amoxicillin sugar free suspension bp 125mg/5ml amoxicillin ... · amoxicillin sugar free suspension...

AMOXICILLIN SUGAR FREE SUSPENSION BP 125MG/5ML AMOXICILLIN SUGAR FREE SUSPENSION BP 250MG/5ML

PL 21880/0123-4

UK PAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment 0 Summary of Product Characteristics Page 11 Label-Leaflet Page 23

MHRA PAR-Amoxicillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml 1


PL 21880/0123-4

LAY SUMMARY The MHRA granted Medreich Plc Marketing Authorisations (licences) for the medicinal products Amoxicillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml on 17 November 2011. These are prescription-only medicines (POM). Amoxicillin is an antibiotic for treating infections. It belongs to a group of antibiotics called “Penicillins” and works by killing the bacteria that can cause infections. Amoxicillin can treat a wide range of infections including those of the chest (bronchitis or pneumonia), ears (otitis media), nose, throat, urinary tract, heart, skin and teeth and also for prevention of endocarditis (inflammation of the heart lining, heart muscles and heart valves) during dental procedures. It is also used to treat typhoid fever, gonorrhoea (a sexually transmitted infection) and other gynaecological infections, infections caused by a group of bacteria called Salmonella, inflammation of abdominal linings (peritonitis), inflammation of the bone and bone marrow (osteomyelitis) and inflammation of the membranes that cover the brain and spinal cord (meningitis). These applications are duplicates of previously granted applications for Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8), which were granted to the Marketing Authorisation Holder LPC Medical (UK) Limited on 07 February 2005. No new or unexpected safety concerns arose from these simple applications and it was, therefore, judged that the benefits of taking Amoxicillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml outweigh the risks; hence Marketing Authorisations have been granted.



PL 21880/0123-4

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 7

Clinical assessment (including statistical assessment)

Page 8

Overall conclusions and risk benefit assessment Page 9


INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Marketing Authorisations for the medicinal products Amoxicillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml on (PL 21880/0123-4) to Medreich Plc on 17 November 2011. These are prescription-only medicines (POM). Amoxicillin is a broad spectrum antibiotic indicated for the treatment of commonly-occurring bacterial infections including: acute and chronic bronchitis, pneumonia, ear, nose and throat infections, otitis media, urinary tract infection, gonorrhoea, invasive salmonellosis, gynaecological infections, peritonitis osteomyelitis, meningitis, endocarditis, typhoid fever, and prophylaxis of endocarditis in patients at risk from such procedures as dental extractions. Amoxicillin is well absorbed by the oral route. Oral administration, usually at a dosage of three times a day, produces high serum levels independent of the time at which food is taken. Amoxicillin gives good penetration into bronchial secretions and high urinary concentrations of unchanged antibiotic. It is rapidly bactericidal and possesses the safety profile of penicillin. These applications were submitted as simple abridged applications according to Article 10c (formerly Article 10.1(a)(i)) of Directive 2001/83/EC, cross-referring to Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8) approved on 07 February 2005 to the Marketing Authorisation Holder LPC Medical (UK) Limited. No new data were submitted nor were necessary for these simple applications, as the data are identical to that of the previously granted cross-reference products.


PHARMACEUTICAL ASSESSMENT LICENCE NO: PL 21880/0123-4 PROPRIETARY NAME: Amoxicillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml. COMPANY NAME: Medreich Plc E.C. ARTICLE: Article 10(c) of Directive 2001/83/EC LEGAL STATUS: POM 1 INTRODUCTION These are simple, informed consent applications for Amoxicillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml submitted under Article 10(c) of Directive 2001/83/EC. The applications cross-refer to Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8) approved on 07 February 2005, to LPC Medical (UK) Limited. 2 MARKETING AUTHORISATION APPLICATION (MAA) 2.1 Name(s) The proposed names of the products are Amoxicillin Sugar Free Suspension BP 125mg/5ml and Amoxicillin Sugar Free Suspension BP 250mg/5ml.The products have been named in line with current requirements. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes The products contains amoxicillin trihydrate BP equivalent to amoxicillin BP 125 mg/5ml or 250 mg/5ml and are packaged in 100 ml high density polyethylene (HDPE) bottles with tamper-evident and child resistant cap The proposed shelf life is 3 years (unopened) and 7 days after reconstitution with the advice to ‘Store below 25°C’. The proposed shelf-life and storage conditions are consistent with the details registered for the cross-referenced products. 2.3 Legal status On approval, the products will be available by supply through pharmacies, subject to a medical prescription (POM). 2.4 Marketing Authorisation Holder/Contact Persons/Company The proposed Marketing Authorisation Holder is Medreich Plc, 9 Royal Parade, Kew Gardens Surrey, UK. The Qualified Person (QP) responsible for pharmacovigilance is stated and their CV is included. 2.5 Manufacturers The proposed manufacturing site is consistent with that registered for the reference products and evidence of compliance with current Good Manufacturing Practice has been provided. 2.6 Qualitative and quantitative composition The compositions are consistent with the details registered for the reference products.


2.7 Manufacturing process The manufacturing process is consistent with the details registered for the reference products. 2.8 Finished product/shelf-life specification The finished product specifications are in line with the details registered for the reference products. 2.9 Drug substance specification The drug substance specifications are consistent with the details registered for the cross-reference products. 2.10 TSE Compliance None of the excipients contain materials of animal or human origin. This is consistent with the reference products. 2.11 Bioequivalence No bioequivalence data are required to support these informed consent applications, as the proposed products are manufactured to the same formula utilising the same process as the reference products Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8). 3 EXPERT REPORT The applicant has included a detailed pharmaceutical expert report, written by an appropriately qualified person. 4. PRODUCT NAME & APPEARANCE See 2.1 for details of the proposed product names. The appearance of the products is identical to that of the reference products. 5. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The proposed SmPCs are consistent with the details registered for the reference products. 6. PATIENT INFORMATION LEAFLET (PIL)/LABELLING PIL The patient information leaflet has been prepared in line with the details registered for the reference products. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The leaflet conforms to the requirements. The test shows that the patients/users are able to act upon the information that the leaflet contains. Label-leaflet The proposed artwork complies with the relevant statutory requirements. In line with current legislation, the applicant has also included the name of the product in Braille on the outer packaging and has included sufficient space for a standard UK pharmacy dispensing label. 7. CONCLUSIONS The data submitted with these applications is acceptable. The grant of Marketing Authorisations is recommended.


NON-CLINICAL ASSESSMENT

As these applications are identical to the reference products Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8), no new non-clinical data have been supplied with these applications and none are required. A non-clinical expert report has been written by a suitably qualified person and is satisfactory. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environment Risk Assessment (ERA). As these applications are for identical versions of already authorised reference products, it is not expected that the environmental exposure to amoxicillin will increase following the marketing approval of the proposed products. .


CLINICAL ASSESSMENT

As these applications are identical to the reference products Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8), no new clinical data have been supplied with these applications and none are required. A clinical expert report has been written by a suitably qualified person and is satisfactory. The Marketing Authorisation Holder has provided a suitable pharmacovigilance system that fulfils the requirements and provides adequate evidence that the Marketing Authorisation Holder has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country.


OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT

QUALITY The data for these applications are consistent with that previously assessed for the reference products and as such have been judged to be satisfactory. NON-CLINICAL No new non-clinical data were submitted and none are required for applications of this type. EFFICACY These applications are identical to the previously granted applications for Amoxicillin Sugar Free Suspension 125mg/5ml and 250mg/5ml (PL 19348/0067-8), granted to LPC Medical (UK) on 07 February 2005. SAFETY No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE The SmPCs, PIL and labelling are satisfactory and consistent with that for the reference products. Colour mock-ups of the labelling have been provided and are satisfactory. The approved labelling artwork complies with statutory requirements. The name of the product in Braille appears on the outer packaging. BENEFIT/RISK ASSESSMENT The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. The applicant’s products are identical to the reference products. Extensive clinical experience with amoxicillin is considered to have demonstrated the therapeutic values of the compound. The benefit/risk is therefore considered to be positive.



PL 21880/0123-4

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Marketing Authorisation Applications on 02

November 2010.

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 24 January 2011.

3 Following assessment of the applications the MHRA requested further information on 02 March 2011 and 20 May 2011.

4 The applicant responded to the MHRA’s request, providing further information on 22 March 2011 and 20 September 2011.

5 The applications were determined on 17 November 2011.


SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Amoxicillin Sugar Free Suspension BP 125mg/5ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Amoxicillin Sugar Free Suspension 125mgl5ml contains Amoxicillin Trihydrate BP equivalent to Amoxicillin BP 125mg.

3 PHARMACEUTICAL FORM Pale yellow powder for reconstitution as suspension

4 CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS Amoxicillin is a broad spectrum antibiotic indicated for the treatment of commonly -occurring bacterial infections including acute and chronic bronchitis, pneumonia, ear, nose and throat infections, otitis media, urinary tract infection, gonorrhoea, invasive salmonellosis, gynaecological infections, peritonitis, osteomyelitis, meningitis, endocarditis, typhoid fever, and prophylaxis of endocarditis in patients at risk from such procedures as dental extractions. In some of these infections initiations of treatment of indeed the whole course of treatment may need to be by the partenral route. In children with urinary tract infection, the need for further clinical investigation should be considered.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION Route of adminstration Oral Adult dosage (including elderly patients): Normal Adult Dosage 250mg every eight hours which may be doubled in severe infections. High Dosage Therapy Up to a maximum of 6g daily in divided doses. A dosage of 3g twice daily isrecommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract. Simple Acute Urinary Tract Infections Two 3g doses with 10-12 hours between doses. Gonorrhoea 3g single dose in combination with 1g Probenecid. Dental Prophylaxis For patients under going extraction, scaling or surgery involving gingival tissues and who have not received penicillin treatment in the previous month. (If penicillin has been given within the previous month, a prophylaxis with an alternative type of antibiotic should be considered.) The following categories of patients should be referred to the hospital: A) Patients who will require a general anaesthetic who have been given a penicillin in the previous month. B) Patients with a prosthetic heart valves whether or not they are to receive a general anaesthetic. C) Patients who have had one or more attacks of endocarditis. In dental prophylaxis, the normal adult dose is 3g orally given one hour before treatment with a second dose if considered necessary given six hours later. Children (up to ten years of age): 125mg every eight hours which may be doubled in severe infections. In dental prophylaxis, the same precautions apply as with adults, the normal dosage in children, 5 - 10 years is half the adult dose and quarter the adult dose in children under 5 years.


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 weighing more than 40 kg should be given the usual adult dosage. 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 14-21days. Prophylaxis for endocarditis: 50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure. 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 ml/min

Dose Interval between administration

> 30 Usual dose No adjustment necessary

10 – 30 Usual dose 12 h (corresponding to 2/3 of the dose)

< 10 Usual dose 24 h (corresponding to 1/3 of the dose)

Dental prophylaxis involving general anaesthesia In patients under going general anaesthesia, if oral amoxicillin is considered appropriate, the 3g may be given four hours prior to anesthesia and 3g, six hours after anesthesia.

4.3 CONTRAINDICATIONS Amoxicillin is a penicillin and should not be given to penicillin-hypersensitive patients and patients with hypersensitivity to the listed ingredients. Attention should be paid to possible cross-sensitivity with other beta-Iactam antibiotics e.g. cephalosporins.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins. 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 hypersensitivity to beta-Iactam antibiotics (see 4.3). Erythematous (morbilliform) rashes have been associated with glandular fever in patients receiving amoxicillin. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria (see Section 4.9 Overdose).


In patients with renal impairment, the rate of excretion of amoxicillin will be reduced depending on the degree of impairment and it may be necessary to reduce the total daily unit amoxicillin dosage accordingly. 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 When given to patients taking combination oral contraceptives, amoxicillin can cause a reduction in their effect and patients should be warned accordingly. Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Penicillins reduce excretion of methotrexate (increased risk of toxicity) Excretion of penicillins reduced by sulfinpyrazone It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods. Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin may result in increased and prolonged blood levels of amoxicillin.

4.6 FERTILITY, PREGNANCY AND LACTATION

Use in Pregnancy: It is understood that animal studies with amoxicillin have shown no teratogenic effects. The product has been in extensive clinical use since 1972 and its suitability in human pregnancy has been well documented in clinical studies. When antibiotic therapy is required during pregnancy, amoxicillin may be considered appropriate when the potential benefits outweigh the potential risks associated with treatment. Use in Lactation: Amoxicillin may be given during 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 breast-fed infant.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES No known adverse effects are reported.

4.8 UNDESIRABLE EFFECTS The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000). The majority of side effects listed below are not unique to amoxicillin and may occur when using other penicillins. Unless otherwise stated, the frequency of adverse events has been derived from more than 30 years of post-marketing reports. Blood and lymphatic system disorders Very rare: Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin (see Section 4.5 – Interaction with other Medicaments and other Forms of Interaction)


Immune system disorders Very rare: As with other antibiotics, severe allergic reactions, including angioneurotic oedema, anaphylaxis (see Section 4.4 - Special Warnings and Precautions for Use), serum sickness and hypersensitivity vasculitis. If a hypersensitivity reaction is reported, the treatment must be discontinued. (See also Skin and subcutaneous tissue disorders). Nervous system disorders Very rare: Hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses. Gastro intestinal disorders Clinical Trial Data *Common: Diarrhoea and nausea. *Uncommon: Vomiting. Post-marketing Data Very rare: Mucocutaneous candidiasis and antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis). Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. Hepato-biliary disorders Very rare: Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. The significance of a rise in AST and/or AL T is unclear. Skin and subcutaneous tissue disorders Clinical Trial Data *Common: Skin rash *Uncommon: Urticaria and pruritus Post-marketing Data Very rare: Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (See also Immune system disorders). Renal and urinary tract disorders Very rare: Interstitial nephritis. Very rare: Crystalluria (see Section 4.9 Overdose) *The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin.

4.9 OVERDOSE Gross overdosage will produce very high urinary concentrations. Problems are unlikely if adequate fluid intake and urinary output are maintained; however crystalluria is a possibility. 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 Amoxicillin is well absorbed by the oral route. Oral administration, usually at convenient t.d.s. dosage, produces high serum levels independent of the time at which food is taken. Amoxicillin gives good penetration into bronchial secretions and high urinary concentrations of unchanged antibiotic. It is rapidly bactericidal and possesses the safety profile of penicillin.


5.2 PHARMACOKINETIC PROPERTIES Amoxicillin is rapidly absorbed when given by mouth; it is not converted to ampicillin. It is widely distributed and is reported to produce peak antibiotic plasma concentrations that are up to twice as high as those from the same dose of ampicillin. Peak plasma-amoxicillin concentrations of about 5 g per ml have been observed 2 hours after a dose of 250mg, with detectable amounts present for up to 8 hours. Doubling the dose can produce double the concentration. The presence of food in the stomach does not appear to diminish absorption significantly. Up to 20% is bound to plasma proteins in the circulation and plasma half-lives of about one hour have been reported. Amoxicillin diffuses across the placenta; little appears to be excreted in breast milk. It penetrates will into purulent and mucoid sputum and low concentrations have been found in ocular fluid. 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 inuline 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.

5.3 PRECLINICAL SAFETY DATA Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS Sodium Benzoate BP Disodium Edetate BP Sodium Citrate BP Citric Acid BP Colloidal Anhydrous Silica BP Sorbitol Saccharin Sodium BP Banana Flavour Quinoline Yellow, EI04 Xantham Gum USNF

6.2 INCOMPATIBILITIES None Known

6.3 SHELF LIFE 3 years unopened. 7 days after reconstitution.

6.4 SPECIAL PRECAUTIONS FOR STORAGE Store below 25°C.

6.5 NATURE AND CONTENTS OF CONTAINER High density polyethylene bottles with tamper-evident and child resistant cap of the appropriate size to accommodate 100ml. And High density polyethylene bottles with tamper-evident cap of the appropriate size to accommodate 100ml.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL Quantities of potable water to be added are: 84ml to reconstitute 100ml of 125/5ml Amoxicillin Sugar Free Suspension.


7 MARKETING AUTHORISATION HOLDER Medreich Plc 9 Royal Parade Kew Gardens Surrey TW9 3QD England

8 MARKETING AUTHORISATION NUMBER(S) PL 21880/0123

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/11/2011 10 DATE OF REVISION OF THE TEXT

17/11/2011


1 NAME OF THE MEDICINAL PRODUCT Amoxicillin Sugar Free Suspension BP 250mgl5ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Amoxicillin Sugar Free Suspension 250mgl5ml contains Amoxicillin Trihydrate BP equivalent to Amoxicillin BP 250mg.

3 PHARMACEUTICAL FORM Pale yellow powder for reconstitution as suspension

4 CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS Amoxicillin is a broad spectrum antibiotic indicated for the treatment of commonly -occurring bacterial infections including acute and chronic bronchitis, pneumonia, ear, nose and throat infections, otitis media, urinary tract infection, gonorrhoea, invasive salmonellosis, gynaecological infections, peritonitis, osteomyelitis, meningitis, endocarditis, typhoid fever, and prophylaxis of endocarditis in patients at risk from such procedures as dental extractions. In some of these infections initiations of treatment of indeed the whole course of treatment may need to be by the partenral route. In children with urinary tract infection, the need for further clinical investigation should be considered.

4.2 POSOLOGY AND METHOD OF ADMINISTRATION Route of adminstration Oral Adult dosage (including elderly patients): Normal Adult Dosage 250mg every eight hours which may be doubled in severe infections. High Dosage Therapy Up to a maximum of 6g daily in divided doses. A dosage of 3g twice daily isrecommended in appropriate cases for the treatment of severe or recurrent purulent infection of the respiratory tract. Simple Acute Urinary Tract Infections Two 3g doses with 10-12 hours between doses. Gonorrhoea 3g single dose in combination with 1g Probenecid. Dental Prophylaxis For patients under going extraction, scaling or surgery involving gingival tissues and who have not received penicillin treatment in the previous month. (If penicillin has been given within the previous month, a prophylaxis with an alternative type of antibiotic should be considered.) The following categories of patients should be referred to the hospital: A) Patients who will require a general anaesthetic who have been given a penicillin in the previous month. B) Patients with a prosthetic heart valves whether or not they are to receive a general anaesthetic. C) Patients who have had one or more attacks of endocarditis. In dental prophylaxis, the normal adult dose is 3g orally given one hour before treatment with a second dose if considered necessary given six hours later. Children (up to ten years of age): 125mg every eight hours which may be doubled in severe infections. In dental prophylaxis, the same precautions apply as with adults, the normal dosage in children, 5 - 10 years is half the adult dose and quarter the adult dose in children under 5 years. 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 weighing more than 40 kg should be given the usual adult dosage. 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 14-21days. Prophylaxis for endocarditis: 50 mg amoxicillin/kg body weight given as a single dose one hour preceding the surgical procedure. 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 ml/min

Dose Interval between administration

> 30 Usual dose No adjustment necessary

10 – 30 Usual dose 12 h (corresponding to 2/3 of the dose)

< 10 Usual dose 24 h (corresponding to 1/3 of the dose)

Dental prophylaxis involving general anaesthesia In patients under going general anaesthesia, if oral amoxicillin is considered appropriate, the 3g may be given four hours prior to anesthesia and 3g, six hours after anesthesia.

4.3 CONTRAINDICATIONS Amoxicillin is a penicillin and should not be given to penicillin-hypersensitive patients and patients with hypersensitivity to the listed ingredients. Attention should be paid to possible cross-sensitivity with other beta-Iactam antibiotics e.g. cephalosporins.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE Before initiating therapy with amoxicillin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins. 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 hypersensitivity to beta-Iactam antibiotics (see 4.3). Erythematous (morbilliform) rashes have been associated with glandular fever in patients receiving amoxicillin. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxicillin crystalluria (see Section 4.9 Overdose). In patients with renal impairment, the rate of excretion of amoxicillin will be reduced depending on the degree of impairment and it may be necessary to reduce the total daily unit amoxicillin dosage accordingly.


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 When given to patients taking combination oral contraceptives, amoxicillin can cause a reduction in their effect and patients should be warned accordingly. Concurrent administration of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently. Penicillins reduce excretion of methotrexate (increased risk of toxicity) Excretion of penicillins reduced by sulfinpyrazone It is recommended that when testing for the presence of glucose in urine during amoxicillin treatment, enzymatic glucose oxidase methods should be used. Due to the high urinary concentrations of amoxicillin, false positive readings are common with chemical methods. Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin may result in increased and prolonged blood levels of amoxicillin.

4.6 FERTILITY, PREGNANCY AND LACTATION

Use in Pregnancy: It is understood that animal studies with amoxicillin have shown no teratogenic effects. The product has been in extensive clinical use since 1972 and its suitability in human pregnancy has been well documented in clinical studies. When antibiotic therapy is required during pregnancy, amoxicillin may be considered appropriate when the potential benefits outweigh the potential risks associated with treatment. Use in Lactation: Amoxicillin may be given during 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 breast-fed infant.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES No known adverse effects are reported.

4.8 UNDESIRABLE EFFECTS The following convention has been utilised for the classification of undesirable effects:- Very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), very rare (<1/10,000). The majority of side effects listed below are not unique to amoxicillin and may occur when using other penicillins. Unless otherwise stated, the frequency of adverse events has been derived from more than 30 years of post-marketing reports. Blood and lymphatic system disorders Very rare: Reversible leucopenia (including severe neutropenia or agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin (see Section 4.5 – Interaction with other Medicaments and other Forms of Interaction) Immune system disorders Very rare: As with other antibiotics, severe allergic reactions, including angioneurotic oedema, anaphylaxis (see Section 4.4 - Special Warnings and Precautions for Use), serum sickness and hypersensitivity vasculitis.


If a hypersensitivity reaction is reported, the treatment must be discontinued. (See also Skin and subcutaneous tissue disorders). Nervous system disorders Very rare: Hyperkinesia, dizziness and convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses. Gastro intestinal disorders Clinical Trial Data *Common: Diarrhoea and nausea. *Uncommon: Vomiting. Post-marketing Data Very rare: Mucocutaneous candidiasis and antibiotic associated colitis (including pseudomembraneous colitis and haemorrhagic colitis). Superficial tooth discolouration has been reported in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing. Hepato-biliary disorders Very rare: Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. The significance of a rise in AST and/or AL T is unclear. Skin and subcutaneous tissue disorders Clinical Trial Data *Common: Skin rash *Uncommon: Urticaria and pruritus Post-marketing Data Very rare: Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis and acute generalised exanthematous pustulosis (AGEP) (See also Immune system disorders). Renal and urinary tract disorders Very rare: Interstitial nephritis. Very rare: Crystalluria (see Section 4.9 Overdose) *The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking amoxicillin.

4.9 OVERDOSE Gross overdosage will produce very high urinary concentrations. Problems are unlikely if adequate fluid intake and urinary output are maintained; however crystalluria is a possibility. 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 Amoxicillin is well absorbed by the oral route. Oral administration, usually at convenient t.d.s. dosage, produces high serum levels independent of the time at which food is taken. Amoxicillin gives good penetration into bronchial secretions and high urinary concentrations of unchanged antibiotic. It is rapidly bactericidal and possesses the safety profile of penicillin.

5.2 PHARMACOKINETIC PROPERTIES Amoxicillin is rapidly absorbed when given by mouth; it is not converted to ampicillin. It is widely distributed and is reported to produce peak antibiotic plasma concentrations that are up to twice as high as those from the same dose of ampicillin. Peak plasma-amoxicillin concentrations of about 5 g per ml


have been observed 2 hours after a dose of 250mg, with detectable amounts present for up to 8 hours. Doubling the dose can produce double the concentration. The presence of food in the stomach does not appear to diminish absorption significantly. Up to 20% is bound to plasma proteins in the circulation and plasma half-lives of about one hour have been reported. Amoxicillin diffuses across the placenta; little appears to be excreted in breast milk. It penetrates will into purulent and mucoid sputum and low concentrations have been found in ocular fluid. 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 inuline 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.

5.3 PRECLINICAL SAFETY DATA

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS Sodium Benzoate BP Disodium Edetate BP Sodium Citrate BP Citric Acid BP Colloidal Anhydrous Silica BP Sorbitol Saccharin Sodium BP Banana Flavour Quinoline Yellow, EI04 Xantham Gum USNF

6.2 INCOMPATIBILITIES None Known

6.3 SHELF LIFE 3 years unopened. 7 days after reconstitution.

6.4 SPECIAL PRECAUTIONS FOR STORAGE Store below 25°C.

6.5 NATURE AND CONTENTS OF CONTAINER High density polyethylene bottles with tamper-evident and child resistant cap of the appropriate size to accommodate 100ml. And High density polyethylene bottles with tamper-evident cap of the appropriate size to accommodate 100ml.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL Quantities of potable water to be added are: 84ml to reconstitute 100ml of 125/5ml Amoxicillin Sugar Free Suspension.

7 MARKETING AUTHORISATION HOLDER Medreich Plc 9 Royal Parade Kew Gardens Surrey TW9 3QD


England

8 MARKETING AUTHORISATION NUMBER(S) PL 21880/0124

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 17/11/2011 10 DATE OF REVISION OF THE TEXT

17/11/2011



PRODUCT INFORMATION LEAFLET AND LABEL

icillin Sugar Free Suspension BP 125mg/5ml and 250mg/5ml 25

MHRA PAR-Amox

amoxicillin sugar free suspension bp 125mg/5ml amoxicillin ... · amoxicillin sugar free suspension...

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