Active ingredients: Amoxicillin, Clavulanic acid
Clavulin 875 mg / 125 mg film-coated tablets
Clavulin package inserts are available for pack sizes:- Clavulin 875 mg / 125 mg film-coated tablets
- Clavulin 875 mg / 125 mg powder for oral suspension in sachets
Why is Clavulin used? What is it for?
Clavulin is an antibiotic that works by killing bacteria that cause infections. It contains two different medicines called amoxicillin and clavulanic acid. Amoxicillin belongs to a group of medicines called 'penicillins' whose activity can sometimes be blocked (made inactive). The other active component (clavulanic acid) prevents this from happening.
Clavulin is used in infants and children to treat the following infections:
- middle ear and sinus infections
- respiratory tract infections
- urinary tract infections
- skin and soft tissue infections including dental infections
- bone and joint infections
Contraindications When Clavulin should not be used
Do not take Clavulin:
- if you are allergic to amoxicillin, clavulanic acid or any of the other ingredients of this medicine
- if you have ever had an allergic (hypersensitivity) reaction to any other antibiotic. This can include a skin rash or swelling of the face or neck
- if you have ever had liver problems or jaundice (yellowing of the skin) when taking an antibiotic.
Do not take Clavulin if any of these apply to you. If you are unsure, talk to your doctor or pharmacist before taking Clavulin.
Precautions for use What you need to know before taking Clavulin
Take special care with Clavulin
Talk to your doctor, pharmacist or nurse before taking this medicine if:
- have infectious mononucleosis
- does not urinate regularly.
If you are not sure if any of the above apply to you, talk to your doctor or pharmacist before taking Clavulin.
In some cases, the doctor may do an "investigation to assess the type of bacterium that caused the infection."
Based on the results, he / she may prescribe a different strength of Clavulin or a different medicine.
Conditions you need to look out for
Clavulin can make some existing conditions worse, or cause serious side effects. These may include allergic reactions, seizures and inflammation of the gut. You must look out for certain symptoms while taking Clavulin, in order to reduce any risk. See "Conditions you need to look out for"
Blood and urine tests
If you are having blood tests (such as red blood cell tests or liver function tests) or urine tests (for glucose), please tell your doctor or nurse that you are taking Clavulin. This is because Clavulin can affect the results of this type of examination.
Interactions Which drugs or foods may change the effect of Clavulin
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those available without a prescription and herbal products.
If you are taking allopurinol (used for gout) with Clavulin, it is very likely that your child may have an allergic skin reaction.
If you are taking probenecid (used for gout), your doctor may decide to change the dose of Clavulin.
If you are taking medicines (such as warfarin) that help prevent blood clots from forming together with Clavulin, then you may need to have additional blood tests.
Clavulin can affect the way methotrexate (a medicine used to treat cancer or rheumatic diseases) works.
Clavulin can affect how mycophenolate mofetil (a medicine used to prevent rejection of transplanted organs) works.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, please tell your doctor or pharmacist, ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Clavulin may cause side effects and the symptoms may make you unable to drive. Do not drive or operate machinery until you feel well
Dosage and method of use How to use Clavulin: Dosage
Always take Clavulin exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Adults and children weighing 40 kg or more
- Usual dose - 1 tablet twice a day
- Higher dose - 1 tablet three times a day
Children weighing less than 40 kg
Children 6 years of age or younger should preferably be treated with Clavulin oral suspension or sachets.
Ask your doctor or pharmacist for advice on administering Clavulin tablets to children weighing less than 40 kg. The tablets are not suitable for children weighing less than 25 kg.
Patients with kidney and liver problems
- If you have kidney problems the dose may be lowered. Your doctor may choose a different strength or a different medicine.
- If you have liver problems, you may have more frequent blood tests to check how your liver is working.
How to take Clavulin
- Swallow the tablet whole with a glass of water at the start of a meal or just before. The tablets can be divided along the score line to make it easier to take. Both pieces of the tablet should be taken at the same time.
- Space the doses evenly throughout the day, at least 4 hours apart. Do not take 2 doses in 1 hour.
- Do not take Clavulin for more than 2 weeks. If you still feel unwell you should go back to the doctor.
Overdose What to do if you have taken too much Clavulin
If you take more Clavulin than you should
If you take too much Clavulin, the signs may include upset stomach (nausea, vomiting or diarrhea) or convulsions. Talk to your doctor as soon as possible. Bring the medicine pack or bottle to show to the doctor.
If you forget to take Clavulin
If you forget to take a dose, take it as soon as you remember. You should not take the next dose too soon, but you should wait about 4 hours before taking the next dose.
If you stop taking Clavulin
Keep taking Clavulin until the treatment is finished, even if you feel better. You need every dose to help fight the infection. If some bacteria survive, they can cause the infection to come back.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist or nurse
Side Effects What are the side effects of Clavulin
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Conditions you need to look out for
Allergic reactions:
- skin rashes
- inflammation of blood vessels (vasculitis) which may be visible as red or purple spots on the skin, but which can affect other parts of the body
- fever, joint pain, swollen glands in the neck, armpits or groin
- swelling, sometimes of the face or mouth (angioedema), causing difficulty in breathing
- collapse.
Contact your doctor immediately if you get any of these symptoms. Stop taking Clavulin.
Intestinal inflammation
Inflammation of the gut, which causes watery diarrhea usually with blood and mucus, stomach pain and / or fever.
If you get these symptoms, contact your doctor as soon as possible for advice.
Very common side effects
They may affect more than 1 in 10 people
- diarrhea (in adults).
Common side effects
They may affect up to 1 in 10 people
- thrush (candida - a "yeast infection of the vagina, mouth or skin folds)
- nausea, especially when taking high doses → if you suffer from it, take Clavulin before food
- He retched
- diarrhea (in children).
Uncommon side effects
They may affect up to 1 in 100 people
- rash, itching
- raised, itchy rash (hives)
- indigestion
- dizziness
- headache.
Uncommon side effects may show up in blood tests:
- increase in some proteins (enzymes) produced by the liver.
Rare side effects
They may affect up to 1 in 1000 people
- rash, which may appear as blisters and look like small targets (central dark spot surrounded by a "paler" area, with a dark ring around the edge - erythema multiforme)
if you notice any of these symptoms contact your doctor urgently
Rare side effects may show up in blood tests:
- low number of cells involved in blood clotting
- low white blood cell count.
Other side effects
Other side effects occur in a very limited number of people, but their exact frequency is not known.
- Allergic reactions (see above)
- Inflammation of the intestine (see above)
- Inflammation of the protective membrane surrounding the brain (aseptic meningitis)
- Severe skin reactions: a widespread rash with blisters and peeling of the skin, particularly around the mouth, nose, eyes and genitals (Stevens-Johnson syndrome), and a more severe form, causing extensive peeling of the skin (more than 30% of the body surface - toxic epidermal necrolysis); widespread red rash with small pus-containing blisters (bullous exfoliative dermatitis); a rash, red, with crusts and bumps under the skin and blisters (pustular rash).
If you get any of these symptoms, contact your doctor immediately.
- inflammation of the liver (hepatitis)
- jaundice, caused by an increase in the blood of bilirubin (a substance produced in the liver) which may make the skin and whites of the eyes appear yellow
- inflammation of the kidney tubules
- blood takes longer to clot
- hyperactivity
- seizures (in people taking high doses of Clavulin or who have kidney problems)
- black tongue that appears covered with hair
- stains on the teeth (in children), usually removed by brushing.
Side effects that may show up in blood or urine tests:
- severe reduction in the number of white blood cells
- low number of red blood cells (haemolytic anemia)
- crystals in the urine.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Italian Medicines Agency website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep out of the sight and reach of children.
Do not use Clavulin after the expiry date which is stated on the package.
The expiry date refers to the last day of the month.
The tablets stored in a sachet with desiccant must be used within 30 days of opening.
Store in original container to protect from moisture
Do not use the tablets if they are chipped or damaged.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
OTHER INFORMATION
What it contains
Clavulin 875/125 mg film-coated tablets
The active ingredients are amoxicillin and clavulanic acid.
Each tablet contains:
amoxicillin trihydrate corresponding to 875 mg of amoxicillin and potassium clavulanate corresponding to 125 mg of clavulanic acid.
The excipients are:
Tablet core - magnesium stearate, carboxymethyl starch sodium A, colloidal anhydrous silica, microcrystalline cellulose.
Tablet coating - titanium dioxide (E171), hypromellose, macrogol and silicone oil (dimethicone).
What Clavulin looks like and contents of the pack
CLAVULIN 875 mg / 125 mg - film-coated tablets - are white to off-white, capsule shaped with AC imprinted on both sides and with a score line on one side.
- the tablets are packed in blisters, contained in a cardboard box.
Each pack contains 12 tablets.
Not all pack sizes may be marketed.
Behavioral hygiene
Antibiotics are used for the treatment of bacterial infections. They are not effective for viral infections. Sometimes an infection caused by bacteria does not respond to antibiotic therapy.
The most common reason this happens is that the bacteria causing the infection are resistant to the antibiotic being used. This means that bacteria survive and multiply despite the antibiotic. Bacteria become resistant to antibiotics for several reasons. Using antibiotics properly can reduce the onset of bacterial resistance.
When your doctor prescribes antibiotic therapy, it is only indicated for the current illness. Pay attention to the following tips, in order to avoid the emergence of bacterial resistance that causes the blocking of antibiotic activity.
- It is very important that you take the antibiotic at the right dose, at the right times and for the right number of days. Read the instructions in the package leaflet and if you are not clear about anything, ask your doctor or pharmacist about it.
- Do not take antibiotics unless they have been specifically prescribed for you and use them only for the infection for which they were prescribed.
- Do not use antibiotics that other people have been prescribed even if you have an infection similar to theirs.
- Do not give the antibiotics that have been specifically prescribed for you to others.
- If you have any antibiotic left over at the end of your treatment, take it back to your pharmacist so that it can be disposed of properly.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
CLAVULIN 875 MG / 125 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains amoxicillin trihydrate corresponding to 875 mg of amoxicillin and potassium clavulanate corresponding to 125 mg of clavulanic acid.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
White to off-white, capsule-shaped tablet debossed with "AC" on both sides and a score line on one side.
The score line is intended to facilitate breaking of the tablet to facilitate swallowing and not to divide the dose into equal parts.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Clavulin is indicated for the treatment of the following infections in adults and children (see sections 4.2, 4.4 and 5.1):
• Acute bacterial sinusitis (adequately diagnosed)
• Acute otitis media
• Acute exacerbations of chronic bronchitis (adequately diagnosed)
• Community-acquired pneumonia
• Cystitis
• Pyelonephritis
• Skin and soft tissue infections especially cellulitis, animal bites, severe tooth abscess with widespread cellulite
• Bone and joint infections, especially osteomyelitis.
Official guidelines on the appropriate use of antibacterial agents should be considered.
04.2 Posology and method of administration
Doses are expressed in terms of amoxicillin / clavulanic acid content except when doses are defined in terms of a single component.
The dose of Clavulin that is chosen for the treatment of each individual infection should take into account: Expected pathogens and their likely susceptibility to antibacterial agents (see section 4.4)
Severity and site of the infection
Patient age, weight and renal function, as described below.
The use of alternative formulations of Clavulin (eg those providing higher doses of amoxicillin and / or different amoxicillin-clavulanic acid ratios) should be considered as necessary (see sections 4.4 and 5.1).
For adults and children weighing ≥ 40 kg this formulation of Clavulin provides a total daily dose of 1750 mg amoxicillin / 250 mg clavulanic acid twice daily and 2625 mg amoxicillin / 375 mg clavulanic acid for the dosage three times a day, when given as recommended below. For children of weight
The duration of therapy should be defined based on the patient's response. Some infections (e.g. osteomyelitis) require longer treatment periods. Treatment should not be continued beyond 14 days without medical supervision (see section 4.4 regarding prolonged therapy).
Weight adults and children 40 kg
Recommended doses:
standard dose: (for all indications) 875 mg / 125 mg twice daily.
higher dose - (particularly for infections such as otitis media, sinusitis, lower respiratory tract infections and urinary tract infections): 875 mg / 125 mg three times a day.
Weight children
It is recommended that children be treated with Clavulin tablets, suspension or pediatric sachets.
Recommended doses: 25 mg / 3.6 mg / kg / day to 45 mg / 6.4 mg / kg / day taken in two divided doses; up to 70 mg / 10 mg / kg / day in two divided doses may be considered for some infections (such as otitis media, sinusitis and lower respiratory tract infections).
In view of the fact that the tablets cannot be divided, children weighing less than 25 kg should not be treated with Clavulin tablets.
The table below presents the received dose (mg / kg / body weight) in children weighing between 25 kg and 40 kg following a single administration of one 875/125 mg tablet.
Children weighing less than 25 kg should preferably be treated with Clavulin suspension or pediatric sachets.
No clinical data are available for Clavulin 7: 1 formulations for doses greater than 45 mg / 6.4 mg per kg per day in children less than 2 years of age.
No clinical data are available for Clavulin 7: 1 formulations in infants less than 2 months of age. Therefore, no dosage recommendations can be made in this population.
Senior citizens
No dosage adjustment is considered necessary.
Kidney failure
No dose adjustment is required in patients with creatinine clearance (CrCl) greater than 30 mL / min.
In patients with creatinine clearance below 30 mL / min, there is no recommendation for the use of Clavulin formulations with an amoxicillin-clavulanic acid ratio of 7: 1, as no dosage adjustments are available.
Hepatic insufficiency
Dose with caution and monitor liver function at regular intervals (see sections 4.3 and 4.4).
Method of administration
Clavulin is for oral use.
Administer at the start of a meal to minimize potential gastrointestinal intolerance and optimize absorption of amoxicillin / clavulanic acid.
Therapy can be initiated parenterally according to the Summary of Product Characteristics of the IV formulation and continued with an oral preparation.
04.3 Contraindications
Hypersensitivity to the active substance, to any penicillin or to any of the excipients.
History of severe immediate hypersensitivity reactions (e.g. anaphylaxis) to other beta-lactam agents (e.g. cephalosporins, carbapenems or monobactams).
History of jaundice / hepatic failure due to amoxicillin / clavulanic acid (see section 4.8).
04.4 Special warnings and appropriate precautions for use
Before initiating therapy with Clavulin, a thorough investigation of previous hypersensitivity reactions to penicillins, cephalosporins or other beta-lactam agents should be conducted (see sections 4.3 and 4.8).
Severe and occasionally fatal hypersensitivity reactions (anaphylactoid reactions) have been reported in patients receiving penicillin. These reactions are more likely to occur in individuals with a history of penicillin hypersensitivity and in atopic individuals. If an allergic reaction occurs, amoxicillin / clavulanic acid therapy should be discontinued and appropriate alternative therapy instituted.
If an infection is proven to be due to an amoxicillin-susceptible organism, a change of therapy from amoxicillin / clavulanic acid to amoxicillin according to official guidelines should be considered.
This formulation of Clavulin is not suitable for use where there is a high risk that the alleged pathogens have reduced susceptibility or resistance to beta-lactam agents, not mediated by beta-lactamases susceptible to inhibition by clavulanic acid. This formulation should not be used for treating S. pneumonia penicillin-resistant.
Convulsions may occur in patients with impaired renal function or in those receiving high doses (see section 4.8).
The administration of amoxicillin / clavulanic acid should be avoided if infectious mononucleosis is suspected, as the use of amoxicillin has been associated with the onset of morbilliform rash in this condition.
Concomitant use of allopurinol during treatment with amoxicillin may increase the likelihood of allergic skin reactions.
Prolonged use may occasionally cause the development of resistant organisms.
The appearance of generalized erythema with pustules caused by fever during the initial phase of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section 4.8). This reaction requires a suspension of Clavulin and any subsequent administration of amoxicillin is contraindicated.
Amoxicillin / clavulanic acid should be used with caution in patients with evident hepatic impairment (see sections 4.2, 4.3 and 4.8).
Hepatic events have been reported particularly in male and elderly patients and may be associated with prolonged treatment. These events have rarely been reported in children. In all populations, signs and symptoms generally occur during or soon after treatment but in some cases they may be evident only several weeks after stopping treatment. These events are usually reversible. Hepatic events can be serious and, in extremely rare circumstances, deaths have been reported, which almost always occurred in patients with pre-existing serious illness or who were taking drugs known to have potential hepatic effects (see section 4.8).
Antibiotic-associated colitis has been reported with almost all antibacterial agents and can be mild to life-threatening in severity (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or after the administration of any antibiotic. Should antibiotic-associated colitis occur, amoxicillin / clavulanic acid should be discontinued immediately, a physician consulted and appropriate therapy initiated. In this situation, peristaltic drugs are contraindicated.
During prolonged therapy, it is advisable to periodically check systemic-organic function, including renal, hepatic and haematopoietic function.
Prolongation of prothrombin time has been reported rarely in patients receiving amoxicillin / clavulanic acid. Appropriate monitoring should be performed in the case of concomitant administration of anticoagulants. Dose adjustments of oral anticoagulants may be required to maintain the desired level of anticoagulation (see sections 4.5 and 4.8).
In patients with renal insufficiency, the dosage should be adjusted according to the degree of insufficiency (see section 4.2).
In patients with reduced urine output, crystalluria has been observed very rarely, especially with parenteral therapy. During the administration of high doses of amoxicillin, it is advisable to maintain adequate fluid intake and urine output in order to reduce the possibility of amoxicillin crystalluria. In patients with bladder catheters, regular control of patency should be maintained (see section 4.9).
During treatment with amoxicillin, enzymatic methods with glucose oxidase should be used whenever testing for the presence of glucose in urine as false positive results may occur with non-enzymatic methods.
The presence of clavulanic acid in Clavulin can cause non-specific binding of IgG and albumin by the red blood cell membranes, leading to a false positive in the Coombs test.
Positive test results have been reported using the Bio-Rad Laboratories Platelia test Aspergillus EIA in patients receiving amoxicillin / clavulanic acid and who were consequently found free of Aspergillus. With the bio-Rad Laboratories Platelia test Aspergillus EIA, cross reactions with non-polysaccharides have been reported-Aspergillus and polyphuranose. Therefore positive test results in patients receiving amoxicillin / clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.
04.5 Interactions with other medicinal products and other forms of interaction
Oral anticoagulants
Oral anticoagulants and penicillins have been widely used in clinical practice with no reports of interactions. However, in the literature there are cases of increased international normalized ratio in patients maintained on acenocoumarol or warfarin, who were prescribed treatment with amoxicillin. If co-administration is necessary, the prothrombin time or international normalized ratio should be carefully monitored in case of addition or withdrawal of amoxicillin. In addition, dose adjustments of oral anticoagulants may be required (see sections 4.4 and 4.8).
Methotrexate
Penicillins can reduce the excretion of methotrexate, causing a potential increase in toxicity.
Probenecid
Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concomitant use of probenecid may result in a prolonged increase in blood levels of amoxicillin but not of clavulanic acid.
Mycophenolate mofetil
In patients treated with mycophenolate mofetil, following the initiation of treatment with amoxicillin and oral clavulanic acid, there was a reduction in the pre-dose concentration of mycophenolic acid active metabolite (MPA) by approximately 50%. -dose may not accurately represent changes in overall MPA exposure. Therefore, a change in mycophenolate mofetil dose should not normally be necessary in the absence of clinical signs of graft dysfunction. However, close clinical monitoring should be performed during the combination and immediately after antibiotic treatment.
04.6 Pregnancy and lactation
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal / fetal development, parturition or postnatal development (see section 5.3). Limited data on the use of amoxicillin / clavulanic acid during pregnancy in humans does not indicate an increased risk of congenital malformations. In a single study in women with premature, preterm, fetal membrane rupture, prophylactic treatment with amoxicillin / clavulanic acid may be associated with an increased risk of necrotizing enterocolitis in neonates. Use in pregnancy should be avoided unless considered essential by the physician.
Feeding time
Both substances are excreted in breast milk (the effects of clavulanic acid on the nursing infant are not known). As a result, diarrhea and fungal mucosal infections are possible in the nursing infant, so that breastfeeding must be discontinued. . Amoxicillin / clavulanic acid should be administered during the lactation period only after the risk / benefit has been evaluated by the physician.
04.7 Effects on ability to drive and use machines
No studies on the ability to drive and use machines have been performed. However, undesirable effects (eg allergic reactions, dizziness, convulsions) may occur which may affect the ability to drive and use machines (see section 4.8). .
04.8 Undesirable effects
The most commonly reported adverse reactions (ADRs) are diarrhea, nausea and vomiting.
ADRs from clinical trials and post-marketing investigations with Clavulin are reported below according to the MedDRA classification for Systems and Organs
The following terminology has been used to rank the frequency of undesirable effects.
Very common (1/10)
Common (from 1/100 to
Uncommon (1 / 1,000 to
Rare (from 1 / 10,000 to
Very rare (
Not known (cannot be estimated from the available data)
1 See section 4.4
2 See section 4.4
3 Nausea is more often associated with higher oral dosages. If gastrointestinal reactions are evident, these can be reduced by taking Clavulin at the start of a meal
4 Including pseudomembranous colitis and haemorrhagic colitis (see section 4.4)
5 A moderate increase in AST and / or ALT has been observed in patients treated with beta-lactam class antibiotics, but the significance of these observations is unknown.
6 These effects have been reported with other penicillins and cephalosporins (see section 4.4).
7 If any skin hypersensitivity reaction occurs, treatment should be discontinued (see section 4.4)
8 See section 4.9
9 See section 4.3
10 See section 4.4
04.9 Overdose
Symptoms and signs of overdose
Gastrointestinal symptoms and alterations in the water and electrolyte balance may be evident.Amoxicillin crystalluria, in some cases leading to renal failure, has been observed (see section 4.4).
Convulsions can occur in patients with impaired renal function or in patients receiving high doses.
Precipitation of amoxicillin in bladder catheters has been reported, predominantly after intravenous administration of large doses. Regular control of patency should be maintained (see section 4.4).
Treatment of intoxication
Gastrointestinal symptoms can be treated symptomatically, with attention to the water-electrolyte balance.
Amoxicillin / clavulanic acid can be removed from the circulation by hemodialysis.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: combination of penicillins, including beta-lactamase inhibitors.
ATC code: J01CR02.
Mechanism of action
Amoxicillin, a semi-synthetic penicillin (beta-lactam antibiotic), inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) of the biosynthetic pathway of bacterial peptidoglycan, an integral structural component of the bacterial cell wall. synthesis of the peptidoglycan leads to the weakening of the structure, which is usually followed by cell lysis and bacterial death.
Amoxicillin is susceptible to degradation by beta-lactamases and therefore the spectrum of activity of amoxicillin alone does not include organisms that produce these enzymes.
Clavulanic acid is a beta-lactam structurally related to penicillins. Inactivates some beta-lactam enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid alone does not exert a clinically useful antibacterial effect.
PK / PD relationship
The time above the minimal inhibitory concentration (T> MIC) is considered to be the major determinant of the efficacy of amoxicillin.
Mechanisms of resistance
The two main mechanisms of resistance to amoxicillin / clavulanic acid are:
• Inactivation by bacterial beta-lactamases which are not themselves inhibited by clavulanic acid, including classes B, C and D.
• Alteration of PBPs, which reduces the affinity of the antibacterial agent for the target.
Bacteria impermeability or efflux pump mechanisms can cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.
Breakpoints
MIC breakpoints for amoxicillin / clavulanic acid are defined by The European Committee on Antimicrobial Susceptibility Testing (EUCAST).
1 Values reported refer to amoxicillin concentrations. For the purposes of the susceptibility test, the concentration of clavulanic acid is fixed at 2 mg / l
2 Values reported are for oxacillin
3 Breakpoint values in the table are based on ampicillin breapoints
4 The resistance breakpoint of R> 8 mg / l ensures that all isolates with resistance mechanisms are reported as resistant
5 Breakpoint values in the table are based on benzylpenicillin breakpoints
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 if the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.
Commonly susceptible species
Aerobic Gram-positive micro-organisms
Enterococcus faecalis
Gardnerella vaginalis
Staphylococcus aureus (methicillin-sensitive) £
Streptococcus agalactiae
Streptococcus pneumoniae1
Streptococcus pyogenes and other beta-haemolytic streptococci
Streptococcus viridans group
Aerobic Gram-negative micro-organisms
Capnocytophaga spp.
Eikenella corrodens
Haemophilus influenzae2
Moraxella catarrhalis
Pasteurella multocida
Anaerobic micro-organisms
Bacteroides fragilis
Fusobacterium nucleatum
Prevotella spp.
Species for which acquired stamina can be a problem
Aerobic Gram-positive micro-organisms
Enterococcus faecium §
Aerobic Gram-negative micro-organisms
Escherichia coli
Klebsiella oxytoca
Klebsiella pneumoniae
Proteus mirabilis
Proteus vulgaris
Inherently resistant organisms
Aerobic Gram-negative micro-organisms
Acinetobacter sp.
Citrobacter freundii
Enterobacter sp.
Legionella pneumophila
Morganella morganii
Providencia spp.
Pseudomonas sp.
Serratiasp.
Stenotrophomonas maltophilia
Other micro-organisms
Chlamydophila pneumoniae
Chlamydophila psitaci
Coxiella burnetti
Mycoplasma pneumoniae
§ Natural intermediate susceptibility in the absence of acquired resistance mechanisms
£ All methicillin-resistant staphylococci are resistant to amoxicillin / clavulanic acid
1 Streptococcus pneumoniae which is a penicillin resistant microorganism should not be treated with this presentation of amoxicillin / clavulanic acid (see sections 4.2 and 4.4).
2 Strains with reduced susceptibility have been found in many EU countries with a frequency higher than 10%
05.2 Pharmacokinetic properties
Absorption
Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH. Both components are absorbed quickly and well with the oral route of administration. Absorption of amoxicillin / clavulanic acid is optimized when taken at the start of a meal. Following oral administration, amoxicillin and clavulanic acid are approximately 70% bioavailable. The plasma profiles of both components are similar and the time to reach peak plasma concentrations (Tmax) in each case is approximately one "hour.
Pharmacokinetic results from separate studies are presented below, in which amoxicillin / clavulanic acid (875/125 mg tablets administered twice daily) was administered in the fasted state to groups of healthy volunteers.
The serum concentrations of amoxicillin and clavulanic acid achieved with amoxicillin / clavulanic acid are similar to those produced by oral administration of equivalent doses of amoxicillin and clavulanic acid alone.
Distribution
About 25% of clavulanic acid in plasma and 18% of amoxicillin is bound to proteins. 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, amoxicillin and clavulanic acid have been found in the gallbladder, abdominal tissue, skin, fat, muscle tissue, synovial and peritoneal fluid, bile and pus. Amoxicillin is not adequately distributed in the cerebrospinal fluid.
Animal studies show no significant tissue retention of drug-derived material of either component. Amoxicillin, like most penicillins, can be detected in breast milk. Traces of clavulanic acid may be detected in breast milk (see section 4.6).
Both amoxicillin and clavulanic acid have been shown to cross the placental barrier (see section 4.6).
Biotransformation
Amoxicillin is partially excreted in the urine as inactive penicilloic acid in amounts equivalent to up to 10-25% of the initial dose. Clavulanic acid is extensively metabolised in humans, and eliminated in the urine and faeces, and as dioxide of carbon in the exhaled air.
Elimination
The major route of elimination for amoxicillin is via the kidney, while for clavulanic acid it is via 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 / hour in healthy subjects. Approximately 60-70% of amoxicillin and approximately 40-65% of "Clavulanic acid is excreted unchanged in the urine during the first 6 hours following administration of a single 250 mg / 125 mg or 500 mg / 125 mg tablet of Clavulin. Several studies have found that urinary excretion was 50-85. % for amoxicillin and between 27-60% for clavulanic acid over a 24 hour period. In the case of clavulanic acid, the greatest amount of drug is excreted during the first 2 hours following administration.
Concomitant use of probenecid delays the excretion of amoxicillin but does not delay the renal excretion of clavulanic acid (see section 4.5).
Age
The elimination half-life of amoxicillin is similar in children aged approximately 3 months to 2 years, older children and adults. In very young infants (including those born preterm) in the first week of life the dosing interval should not exceed two doses per day due to immaturity of the renal elimination system. As elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function.
Type
Following oral administration of amoxicillin / clavulanic acid to healthy male and female subjects, gender has no significant impact on the pharmacokinetics of either amoxicillin or clavulanic acid.
Kidney failure
Total serum clearance of amoxicillin / clavulanic acid decreases proportionally with decreased renal function. The reduction in drug clearance is more pronounced for amoxicillin than for clavulanic acid, as more amoxicillin is excreted by Street renal. Therefore, the posology in renal insufficiency should prevent excessive accumulation of amoxicillin by maintaining adequate levels of clavulanic acid (see section 4.2).
Hepatic insufficiency
Patients with hepatic insufficiency should be dosed with caution and liver function monitored at regular intervals.
05.3 Preclinical safety data
Non-clinical data reveal no particular risk for humans based on safety pharmacology, genotoxicity and reproductive toxicity studies.
Repeat dose toxicity studies with amoxicillin / clavulanic acid in dogs demonstrated gastric irritation and vomiting, and discolouration of the tongue.
Carcinogenicity studies have not been conducted with Clavulin or its components.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Magnesium stearate
Sodium starch carboxymethyl A.
Anhydrous colloidal silica
Microcrystalline cellulose
Filming of the tablet
Titanium dioxide (E171)
Hypromellose
Macrogol Dimethicone
06.2 Incompatibility
Not relevant.
06.3 Period of validity
2 years.
06.4 Special precautions for storage
Store in the original container in order to protect from moisture. Store at a temperature not exceeding 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
PVC / Aluminum / Polyamide laminate blister with cold fixed aluminum cover sheet (CFB) containing 12 tablets.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
GlaxoSmithKline S.p.A. - Via A. Fleming, 2 - 37135 Verona
Dealer for sale: Athena Pharma Italia S.r.l. - Viale Città d "Europa, 681 Rome
08.0 MARKETING AUTHORIZATION NUMBER
CLAVULIN 875 mg + 125 mg: 12 tablets A.I.C .: 026138139
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
CLAVULIN 875 mg + 125 mg - 12 tablets 11.12.87 / 01.06.10
