Clementin
Clementin Drug Description
[Amoxicillin/Clavulanate
Clementin is an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the -lactamase inhibitor, clavulanate potassium (the potassium salt of clavulanic acid). Amoxicillin is an analog of ampicillin, derived from the basic penicillin nucleus, 6-aminopenicillanic acid. The amoxicillin molecular formula is C16H19N3O5S 3H2O and the molecular weight is 419.46. Chemically, amoxicillin is (2S, 5R, 6R)-6-[( R)-(-)-2-Amino-2-( p-hydroxyphenyl) acetamido]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[ 3.2.0] heptane-2-carboxylic acid trihydrate.
Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a -lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of -lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid mediated -lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. The clavulanate potassium molecular formula is C8H8KNO5 and the molecular weight is 237.25. Chemically clavulanate potassium is potassium (Z)-( 2R, 5R)-3-( 2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[ 3.2.0] -heptane-2-carboxylate.
Clementin - Clinical Pharmacology
Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of Clementin. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While Clementin can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In one study, the relative bioavailability of clavulanate was reduced when Clementin was dosed at 30 and 150 minutes after the start of a high fat breakfast. The safety and efficacy of Clementin have been established in clinical trials where Clementin was taken without regard to meals.
Mean * amoxicillin and clavulanate potassium pharmacokinetic parameters are shown in the table below: Dose * and regimen AUC0-24 (µg. hr/ mL) Cmax (µg/ mL) amoxicillin/ clavulanate potassium amoxicillin (± S. D.) clavulanate potassium (± S. D.) amoxicillin (± S. D.) clavulanate potassium (± S. D.) 250/ 125 mg q8h 26.7 ± 4.56 12.6 ± 3.25 3.3 ± 1.12 1.5 ± 0.70 500/ 125 mg q12h 33.4 ± 6.76 8.6 ± 1.95 6.5 ± 1.41 1.8 ± 0.61 500/ 125 mg q8h 53.4 ± 8.87 15.7 ± 3.86 7.2 ± 2.26 2.4 ± 0.83 875/ 125 mg q12h 53.5 ± 12.31 10.2 ± 3.04 11.6 ± 2.78 2.2 ± 0.99 * Mean values of 14 normal volunteers (n= 15 for clavulanate potassium in the low-dose regmens).
Peak concentrations occurred approximately 1.5 hours after the dose. * Administered at the start of a light meal. Amoxicillin serum concentrations achieved with Clementin are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of Clementin is 1.3 hours and that of clavulanic acid is 1.0 hour. Approximately 50% to 70% of the amoxicillin and approximately 25% to 40% of the clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single Clementin 250 mg or 500 mg tablet. Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.
Clementin - Indications & Dosage
DOSAGE AND ADMINISTRATION
Since both the Clementin 250 mg and 500 mg tablets contain the same amount of clavulanic acid (125 mg, as the potassium salt), 2 Clementin 250 mg tablets are not equivalent to 1 Clementin 500 mg tablet. Therefore, 2 Clementin 250 mg tablets should not be substituted for 1 Clementin 500 mg tablet.
Dosage: Adults
The usual adult dose is 1 Clementin 500 mg tablet every 12 hours or 1 Clementin 250 mg tablet every 8 hours. For more severe infections and infections of the respiratory tract, the dose should be 1 Clementin 875 mg tablet every 12 hours or 1 Clementin 500 mg tablet every 8 hours. Patients with impaired renal function do not generally require a reduction in dose unless the impairment is severe. Severely impaired patients with a glomerular filtration rate of <30>
They should receive an additional dose both during and at the end of dialysis. Hepatically impaired patients should be dosed with caution and hepatic function monitored at regular intervals. (See WARNINGS.)
Pediatric Patients:Pediatric patients weighing 40 kg or more should be dosed according to the adult recommendations. Due to the different amoxicillin to clavulanic acid ratios in the Clementin 250 mg tablet (250/ 125) versus the Clementin 250 mg chewable tablet (250/ 62.5), the Clementin 250 mg tablet should not be used until the pediatric patient weighs at least 40 kg or more.
Administration
Clementin may be taken without regard to meals; however, absorption of clavulanate potassium is enhanced when Clementin is administered at the start of a meal. To minimize the potential for gastrointestinal intolerance, Clementin should be taken at the start of a meal.
HOW SUPPLIED Clementin 250 MG TABLETS
Each white oval filmcoated tablet, debossed with Clementin on 1 side and 250/ 125 on the other side, contains 250 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
white capsule-shaped tablet, debossed with Clementin 875 on 1 side and scored on the other side, contains 875 mg amoxicillin as the trihydrate and 125 mg clavulanic acid as the potassium salt.
Clementin 125 MG/ 5 ML (125 mg amoxicillin/ 31.25 mg clavulanic acid) FOR ORAL SUSPENSIONN 75 mL bottle or 100 mL bottle
Clementin 250 MG/ 5 ML (250 mg amoxicillin/ 62.5 mg clavulanic acid) FOR ORAL SUSPENSION: ... 100 mL bottle NDC 0029-6090-22........... 150 mL bottle
Clementin 400 MG/ 5 ML (400 mg amoxicillin/ 57 mg clavulanic acid) FOR ORAL SUSPENSION:
The number of bacteriologically evaluable patients was comparable between the two dosing regimens.
Clementin produced comparable bacteriological success rates in patients assessed 2 to 4 days immediately following end of therapy. The bacteriologic efficacy rates were comparable at one of the follow-up visits (5 to 9 days post-therapy) and at a late post-therapy visit (in the majority of cases, this was 2 to 4 weeks post-therapy), as seen in the table below: 875 mg q12h 500 mg q8h 2 to 4 days 81%, n= 58 80%, n= 54 5 to 9 days 58.5%, n= 41 51.9%, n= 52 2 to 4 weeks 52.5%, n= 101 54.8%, n= 104
As noted before, though there was no significant difference in the percentage of adverse events in each group, there was a statistically significant difference in rates of severe diarrhea or withdrawals with diarrhea between the regimens.
INDICATIONS AND USAGE
Clementin is indicated in the treatment of infections caused by susceptible strains of the designated organisms in the conditions listed below:
Lower Respiratory Tract Infections caused by -lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.
Otitis Media caused by -lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.
Sinusitis caused by -lactamase-producing strains of Haemophilus influenzae and Moraxella (Branhamella) catarrhalis.
Skin and Skin Structure Infections caused by -lactamase-producing strains of Staphylococcus aureus, Escherichia coli and Klebsiella spp.
Urinary Tract Infections caused by -lactamase-producing strains of Escherichia coli, Klebsiella spp. and Enterobacter spp.
While Clementin is indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to Clementin treatment due to its amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and -lactamase-producing organisms susceptible to Clementin should not require the addition of another antibiotic. Because amoxicillin has greater in vitro activity against Streptococcus pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin and Clementin. (See Microbiology subsection.)
Bacteriological studies, to determine the causative organisms and their susceptibility to Clementin , should be performed together with any indicated surgical procedures. Therapy may be instituted prior to obtaining the results from bacteriological and susceptibility studies to determine the causative organisms and their susceptibility to Clementin when there is reason to believe the infection may involve any of the -lactamase-producing organisms listed above. Once the results are known, therapy should be adjusted, if appropriate.
Clementin - Warnings & Precautions
WARNINGSSERIOUS AND OCCASIONALLY FATAL HYPERSENSITIVITY (ANAPHYLACTIC)REACTIONS HAVE BEEN REPORTED IN PATIENTS ON PENICILLIN THERAPY. THESE REACTIONS ARE MORE LIKELY TO OCCUR IN INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY AND/ OR A HISTORY OF SENSITIVITY TO MULTIPLE ALLERGENS. THERE HAVE BEEN REPORTS OF INDIVIDUALS WITH A HISTORY OF PENICILLIN HYPERSENSITIVITY WHO HAVE EXPERIENCED SEVERE REACTIONS WHEN TREATED WITH CEPHALOSPORINS. BEFORE INITIATING THERAPY WITH CLEMENTIN, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, CLEMENTIN SHOULD BE DISCONTINUED AND THE APPROPRIATE THERAPY INSTITUTED. SERIOUS ANAPHYLACTIC REACTIONS REQUIRE IMMEDIATE EMERGENCY TREATMENT WITH EPINEPHRINE. OXYGEN, INTRAVENOUS STEROIDS AND AIRWAY MANAGEMENT, INCLUDING INTUBATION, SHOULD ALSO BE ADMINISTERED AS INDICATED.
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including Clementin, and has ranged in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic associated colitis." After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis
.
Clementin should be used with caution in patients with evidence of hepatic dysfunction.
Hepatic toxicity associated with the use of Clementin is usually reversible.
On rare occasions, deaths have been reported (less than 1 death reported per estimated 4 million prescriptions worldwide).
These have generally been cases associated with serious underlying diseases or concomitant medications. (See CONTRAINDICATIONS and ADVERSE REACTIONS? Liver.) PRECAUTIONSGeneral While Clementin possesses the characteristic low toxicity of the penicillin group of antibiotics, periodic assessment of organ system functions, including renal, hepatic and hematopoietic function, is advisable during prolonged therapy. A high percentage of patients with mononucleosis who receive ampicillin develop an erythematous skin rash. Thus, ampicillin class antibiotics should not be administered to patients with mononucleosis. The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur (usually involving Pseudomonas or Candida), the drug should be discontinued and/ or appropriate therapy instituted. Drug Interactions: Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with Clementin may result in increased and prolonged blood levels of amoxicillin. Co-administration of probenecid cannot be recommended. The concurrent administration of allopurinol and ampicillin increases substantially the incidence of rashes in patients receiving both drugs as compared to patients receiving ampicillin alone. It is not known whether this potentiation of ampicillin rashes is due to allopurinol or the hyperuricemia present in these patients.
There are no data with Clementin and allopurinol administered concurrently. In common with other broad-spectrum antibiotics, Clementin may reduce the efficacy of oral contraceptives.
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