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

amoxapine

a-MOX-a-peen

Oral route(Tablet)

Antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults in short-term studies with major depressive disorder (MDD) and other psychiatric disorders. Short term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24, and there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. This risk must be balanced with the clinical need. Monitor patients closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Not approved for use in pediatric patients .

Commonly used brand name(s)

In the U.S.

• Asendin

Available Dosage Forms:

• Tablet

Therapeutic Class: Antidepressant

Pharmacologic Class: Antidepressant, Tricyclic

Chemical Class: Dibenzoxazepine

Uses For amoxapine

Amoxapine is used to treat the symptoms of depression. It works on the central nervous system (CNS) to increase levels of certain chemicals in the brain. amoxapine is a tricyclic antidepressant (TCA).

amoxapine is available only with your doctor's prescription.

Before Using amoxapine

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For amoxapine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to amoxapine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies have not been performed on the relationship of age to the effects of amoxapine in the pediatric population. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of amoxapine in the elderly. However, elderly patients are more likely to have unwanted effects (e.g., movement disorders, unusual drowsiness) or age-related kidney or liver problems, which may require an adjustment in the dose for patients receiving amoxapine.

Pregnancy

	Pregnancy Category	Explanation
All Trimesters	C	Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking amoxapine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using amoxapine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Bepridil


• Cisapride


• Clorgyline


• Dronedarone


• Grepafloxacin


• Isocarboxazid


• Levomethadyl


• Linezolid


• Mesoridazine


• Methylene Blue


• Metoclopramide


• Moclobemide


• Phenelzine


• Pimozide


• Ranolazine


• Selegiline


• Sparfloxacin


• Terfenadine


• Thioridazine


• Tranylcypromine

Using amoxapine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acecainide


• Alfuzosin


• Amiodarone


• Amisulpride


• Amitriptyline


• Amprenavir


• Apomorphine


• Aprindine


• Arsenic Trioxide


• Asenapine


• Astemizole


• Azimilide


• Azithromycin


• Bretylium


• Chloral Hydrate


• Chloroquine


• Chlorpromazine


• Ciprofloxacin


• Citalopram


• Clarithromycin


• Clomipramine


• Clonidine


• Clozapine


• Crizotinib


• Dasatinib


• Desipramine


• Dextromethorphan


• Disopyramide


• Dofetilide


• Dolasetron


• Droperidol


• Enflurane


• Epinephrine


• Erythromycin


• Etilefrine


• Flecainide


• Fluconazole


• Fluoxetine


• Foscarnet


• Gatifloxacin


• Gemifloxacin


• Granisetron


• Halofantrine


• Haloperidol


• Halothane


• Ibutilide


• Iloperidone


• Imipramine


• Indacaterol


• Iproniazid


• Isoflurane


• Isradipine


• Lapatinib


• Levofloxacin


• Lidoflazine


• Lopinavir


• Lorcainide


• Lumefantrine


• Mefloquine


• Methadone


• Methoxamine


• Midodrine


• Moricizine


• Moxifloxacin


• Nefopam


• Nialamide


• Nilotinib


• Norepinephrine


• Norfloxacin


• Nortriptyline


• Octreotide


• Ofloxacin


• Ondansetron


• Oxilofrine


• Paliperidone


• Pargyline


• Pazopanib


• Pentamidine


• Perflutren Lipid Microsphere


• Phenylephrine


• Posaconazole


• Procainamide


• Procarbazine


• Prochlorperazine


• Promethazine


• Propafenone


• Protriptyline


• Quetiapine


• Quinidine


• Quinine


• Rasagiline


• Risperidone


• Saquinavir


• Sematilide


• Sertindole


• Sertraline


• Sodium Phosphate


• Sodium Phosphate, Dibasic


• Sodium Phosphate, Monobasic


• Solifenacin


• Sorafenib


• Sotalol


• Spiramycin


• Sulfamethoxazole


• Sultopride


• Sunitinib


• Tapentadol


• Tedisamil


• Telavancin


• Telithromycin


• Tetrabenazine


• Toloxatone


• Toremifene


• Tramadol


• Trazodone


• Trifluoperazine


• Trimethoprim


• Trimipramine


• Vandetanib


• Vardenafil


• Vasopressin


• Vemurafenib


• Venlafaxine


• Voriconazole


• Ziprasidone


• Zolmitriptan


• Zotepine

Using amoxapine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol


• Arbutamine


• Atomoxetine


• Cannabis


• Carbamazepine


• Dicumarol


• Paroxetine


• Phenprocoumon


• S-Adenosylmethionine

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using amoxapine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use amoxapine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

The presence of other medical problems may affect the use of amoxapine. Make sure you tell your doctor if you have any other medical problems, especially:

• Bipolar disorder (mood disorder with alternating episodes of mania and depression), or risk of or


• Heart attack, recent—Should not be used in patients with these conditions.

• Glaucoma, history of or


• Heart disease or


• Schizophrenia or


• Seizures, history of or


• Urinary retention (trouble urinating), history of—Use with caution. May make these conditions worse.

Proper Use of amoxapine

Take amoxapine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

amoxapine should come with a medication guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of amoxapine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of amoxapine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  
  • For depression:
    
    • Adults—At first, 50 milligrams (mg) two or three times per day. Your doctor may increase your dose as needed. However, the dose is usually not more than 300 mg per day unless you are in a hospital. Some hospitalized patients may need higher doses. If you are taking amoxapine once a day, it is best to take it at bedtime.
    
    
    • Older Adults—At first, 25 milligrams (mg) two or three times per day. Your doctor may increase your dose as needed. However, the dose is usually not more than 300 mg per day unless you are in a hospital. Some hospitalized patients may need higher doses. If you are taking amoxapine once a day, it is best to take it at bedtime.
    
    
    • Children—Use and dose must be determined by your doctor.
    
    
  
  

Missed Dose

If you miss a dose of amoxapine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Precautions While Using amoxapine

It is very important that your doctor check your progress at regular visits to allow for changes in your dose and to check for any unwanted effects.

Amoxapine may cause some people to be agitated, irritable, or display other abnormal behaviors. It may also cause some people to have suicidal thoughts and tendencies or to become more depressed. If you, your child, or your caregiver notice any of these side effects, tell your doctor or your child's doctor right away.

Do not take amoxapine if you have taken a monoamine oxidase (MAO) inhibitor (isocarboxazid [Marplan®], phenelzine [Nardil®], selegiline [Eldepryl®, or tranylcypromine [Parnate®]) in the past two weeks. Do not start taking a MAO inhibitor within two weeks of stopping amoxapine. If you do, you may develop confusion, agitation, restlessness, stomach or intestinal symptoms, sudden high body temperature, extremely high blood pressure, or severe convulsions.

amoxapine may cause tardive dyskinesia (a movement disorder). Check with your doctor right away if you have any of the following symptoms while taking amoxapine: lip smacking or puckering, puffing of the cheeks, rapid or worm-like movements of the tongue, uncontrolled chewing movements, or uncontrolled movements of the arms and legs.

Check with your doctor right away if you are having convulsions (seizures); difficulty with breathing; a fast heartbeat; high fever; high or low blood pressure; increased sweating; loss of bladder control; severe muscle stiffness; unusually pale skin; or tiredness. These could be symptoms of a serious condition called neuroleptic malignant syndrome (NMS).

Do not stop taking amoxapine without first checking with your doctor . Your doctor may want you to gradually reduce the amount you are using before stopping it completely. This may help prevent a possible worsening of your condition and reduce the possibility of withdrawal symptoms such as headache, nausea, or a general feeling of discomfort or illness.

amoxapine will add to the effects of alcohol and other central nervous system (CNS) depressants (medicines that cause drowsiness). Some examples of CNS depressants are antihistamines or medicine for hay fever, other allergies or colds; sedatives, tranquilizers, or sleeping medicines; prescription pain medicine or narcotics; barbiturates; medicine for seizures; muscle relaxants; or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are using amoxapine.

amoxapine may cause some people to become drowsy or less alert than they are normally. Make sure you know how you react to amoxapine before you drive, use machines, or do anything else that could be dangerous if you are drowsy or not alert.

amoxapine Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common

• Excitement


• fast, irregular, pounding, or racing heartbeat or pulse


• fear or nervousness


• mood or mental changes


• nightmares


• restlessness


• shakiness and unsteady walk


• shakiness in legs, arms, hands, or feet


• sleeplessness


• swelling


• trouble sleeping


• unable to sleep


• unsteadiness, trembling, or other problems with muscle control or coordination

Rare

• Abdominal or stomach pain


• actions that are out of control


• black, tarry stools


• bleeding gums


• bloating


• blood in urine or stools


• blurred vision


• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings


• chest pain or discomfort


• chills


• clay-colored stools


• confusion


• confusion about identity, place, and time


• constipation


• continuing ringing or buzzing or other unexplained noise in ears


• convulsions


• cough or hoarseness


• dark urine


• decrease in frequency of urination


• decrease in urine volume


• difficulty in breathing


• difficulty in passing urine (dribbling)


• difficulty in speaking


• disturbed concentration


• dizziness, faintness, or lightheadedness when getting up from a lying or sitting position suddenly


• double vision


• drooling


• extremely high fever or body temperature


• false beliefs that cannot be changed by facts


• fast, weak heartbeat


• fever with or without chills


• general feeling of tiredness or weakness


• headache


• hearing loss


• high fever


• high or low blood pressure


• hives or welts


• inability to move arms, legs, or facial muscles


• inability to speak


• increased need to urinate


• increased sweating


• indigestion


• irritability


• itching


• lack of coordination


• light-colored stools


• lip smacking or puckering


• loss of appetite


• loss of bladder control


• lower back or side pain


• muscle cramps


• muscle spasm or jerking of all extremities


• muscle trembling, jerking, or stiffness


• nausea and vomiting


• nervousness


• numbness


• pain or discomfort in arms, jaw, back, or neck


• painful or difficult urination


• pains in stomach, side, or abdomen, possibly radiating to the back


• pale, clammy skin


• passing urine more often


• pinpoint red spots on skin


• pounding in the ears


• puffing of cheeks


• rapid or worm-like movements of tongue


• redness of skin


• seeing, hearing, or feeling things that are not there


• severe muscle stiffness


• shortness of breath


• shuffling walk


• skin rash


• slow speech


• sore throat


• sores, ulcers, or white spots on lips or in mouth


• stiffness of limbs


• sudden loss of consciousness


• sweating


• swollen glands


• talking, feeling, and acting with excitement


• testicular swelling


• thirst


• trouble in holding or releasing urine


• twisting movements of body


• uncontrolled chewing movements


• uncontrolled movements, especially of face, neck, and back


• unpleasant breath odor


• unusual bleeding or bruising


• unusually pale skin


• upper right abdominal pain


• vomiting of blood


• yellow eyes and skin

Get emergency help immediately if any of the following symptoms of overdose occur:

Symptoms of overdose

• Change in consciousness


• drowsiness


• epileptic seizure that will not stop


• fatigue


• increased blood pressure


• increased thirst


• loss of consciousness


• swelling of face, fingers, or lower legs


• total body jerking


• troubled breathing


• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Dry mouth

Less common

• Increased appetite


• increased flow of breast milk

Rare

• Agitation


• breast enlargement


• change in taste bad unusual or unpleasant (after)taste


• decreased interest in sexual intercourse


• depression


• excess air or gas in stomach or intestines


• full feeling


• hair loss, thinning of hair


• heartburn


• inability to have or keep an erection


• increased in sexual ability, desire, drive, or performance


• increased interest in sexual intercourse


• increased sensitivity of skin to sunlight


• loss in sexual ability, desire, drive, or performance


• menstrual changes


• nasal stuffiness


• painful ejaculation


• passing gas


• rapid weight gain


• redness or other discoloration of skin


• seizures


• severe sunburn


• stupor


• swollen, painful, or tender lymph glands on side of face or neck


• tearing of the eyes


• unexpected or excess milk flow from breasts

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

See also: amoxapine side effects (in more detail)

The information contained in the Thomson Reuters Micromedex products as delivered by Drugs.com is intended as an educational aid only. It is not intended as medical advice for individual conditions or treatment. It is not a substitute for a medical exam, nor does it replace the need for services provided by medical professionals. Talk to your doctor, nurse or pharmacist before taking any prescription or over the counter drugs (including any herbal medicines or supplements) or following any treatment or regimen. Only your doctor, nurse, or pharmacist can provide you with advice on what is safe and effective for you.

The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.

More amoxapine resources

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

• amoxapine Concise Consumer Information (Cerner Multum)


• Amoxapine Prescribing Information (FDA)


• Amoxapine Professional Patient Advice (Wolters Kluwer)


• Amoxapine MedFacts Consumer Leaflet (Wolters Kluwer)


• Amoxapine Monograph (AHFS DI)

Compare amoxapine with other medications

• Depression

Azelex

Generic Name: azelaic acid topical (AZ eh LAY ik AS id)

Brand Names: Azelex, Finacea, Finacea Plus, Finevin

What is Azelex (azelaic acid topical)?

Azelaic acid is a naturally occurring acid. It helps the skin to renew itself more quickly and therefore reduces pimple and blackhead formation. It also helps to kill the bacteria that cause acne and rosacea.

Azelaic acid topical (for the skin) is used to treat acne and rosacea.

Azelaic acid topical may also be used for purposes not listed in this medication guide.

What is the most important information I should know about Azelex (azelaic acid topical)?

You should not use this medication if you are allergic to azelaic acid or propylene glycol. Avoid getting this medication in your eyes, nose, mouth, rectum, or vagina. Do not use on sunburned, windburned, dry, chapped, irritated, or broken skin. Wait until these conditions have healed before using this medication. Do not cover the area after applying azelaic acid. Doing so could cause too much medicine to be absorbed by your body and could be harmful.

It may take up 4 weeks or longer before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 12 weeks of treatment.

If you have excessive burning, dryness, or irritation, ask your doctor about using azelaic acid once daily.

What should I discuss with my healthcare provider before using Azelex (azelaic acid topical)?

You should not use this medication if you are allergic to azelaic acid or propylene glycol. FDA pregnancy category B. Azelaic acid topical is not expected to harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. It is not known whether azelaic acid topical passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How should I use Azelex (azelaic acid topical)?

Use exactly as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Wash your hands before and after applying this medication.

Clean the affected area with a mild soap or a soapless cleansing lotion and pat dry with a soft towel. Apply the medication as directed.

Azelaic acid topical is usually applied twice daily, in the morning and at bedtime. Follow your doctor's instructions.

Do not cover the affected area after applying azelaic acid. Doing so could cause too much medicine to be absorbed by the body and could be harmful.

It may take up 4 weeks or longer before your symptoms improve. Keep using the medication as directed and tell your doctor if your symptoms do not improve after 12 weeks of treatment.

If you have excessive burning, dryness, or irritation, ask your doctor about using azelaic acid once daily.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Apply the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include some of the serious side effects listed in this medication guide.

What should I avoid while using Azelex (azelaic acid topical)?

Avoid getting this medication in your eyes, nose, mouth, rectum, or vagina. If this does happen, rinse with water. Do not use on sunburned, windburned, dry, chapped, irritated, or broken skin. Wait until these conditions have healed before using this medication.

Avoid using other medications on the areas you treat with azelaic acid topical unless you doctor tells you to.

Avoid using skin products that can cause irritation, such as harsh soaps or skin cleansers, or skin products with alcohol, spices, astringents, or lime.

Your doctor may recommend avoiding spicy foods, hot foods or drinks, alcoholic beverages and other foods or beverages that may cause flushing or redness of the skin during treatment with azelaic acid topical.

Do not cover the area after applying azelaic acid. Doing so could cause too much medicine to be absorbed by your body and could be harmful.

Azelex (azelaic acid topical) side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat. Stop using this medication and call your doctor at once if you have a serious side effect such as:

• 
  

  severe burning, stinging, or warmth;

  
  


• 
  

  severe itching or tingling;

  
  


• 
  

  severe redness, dryness, peeling, or other irritation; or

  
  


• 
  

  changes in skin color.

  
  

Less serious side effects are more likely, and you may have none at all.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Azelex (azelaic acid topical)?

It is not likely that other drugs you take orally or inject will have an effect on topically applied azelaic acid. But many drugs can interact with each other. Tell your doctor about all medications you use. This includes prescription, over-the-counter, vitamin, and herbal products. Do not start a new medication without telling your doctor.

More Azelex resources

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

• Azelex Prescribing Information (FDA)


• Azelex Cream MedFacts Consumer Leaflet (Wolters Kluwer)


• Azelex Topical Advanced Consumer (Micromedex) - Includes Dosage Information


• Finacea Gel MedFacts Consumer Leaflet (Wolters Kluwer)


• Finacea Prescribing Information (FDA)


• Finacea Consumer Overview


• Finacea Plus Gel MedFacts Consumer Leaflet (Wolters Kluwer)

Compare Azelex with other medications

• Acne
• Rosacea

Where can I get more information?

• Your pharmacist can provide more information about azelaic acid topical.

See also: Azelex side effects (in more detail)

Alteplase

Class: Thrombolytic Agents
Brands: Activase, Cathflo Activase

Introduction

Thrombolytic agent;^{1 2 46} biosynthetic (recombinant DNA origin) form of human tissue-type plasminogen activator (t-PA).^{4 5 8 11 12 13 14 15 19 21 31 35 36 46 62 67}

Uses for Alteplase

Coronary Artery Thrombosis and MI

Management of selected cases of acute evolving transmural MI,^{1 2 34 37 38 41 42 43 46 47 48 65 75 80 83 141 193 352 353} with heparin and/or platelet-aggregation inhibitors (e.g., aspirin, clopidogrel, GP IIb/IIIa-receptor inhibitors) as adjunctive therapy.^{1 2 14 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 50 57 59 65 68 69 72 75 78 79 80 83 84 85 117 141 154 155 163 168 193 327 352 353 360} Lysis of coronary artery thrombi associated with acute evolving transmural MI^{1 2 14 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 50 57 59 65 68 69 72 75 78 79 80 83 84 85 117 141 154 155 163 168 193} and the resulting reperfusion can limit infarct size,^{1 48 193} improve ventricular function,^{1 2 4 38 42 46 47 48 50 69 193 353} and reduce the incidence of CHF^{1 2 38} and associated post-MI mortality.^{1 42 46 193 194 226}

Greater benefit in patients with an anterior MI, left bundle branch block, a history of diabetes mellitus, prior MI, hypotension (SBP <100 mm Hg), or tachycardia (>100 bpm).^{47 48 242 311 352}

Clinical benefit diminishes as the time period from symptom onset to initiation of therapy increases.^{42 51 52 67 68 193 205 309 311 319} If possible, administer thrombolytic therapy within 30 minutes of hospital admission or first contact with the health-care system.^{327 352 353 360}

Use of alteplase or tenecteplase rather than streptokinase (no longer commercially available in US) recommended by the American College of Chest Physicians (ACCP) in patients with acute MI who can be treated within 6 hours of symptom onset.^{326 353}

Delayed therapy (e.g., initiated within 7–24 hours) may benefit patients with persisting ischemic pain and ST-segment elevation or left bundle branch block.^{310 311 353}

Not routinely recommended for patients presenting 12–24 hours after onset of MI symptoms.^{310 319}

ACCP, ACC, and AHA currently recommend consideration of either thrombolytic therapy or urgent angiography and PCI for the reduction of mortality in patients with an acute evolving MI.^{310 311 327 352 360}

ACCP suggests thrombolytic therapy in high-risk patients with ischemic symptoms characteristic of an acute MI or hemodynamic compromise present for 12–24 hours who have persistent ST-segment elevation or left bundle-branch block with concomitant ST-segment elevation changes if primary PCI is not readily available.³⁵³ ACC and AHA state that thrombolytic therapy is reasonable within 12–24 hours of symptom onset in patients with persistent ischemic symptoms accompanied by ST-segment elevation, provided no contraindications exist.^{352 360}

Thrombolytic therapy may be reasonable in patients with true posterior MI presenting within 12 hours after onset of symptoms, provided no contraindications exist.^{352 353 360}

ACCP recommends against use of thrombolytic therapy with or without a GPIIb/IIIa inhibitor in patients undergoing primary PCI for acute ST-segment elevation MI.³⁵³

PE

Lysis of acute pulmonary emboli involving obstruction of blood flow to a lobe or multiple segments of the lungs^{1 15 46 86 87 88 89 90 91 92 93 269 270 271 272 273 274 275 276 355}

Lysis of acute pulmonary emboli accompanied by unstable hemodynamics (i.e., when BP cannot be maintained without supportive measures).^{1 15 46 86 87 88 89 90 91 92 93 269 270 271 272 273 274 275 276 314 355}

Generally reserve IV thrombolytic therapy for those with acute massive PE accompanied by unstable hemodynamics (e.g., shock) who do not have major contraindications because of bleeding risk or those with stable hemodynamics with other poor prognostic factors (e.g., marked dyspnea, anxiety, and low oxygen saturation; elevated troponin concentrations indicating right ventricular microinfarction; echocardiographic evidence of right ventricular dysfunction, right ventricular enlargement on a chest computed-tomography [CT] scan).³⁵⁵

Perform a rapid risk assessment to determine if thrombolytic therapy is appropriate; irreversible cardiogenic shock may occur if therapy is delayed in patients with evidence of hemodynamic compromise.³⁵⁵

Acute Ischemic Stroke

Management of acute ischemic stroke to improve neurologic recovery and reduce the incidence of disability.^{1 2 3 4 5 6 315 322 354 357 358 360 378 379 387 388 389 390 391 392 393 394 395 396 397}

Should be initiated within 3–4.5 hours following the onset of symptoms of acute ischemic stroke and only after intracranial hemorrhage has been excluded by cranial CT scan or other diagnostic imaging method sensitive for the presence of hemorrhage.^{1 315 322 354 357 358 360 392 394 395 396} However, because benefit from thrombolytic therapy decreases substantially with time, such therapy should be administered as soon as possible following onset of stroke symptoms to obtain optimal benefit; experts recommend a “door-to-needle” time (i.e., from arrival at the treating facility until injection of alteplase) of no more than 1 hour.^{387 388 389 390 392 393 396 398}

Safety of alteplase treatment administered more than 4.5 hours after symptom onset, in dosages higher than 0.9 mg/kg and without careful blood-pressure management, not established;^{1 2 315 322 354 357 394 395} some data³⁸⁹ suggest increased mortality with alteplase administration more than 4.5 hours following onset of stroke symptoms.^{389 390}

Use of thrombolytic therapy not recommended by American Stroke Association (ASA) and other authorities in patients with major early ischemic changes on baseline CT scan (defined as clearly identifiable hypodensity involving more than one-third of the middle cerebral artery territory).^{354 358 360}

Use of thrombolytic therapy not recommended in patients with minor neurologic deficit or with rapidly improving symptoms.^{1 315 354 360}

Occluded IV Catheters

Restoration of patency to central venous catheters obstructed by a thrombus (assessed by the ability to withdraw blood).^{325 359}

Consider causes of catheter dysfunction other than thrombus formation (e.g., catheter malposition, mechanical failure, constriction by a suture, lipid deposits, drug precipitates) before use.³²⁵

Arterial Thrombosis and Embolism

Intra-arterial thrombolytic therapy for lysis of arterial occlusions† in peripheral vessels and bypass grafts^{94 95 96 97 98 318 356} in patients with acute (<14 days old) thromboembolic arterial ischemia.^{318 356} Such patients should have a low risk for the development of myonecrosis and ischemic nerve damage in the affected extremity during therapy.^{318 356}

Alteplase Dosage and Administration

General

• 
  

  Institute therapy as soon as possible after an acute MI^{1 2 14 31 32 33 34 35 36 37 38 39 40 41 42 43 46 47 48 352} (preferably within 3–6 hours).^{4 14 222 309 352 310 311} (See Coronary Artery Thrombosis and MI under Uses.)

  
  


• 
  

  Initiate therapy for acute ischemic stroke within 3–4.5 hours of symptom onset.^{1 315 322 354 357 358 392 394 395 396} Prior to administration, exclude intracranial hemorrhage by cranial CT scan or other sensitive diagnostic imaging method.^{1 315 322 354} May initiate therapy prior to the availability of coagulation results in patients without recent anticoagulant therapy (e.g., oral anticoagulants, heparin).¹ Discontinue infusion if pretreatment coagulation results are abnormal (e.g., INR >1.7, PT >15 seconds, elevated aPTT).¹

  
  

Administration

Administer by IV infusion, preferably via a controlled-infusion device² using separate IV tubing (Activase).^{1 2}

Administer by intracatheter instillation into occluded central venous catheters (Cathflo Activase).^{1 2 325}

Also has been administered by intracoronary† injection,^{30 221} selective intra-arterial† infusion,^{89 90 102 103 104 354} and intraocularly† via intracameral injection¹⁰⁴ in a limited number of patients.

IV Administration

For solution and drug compatibility information, see Stability: Compatibility.

For coronary artery thrombosis and MI, administer by IV infusion over 3 hours or as an “accelerated” infusion over 1.5 hours.^{1 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 47 48 50 57 75 84 85 117 141 154 155 163 188 193 210} An accelerated infusion regimen generally is recommended by ACCP, ACC, and AHA.^{310 311 353}

Reconstitution

Reconstitute vial containing 50 mg of alteplase by adding 50 mL of sterile water for injection without preservatives to provide a concentration of 1 mg/mL.¹ Use a large-bore (e.g., 18-gauge) needle and direct diluent into the lyophilized cake of powder.^{1 2} Do not use diluents other than sterile water for injection without preservatives.^{1 2}

Reconstitute vial containing 100 mg of alteplase with 100 mL of sterile water for injection without preservatives using supplied transfer device to provide a concentration of 1 mg/mL.¹

Slight foaming is not unusual during reconstitution.¹ Leave vial undisturbed for several minutes after addition of the diluent to allow dissipation of any large bubbles.¹

Dilution

Administer as reconstituted (1 mg/mL) or dilute further just prior to administration to a concentration of approximately 0.5 mg/mL using 0.9% sodium chloride injection or 5% dextrose injection.^{1 2} More dilute solutions should not be used; drug may precipitate at concentrations of <0.5 mg/mL.²²¹ Do not use other infusion solutions (e.g., sterile water for injection without preservatives, preservative-containing solutions).^{1 2} Mix solution with gentle swirling and/or slow inversion of the infusion container; avoid excessive agitation.^{1 2}

Use reconstituted or diluted solutions within 8 hours.¹ Discard any unused solutions.¹

Administration into Occluded Central Venous Catheters

For clearing occluded central venous catheters, administer into occluded catheter.³²⁵

Reconstitution

Reconstitute solution for IV catheter clearance with 2.2 mL of sterile water for injection according to the manufacturer’s directions to provide a solution containing 1 mg/mL.³²⁵ Do not use bacteriostatic water for injection as a diluent.³²⁵

Slight foaming is not unusual during reconstitution.³²⁵ Leave vial undisturbed for several minutes after addition of diluent to allow dissipation of large bubbles.³²⁵

Dosage

Expressed in mg, but also may be expressed in international units (IU); each mg is equivalent to 580,000 units.^{1 2}

Pediatric Patients

Occluded Central Venous IV Catheters

Intracatheter injection

Patients weighing <30 kg: 110% of the lumen volume of the catheter, with dosage not >2 mg (2 mL).³²⁵ Assess catheter function after at least 30 minutes by attempting to aspirate blood.³²⁵ If necessary, repeat aspiration attempt after 120 minutes of dwell time.³²⁵ Administer a second injection (110% of lumen volume, not >2 mg [2 mL]) in resistant cases;³²⁵ ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.³⁵⁹ When patency is restored, aspirate 4–5 mL of blood in patients weighing ≥10 kg or 3 mL of blood in patients weighing <10 kg to remove all drug and clot residual.³²⁵ Irrigate catheter gently with 0.9% sodium chloride injection.³²⁵ If catheter patency not successfully established after 2 doses of alteplase, further evaluation required to determine cause of the occlusion.³⁵⁹

Patients weighing ≥30 kg: 2 mg (2 mL) into occluded catheter.³²⁵ Assess catheter function after at least 30 minutes by attempting to aspirate blood.³²⁵ If necessary, repeat aspiration attempt after 120 minutes of dwell time.³²⁵ Administer a second 2-mg injection (for a total of 4 mg) in resistant cases;³²⁵ ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.³⁵⁹ When patency is restored, aspirate 4–5 mL of blood to remove all drug and clot residual.³²⁵ Irrigate catheter gently with 0.9% sodium chloride injection.³²⁵ If catheter patency not successfully established after 2 doses of alteplase, further evaluation required to determine cause of the occlusion.³⁵⁹

Adults

Coronary Artery Thrombosis and MI

3-Hour Infusion

IV

Infuse total of 100 mg (58 million IU) over 3 hours.^{1 2} Initially, infuse 60 mg (34.8 million IU) during the first hour;^{1 2} 6–10 mg of this dose is rapidly infused over 1–2 minutes.^{1 2} Subsequently, infuse 20 mg (11.6 million IU) per hour for the next 2 hours.^{1 2}

In adults weighing <65 kg (lean or actual body weight, whichever is less), infuse 1.25 mg/kg over 3 hours.^{1 221} Initially, 0.75 mg/kg during the first hour; 0.045–0.075 mg/kg of this dose is rapidly infused over 1–2 minutes.^{199 221} Subsequently, infuse 0.25 mg/kg per hour for the next 2 hours.^{199 221}

Accelerated Infusion

IV

In adults weighing >67 kg, initially, infuse total dose of 100 mg.^{1 7 352} Initially, inject 15 mg rapidly over 1–2 minutes,^{1 7 352} followed by 50 mg over the next 30 minutes, then 35 mg over the next hour.^{1 352}

Alternatively, in patients weighing ≤67 kg, inject 15 mg rapidly over 1–2 minutes,^{1 7 352} followed by 0.75 mg/kg (up to 50 mg) over the next 30 minutes, then 0.5 mg/kg (up to 35 mg) over the next hour.^{1 352}

PE

IV

100 mg (58 million IU) infused over 2 hours.^{1 91 271 273 355} Prior to administration of thrombolytic therapy, administer IV unfractionated heparin in full treatment dosages; may continue or temporarily interrupt heparin therapy during alteplase infusion.³⁵⁵ Institute or reinstitute heparin therapy near the end of or immediately following alteplase infusion when aPTT or thrombin time returns to twice the normal value or less.^{1 355}

Acute Ischemic Stroke

IV

0.9 mg/kg (up to 90 mg) infused over 1 hour.^{1 354 357} Initially, administer 10% of the dose rapidly over 1 minute.¹ Do not exceed dose of 0.9 mg/kg (maximum 90 mg).¹

Occluded Central Venous IV Catheters

Intracatheter injection

2 mg (2 mL) into occluded catheter in patients weighing ≥30 kg; allow to dwell for at least 30 minutes.³²⁵ Assess catheter function after 30 minutes by attempting to aspirate blood.³²⁵ If necessary, repeat aspiration attempt after 120 minutes of dwell time.³²⁵ Administer a second 2-mg injection (for a total of 4 mg) in resistant cases;³²⁵ ACCP suggests a second dose of alteplase after 30 minutes of dwell time if the catheter remains occluded.³⁵⁹

When patency is restored, aspirate 4–5 mL of blood to remove all drug and clot residual.³²⁵ Irrigate catheter gently with 0.9% sodium chloride injection.³²⁵

If catheter patency is not successfully established after 2 doses of alteplase, further evaluation required to determine cause of the occlusion.³⁵⁹

Arterial Thrombosis and Embolism†

Intra-arterial†

0.05–0.1 mg/kg per hour for 1–8 hours for lysis of arterial occlusion† in a peripheral vessel or bypass graft.^{94 95 96 97} Even lower dosages (e.g., 0.02 mg/kg per hour over 1–7 hours) may be effective.²¹¹

Prescribing Limits

Pediatric Patients

Occluded Central Venous IV Catheters

Intracatheter Injection

Maximum 2 mg per each attempt at clearing an occluded catheter, for a total dosage of 4 mg (2 courses).³²⁵

Adults

Coronary Artery Thrombosis and MI

IV

Maximum 100 mg.¹ 150 mg dose not recommended because of possible increased incidence of intracranial bleeding.¹

Acute Ischemic Stroke

IV

Maximum 0.9 mg/kg (up to 90 mg) total dose.¹

Occluded Central Venous IV Catheters

Intracatheter Injection

Maximum 2 mg per each attempt at clearing an occluded catheter, for a total dosage of 4 mg (2 courses).³²⁵

Cautions for Alteplase

Contraindications

• Acute MI or PE


• 
  

  Active internal bleeding.^{1 2 310 311 352 353}

  
  


• 
  

  History of cerebrovascular accident or intracranial hemorrhage.^{1 2 310 311 352 353}

  
  


• 
  

  Intracranial neoplasm.^{1 2 310 311 352 353}

  
  


• 
  

  Aneurysm.^{1 2 310 311 352 353}

  
  


• 
  

  Recent intracranial or intraspinal surgery or trauma.^{1 2 310 311 352 353}

  
  


• 
  

  Known bleeding diathesis.^{1 2 154 310 311 352}

  
  


• 
  

  Arteriovenous malformation.^{1 2 154 310 311 352}

  
  


• 
  

  Severe uncontrolled hypertension.^{1 2 154 310 311 352}

  
  


• 
  

  Suspected aortic dissection.^{1 2 154 310 311 352}

  
  

• Acute Ischemic Stroke


• 
  

  Evidence of active internal bleeding, intracranial hemorrhage on pretreatment evaluation, suspicion of subarachnoid hemorrhage, history of intracranial hemorrhage, or recent (within 3 weeks) GI or urinary tract hemorrhage.^{1 315 322 354 358 360}

  
  


• 
  

  Known bleeding diathesis.^{1 315 322 354 358 360}

  
  


• 
  

  Recent (within 3 months) intracranial or intraspinal surgery, serious head trauma, or recent previous stroke.^{1 315 322 354 358 360}

  
  


• 
  

  Uncontrolled hypertension at time of treatment (e.g., SBP or DBP>185 or 110 mm Hg, respectively) or hypertension requiring aggressive treatment.^{1 315 322 354 358 360}

  
  


• 
  

  Arteriovenous malformation or aneurysm.^{1 315 322 354 358 360}

  
  


• 
  

  Seizure at onset of stroke.^{1 315 322 354 358 360}

  
  


• 
  

  Intracranial neoplasm.^{1 315 322 354 358 360}

  
  

Warnings/Precautions

Warnings

Effects on Hemostasis

Routine monitoring of hemostatic indices (e.g., fibrinogen concentrations, thrombin times) generally not recommended during therapy for acute MI.^{15 221 222} However, such monitoring is recommended for patients who exhibit bleeding.²²²

Possible bleeding and hemorrhagic complications,^{1 14 43 44 62 145 146 154 155 156} including intracranial hemorrhage and other major bleeding complications.^{141 222 319} May be more common in geriatric patients,^{62 154 156 319} patients with low body weight,³¹⁹ and those with a history of cerebrovascular accident or severe or poorly controlled hypertension.^{141 222 319}

Weigh increased risks of therapy against anticipated benefits in patients with recent major surgery (e.g., coronary artery bypass), cerebrovascular disease, obstetric delivery, organ biopsy, previous puncture of noncompressible vessels, hypertension (SBP ≥175 mm Hg and/or DBP ≥110 mm Hg);^{1 2 310 311 315 319 322} high likelihood of hemostatic defects (e.g., secondary to severe hepatic or renal disease), internal (e.g., GI or GU) bleeding, or recent (within 2–4 weeks) trauma.^{1 2 222 310 311 315} Also, weigh risks against benefits of therapy in patients with diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions.^{1 2 310 311} Weigh risks against benefits in patients receiving concurrent oral anticoagulant therapy (e.g., warfarin).^{1 2 310 311} Weigh risks against benefits in patients with any condition in which bleeding constitutes a substantial hazard or would be particularly difficult to manage because of its location.^{1 2 310 311}

Initiate therapy only after careful screening for contraindications (e.g., previous neurologic events, severe hypertension, and potential bleeding sites).^{142 244}

Minimize risk of bleeding by carefully selecting patients and monitoring all potential bleeding sites (e.g., sites of all venous cutdowns, arterial and venous punctures, needle punctures).^{1 14 15 44 46 154} Avoid IM injections and nonessential handling of patient.^{1 46} Perform invasive venous procedures carefully and as infrequently as possible.^{1 46} If bleeding from the site of an invasive procedure or other trauma is not serious, continue therapy and closely observe the patient;^{221 222} initiate local measures (e.g., application of pressure) immediately.¹ Avoid arterial and venous invasive procedures in areas inaccessible to manual compression (e.g., internal jugular or subclavian punctures) before and during therapy.^{1 221 222 354} Use of an artery in an upper extremity (e.g., radial or brachial) is preferable if arterial puncture is essential.^{1 46 222} Apply pressure to the puncture site for ≥30 minutes, followed by a pressure dressing and frequent inspection of the puncture site for bleeding.^{1 155}

Possible severe and fatal spontaneous bleeding (e.g., cerebral,^{1 34 37 42 43 47 48} retroperitoneal,^{1 37 44 47} GU,^{1 31 41 44 47} respiratory tract,¹ GI bleeding).^{1 33 36 39 41 43 44 47 48 154} Less severe spontaneous bleeding (e.g., superficial hematoma or ecchymoses,^{1 40 41 48} hematuria,^{41 43} hemoptysis,^{41 43} epistaxis,¹ and gingival bleeding)^{1 41 43} also may occur.^{40 41}

If serious spontaneous bleeding occurs, immediately discontinue alteplase therapy^{1 14} and initiate appropriate hemostatic therapy as needed.^{14 15 221 222} If serious bleeding at a critical location (e.g., intracranial, GI, retroperitoneal, pericardial) occurs with intracatheter instillation of alteplase, discontinue therapy immediately and withdraw the drug from the catheter.³²⁵

Extravasation during IV infusion may cause ecchymosis and/or inflammation.¹ Terminate infusion at that IV site and apply local therapy.¹

Cardiovascular Effects

Possible fatal cardiogenic shock, heart failure, myocardial rupture, electromechanical dissociation, pericardial effusion, pericarditis, mitral regurgitation, cardiac tamponade, hypotension, pulmonary edema, thromboembolism, or recurrent thromboembolic events.¹

Weigh risks against anticipated benefits of therapy in patients with a high likelihood of left heart thrombus (e.g., mitral stenosis with atrial fibrillation, profound left ventricular dyskinesia),^{1 2 196} acute pericarditis,^{1 2 198} subacute bacterial endocarditis, septic thrombophlebitis, or an occluded arteriovenous cannula at a seriously infected site.^{1 2 222 310 311 315}

Possible coronary artery reocclusion.^{4 14 31 34 35 37 39 40 41 60 74 208} Reocclusion rate greater with standard than with accelerated infusion.³¹⁶ Reduce incidence of reocclusion through concomitant anticoagulation (e.g., heparin and/or oral anticoagulants)^{1 2 30 31 32 33 34 35}