Symptoms and signs of overdose
Gastrointestinal symptoms (such as nausea, vomiting and diarrhoea) and disturbance of the fluid and electrolyte balances may be evident. Hiconcil 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.
Hiconcil 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 Hiconcil, 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 Hiconcil. #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 Hiconcil.
Pharmacotherapeutic group: penicillins with extended spectrum; ATC code: J01CA04.
Mechanism of action
Hiconcil 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.
Hiconcil is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of Hiconcil 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 Hiconcil.
Mechanisms of resistance
The main mechanisms of resistance to Hiconcil 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 Hiconcil 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 Hiconcil. Methicillin resistant isolates are, with few exceptions, resistant to all beta-lactam agents. 3Susceptibility to Hiconcil 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 Hiconcil. 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 Hiconcil 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 Hiconcil |
| 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 Hiconcil due to production of penicillinase. In addition, all methicillin-resistant strains are resistant to Hiconcil. |
Absorption
Hiconcil fully dissociates in aqueous solution at physiological pH. It is rapidly and well absorbed by the oral route of administration. Following oral administration, Hiconcil is approximately 70% bioavailable. The time to peak plasma concentration (Tmax) is approximately one hour.
The pharmacokinetic results for a study, in which an Hiconcil 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 Hiconcil.
Distribution
About 18% of total plasma Hiconcil is bound to protein and the apparent volume of distribution is around 0.3 to 0.4 l/kg.
Following intravenous administration, Hiconcil has been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Hiconcil does not adequately distribute into the cerebrospinal fluid.
From animal studies there is no evidence for significant tissue retention of drug-derived material. Hiconcil, like most penicillins, can be detected in breast milk.
Hiconcil has been shown to cross the placental barrier.
Biotransformation
Hiconcil 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 Hiconcil is via the kidney.
Hiconcil 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 Hiconcil is excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg dose of Hiconcil. Various studies have found the urinary excretion to be 50-85% for Hiconcil over a 24 hour period
Concomitant use of probenecid delays Hiconcil excretion.
Age
The elimination half-life of Hiconcil 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 Hiconcil to healthy males and female subjects, gender has no significant impact on the pharmacokinetics of Hiconcil.
Renal impairment
The total serum clearance of Hiconcil decreases proportionately with decreasing renal function.
Hepatic impairment
Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.
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.
