Each Soft gelatin capsule contains : Calcium Carbonate IP 500 mg equivalent to elemental calcium 200 mg, Calcitriol BP 0.25 mcg, Soya Isoflavone 40% 60mg. Excipients : q.s. Approved colours used in the capsule shell. Appropriate overages added.

Each soft gelatin capsule contains: Calcium Carbonate IP equivalent to Elemental Calcium 400mg, Calcitriol BP 0.25mcg, Zinc (as Zinc Sulphate Monohydrate USP) 7.5mg Excipients : q.s.

AugTaz-KID 125 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 125 mg

Tazobactam Sodium IP equivalent to Tazobactam 15.625 mg

This pack contains Sterile Water for Injections IP 5 ml.

AugTaz-250 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 250 mg

Tazobactam Sodium IP equivalent to Tazobactam 31.25 mg

This pack contains Sterile Water for Injections IP 5 ml.

AugTaz-500 mg

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 500 mg

Tazobactam Sodium IP equivalent to Tazobactam 62.5 mg

This pack contains Sterile Water for Injections IP 5 ml.

AugTaz-1 g

Each vial contains :

Ceftriaxone Sodium IP equivalent to Ceftriaxone 1.0 g

Tazobactam Sodium IP equivalent to Tazobactam 125 mg

This pack contains Sterile Water for Injections IP 10 ml.

AugTazis a combination of Ceftriaxone, a semi - synthetic third generation broad spectrum cephalosporin antibiotic along with a β- lactamase inhibitor Tazobactam. Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone.

Ceftriaxone Sodium :

Chemical Name : (6R, 7R)-7-[2-(2-Amino-4-thiazolyl) glyoxylamido]-8-oxo-3- Chemical Name : (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl) [[(1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-as-triazin-3-yl)thio]methyl]-5-thia-1-azabicyclo -4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide. [4.2.0]oct-2-ene-2-carboxylic acid, 72-(Z)-(O-methyloxime), disodium salt, sesquaterhydrate.

Molecular Formula :C₁₈H₁₆N₈Na₂O₇S₃•3.5H₂O

Molecular Weight : 661.59

RATIONALE OF THE COMBINATION :

Ceftriaxone is a third generation semi-synthetic parenteral cephalosporin that has excellent activity against variety of gram -ve organisms and some gram +ve organisms like Streptococcus pneumoniae, Staphylococcus aureus, H.influenzae, Neisseria meningitides and members of Enterobacteriaceae. Ceftriaxone is indicated in number of community and hospital acquired infections caused by the susceptible organisms both in adults and in children including neonates. Tazobactam is penicillanic acid sulfone derivative with beta-lactamase inhibitory properties, having good affinity for a variety of both plasmid mediated and chromosomal beta lactamases produced by gram +ve and gram –ve bacteria which are originally sensitive to Ceftriaxone. Therefore, it enhances the activity of penicillins and cephalosporins against many resistant strains of bacteria. It is regarded as more potent than other β-lactamase inhibitors (like sulbactam). Clinical role of Ceftriaxone can be compromised due to increasing proportion of extended spectrum β-lactamase (ESBL) producing bacteria which exhibit resistance to Ceftriaxone. To treat such infections Ceftriaxone can be combined with a beta lactamases inhibitor of better efficacy like Tazobactam. The combination of Ceftriaxone and Tazobactam will be effective not only against the beta lactamase producing organisms but also against the originally Ceftriaxone-susceptible bacteria.

Ceftriaxone is a third generation semi-synthetic parenteral cephalosporin that has excellent activity against variety of gram -ve organisms and some gram +ve organisms like Streptococcus pneumoniae, Staphylococcus aureus, H.influenzae, Neisseria meningitides and members of Enterobacteriaceae. Ceftriaxone is indicated in number of community and hospital acquired infections caused by the susceptible organisms both in adults and in children including neonates. Tazobactam is penicillanic acid sulfone derivative with beta-lactamase inhibitory properties, having good affinity for a variety of both plasmid mediated and chromosomal beta lactamases produced by gram +ve and gram –ve bacteria which are originally sensitive to Ceftriaxone. Therefore, it enhances the activity of penicillins and cephalosporins against many resistant strains of bacteria. It is regarded as more potent than other β-lactamase inhibitors (like sulbactam). Clinical role of Ceftriaxone can be compromised due to increasing proportion of extended spectrum β-lactamase (ESBL) producing bacteria which exhibit resistance to Ceftriaxone. To treat such infections Ceftriaxone can be combined with a beta lactamases inhibitor of better efficacy like Tazobactam. The combination of Ceftriaxone and Tazobactam will be effective not only against the beta lactamase producing organisms but also against the originally Ceftriaxone-susceptible bacteria.

Ceftriaxone is a parenteral cephalosporin which acts by inhibition of cell wall biosynthesis and thus is bactericidal in its action. It has excellent activity against variety of aerobic and anaerobic, gram-positive and gram-negative pathogens. Tazobactam (sodium) is a new β-lactamase inhibitor with a range of activity that includes extended spectrum plasmid mediated beta lactamases. Tazobactam lacks significant antibacterial activity of its own. It combines irreversibly with the common plasmid-encoded β-lactamases including the extended spectrum group of beta lactamases. By rendering β–lactamase inactive, Tazobactam is able to protect the activity of Ceftriaxone.

MICROBIOLOGY :

AugTaz has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections.

Aerobic gram-negative microorganisms

• Escherichia coli
• Haemophilus influenzae (including ampicillin-resistant and β-lactamase producing strains)
• Klebsiella pneumoniae
• Moraxella catarrhalis (including β--lactamase producing strains)
• Morganella morganii
• Neisseria gonorrhoeae (including penicillinase- and nonpenicillinase-producing strains)
• Neisseria meningitidis
• Proteus spp
• Serratia marcescens
• Ceftriaxone is also active against many strains of Pseudomonas aeruginosa

Aerobic gram-positive microorganisms

• Staphylococcus aureus (including penicillinase-producing strains)
• Staphylococcus epidermidis
• Streptococcus pneumoniae
• Streptococcus pyogenes
• Viridans group streptococci

Anaerobic microorganisms

• Bacteroides fragilis
• Clostridium species
• Peptostreptococcus species

Absorption

Ceftriaxone demonstrates nonlinear dose-dependent pharmacokinetics because of its protein binding. Mean peak plasma concentrations of about 40 and 80 micrograms/mL have been reported 2 hours after intramuscular injection of 0.5 and 1 g of Ceftriaxone respectively. Mean peak plasma concentrations after bolus intravenous injection are about 120 mg/l following a 500 mg dose and about 200 mg/l following a 1g dose.

Distribution

Ceftriaxone is widely distributed in body tissues and fluids. It crosses both inflamed and non-inflamed meninges, generally achieving therapeutic concentrations in the CSF. Tazobactam is widely distributed into tissues and body fluids including, intestinal mucosa, gallbladder, lung, female reproductive tissues (uterus, ovary and fallopian tube) interstitial fluid and bile. The protein binding of Ceftriaxone is 85-95% and that of Tazobactam is 30%.

Metabolism & Excretion

About 40-65% of a dose of Ceftriaxone is excreted unchanged in urine. The remainder is excreted in bile. The plasma half life of Ceftriaxone is not dose-dependent and varies between 6-9 hours. Tazobactam and its metabolite is eliminated primarily by renal excretion with 80% of the administered dose excreted as unchanged drug and the remainder as the single metabolite.

AugTaz is indicated for the treatment of the following infections when caused by susceptible organisms :

• Respiratory Tract Infections and Pneumonia
• Bacterial Septicemia
• Uncomplicated Gonorrhea (Cervical/Urethral and rectal)
• Surgical Prophylaxis
• Intra-Abdominal Infections
• Urinary Tract Infections (Complicated and Uncomplicated)
• Bone and Joint Infections
• Skin and Skin Structure Infections
• Acute bacterial otitis media
• Meningitis
• Pelvic Inflammatory Disease

Adults

The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 grams, in order to achieve >90% target attainment. The total daily dose should not exceed 4 grams. If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism. For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended. Generally, Ceftriaxone Injection therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required. When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.No dosage adjustment is necessary for patients with impairment of renal or hepatic function.

Pediatric Patients

For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams. For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams. In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

Neonates

Hyperbilirubinemic neonates, especially prematures, should not be treated with Ceftriaxone Injection. The product may be administered by deep intramuscular injection or as a slow intravenous injection after reconstitution of the solution according to the directions given below. The dosage and mode of administration should be determined by the severity of the infection, susceptibility of the causative organism and the patient’s condition.

Intramuscular injection :Contents of one vial should be dissolved in 0.45 ml of Sterile Water for Injections IP for AugTaz-KID 125 mg of injection, 0.9 ml of Sterile Water for Injections IP for AugTaz-250 mg injection, 1.8 ml of Sterile Water for Injections IP for AugTaz-500 mg injection and 3.6 ml of Sterile Water for Injections IP for AugTaz-1 g injection. The solution should be administered by deep intramuscular injection. Doses greater than 1 g (of Ceftriaxaone) should be divided and injected at more than one site.

Intravenous injection : Contents of one vial should be dissolved in 1.2 ml of Sterile Water for Injections IP for AugTaz-KID 125 mg of injection, 2.4 ml of Sterile Water for Injections IP for AugTaz-250 mg injection, 4.8 ml of Sterile Water for Injections IP for AugTaz-500 mg injection and 9.6 ml of Sterile Water for Injections IP for AugTaz-1 g injection. The solution should be administered over at least 2-4 minutes, directly into the vein or via the tubing of an intravenous infusion

AugTaz should not be given to patients with a history of hypersensitivity to Cephalosporins, Penicillins or β-lactamase inhibitors

For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams. For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams. In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

Pregnancy : Pregnancy Category B.

There are no adequate and well-controlled studies in pregnant women and AugTaz should be used during pregnancy only if clearly needed.

Nursing Mothers :

Low concentrations of Ceftriaxone are excreted in human milk. Caution should be exercised when Ceftriaxone for injection is administered to a nursing woman

Pediatric Use :

Safety and effectiveness of Ceftriaxone for injection in neonates, infants and pediatric patients have been established. In vitro studies have shown that Ceftriaxone, like some other cephalosporins, can displace bilirubin from serum albumin.

Clostridium difficile :

Clostridium difficile associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including Ceftriaxone, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Interaction with Calcium - Containing products

Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute Ceftriaxone vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of Ceftriaxone-calcium can also occur when Ceftriaxone is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, Ceftriaxone and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid. In vitro studies using adult and neonatal plasma from umbilical cord blood demonstrated that neonates have an increased risk of precipitation of Ceftriaxone-calcium.

Probenecid : The elimination of Ceftriaxone is not altered by probenecid.

Aminoglycoside antibiotics and diuretics: No impairment of renal function has so far been observed after concurrent administration of large doses of Ceftriaxone and potent diuretics (e.g.furosemide). There is no evidence that Ceftriaxone increases renal toxicity of aminoglycosides.

Alcohol : No effect similar to that of disulfiram has been demonstrated after ingestion of alcohol subsequent to the administration of Ceftriaxone

Antibiotics : In an in vitro study, antagonistic effects have been observed with the combination of chloramphenicol and Ceftriaxone

Anticoagulants : As Ceftriaxone has an N-methylthiotriazine side-chain, it might have the potential to cause hypoprothrombinaemia resulting in an increased risk of bleeding in patients treated with anticoagulants

Oral Contraceptives : Ceftriaxone may adversely affect the efficacy of oral hormonal contraceptives. Consequently, it is advisable to use supplementary (non-hormonal) contraceptive measures during treatment and in the month following treatment. Based on literature reports Ceftriaxone is incompatible with amsacrine, vancomycin, fluconazole and aminoglycosides.

Interference with Laboratory Tests

In patients treated with Ceftriaxone, the Coombs' test may in rare cases be false-positive

Ceftriaxone for injection is generally well tolerated. In clinical trials, the following adverse reactions, which were considered to be related to ceftriaxone for injection therapy or of uncertain etiology, were observed :

Local reactions : Pain, induration, tenderness, phlebitis; General disorders and administration site conditions : Injection site pain; Hypersensitivity : Rash. Less frequently reported were pruritus, fever or chills; Infections and Infestations : Genital fungal infection Hematologic : Eosinophilia, thrombocytosis and leukopenia. Less frequently reported were anemia, hemolytic anemia, neutropenia, lymphopenia, thrombocytopenia and prolongation of the prothrombin time; Blood and Lymphatic disorders : Granulocytopenia, coagulopathy; Gastrointestinal : Diarrhea/loose stools. Less frequently reported were nausea or vomiting, and dysgeusia. The onset of pseudomembranous colitis symptoms may occur during or after antibacterial treatment; Hepatic : Elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT). Less frequently reported were elevations of alkaline phosphatase and bilirubin; Renal : Elevations of the BUN. Less frequently reported were elevations of creatinine and the presence of casts in the urine. Central Nervous System : Headache or dizziness were reported occasionally; Genitourinary : Moniliasis or vaginitis were reported occasionally. Skin and mucous membranes : Stevens-Johnson syndrome (SJS) is reported. Miscellaneous : Diaphoresis and flushing were reported occasionally. Other rarely observed adverse reactions include abdominal pain, agranulocytosis, allergic pneumonitis, anaphylaxis, basophilia, biliary lithiasis, bronchospasm, colitis, dyspepsia, epistaxis, flatulence, gallbladder sludge, glycosuria, hematuria, jaundice, leukocytosis, lymphocytosis, monocytosis, nephrolithiasis, palpitations, a decrease in the prothrombin time, renal precipitations, seizures, and serum sickness. Investigations : Blood creatinine increased.

Cephalosporin class adverse reactions

In addition to the adverse reactions listed above which have been observed in patients treated with ceftriaxone, the following adverse reactions and altered laboratory test results have been reported for cephalosporin class antibiotics :

Adverse reactions

Allergic reactions, drug fever, serum sickness-like reaction, renal dysfunction, toxic nephropathy, reversible hyperactivity, hypertonia, hepatic dysfunction including cholestasis, aplastic anemia, hemorrhage, and superinfection.

Altered laboratory tests

Positive direct Coombs' test, false-positive test for urinary glucose, and elevated LDH. Several cephalosporins have been implicated in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced. If seizures associated with drug therapy occur, the drug should be discontinued. Anticonvulsant therapy can be given if clinically indicated.

In the case of overdose nausea, vomiting and diarrhoea can occur. Ceftriaxone concentration can not be reduced by haemodialysis or peritoneal dialysis. There is no specific antidote. Treatment is symptomatic.

Store below 30°C. Protect from light & moisture

Keep out of reach of children. After reconstitution, do not use in case any foreign particulate matter is observed inside the vial.

Refer on the pack.

AugTaz-KID 125 mg : A vial of 140.625 mg with SWFI IP 5 ml.

AugTaz-250 mg : A vial of 281.25 mg with SWFI IP 5 ml.

AugTaz-500 mg : A vial of 562.5 mg with SWFI IP 5 ml.

AugTaz-1 g : A vial of 1.125 g with SWFI IP 10 ml.

Amoxycillin, Potassium Clavulanate and Lactic Acid Bacillus Tablets

Augpen LB 625 mg

Each film coated tablet contains:

Amoxicillin Trihydrate IP equivalent to Amoxicillin 500 mg

Potassium Clavulanate Diluted IP equivalent to Clavulanic Acid 125 mg

Lactic Acid Bacillus 60 million spores

Excipients q.s.

Colours: Iron Oxide Yellow & Titanium Dioxide IP

(Appropriate overages of Lactic Acid Bacillus spores added.)

Augpen LB 1 g

Each film coated tablet contains:

Amoxicillin Trihydrate IP equivalent to Amoxicillin 875 mg

Potassium Clavulanate Diluted IP equivalent to Clavulanic Acid 125 mg

Lactic Acid Bacillus 60 million spores

Excipients q.s.

Colours: Iron Oxide Yellow & Titanium Dioxide IP

(Appropriate overages of Lactic Acid Bacillus spores added.)

Film coated tablet, 625 mg and 1 g

4.1 Therapeutic indications

Augpen LB 625mg

For the treatment of bacterial infections such as sinusitis otitis media, tonsillitis, acute and chronic bronchitis, skin and soft tissue infections, pelvic infections, ocsteromylitis, post-operative pain in adults, prone to antibiotic associated diarrhoea.

Augpen LB 1g

For the treatment of mild to moderate bacterial lower respiratory tract infections in adults, prone to antibiotic associated diarrhoea.

4.2 Posology and method of administration

Dosage depends on the age and renal function of the patient and the severity of the infection. To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of Augpen LB 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. Tablets should be swallowed whole without chewing. If required, tablets may be broken in half and swallowed without chewing. Augpen LB tablets are not recommended in children of 12 years and under.

Adults and children over 12 years

The usual recommended daily dosage is:

Renal impairment

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

The Augpen LB 1g BID tablet should only be used in patients with a creatinine clearance (CrCl) rate of more than 30 mL/min.

Hepatic impairment

Dose with caution; monitor hepatic function at regular intervals.

4.3 Contraindications

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

4.4 Special warnings and precautions for use

Before initiating therapy with Augpen LB, careful enquiry should be made concerning previous hypersensitivity reactions to penicillins, 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 LB 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 LB 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 LB 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 LB. The clinical significance of these changes is uncertain but Augpen LB should be used with caution in patients with evidence of hepatic dysfunction.

4.5 Drug Interactions

Concomitant use of probenecid is not recommended. Probenecid decreases the renal tubular secretion of Amoxycillin. Concomitant use with Augpen LB may result in increased and prolonged blood levels of Amoxycillin but not of Clavulanic Acid. 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 LB and Allopurinol.

In common with other antibiotics, Augpen LB 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 LB.

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

Use in pregnant women

Reproduction studies in animals (mice and rats) with orally and parenterally administered Augpen LB 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 LB 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.

Use in lactating women

Augpen LB 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 LB 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 penicillins 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: www.medico@zuventus.com 
• Website: https://www.zuventus.com/drug-safety-reporting

By reporting side effects, you can help provide more information on the safety of this medicine.

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 LB 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. 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 penicillins. It inactivates some beta-lactamase enzymes thereby preventing inactivation of Amoxycillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect. Lactobacillus is an aerobic gram-positive, ubiquitous inhabitant of the human oral cavity, vagina and gastrointestinal tract. It inhibits the colonization of pathogenic bacteria upon the intestinal epithelium.

5.2 Pharmacodynamic properties

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 (Tmax) in each case is approximately one hour. The pharmacokinetic results for a study, in which Amoxycillin/Clavulanic acid (500 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 amoxicillin is bound to protein. The apparent volume of distribution is around 0.3-0.4 l/kg for amoxicillin and around 0.2 l/kg for clavulanic acid. Following intravenous administration, both amoxicillin and clavulanic acid have been found in gall bladder, abdominal tissue, skin, fat, muscle tissues, synovial and peritoneal fluids, bile and pus. Amoxicillin 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. Amoxicillin, like most penicillins, can be detected in breast milk. Trace quantities of clavulanic acid can also be detected in breast milk. Both amoxicillin and clavulanic acid have been shown to cross the placental barrier.

Biotransformation

Amoxicillin 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 amoxicillin is via the kidney, whereas for clavulanic acid it is by both renal and non-renal mechanisms.

Amoxicillin/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 amoxicillin and approximately 40 to 65% of the clavulanic acid are excreted unchanged in urine during the first 6 h after administration of single Augmentin 250 mg/125 mg or 500 mg/125 mg tablets. Various studies have found the urinary excretion to be 50-85% for amoxicillin 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 amoxicillin excretion but does not delay renal excretion of clavulanic acid.

6.1 Animal Toxicology or Pharmacology

No known animal toxicology data.

Augpen LB is a fixed dose combination of Amoxycillin, a broad spectrum antibiotic, Clavulanic acid, a potent beta lactamase enzyme inhibitor and Lactic Acid Bacillus (Lactobacillus sporogenes species) a probiotic for treatment of infection caused by susceptible bacteria.

8.1 Incompatibilities

None

8.2 Shelf-life

Refer on pack.

8.3 Packaging information

Alu-Alu blister strip of 10 tablets.

8.4 Storage and handling instructions

Store below 25°C. Protect from light & moisture.

Keep out of reach of children.

• Patients should be informed that Augpen LB 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 counselled that antibacterial drugs, including Augpen LB, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When Augpen LB 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 LB or other antibacterial drugs in the future.

• Counsel patients that diarrhea is a common problem caused by antibacterials, and it usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, 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 aware that Augpen LB contains a penicillin class drug product that can cause allergic reactions in some individuals.

06 March 2024

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.

06 March 2024

Amoxycillin and Potassium Clavulanate Oral Suspension IP

Augpen HS Suspension

Each 5 ml of reconstituted suspension contains :

Amoxycillin Trihydrate IP

equivalent to Amoxycillin 200 mg

Potassium Clavulanate Diluted IP

equivalent to Clavulanic Acid 28.5 mg

Excipients q.s

This pack contains Sterile Water for Injections IP

28 ml for reconstitution

Augpen DS Suspension

Each 5 ml of reconstituted suspension contains :

Amoxycillin Trihydrate IP

equivalent to Amoxycillin 400 mg

Potassium Clavulanate Diluted IP

equivalent to Clavulanic Acid 57 mg

Excipients q.s

This pack contains Sterile Water for Injections IP

28 ml for reconstitution

Oral suspension Amoxycillin and Potassium Clavulanate [200mg / 400 mg + 28.5 mg / 57 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

Dosage depends on the age, weight and renal function of the patient and the severity of the infection. Dosages are expressed throughout in terms of Amoxycillin/Clavulanate content except when doses are stated in terms of an individual component. To minimise potential gastrointestinal intolerance, administer at the start of a meal. The absorption of Augpen is optimised when taken at the start of a meal. Treatment should not exceed 14 days without review.

Therapy can be started parenterally and continued with an oral preparation.

The usual recommended daily dosage is :

• 25/3.6 mg/kg/day in mild to moderate infections (upper respiratory tract infections e.g. recurrent tonsillitis, lower respiratory infections and skin and soft tissue infections).
• 45/6.4 mg/kg/day for the treatment of more serious infections (upper respiratory tract infections e.g. otitis media and sinusitis, lower respiratory tract infections e.g. bronchopneumonia and urinary tract infections).

No clinical data are available on doses above 45/6.4 mg/kg/day in children under 2 years. There are no clinical data for Augpen suspension 228 mg / 5 mL and 457 mg / 5 mL to make dosage recommendations for children under 2 months old. The tables below give dosage guidance for children

Children 2 years and over

Patient counselling information

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 / 5mL 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 (Tmax) 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

Augpen HS : A bottle of 3.3 g / 30 ml with SWFI IP 28 ml.

Augpen DS : A bottle of 5.4 g / 30 ml with SWFI IP 28 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.

15 March 2022