Amoxicillin and Clavulanate Chewable

Generic Name: amoxicillin and clavulanate potassium

Dosage Form: tablet, chewable
AMOXICILLIN AND CLAVULANATE POTASSIUM TABLETS USP, (CHEWABLE)

2270

2272

Rx only

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium chewable tablets and other antibacterial drugs, amoxicillin and clavulanate potassium chewable tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

Amoxicillin and Clavulanate Chewable Description

Amoxicillin and clavulanate potassium tablets USP, (chewable) are an oral antibacterial combination consisting of the semisynthetic antibiotic amoxicillin and the ß-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. 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 and may be represented structurally as:

C16H19N3O5S·3H2O M.W. 419.46

Clavulanic acid is produced by the fermentation of Streptomyces clavuligerus. It is a ß-lactam structurally related to the penicillins and possesses the ability to inactivate a wide variety of ß-lactamases by blocking the active sites of these enzymes. Clavulanic acid is particularly active against the clinically important plasmid-mediated ß-lactamases frequently responsible for transferred drug resistance to penicillins and cephalosporins. Chemically, clavulanate potassium is potassium (Z)-(2R,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]-heptane-2-carboxylate and may be represented structurally as:

C8H8KNO5 M.W. 237.25

Each chewable tablet contains 200 mg amoxicillin as the trihydrate and 28.5 mg clavulanic acid as the potassium salt or contains 400 mg amoxicillin as the trihydrate and 57 mg clavulanic acid as the potassium salt. Each amoxicillin and clavulanate potassium tablet USP, (chewable) 200 mg/28.5 mg contains 0.14 mEq potassium. Each amoxicillin and clavulanate potassium tablet USP, (chewable) 400 mg/57 mg contains 0.29 mEq potassium.

Inactive Ingredients: aspartame*, colloidal silicon dioxide, FD&C Red #40 aluminum lake, magnesium stearate, mannitol, microcrystalline cellulose, SA84 artificial ripe banana flavor, and S.D. artificial cherry flavor.

* See PRECAUTIONS, Information for the Patient. 

Amoxicillin and Clavulanate Chewable - Clinical Pharmacology

Amoxicillin and clavulanate potassium are well absorbed from the gastrointestinal tract after oral administration of amoxicillin and clavulanate potassium. Dosing in the fasted or fed state has minimal effect on the pharmacokinetics of amoxicillin. While amoxicillin and clavulanate potassium can be given without regard to meals, absorption of clavulanate potassium when taken with food is greater relative to the fasted state. In 1 study, the relative bioavailability of clavulanate was reduced when amoxicillin and clavulanate potassium was dosed at 30 and 150 minutes after the start of a high-fat breakfast. The safety and efficacy of amoxicillin and clavulanate potassium have been established in clinical trials where amoxicillin and clavulanate potassium was taken without regard to meals.

Oral administration of single doses of amoxicillin and clavulanate potassium chewable tablets, 400 mg/57 mg and 400 mg/57 mg per 5 mL suspension to 28 adult volunteers yielded comparable pharmacokinetic data:

* Administered at the start of a light meal. † Mean values of 28 normal volunteers. Peak concentrations occurred approximately 1 hour after the dose.
Dose*	AUC0-∞(mcg•hr/mL)		Cmax (mcg/mL)†
(amoxicillin/clavulanate potassium)	amoxicillin (± S.D.)	clavulanate potassium (± S.D.)	amoxicillin (± S.D.)	clavulanatepotassium (± S.D.)
400 mg/57 mg (5 mL of suspension)	17.29 ± 2.28	2.34 ± 0.94	6.94 ± 1.24	1.10 ± 0.42
400 mg/57 mg (1 chewable tablet)	17.24 ± 2.64	2.17 ± 0.73	6.67 ± 1.37	1.03 ± 0.33

Oral administration of 5 mL of amoxicillin and clavulanate potassium oral suspension, 250 mg/62.5 mg per 5 mL or the equivalent dose of 10 mL amoxicillin and clavulanate potassium oral suspension, 125 mg/31.25 mg per 5 mL provides average peak serum concentrations approximately 1 hour after dosing of 6.9 mcg/mL for amoxicillin and 1.6 mcg/mL for clavulanic acid. The areas under the serum concentration curves obtained during the first 4 hours after dosing were 12.6 mcg•hr/mL for amoxicillin and 2.9 mcg•hr/mL for clavulanic acid when 5 mL of amoxicillin and clavulanate potassium oral suspension, 250 mg/62.5 mg per 5 mL or equivalent dose of 10 mL of amoxicillin and clavulanate potassium oral suspension, 125 mg/31.25 mg per 5 mL was administered to adult volunteers. One amoxicillin and clavulanate potassium chewable tablet, 250 mg/62.5 mg or two amoxicillin and clavulanate potassium chewable tablets, 125 mg/31.25 mg are equivalent to 5 mL of amoxicillin and clavulanate potassium oral suspension, 250 mg/62.5 mg per 5 mL and provide similar serum levels of amoxicillin and clavulanic acid.

Amoxicillin serum concentrations achieved with amoxicillin and clavulanate potassium are similar to those produced by the oral administration of equivalent doses of amoxicillin alone. The half-life of amoxicillin after the oral administration of amoxicillin and clavulanate potassium is 1.3 hours and that of clavulanic acid is 1.0 hour. Time above the minimum inhibitory concentration of 1.0 mcg/mL for amoxicillin has been shown to be similar after corresponding q12h and q8h dosing regimens of amoxicillin and clavulanate potassium in adults and children.

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 10 mL of amoxicillin and clavulanate potassium oral suspension, 250 mg/62.5 mg per 5 mL.

Concurrent administration of probenecid delays amoxicillin excretion but does not delay renal excretion of clavulanic acid.

Neither component in amoxicillin and clavulanate potassium is highly protein-bound; clavulanic acid has been found to be approximately 25% bound to human serum and amoxicillin approximately 18% bound.

Amoxicillin diffuses readily into most body tissues and fluids with the exception of the brain and spinal fluid. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like amoxicillin, is well distributed in body tissues.

Two hours after oral administration of a single 35 mg/kg dose of amoxicillin and clavulanate potassium oral suspension to fasting children, average concentrations of 3.0 mcg/mL of amoxicillin and 0.5 mcg/mL of clavulanic acid were detected in middle ear effusions.

Microbiology

Amoxicillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative microorganisms. Amoxicillin is, however, susceptible to degradation by ß-lactamases, and therefore, the spectrum of activity does not include organisms which produce these enzymes. Clavulanic acid is a ß-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of ß-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid mediated ß-lactamases frequently responsible for transferred drug resistance.

The formulation of amoxicillin and clavulanic acid in amoxicillin and clavulanate potassium protects amoxicillin from degradation by ß-lactamase enzymes and effectively extends the antibiotic spectrum of amoxicillin to include many bacteria normally resistant to amoxicillin and other ß-lactam antibiotics. Thus, amoxicillin and clavulanate potassium possesses the distinctive properties of a broad-spectrum antibiotic and a ß-lactamase inhibitor.

Amoxicillin/clavulanic acid has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS AND USAGE.

Gram-Positive Aerobes:

Staphylococcus aureus (ß-lactamase and non–ß-lactamase–producing)§

§ Staphylococci which are resistant to methicillin/oxacillin must be considered resistant to amoxicillin/clavulanic acid.

Gram-Negative Aerobes:

Enterobacter species (Although most strains of Enterobacter species are resistant in vitro, clinical efficacy has been demonstrated with amoxicillin and clavulanate potassium in urinary tract infections caused by these organisms.)

Escherichia coli (ß-lactamase and non–ß-lactamase–producing)

Haemophilus influenzae (ß-lactamase and non–ß-lactamase–producing)

Klebsiella species (All known strains are ß-lactamase–producing.)

Moraxella catarrhalis (ß-lactamase and non–ß-lactamase–producing)

The following in vitro data are available, but their clinical significance is unknown.

Amoxicillin/clavulanic acid exhibits in vitro minimal inhibitory concentrations (MICs) of 2 mcg/mL or less against most (≥ 90%) strains of Streptococcus pneumoniae||; MICs of 0.06 mcg/mL or less against most (≥ 90%) strains of Neisseria gonorrhoeae; MICs of 4 mcg/mL or less against most (≥ 90%) strains of staphylococci and anaerobic bacteria; and MICs of 8 mcg/mL or less against most (≥ 90%) strains of other listed organisms. However, with the exception of organisms shown to respond to amoxicillin alone, the safety and effectiveness of amoxicillin/clavulanic acid in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

|| Because amoxicillin has greater in vitro activity against S. pneumoniae than does ampicillin or penicillin, the majority of S. pneumoniae strains with intermediate susceptibility to ampicillin or penicillin are fully susceptible to amoxicillin.

Gram-Positive Aerobes:

Enterococcus faecalis¶

Staphylococcus epidermidis (ß-lactamase and non–ß-lactamase–producing)

Staphylococcus saprophyticus (ß-lactamase and non–ß-lactamase–producing)

Streptococcus pneumoniae¶**

Streptococcus pyogenes¶ **

viridans group Streptococcus¶**

Gram-Negative Aerobes:

Eikenella corrodens (ß-lactamase and non–ß-lactamase–producing)

Neisseria gonorrhoeae¶ (ß-lactamase and non–ß-lactamase–producing)

Proteus mirabilis¶ (ß-lactamase and non–ß-lactamase–producing)

Anaerobic Bacteria:

Bacteroides species, including Bacteroides fragilis (ß-lactamase and non–ß-lactamase–producing)

Fusobacterium species (ß-lactamase and non–ß-lactamase–producing)

Peptostreptococcus species**

¶ Adequate and well-controlled clinical trials have established the effectiveness of amoxicillin alone in treating certain clinical infections due to these organisms.

** These are non–ß-lactamase–producing organisms, and therefore, are susceptible to amoxicillin alone.

Susceptibility Testing:Dilution Techniques: Quantitative methods are used to determine antimicrobial MICs. These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of amoxicillin/clavulanate potassium powder.

The recommended dilution pattern utilizes a constant amoxicillin/clavulanate potassium ratio of 2 to 1 in all tubes with varying amounts of amoxicillin. MICs are expressed in terms of the amoxicillin concentration in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid. The MIC values should be interpreted according to the following criteria: INTERPRETIVE CRITERIA FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Gram-Negative Enteric Aerobes:

MIC (mcg/mL)	Interpretation
≤ 8/4	Susceptible (S)
16/8	Intermediate (I)
≥ 32/16	Resistant (R)

For Staphylococcus aureus* and Haemophilus influenzae:

* Staphylococci which are susceptible to amoxicillin/clavulanic acid but resistant to methicillin or oxacillin must be considered as resistant.
MIC (mcg/mL)	Interpretation
≤ 4/2	Susceptible (S)
≥ 8/4	Resistant (R)

ForS. pneumoniaefrom non-meningitis sources: Isolates should be tested using amoxicillin/clavulanic acid and the following criteria should be used:

MIC (mcg/mL)	Interpretation
≤ 2/1	Susceptible (S)
4/2	Intermediate (I)
≥ 8/4	Resistant (R)

Note: These interpretive criteria are based on the recommended doses for respiratory tract infections.

A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of “Intermediate” indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard amoxicillin/clavulanate potassium powder should provide the following MIC values:

* Expressed as concentration of amoxicillin in the presence of clavulanic acid at a constant 2 parts amoxicillin to 1 part clavulanic acid.
Microorganism	MIC Range (mcg/mL)*
E. coli ATCC 25922	2 to 8
E. coli ATCC 35218	4 to 16
H. influenzae ATCC 49247	2 to 16
S. aureus ATCC 29213	0.12 to 0.5
S. pneumoniae ATCC 49619	0.03 to 0.12

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg of amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) to test the susceptibility of microorganisms to amoxicillin/clavulanic acid.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) disk should be interpreted according to the following criteria:

INTERPRETIVE CRITERIA FOR AMOXICILLIN/CLAVULANIC ACID SUSCEPTIBILITY TESTING

For Gram-Negative Enteric Aerobes:

Zone Diameter (mm)	Interpretation
≥ 18	Susceptible (S)
14 to 17	Intermediate (I)
≤ 13	Resistant (R)

For Staphylococcus aureus* and Haemophilus influenzae†

* Staphylococci which are resistant to methicillin or oxacillin must be considered as resistant to amoxicillin/clavulanic acid. † A broth microdilution method should be used for testing Haemophilus influenzae. Beta-lactamase–negative, ampicillin-resistant strains must be considered resistant to amoxicillin/clavulanic acid.
Zone Diameter (mm)	Interpretation
≥ 20	Susceptible (S)
≤ 19	Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for amoxicillin/clavulanic acid.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg amoxicillin/clavulanate potassium (20 mcg amoxicillin plus 10 mcg clavulanate potassium) disk should provide the following zone diameters in these laboratory quality control strains:

Microorganism	Zone Diameter (mm)
E. coli ATCC 25922	18 to 24 mm
E. coli ATCC 35218	17 to 22 mm
S. aureus ATCC 25923	28 to 36 mm
H. influenza ATCC 49247	15 to 23 mm

Indications and Usage for Amoxicillin and Clavulanate Chewable

Amoxicillin and clavulanate potassium chewable tablets are 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 ß-lactamase–producing strains of H. influenzae and M. catarrhalis.

Otitis Media – caused by ß-lactamase–producing strains of H. influenzae and M. catarrhalis.

Sinusitis – caused by ß-lactamase–producing strains of H. influenzae and M. catarrhalis.

Skin and Skin Structure Infections – caused by ß-lactamase–producing strains of S. aureus, E. coli, and Klebsiella spp.

Urinary Tract Infections – caused by ß-lactamase–producing strains of E. coli, Klebsiella spp. and Enterobacter spp.

While amoxicillin and clavulanate potassium chewable tablets are indicated only for the conditions listed above, infections caused by ampicillin-susceptible organisms are also amenable to treatment with amoxicillin and clavulanate potassium chewable tablets due to their amoxicillin content. Therefore, mixed infections caused by ampicillin-susceptible organisms and ß-lactamase–producing organisms susceptible to amoxicillin and clavulanate potassium chewable tablets should not require the addition of another antibiotic. Because amoxicillin has greater in vitro activity against S. 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 amoxicillin and clavulanate potassium chewable tablets (see Microbiology).

To reduce the development of drug-resistant bacteria and maintain the effectiveness of amoxicillin and clavulanate potassium chewable tablets and other antibacterial drugs, amoxicillin and clavulanate potassium chewable tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Bacteriological studies, to determine the causative organisms and their susceptibility to amoxicillin and clavulanate potassium chewable tablets, should be performed together with any indicated surgical procedures.

Contraindications

Amoxicillin and clavulanate potassium chewable tablets are contraindicated in patients with a history of allergic reactions to any penicillin. They are also contraindicated in patients with a previous history of cholestatic jaundice/hepatic dysfunction associated with amoxicillin and clavulanate potassium.

Warnings

SERIOUS 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 AMOXICILLIN AND CLAVULANATE POTASSIUM, CAREFUL INQUIRY SHOULD BE MADE CONCERNING PREVIOUS HYPERSENSITIVITY REACTIONS TO PENICILLINS, CEPHALOSPORINS, OR OTHER ALLERGENS. IF AN ALLERGIC REACTION OCCURS, AMOXICILLIN AND CLAVULANATE POTASSIUM 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.

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including amoxicillin and clavulanate potassium, 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.

C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Amoxicillin and clavulanate potassium should be used with caution in patients with evidence of hepatic dysfunction. Hepatic toxicity associated with the use of amoxicillin and clavulanate potassium 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).

Precautions

General

While amoxicillin and clavulanate potassium 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.

Prescribing amoxicillin and clavulanate potassium chewable tablets in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Information for the Patient

Amoxicillin and clavulanate potassium may be taken every 8 hours or every 12 hours, depending on the strength of the product prescribed. Each dose should be taken with a meal or snack to reduce the possibility of gastrointestinal upset. Many antibiotics can cause diarrhea. If diarrhea is severe or lasts more than 2 or 3 days, call your doctor.

Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, 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 the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

Patients should be counseled that antibacterial drugs including amoxicillin and clavulanate potassium chewable tablets, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When amoxicillin and clavulanate potassium chewable tablets are 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 amoxicillin and clavulanate potassium chewable tablets or other antibacterial drugs in the future.

Phenylketonurics

Each amoxicillin and clavulanate potassium chewable tablet, 200 mg/28.5 mg contains 3.4 mg phenylalanine; each amoxicillin and clavulanate potassium chewable tablet, 400 mg/57 mg contains 6.7 mg phenylalanine. Contact your physician or pharmacist.

Drug Interactions

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use with amoxicillin and clavulanate potassium may result in increased and prolonged blood levels of amoxicillin. Coadministration of probenecid cannot be recommended.

Abnormal prolongation of prothrombin time (increased international normalized ratio [INR]) has been reported rarely in patients receiving amoxicillin 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.

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 amoxicillin and clavulanate potassium and allopurinol administered concurrently.

In common with other broad-spectrum antibiotics, amoxicillin and clavulanate potassium may reduce the efficacy of oral contraceptives.

Drug/Laboratory Test Interactions

Oral administration of amoxicillin and clavulanate potassium will result in high urine concentrations of amoxicillin. High urine concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using CLINITEST®, Benedict’s Solution, or Fehling’s Solution. Since this effect may also occur with amoxicillin and therefore amoxicillin and clavulanate potassium, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as CLINISTIX®) be used.

Following administration of ampicillin to pregnant women, a transient decrease in plasma concentration of total conjugated estriol, estriol-glucuronide, conjugated estrone, and estradiol has been noted. This effect may also occur with amoxicillin and therefore amoxicillin and clavulanate potassium.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential.

Mutagenesis

The mutagenic potential of amoxicillin and clavulanate potassium was investigated in vitro with an Ames test, a human lymphocyte cytogenetic assay, a yeast test and a mouse lymphoma forward mutation assay, and in vivo with mouse micronucleus tests and a dominant lethal test. All were negative apart from the in vitro mouse lymphoma assay where weak activity was found at very high, cytotoxic concentrations.

Impairment of Fertility

Amoxicillin and clavulanate potassium at oral doses of up to 1,200 mg/kg/day (5.7 times the maximum human dose, 1,480 mg/m2/day, based on body surface area) was found to have no effect on fertility and reproductive performance in rats, dosed with a 2:1 ratio formulation of amoxicillin:clavulanate.

Pregnancy

Teratogenic Effects

Pregnancy (Category B).

Reproduction studies performed in pregnant rats and mice given amoxicillin and clavulanate potassium at oral dosages up to 1,200 mg/kg/day, equivalent to 7,200 and 4,080 mg/m2/day, respectively (4.9 and 2.8 times the maximum human oral dose based on body surface area), revealed no evidence of harm to the fetus due to amoxicillin and clavulanate potassium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

Oral ampicillin-class antibiotics are generally poorly absorbed during labor. Studies in guinea pigs have shown that intravenous administration of ampicillin decreased the uterine tone, frequency of contractions, height of contractions, and duration of contractions. However, it is not known whether the use of amoxicillin and clavulanate potassium in humans during labor or delivery has immediate or delayed adverse effects on the fetus, prolongs the duration of labor, or increases the likelihood that forceps delivery or other obstetrical intervention or resuscitation of the newborn will be necessary. In a single study in women with premature rupture of fetal membranes, it was reported that prophylactic treatment with amoxicillin and clavulanate potassium may be associated with an increased risk of necrotizing enterocolitis in neonates.

Nursing Mothers

Ampicillin-class antibiotics are excreted in the milk; therefore, caution should be exercised when amoxicillin and clavulanate potassium is administered to a nursing woman.

Pediatric Use

Because of incompletely developed renal function in neonates and young infants, the elimination of amoxicillin may be delayed. Dosing of amoxicillin and clavulanate potassium should be modified in pediatric patients younger than 12 weeks (3 months) (see DOSAGE AND ADMINISTRATION, Pediatric Patients).

Adverse Reactions

Amoxicillin and clavulanate potassium is generally well tolerated. The majority of side effects observed in clinical trials were of a mild and transient nature and less than 3% of patients discontinued therapy because of drug-related side effects. From the original premarketing studies, where both pediatric and adult patients were enrolled, the most frequently reported adverse effects were diarrhea/loose stools (9%), nausea (3%), skin rashes and urticaria (3%), vomiting (1%) and vaginitis (1%). The overall incidence of side effects, and in particular diarrhea, increased with the higher recommended dose. Other less frequently reported reactions include: Abdominal discomfort, flatulence, and headache.

In pediatric patients (aged 2 months to 12 years), 1 U.S./Canadian clinical trial was conducted which compared amoxicillin and clavulanate potassium 45 mg/6.4 mg/kg/day (divided q12h) for 10 days versus amoxicillin and clavulanate potassium 40 mg/10 mg/kg/day (divided q8h) for 10 days in the treatment of acute otitis media. A total of 575 patients were enrolled, and only the suspension formulations were used in this trial. Overall, the adverse event profile seen was comparable to that noted above; however, there were differences in the rates of diarrhea, skin rashes/urticaria, and diaper area rashes (see CLINICAL STUDIES).

The following adverse reactions have been reported for ampicillin-class antibiotics:

Gastrointestinal: Diarrhea, nausea, vomiting, indigestion, gastritis, stomatitis, glossitis, black “hairy” tongue, mucocutaneous candidiasis, enterocolitis, and hemorrhagic/pseudomembranous colitis. Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment (see WARNINGS).

Hypersensitivity Reactions: Skin rashes, pruritus, urticaria, angioedema, serum sickness–like reactions (urticaria or skin rash accompanied by arthritis, arthralgia, myalgia, and frequently fever), erythema multiforme (rarely Stevens-Johnson syndrome), acute generalized exanthematous pustulosis, hypersensitivity vasculitis, and an occasional case of exfoliative dermatitis (including toxic epidermal necrolysis) have been reported. These reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, the drug should be discontinued, unless the opinion of the physician dictates otherwise. Serious and occasional fatal hypersensitivity (anaphylactic) reactions can occur with oral penicillin (see WARNINGS).

Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted in patients treated with ampicillin-class antibiotics, but the significance of these findings is unknown. Hepatic dysfunction, including hepatitis and cholestatic jaundice, (see CONTRAINDICATIONS), increases in serum transaminases (AST and/or ALT), serum bilirubin and/or alkaline phosphatase, has been infrequently reported with amoxicillin and clavulanate potassium. It has been reported more commonly in the elderly, in males, or in patients on prolonged treatment. The histologic findings on liver biopsy have consisted of predominantly cholestatic, hepatocellular, or mixed cholestatic-hepatocellular changes. The onset of signs/symptoms of hepatic dysfunction may occur during or several weeks after therapy has been discontinued. The hepatic dysfunction, which may be severe, 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.

Renal: Interstitial nephritis and hematuria have been reported rarely. Crystalluria has also been reported (see OVERDOSAGE).

Hemic and Lymphatic Systems: Anemia, including hemolytic anemia, thrombocytopenia, thrombocytopenic purpura, eosinophilia, leukopenia, and agranulocytosis have been reported during therapy with penicillins. These reactions are usually reversible on discontinuation of therapy and are believed to be hypersensitivity phenomena. A slight thrombocytosis was noted in less than 1% of the patients treated with amoxicillin and clavulanate potassium. There have been reports of increased prothrombin time in patients receiving amoxicillin and clavulanate potassium and anticoagulant therapy concomitantly.

Central Nervous System: Agitation, anxiety, behavioral changes, confusion, convulsions, dizziness, insomnia, and reversible hyperactivity have been reported rarely.

Miscellaneous: Tooth discoloration (brown, yellow, or gray staining) has been rarely reported. Most reports occurred in pediatric patients. Discoloration was reduced or eliminated with brushing or dental cleaning in most cases.

Overdosage

Following overdosage, patients have experienced primarily gastrointestinal symptoms including stomach and abdominal pain, vomiting, and diarrhea. Rash, hyperactivity, or drowsiness have also been observed in a small number of patients.

In the case of overdosage, discontinue amoxicillin and clavulanate potassium, treat symptomatically, and institute supportive measures as required. If the overdosage is very recent and there is no contraindication, an attempt at emesis or other means of removal of drug from the stomach may be performed. A prospective study of 51 pediatric patients at a poison center suggested that overdosages of less than 250 mg/kg of amoxicillin are not associated with significant clinical symptoms and do not require gastric emptying.3

Interstitial nephritis resulting in oliguric renal failure has been reported in a small number of patients after overdosage with amoxicillin.

Crystalluria, in some cases leading to renal failure, has also been reported after amoxicillin overdosage in adult and pediatric patients. In case of overdosage, adequate fluid intake and diuresis should be maintained to reduce the risk of amoxicillin crystalluria.

Renal impairment appears to be reversible with cessation of drug administration. High blood levels may occur more readily in patients with impaired renal function because of decreased renal clearance of both amoxicillin and clavulanate. Both amoxicillin and clavulanate are removed from the circulation by hemodialysis.

Amoxicillin and Clavulanate Chewable Dosage and Administration

Dosage

Pediatric Patients

Based on the amoxicillin component, amoxicillin and clavulanate potassium tablets USP, (chewable) should be dosed as follows:

Neonates and infants aged < 12 weeks (3 months):Due to incompletely developed renal function affecting elimination of amoxicillin in this age group, the recommended dose of amoxicillin and clavulanate potassium tablets USP, (chewable) is 30 mg/kg/day divided q12h, based on the amoxicillin component. Clavulanate elimination is unaltered in this age group. Experience with the 200 mg/28.5 mg per 5 mL formulation in this age group is limited and, thus, use of the 125 mg/31.25 mg per 5 mL oral suspension is recommended.

Patients Aged 12 Weeks (3 Months) and Older

* The q12h regimen is recommended as it is associated with significantly less diarrhea (see CLINICAL STUDIES). However, the q12h formulations (200 mg/28.5 mg per 5 mL and 400 mg/57 mg per 5 mL) contain aspartame and should not be used by phenylketonurics. † Each strength of amoxicillin and clavulanate potassium suspension is available as a chewable tablet for use by older children. ‡ Duration of therapy studied and recommended for acute otitis media is 10 days.
INFECTIONS	DOSING REGIMEN
	q12h*	q8h
	200 mg/28.5 mg per 5 mL or 400 mg/57 mg per 5 mL oral suspension†	125 mg/31.25 mg per 5 mL or 250 mg/62.5 mg per 5 mL oral suspension
Otitis media‡, sinusitis, lower respiratory tract infections, and more severe infections	45 mg/kg/day q12h	40 mg/kg/day q8h
Less severe infections	25 mg/kg/day q12h	20 mg/kg/day q8h

Pediatric Patients Weighing 40 kg and More:Should be dosed according to the following adult recommendations: The usual adult dose is one amoxicillin and

Modrenal

Modrenal 60 mg and 120 mg capsules

(trilostane)

Read all of this leaflet carefully before you start taking this medicine.

• Keep this leaflet. You may need to read it again.


• If you have any further questions, ask your doctor or pharmacist.


• This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.


• If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

In this leaflet:

• 1. What Modrenal Capsules are and what they are used for


• 2. Before you take Modrenal Capsules


• 3. How to take Modrenal Capsules


• 4. Possible side effects


• 5. How to store Modrenal Capsules


• 6. Further information

What Modrenal Capsules Are And What They Are Used For

Modrenal Capsules contain the active ingredient trilostane which reversibly reduces the production of steroids (hormones). Modrenal Capsules are used to treat:

• an excessive production of steroids, also known as adrenal cortical hyperfunction.
  
  Cushing’s disease is one example of an excessive production of steroids.


• postmenopausal breast cancer in women who have been on other therapy.

Before You Take Modrenal Capsules

Do NOT take Modrenal Capsules if you:

• are allergic to trilostane or any of the other ingredients in the product (see Section 6 and end of Section 2)


• are pregnant.

Modrenal Capsules must not be given to children.

Take special care with Modrenal Capsules

Speak to your doctor if you:

• become pregnant while taking Modrenal Capsules


• have severe liver or kidney problems

Your doctor will carry out regular blood tests and may adjust your dose. Your doctor may prescribe additional drugs if you have:

• an abnormally low concentration of potassium ions in your blood (hyperkalaemia)


• a low concentration of sodium in your blood which results in low blood pressure (hyponatraemia)


• a low concentration of corticosteroids.

Taking other medicines

Please inform your doctor if you are taking or have recently taken any other medicines, including those obtained without a prescription.

In particular, tell your doctor if you are taking any of the following:

• hormonal contraceptives – use other contraceptive methods during treatment


• thiazide diuretics – when taken together with Modrenal this can lead to dizziness due to low blood pressure and your doctor may need to add another medication


• high doses of "aspirin-like" drugs (called nonsteroidal anti-inflammatory drugs or NSAIDs) for pain.

Taking Modrenal Capsules with food and drink

Taking the capsules with food may help to reduce the side effects.

Pregnancy and breast-feeding

During treatment with Modrenal you must avoid becoming pregnant and if necessary you should use barrier or non-hormonal methods of contraception.

Your doctor will advise you if you are breast-feeding.

Ask your doctor for advice before taking any medicine.

Driving and using machines

Modrenal capsules are not expected to affect your ability to drive or operate machinery, but if you feel drowsy or tired, you should not perform any tasks requiring special attention until you know how the medicine affects you.

Further information about some of the other ingredients in Modrenal Capsules

Lactose is an ingredient in Modrenal Capsules. Tell your doctor if you know you have an intolerance to some sugars.

How To Take Modrenal Capsules

Always take Modrenal Capsules exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure.

For oral use in adults only. These capsules should not be given to children.

Modrenal Capsules must be swallowed whole with a drink of water. Taking them with food may help to reduce the side effects.

Excessive production of steroids

The initial dose is 240 mg/day (2 to 4 capsules) in divided doses for at least 3 days, then the dose will be adjusted by your doctor, following blood/urine tests.

The usual dose is 120 – 480 mg/day but may be increased to 960 mg if your doctor considers this necessary.

Postmenopausal breast cancer

The initial dose is 240 mg/day (2 to 4 capsules) to be taken in divided doses. At the start of treatment, you will also be given 30 mg hydrocortisone daily, in divided doses.

The dose of Modrenal will be increased every 3 days to 480 mg to 720 mg to 960 mg. The dose may be reduced to 720 mg if you cannot tolerate the higher dose.

If you are admitted to hospital, please let the staff know that you are taking Modrenal Capsules.

If you take more Modrenal Capsules than you should

If you or someone else takes too many capsules, contact your doctor or nearest hospital casualty department immediately. Take this leaflet and any remaining capsules with you, if possible.

If you forget to take Modrenal Capsules

If you miss a dose, take your next dose at the correct time. Do not take a double dose to make up for the forgotten one.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Modrenal Side Effects

Like all medicines, Modrenal Capsules can cause side effects, although not everybody gets them.

The following side effects have been reported:

• flushing, tingling in mouth, swelling of the palate, runny nose, sickness, vomiting, diarrhoea, cramps and skin rash.

These side effects are mild and reversible and tend to wear off as treatment goes on, but if they persist, or you are worried, tell your doctor. Your dose may need to be adjusted or you may require additional treatment to control the symptoms (e.g. antacids, anti-diarrhoeal medicines with a small dose of aspirin).

Rarely, a stomach ulcer may bleed (you may vomit blood or pass tarry stools), but this is only likely if you are taking regular high doses of "aspirin-like" drugs for pain. If this occurs tell your doctor immediately.

Very rarely, in cancer patients, a decrease in one type of a white blood cell (granulocytes) may occur. Your doctor will monitor your blood levels for this and may adjust your dose if necessary.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

How To Store Modrenal Capsules

Keep out of the reach and sight of children.

Store below 25°C in the original package.

Do not use Modrenal Capsules after the expiry date stated on the container.

Medicines should not be disposed of via wastewater or household waste. Ask your Pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

Further Information

What Modrenal Capsules contain

The active substance is trilostane, 60mg or 120mg per capsule.

The other ingredients are lactose, maize starch, magnesium stearate.

The capsule shells contain gelatin, titanium dioxide (E171) and iron oxide red or iron oxide yellow (E172).

What Modrenal Capsules look like and contents of the pack

• The 60 mg capsules are pink and black and marked with “60”


• The 120 mg capsules are pink and yellow and marked with “120”

They are available in packs of 100 capsules in brown glass bottles with screw top lids.

Marketing Authorisation Holder

Bioenvision Limited

Bassett House

5 Southwell Park Road

Camberley

Surrey

GU15 3PU

United Kingdom

Manufacturer

Almac Pharma Services Limited

Almac House

20 Seagoe Industrial Estate

Craigavon

Co. Armagh

BT63 5QD

This leaflet was last approved in 11/2008

Paregoric

Pronunciation: par-eh-GORE-ik
Generic Name: Paregoric
Brand Name: Generic only. No brands available.

Paregoric is used for:

Treating diarrhea.

Paregoric is an opiate. It works by decreasing intestinal muscle contractions, which helps to reduce diarrhea.

Do NOT use Paregoric if:

• you are allergic to any ingredient in Paregoric or any other opium- or morphine-related medicine (eg, codeine)


• you are taking sodium oxybate (GHB)


• you have severe bowel motility problems (eg, paralytic ileus), diarrhea due to poisoning, or severe diarrhea associated with antibiotic use (pseudomembranous colitis)


• you have seizures, severely slow or difficult breathing or severe asthma, or you are having an asthma attack

Contact your doctor or health care provider right away if any of these apply to you.

Before using Paregoric:

Some medical conditions may interact with Paregoric. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines or other substances


• if you have a history of asthma, chronic obstructive pulmonary disease (COPD), or other lung or breathing problems


• if you have a history of recent head injury, increased pressure in the brain, brain blood vessel problems, growths in the brain (eg, tumors), or seizures


• if you have a history of heart problems, fast or irregular heartbeat, low blood pressure, liver or kidney problems, an underactive thyroid, adrenal gland problems (eg, Addison disease), stomach or bowel problems, gallbladder problems, inflammation of the pancreas, a blockage of the bladder or bowel, an enlarged prostate, or the blood disease porphyria


• if you have a history of drug or alcohol abuse, mood or mental problems, or suicidal thoughts or behavior

Some MEDICINES MAY INTERACT with Paregoric. Tell your health care provider if you are taking any other medicines, especially any of the following:

• Barbiturates (eg, phenobarbital), cimetidine, furazolidone, monoamine oxidase (MAO) inhibitors (eg, phenelzine), narcotics (eg, codeine), phenothiazines (eg, chlorpromazine), or sodium oxybate (GHB) because the risk of side effects such as severe drowsiness, slow or difficult breathing, confusion, and seizures may be increased


• Buprenorphine, butorphanol, nalbuphine, naltrexone, or pentazocine because the effectiveness of Paregoric may be decreased

This may not be a complete list of all interactions that may occur. Ask your health care provider if Paregoric may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Paregoric:

Use Paregoric as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Paregoric may be taken with or without food.


• Use the dropper that comes with Paregoric to measure your dose. Ask your pharmacist for help if you are unsure of how to measure your dose.


• If you miss a dose of Paregoric and you are using it regularly, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses at once.

Ask your health care provider any questions you may have about how to use Paregoric.

Important safety information:

• Paregoric may cause dizziness or drowsiness. Do not drive, operate machinery, or do anything else that could be dangerous until you know how you react to Paregoric. Using Paregoric alone, with other medicines, or with alcohol may lessen your ability to drive or perform other potentially dangerous tasks.


• Avoid drinking alcohol or taking other medications that cause drowsiness (eg, sedatives, tranquilizers) while taking Paregoric. Paregoric will add to the effects of alcohol and other depressants. Ask your pharmacist if you have questions about which medicines are depressants.


• Paregoric may cause dizziness, lightheadedness, or fainting. Alcohol, hot weather, exercise, and fever can increase these effects. To prevent them, sit up or stand slowly, especially in the morning. Also, sit or lie down at the first sign of dizziness, lightheadedness, or weakness.


• Before you have any medical or dental treatments, emergency care, or surgery, tell the doctor or dentist that you are using Paregoric.


• Use Paregoric with caution in the ELDERLY because they may be more sensitive to its effects.


• Use Paregoric with extreme caution in CHILDREN because they may be more sensitive to its effects.


• PREGNANCY AND BREAST-FEEDING: If you become pregnant while taking Paregoric, discuss with your doctor the benefits and risks of using Paregoric during pregnancy. Paregoric is excreted in breast milk. If you are or will be breast-feeding while you are using Paregoric, check with your doctor or pharmacist to discuss the risks to your baby.

When used for long periods of time or at high doses, Paregoric may not work as well and may require higher doses to obtain the same effect as when originally taken. This is known as TOLERANCE. Talk with your doctor if Paregoric stops working well. Do not take more than prescribed.

When used for long periods of time or at high doses, some people develop a need to continue taking Paregoric. This is known as DEPENDENCE or addiction.

If you suddenly stop taking Paregoric, you may experience WITHDRAWAL symptoms including anxiety; diarrhea; fever, runny nose, or sneezing; goose bumps and abnormal skin sensations; nausea; vomiting; pain; rigid muscles; rapid heartbeat; seeing, hearing, or feeling things that are not there; shivering or tremors; sweating; and trouble sleeping.

Possible side effects of Paregoric:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Constipation; dizziness; drowsiness; lightheadedness; nausea; vomiting.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); confusion; difficulty urinating; fast or slow heartbeat; seizures; severe dizziness, lightheadedness, or fainting; slowed or difficult breathing; tremor; vision changes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

See also: Paregoric side effects (in more detail)

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include cold and clammy skin; confusion; loss of consciousness; seizures; severe drowsiness, dizziness, or lightheadedness; slow breathing; slow heartbeat.

Proper storage of Paregoric:

Store Paregoric at room temperature, between 59 and 86 degrees F (15 and 30 degrees C). Store away from heat, moisture, and light. Do not store in the bathroom. Keep Paregoric out of the reach of children and away from pets.

General information:

• If you have any questions about Paregoric, please talk with your doctor, pharmacist, or other health care provider.


• Paregoric is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Paregoric. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Paregoric resources

• Paregoric Side Effects (in more detail)
• Paregoric Use in Pregnancy & Breastfeeding
• Paregoric Drug Interactions
• Paregoric Support Group
• 5 Reviews for Paregoric - Add your own review/rating

• Paregoric Concise Consumer Information (Cerner Multum)


• Opium Monograph (AHFS DI)


• opium Advanced Consumer (Micromedex) - Includes Dosage Information

Compare Paregoric with other medications

• Diarrhea

Solpadeine Migraine Ibuprofen & Codeine Tablets

1. Name Of The Medicinal Product

Solpadeine Migraine Ibuprofen & Codeine Tablets

2. Qualitative And Quantitative Composition

Ibuprofen Ph Eur 200 mg

Codeine Phosphate Hemihydrate Ph Eur 12.8 mg

3. Pharmaceutical Form

White film-coated capsule-shaped tablets.

4. Clinical Particulars

4.1 Therapeutic Indications

For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone in such conditions as soft tissue injuries, including sprains, strains and musculo-tendonitis, backache, non-serious arthritic and rheumatic conditions, neuralgia, migraine, headache, dental pain and dysmenorrhoea.

4.2 Posology And Method Of Administration

Dosage:

Do not take for more than 3 days continuously without medical review.

Adults:

The lowest effective dose should be used for the shortest duration necessary to relieve symptoms.

200 mg – 400 mg, up to three times a day as required, preferably with or after food.

Leave at least four hours between doses and do not take more than 1200 mg in any 24 hour period.

Children under 12 years:

Not recommended

Elderly:

Non-steroidal anti-inflammatory drugs (NSAIDs) should be used with particular caution in elderly patients who are prone to adverse events.

Route of Administration:

For oral administration and short-term use only.

4.3 Contraindications

Solpadeine Migraine Ibuprofen & Codeine Tablets are contraindicated in individuals with hypersensitivity to the active ingredients.

Patients who have previously shown hypersensitivity reactions (e.g. asthma, rhinitis, angioedema or urticaria) in response to aspirin or other non-steroidal anti-inflammatory drugs.

Active or previous peptic ulcer.

History of upper gastrointestinal bleeding or perforation, related to previous NSAIDs therapy.

Use with concomitant NSAIDs including cyclo-oxygenase-2 specific inhibitors (See section 4.5 Interactions).

Severe hepatic failure, renal failure or heart failure (See section 4.4, Special warnings and precautions for use)

Last trimester of pregnancy (See section 4.6 Pregnancy and lactation).

Severe heart failure.

4.4 Special Warnings And Precautions For Use

Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms (see GI and cardiovascular risks below).

The elderly have an increased frequency of adverse reactions to NSAIDs especially gastrointestinal bleeding and perforation which may be fatal.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients taking other medications should consult a doctor prior to taking this product (see section 4.5).

Respiratory:

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

Other NSAIDs:

The use of Solpadeine Migraine Ibuprofen & Codeine Tablets with concomitant NSAIDs including cyclo-oxygenase-2 selective inhibitors should be avoided (see section 4.5).

SLE and mixed connective tissue disease:

Systemic lupus erythematosus and mixed connective tissue disease – increased risk of aseptic meningitis (see section 4.8).

Renal:

Renal impairment as renal function may further deteriorate (see sections 4.3 and 4.8)

Hepatic:

Hepatic dysfunction (see sections 4.3 and 4.8).

Cardiovascular and cerebrovascular effects:

Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy.

Clinical trial and epidemiological data suggest that use of ibuprofen, particularly at high doses (2400 mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g.

Impaired female fertility:

There is limited evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment (see section 4.6).

Gastrointestinal:

NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease as these conditions may be exacerbated (see section 4.8).

Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients (see section 4.8).

GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.

The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available.

Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.

Caution should be advised in patients receiving concomitant medications which could increase the risk of ulceration or bleeding, such as oral corticosteroids, anticoagulants such as warfarin, selective serotonin-reuptake inhibitors or anti-platelet agents such as aspirin (see section 4.5).

When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.

Dermatological:

Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at higher risk of these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. Solpadeine Migraine Ibuprofen & Codeine Tablets should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.

Solpadeine Migraine Ibuprofen & Codeine Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers

The leaflet will state:

Headlines section (to be prominently displayed)

• This medicine is for the short term treatment of acute moderate pain when other painkillers have not worked.

• You should only take this product for a maximum of 3 days at a time. If you need to take it for longer than 3 days you should see your doctor or pharmacist for advice.

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it.

• If you take this medicine for headaches for more than 3 days it can make them worse.

Section 1 What the medicine is for:

• Solpadeine Migraine is for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone. It can be used for migraine, headaches, period and dental pain, muscle and joint pain, backache, fibrositis, tennis elbow, sports injuries (e.g. sprains, strains) and for pain due to non serious arthritis..

Section 2 Before taking

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it.

• If you take a painkiller for headaches for more than 3 days it can make them worse.

• Usually it is safe to take this medicine while breast feeding as the levels of the active ingredients of this medicine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels in their breast milk. If any of the following side effects develop in you or your baby, stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing.

Section 3 Dosage

• Do not take for more than 3 days. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist.

• Possible withdrawal effects

This medicine contains codeine and can cause addiction if you take it continuously for more than 3 days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.

Section 4 Side effects

• Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday – Friday) or fill in a paper form available from your local pharmacy.

• How do I know if I am addicted?

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:

      • You need to take the medicine for longer periods of time

      • You need to take more than the recommended dose

      • When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again.

The label will state:

Front of pack

• Can cause addiction

• Use for 3 days only

Back of pack

• Solpadeine Migraine Ibuprofen & Codeine Tablets are for the short term treatment of acute moderate pain when other painkillers have not worked. Wait at least four hours after taking any other painkiller before you take this medicine. For: migraine, headache.

They can also be used for neuralgia, period pain, dental pain, muscle and joint pain, backache, fibrositis, tennis elbow, sports injuries (e.g. sprains, strains) and for pain due to non serious arthritis.

• If you need this medicine continuously for more than 3 days you should see your doctor or pharmacist

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worse.

Read the enclosed leaflet before taking this product.

Do not take if you:

• Have or have ever had a stomach ulcer, perforation or bleeding of the stomach

• are allergic to ibuprofen, codeine, or any other ingredient of the product , aspirin or other related painkillers,

• are taking other NSAID painkillers, or aspirin with a daily dose above 75mg

• suffer from severe liver or heart problems, or kidney problems

• are pregnant

• are breastfeeding, unless prescribed by your doctor. The use of codeine containing products while breastfeeding may harm your baby.

Speak to a pharmacist or your doctor before you taking if you:

• have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke or bowel problems

• are a smoker

If symptoms persist or worsen, consult your doctor.

Do not exceed the stated dose.

Keep out of the reach and sight of children.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Caution should be exercised in patients taking mono-amine oxidase inhibitors, thiazide diuretics or oral anticoagulants.

Ibuprofen should not be used in combination with:

Aspirin: Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, as this may increase the risk of adverse reactions (See 4.3 Contraindications).

Other NSAIDS: As these may increase the risk of adverse effects (See section 4.3 Contraindications).

Ibuprofen should be used with caution in combination with:

Anticoagulants: NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See section 4.4).

Antihypertensives and diuretics: NSAIDS may diminish the effects of these drugs.

Corticosteroids: May increase the risk of adverse reactions in the gastrointestinal tract (See section 4.4 Special warnings).

Lithium: There is evidence for potential increases in plasma levels of lithium.

Methotrexate: There is a potential for an increase in plasma methotrexate.

Zidovudine: There is evidence of an increased risk of haemarthroses and haematoma in HIV (+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen.

4.6 Pregnancy And Lactation

Based on animal studies and clinical experience there is no evidence to suggest that foetal abnormalities are associated with the use of ibuprofen or codeine. Use should be avoided in during the first 6 months of pregnancy and lactation unless essential.

During the 3^rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and its duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications).

See section 4.4 regarding female fertility.

At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant.

However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

4.8 Undesirable Effects

Codeine may cause constipation, nausea, dizziness and drowsiness according to dosage and individual susceptibility.

Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.

Prolonged use of a painkiller for headaches can make them worse.

Hypersensitivity reactions have been reported and these may consist of:

a) Non-specific allergic reactions and anaphylaxis

b) Respiratory tract reactivity, e.g. asthma, aggravated asthma, bronchospasm, dyspnoea

c) Various skin reactions, e.g. pruritus, urticaria, angioedema and more rarely exfoliative and bullous dermatoses (including epidermal necrolysis and erythema multiforme)

The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short term use. In treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.

Hypersensitivity reactions:

Uncommon: Hypersensitivity reactions with urticaria and pruritus.

Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

Gastrointestinal:

Uncommon: abdominal pain, nausea and dyspepsia.

Rare: diarrhoea, flatulence, constipation and vomiting.

Very rare: peptic ulcer, perforation or gastrointestinal haemorrhage, sometimes fatal, particularly in the elderly. Exacerbation of ulcerative colitis and Crohn's disease (See section 4.4).

Nervous system:

Uncommon: Headache

Renal:

Very Rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.

Hepatic:

Very rare: liver disorders.

Haematological:

Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.

Skin:

Uncommon: Various skin rashes

Very rare: Severe forms of skin reactions such as erythema multiforme and epidermal necrolysis can occur.

Immune system:

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (See section 4.4)

Others:

Hearing disturbance.

Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.

Clinical trial and epidemiological data suggest that use of ibuprofen (particularly at high doses 2400mg daily) and in long-term treatment may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4).

4.9 Overdose

Overuse of this product, defined as consumption of quantites in excess of the recommended dose, or consumption for a prolonged period of time may lead to physical or psychological dependency. Symptoms of restlessness and irritability may result when treatment is stopped.

Codeine

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Symptoms

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management

This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.

Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life, so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.

Ibuprofen

In children ingestion of more than 400 mg/kg may cause symptoms. In adults the dose response effect is less clear cut. The half-life in overdose is 1.5-3 hours.

Symptoms:

Most patients who have ingested clinically important amounts of NSAIDs will develop no more than nausea, vomiting, epigastric pain, or more rarely diarrhoea. Tinnitus, headache and gastrointestinal bleeding are also possible. In more serious poisoning, toxicity is seen in the central nervous system, manifesting as drowsiness, occasionally excitation and disorientation or coma. Occasionally patients develop convulsions. In serious poisoning metabolic acidosis may occur and the prothrombin time/INR may be prolonged, probably due to interference with the actions of circulating clotting factors. Acute renal failure and liver damage may occur. Exacerbation of asthma is possible in asthmatics.

Management:

Management should be symptomatic and supportive and include the maintenance of a clear airway and monitoring of cardiac and vital signs until stable. Consider oral administration of activated charcoal if the patient presents within 1 hour of ingestion of a potentially toxic amount. If frequent or prolonged, convulsions should be treated with intravenous diazepam or lorazepam. Give bronchodilators for asthma.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Ibuprofen is a propionic acid derivative NSAID that has demonstrated its efficacy by inhibition of prostaglandin synthesis. In humans ibuprofen reduces inflammatory pain, swellings and fever. Furthermore, ibuprofen reversibly inhibits platelet aggregation.

Codeine is a centrally-acting opioid analgesic.

5.2 Pharmacokinetic Properties

Ibuprofen is rapidly absorbed following administration and is distributed throughout the whole body. The excretion is rapid and complete via kidneys.

Maximum plasma concentrations are reached 45 minutes after ingestion if taken on an empty stomach. When taken with food, peak levels are observed after 1-2 hours. These times may vary with different dosage forms.

The half-life of ibuprofen is about 2 hours.

In limited studies, ibuprofen appears in the breast milk in very low concentrations.

Codeine phosphate is absorbed from the gastrointestinal tract, with a relative bioavailability (versus parenteral administration) of about 75%. The half-life in plasma is about 2.5 - 3 hours, whilst its analgesic effect occurs from 15 minutes up to 4 - 6 hours after oral administration. Peak plasma concentrations occur about one hour post-dose. Codeine and its metabolites are excreted almost entirely via the kidneys.

5.3 Preclinical Safety Data

Both ibuprofen and codeine are well established analgesics with well-documented preclinical safety profiles.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Microcrystalline cellulose

Hydrogenated vegetable oil

Sodium starch glycollate

Colloidal silicon dioxide

Cellactose 80

Hydroxypropyl methyl cellulose

Polyethylene glycol 400

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

Three years

6.4 Special Precautions For Storage

None.

6.5 Nature And Contents Of Container

White opaque polyvinyl chloride (250μm)/aluminium foil (20μm) blister packs containing 4, 6, 12 or 24 tablets.

6.6 Special Precautions For Disposal And Other Handling

Not applicable.

7. Marketing Authorisation Holder

SmithKline Beecham (SWG) Limited

980 Great West Road

Brentford

Middlesex

TW8 9GS

United Kingdom

Trading as: GlaxoSmithKline Consumer Healthcare, Brentford, TW8 9GS, U.K.

8. Marketing Authorisation Number(S)

PL 00071/0431

9. Date Of First Authorisation/Renewal Of The Authorisation

20/10/2006

10. Date Of Revision Of The Text

29/03/2011