ADVENT I.V. Injection

Amoxycillin sodium + Clavulanic acid

Prescribing information

Qualitative and Quantitative Composition

ADVENT Injection 1.2 g

Each vial contains:

Amoxycillin Sodium, IP,

equivalent to Amoxycillin ...... 1,000 mg

Clavulanate Potassium, IP,

equivalent to Clavulanic Acid ....200 mg

ADVENT Injection 600 mg

Each vial contains

Amoxycillin Sodium IP

equivalent to Amoxycillin .....................500 mg

Potassium Clavulanate IP

equivalent to Clavulanic acid ....... 100 mg

ADVENT Injection 300 mg

Each vial contains

Amoxycillin Sodium IP

equivalent to Amoxycillin .....................250 mg

Potassium Clavulanate IP

equivalent to Clavulanic acid ...........50 mg

ADVENT Injection 150 mg

Each vial contains

Amoxycillin Sodium IP

equivalent to Amoxycillin .....................125 mg

Potassium Clavulanate IP

equivalent to Clavulanic acid ...........25 mg

Dosage Form and Strength

Powder for reconstitution for intravenous (I.V.) injection or infusion

To reduce the development of drug‑resistant bacteria and maintain the effectiveness of amoxycillin/clavulanate potassium and other antibacterial drugs, amoxycillin/clavulanic acid should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

ADVENT I.V. is a combination penicillin-class antibacterial and beta-lactamase inhibitor indicated in the treatment of infections in adults and children due to susceptible strains of the designated organisms in the conditions listed below*:

Upper respiratory tract infections (including ENT), e.g. recurrent tonsillitis, sinusitis, otitis media. Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections, epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms)
Lower respiratory tract infections (including ENT), e.g. acute exacerbations of chronic bronchitis (adequately diagnosed), community-acquired pneumonia
Genito-urinary tract infections, e.g. cystitis, pyelonephritis, urethritis, female genital infections
Skin and soft tissue infections, e.g. boils, abscesses, cellulitis, severe dental abscess with spreading cellulitis, wound infections
Bone and joint infections, e.g. osteomyelitis
Other infections, e.g. intra-abdominal sepsis
Prophylaxis against infections associated with major surgical procedures such as those involving the following:

Gastrointestinal tract
Pelvic cavity
Head and neck
Biliary tract
Cardiac
Renal
Joint replacement

Posology and Method of Administration

Doses are expressed throughout in terms of amoxicillin/clavulanic acid content except when doses are stated in terms of an individual component.

The dose of ADVENT I.V 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 use of alternative presentations of ADVENT I.V (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary.

The duration of therapy should be determined by the response of the patient. Some infections (e.g. osteomyelitis) require longer periods of treatment. Treatment should not be extended beyond 14 days without review.

Consideration should be given to local guidelines on appropriate dosing frequencies for amoxicillin/clavulanic acid.

Dosage

Adults and children ≥ 40 kg

For treatment of infections as indicated:

ADVENT 1000 mg/ 200 mg every 8 hours.

For surgical prophylaxis

For procedures less than 1 hour in duration, the recommended dose of ADVENT I.V is 1000 mg/200 mg to 2000 mg/200 mg given at induction of

anaesthesia (Doses of 2000 mg/200 mg can be achieved by using an

alternative intravenous formulation of ADVENT I.V).

For procedures greater than 1 hour in duration, the recommended dose of

ADVENT I.V is 1000 mg/200 mg to 2000 mg/200 mg given at induction of

anaesthesia, with up to 3 doses of 1000 mg/200 mg in 24 hours.

Clear clinical signs of infection at operation will require a normal course of

intravenous or oral therapy post-operatively.

Children < 40 kg

Recommended doses:

Children aged less than 3 months or weighing less than 4 kg:

Children

(aged 3 months and above)

30 mg/kg* ADVENT I.V. every 12 hours in premature infants and in full-term infants during the perinatal period, increasing to 8 hours thereafter.

Usually 30 mg/kg* ADVENT I.V. 8-hourly.

*Each 30 mg of ADVENT I.V. provides 5 mg clavulanic acid and 25 mg amoxycillin. Therapy can be started parenterally and continued with the oral preparation of ADVENT.

Elderly

No dose adjustment is considered necessary.

Renal impairment

Dose adjustments are based on the maximum recommended level of amoxicillin.

No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 ml/min.

Adults and children ≥ 40 kg

CrCl: 10-30 ml/min	Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given twice daily
CrCl < 10 ml /min	Initial dose of 1000 mg/200 mg and then 500 mg/100 mg given every 24 hours
Haemodialysis	Initial dose of 1000 mg/200 mg and then followed by 500 mg/100 mg every 24 hours, plus a dose of 500 mg/100 mg at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased)

Children < 40 kg

CrCl: 10 to 30 ml/min

25 mg/5 mg per kg given every 12 hours

CrCl < 10 ml /min

25 mg/5 mg per kg given every 24 hours

Haemodialysis

25 mg/5 mg per kg given every 24 hours, plus a dose of 12.5 mg/2.5 mg per kg at

the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased).

Hepatic impairment

Dose with caution and monitor hepatic function at regular intervals

Preparation

1.2 g Vial: To reconstitute, dissolve contents in 10 ml of Sterile Water for Injections IP (final volume, 10.9 mL).

600 mg Vial: To reconstitute, dissolve contents in 10 mL of Sterile Water for Injections IP, (final volume: 10.5 mL).

300 mg Vial: To reconstitute, dissolve contents in 5 mL of Sterile Water for Injections IP, (final volume: 5.25 mL).

150 mg Vial: To reconstitute, dissolve contents in 2.5 mL of Sterile Water for Injections IP, (final volume: 2.625 mL).

A transient pink colouration may appear during reconstitution. Reconstituted solutions are normally a pale straw colour.

Administration

I.V. Injection

The stability of ADVENT I.V. solution is concentration-dependent; thus, ADVENT I.V. should be used immediately upon reconstitution and given by slow I.V. injection over a period of 3–4 minutes. ADVENT I.V. may be injected directly into a vein or via a drip tube. ADVENT I. V. is not suitable for intramuscular administration.

I.V. Infusion

ADVENT I.V. may be reconstituted with Sterile Water for Injections, IP, and further may be diluted with compound sodium chloride I.V. Infusion IP (Ringer’s solution). Add, without delay*, the 1.2 g reconstituted solution to 100 mL infusion fluid, 600 mg to 50 ml infusion fluid. Similar reductions in infusion fluids, will be applicable for 300 mg and 150 mg reconstituted solution, respectively. Infuse over 30–40 minutes. Children aged less than 3 months should be administered ADVENT I.V. by infusion only.

*Solutions should be made up to full infusion volume immediately after reconstitution. Any residual antibiotic solutions should be discarded.

Stability and Compatibility

Satisfactory antibiotic concentrations are retained at room temperature (25°C) in the recommended volumes of the following diluent/infusions fluids. If reconstituted and maintained at room temperature, infusions should be completed within the times stated.

I.V. Infusion Fluids Stability Period (25°C)

Sterile Water for Injections IP 20 minutes

Compound Sodium Chloride I.V. Infusion IP 2 hours

(Ringer’s solution)

Reconstituted solutions should not be frozen.

ADVENT I.V.is less stable in infusions containing glucose, dextran or bicarbonate. Reconstituted solutions of ADVENT I.V. should, therefore, not be added to such infusions but may be injected into the drip tubing over a period of 3–4 minutes.

To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of ADVENT I.V. is optimised when taken at the start of a meal. Treatment should not be extended beyond 14 days without review. Therapy can be started parenterally and continued with an oral preparation.

Contraindications

Amoxycillin/clavulanic acid is contraindicated in patients with a history of serious hypersensitivity reactions (e.g. anaphylaxis or Stevens-Johnson syndrome) to amoxycillin, clavulanate or to other beta‑lactam antibacterial drugs (e.g., penicillins and cephalosporins).

Amoxycillin/clavulanic acid is contraindicated in patients with a previous history of cholestatic jaundice/hepatic impairment associated with amoxycillin/clavulanic acid.

Special Warnings and Precautions for Use

Hypersensitivity Reactions

Serious, and occasionally fatal, hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterials, including amoxycillin/clavulanate potassium. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and/or a history of sensitivity to multiple allergens and in atopic individuals. 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 amoxycillin/clavulanic acid, careful inquiry should be made regarding previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, amoxycillin/clavulanic acid should be discontinued and appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, I.V. steroids, and airway management, including intubation, should also be administered as indicated.

Hepatic Dysfunction

Hepatic events have been reported predominantly in males and 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

Clostridium difficile-associated Diarrhoea (CDAD)

CDAD has been reported with the use of nearly all antibacterial agents, including amoxycillin/clavulanate potassium, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require a colectomy. CDAD must be considered in all patients who present with diarrhoea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Antibiotic-associated colitis

This has been reported with nearly all antibacterial agents including amoxicillin 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, 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.

Skin Rash in Patients with Mononucleosis

A high percentage of patients with mononucleosis who receive amoxycillin develop an erythematous skin rash. Thus, amoxycillin/clavulanic acid should not be administered to patients with mononucleosis.

Potential for Microbial Overgrowth

The possibility of superinfections with fungal or bacterial pathogens should be considered during therapy. If superinfection occurs, amoxycillin/clavulanate potassium should be discontinued and appropriate therapy instituted.

Development of Drug-resistant Bacteria

Prescribing amoxycillin/clavulanic acid in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient, and increases the risk of the development of drug‑resistant bacteria.

General

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 may not be suitable for use when there is a high risk that the presumptive pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. As no specific data for T>MIC are available and the data for comparable oral presentations are borderline, this presentation (without additional amoxicillin) may not be suitable for the treatment of penicillin-resistant S. pneumoniae.

Periodic assessment of organ system functions, including renal, hepatic and haematopoietic function, is advisable during prolonged therapy. In patients with bladder catheters, a regular check of patency should be maintained.

If the parenteral administration of high doses is necessary, the sodium content must be taken into account in patients on a restricted sodium diet. Convulsions may occur in patients with impaired renal function or in those receiving high doses

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During administration of high doses of amoxycillin it is advisable to maintain adequate fluid intake and urinary output in order to reduce the possibility of amoxycillin crystalluria. In patients with bladder catheters, a regular check of patency should be maintained.

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

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). This reaction requires drug discontinuation and contraindicates any subsequent administration of amoxicillin.

Drug Interactions

Probenecid

Probenecid decreases the renal tubular secretion of amoxycillin but does not delay renal excretion of clavulanic acid. Concurrent use with amoxycillin/clavulanate potassium may result in increased and prolonged blood concentrations of amoxycillin. Co-administration of probenecid is not recommended.

Oral Anticoagulants

Abnormal prolongation of prothrombin time (increased International Normalised Ratio [INR]) has been reported in patients receiving amoxycillin and oral anticoagulants. Appropriate monitoring should be undertaken when anticoagulants are prescribed concurrently with amoxycillin/clavulanic acid. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation.

Allopurinol

The concurrent administration of allopurinol and amoxycillin increases the incidence of rashes in patients receiving both drugs as compared with patients receiving amoxycillin alone. It is not known whether this potentiation of amoxycillin rashes is due to allopurinol or the hyperuricaemia present in these patients.

Oral Contraceptives

Amoxycillin/clavulanate potassium may affect intestinal flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral oestrogen/progesterone contraceptives.

Methotrexate

Penicillins may reduce the excretion of methotrexate, causing a potential increase in toxicity.

Mycophenolate Mofetil

In patients receiving mycophenolate mofetil, reduction in the pre-dose concentration of the active metabolite, mycophenolic acid (MPA), of approximately 50% has been reported following commencement of oral amoxycillin 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.

Effects on Laboratory Tests

High urine concentrations of amoxycillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST®, Benedict’s solution, or Fehling’s solution. Since this effect may also occur with amoxycillin/clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. False positive results may occur with non-enzymatic methods.

Following administration of amoxycillin to pregnant women, a transient decrease in plasma concentration of total conjugated oestriol, oestriol-glucuronide, conjugated oestrone, and oestradiol has been noted.

Use in Special Populations

Pregnancy

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. There are no adequate and well-controlled studies in pregnant women. Limited data on the use of amoxycillin/clavulanic acid during pregnancy in humans do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the foetal membrane it was reported that prophylactic treatment with amoxycillin/clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Lactating Women

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. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

Paediatric Use

Because of incompletely developed renal function in neonates and young infants, the elimination of amoxycillin may be delayed; clavulanate elimination is unaltered in this age group. Dosing of amoxycillin/clavulanic acid should be modified in paediatric patients aged <12 weeks (<3 months).

Geriatric Use

Of the 3,119 patients in an analysis of clinical studies of amoxycillin/clavulanate potassium, 32% were ≥65 years old, and 14% were ≥75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but the greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidneys, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. 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.

Renal Impairment

Amoxycillin is primarily eliminated by the kidneys and dosage adjustment is usually required in patients with severe renal impairment (GFR <30 mL/min). See Posology and Method of Administration, Renal Impairment for specific recommendations in patients with renal impairment.

Effects on Ability to Drive and Use Machines

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 and use machines.

Undesirable Effects

The following are discussed in more detail in other sections of the labelling:

Anaphylactic Reactions
Hepatic Dysfunction
CDAD

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most frequently reported adverse reactions were diarrhoea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%), and vaginitis (1%). Less than 3% of patients discontinued therapy because of drug‑related adverse reactions. The overall incidence of adverse reactions and, in particular, diarrhoea, increased with the higher recommended dose. Other less frequently reported adverse reactions (<1%) included abdominal discomfort, flatulence, and headache.

In paediatric patients (aged 2 months to 12 years), one US/Canadian clinical trial was conducted, which compared 45/6.4 mg/kg/day (divided every 12 hours) of amoxycillin/clavulanate potassium for 10 days versus 40/10 mg/kg/day (divided every 8 hours) of amoxycillin/clavulanate potassium for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse reactions seen were comparable with that noted above; however, there were differences in the rates of diarrhoea, skin rashes/urticaria, and diaper area rashes.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following have been identified during the postmarketing use of amoxycillin/clavulanate potassium. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to amoxycillin/clavulanate potassium.

Gastrointestinal: Indigestion, gastritis, stomatitis, glossitis, black ‘hairy’ tongue, mucocutaneous candidiasis, enterocolitis, and haemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.

Hypersensitivity Reactions: Pruritus, angio-oedema, serum sickness-like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme, Stevens‑Johnson syndrome, acute generalised exanthematous pustulosis, hypersensitivity vasculitis, and cases of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported.

Liver: Hepatic dysfunction, including hepatitis and cholestatic jaundice, increases in serum transaminases (AST and/or ALT), serum bilirubin, and/or alkaline phosphatase, has been reported with amoxycillin/clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic‑hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, is usually reversible. Deaths have been reported.

Renal: Interstitial nephritis, haematuria, and crystalluria have been reported.

Haemic and Lymphatic Systems: Anaemia, including haemolytic anaemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leucopaenia (including neutropenia), and agranulocytosis have been reported. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. Thrombocytosis was noted in less than 1% of the patients treated with amoxycillin/clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxycillin/clavulanate potassium and anticoagulant therapy concomitantly.

Central Nervous System: Agitation, anxiety, behavioural changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported.

Miscellaneous: Tooth discolouration (brown, yellow or grey staining) has been reported. Most reports occurred in paediatric patients. Discolouration was reduced or eliminated with brushing or dental cleaning in most cases.

The adverse drug reactions derived from clinical studies and postmarketing surveillance with amoxycillin/clavulanic acid, sorted by MedDRA System Organ Class are listed below:

Immune System Disorders: Angioneurotic oedema (occurrence cannot be estimated from the available data)

Nervous System Disorders: Aseptic meningitis (occurrence cannot be estimated from the available data)

Vascular Disorders: Thrombophlebitis (occurrence ≥1/10,000 to <1/1,000)

Skin and Subcutaneous Tissue Disorders: Drug reaction with eosinophilia and systemic symptoms (DRESS) (occurrence cannot be estimated from the available data).

If you experience any side effects, talk to your doctor or pharmacist or write to drugsafety@cipla.com. You can also report side effects directly via the National Pharmacovigilance Programme of India by calling on 1800 267 7779 (Cipla number) or you can report to PvPI on 1800 180 3024. By reporting side effects, you can help provide more information on the safety of this product.

Overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. In case of overdosage, discontinue medication, treat symptomatically, and institute supportive measures as required. A prospective study of 51 paediatric patients at a poison control centre suggested that overdosages of less than 250 mg/kg of amoxycillin are not associated with significant clinical symptoms.

Interstitial nephritis resulting in oliguric renal failure has been reported in patients after overdosage with amoxycillin/clavulanate potassium. Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxycillin/clavulanate potassium overdosage in adult and paediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxycillin/clavulanate potassium crystalluria.

Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of patency should be maintained.

Renal impairment appears to be reversible with cessation of drug administration. Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of amoxycillin/clavulanate potassium. Amoxycillin/clavulanate potassium may be removed from circulation by haemodialysis.

Pharmacological Properties

Mechanism of Action

Amoxycillin 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.

Amoxycillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and, therefore, the spectrum of activity of amoxycillin alone does not include the organisms that produce these enzymes.

Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes, thereby preventing inactivation of amoxycillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.

Pharmacodynamic Properties

Pharmacotherapeutic group: Combinations of penicillins, incl. beta-lactamase inhibitors; ATC code: J01CR02.

Pharmacokinetic/Pharmacodynamic Relationship

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

Mechanisms of Resistance

The two main mechanisms of resistance to amoxycillin/clavulanic acid are as follows:

• Inactivation by those bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including classes B, C and D.

• 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.

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.

Commonly Susceptible Species

Aerobic Gram-positive Microorganisms

Enterococcus faecalis

Gardnerella vaginalis

Staphylococcus aureus (methicillin-susceptible)^£

Coagulase-negative staphylococci (methicillin-susceptible)

Streptococcus agalactiae

Streptococcus pneumoniae¹

Streptococcus pyogenes and other beta-haemolytic streptococci

Streptococcus viridans group

Aerobic Gram-negative Microorganisms

Actinobacillus actinomycetemcomitans

Capnocytophaga spp.

Eikenella corrodens

Haemophilus influenzae²

Moraxella catarrhalis

Neisseria gonorrhoeae^§

Pasteurella multocida

Anaerobic Microorganisms

Bacteroides fragilis

Fusobacterium nucleatum

Prevotella spp.

Species for which Acquired Resistance May Be a Problem

Aerobic Gram-positive Microorganisms

Enterococcus faecium^$

Aerobic Gram-negative Microorganisms

Escherichia coli

Klebsiella oxytoca

Klebsiella pneumoniae

Proteus mirabilis

Proteus vulgaris

Inherently Resistant Organisms

Aerobic Gram-negative Microorganisms

Acinetobacter spp.

Citrobacter freundii

Enterobacter spp.

Legionella pneumophila

Morganella morganii

Providencia spp.

Pseudomonas spp.

Serratia spp.

Stenotrophomonas maltophilia

Other Microorganisms

Chlamydia trachomatis

Chlamydophila pneumoniae

Chlamydophila psittaci

Coxiella burnetti

Mycoplasma pneumoniae

^$ Natural intermediate susceptibility in the absence of acquired mechanism of resistance.

^£ All methicillin-resistant staphylococci are resistant to amoxycillin/clavulanic acid.

^§ All strains with resistance to amoxycillin that is not mediated by beta-lactamases are resistant to amoxycillin/clavulanic acid.

¹ This presentation of amoxycillin/clavulanic acid may not be suitable for treatment of Streptococcus pneumoniae that are resistant to penicillin.

Pharmacokinetic Properties

The pharmacokinetic results for studies in which amoxycillin/clavulanic acid was administered to groups of healthy volunteers as either 500 mg/100 mg or 1,000 mg/200 mg given as a bolus I.V. injection are presented below.

*Mean (± SD) Pharmacokinetic Parameters* *Bolus I.V.* *Injection*
Dose Administered	Amoxycillin
	Dose	Mean peak serum conc. (microgram/mL)	T 1/2 (h)	AUC (h.mg/ml)	Urinary recovery (%, 0 to 6 hours)
AMX/CA 500 mg/100 mg	500 mg	32.2	1.07	25.5	66.5
AMX/CA 1,000 mg/200 mg	1000 mg	105.4	0.9	76.3	77.4
Clavulanic acid
AMX/CA 500 mg/100 mg	100 mg	10.5	1.12	9.2	46.0
AMX/CA 1,000 mg/200 mg	200 mg	28.5	0.9	27.9	63.8

AMX – amoxycillin, CA – clavulanic acid

Amoxycillin and clavulanic acid, are fully dissociated in an aqueous solution at physiological pH.

About 25% of total plasma clavulanic acid and 18% of total plasma amoxycillin is bound to protein. The apparent volume of distribution is around 0.3–0.4 L/kg for amoxycillin and around 0.2 L/kg for clavulanic acid.

Following I.V. administration, both amoxycillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxycillin does not adequately distribute into the cerebrospinal fluid.

From animal studies, there is no evidence for significant tissue retention of drug derived material for either component. Amoxycillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk.

Both amoxycillin and clavulanic acid have been shown to cross the placental barrier.

Amoxycillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in humans and eliminated in the urine and faeces, and as carbon dioxide in expired air.

The major route of elimination for amoxycillin is via the kidneys, whereas for clavulanic acid, it is by both renal and non-renal mechanisms.

Amoxycillin/clavulanic acid has a mean elimination half-life of approximately 1 hour and a mean total clearance of approximately 25 L/hour in healthy subjects. Approximately 60–70% of the amoxycillin and approximately 40–65% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 500/100 mg or a single 1,000/200 mg bolus I.V. injection. Various studies have found the urinary excretion to be 50–85% for amoxycillin and between 27 and 60% for clavulanic acid over a 24-hour period. In the case of clavulanic acid, the largest amount of drug is excreted during the first 2 hours after administration.

Concomitant use of probenecid delays amoxycillin excretion but does not delay renal excretion of clavulanic acid.

Age

The elimination half-life of amoxycillin 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. As 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.

Renal Impairment

The total serum clearance of amoxycillin/clavulanic acid decreases proportionately with decreasing renal function. The reduction in drug clearance is more pronounced for amoxycillin than for clavulanic acid, as a higher proportion of amoxycillin is excreted via the renal route. Doses in renal impairment must, therefore, prevent undue accumulation of amoxycillin while maintaining adequate levels of clavulanic acid.

Hepatic Impairment

Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals.

Non-Clinical Properties

Non-clinical data reveal no special hazard for humans based on 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 or its components.

Description

Amoxycillin and clavulanate potassium powder for reconstitution for intravenous (I.V.) or infusion consists of the semisynthetic antibiotic, amoxicillin, and the β-lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxycillin is an analogue of ampicillin, derived from the basic penicillin nucleus, 6- aminopenicillanic acid. The amoxycillin molecular formula is C 16H19N3O5S•3H2O, and the molecular weight is 419.46. Chemically, amoxycillin is (2S,5R,6R)-6-[(R)-(-)-2-Amino-2-(p-hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid trihydrate.

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a β-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of β-lactamases by blocking the active sites of these enzymes.

Clavulanic acid is particularly active against the clinically important plasmid-mediated β-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5, and the molecular weight is 237.25. Chemically, clavulanate potassium is potassium (Z )-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4- oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate.

Pharmaceutical Particulars

Incompatibilities

This medicinal product must not be mixed with other medicinal product. ADVENT IV should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.

If ADVENT IV is prescribed concurrently with an aminoglycoside, the antibiotics should not be mixed in the syringe, intravenous fluid container or giving set because loss of activity of the aminoglycoside can occur under these conditions.

Shelf-Life

See on pack

Packaging Information

ADVENT 1.2 gm Injection…………………..Vial of 20 ml

ADVENT 600 mg Injection…………………..Vial of 10 ml

ADVENT 300 mg/150 mg Injection……….....Vial of 5 ml

Storage and Handling Instructions

Store below 25⁰C. Protect from light and moisture. Do not freeze. Dissolve the contents of the vial using sterile water for injection IP. ADVENT I.V. solutions should be used within 20 minutes of reconstitution. For infusion, the reconstituted solution can be further diluted with compound sodium chloride I.V. Infusion IP (Ringer’s solution) that has a stability period (25⁰C) of 2 hours.

Patient Counselling Information

● What is ADVENT I.V?

ADVENT is an antibiotic and works by killing bacteria that cause infections. It contains two different medicines, namely, amoxycillin and clavulanic acid. Amoxycillin belongs to a group of medicines called ‘penicillins’, which can sometimes be stopped from working (made inactive). The other active component (clavulanic acid) stops this from happening.

ADVENT is used in adults and children to treat the following infections:

• Severe ear, nose and throat infections

• Respiratory tract infections

• Urinary tract infections

• Skin and soft tissue infections, including dental infections

• Bone and joint infections

• Intra-abdominal infections

• Genital organ infections in women

ADVENT is used in adults and children to prevent infections associated with major surgical procedures.

● What precautions have to be followed when taking ADVENT?

Do not take if you have an allergy to the drug.

You should not use ADVENT

• if you are allergic to amoxicillin, clavulanic acid, penicillin or any of the other ingredients of this medicine; and,

• if you have ever had a severe allergic reaction to any other antibiotic. This can include a skin rash or swelling of the face or throat

Before you take ADVENT, tell your doctor about other medications.

Tell your doctor, pharmacist or nurse if you are using, have recently used or might use any other medicines.

• If you are taking allopurinol (used for gout) with ADVENT, it may be more likely that you will have an allergic skin reaction.

• If you are taking probenecid (used for gout), your doctor may decide to adjust your dose of ADVENT.

• If medicines to help stop blood clots (such as warfarin) are taken with ADVENT then extra blood tests may be needed.

• ADVENT can affect how methotrexate (a medicine used to treat cancer or rheumatic diseases) works.

• ADVENT can affect how mycophenolate mofetil (a medicine used to prevent the rejection of transplanted organs) works.

● How is ADVENT given?

You should never give yourself this medicine. A qualified person, such as a doctor or a nurse, will give you this medicine.

Patients with kidney and liver problems:

• If you have kidney problems, you may be given a different dose. A different strength or a different medicine may be chosen by your doctor.

• If you have liver problems, your doctor will keep a close check on you and you may have more regular liver function tests.

● How will ADVENT be given?

• ADVENT will be given as an injection into a vein or by I.V. infusion.

• Make sure you drink plenty of fluids while having ADVENT.

• You will not normally be given ADVENT for longer than 2 weeks without the doctor reviewing your treatment.

If more ADVENT is given to you than recommended

It is unlikely you will be given too much, but if you think you have been given too much ADVENT, tell your doctor, pharmacist or nurse immediately. Signs may be an upset stomach (feeling sick, being sick or diarrhoea) or convulsions. If you have any further questions about how this medicine is given, ask your doctor, pharmacist or nurse.

● What are the possible side effects?

Like all medicines, this medicine can cause side effects, although not everybody gets them. The side effects below may happen with this medicine.

Conditions you need to look out for

Allergic reactions

• Skin rash

• Inflammation of blood vessels (vasculitis), which may be visible as red or purple raised spots on the skin, but can affect other parts of the body.

• Fever, joint pain, swollen glands in the neck, armpit or groin.

• Swelling, sometimes of the face or throat (angio-oedema), causing difficulty in breathing

• Collapse. Contact your doctor immediately if you get any of these symptoms.

Stop taking ADVENT in case of the following:

• Inflammation of large intestine.

• Inflammation of the large intestine, causing watery diarrhoea usually with blood and mucus, stomach pain and/or fever.

Contact your doctor as soon as possible for advice if you get these symptoms:

Common side effects

These may affect up to 1 in 10 people.

• Thrush (candida – a yeast infection of the vagina, mouth or skin folds)

• Diarrhoea

Uncommon side effects

These may affect up to 1 in 100 people.

• Skin rash, itching

• Raised itchy rash (hives)

• Feeling sick (nausea), especially when taking high doses

• Vomiting

• Indigestion

• Dizziness

• Headache

Uncommon side effects that may show up in your blood tests

• Increase in some substances (enzymes) produced by the liver.

Rare side effects

These may affect up to 1 in 1,000 people.

• Skin rash, which may blister, and looks like small targets (central dark spots surrounded by a paler area, with a dark ring around the edge – erythema multiforme); if you notice any of these symptoms, contact a doctor urgently.

• Swelling and redness along a vein which is extremely tender when touched.

Rare side effects that may show up in your blood tests

• Low number of cells involved in blood clotting.

• Low number of white blood cells.

Frequency not known (frequency cannot be estimated from the available data)

• Allergic reactions (see above).

• Inflammation of the large intestine (see above).

• Inflammation of the protective membrane surrounding the brain (aseptic meningitis)

• Serious skin reactions – a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome), and a more severe form, causing extensive peeling of the skin (more than 30% of the body surface – toxic epidermal necrolysis); widespread red skin rash with small pus-containing blisters (bullous exfoliative dermatitis); a red, scaly rash with bumps under the skin and blisters (exanthemous pustulosis); flu-like symptoms with a rash, fever, swollen glands; and abnormal blood test results [including increased white blood cells (eosinophilia) and liver enzymes) and drug reaction with eosinophilia and systemic symptoms (DRESS)].

Contact your doctor immediately if you get any of these symptoms:

• Inflammation of the liver (hepatitis)

• Jaundice, caused by increases in the blood of bilirubin (a substance produced in the liver), which may make your skin and the whites of the eyes appear yellow

• Inflammation of tubes in the kidney

• Blood takes longer to clot

• Convulsions (in people taking high doses of ADVENT or who have kidney problems)

Side effects that may show up in your blood or urine tests

• Severe reduction in the number of white blood cells

• Low number of red blood cells (haemolytic anaemia)

• Crystals in the urine

● How should I store this medicine?

ADVENT I.V. is for use in a hospital only and the expiry date and the storage instructions stated on the label are exclusively meant for the doctor, nurse or pharmacist. The doctor, pharmacist or nurse will make up your medicine. It should be used within 20 minutes of reconstitution. Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date shown on the carton. The expiry date refers to the last day of that month. Do not store above 25°C. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

● General information about the safe and effective use of this drug

Talk to your doctor or pharmacist or nurse before having ADVENT if you

• have glandular fever;

• are being treated for liver or kidney problems; and,

• are not passing water regularly.

If you are not sure if any of the above apply to you, talk to your doctor, pharmacist or nurse before taking ADVENT.

In some cases, your doctor may investigate the type of bacteria that is causing your infection. Depending on the results, you may be given a different strength of ADVENT or a different medicine.

Conditions you need to look out for: ADVENT can make some existing conditions worse, or cause serious side effects. These include allergic reactions, convulsions (fits) and inflammation of the large intestine. You must look out for certain symptoms while you are taking ADVENT so as to reduce the risk of any problems.
Blood and urine tests: If you are having blood tests (such as red blood cell status tests or liver function tests) or urine tests (for glucose), let the doctor or nurse know that you are taking ADVENT. This is because ADVENT can affect the results of these types of tests.

Pregnancy, breastfeeding and fertility

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor, pharmacist or nurse for advice before taking this medicine.

Driving and using machines

ADVENT can have side effects and the symptoms may make you unfit to drive. Do not drive or operate machinery unless you are feeling well.