CURAM^® DUO 400/57

MIMS Revision Date: 01 August 2024

1 Name of Medicine

Amoxicillin trihydrate and potassium clavulanate.

2 Qualitative and Quantitative Composition

Curam Duo 400/57 contains 400 mg/5 mL amoxicillin (as trihydrate) and 57 mg/5 mL clavulanic acid (as potassium clavulanate).
Excipients with known effect. When reconstituted as directed, Curam Duo 400/57 contains aspartame 8.5 mg/5 mL.
Each 5 mL of suspension contains 0.29 mmol of potassium. Also contains sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for suspension: off-white powder and off-white suspension.

4 Clinical Particulars

4.1 Therapeutic Indications

Curam Duo 400/57 (amoxicillin and clavulanic acid) is indicated for the short-term treatment of the following bacterial infections when caused by sensitive organisms (see Section 5.1 Pharmacodynamic Properties, Microbiology):
skin and skin structure infections;
urinary tract infections (complicated and uncomplicated);
upper respiratory tract infections including sinusitis and otitis media;
lower respiratory tract infections including acute exacerbations of chronic bronchitis and community acquired pneumonia.
Appropriate culture and susceptibility studies should be performed to identify the causative organism(s) and determine its (their) susceptibility to Curam Duo 400/57 (amoxicillin and clavulanic acid). However, when there is reason to believe an infection may involve any of the beta-lactamase producing organisms listed in Microbiology, therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies. Once these results are known, therapy should be adjusted if appropriate.
The treatment of mixed infections caused by amoxicillin susceptible organisms and beta-lactamase producing organisms susceptible to Curam Duo 400/57 (amoxicillin and clavulanic acid) should not require the addition of another antibiotic due to the amoxicillin content of Curam Duo 400/57.

4.2 Dose and Method of Administration

Dosage. Adults. Curam Duo 400/57 (amoxicillin and clavulanic acid) should be taken immediately before or with the first mouthful of food, to minimise potential gastrointestinal intolerance and to optimise absorption.
Infants and children. Children aged 2 months up to 12 years. For moderate to severe infections the dose should be 45 mg/kg/day, based on the amoxicillin component, (or clavulanic acid 6.4 mg/kg/day) in two divided doses every 12 hours.
The children's dosage is intended for individuals whose weight will not cause dosage to be calculated greater than that recommended for adults.
There are no clinical data available for Curam Duo 400/57 (amoxicillin and clavulanic acid) in infants with immature renal function. The use of Curam Duo 400/57 (amoxicillin and clavulanic acid) in this group cannot be recommended.
Method of administration. Directions for reconstituting the oral suspension. Prepare the oral suspension at time of dispensing as follows. Tap bottle until all the powder flows freely. Add approximately one-half of the total amount of water for reconstitution and shake vigorously to suspend powder. Add remainder of the water and again shake vigorously.
Add 55 mL of water to 10.1 g of the powder for reconstitution of 60 mL ready for use suspension.
Add 63 mL of water to 11.80 g of the powder for reconstitution of 70 mL ready for use suspension.
Add 68 mL of water to 12.60 g of the powder for reconstitution of 75 mL ready for use suspension.
Add 89 mL of water to 16.50 g powder for reconstitution of 100 mL ready for use suspension.
Add 125 mL of water to 23.10 g of the powder for reconstitution of 140 mL ready for use suspension.
Each 5 mL will contain amoxicillin (as the trihydrate) 400 mg and clavulanic acid (as the potassium salt) 57 mg.
Shake oral suspension well before using. Reconstituted suspension must be stored under refrigeration (2°C to 8°C) and discarded after seven days.
Dosage adjustment. Renal impairment. Curam Duo 400/57 (amoxicillin and clavulanic acid) is not recommended for use in children with renal impairment or in haemodialysis. In children with renal impairment, dosage should be adjusted according to degree of impairment using the alternative Curam 125/31.25 formulation.
Hepatic impairment. Data are currently insufficient for a dosage recommendation. Dose with caution and monitor hepatic function at regular intervals.

4.3 Contraindications

Curam Duo 400/57 (amoxicillin and clavulanic acid) is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients.
Curam Duo 400/57 (amoxicillin and clavulanic acid) is contraindicated in patients with a history of allergic reaction to beta-lactams, e.g. penicillins, cephalosporins, carbapenems or monobactams.
Curam Duo 400/57 (amoxicillin and clavulanic acid) is also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanic acid.

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances:
Curam Duo 400/57 (amoxicillin and clavulanic acid) contains aspartame, and should be used with caution in patients with phenylketonuria.
Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.
Serious and occasionally fatal hypersensitivity (including anaphylactoid and severe cutaneous adverse reactions) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before initiating therapy with any penicillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other allergens. Hypersensitivity reactions can also progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. Presenting symptoms of such reactions can include chest pain occurring in association with an allergic reaction to amoxicillin/clavulanic acid (see Section 4.8 Adverse Effects (Undesirable Effects)). If an allergic reaction occurs, Curam Duo 400/57 (amoxicillin and clavulanic acid) should be discontinued and the appropriate therapy instituted. Serious anaphylactoid reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous steroids and airway management, including intubation, should also be administered as indicated.
Drug-induced enterocolitis syndrome (DIES) has been reported mainly in children receiving amoxicillin/clavulanate (see Section 4.8 Adverse Effects (Undesirable Effects)). DIES is an allergic reaction with the leading symptom of protracted vomiting (1-4 hours after administration of amoxicillin/clavulanate) in the absence of allergic skin or respiratory symptoms. Further symptoms could comprise abdominal pain, diarrhoea, hypotension or leucocytosis with neutrophilia. There have been severe cases including progression to shock.
Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including amoxicillin. A toxin produced by Clostridium difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibiotic agent effective against Clostridium difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated. Drugs which delay peristalsis, e.g. opiates and diphenoxylate with atropine (Lomotil) may prolong and/or worsen the condition and should not be used.
As with any potent drug, periodic assessment of organ system functions, including renal, hepatic and haemopoietic function is advisable during prolonged therapy.
Since Curam Duo 400/57 (amoxicillin and clavulanic acid) contains amoxicillin, an aminopenicillin, it is not the treatment of choice in patients presenting with sore throat or pharyngitis because of the possibility that the underlying cause is infectious mononucleosis, in the presence of which there is a high incidence of rash if amoxicillin is used.
Curam Duo 400/57 (amoxicillin and clavulanic acid) should be given with caution to patients with lymphatic leukaemia since they are especially susceptible to amoxicillin induced skin rashes.
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.
Prolonged use may also occasionally result in overgrowth of non-susceptible organisms.
Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving amoxicillin/clavulanic acid 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.
The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Aerobacter, Pseudomonas or Candida), the drug should be discontinued and/or appropriate therapy instituted.
Cholestatic hepatitis, which may be severe but is usually reversible, has been reported. Signs and symptoms may not become apparent until several weeks after treatment has ceased. In most cases resolution has occurred with time. However, in extremely rare circumstances, deaths have been reported. These have almost always been cases associated with serious underlying disease or concomitant medications. Hepatic events subsequent to amoxicillin and clavulanic acid have occurred predominantly in males and elderly patients and may be associated with prolonged treatment. These events have been very rarely reported in children.
Use in hepatic impairment. Curam Duo 400/57 (amoxicillin and clavulanic acid) should be used with care in patients with evidence of hepatic dysfunction.
Use in renal impairment. 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 (including acute renal injury) (see Section 4.8 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).
Use in the elderly. No data available.
Paediatric use. In children with renal impairment, dosage should be adjusted according to degree of impairment using the Curam 125/31.25 formulation. Curam Duo 400/57 suspension is not recommended for use in children with renal impairment.
Effects on laboratory tests. Oral administration of Curam Duo 400/57 (amoxicillin and clavulanic acid) will result in high urine concentrations of amoxicillin. Since high urine concentrations of ampicillin may result in false positive reactions when testing for the presence of glucose in urine using Clinitest, Benedict's solution or Fehling's solution, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix or Tes-Tape) be used.
The presence of clavulanic acid in amoxicillin/clavulanic acid tablets 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.
Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated oestriol, oestriol-glucuronide, conjugated oestrone and oestradiol has been noted. This effect may also occur with amoxicillin and therefore Curam Duo 400/57 (amoxicillin and clavulanic acid).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin but does not notably affect clavulanic acid excretion. Concurrent use with Curam Duo 400/57 (amoxicillin and clavulanic acid) may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.
The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricaemia present in these patients. There are no data with Curam Duo 400/57 (amoxicillin and clavulanic acid) and allopurinol administered concurrently.
In common with other antibiotics, Curam Duo 400/57 (amoxicillin and clavulanic acid) may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of oral contraceptives. Patients should be warned accordingly.
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.
Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) 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. However, close clinical monitoring should be performed during the combination and shortly after antibiotic treatment.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility. Amoxicillin and clavulanic acid at oral doses of up to 1,200 mg/kg/day had no effect on fertility and reproductive performance in rats dosed with a 2:1 ratio formulation of amoxicillin and clavulanate.
Use in pregnancy. (Category B1)
Animal studies with orally and parenterally administered amoxicillin and clavulanic acid have shown no teratogenic effects. There is limited experience of the use of amoxicillin and clavulanic acid in human pregnancy. In women with preterm, premature rupture of the foetal membrane (pPROM), prophylactic treatment with amoxicillin and clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. As with all medicines, use should be avoided in pregnancy, especially during the first trimester, unless considered essential by the doctor.
Use in labour and delivery. Oral ampicillin class antibiotics are generally poorly absorbed during labour. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions and duration of contractions. However, it is not known whether the use of Curam Duo 400/57 (amoxicillin and clavulanic acid) in humans during labour or delivery has immediate or delayed adverse effects on the foetus, prolongs the duration of labour or increases the likelihood that forceps delivery or other obstetric intervention or resuscitation of the newborn infant will be necessary.
Use in lactation. Both amoxicillin and clavulanic acid are excreted into breast milk. Consequently, diarrhoea and fungus infection of the mucous membranes are possible in the breastfed infant. The possibility of sensitisation should be taken into account. Therefore, caution should be exercised when Curam Duo 400/57 (amoxicillin and clavulanic acid) is administered to a breastfeeding woman.

4.7 Effects on Ability to Drive and Use Machines

Adverse effects on the ability to drive or operate machinery have not been observed. However, undesirable effects may occur (e.g. allergic reactions, dizziness, convulsions), which may influence the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Amoxicillin and clavulanic acid is generally well tolerated. The majority of events were of a mild and transient nature.
Clinical trials. The following adverse events reported in a pivotal clinical trial with amoxicillin and clavulanic acid 400 mg/57 mg/5 mL oral suspension (45/6.4 mg/kg/day every 12 hours for ten days) and are compared to amoxicillin and clavulanic acid 125 mg/31.25 mg/5 mL oral suspension (40/10 mg/kg/day every 8 hours for ten days) in Table 1.

Post-marketing. In addition, the following adverse reactions have been reported for ampicillin class antibiotics and may occur with Curam Duo 400/57 (amoxicillin and clavulanic acid). Very common: greater than or equal to 1/10; common: greater than or equal to 1/100 and < 1/10; uncommon: greater than or equal to 1/1,000 and < 1/100; rare: greater than or equal to 1/10,000 and < 1/1,000; very rare: < 1/10,000. Not known: cannot be estimated from the available data.
Infections and infestations. Common: mucocutaneous candidiasis.
Not known: overgrowth of non-susceptible organisms.
Cardiac disorders. Not known: Kounis syndrome (see Section 4.4 Special Warnings and Precautions for Use).
Gastrointestinal disorders. Very common: diarrhoea.
Common: nausea, vomiting.
Uncommon: indigestion.
Rare: gastritis, stomatitis, glossitis, black 'hairy' tongue, enterocolitis, antibiotic associated colitis (including pseudomembranous colitis and haemorrhagic colitis) (see Section 4.4 Special Warnings and Precautions for Use).
Not known: drug-induced enterocolitis syndrome, pancreatitis acute.
Hepatobiliary. Uncommon: moderate rise in AST and/or ALT.
Rare: hepatitis, cholestatic jaundice which may be severe but is usually reversible.
Nervous system disorders. Uncommon: dizziness, headache.
Very rare: reversible hyperactivity, convulsions. Convulsions may occur in patients with impaired renal function or those receiving high doses.
Not known: aseptic meningitis.
Haemopoietic and lymphatic systems. Uncommon: thrombocytosis.
Rare: anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, reversible leucopenia (including neutropenia or agranulocytosis); these are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena; prolongation of bleeding time and prothrombin time.
Not known: haemolytic anaemia.
Hypersensitivity and skin. Common: skin rashes, pruritus, urticaria.
Rare: angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, erythema multiforme, Stevens-Johnson syndrome, hypersensitivity, vasculitis, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalised exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) (baboon syndrome) have been reported rarely. Whenever such reactions occur, Curam Duo 400/57 (amoxicillin and clavulanic acid) should be discontinued, unless in the opinion of the doctor no alternative treatment is available and continued use of Curam Duo 400/57 (amoxicillin and clavulanic acid) is considered essential. Serious and occasional fatal hypersensitivity (anaphylactic) reactions and angioneurotic oedema can occur with oral penicillins (see Section 4.4 Special Warnings and Precautions for Use).
Not known: linear IgA disease.
Renal and urinary disorders. Rare: interstitial nephritis.
Not known: crystalluria (including acute renal injury) (see Section 4.9 Overdose).
Miscellaneous. Rare: superficial tooth discolouration which can usually be removed by brushing.
Reporting suspected adverse effects. Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Problems of overdosage with Curam Duo 400/57 (amoxicillin and clavulanic acid) are unlikely to occur. If encountered, gastrointestinal symptoms and disturbance of the fluid and electrolyte balance may be evident. They may be treated symptomatically, with attention to the water/ electrolyte balance.
Amoxicillin crystalluria, in some cases leading to renal failure, has been observed. (See Section 4.4 Special Warnings and Precautions for Use).
Amoxicillin may be removed from the circulation by haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.
Mechanism of action. Microbiology. Like other penicillins, amoxicillin has a bactericidal effect on sensitive organisms during the stage of active multiplication. However, amoxicillin is susceptible to hydrolysis by beta-lactamases and the addition of clavulanic acid in Curam Duo 400/57 extends the antimicrobial spectrum of amoxicillin to include organisms normally resistant to amoxicillin due to beta-lactamase production.
In vitro studies. In vitro studies do not always reflect the target patient population, in which the host's immune system usually plays an important role in the clinical and microbiological outcome of infection. For example, they are essentially simulations of infection in immunocompromised persons in that the total antibacterial activity observed is solely dependent on the medicine. Also methodological differences between laboratories and the difficulties of dilution and diffusion techniques can make the data unreliable.
Susceptibility tests. Dilution or diffusion techniques - either quantitative (MIC) or breakpoint, should be used following a regularly updated, recognised and standardised method (e.g. CLSI formerly NCCLS). Standardised susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures.
Current standards for amoxicillin/clavulanic acid powder should provide the following MIC values. See Table 2.

Recommended interpretive criteria based on usual dosage regimens and routes of administration (interpretive breakpoints) as defined by the Clinical and Laboratory Standard Institute (CLSI) guidelines are listed below.
Susceptible (S). A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable.
Intermediate (I). A report of "intermediate" category includes isolates with antimicrobial agent MICs that approach usually attainable blood and tissue levels and for which response rates may be lower than for susceptible isolates. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation.
Resistant (R). A report of "resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Note. The prevalence of resistance may vary geographically for selected species and local information on resistance is desirable, particularly when treating severe infections.
Streptococcus pneumoniae. Antimicrobial susceptibility and resistance by S. pneumoniae is usually defined and discussed in the context of activity by penicillin. By definition, a S. pneumoniae isolate with a minimum inhibitory concentration (MIC) ≤ 0.06 microgram/mL or less is considered to be susceptible. Non-susceptible isolates are defined as intermediate non-susceptible (0.12-1 microgram/mL) or resistant (≥ 2 microgram/mL). Until 2000, the MIC interpretive standards for penicillin and amoxicillin were similar for S. pneumoniae.
For S. pneumoniae from non-meningitis sources, isolates should be tested using amoxicillin/clavulanic acid and the following criteria should be used (see Table 3):
Resistance in Streptococcus pneumoniae. Following antimicrobial resistance in clinically significant isolates of Streptococcus pneumoniae was reported by the Australian Group for Antimicrobial Resistance (AGAR). See Table 4.
Further evidence of the increase in antibiotic resistance is provided by a 1997 Australian wide surveillance study showing that approximately 25% of the 1,020 isolated strains were non-susceptible to penicillin (16.8% were intermediately resistant and 8.6% were resistant). Rates of resistance to amoxicillin-clavulanate was found to be 3.1%.
Resistance in Haemophilus influenzae. See Table 5.
These interpretive standards are applicable only to broth microdilution test with Haemophilus influenzae using Haemophilus test medium (HTM).
Minimal Inhibitory Concentrations (MICs) to 16 different antibiotics were determined for collection of 970 isolates of H. influenzae within Australia. The overall rate of beta-lactamase production was 16% but there was wide variation between the states. In invasive strains, beta-lactamase production was 22.3% but in respiratory tract isolates, it was 35.3%. In noninvasive strains, the resistance to amoxicillin-clavulanate was 2.1%.
Clinical trials. A randomised, single blind study in 868 children aged 2 months to 12 years with acute otitis media compared the efficacy of amoxicillin and clavulanic acid oral suspension (7:1 ratio) amoxicillin 45 mg/kg/day (clavulanic acid 6.4 mg/kg/day) administered every 12 hours for five days (n=293) or ten days (n=287) with amoxicillin and clavulanic acid oral suspension (4:1 ratio) amoxicillin 40 mg/kg/day (clavulanic acid 10 mg/kg/day) given every eight hours for ten days (n=288). At the end of therapy (days 12 to 14) equivalent per protocol clinical success rates of 78.8% (n=189) and 86.5% (n=178), respectively, were demonstrated for the 8 and 12 hourly ten-day treatment groups, compared with a 71.1% (n=197) success rate for the 12 hourly five day treatment group. At 32 to 38 days follow-up, equivalent success rates were demonstrated for 8 and 12 hourly ten-day regimens of 64.2 and 63.1%, respectively, compared with a 57.8% success rate for the 12 hourly five-day treatment group.

5.2 Pharmacokinetic Properties

Absorption. Amoxicillin and clavulanic acid are stable in the presence of gastric acid. These two components are rapidly absorbed if administered before or with a meal, but if given after meals, the serum levels of clavulanic acid are significantly reduced. To optimise absorption of clavulanic acid, amoxicillin and clavulanic acid oral suspension should be administered at the start of a meal. The pharmacokinetics of amoxicillin are not affected by food.
In children aged 2 to 12 years, oral administration of amoxicillin and clavulanic acid oral suspension (7:1 ratio) every 12 hours at a dose of amoxicillin 45 mg/kg/day (clavulanic acid 6.4 mg/kg/day) was compared to amoxicillin and clavulanic acid oral suspension (4:1 ratio) every eight hours at a dose of amoxicillin 40 mg/kg/day (clavulanic acid 10 mg/kg/day), either immediately prior to the start of a meal or at least three hours after a meal.
In this study, the following mean pharmacokinetic parameters were observed for amoxicillin for amoxicillin and clavulanic acid oral suspension (45 mg/kg/day) taken every 12 hours and amoxicillin and clavulanic acid oral suspension (40 mg/kg/day) taken every 8 hours respectively: peak plasma concentration (C_max) of 12.0 and 7.33 microgram/mL, area under the plasma concentration time curve between 0 and 24 hours after the first dose (AUC_{(0 to 24 hours)}) of 35.2 and 18.6 microgram.hour/mL, half-life (t_1/2) of 1.22 and 1.02 hours, median time to peak plasma concentration (T_max) of 1.0 and 2.1 hours and the mean predicted time above the minimum inhibitory concentration (T_{MIC24 hours}) of 12.3 and 14.0 hours.
The following pharmacokinetic parameters were observed for clavulanic acid for amoxicillin and clavulanic acid oral suspension (45 mg/kg/day) taken every 12 hours and amoxicillin and clavulanic acid oral suspension (40 mg/kg/day) taken every 8 hours, respectively: C_max of 5.49 and 2.66 microgram/mL, AUC_{(0 to 24 hours)} of 13.3 and 5.51 microgram.hour/mL, t_1/2 of 0.99 and 0.94 hours and median T_max of 1.0 and 1.6 hours, and mean predicted T_{MIC24 hours} of 9.80 and 9.81 hours.
The clinical efficacy of amoxicillin and clavulanic acid oral suspension (7:1 ratio) and amoxicillin and clavulanic acid oral suspension (4:1 ratio) have been shown to be comparable in the approved indications, despite the differences in some pharmacokinetic parameters.
Oral administration of single doses of Curam Duo 400/57 amoxicillin 400 mg/5 mL and clavulanic acid 57 mg/5 mL oral suspension to fasting adult volunteers yielded comparable pharmacokinetic data to reference amoxicillin 400 mg/5 mL and clavulanic acid 57 mg/5 mL oral suspension and these data are tabulated in Table 6.

Distribution. Following oral administration, both amoxicillin and clavulanic acid have been shown to diffuse in significant concentrations into pus, bile, pleural, synovial and peritoneal fluids. Therapeutic concentrations of both compounds have been detected in gall bladder, abdominal tissue, skin fat and muscle tissues. Both penetrate poorly into the cerebrospinal fluid (CSF) when the meninges are normal. Amoxicillin penetrates into the CSF better through inflamed meninges but the maximum concentrations are still much lower than the peak serum levels. There are no data at present on the CSF penetration of clavulanic acid in patients with meningeal inflammation.
Neither amoxicillin nor clavulanic acid is highly protein bound. Clavulanic acid has been variously reported to be bound to human serum in the range of 9 to 30% and amoxicillin approximately 20% bound. From animal studies, there is no evidence to suggest either component accumulates in any organ.
Metabolism. No data available.
Excretion. As with other penicillins, renal excretion is the major route of amoxicillin clearance, while clavulanate clearance is via both renal and nonrenal mechanisms. Approximately 70% of the dose of amoxicillin is excreted in urine as amoxicillin. For clavulanic acid, following the administration of 125 mg of radiolabelled potassium clavulanate orally to normal volunteers 68% of the administered radioactivity was recovered in the urine in 24 hours. Of this, 34% (i.e. 23% of the administered dose) represented unchanged clavulanic acid. 2,5-dihydro-4-(2-hydroxyethyl)-5-oxo-1H-pyrrole-3-carboxylic acid (the major metabolite) and 1-amino-4-hydroxy-butan-2-one accounted for a further 23 and 12% (i.e. 16 and 8%, respectively, of the administered dose). Small amounts of other yet unidentified metabolites were also present. These metabolites were also present in the urine of rat and dog. The extent of urinary excretion of clavulanic acid and its metabolites is lower in rat urine than in dog and human urine.
Concurrent administration of probenecid delays amoxicillin excretion but does not notably delay renal excretion of clavulanic acid.
Similar elimination pharmacokinetics occur in adults, children and infants with mature renal function.

5.3 Preclinical Safety Data

Genotoxicity. The genotoxic potential of amoxicillin and clavulanic acid was investigated in assays for chromosomal damage (mouse micronucleus test and a dominant lethal test) and gene conversion. All were negative.
Carcinogenicity. Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Curam Duo 400/57 (amoxicillin and clavulanic acid).

6 Pharmaceutical Particulars

6.1 List of Excipients

Lemon flavouring 15.12.0598 (ARTG PI: 10094), peach-apricot flavour 26F22 (ARTG PI: 10089), citric acid, sodium citrate, aspartame, purified talc, orange 55301 AP0551 (ARTG PI: 12686), guar gum and silicon dioxide. Contains sulfites.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store dry powder below 25°C. Under these conditions, the shelf life is 3 years.
Store reconstituted suspension at 2°C to 8°C in a refrigerator. Under these conditions, the shelf life is 7 days.

6.5 Nature and Contents of Container

Packaged in 60 mL, 120 mL or 150 mL amber glass bottle with screw closure.
Also contains a 5 mL measuring spoon.
Not all presentations may be marketed in Australia.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Amoxicillin trihydrate. Curam Duo 400/57 is a combination product containing the semisynthetic antibiotic, amoxicillin (as the trihydrate) and the beta-lactamase inhibitor, clavulanic acid (as the potassium salt). Amoxicillin is susceptible to hydrolysis by beta-lactamases.
Chemical structure.

Chemical name: (2S,5R,6R)-6-[[(2R)-2-Amino-2-(4-hydroxyphenyl) acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0] heptane-2-carboxylic acid trihydrate.
Molecular formula: C₁₆H₁₉N₃O₅S.3H₂O.
Molecular weight: 419.5.
Potassium clavulanate. Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is an irreversible inhibitor of many beta-lactamase enzymes except type 1 (Richmond). It is a beta-lactam compound with only weak antibacterial activity.
Chemical structure.
Chemical name: potassium (2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo [3.2.0]heptane-2-carboxylate.
Molecular formula: C₈H₈KNO₅.
Molecular weight: 237.3
CAS number. Amoxicillin trihydrate. 61336-70-7.
Potassium clavulanate. 61177-45-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Date of First Approval

06 March 2009

Date of Revision

27 June 2024

Summary Table of Changes