Augpen Drops

Amoxycillin and Potassium Clavulanate Oral Suspension IP [80 mg + 11.4 mg]

Each 1 ml of reconstituted suspension contains :

Amoxycillin Trihydrate IP

equivalent to Amoxycillin 80 mg

Potassium Clavulanate Diluted IP

equivalent to Clavulanic Acid 11.4 mg

Excipients q.s

This pack contains Sterile Water for Injections IP 10 ml for reconstitution

Oral suspension Amoxycillin and Potassium Clavulanate [80 mg + 11.4 mg]

4.1 Therapeutic indication

For the treatment of LRTI infections (e.g. Pneumonia, Bronchitis), Acute otitis media, Sinusitis, UTI, Skin and soft tissue infections, Bone and joint infections.

4.2 Posology and method of administration

Dose of Augpen Drops (in mL) to be given every 12 hours to children aged 3 to 24 months (based on body weight)

Directions for use

At the time of dispensing, the dry powder should be reconstituted to form an oral suspension. First shake the bottle to loosen the powder. Add SWFI (given with the pack) to two-thirds of the fill mark on the bottle. Put the cap and shake the bottle vigorously until all of the powder is suspended. Add more SWFI until the level of the fill line is attained and shake again. When first reconstituted, allow to stand for 5 minutes to ensure full dispersion. After reconstitution, keep in refrigerator (at 2°C to 8°C) when not in use. Use the reconstituted suspension within 7 days of preparation.

4.3 Contraindications

• Patients with a history of hypersensitivity to beta-lactams, e.g. penicillin and cephalosporins
• Patients with a previous history of Augpen-associated jaundice/hepatic dysfunction

4.4 Special warnings and precautions for use

Before initiating therapy with Augpen, careful enquiry should be made concerning previous hypersensitivity reactions to penicillin, cephalosporins or other allergens. 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 (see Contraindications). If an allergic reaction occurs, Augpen therapy must be discontinued and appropriate alternative therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with adrenaline. Oxygen, intravenous (I.V.) steroids and airway management (including intubation) may also be required. Augpen 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 Amoxycillin. Prolonged use may also occasionally result in overgrowth of non-susceptible organisms. Pseudomembranous colitis has been reported with the use of antibiotics and may range in severity from mild to life-threatening. Therefore, it is important to consider its diagnosis in patients who develop diarrhoea during or after antibiotic use. If prolonged or significant diarrhoea occurs or the patient experiences abdominal cramps, treatment should be discontinued immediately and the patient investigated further. Abnormal prolongation of prothrombin time (increased INR) has been reported rarely in patients receiving Augpen 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

Changes in liver function tests have been observed in some patients receiving Augpen. The clinical significance of these changes is uncertain but Augpen should be used with caution in patients with evidence of hepatic dysfunction.

Cholestatic jaundice, which may be severe, but is usually reversible, has been reported rarely. Signs and symptoms may not become apparent for up to six weeks after treatment has ceased. In patients with renal impairment Augpen Suspension 228 mg / 5 mL and 457 mg / 5 mL are not recommended.

In patients with reduced urine output, crystalluria has been observed very rarely, predominantly with parenteral therapy. During the 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. Augpen 228 mg / 5 mL and 457 mg / 5 mL suspensions contain 12.5 mg Aspartame per 5 mL dose and therefore care should be taken in patients with phenylketonuria.

4.5 Drugs interactions

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of Amoxycillin. Concomitant use with Augpen may result in increased and prolonged blood levels of Amoxycillin but not of Clavulanate. Concomitant use of allopurinol during treatment with Amoxycillin can increase the likelihood of allergic skin reactions. There are no data on the concomitant use of Augpen and Allopurinol. In common with other antibiotics, Augpen may affect the gut flora, leading to lower oestrogen reabsorption and reduced efficacy of combined oral contraceptives. In the literature there are rare cases of increased international normalised ratio in patients maintained on Acenocoumarol or Warfarin and prescribed a course of Amoxycillin. If co-administration is necessary, the prothrombin time or international normalised ratio should be carefully monitored with the addition or withdrawal of Augpen. In patients receiving Mycophenolate Mofetil, reduction in pre-dose concentration of the active metabolite Mycophenolic Acid 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.

4.6 Use in special populations

Pregnancy and lactation

Reproduction studies in animals (mice and rats) with orally and parenterally administered Augpen have shown no teratogenic effects. In a single study in women with preterm, premature rupture of the foetal membrane (pPROM), it was reported that prophylactic treatment with Augpen 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 Physician. Augpen may be administered during the period of lactation. With the exception of the risk of sensitisation, associated with the excretion of trace quantities in breast milk, there are no detrimental effects for the infant.

4.7 Effects on ability to drive and use machines

Adverse effects on the ability to drive or operate machinery have not been observed

4.8 Undesirable effects

Data from large clinical trials were used to determine the frequency of very common to rare undesirable effects. The frequencies assigned to all other undesirable effects (i.e., those occurring at < 1/10,000) were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency.

Infections and infestations

Common : Mucocutaneous candidiasis

Blood and lymphatic system disorders

Rare : Reversible leucopenia (including neutropenia) and thrombocytopenia.

Very rare : Reversible agranulocytosis and haemolytic anaemia. Prolongation of bleeding time and prothrombin time.

Immune system disorders

Very rare : Angioneurotic oedema, anaphylaxis, Serum sickness-like syndrome, Hypersensitivity vasculitis

Nervous system disorders

Uncommon : Dizziness, Headache

Very rare : Reversible hyperactivity, Aseptic meningitis, Convulsions. Convulsions may occur in patients with impaired renal function or in those receiving high doses.

Gastrointestinal disorders

Adults

Very common : Diarrhoea

Common : Nausea, Vomiting

Children

Common : Diarrhoea, Nausea, Vomiting

All populations

Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, they may be reduced by taking Augpen at the start of a meal.

Uncommon : Indigestion

Very rare : Antibiotic-associated colitis (including pseudomembranous colitis and haemorrhagic colitis), black hairy tongue, superficial tooth discolouration has been reported very rarely in children. Good oral hygiene may help to prevent tooth discolouration as it can usually be removed by brushing

Hepatobiliary disorders

Uncommon : A moderate rise in AST and/or ALT has been noted in patients treated with beta-lactam class antibiotics, but the significance of these findings is unknown. Very rare : Hepatitis and cholestatic jaundice. These events have been noted with other penicillin and cephalosporins.

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. 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.

Skin and subcutaneous tissue disorders

Uncommon : Skin rash, Pruritus, Urticaria

Rare : Erythema multiforme

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative-dermatitis, acute generalised exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS).

If any hypersensitivity dermatitis reaction occurs, treatment should be discontinued

Renal and urinary disorders

Very rare : Interstitial nephritis, Crystalluria

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 email to :medico@zuventus.com

4.9 Overdose

Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Gastrointestinal symptoms may be treated symptomatically with attention to the water-electrolyte balance. Amoxycillin crystalluria, in some cases leading to renal failure, has been observed. Augpen can be removed from the circulation by haemodialysis.

5.1 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.

5.2 Pharmacodynamic properties

Amoxycillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity of Amoxycillin alone does not include organisms which produce these enzymes. Clavulanic Acid is a beta-lactam structurally related to penicillin. It inactivates some beta-lactamase enzymes thereby preventing inactivation of Amoxycillin. Clavulanic Acid alone does not exert a clinically useful antibacterial effect.

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.

5.3 Pharmacokinetic properties

Absorption

Amoxycillin and Clavulanic Acid, are fully dissociated in aqueous solution at physiological pH. Both components are rapidly and well absorbed by the oral route of administration. Following oral administration, Amoxycillin and Clavulanic Acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to peak plasma concentration (T_max) in each case is approximately one hour.

The pharmacokinetic results for a study, in which Amoxycillin/Clavulanic Acid (250 mg / 125 mg tablets three times daily) was administered in the fasting state to groups of healthy volunteers are presented below.

Amoxycillin and Clavulanic Acid serum concentrations achieved with Amoxycillin/Clavulanic Acid are similar to those produced by the oral administration of equivalent doses of Amoxycillin or Clavulanic Acid alone.

Distribution

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 intravenous 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 penicillin, 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.

Biotransformation

Amoxycillin is partly excreted in the urine as the inactive penicilloic acid in quantities equivalent to up to 10 to 25% of the initial dose. Clavulanic Acid is extensively metabolized in man and eliminated in urine and faeces, and as Carbon Dioxide in expired air.

Elimination

The major route of elimination for Amoxycillin is via the kidney, whereas for Clavulanic Acid it is by both renal and non-renal mechanisms.

Amoxycillin/Clavulanic Acid has a mean elimination half-life of approximately one hour and a mean total clearance of approximately 25 l/h in healthy subjects. Approximately 60 to 70% of the Amoxycillin and approximately 40 to 65% of the Clavulanic Acid are excreted unchanged in urine during the first 6 h after administration of single Augpen 250 mg / 125 mg or 500 mg / 125 mg tablets. Various studies have found the urinary excretion to be 50 - 85% for Amoxycillin and between 27 - 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

6.1 Animal toxicology or pharmacology

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 Amoxycillin/Clavulanic Acid demonstrate gastric irritancy and vomiting, and discoloured tongue. Carcinogenicity studies have not been conducted with Amoxycillin/Clavulanic Acid.

Augpen is an oral antibacterial combination consisting of Amoxycillin and the beta-lactamase inhibitor, Clavulanate Potassium (the Potassium salt of Clavulanic Acid).

8.1 Incompatibilities

Not applicable

8.2 Shelf-life

18 Months

8.3 Packaging information

A bottle of 2.2 g / 10 ml with SWFI IP 10 ml.

8.4 Storage and handing instructions Store below 25°C. Protect from moisture.

Keep out of reach of children.

SHAKE WELL BEFORE USE.

Store the reconstituted oral suspension in the refrigerator (at 2°C to 8°C).

The normal colour of reconstituted suspension is off white and should be consumed within 7 days of preparation.

DO NOT USE THE RECONSTITUTED SUSPENSION IF THE COLOUR IS BROWN IN APPEARANCE.

Patients should be informed that Augpen may be taken every 8 hours or every 12 hours, depending on the dose prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset.

Patients should be counseled that antibacterial drugs, including Augpen, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Augpen is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may : (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Augpen or other antibacterial drugs in the future. Counsel patients that diarrhea is a common problem caused by antibacterial, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterial, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as 2 or more months after having taken their last dose of the antibacterial. If diarrhea is severe or lasts more than 2 or 3 days, patients should contact their physician. Patients should be advised to keep suspension refrigerated. Shake well before using. When dosing a child with the suspension (liquid) of Augpen, use a dosing spoon or medicine dropper. Be sure to rinse the spoon or dropper after each use. Bottles of suspension of Augpen may contain more liquid than required. Follow your doctor’s instructions about the amount to use and the days of treatment your child requires. Discard any unused medicine. Patients should be aware that Augpen contains a penicillin class drug product that can cause allergic reactions in some individuals.