Symptoms and signs of overdose
Gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) and disturbance of the fluid and electrolyte balances may be evident. Amosin 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.
Treatment of intoxication
Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Amosin can be removed from the circulation by haemodialysis.
Not applicable.
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 Amosin, presented by MedDRA System Organ Class are listed below.
The following terminologies have been used in order to classify the occurrence of undesirable effects.
Very common (>1/10)
Common (>1/100 to <1/10)
Uncommon (>1/1,000 to <1/100)
Rare (>1/10,000 to <1/1,000)
Very rare (<1/10,000)
Not known (cannot be estimated from the available data)
| Infections and infestations | |
| Very rare | Mucocutaneous candidiasis |
| Blood and lymphatic system disorders: | |
| Very rare | Reversible leucopenia (including severe neutropenia and agranulocytosis), reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin time. |
| Immune system disorders | |
| Very rare | Severe allergic reactions including angioneurotic oedema, anaphylaxis, serum sickness and hypersensitivity vasculitis. |
| Not Known | Jarisch-Herxheimer reaction. |
| Nervous system disorders | |
| Very rare | |
| Gastrointestinal disorders | |
| Clinical trial data | |
| *Common | Diarrhoea and nausea |
| *Uncommon | Vomiting |
| Post-marketing data | |
| Very rare | Antibiotic-associated colitis. Black hairy tongue Superficial tooth discolouration# |
| Hepatobiliary disorders | |
| Very rare | Hepatitis and cholestatic jaundice. A moderate rise in AST and/or ALT. |
| 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, acute generalised exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). |
| Renal and urinary tract disorders | |
| Very rare | Interstitial nephritis Crystalluria |
| *The incidence of these AEs was derived from clinical studies involving a total of approximately 6,000 adult and paediatric patients taking Amosin. #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 | |
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 the yellow card scheme at www.mhra.gov.uk/yellowcard.
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 Amosin.
Amosin Oral Suspension is indicated for the treatment of the following infections in adults and children :
- Acute bacterial sinusitis
- Acute otitis media
- Acute streptococcal tonsillitis and pharyngitis
- Acute exacerbations of chronic bronchitis
- Community acquired pneumonia
- Acute cystitis
- Asymptomatic bacteriuria in pregnancy
- Acute pyelonephritis
- Typhoid and paratyphoid fever
- Dental abscess with spreading cellulitis
- Prosthetic joint infections
- Helicobacter pylori eradication
- Lyme disease
.
Amosin Oral Suspension is also indicated for the prophylaxis of endocarditis.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
Pharmacotherapeutic group: penicillins with extended spectrum; ATC code: J01CA04.
Mechanism of action
Amosin 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.
Amosin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of Amosin alone does not include organisms which produce these enzymes.
Pharmacokinetic/pharmacodynamic relationship
The time above the minimum inhibitory concentration (T>MIC) is considered to be the major determinant of efficacy for Amosin.
Mechanisms of resistance
The main mechanisms of resistance to Amosin 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 Amosin are those of the European Committee on Antimicrobial Susceptibility Testing (EUCAST) version 5.0.
| Organism | MIC breakpoint (mg/L) | |
| Susceptible ≤ | Resistant > | |
| Enterobacteriaceae | 81 | 8 |
| Staphylococcus spp. | Note2 | 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 | 26 | 26 |
| Moraxella catarrhalis | Note 7 | Note 7 |
| Neisseria meningitidis | 0.125 | 1 |
| Gram positive anaerobes except Clostridium difficile8 | 4 | 8 |
| Gram negative anaerobes8 | 0.5 | 2 |
| Helicobacter pylori | 0.1259 | 0.1259 |
| Pasteurella multocida | 1 | 1 |
| Non- species related breakpoints10 | 2 | 8 |
| 1Wild type Enterobacteriaceae are categorised as susceptible to aminopenicillins. Some countries prefer to categorise wild type isolates of E. coli and P. mirabilis as intermediate. When this is the case, use the MIC breakpoint S ≤ 0.5 mg/L 2Most staphylococci are penicillinase producers, which are resistant to Amosin. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents. 3Susceptibility to Amosin can be inferred from ampicillin 4The susceptibility of streptococcus groups A, B, C and G to penicillins is inferred from the benzylpenicillin susceptibility. 5Breakpoints relate only to non-meningitis isolates. For isolates categorised as intermediate to ampicillin avoid oral treatment with Amosin. Susceptibility inferred from the MIC of ampicillin. 6Breakpoints are based on intravenous administration. Beta-lactamase positive isolates should be reported resistant. 7Beta lactamase producers should be reported resistant 8Susceptibility to Amosin can be inferred from benzylpenicillin. 9The breakpoints are based on epidemiological cut-off values (ECOFFs), which distinguish wild-type isolates from those with reduced susceptibility. 10The non-species related breakpoints are based on doses of at least 0.5 g x 3or 4 doses daily (1.5 to 2 g/day) | ||
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 Amosin |
| 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-negative aerobes: Escherichia coli Haemophilus influenzae Helicobacter pylori Proteus mirabilis Salmonella typhi Salmonella paratyphi Pasteurella multocida |
| Gram-positive aerobes: Coagulase negative staphylococcus Staphylococcus aureus£ Streptococcus pneumoniae Viridans group streptococcus |
| 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). |
| Others: Chlamydia spp. Mycoplasma spp. Legionella spp. |
| †Natural intermediate susceptibility in the absence of acquired mechanism of resistance. £ Almost all S.aureus are resistant to Amosin due to production of penicillinase. In addition, all methicillin-resistant strains are resistant to Amosin. |
Absorption
Amosin fully dissociates in aqueous solution at physiological pH. It is rapidly and well absorbed by the oral route of administration. Following oral administration, Amosin is approximately 70% bioavailable. The time to peak plasma concentration (Tmax) is approximately one hour.
The pharmacokinetic results for a study, in which an Amosin dose of 250 mg three times daily was administered in the fasting state to groups of healthy volunteers are presented below.
| Cmax | Tmax * | 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 of 250 to 3000 mg the bioavailability is linear in proportion to dose (measured as Cmax and AUC). The absorption in not influenced by simultaneous food intake.
Haemodialysis can be used for elimination of Amosin.
Distribution
About 18% of total plasma Amosin is bound to protein and the apparent volume of distribution is around 0.3 to 0.4 l/kg.
Following intravenous administration, Amosin has been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amosin does not adequately distribute into the cerebrospinal fluid.
From animal studies there is no evidence for significant tissue retention of drug-derived material. Amosin, like most penicillins, can be detected in breast milk.
Amosin has been shown to cross the placental barrier.
Biotransformation
Amosin 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 Amosin is via the kidney.
Amosin 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 Amosin is excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg dose of Amosin. Various studies have found the urinary excretion to be 50-85% for Amosin over a 24 hour period
Concomitant use of probenecid delays Amosin excretion.
Age
The elimination half-life of Amosin 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 Amosin to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of Amosin.
Renal impairment
The total serum clearance of Amosin decreases proportionately with decreasing renal function.
Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
Hypersensitivity reactions
Before initiating therapy with Amosin, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents.
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, Amosin therapy must be discontinued and appropriate alternative therapy instituted.
Non-susceptible microorganisms
Amosin 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 Amosin. 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.
Renal impairment
In patients with renal impairment the dose should be adjusted accordingly to the degree of impairment.
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. This reaction requires Amosin discontinuation and contra-indicates any subsequent administration.
Amosin 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 Amosin.
Jarisch-Herxheimer reaction
The Jarisch-Herxheimer reaction has been seen following Amosin treatment of Lyme disease. It results directly from the bactericidal activity of Amosin 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 also 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. 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, Amosin 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.
Anticoagulants
Prolongation of prothrombin time has been reported rarely in patients receiving Amosin. 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.
Crystalluria
In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the administration of high doses of Amosin, it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of Amosin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained.
Interference with diagnostic tests
Elevated serum and urinary levels of Amosin are likely to affect certain laboratory tests. Due to the high urinary concentrations of Amosin, false positive readings are common with chemical methods.
It is recommended that when testing for the presence of glucose in urine during Amosin treatment, enzymatic glucose oxidase methods should be used.
The presence of Amosin may distort assay results for oestriol in pregnant women.
Important Information about excipients
This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
This medicinal product contains sodium benzoate (E211) which is a mild irritant to the eyes, skin and mucous membrane. May increase the risk of jaundice in new born babies.
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 or use machines.
Posology
The dose of Amosin Oral Suspension that is selected to treat an individual infection should take into account:
- The expected pathogens and their likely susceptibility to antibacterial agents
- The severity and the site of 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.).
Adults and children > 40kg
| Indication* | Dose* |
| Acute bacterial sinusitis | 250 mg to 500 mg every 8 hours or 750 mg to 1 g every 12 hours |
| Asymptomatic bacteriuria in pregnancy | |
| Acute pyelonephritis | For severe infections 750 mg to 1 g every 8 hours |
| Dental abscess with spreading cellulitis | |
| Acute cystitis | Acute cystitis may be treated with 3 g twice daily for one day |
| Acute otitis media Acute streptococcal tonsillitis and pharyngitis Acute exacerbations of chronic bronchitis | 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 |
| 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 | 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 | |
Children < 40 kg
Children may be treated with Amosin Capsules, dispersible tablets suspensions or sachets
Amosin Paediatric Suspension is recommended for children under six months of age.
Children weighing 40 kg or more should be prescribed the adult dosage.
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 | 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 |
| +Consideration should be given to the official treatment guidelines for each indication. *Twice daily dosing regimens should only be considered when the dose is in the upper range. | |
Elderly
No dose adjustment is considered necessary.
Renal impairment
| GFR (ml/min) | Adults and children > 40 kg | Children < 40 kg# |
| greater than 30 | No adjustment necessary | No adjustment necessary |
| 10 to 30 | Maximum 500 mg twice daily | 15 mg/kg given twice daily (maximum 500 mg twice daily) |
| less than 10 | Maximum 500mg/day. | 15 mg/kg given as a single daily dose (maximum 500 mg) |
| # In the majority of cases, parenteral therapy is preferred. | ||
In patients receiving haemodialysis
Amosin may be removed from the circulation by haemodialysis.
| Haemodialysis | |
| Adults and children over 40 kg | 500mg every 24 h Prior to haemodialysis one additional dose of 500mg should be administered. In order to restore circulating drug levels, another dose of 500 mg should be administered after haemodialysis. |
| Children under 40kg | 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. |
In patients receiving peritoneal dialysis
Amosin maximum 500 mg/day.
Hepatic impairment
Dose with caution and monitor hepatic function at regular intervals.
Method of administration
Amosin Oral Suspension is for oral use.
Absorption of Amosin Oral Suspension is unimpaired by food.
Therapy can be started parenterally according to the dosing recommendations of the intravenous formulation and continued with an oral preparation.
Check cap seal is intact before use.
Invert and shake bottle to loosen powder.
To prepare add 64ml of potable water and shake until all contents are dispersed
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
