Metronidazole Oral

1 INDICATIONS AND USAGE LIKMEZ is a nitroimidazole antimicrobial indicated for Trichomoniasis in adults ( 1.1 ) Amebiasis in adults and pediatric patients ( 1.2 ) Anaerobic Bacterial Infections in adults ( 1.3 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of LIKMEZ and other antibacterial drugs, LIKMEZ should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria ( 1.4 ). 1.1 Trichomoniasis LIKMEZ is indicated for the treatment of: Symptomatic trichomoniasis caused by Trichomonas vaginalis in adult females and males when the diagnosis is confirmed by appropriate laboratory procedures. Asymptomatic trichomoniasis caused by Trichomonas vaginalis in adult females when the organism is associated with endocervicitis, cervicitis, or cervical erosion. Because trichomoniasis is a sexually transmitted disease with potentially serious sequelae, treat sexual partners of patients simultaneously to prevent re-infection. 1.2 Amebiasis LIKMEZ is indicated for the treatment of acute intestinal amebiasis (amoebic dysentery) and amebic liver abscess in adults and pediatric patients. In amebic liver abscess, treatment with LIKMEZ does not obviate the need for aspiration or drainage of pus. 1.3 Anaerobic Bacterial Infections LIKMEZ is indicated in the treatment of the following serious infections caused by susceptible anaerobic bacteria in adults: Intra-abdominal infections, including peritonitis, intra-abdominal abscess, and liver abscess, caused by Bacteroides species including the B. fragilis group ( B. fragilis, B. ovatus, B. thetaiotaomicron, B. vulgatus ), Parabacteroides distasonis, Clostridium species, Eubacterium species, Peptococcus species , and Peptostreptococcus species. Skin and skin structure infections caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species , Peptostreptococcus species, and Fusobacterium species. Gynecologic infections, including endometritis, endomyometritis, tubo-ovarian abscess, and postsurgical vaginal cuff infection, caused by Bacteroides species including the B. fragilis group, Clostridium species, Peptococcus species , Peptostreptococcus species, and Fusobacterium species. Bacterial septicemia caused by Bacteroides species including the B. fragilis group and Clostridium species. Bone and joint infections, (as adjunctive therapy), caused by Bacteroides species including the B. fragilis group. Central nervous system (CNS) infections, including meningitis and brain abscess, caused by Bacteroides species including the B. fragilis group. Lower respiratory tract infections, including pneumonia, empyema, and lung abscess, caused by Bacteroides species including the B. fragilis group. Endocarditis caused by Bacteroides species including the B. fragilis group. Indicated surgical procedures should be performed in conjunction with LIKMEZ therapy. In a mixed aerobic and anaerobic infection, antimicrobials appropriate for the treatment of aerobic infection should be used in addition to LIKMEZ. 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of LIKMEZ and other antibacterial drugs, LIKMEZ 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.

2 DOSAGE AND ADMINISTRATION Trichomoniasis: Adult Female and Male Patients: One-day treatment: 2 g (20 mL) of LIKMEZ, given either as a single oral dose or in 2 divided oral doses of 1 g (10 mL) each, given on the same day. ( 2.1 ) Seven-day course of treatment: 250 mg (2.5 mL) of LIKMEZ given three times daily for 7 consecutive days. ( 2.1 ) Individualize the dosing regimen. ( 2.1 ) Amebiasis: Adult Patients: For acute intestinal amebiasis (acute amebic dysentery): 750 mg (7.5 mL) orally three times daily for 5 days to 10 days. ( 2.2 ) For amebic liver abscess: 500 mg (5 mL) or 750 mg (7.5 mL) orally three times daily for 5 days to 10 days. ( 2.2 ) Pediatric Patients : 35 mg/kg/24 hours to 50 mg/kg/24 hours, divided into three doses, to a maximum dose of 2,250 mg/24 hours (maximum dose 750 mg/dose or 7.5 mL/dose),orally for 10 days. ( 2.2 ) Anaerobic Bacterial Infections: In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. ( 2.3 ) Adult Patients: 7.5 mg/kg every six hours (approx. 500 mg (5 mL) for a 70-kg adult) to a maximum dose of 4 g (40 mL) during a 24-hour period, orally for 7 to 10 days. ( 2.3 ) Infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. ( 2.3 ) Patients with Severe Hepatic Impairment (Child-Pugh C) Reduce the dose of LIKMEZ by 50%. ( 2.4 ) Patients Undergoing Hemodialysis: Consider a supplemental dose of LIKMEZ following the hemodialysis session, depending on the patient’s clinical situation. ( 2.5 ) 2.1 Recommended Dosage for Trichomoniasis Adult Female and Male Patients : One-day Treatment – Administer 2 g (20 mL) of LIKMEZ, either as a single oral dose or in 2 divided oral doses of 1 g (10 mL) each, given on the same day. Seven-day Course of Treatment − Administer 250 mg (2.5 mL) of LIKMEZ orally 3 times daily for 7 consecutive days. The dosage regimen should be individualized. Single-dose treatment may help improve compliance, especially if administered under supervision, in those patients who cannot be relied on to continue the seven-day regimen. A seven-day course of treatment may minimize reinfection by protecting the patient long enough for the sexual contacts to obtain appropriate treatment. There are some data from controlled comparative studies that cure rates as determined by vaginal smears and signs and symptoms, may be higher after a seven-day course of treatment than after a one-day treatment regimen. Further, some patients may tolerate one treatment regimen better than the other. When repeat courses of LIKMEZ are required, it is recommended that an interval of four to six weeks elapse between courses and that the presence of the trichomonad be reconfirmed by appropriate laboratory measures. Total and differential leukocyte counts should be made before and after re-treatment. 2.2 Recommended Dosage for Amebiasis Adult Patients : For acute intestinal amebiasis (acute amebic dysentery): Administer 750 mg (7.5 mL) of LIKMEZ orally three times daily for 5 days to 10 days. For amebic liver abscess: Administer 500 mg (5 mL) or 750 mg (7.5 mL) of LIKMEZ orally three times daily for 5 days to 10 days. Pediatric Patients: Administer 35 mg/kg/24 hours to 50 mg/kg/24 hours of LIKMEZ, divided into three doses, to a maximum dose of 2250 mg/24 hours (maximum dose 750 mg/dose or 7.5 mL/dose), orally for 10 days. 2.3 Recommended Dosage for Anaerobic Bacterial Infections In the treatment of most serious anaerobic infections, intravenous metronidazole is usually administered initially. Adult Patients: Administer 7.5 mg/kg of LIKMEZ orally every six hours (approx. 500 mg (5 mL) for a 70 kg adult) for 7 days to 10 days. Infections of the bone and joint, lower respiratory tract, and endocardium may require longer treatment. Do not exceed a maximum of 4 g (40 mL) during a 24-hour period. 2.4 Recommended Dosage in Patients with Severe Hepatic Impairment For patients with severe hepatic impairment (Child-Pugh C), reduce the dose of LIKMEZ by 50% [ see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ]. 2.5 Recommended Dosage in Patients Undergoing Hemodialysis Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. The clearance of metronidazole will depend on the type of dialysis membrane used, the duration of the dialysis session, and other factors. If the administration of LIKMEZ cannot be separated from the hemodialysis session, consider a supplemental dose of LIKMEZ following the hemodialysis session, depending on the patient’s clinical situation [ see Clinical Pharmacology (12.3) ] . No adjustment in LIKMEZ dose is needed in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) [ see Clinical Pharmacology (12.3) ] . 2.6 Important Administration Instructions Shake the bottle well before administering the recommended dosage. Use a calibrated oral dosing device to correctly measure the prescribed dose of medication. Do not use household teaspoons or tablespoons to measure doses. Calibrated oral dosing devices may be obtained from the pharmacy.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Central and Peripheral Nervous System Effects [ see Warnings and Precautions (5.2) ] Blood Dyscrasias [ see Warnings and Precautions (5.4 )] Common adverse reactions include nausea, headache, anorexia, vomiting, diarrhea, abdominal cramping, epigastric distress, and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Saptalis Pharmaceuticals, LLC at 1-833-727-8254 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following reactions have been reported during treatment with metronidazole: Central and Peripheral Nervous System: The most serious adverse reactions reported in patients treated with metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. Persistent peripheral neuropathy has been reported in some patients receiving prolonged administration of metronidazole. In addition, headache, syncope, dizziness, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia have been reported. Gastrointestinal: The most common adverse reactions reported have been referable to the gastrointestinal tract, particularly nausea, sometimes accompanied by headache, anorexia, and occasionally vomiting; diarrhea; epigastric distress; and abdominal cramping and constipation. Mouth: A sharp, unpleasant metallic taste is not unusual. Furry tongue, glossitis, and stomatitis have occurred; these may be associated with a sudden overgrowth of Candida which may occur during therapy. Dermatologic: Erythematous rash and pruritus. Hematopoietic: Reversible neutropenia (leukopenia); reversible thrombocytopenia. Cardiovascular: QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. Flattening of the T‑wave may be seen in electrocardiographic tracings. Hypersensitivity: Urticaria, erythematous rash, Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing, nasal congestion, dryness of the mouth (or vagina or vulva), and fever. Renal: Dysuria, cystitis, polyuria, incontinence, and a sense of pelvic pressure. Instances of darkened urine have been reported by approximately one patient in 100,000. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Other: Proliferation of Candida in the vagina, dyspareunia, decrease of libido, proctitis, and fleeting joint pains sometimes resembling “serum sickness". Cases of pancreatitis, which generally abated on withdrawal of the drug, have been reported. Patients with Crohn’s disease are known to have an increased incidence of gastrointestinal and certain extraintestinal cancers. There have been some reports in the medical literature of breast and colon cancer in Crohn’s disease patients who have been treated with metronidazole at high doses for extended periods of time. A cause-and-effect relationship has not been established. Crohn’s disease is not an approved indication for LIKMEZ. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of metronidazole. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) [ see Contraindications (4.4) ] .

12.3 Pharmacokinetics Metronidazole pharmacokinetics are similar for both oral and intravenous dosage forms. The C max is dose proportional between 250 mg, 500 mg, and 2,000 mg for metronidazole oral tablets, producing peak plasma concentrations of 6 mcg/mL, 12 mcg/mL, and 40 mcg/mL, respectively. Absorption Following oral administration, LIKMEZ is well absorbed, with peak plasma concentrations occurring between 0.25 and 6 hours after administration. Two pharmacokinetic studies (Study 1 and Study 2) performed in healthy adult volunteers evaluated the bioavailability of LIKMEZ under fasting and fed conditions. Effect of Food Food delays T max and lowers C max when compared to fasted conditions, but systemic exposure (AUC) is similar in fed and fasted state (see Table 1). Table 1: Mean (± S.D.) Pharmacokinetic Parameters Following Single Oral Doses of 500 mg LIKMEZ in Healthy Adults Under Fed and Fasting Conditions Formulation C max (mcg/mL) AUC 0-∞ (mcg.h/mL) Tmax Median (min max) (h) Study 1- Fasting state (n = 44) LIKMEZ 13 ± 3 146 ± 36 0.75 (0.25 to 6) Study 2- Fed State Fed study administered LIKMEZ following a high-fat, high-calorie breakfast (approximately 1,000 calories, 26.5% carbohydrates, 16.5% protein, and 57% fat). (n = 46) LIKMEZ 10 ± 1 144 ± 30 2.33 (0.25 to 4) Distribution Metronidazole is the major component appearing in the plasma, with lesser quantities of metabolites also being present. Less than 20% of the circulating metronidazole is bound to plasma proteins. Metronidazole appears in cerebrospinal fluid, saliva, and breast milk in concentrations similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses. Elimination Metabolism The metabolites of metronidazole that appear in the urine result primarily from side-chain oxidation [1-(-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-ylacetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Both the parent compound and the hydroxyl metabolite possess in vitro antimicrobial activity. Excretion The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. Renal clearance of metronidazole is approximately 10 mL/min/1.73 m 2 . The average elimination half-life of LIKMEZ in healthy adult subjects is nine hours. Specific Populations Geriatric Patients Following a single 500 mg oral or IV dose of metronidazole, subjects >70 years old with no apparent renal or hepatic dysfunction had a 40% to 80% higher mean AUC of hydroxy‑metronidazole (active metabolite), with no apparent increase in the mean AUC of metronidazole (parent compound), compared to young healthy controls <40 years old [ see Use in Specific Populations (8.5) ] . Pediatric Patients In one study, newborn infants appeared to demonstrate diminished capacity to eliminate metronidazole. The elimination half-life, measured during the first 3 days of life, was inversely related to gestational age. In infants whose gestational ages were between 28 weeks and 40 weeks, the corresponding elimination half-lives ranged from 109 hours to 22.5 hours. Male and Female Patients Studies reveal no significant bioavailability differences between males and females; however, because of weight differences, the resulting plasma levels in males are generally lower. Patients with Renal Impairment Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. Subjects with end-stage renal disease (ESRD; CL CR = 8.1±9.1 mL/min) and who received a single intravenous infusion of metronidazole 500 mg had no significant change in metronidazole pharmacokinetics but had 2-fold higher C max of hydroxy-metronidazole and 5‑fold higher C max of metronidazole acetate, compared to healthy subjects with normal renal function (CL CR = 126±16 mL/min). Thus, on account of the potential accumulation of metronidazole metabolites in ESRD patients, monitoring for metronidazole associated adverse reactions are recommended [ see Use in Specific Populations (8.6) ] . Following a single intravenous infusion or oral dose of metronidazole 500 mg, the clearance of metronidazole was investigated in ESRD subjects undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A hemodialysis session lasting for 4 hours to 8 hours removed 40% to 65% of the administered metronidazole dose, depending on the type of dialyzer membrane used and the duration of the dialysis session. If the administration of metronidazole cannot be separated from the dialysis session, supplementation of metronidazole dose following hemodialysis should be considered [ see Dosage and Administration (2.5) ] . A peritoneal dialysis session lasting for 7.5 hours removed approximately 10% of the administered metronidazole dose. No adjustment in metronidazole dose is needed in ESRD patients undergoing CAPD. Patients with Hepatic Impairment Following a single intravenous infusion of 500 mg metronidazole, the mean AUC 24 of metronidazole was higher by 114% in patients with severe (Child-Pugh C) hepatic impairment, and by 54% and 53% in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment, respectively, compared to healthy control subjects. There were no significant changes in the AUC 24 of hydroxyl-metronidazole in these hepatically impaired patients. A reduction in metronidazole dosage by 50% is recommended in patients with severe (Child-Pugh C) hepatic impairment. No dosage adjustment is needed for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be monitored for metronidazole associated adverse reactions [ see Use in Specific Populations (8.7) and Dosage and Administration (2.4) ] .