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CLINICAL PHARMACOLOGY TROBICIN Sterile Powder is rapidly absorbed after intramuscular injection. A single, two-gram injection produces peak serum concentrations averaging about 100 mcg/mL at one hour; a single, four-gram injection produces peak serum concentrations averaging 160 mcg/mL at two hours. Average serum concentrations of 15 mcg/mL for the two-gram dose and 31 mcg/mL for the four-gram dose were present eight hours after dosing. Microbiology Spectinomycin hydrochloride is an inhibitor of protein synthesis in the bacterial cell; the site of action is the 30S ribosomal subunit. Definitive in vitro studies have shown no cross-resistance of N. gonorrhoeae between spectinomycin hydrochloride and penicillin. The antibiotic is not significantly bound to plasma protein. The in vitro susceptibility of Neisseria gonorrhoeae to spectinomycin hydrochloride can be tested by dilution and diffusion techniques. Dilution Techniques Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (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 dilution method1,2 (broth, agar, or microdilution) or equivalent using standardized inoculum and concentrations of spectinomycin. The MIC values should be interpreted according to the criteria in Table 1. 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 procedure2,3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 100 µg of spectinomycin to test the susceptibility of N. gonorrhoeae to spectinomycin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for spectinomycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 100 µg spectinomycin disk should be interpreted according to the following criteria in Table 1. Table 1: Interpretive Criteria for Spectinomycin vs. Neisseria sonorrhoeae MIC (mcg/mL) Disk diffusion (zone diameter mm) S I* R S I* R ≤32 64 ≥128 ≥18 15-17 ≤14 *The clinical effectiveness of spectinomycin for treating organisms that produce intermediate results is unknown. Quality Control Standardized susceptibility test procedures require the use of laboratory control microorganisms to monitor and ensure the accuracy and precision of the supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard spectinomycin powder should provide MIC values as given below. For the diffusion technique, the 100 jag spectinomycin disk should provide the following zone diameters with the quality control strains: Table 2: In Vitro Susceptibility Test Quality Control Ranges for Spectinomycin Organism MIC range mcg/mL Disk Diffusion range (mm) N. gonorrhoeae ATCC® 49226 8-32 23-29 ATCC = American Type Culture Collection REFERENCE 1. Clinical and Laboratory Standards Institute. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - 8th ed. CLSI document M07-A8. (ISBN 1-56238-689-1). CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087-1898 USA. 2009. 2. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing; 21st Informational Supplement. CLSI document M100-S21. (ISBN 1-56238-742-1). CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087-1898 USA. 2011 3. Clinical and Laboratory Standards Institute. Performance Standards for Antimicrobial Disk Susceptibility Tests; Approved Standard - 10fh ed. CLSI document M02-A10. (ISBN 1-56238-688-3). CLSI, 940 West Valley Road, Suite 1400, Wayne, PA, 19087-1898 USA. 2009.

Trobicin™ (spectinomycin) For Injectable Suspension, USP To reduce the development of drug-resistant bacteria and maintain the effectiveness of TROBICIN Sterile Powder and other antibacterial drugs, TROBICIN Sterile Powder should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. For intramuscular Injection DESCRIPTION TROBICIN Sterile Powder contains spectinomycin hydrochloride which is an aminocyclitol antibiotic produced by a species of soil microorganism designated as Streptomyces spectabilis. Sterile spectinomycin hydrochloride is the pentahydrated dihydrochloride salt of spectinomycin. The structural formula is represented below: Spectinomycin hydrochloride is isolated as a white to pale buff crystalline dihydrochloride pentahydrate powder, molecular weight 495, and is stable in the dry state for 36 months.

INDICATIONS TROBICIN Sterile Powder is indicated in the treatment of acute gonorrheal urethritis and proctitis in the male and acute gonorrheal cervicitis and proctitis in the female when due to susceptible strains of Neisseria gonorrhoeae. Men and women with known recent exposure to gonorrhea should be treated as those known to have gonorrhea. To reduce the development of drug-resistant bacteria and maintain the effectiveness of TROBICIN Sterile Powder and other antibacterial drugs, TROBICIN Sterile Powder 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. DOSAGE AND ADMINISTRATION Preparation of Drug for Intramuscular Injection TROBICIN Sterile Powder, 2 grams: reconstitute with 3.2 mL of Sterile Water for Injection, USP . Shake vials vigorously immediately after adding Sterile Water for Injection, USP and before withdrawing dose. It is recommended that disposable syringes and needles be used. A 20-gaugc needle is recommended. Dosage Intramuscular injections should be made deep into the upper outer quadrant of the gluteal muscle. Adults (Men and Women) Inject 5 mL intramuscularly for a 2-gram dose. This is also the recommended dose for patients being treated after failure of previous antibiotic therapy. In geographic areas where antibiotic resistance is known to be prevalent, initial treatment with 4 grams (10 mL) intramuscularly is preferred. The 10-mL injection may be divided between two gluteal injection sites. Storage Conditions Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F) [see USP]. Store prepared suspension at controlled room temperature 20° to 25°C (68° to 77°F) and use within 24 hours. HOW SUPPLIED TROBICIN Sterile Powder is available as: TROBICIN Sterile Powder, 2-gram vial NDC 0069-8558-22. When reconstituted with 3.2 mL of Sterile Water for Injection, USP , each vial yields a sufficient quantity for withdrawal of 5 mL of a suspension containing 400 mg spectinomycin per mL (as the hydrochloride). Five mL provides 2 grams spectinomycin. For intramuscular use only. TROBICIN Susceptibility Powder - 100 mg. See package insert for in vitro testing procedure. Distributed by: Pharmacia & Upjohn Co. Division of Pfizer Inc NY, NY, 10017. Revised: August 2012

PATIENT INFORMATION Patients should be counseled that antibacterial drugs including TROBICIN Sterile Powder should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When TROBICIN Sterile Powder is 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 TROBICIN Sterile Powder or other antibacterial drugs in the future.

OVERDOSE Information on overdosage in humans is not available. Hemodialysis has been reported to aid in the removal of intravenously administered spectinomycin from the body. Kusumi R, Metzler C, Pass R; Pharmacokinetics of Spectinomycin in Volunteers with Renal Insufficiency, Chemotherapy, 27:95-98 (1981). CONTRAINDICATIONS The use of TROBICIN Sterile Powder is contraindicated in patients previously found hypersensitive to it.

SIDE EFFECTS The following reactions were observed during the single dose clinical trials: soreness at the injection site, urticaria, dizziness, nausea, chills, fever and insomnia. During multiple dose subchronic tolerance studies in normal human volunteers, the following were noted: a decrease in hemoglobin, hematocrit and creatinine clearance; elevation of alkaline phosphatase, BUN and SGPT. In single and multiple dose studies in normal volunteers, a reduction in urine output was noted. Extensive renal function studies demonstrated no consistent changes indicative of renal toxicity. A few cases of anaphylaxis or anaphylactoid reactions have been reported. If serious allergic reactions occur, the usual agents (epinephrine, corticosteroids, and/or antihistamines) should be available for emergency use. In cases of severe anaphylaxis, airway support and oxygen may also be required. DRUG INTERACTIONS No information provided.

WARNINGS Spectinomycin hydrochloride is not effective in the treatment of syphilis. Antibiotics used in high doses for short periods of time to treat gonorrhea may mask or delay the symptoms of incubating syphilis. Since the treatment of syphilis demands prolonged therapy with any effective antibiotic, patients being treated for gonorrhea should be closely observed clinically. All patients with gonorrhea should have a serologic test for syphilis at the time of diagnosis. Patients treated with Spectinomycin hydrochloride should have a follow-up serologic test for syphilis after three months. PRECAUTIONS The usual precautions should be observed with atopic individuals. The clinical effectiveness of TROBICIN Sterile Powder should be monitored to detect evidence of development of resistance by Neisseria gonorrhoeae. Prescribing TROBICIN Sterile Powder 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. Carcinogenesis, Mutagenesis, Impairment of Fertility Genotoxicity of spectinomycin hydrochloride was evaluated in six assay test systems including two Ames tests, two micronucleus tests in mice, unscheduled DNA synthesis in rat primary hepatocytes, and a chromosomal aberration test in Chinese hamster ovary cells. Spectinomycin was not shown to be mutagenic or genotoxic in these tests. No adverse effects on fertility or general reproductive performance were observed when spectinomycin was administered subcutaneously to rats at dose levels up to 300 mg/kg (equivalent to the recommended maximum human dose based on mg/m2). A three-generation reproduction study in rats administered spectinomycin hydrochloride orally at dose levels up to 400 mg/kg (equivalent to the recommended maximum human dose based on mg/m2) produced no evidence of drug-induced toxicity during growth, gestation, or lactation periods of any parental generation. Pregnancy rates of the 400 mg/kg/day groups were consistently lower than those of the control groups. A histopathological examination of the testes and ovaries of the third generation animals was normal. Pregnancy Teratogenic Effects - Pregnancy Category B Spectinomycin was not teratogenic or embryocidal when orally or subcutaneously administered to rats at doses of 300 mg/kg/day (equivalent to the recommended maximum human dose based on mg/m2). No teratogenic effects were observed when spectinomycin was administered intraperitoneally to mice or rats at dose levels of 400 or 1600 mg/kg/day, respectively. Spectinomycin was administered intramuscularly or subcutaneously to pregnant rabbits at dose levels up to 300 mg/kg/day (equivalent to the recommended maximum human dose based on mg/m2). Embryonic and fetal development were unaffected by treatment. Since there are no controlled studies of spectinomycin in pregnant women, and because animal reproduction studies are not always predictive of human responses, spectinomycin should be used during pregnancy only if clearly needed. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when spectinomycin is administered to a nursing woman. Pediatric Use Safety and effectiveness in the pediatric population have not been established. (See WARNINGS.)