LIKMEZ

LIKMEZ (metronidazole) oral suspension is a nitroimidazole antimicrobial. The chemical name of metronidazole is 2-methyl-5-nitro-1H-imidazole-1-ethanol. The structural formula is shown as: Metronidazole is a white to pale yellow crystalline powder with a molecular formula of C 6 H 9 N 3 O 3 and a molecular weight of 171.2 g/mole. The pKa of metronidazole is 14.44 ± 0.10. The pH of a 1% aqueous solution of metronidazole is 5.5-7.5. It is slightly soluble in water, acetone, alcohol, and methylene chloride. LIKMEZ is an oral suspension containing 500 mg of metronidazole per 5 mL, and the following inactive ingredients: Glycerin, magnesium aluminum silicate, methylparaben, microcrystalline cellulose, natural peppermint flavor, natural strawberry flavor, propylparaben, purified water, sodium phosphate dibasic, sodium phosphate monobasic, sucralose, and sucrose. Structure

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.

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.

Prior history of hypersensitivity to metronidazole or other nitroimidazole derivatives ( 4.1 ) Patients who have used disulfiram within the last two weeks. ( 4.2 , 7.1 ) Patients who consume alcohol or products containing propylene glycol during and for at least three days after LIKMEZ therapy. ( 4.3 , 7.2 ) Patients with Cockayne syndrome ( 4.4 , 6.2 ) 4.1 Hypersensitivity Reactions LIKMEZ is contraindicated in patients with known hypersensitivity to metronidazole or other nitroimidazole derivatives [ see Adverse Reactions (6.1) ] . 4.2 Psychotic Reactions with Disulfiram LIKMEZ is contraindicated in patients who have used disulfiram within the last two weeks. Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently [ see Drug Interactions (7.1) ] . 4.3 Interaction with Alcohol LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least three days after LIKMEZ therapy. Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing [ see Drug Interactions (7.2) ] . 4.4 Cockayne Syndrome LIKMEZ is contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole in patients with Cockayne syndrome [ see Adverse Reactions (6.2) ] .

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) ] .

Disulfiram: Psychotic reactions can occur in patients who are using LIKMEZ and disulfiram concurrently. ( 4.2 , 7.1 ) Alcohol or Other Products Containing Propylene Glycol: Abdominal cramps, nausea, vomiting, headaches, and flushing can occur in patients who are using LIKMEZ and alcohol or other products containing propylene glycol concurrently. ( 4.3 , 7.2 ) Warfarin and Other Oral Anticoagulants : LIKMEZ can potentiate the anticoagulant effect. Carefully monitor prothrombin time and International Normalized Ratio (INR). ( 7.3 ) Lithium: Increased lithium serum concentrations; measure serum lithium and serum creatinine concentrations during therapy. ( 7.4 ) Busulfan : Increased busulfan serum concentrations; avoid concomitant use, monitor for plasma concentrations and adjust the busulfan dose accordingly. ( 7.5 ) CYP Inducers and CYP Inhibitors : Prolonged or accelerated half-life of metronidazole or concomitant medications. ( 7.6 , 7.7 ) Drugs with the Potential for Prolonging the QT Interval: QT prolongation when used with LIKMEZ ( 7.8 ) Interference with Laboratory Tests: Metronidazole may interfere with certain serum chemistry laboratory values ( 7.9 ) 7.1 Disulfiram Psychotic reactions have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. LIKMEZ is contraindicated in patients who have taken disulfiram within the last two weeks [ see Contraindications (4.2) ] . 7.2 Alcoholic Beverages LIKMEZ is contraindicated in patients who consume alcohol or products containing propylene glycol during and for at least 3 days after therapy with LIKMEZ. Use of LIKMEZ with alcohol or other products containing propylene glycol is associated with a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) [ see Contraindications (4.3) ] . 7.3 Warfarin and other Oral Anticoagulants Metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time. When LIKMEZ is prescribed for patients on this type of anticoagulant therapy, prothrombin time and INR should be carefully monitored. 7.4 Lithium In patients stabilized on relatively high doses of lithium, short-term use of LIKMEZ has been associated with elevation of serum lithium concentrations and signs of lithium toxicity due to the interaction between metronidazole and lithium. Monitor serum lithium and serum creatinine concentrations for several days after beginning treatment with LIKMEZ to detect any increase that may precede clinical symptoms of lithium toxicity. 7.5 Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity. Do not administer LIKMEZ concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to LIKMEZ are available, and concomitant administration with busulfan is medically needed, monitor for busulfan plasma concentrations and adjust the busulfan dose accordingly. 7.6 Inhibitors of CYP450 Liver Enzymes The simultaneous administration of LIKMEZ and drugs that decrease microsomal liver enzymes, such as cimetidine, may prolong the half-life and decrease plasma clearance of metronidazole. 7.7 Inducers of CYP450 Liver Enzymes The simultaneous administration of LIKMEZ and drugs that induce microsomal liver enzymes, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole, resulting in reduced plasma concentrations of metronidazole. Impaired clearance of phenytoin has also been reported. 7.8 Drugs that Prolong the QT Interval QT prolongation has been reported, particularly when metronidazole was administered with drugs with the potential for prolonging the QT interval. 7.9 Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide adenine dinucleotide (NAD + ⇌ NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.