50 mg/kg orally, single dose 30 to 60 minutes before procedure
Lyme disease (see section 4.4)	Early stage: 25 to 50 mg/kg/day in three divided doses for 10 to 21 days Late stage (systemic involvement): 100 mg/kg/day in three divided doses for 10 to 30 days
* Twice daily dosing regimens should only be considered when the dose is in the upper range

+Consideration should be given to the official treatment guidelines for each indication.

4.4 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 beta-lactam agents (see section 4.3 and 4.8).

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) has been reported in patients receiving penicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin should therapy must be discontinued and appropriate alternative therapy instituted.

4.5 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. Concurrent Concomitant use of probenecid with amoxicillin 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

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, tn in the literature there are rare 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 (see sections 4.4 and 4.8).

Methotrexate

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

4.8 Undesirable effects

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and skin rash.

The ADRs derived from clinical studies and post-marketing surveillance with amoxicillin, presented by MedDRA System Organ Class are listed below.

The following convention terminologies has have been utilised used for the classification of undesirable side effects: in order to classify the occurrence of undesirable effects.

System Organ Class (SOC)	Frequency
	Very common	Common	Uncommon	Rare	Very rare	Not known
Infections and infestations					Mucocutaneous candidiasis
Blood and lymphatic system disorders					Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia.   Prolongation of bleeding time and prothrombin time (see section 4.45)
Immune System disorders					Severe allergic reactions, including angioneurotic oedema, anaphylaxis, serum sickness and hypersensitivity vasculitis (see section 4.4).	Jarisch-Herxheimer reaction (see section 4.4).
Nervous system disorders					Hyperkinesia, dizziness and convulsions (see section 4.4).
Gastrointestinal disorders		*Clinical Trial Data: Diarrhoea and nausea	*Clinical Trial Data: Vomiting		Post-marketing Data: Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis) (see section 4.4).   Black hairy tongue   Superficial tooth discolouration#
Hepatobiliary disorders					Hepatitis and cholestatic jaundice. A moderate rise in AST and/ or ALT.
Skin and subcutaneous tissue disorders		*Clinical Trial Data: Skin rash	*Clinical Trial Data: Urticaria and pruritus		Post-marketing Data: Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (see section 4.4).
Renal and urinary tract disorders					Interstitial nephritis, Ccrystalluria (see section 4.4 and  4.9)
*The incidence of these adverse effects was derived from clinical studies involving a total of approximately 6,000 adults and paediatric patients taking amoxicillin.   # Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it usually be removed by brushing.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains amoxicillin trihydrate equivalent to 250 mg amoxicillin (anhydrous).
Each capsule contains amoxicillin trihydrate equivalent to 500 mg amoxicillin (anhydrous).

For the full list of excipients, see section 6.1.

 

 

 

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

 

 

Geramox is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1):

 

:

 

 

 

 

 

•  Acute bacterial sinusitis

• Upper respiratory tract infections
•  Acute otitis media
•  Acute streptococcal tonsillitis and pharyngitis
•  Acute exacerbations of chronic bronchitis
•  Community acquired pneumonia
•  Acute cystitis
• Lobar and bronchopneumonia
• Cystitis, urethritis, pyelonephritis
•  Asymptomatic bacteriuria in pregnancy
•  Acute pyelonephritis
• Gynaecological infections including puerperal sepsis and septic abortion
• Gonorrhoea
• Peritonitis
• Intra-abdominal sepsis
• Septicaemia
• Bacterial endocarditis
•  Typhoid and paratyphoid fever
• Skin and soft tissue infections
•  Dental abscess (as adjunct to surgical management) with spreading cellulitis
•  Prosthetic joint infections
• 
• Helicobacter pylori eradication
•  Lyme disease

Geramox is also indicated of the prophylaxis of endocarditis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.

 

 

 

In children with urinary tract infection, the need for investigation should be considered.
Parenteral therapy is indicated if the oral route is considered impracticable or unsuitable and particularly for the urgent treatment of severe episodes of the above conditions.
Oral prophylaxis of endocarditis: Geramox may be used for the prevention of bacteraemia associated

 

 

 

4.2 Posology and method of administration

 

 

Posology

 

 

 

The dose of Geramox that is selected to treat an individual infection should take into account:
The expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)
The severity and the site of the 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 period of treatment (see section 4.4 regarding prolonged therapy).

 

 

 

Adults   and children ≥ 40 kg Indication	Dose
Acute bacterial sinusitis	250 mg to 500 mg every 8 hours or 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours Acute cystitis may be treated with 3 g twice daily for one day
Asymptomatic bacteriuria in pregnancy
Acute pyelonephritis
Dental abscess with spreading cellulitis
Acute cystitis
Acute otitis media	500 mg every 8 hours, 750 mg to 1 g every 12 hours For severe infections 750 mg to 1 g every 8 hours for 10 days
Acute streptococcal tonsillitis and pharyngitis
Acute exacerbations of chronic bronchitis
Community acquired pneumonia	500 mg to 1 g every 8 hours
Typhoid and paratyphoid fever	500 mg to 2 g every 8 hours
Prosthetic joint infections	500 mg to 1 g every 8 hours
Prophylaxis of endocarditis	2 g orally, single dose 30 to 60 minutes before procedure
Helicobacter pylori     eradication	750 mg to 1 g 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 (see section 4.4)	Early stage: 500 mg to 1 g 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): 500 mg to 2 g every 8 hours up to a maximum of 6 g/day in

 

Consideration should be given to the official treatment guidelines for each indication

 

 

 

Standard adult dosage: The usual daily dosage is 750 mg in divided doses (i.e. 250 mg three times daily by the oral route).
In cases of severe infection the dosage may be doubled, or amoxicillin given by injection.
High dosage therapy: (maximum recommended oral dosage of 6 g daily in divided doses): A dosage of 3 g twice daily is recommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract.

Short course therapy:
Simple acute urinary tract infection: two 3 g doses with 10-12 hours between the doses.
Gonorrhoea: 3 g as a single dose.
Dental Abscess: two 3 g doses with 8 hours between the doses.

 

 

Prophylaxis of endocarditis

 

 

For dental procedures where an oral dose is appropriate:
Adults
3 g dose followed by (6 hours later) a further 3 g dose (or a 1 g IM if oral dose not tolerated) if necessary.
Patients with renal impairment: In renal impairment the excretion of the antibiotic will be delayed and depending on the degree of impairment it may be necessary to reduce the total daily dosage.

 

 

 

Adults     Glomerular filtration rate	Oral treatment
> 30 ml/min	No adjustment necessary
10-30 ml/min	Amox. Max 500 mg b.d.
< 10 ml/min	Amox. Max 500 mg/day

 

Paediatric population

 

 

Children weighing < 40 kg

 

 

 

The daily dosage for children is 40 - 90 mg/kg/day in two to three divided doses* (not exceeding 3 g/day) depending on the indication, severity of the disease and the susceptibility of the pathogen (see special dosage recommendations below and sections 4.4, 5.1 and 5.2).

*PK/PD data indicate that dosing three times daily is associated with enhanced efficacy, thus twice daily dosing is only recommended when the dose is in the upper range.

 

 

 

 

 

 

Children may be treated with amoxicillin capsules, dispersible tablets or suspensions.

 

Children weighing 40 kg or more should be prescribed the adult dosage.

 

 

 

Appropriate paediatric formulation, e.g. Geramox Powder for Oral suspension is recommended for children under six months of age.

 

 

 

Recommended doses:     Indication	Dose
Acute bacterial sinusitis	20 to 90 mg/kg/day in divided doses*
Acute otitis media
Community acquired pneumonia

* Twice daily dosing regimens should only be considered when the dose is in the upper range

 

Special dosage recommendation
Tonsillitis: 50 mg/kg/day in two divided doses.

Acute otitis media: In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, dosage regimens should be guided by national/local recommendations.

Early Lyme disease (isolated erythema migrans): 50 mg/kg/day in three divided doses, over 14-21 days.

Prophylaxis for endocarditis: 50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure.

 

 

 

Special population

 

 

 

 

Elderly

 

 

 

 

No dose adjustment is considered necessary.

 

 

 

Renal impairment

 

 

 

 

Dosage in impaired renal function:
The dose should be reduced in patients with severe renal function impairment. In patients with a creatinine clearance of less than 30 ml/min an increase in the dosage interval and a reduction in the total daily dose is recommended (see section 4.4 and 5.2).
Renal impairment in children under 40 kg:

 

 

Creatinine clearance GFR (ml/min)	Adults and children ≥ 40 kg   Dose	Interval between administration   Children < 40 kg *
> 30	Usual dose     No adjustment necessary	No adjustment necessary
10 – 30	Usual dose     Maximum 500 mg twice daily	15 mg/kg given twice daily (maximum 500 mg twice daily)     12 h   (corresponding to 2/3 of the dose)
< 10	Usual dose     Maximum 500 mg a day	15 mg/kg given as a singly dose (maximum 500 mg)     24 h   (corresponding to 1/3 of the dose)

*In the majority of cases, parenteral therapy is preferred.

 

 

 

 

For small children (younger than 6 years of age) appropriate paediatric formulation should be used.

 

 

 

In patients receiving haemodialysis:
Amoxicillin may be removed from the circulation by haemodialysis.

 

 

Haemodialysis
Adults and children ≥ 40 kg	15 mg/kg/day given as a single daily dose. Prior to haemodialysis one additional dose of 15 mg/kg should be administered. In order to restore circulating drug levels, another dose of 15 mg/kg should be administered after haemodialysis.

 

In patients receiving peritoneal dialysis:

Amoxicillin maximum 500 mg/day.

 

 

 

Hepatic impairment

 

 

 

 

Dose with caution and monitor hepatic function at regular intervals (see sections 4.4 and 4.8).

 

 

 

Method of administration

Geramox is for oral use.

 

 

The absorption of Geramox is virtually unimpaired by the presence of food

 

Swallow with water without opening capsule

 

 

 

 

Absorption of Geramox is unimpaired by food.

Therapy can be started parenterally according to the dosing recommendation of the intravenous formulation and continued with an oral preparation.

 

 

 

4.3 Contraindications

 

 

Hypersensitivity to the active substance,

 

beta-lactam antibiotics including to any of the penicillins, cephalosporins or to any of the excipients listed in section 6.1.

 

 

 

 

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

 

 

 

 

4.4 Special warnings and precautions for use

 

 

Hypersensitivity reactions

 

 

 

 

Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins

 

, or cephalosporins or other beta-lactam agents (see section 4.3 and 4.8). Cross-sensitivity between penicillins and cephalosporins is well documented.

 

 

 

 

 

Serious and occasionally fatal hypersensitivity reactions (anaphylaxis) has been reported in patients receiving

 

beta-lactam antibioticspenicillin therapy. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin should 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 (see section 5.1). This particularly applies when considering the treatment of patients with urinary tract infections and severe infections of the ear, nose and throat.

Convulsions

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 (see section 4.8).

Renal impairment

In patients with renal impairment, the dose should be adjusted according to the degree of impairment (see section 4.2).

Skin reactions

The occurrence at the treatment initiation of a feverish generalised erythema associated with pustula may be a symptom of acute generalised exanthemous pustulosis (AEGP, see section 4.8). This reaction requires amoxicillin discontinuation and contra-indicates any subsequent administration.

Amoxicillin 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.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction has been seen following amoxicillin treatment of Lyme disease (see section 4.8). It results directly from the bactericidal activity of amoxicillin on the causative bacteria of Lyme disease, the spirochaete 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 may occasionally result in overgrowth of non-susceptible organisms.

Antibiotic-associated colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during, or subsequent to, the administration of any antibiotics. Should antibiotic-associated colitis occur, amoxicillin should immediately be discontinued, a physician consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contra-indicated in this situation.

Prolonged therapy

Periodic assessment of organ system functions; including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Elevated liver enzymes and changes in blood counts have been reported (see section 4.8).

Anticoagulants

Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin. Appropriate monitoring should be undertaken when anticoagulants are prescribed concomitantly. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section 4.5 and 4.8).

Crystalluria

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. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.8 and 4.9).

Interference with diagnostic tests

Elevated serum and urinary levels of amoxicillin are likely to affect certain laboratory tests. Due to the 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.

 

 

 

 

Amoxicillin should be avoided if infectious mononucleosis (glandular fever) is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

Prolonged use of an anti-infective agent may occasionally result in overgrowth of non-susceptible organisms.

Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin 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.

Dosage should be adjusted in patients with renal impairment (see Section 4.2).

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.

Precaution should be taken in premature children and during the neonatal period: renal, hepatic and haematological functions should be monitored.

 

 

 

 

4.5 Interaction with other medicinal products and other forms of interaction

 

 

Probenecid

Concomitant use of probenecid is not recommended.

 

 

Probenecid decreases the renal tubular secretionexcretion of amoxicillin. Concurrent use with amoxicillin 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

 

 

 

 

In common with other antibiotics, amoxicillin may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives.

 

 

 

 

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However,

 

 

Itn the literature there are rare 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 (see sections 4.4 and 4.8).

 

 

 

 

Methotrexate

 

 

 

Interaction between amoxicillin and methotrexate leading to methotrexate toxicity has been reported. Serum methotrexate levels should be closely monitored in patients who receive amoxicillin and methotrexate simultaneously. Amoxicillin decreases the renal clearance of methotrexate, probably by competition at the common tubular secretion system

 

 

 

 

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

 

 

.

 

 

 

 

4.6 Fertility, pregnancy and lactation

 

 

Pregnancy

Animal studies with amoxicillin

 

do not indicate direct or indirect harmful effects with respect to reproductive toxicityhave shown no teratogenic effects. Limited data on the use of amoxicillin during pregnancy in humans do not indicate an increased risk of congenital malformationsThe product has been in extensive clinical use since 1972 and its suitability in human pregnancy has been well documented in clinical studies. Amoxicillin may be used in pregnancy when the potential benefits outweigh the potential risks associated with treatment.

 

Breast

 

-feeding

 

 

 

 

Amoxicillin may be administered during the period of lactation. With the exception of the risk of sensitisation associated with the excretion of trace quantities of amoxicillin in breast milk, there are no known detrimental effects for the infant

 

 

 

 

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

 

 

.

 

 

 

 

Fertility

There are no data on the effects of amoxicillin on fertility in humans. Reproductive studies in animals have shown no effects on fertility

 

 

 

 

4.7 Effects on ability to drive and use machines

 

 

No studies on the effects on the ability to drive and use machines have been performed.

 

 

 

 

However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines (see section 4.8).

 

 

 

 

 

4.8 Undesirable effects

 

 

The most commonly reported adverse drug reactions (ADRs) are diarrhoea, nausea and skin rash.

The ADRs derived from clinical studies and post-marketing surveillance with amoxicillin, presented by MedDRA System Organ Class are listed below.

 

 

 

 

The following convention has been utilised for the classification of undesirable side effects:

Very common (≥

 

1/10),
cCommon (≥1/100 to < 1/10),
uUncommon (≥1/1,000 to < 1/100),
rRare (≥1/10,000 to < 1/1,000),
vVery rare (< 1/10,000).

 

 

 

 

 

Not known (cannot be estimated from the available data)

 

 

 

 

The majority of the side effects listed below are not unique to amoxicillin and may occur when using other penicillin.

 

System Organ Class (SOC)						Frequency
Very common	Common		Uncommon		Rare		Very rare			Not known
Infections and infestations						Mucocutaneous candidiasis
Blood and lymphatic system disorders						Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin (see section 4.5)
Immune System disorders				As with other antibiotics, s     Severe allergic reactions, including angioneurotic oedema, anaphylaxis (see section 4.4), serum sickness and hypersensitivity vasculitis (see section 4.4).   If a hypersensitivity reaction is reported, the treatment must be discontinued. (See also skin and subcutaneous tissue disorders).				Jarisch-Herxheimer reaction (see section 4.4).
Nervous system disorders						Hyperkinesia, dizziness and convulsions   (see section 4.4). Convulsions may occur in patients with impaired renal function or in those receiving high doses.
Gastrointestinal disorders		*Clinical Trial Data:     Diarrhoea and nausea				*Clinical Trial Data:     Vomiting			Post-marketing Data:     Antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis) (see section 4.4).   Black hairy tongue
Hepatobiliary disorders						Hepatitis and cholestatic jaundice. A moderate rise in AST and/ or ALT. The significance of a rise in AST and/or ALT is unclear.
Skin and subcutaneous tissue disorders		*Clinical Trial Data:     Skin rash				*Clinical Trial Data:     Urticaria and pruritus			Post-marketing Data: Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute

System Organ Class (SOC)

Frequency

common	Common	Uncommon	Rare		Very rare	Not known
generalised exanthematous pustulosis (AGEP)   (see section 4.4)   (See also Immune system disorders)     .
Renal and urinary disorders				Interstitial nephritis, crystalluria (see section 4.9)
*The incidence of these adverse effects was derived from clinical studies involving a total of approximately 6,000 adults

 

4.9 Overdose

 

 

Symptoms

 

and signs of overdose

 

Gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) 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 (see sections 4.4 and 4.8).

 

 

Gross overdose will produce very high urinary concentrations, more so after parenteral administration. Problems are unlikely to occur if adequate fluid intake and urinary output are maintained; however amoxicillin crystalluria in some cases leading to renal failure, has been observed (see section 4.4).

 

Management

 

 

Treatment of intoxication

 

Gastrointestinal

 

 

Ssymptoms of water/electrolyte imbalance should be treated symptomatically with attention to the water/electrolyte balance. More specific measures may be necessary in patients with impaired renal function: the antibiotic is removed by haemodialysis.

 

 

 

 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

 

 

Pharmacotherapeutic group:

 

Beta-lactam antibacterials, penicillins, Ppenicillins 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 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.

 

 

Amoxicillin trihydrate is a broad spectrum antibiotic which possesses the safety profile of the penicillins and is rapidly bactericidal against a wide range of Gram-negative and Gram-positive organisms.

 

 

 

 

 

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) version 5.0.

 

 

 

Organism		MIC breakpoint (mg/L)
Susceptible ≤		Resistant >
Enterobacteriaceae	8 1		8
Staphylococcus     spp.	Note 2		Note 2
Enterococcus     spp.3	4		8
Streptococcus groups A, B, C and G	Note 4		Note 4
Streptococcus pneumoniae	Note 5		Note 5
Viridans group steprococci	0.5		2
Haemophilus influenzae	2 6		2 6
Moraxella catarrhalis	Note 7		Note 7
Neisseria meningitidis	0.125		1
Gram positive anaerobes except     Clostridium difficile 8	4		8
Gram negative anaerobes     8	0.5		2
Helicobacter pylori	0.125     9		0.125     9
Pasteurella multocida	1		1
Non- species related breakpoints     10	2		8
1     Wild 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   2     Most staphylococci are penicillinase producers, which are resistant to amoxicillin. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents.   3     Susceptibility to amoxicillin can be inferred from ampicillin   4     The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility.   5     Breakpoints 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.   6     Breakpoints are based on intravenous administration. Beta-lactamase positive isolates should be reported resistant.   7     Beta lactamase producers should be reported resistant   8     Susceptibility to amoxicillin can be inferred from benzylpenicillin.   9     The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type

The prevalence of resistance may vary geographically and with time for selected species, and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.   In vitro susceptibility of micro-organisms to Amoxicillin
Commonly Susceptible Species
Gram-positive aerobes	Enterococcus faecalis Beta-hemolytic streptococci (Groups A, B, C and G) Listeria monocytogenes
Species for which acquired resistance may be a problem
Gram-positive aerobes	Coagulase negative staphylococcus Staphylococcus aureus     £   Streptococcus pneumoniae Viridans group streptococcus
Gram-negative aerobes	Escherichia coli Haemophilus influenzae Helicobacter pylori Proteus mirabilis Salmonella     typhi   Salmonella     paratyphi   Pasteurella multocida
Gram-positive anaerobes	Clostridium     spp.
Gram-negative anaerobes	Fusobacterium     spp.
Other	Borrelia burgdorferi
Inherently resistant organisms
Gram-positive aerobes	Enterococcus faecium     †
Gram-negative aerobes	Acinetobacter     spp.   Enterobacter     spp.   Klebsiella     spp.   Pseudomonas     spp.
Gram-negative anaerobes	Bacteroides     spp. (many strains of Bacteroides fragilis are resistant).
Other	Chlamydia     spp.   Mycoplasma     spp.   Legionella     spp.
†   Natural intermediate susceptibility in the absence of acquired mechanism of resistance.   £   Almost all S.aureus are resistant to amoxicillin due to production of penicillinase. In addition, all methicillin-resistant strains are resistant to amoxicillin.

 

5.2 Pharmacokinetic properties

 

 

Amoxicillin trihydrate is well absorbed by the oral and parenteral routes, peak levels are achieved 1-2 hours after administration.

Oral administration produces high serum levels independent of the time at which the food is taken. Geramox gives good penetration into the bronchial secretions and the high urinary concentrations of unchanged antibiotic. The average serum half life is 60 minutes. Elimination is mainly via the urine.

Paediatric population

In preterm infants with gestational age 26-33 weeks, the total body clearance after intravenous dosing of amoxicillin, day 3 of life, ranged between 0.75 – 2 ml/min, very similar to the inulin clearance (GFR) in this population. Following oral administration, the absorption pattern and the bioavailability of amoxicillin in small children may be different to that of adults. Consequently, due to the decreased CL, the exposure is expected to be elevated in this group of patients, although this increase in exposure may in part be diminished by decreased bioavailability when given orally.

 

 

 

 

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.

 

 

 

The pharmacokinetic results for a study, in which an amoxicillin dose of 250 mg three times daily was administered in the fasting state to groups of healthy volunteers are presented below. C     max	T     max *	AUC     (0-24h)	T ½
(μg/ml)	(h)	(μg.h/ml)	(h)
3.3 ± 1.12	1.5 (1.0-2.0)	26.7 ± 4.56	1.36 ± 0.56
*median (range)

 

In the range 250 to 3000 mg the bioavailability is linear in proportion to dose (measured as Cmax and AUC). The absorption is not influenced by simultaneous food intake.

Haemodialysis can be used for elimination of amoxicillin.

Distribution

About 18% of total plasma amoxicillin is bound to protein and the apparent volume of distribution is around 0.3 to 0.4 l/kg.

Following intravenous administration, amoxicillin has 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.

From animal studies there is no evidence for significant tissue retention of drug-derived material. Amoxicillin, like most penicillins, can be detected in breast milk (see section 4.6).

Amoxicillin has been shown to cross the placental barrier (see section 4.6).

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 25 l/hour in healthy subjects. Approximately 60 to 70% of the amoxicillin is excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg dose of amoxicillin. Various studies have found the urinary excretion to be 50-85% for amoxicillin over a 24 hour period.

Concomitant use of probenecid delays amoxicillin excretion (see section 4.5).

 

 

 

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.

Gender

Following oral administration of amoxicillin/ to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of amoxicillin.

Renal impairment

The total serum clearance of amoxicillin decreases proportionately with decreasing renal function (see sections 4.2 and 4.4).

Hepatic impairment

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

 

 

 

5.3 Preclinical safety data

 

 

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Carcinogenicity studies have not been conducted with amoxicillin

 

 

There are no non-clinical safety data of relevance to the prescriber that are additional to those included in other sections of the SmPC.

 

 

 

 

 

7. MARKETING AUTHORISATION HOLDER

 

 

Generics [UK] Ltd

 

12 Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom.

 

 

 

 

section1:
Capsule, hard updated to Capsules, Hard

section 2:
Amoxicillin Trihydrate updated to amoxicillin trihydrate
Excipients with known effects: removed

secion 3:
Capsules, hard (capsule). updated to Capsule, hard.

section 4: 4.1
Therapeutic Indications updated to Therapeutic indications

section 4.2:
removed text: Geramox Capsules are for oral use.
removed text:The absorption of Geramox is virtually unimpaired by the presence of food.
renal impairment updated to read 'Patients with renal impairment.....'

Under section: Children weighing<40kg:
text added: Method of administration
                 Geramox is for oral use
                 The absorption of Geramox is virtually unimpaired by the presence of food.

section  4.3:
sentence updated from:
Use in patients with a history of hypersensitivity to the active substance, beta-lactum antiobiotics including penicillins, or Cephalosporins.
to:
Hypersensitivity to the active substance, beta-lactum antiobiotics including penicillins, cephalosporings or to any of the excipients listed in section 6.1.


section 4.4:
updated the sentence: Prolonged use of an anti-infective agent may occasionally result in overgroeth of non-susceptible super infection by organisms resistant to that anti-infective.
to:
Prolonged use of an anti-infective agent may occasionally result in overgroeth of non-susceptible organisms.

removed the sentence: Germamox Capsules contain soya oil. If you are allergic to peanut or soya, do not use this medicinal product.

section 4.8: Table updated
Gastrointestinal disorders...very rare.....removed 'Superficical tooth discolouration has been reported in children. Good overall hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.'
Renal and urinary tract disorders updated to Renal and urinary disorders.

Reporting of suspected adverse reactions updated to new HPRA details

secion 4.9
Section divided into 'Symptoms' & 'Management'
Sentence:' Symptoms of water/electrolyte imbalance should be treated symptomatically' moved under 'Management' section.

section 5.1:
added: Pharmacotherapeutic group: Beta-lactam antibacterials, penicillins, Penicillincs, Penicillincs with extended spectrum. ATC code: J01CA04

section 5.2:
sentence 'Amoxicillin Trihydrate is well absorbed by the oral and parenteral routes, peak levels are achieved 1-2 hours later after administration' updated to
'Amoxicillin trihydrate is well absorbed by the oral and parenteral routes, peak levels are achieved 1-2 hours after administration'

header 'Paediatric population' added

section 5.3 Preclinical Safety Data updated to Preclinical safety data
sentence 'There are no pre-clinical safety data.... updated to 'There are no non-clinical data'...

section 6.1
List of Excipients updated to List of excipients

Capsule contents:
Sodium starch glycolate Type A updated to Sodium starch glycolate
Microcrystalline cellulose updated to Cellulose, microcrystalline
Colloidal silicon dioxide updated to Silica, colloidal anydrous

section 6.6
removed text: 'of a used medicinal product or waste materials derived from such medicinal product and other handling of the product'.

Section 2 Excipients
Section 4.4 Special Warnings and precautions for use
Section 4.5 Interaction with other medicinal products & other forms of interaction
Section 4.8 Reporting of adverse reactions
Section 6.1 List of Excipients
Date of Revision

Numerous changes made to SPC for Article 45 safety variation & PSUR updates.
Sections updated:
4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.9, 5 & revision date

section 3 Pharmaceutical form updated
section 9 date of first authorisation/renewal updated to 30April2008
section 10 Date of revision of text updated to May 2010