Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS/Zisuva 600/Zisuva 1200

Amoxicillin trihydrate, potassium clavulanate.

Zisuva 375: Each 375-mg film coated tablet contains: Amoxicillin Trihydrate BP Equivalent to Amoxicillin 250 mg, Potassium Clavulanate BP (as Diluted Potassium Clavulanate BP) Equivalent to Clavulanic Acid 125 mg.
Zisuva 625: Each 625-mg film coated tablet contains: Amoxicillin Trihydrate BP Equivalent to Amoxicillin 500 mg, Potassium Clavulanate BP (as Diluted Potassium Clavulanate BP) Equivalent to Clavulanic Acid 125 mg.
Zisuva 1G: Each 1-g film coated tablet contains: Amoxicillin Trihydrate BP Equivalent to Amoxicillin 875 mg, Potassium Clavulanate BP (as Diluted Potassium Clavulanate BP) Equivalent to Clavulanic Acid 125 mg.
Zisuva DS: Each 5 ml of reconstituted suspension contains: Amoxicillin Trihydrate BP equivalent to Amoxicillin 125 mg, Clavulanate Potassium BP (as diluted Potassium Clavulanate BP) equivalent to Clavulanic Acid 31.25 mg.
Zisuva 600: Each vial of ZISUVA 600 contains Amoxicillin Sodium equivalent to Amoxicillin 500 mg, Potassium Clavulanate equivalent to Clavulanic acid 100 mg.
Zisuva 1200: Each vial of ZISUVA 1200 contains Amoxicillin Sodium equivalent to Amoxicillin 1000 mg, Potassium Clavulanate equivalent to Clavulanic acid 200 mg.
Excipients/Inactive Ingredients: Zisuva 375/Zisuva 625/Zisuva 1G: q.s.

Pharmacology: Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Amoxicillin and Potassium Clavulanate is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the β-lactamase inhibitor, Potassium Clavulanate (the potassium salt of clavulanic acid).
Clavulanic acid binds and inhibits beta-lactamases that inactivate amoxicillin resulting in amoxicillin having an expanded spectrum of activity. Amoxicillin inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.
Zisuva 600/Zisuva 1200: Mechanism of action: Amoxicillin 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.
Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria and therefore the spectrum of activity at amoxicillin alone does not include organisms which produce these enzymes.
Clavulanic acid is a beta-lactam structurally related to penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
Pharmacokinetics: Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Amoxicillin and Potassium Clavulanate are well absorbed from the gastrointestinal tract after oral administration of amoxicillin and potassium clavulanate. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and potassium clavulanate can be given without regard to meals, absorption of potassium clavulanate when taken with food is greater relative to the fasted state. In 1 study, the relative bioavailability of clavulanate was reduced when amoxicillin 1 potassium clavulanate was dosed at 30 and 150 minutes after the start of a high - fat breakfast. The safety and efficacy of amoxicillin and potassium clavulanate was taken without regard to meals.
Amoxicillin serum concentration achieved with amoxicillin and potassium clavulanate are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of amoxicillin and potassium clavulanate is 1.3 hours and that of clavulanic acid is 1.0 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single 250 mg or 500 mg tablet of amoxicillin and potassium clavulanate.
Concurrent administration of Probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.
Neither component in amoxicillin and potassium clavulanate is highly protein - bound: clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.
Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Treatment of otitis media, sinusitis, and infections caused by susceptible organisms involving the lower respiratory tract, skin and skin structure, and urinary tract: spectrum same as amoxicillin with additional coverage of beta-lactamase producing B. catarrhalis, H. influenzae, N. gonorrhoeae, and S. aureus (not MRSA). The expanded coverage of this combination makes it a useful alternative when amoxicillin resistance is present and patients cannot tolerate alternative treatments.
Zisuva 600/Zisuva 1200: ZISUVA injection is indicated for the treatment of the following infections in adults and children: Severe infections of the ear, nose and throat (such as mastoiditis, peritonsillar infections, epiglottitis, and sinusitis when accompanied by severe systemic signs and symptoms), Acute exacerbations of chronic bronchitis (adequately diagnosed), Community acquired pneumonia, Cystitis, Pyelonephritis, Skin and soft tissue infections in particular cellulitis, animal bites, severe dental abscess with spreading cellulitis, Bone and joint infections, in particular osteomyelitis, Intra-abdominal infections, Female genital infections.
Prophylaxis against infections associated with major surgical procedures in adults, such as those involving the Gastrointestinal tract, Pelvic cavity, Head and neck, Biliary tract surgery.

(Direction for use): ZISUVA 375 Tablets: 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 ZISUVA 375 Tablets 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 as follows.
The use of alternative presentations of ZISUVA Tablets (e.g. those that provide higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) should be considered as necessary. Treatment should not be extended beyond 14 days without review.
Adults and children ≥ 40 kg: One tablet taken three times a day.
Children < 40 kg: ZISUVA 375 Tablets are not recommended in children <40 kg.
Elderly: No dose adjustment is considered necessary.
Renal Impairment: Dose adjustments are based on the maximum recommended level of amoxicillin. No adjustment in dose is required in patients with creatinine clearance (CrCl) greater than 30ml/min.
Adults and children ≥ 40 kg: CrCl 10-30 ml/min: 250 mg/125 mg twice daily.
CrCl < 10 ml/min: 250 mg/125 mg once daily.
Haemodialysis: Two doses of 250 mg/125 mg every 24 hours, plus two doses of 250mg/125mg during dialysis, to be repeated at the end of dialysis (as serum concentrations of both amoxicillin and clavulanic acid are decreased).
Children < 40 kg: In children < 40 kg with creatinine clearance less than 30 ml/min, the use of ZISUVA 375 Tablets presentations with an amoxicillin to clavulanic acid ratio of 2:1 is not recommended, as no dose adjustments are available. In such patients, ZISUVA formulations with an amoxicillin to clavulanic acid ratio of 4:1 are recommended.
Hepatic impairment: Dose with caution and monitor hepatic function at regular intervals.
ZISUVA 625 mg and 1 g: Usual dosages for the treatment of infection: Adults and children over 12 years: Mild - Moderate infections: One ZISUVA 625 mg tablet twice daily.
Severe infections: One ZISUVA 1g tablet twice daily or One ZISUVA 625 mg tablet 3 times a day.
Therapy can be started parenterally and continued with an oral preparation.
ZISUVA 625mg / 1g tablets are not recommended in children of 12 years and under.
Dosage in renal impairment: Adults: ZISUVA 1g tablet should only be used in patients with a glomerular filtration rate of >30 ml/min. (See Table 1.)

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Dosage in hepatic impairment: Dose with caution; monitor hepatic function at regular intervals.
Method of Administration: Tablet to be consumed in whole, not to be broken.
To minimise potential gastrointestinal intolerance, administer at the start of a meal.
The absorption of ZISUVA is optimised when taken at the start of a meal.
Treatment should not be extended beyond 14 days without review.
Zisuva DS: Neonates and Infants aged < 12 weeks (3 months): The recommended dose of Amoxicillin and Clavulanate Potassium for Oral Suspension 250mg/62.5mg per 5 ml is 30 mg/kg/day.
Adults: Adults who have difficulty swallowing may be given the Amoxicillin and Clavulanate Potassium for Oral Suspension 250mg/62.5mg per 5 ml or 125 mg/31.25 mg per 5 ml suspension in place of 500mg/125mg tablet.
Directions for Mixing Oral Suspension: Shake the bottle to ensure the powder is free flowing. Add freshly boiled and cooled water a little below the mark on the bottle and shake well to get a uniform suspension. Add further water up to the mark and mix well. The reconstituted suspension to be stored in a refrigerator and should be consumed within 7 days,
Method of Administration: For oral administration.
Zisuva 600/Zisuva 1200: Posology: The dose of ZISUVA 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 as follows.
The use of alternative presentations of Zisuva (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 he 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.
Recommended doses for treatment of infections as indicated in previous section: Adults and children ≥ 40 kg: 1000 mg/200 mg every 8-12 hours or; 2000 mg/200 mg every 12 hours.
For very severe infections the dose may be increased to a maximum of 2000 mg/200 mg every 8 hours. (See Table 2.)

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Children < 40 kg Recommended doses: Children aged 3 months and over: 50 mg/5 mg per kg every 8 hours.
Children aged less than 3 months or weighing less than 4 kg: 50 mg/5 mg per kg every 12 hours.
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: See Table 3.

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Children < 40 kg: See Table 4.

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Hepatic impairment: Dose with caution and monitor hepatic function at regular intervals.
Method of Administration: ZISUVA Injection is for intravenous use.
ZISUVA Injection may be administered either by slow intravenous injection over a period of 3 to 4 min directly into a vein or via a drip tube or by infusion over 30 to 40 min. ZISUVA Injection is not suitable for intramuscular administration.
Children aged less than 3 months should be administered ZISUVA Injection by infusion only.
Treatment with ZISUVA Injection may be initiated by the use of an intravenous preparation and completed with an appropriate oral presentation as considered appropriate for the individual patient.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients. In the case of overdosage, discontinue amoxicillin and potassium clavulanate, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.
Zisuva 600/Zisuva 1200: Gastrointestinal symptoms and disturbance of the fluid and electrolyte balances may be evident. Amoxicillin 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 cases.
Amoxicillin has been reported to precipitate in bladder catheters, predominantly after intravenous administration of large doses. A regular check of potency should be maintained.
Treatment of intoxication: Gastrointestinal symptoms may be treated symptomatically, with attention to the water/electrolyte balance.
Amoxicillin/clavulanic acid can be removed from the circulation by hemodialysis.

Zisuva 600/Zisuva 1200: Hypersensitivity to the active substances, to any of the penicillins or to any of the excipients.
History of a severe immediate hypersensitivity reaction (e.g. anaphylaxis) to another beta-lactam agent (e.g. a cephalosporin, carbapenem or monobactam). History of jaundice/hepatic impairment due to amoxicillin/clavulanic acid.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Concerns related to adverse effects: Anaphylactoid/hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactoid) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous lgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients. Low incidence of cross-allergy with cephalosporins exists.
Diarrhea: Incidence of diarrhea is higher than with amoxicillin alone.
Hepatic effects: Although rare, hepatic dysfunction is more common in elderly and/or males, and occurs more frequently with prolonged treatment, and may occur after therapy is complete.
Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile - associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.
Disease-related concerns: Hepatic impairment: Use with caution in patients with hepatic impairment.
Infectious mononucleosis: A high percentage of patients with infectious mononucleosis have developed rash during therapy; ampicillin-class antibiotics not recommended in these patients.
Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.
Dosage form specific issues: Due to differing content of clavulanic acid, not all formulations are interchangeable.
Concerns related to Pregnancy and lactation: Pregnancy: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Limited data on the use of amoxicillin and 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 amoxicillin and clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.
Lactation: 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. Amoxicillin and clavulanic acid should only be used during breast-feeding after benefits - risk assessment by the physician in charge.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Zisuva 600/Zisuva 1200: Before initiating therapy with amoxicillin/clavulanic acid, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents.
Convulsions may occur in patients with impaired renal function or in those receiving high doses. Amoxicillin/clavulanic acid should be avoided if infectious mononucleosis is suspected since the occurrence of a morbilliform rash has been associated with this condition following the use of amoxicillin. Concomitant use of allopurinol during treatment with amoxicillin can increase the likelihood of allergic skin reactions.

Pregnancy: Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Limited data on the use of amoxicillin and 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 amoxicillin and clavulanic acid may be associated with an increased risk of necrotising enterocolitis in neonates. Use should be avoided during pregnancy, unless considered essential by the physician.
Zisuva 600/Zisuva 1200: Limited data on the use of amoxicillin/clavulanic acid during pregnancy in humans do not indicate an Increased risk of congenital malformations. Use should be avoided during pregnancy, unless considered essential by the physician.
Lactation: Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: 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. Amoxicillin and clavulanic acid should only be used during breast-feeding after benefits - risk assessment by the physician in charge.
Zisuva 600/Zisuva 1200: Both substances are excreted into breast milk. Consequently, diarrhea 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 sensitization should be taken into account. Amoxicillin/clavulanic acid should only be used during breast-feeding after benefit/risk assessment by the physician in charge.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Amoxicillin and Potassium Clavulanate is generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature and less than 3% of patients discontinued therapy because of drug-related side effects. The most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported reactions include: Abdominal discomfort, flatulence, and headache.
Gastrointestinal: Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black "hairy" tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.
Zisuva 600/Zisuva 1200: The most commonly reported adverse drug reactions (ADRs) are diarrhea, nausea and vomiting.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Allopurinol: May enhance the potential for allergic or hypersensitivity reactions to Amoxicillin. Risk C: Monitor therapy.
Fusidic Acid: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification.
Methotrexate: Penicillins may decrease the excretion of Methotrexate. Risk C: Monitor therapy.
Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Risk C: Monitor therapy.
Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Risk D: Consider therapy modification.
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Risk D: Consider therapy modification.
Uricosuric Agents: May decrease the excretion of Penicillins. Risk C: Monitor therapy.
Zisuva 600/Zisuva 1200: Oral anticoagulants: Oral anticoagulants and penicillin antibiotics have been widely used in practice without reports of interaction. However, there are cases of increased international normalised ratio in patients maintained on acenocoumarol or warfarin and prescribed a course of amoxicillin. If co-administration is necessary, the prothrombin time or international normalized ratio should be carefully monitored with the addition or withdrawal of amoxicillin. Moreover, adjustments in the dose of oral anticoagulants may be necessary.
Methotrexate: Penicillin may reduce the excretion of methotrexate causing a potential increase in toxicity.
Probenecid: Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in increased and prolonged blood levels of amoxicillin but not of clavulanic acid.
Mycophenolate mofetil: In patients receiving mycophenolate mofetil, reduction in pre-dose concentration of the active metabolite mycophenolic acid (MPA) of approximately 50% has been reported following commencement of oral amoxicillin plus clavulanic acid. The change in pre-dose level may not accurately represent changes in overall MPA exposure. 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.

Zisuva 600/Zisuva 1200: Method of Preparation: Preparation of solutions for intravenous injection: 500 mg/100 mg powder for solution for injection or infusion: Water for Injection is the normal solvent. ZISUVA Injection 500/100 mg should be dissolved in 10 ml of solvent. This yields approximately 10.5 ml of solution for single-dose use. A transient pink coloration may or may not develop during reconstitution. Reconstituted solutions are normally colorless to Pale Yellow in color.
ZISUVA Injection should be administered within 20 min of reconstitution.
1000 mg/200 mg powder for solution for injection or infusion: Water for Injection is the normal solvent. ZISUVA Injection 1000 mg/200 mg should be dissolved in 20 ml of solvent. This yields approximately 20.9 ml of solution for single-dose use. A transient pink coloration may or may not develop during reconstitution. Reconstituted solutions are normally colorless to Pale Yellow in color.
ZISUVA Injection should be administered within 20 min of reconstitution.
Preparation of solutions for intravenous infusion: ZISUVA Injection vials are not suitable for multi-dose use.
500 mg/100 mg powder for solution for infection or infusion: ZISUVA Injection should be reconstituted as described previously for injection. Without delay the reconstituted solution should be added to 50 ml of infusion fluid using a minibag or in-line burette.
1000 mg/200 mg powder for solution for injection or infusion: ZISUVA Injection should be reconstituted as described previously for injection. Without delay the reconstituted solution should be added to 100 ml of infusion fluid using a minibag or in-line burette.
Incompatibilities: ZISUVA Injection should not be mixed with blood products, other proteinaceous fluids such as protein hydrolysates or with intravenous lipid emulsions.
If prescribed concomitantly 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.
ZISUVA Injection solutions should not be mixed with infusions containing glucose, dextran or bicarbonate.
Special Precautions for Disposal: Single dose for IV use only. Discard any unused solution.
The reconstitution/dilution is to be made under aseptic conditions, The solution is to be inspected visually for particulate matter and discoloration prior to administration. The solution should only be used if the solution is clear and free from particles.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Zisuva 375/Zisuva 625/Zisuva 1G/Zisuva DS: Store below 30°C. Protect from light and moisture.
Zisuva 600/Zisuva 1200: Store below 25°C. Protect from light and moisture.
Shelf Life: Powder in vials: 24 Months.

Penicillins

J01CR02 - amoxicillin and beta-lactamase inhibitor ; Belongs to the class of penicillin combinations, including beta-lactamase inhibitors. Used in the systemic treatment of infections.

POM

Zisuva 375: FC tab 1 x 10's.
Zisuva 625: FC tab 2 x 7's.
Zisuva 1G: FC tab 1 x 10's.
Zisuva DS: Powd for oral susp 60 mL x 1's.
Zisuva 600: Powd for inj (vial) (white to off-white, sterile) 1's.
Zisuva 1200: Powd for inj (vial) (white to off-white, sterile) 1's.