Active ingredients: Amoxicillin, Clavulanic acid
CLAVOMED 875 mg + 125 mg film-coated tablets
CLAVOMED 875 mg + 125 mg powder for oral suspension
Why is Clavomed used? What is it for?
CLAVOMED 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.
CLAVOMED is used in adults and children weighing more than 40 kg to treat the following infections:
- Infections of the middle ear and sinuses
- Respiratory tract infections
- Urinary tract infections
- Skin and soft tissue infections including dental infections
- Infections of the bones and joints
Contraindications When Clavomed should not be used
Do not take CLAVOMED:
- If you are allergic (hypersensitive) to amoxicillin, clavulanic acid, penicillin or any of the other ingredients of CLAVOMED
- If you have ever had a severe 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 CLAVOMED if any of the above applies to you. If you are unsure, talk to your doctor or pharmacist before taking CLAVOMED.
Precautions for use What you need to know before taking Clavomed
Talk to your doctor or pharmacist before taking this medicine if you:
- have infectious mononucleosis
- are being treated for liver or kidney problems
- 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 CLAVOMED.
In some cases, your doctor may do an "investigation to assess the type of bacterium that caused your infection."
Based on the results, he / she may prescribe a different strength of amoxicillin / clavulanic acid or a different medicine.
Conditions you need to look out for
CLAVOMED can make some existing conditions worse, or cause serious side effects. These may include allergic reactions, seizures and inflammation of the intestines. You must look out for certain symptoms while taking CLAVOMED, in order to reduce any risk. See "Conditions you need to look out for" in Section 4.
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 CLAVOMED. This is because CLAVOMED can influence the results of this type of examination.
Interactions Which drugs or foods may change the effect of Clavomed
Tell your doctor or pharmacist if you are using or have recently used any other medicines, including those available without a prescription and herbal products.
If you are taking allopurinol (used for gout) with CLAVOMED, this increases the likelihood that you may have an allergic skin reaction.
If you are taking probenecid (used for gout), your doctor may decide to change your amoxicillin / clavulanic acid dose.
If you are taking medicines (such as warfarin) that help prevent blood clots from forming together with CLAVOMED, then you may need to have additional blood tests.
CLAVOMED can affect the way methotrexate (a medicine used to treat cancer or rheumatic diseases) works.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant or are breast-feeding, please tell your doctor or pharmacist.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
CLAVOMED can have side effects and symptoms can make you unsuitable for driving. Do not drive vehicles or use machines if you feel unwell.
Dose, Method and Time of Administration How to use Clavomed: Posology
Always take CLAVOMED exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.
Tablets
Adults and children weighing 40 kg or more
- Usual dose - 1 tablet twice a day
- Higher dose - 1 tablet three times a day
Sachets
Adults and children weighing 40 kg or more
- Usual dose - 1 sachet twice a day
- Higher dose - 1 sachet three times a day
Children 6 years of age or younger should preferably be treated with Amoxicillin and Clavulanic Acid oral suspension or sachets.
Clavomed 875 mg + 125 mg film-coated tablets
Ask your doctor or pharmacist for advice on administering Clavomed tablets to children weighing less than 40 kg.
Clavomed 875 mg + 125 mg sachets are not recommended.
Patients with kidney and liver problems
- If you have kidney problems, the dose may be changed. Your doctor may choose a different strength of amoxicillin / clavulanic acid 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 CLAVOMED
Tablets
- Swallow the tablets whole with a glass of water at the beginning of the meal or shortly before
- Space the doses evenly throughout the day, leaving at least 4 hours to elapse between one and the other. Do not take 2 doses in one hour.
- Do not take CLAVOMED for more than 2 weeks. If you still feel unwell you should go back to the doctor.
Sachets
- Immediately before taking CLAVOMED, open the sachet and mix the contents with half a glass of water.
- Take this medicine at the start of a meal or shortly before.
- Space the doses evenly throughout the day, leaving at least 4 hours to elapse between one and the other. Do not take 2 doses in one hour.
- Do not take CLAVOMED for more than 2 weeks. If you still feel unwell you should go back to the doctor.
If you forget to take CLAVOMED
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 CLAVOMED
Continue taking CLAVOMED 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 product, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Clavomed
If you take too much CLAVOMED, 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.
Side Effects What are the side effects of Clavomed
Like all medicines, CLAVOMED 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 CLAVOMED.
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 this, take CLAVOMED 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)
- 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 - 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 by 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 CLAVOMED 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.
If you get side effects
If any of the side effects becomes serious or bothersome, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.
Expiry and Retention
Store in the original package to protect from light and moisture.
Do not store above 25 ° C.
Keep this medicine out of the reach and sight of children.
Do not use CLAVOMED after the expiry date which is stated on the package. The expiry date refers to the last day of the month.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Clavomed contains
CLAVOMED 875 mg + 125 mg film-coated tablets
Each film-coated tablet contains:
- Active ingredients: amoxicillin trihydrate corresponding to amoxicillin 875 mg potassium clavulanate corresponding to clavulanic acid 125 mg.
- Excipients: Colloidal silica, magnesium stearate, sodium starch glycolate, microcrystalline cellulose, hypromellose, titanium dioxide, macrogol 4000, macrogol 6000, dimethicone.
CLAVOMED 875 mg + 125 mg powder for oral suspension
Each sachet contains:
- Active ingredients: amoxicillin trihydrate corresponding to amoxicillin 875 mg potassium clavulanate corresponding to clavulanic acid 125 mg.
- Excipients: Colloidal silica, lemon flavor, strawberry flavor, xanthan gum, sucrose.
What Clavomed looks like and contents of the pack
Film-coated tablets: box of 12 tablets.
Powder for oral suspension: box of 12 sachets.
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
CLAVOMED
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
CLAVOMED 875 mg + 125 mg film-coated tablets
Each film-coated tablet contains:
Active principles: amoxicillin trihydrate corresponding to amoxicillin 875 mg;
potassium clavulanate corresponding to clavulanic acid 125 mg.
CLAVOMED 875 mg + 125 mg powder for oral suspension
Each sachet contains:
Active principles: amoxicillin trihydrate corresponding to amoxicillin 875 mg;
potassium clavulanate corresponding to clavulanic acid 125 mg.
Excipients: sucrose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Powder for oral suspension.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
CLAVOMED is indicated for the treatment of the following infections in adults and children weighing> 40 kg (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 dental abscess with widespread cellulitis
• 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 CLAVOMED 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 infection
• Patient age, weight and renal function, as described below.
The use of alternative amoxicillin / clavulanic acid formulations (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 CLAVOMED 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. If it is considered necessary to increase the daily dose of amoxicillin, it is recommended to identify an "other formulation of amoxicillin / clavulanic acid to avoid the administration of unnecessary high doses of clavulanic acid (see sections 4.4 and 5.1).
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).
Adults and children weighing ≥ 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 Amoxicillin and Clavulanic Acid 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).
No clinical data are available for Clavomed 7: 1 formulations relating to 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 Clavomed 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 formulations of CLAVOMED 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
CLAVOMED is for oral use.
Administer at the start of a meal to minimize potential gastrointestinal intolerance and optimize absorption of amoxicillin / clavulanic acid.
Tablets
In order to facilitate swallowing, the tablets can be divided but should be taken immediately.
875 mg / 125 mg, powder for oral suspension in sachets
The contents of a single dose sachet should be dissolved in half a glass of water before ingesting it.
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 CLAVOMED, 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 penicillins. 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 in accordance with official guidelines should be considered.
This formulation of CLAVOMED is not suitable for use where there is a high risk that the alleged pathogens have a 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 febrile erythema with pustules 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 CLAVOMED 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 severe and, in extremely rare circumstances, deaths have been reported, which almost always occurred in patients with pre-existing severe illness or who were taking medications 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, antiperistaltic 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 CLAVOMED 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 subsequently 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.
CLAVOMED 875 mg + 125 mg powder for oral suspension contains sucrose, therefore the product should be used with caution in subjects with rare hereditary fructose intolerance problems, with glucose-galactose malabsorption syndrome or with sucrase-isomaltase deficiency.
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 (INR) in patients maintained on acenocoumarol or warfarin, who were prescribed treatment with amoxicillin. If co-administration is necessary, prothrombin time or international normalized ratio should be carefully monitored in case of addition or withdrawal of amoxicillin. Additionally, 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 decreases 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.
04.6 Pregnancy and breastfeeding
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 ratio 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 experience with amoxicillin / clavulanic acid are listed below according to the MedDRA System and Organ classification.
The following terminology has been used to rank the frequency of undesirable effects.
Very common (> 1/10)
Common (> 1/100 e
Uncommon (> 1/10000 e
Rare (> 1/10000 e
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 CLAVOMED 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 disturbances in 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 water and 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 produced by resistant bacteria 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.
Pharmacokinetic / Pharmacodynamic 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 breakpoints
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.
§ Natural intermediate susceptibility in the absence of acquired resistance mechanisms
£ All methicillin-resistant staphylococci are resistant to amoxicillin / clavulanic acid
1 The strains of Streptococcus pneumoniae which are resistant to penicillin should not be treated with this formulation 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 10% higher frequency.
05.2 Pharmacokinetic properties
Absorption
Amoxicillin and clavulanic acid completely dissociate in aqueous solution at physiological pH. Both components are rapidly and well absorbed by 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 the peak plasma concentrations (Tmax) of each component is approximately one "hour.
The pharmacokinetic results of a study in which amoxicillin / clavulanic acid (875/125 mg tablets administered twice daily) was administered in the fasted state to groups of healthy volunteers are presented below.
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 and 18% of amoxicillin present in plasma are bound to proteins. The apparent volume of distribution is approximately 0.3-0.4 L / kg for amoxicillin and approximately 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 eliminated 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 excreted in the urine and faeces, and as carbon dioxide, eliminated in the exhaled air.
Elimination
The major route of elimination for amoxicillin is via the kidney, while for clavulanic acid it occurs via 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. clavulanic acid is excreted unchanged in the urine during the first 6 hours following administration of a single 250/125 mg or 500/125 mg amoxicillin / clavulanic acid tablet. 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 largest amount of drug is excreted during the first 2 hours following administration.
Concomitant use of probenecid delays the renal excretion of amoxicillin but does not delay the renal elimination 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 Streetrenal. 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 treated 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.
Repeated 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 CLAVOMED or its components
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Film-coated tablets
Colloidal silica, magnesium stearate, sodium starch glycolate, microcrystalline cellulose, hypromellose, titanium dioxide, macrogol 4000, macrogol 6000, dimethicone.
Powder for oral suspension
Colloidal silica, lemon flavor, strawberry flavor, xanthan gum, sucrose.
06.2 Incompatibility
No known incompatibilities.
06.3 Period of validity
Tablets: 2 years.
Powder for oral suspension: 3 years.
06.4 Special precautions for storage
Store in the original package to protect from light and moisture.
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Box of 12 tablets of 875 mg + 125 mg.
Box of 12 sachets of 875 mg + 125 mg.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
MEDIOLANUM pharmaceutici S.p.A., Via San Giuseppe Cottolengo 15 - 20143 Milan.
08.0 MARKETING AUTHORIZATION NUMBER
CLAVOMED 875 mg + 125 mg film-coated tablets - 12 tablets AIC n .: 037185028.
CLAVOMED 875 mg + 125 mg powder for oral suspension - 12 sachets AIC n .: 037185016.
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 27 March 2007
Renewal date: 2012
10.0 DATE OF REVISION OF THE TEXT
AIFA Determination of February 2013
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