Tonsillitis and/or Pharyngitis

MOXATAG is a penicillin-class antibacterial indicated for the treatment of tonsillitis and/or pharyngitis secondary to Streptococcus pyogenes (S. pyogenes) in adults and pediatric patients 12 yrs and older.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of MOXATAG and other antibacterial drugs, MOXATAG 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.

Tonsillitis and/or Pharyngitis

The recommended dose of MOXATAG is 775 mg once daily taken within 1 hour of finishing a meal for 10 days. The full 10-day course of therapy should be completed for effective treatment of tonsillitis and/or pharyngitis secondary to S. pyogenes.

Do not chew or crush tablet.

5.1 Anaphylaxis and Hypersensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy. Although anaphylaxis is more frequent following parenteral therapy, it has occurred in patients on oral penicillins. 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 MOXATAG, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens. If an allergic reaction occurs, MOXATAG should be discontinued and 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.

5.2 Clostridium difficile Associated Diarrhea (CDAD)

Clostridium difficile Associated Diarrhea (CDAD) has been reported with nearly all antibacterial agents, including amoxicillin, 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.

5.3 Superinfections

The possibility of superinfections with mycotic or bacterial pathogens should be kept in mind during therapy. If superinfections occur, amoxicillin should be discontinued and appropriate therapy instituted.

5.4 Mononucleosis Rash

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.

5.5 Development of Drug-Resistant Bacteria

Prescribing amoxicillin in the absence of proven or strongly suspected bacterial infection or treating prophylactically is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

5.6 False-Positive Urinary Glucose Tests

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, it is recommended that glucose tests based on enzymatic glucose oxidase reactions (such as Clinistix®) be used.

6.1 Clinical Study Experience

6.2 Adverse Reactions for Other Amoxicillin Products

The following adverse reactions have been reported for other products containing amoxicillin:

Infections and Infestations: Mucocutaneous candidiasis.

Gastrointestinal: Nausea, vomiting, diarrhea, and hemorrhagic/ pseudomembranous colitis.

Onset of pseudomembranous colitis symptoms may occur during or after antibiotic treatment.

Hypersensitivity Reactions: Anaphylaxis (See Warnings and Precautions)

Serum sickness like reactions, erythematous maculopapular rashes, erythema multiforme, Stevens-Johnson Syndrome, exfoliative dermatitis, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, hypersensitivity vasculitis and urticaria have been reported. (NOTE: These hypersensitivity reactions may be controlled with antihistamines and, if necessary, systemic corticosteroids. Whenever such reactions occur, amoxicillin should be discontinued unless, in the opinion of the physician, the condition being treated is life-threatening and amenable only to amoxicillin therapy.)

Liver: A moderate rise in AST (SGOT) and/or ALT (SGPT) has been noted, but the significance of this finding is unknown. Hepatic dysfunction including cholestatic jaundice, hepatic cholestasis and acute cytolytic hepatitis have been reported.

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.

Central Nervous System: Reversible hyperactivity, agitation, anxiety, insomnia, confusion, convulsions, behavioral changes, and/or dizziness have been reported rarely.

Renal: Crystalluria has also been reported

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.

7.1 Probenecid

Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of MOXATAG and probenecid may result in increased and prolonged blood levels of amoxicillin. The clinical relevance of this finding has not been evaluated.

7.2 Other Antibiotics

Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with the bactericidal effects of penicillin. This has been demonstrated in vitro; however, the clinical significance of this interaction is not well documented.

7.3 Oral Contraceptives

As with other antibiotics, amoxicillin may affect the gut flora, leading to lower estrogen reabsorption and potentially resulting in reduced efficacy of combined oral estrogen/progesterone contraceptives.

8.1 Pregnancy

8.2 Labor and Delivery

Oral ampicillin-class antibiotics are poorly absorbed during labor. Studies in guinea pigs showed that intravenous administration of ampicillin slightly decreased the uterine tone and frequency of contractions but moderately increased the height and duration of contractions. However, it is not known whether use of amoxicillin 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.

8.3 Nursing Mothers

Penicillins have been shown to be excreted in human milk. Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman.

8.4 Pediatric Use

The safety and effectiveness of MOXATAG in pediatric patients 12 years of age and older have been established based on results of a clinical trial that included adults and pediatric patients (12 years or older). [see Clinical Studies (14)] Sixty three (21 %) of the study participants were pediatric patients 12 years of age or older. There were no significant differences in treatment response or adverse reactions from adults.

The safety and effectiveness of MOXATAG in pediatric patients younger than 12 years has not been established.

8.5 Geriatric Use

Clinical studies with MOXATAG did not include a sufficient number of patients aged 65 years and over to determine whether they respond differently from younger patients. Other reported clinical experiences with amoxicillin have not yet identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

8.6 Renal Impairment

MOXATAG has not been studied in patients with renal impairment; however, a reduction of amoxicillin dose is generally recommended for patients with severe renal impairment. Therefore, MOXATAG is not recommended for use in patients with severe renal impairment (CrCl <30 mL/min) or patients on hemodialysis.

12.1 Mechanism of Action

Amoxicillin is an antibacterial drug. [see Clinical Pharmacology (12.4)]

12.3 Pharmacokinetics

MOXATAG is an extended-release formulation of amoxicillin intended to provide once-daily dosing. Following the administration of MOXATAG with a low-fat meal in healthy subjects, mean amoxicillin AUC0-∞, Cmax, and Tmax values were 29.8 μg•h/mL, 6.6 μg/mL and 3.1 hours, respectively. The mean plasma concentration-time curve is shown below in Figure 1.

Figure 1. Mean Amoxicillin Plasma Concentrations Following a Single Oral Dose of MOXATAG With a Low-Fat Meal in Healthy Subjects (N=20)

Administration of MOXATAG with food decreases the rate, but not the extent of amoxicillin absorption. Compared to immediate-release amoxicillin suspension, the rate of amoxicillin absorption following administration of MOXATAG was slower, resulting in a lower Cmax and longer Tmax. Total amoxicillin exposure (AUC) achieved with MOXATAG is similar to that observed after oral administration of a comparable dose of immediate-release amoxicillin suspension.

Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. Amoxicillin is approximately 20% protein bound in human serum.

Amoxicillin is primarily cleared by renal excretion. Approximately 60% of an oral dose of immediate-release amoxicillin is eliminated unchanged in urine. The half-life of amoxicillin after oral administration of MOXATAG is approximately 1.5 hours, similar to that of immediate-release amoxicillin. No accumulation of amoxicillin was observed after once-daily dosing of 775 mg of MOXATAG for 7 days.

12.4 Microbiology

Amoxicillin is a semi-synthetic antimicrobial belonging to the penicillin class of antimicrobials with activity against gram-positive bacteria.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate carcinogenic potential. Studies to detect mutagenic potential of amoxicillin alone have not been conducted; however, the following information is available from tests on a 4:1 mixture of amoxicillin and potassium clavulanate (Augmentin). Augmentin was non-mutagenic in the Ames bacterial mutation assay, and the yeast gene conversion assay. Augmentin was weakly positive in the mouse lymphoma assay, but the trend toward increased mutation frequencies in this assay occurred at doses that were also associated with decreased cell survival. Augmentin was negative in the mouse micronucleus test, and in the dominant lethal assay in mice. Potassium clavulanate alone was tested in the Ames bacterial mutation assay and in the mouse micronucleus test, and was negative in each of these assays. In a multi-generation reproduction study in rats, no impairment of fertility or other adverse reproductive effects were seen at doses up to 500 mg/kg (approximately 6 times the human dose in mg/m2).

Storage

Store at 25º C (77º F); excursions permitted to 15–30º C (59–86º F) [See USP Controlled Room Temperature.]

17.1 Instructions for Administration of MOXATAG

Patients should be informed that the recommended dose of MOXATAG is 775 mg once daily taken with food for 10 days. MOXATAG should be taken within 1 hour of finishing a meal and at approximately the same time every day.The full 10 day course of therapy should be completed for effective treatment of tonsillitis and/or pharyngitis secondary to S. pyogenes. Patients should be instructed not to chew or crush the tablet. No other forms of immediate-release amoxicillin can be substituted for MOXATAG.

17.2 Hypersensitivity Reactions

Patients should be informed that serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported while on penicillin therapy. Patients should be questioned regarding any hypersensitivity reactions to penicillins, cephalosporins or other allergens. Whenever such reactions occur, the patient should be instructed to contact their physician immediately. Serious anaphylactic reactions require immediate emergency treatment with epinephrine. Oxygen, intravenous steroids, and airway management, including intubation, should also be administered as indicated.

17.3 Clostridium difficile Associated Diarrhea

Patients should be informed that 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 two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible.

AUGMENTIN is a registered trademark of GlaxoSmithKline.

CLINITEST is a registered trademark of Miles, Inc.

CLINISTIX is a registered trademark of Bayer Corporation.

MOXATAG is a trademark of MiddleBrook Pharmaceuticals, Inc., all rights reserved.

Manufactured in Clonmel, Ireland by Stada Production Ireland for
MiddleBrook Pharmaceuticals, Inc., Germantown, Maryland 20876

U.S. Patents 6,544,555; 6,669,948; 6,723,341

Issue Date 06/08
PC2049L/1
Copyright © 2008, MiddleBrook Pharmaceuticals, Inc. All rights reserved.