4.          CLINICAL PARTICULARS

Method of administration

Shake the bottle before each dose (see section 6.6).
For instructions on reconstitution of the medicinal product before administration, see section 6.6.

4.4 Special warnings and precautions for use

Germentin contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. This medicine should be used with caution in patientsMay be harmful for people with phenylketonuria.

This medicinal productGermentin contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine

This medicinal productGermentin contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

6. PHARMACEUTICAL PARTICULARS
6.4        Special precautions for storage

 

Powder for oral suspension : Do not store above 25°C. Store in the original package in order to protect from moisture.

Reconstituted suspension. Stored in a refrigerator (2 to 8°C) and used within 7 days. Do not freeze.

 

6.6        Special precautions for disposal and other handling

Shake the bottle well before each dose.

 

The suspension may be diluted with an equal quantity of water to provide a half-strength suspension.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

 

7. MARKETING AUTHORISATION HOLDER

Mc Dermott Laboratories Limited
T/A Gerard Llaboratories,
35/36 Baldoyle Industrial Estate,
Grange Road,
Dublin 13.

10. DATE OF REVISION OF THE TEXT

OctoberSeptember 2017

4.4 Special warnings and precautions for use

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid and severe cutaneous adverse) reactions) have been reported in patients on 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/clavulanic acid therapy must be discontinued and appropriate alternative therapy instituted.

4.8 Undesirable effects

Skin and subcutaneous tissue disorders 7
Skin rash	Uncommon
Pruritus	Uncommon
Urticaria	Uncommon
Erythema multiforme	Rare
Stevens-Johnson syndrome	Not known
Toxic epidermal necrolysis	Not known
Bullous exfoliative-dermatitis	Not known
Acute generalised exanthemous pustulosis (AGEP)9	Not known
Drug reaction with eosinophilia and systemic symptoms (DRESS)	Not known

8. MARKETING AUTHORISATION NUMBER

PA 0577/34/002

10. DATE OF REVISION OF THE TEXT

SeptemberJuly 20176



4.2  Posology and method of administration
Older people Elderly

No dose adjustment is considered necessary.


4.4  Special warnings and precautions for use

Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents (see sections 4.3 and 4.8).

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

In the case that an infection is proven to be due to an amoxicillin-susceptible organisms(s) then consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin in accordance with official guidance.

This presentation of Germentin is not suitable for use when there is a high risk that the presumptive pathogens have reduced susceptibility or resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This presentation should not be used to treat penicillin-resistant S. pneumoniae.

Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).

Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin.

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

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

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

Amoxicillin/clavulanic acid should be used with caution in patients with evidence of hepatic impairment (see section 4.2, 4.3 & 4.8).

Hepatic events have been reported predominantly in males and older elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children. In all populations, signs and symptoms usually occur during or shortly after treatment but in some cases may not become apparent until several weeks after treatment has ceased. These are usually reversible. Hepatic events may be severe and, in extremely rare circumstances, deaths have been reported. These have almost always occurred in patients with serious underlying disease or taking concomitant medications known to have the potential for hepatic effects (see section 4.8).

Antibiotic-associated colitis has been reported with nearly all antibacterial agents including amoxicillin 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/clavulanic acid should immediately be discontinued, a physician be consulted and an appropriate therapy initiated. Anti-peristaltic medicinal products are contraindicated in this situation.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function is advisable during prolonged therapy. Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin/clavulanic acid. 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 sections 4.5 and 4.8).

In patients with renal impairment, the dose should be adjusted according to the degree of 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. In patients with bladder catheters, a regular check of patency should be maintained (see section 4.9).

During treatment with amoxicillin, enzymatic glucose oxidase methods should be used whenever testing for the presence of glucose in urine because false positive results may occur with non-enzymatic methods.

The presence of Cclavulanic acid in Germentin may cause a non-specific binding of IgG and albumin by red cell membranes leading to a false positive Coombs test.

There have been reports of positive test results using the Bio-Rad Laboratories Platelia Aspergillus EIA test in patients receiving amoxicillin/clavulanic acid who were subsequently found to be free of Aspergillus infection. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses with Bio-Rad Laboratories Platelia Aspergillus EIA test have been reported. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted cautiously and confirmed by other diagnostic methods.

4.6  Fertility, pregnancy and lactation

Breast-feeding

Both substances are excreted into breast milk (nothing is known of the effects of clavulanic acid on the breast-fed infant). Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant, so that breast-feeding might have to be discontinued. The possibility of sensitisation should be taken into account.

4.8  Undesirable effects

¹ See section 4.4
² See section 4.4
³ Nausea is more often associated with higher oral doses. If gastrointestinal reactions are evident, they may be reduced by taking amoxicillin/clavulanic acid Germentin at the start of a meal.
⁴ Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4)
⁵ A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown.
⁶ These events have been noted with other penicillins and cephalosporins (see section 4.4).
⁷ If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued (see section 4.4).
⁸ See section 4.9
⁹ See section 4.4
¹⁰ See sections 4.3 and 4.4
¹¹ Superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing.

5.1  Pharmacodynamic properties

Pharmacokinetic/pharmacodynamics PK/PD relationship

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

Breakpoints
¹ The reported values are for amoxicillin concentrations. For susceptibility testing purposes, the concentration of clavulanic acid is fixed at 2 mg/l.
² The reported values are oxacillin concentrations.
³ Breakpoint values in the table are based on ampicillin Ampicillin breakpoints.
⁴ The resistant breakpoint of R >8 mg/l ensures that all isolates with resistance mechanisms are reported resistant.
⁵ Breakpoint values in the table are based on benzylpenicillin breakpoints.

5.2  Pharmacokinetic properties

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 older 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.

5.3  Preclinical safety data

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

Repeat dose toxicity studies performed in dogs with amoxicillin/clavulanic acid demonstrate gastric irritancy and vomiting, and discoloured tongue.

Carcinogenicity studies have not been conducted with amoxicillin/clavulanic acid Germentin or its components.

section 2

Excipients with known effect: each 5 ml reconstituted suspension contains 8.5 mg aspartame (E951), less than 0.15mg sorbitol and less than 0.7mg glucose.

 

For the full list of excipients, see section 6.1.

 

section 4.2

Older people

 

No dose adjustment is considered necessary.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

section 4.3

Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients listed in section 6.1.

 

section 4.4

Germentin contains 2.5 mg of aspartame (E951) per ml, a source of phenylalanine. May be harmful for people with phenylketonuria.

 

Germentin contains maltodextrin (glucose). Patients with rare glucose-galactose malabsorption should not take this medicine

 

Germentin contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

section 4.5

 

Allopurinol

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

 

Mycophenolate mofetil

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

table 4.8

Aseptic meningitis

Not known

section 4.8

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

section 5.3

5.3       Preclinical safety data

 

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

section 6.1

PHARMACEUTICAL PARTICULARS

 

6.1       List of excipients

 

Citric acid, anhydrous

Sodium citrate

Aspartame (E951)

Talc

Guar galactomannan

Silicon dioxide

Flavouring agents (lemon containing glucose and sorbitol, peach-apricot containing sorbitol (E420) and orange containing essence of bergamot)

section 6.3 & 6.4

6.3       Shelf life

 

Dry powder: 3 years

Reconstituted suspension: 7 days when refrigerated (2 to 8°C).

 

6.4       Special precautions for storage

 

Powder for oral suspension: Do not store above 25°C. Store in the original package in order to protect from moisture.

Reconstituted suspension. Stored in a refrigerator (2 to 8°C) and used within 7 days. Do not freeze.

 

section 6.5

Not all pack sizes may be marketed.

section 6.6

6.6       Special precautions for disposal and other handling

 

Check cap seal is intact before using. Shake bottle to loosen powder. Add volume of water (as indicated below) invert and shake well. Alternatively fill the bottle with water to just below the mark on bottle label, invert and shake well, then top up with water exactly to the mark, invert and again shake well.

 

Strength	Volume of water to be added at reconstitution (ml)	Final volume of reconstituted oral suspension (ml)
125 mg/31.25 mg/5 ml	Make up to mark	60
	95	100

Shake the bottle well before each dose.

 

The suspension may be diluted with an equal quantity of water to provide a half-strength suspension.

Section 10:Date of revision of the text amended to September 2010

SPC updated as a result of an Article 30 refferal.Significant updates to text too many to detail here.

 following approval of variation to update excipients i.e glucose and sorbitol. Section 2 and 4.4 updated

 following approval of variation to update excipients (sorbitol and glucose) section 2 and 4.4 were updated accordingly

 update of SmPC following renewal approval 0108