LIKMEZ Metronidazole Oral 100 mg/mL Suspension, 200 mL — NDC 81033-066-20 (Billing 81033-0066-20)

5 WARNINGS AND PRECAUTIONS Central and Peripheral Nervous System Effects: Encephalopathy, convulsive seizures, aseptic meningitis and peripheral neuropathy have been reported with metronidazole. Promptly evaluate the benefit/risk of continuation of LIKMEZ if abnormal neurological signs develop. ( 5.2 ) Blood Dyscrasias : Use LIKMEZ with care in patients with a history of blood dyscrasias. LIKMEZ may cause mild transient leukopenia. ( 5.4 )

5.1Potential for Carcinogenicity Metronidazole has been shown to be carcinogenic in mice and rats. Tumors affecting the liver, lungs, mammary, and lymphatic tissues have been detected in several studies of metronidazole in rats and mice, but not hamsters [ see Nonclinical Toxicology (13.1) ] . Avoid unnecessary use of LIKMEZ.

Reserve LIKMEZ for use in the following indications: trichomoniasis [ see Indications and Usage (1.1) ] , amebiasis [ see Indications and Usage (1.2) ] and anaerobic bacterial infections [ see Indications and Usage (1.3) ].

5.2Central and Peripheral Nervous System Effects Encephalopathy, aseptic meningitis, peripheral neuropathy (including optic neuropathy) and convulsive seizures have been reported with metronidazole. Encephalopathy has been reported in association with cerebellar toxicity characterized by ataxia, dizziness, and dysarthria. CNS lesions seen on MRI have been described in reports of encephalopathy.

CNS symptoms are generally reversible within days to weeks upon discontinuation of metronidazole. CNS lesions seen on MRI have also been described as reversible. Peripheral neuropathy, mainly of sensory type has been reported and is characterized by numbness or paresthesia of an extremity.

Cases of aseptic meningitis have been reported with metronidazole [ see Adverse Reactions (6.1) ] . Symptoms may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued. The appearance of abnormal neurological signs and symptoms demands the prompt evaluation of the benefit/risk ratio of the continuation of therapy.

5.3Fungal Superinfections Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with LIKMEZ and requires treatment with an antifungal agent.

5.4Blood Dyscrasias LIKMEZ is a nitroimidazole and should be used with care in patients with evidence of or history of blood dyscrasia. A mild leukopenia has been observed during metronidazole administration; however, no persistent hematologic abnormalities attributable to metronidazole have been observed in clinical studies. Total and differential leukocyte counts are recommended before and after therapy [ see Adverse Reactions (6.1) ] .

5.5Drug-Resistant Bacteria Prescribing LIKMEZ 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.

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 .

6.1Clinical 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.

6.2Postmarketing 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 failur… [Excerpted — this section continues on DailyMed.]

7 DRUG INTERACTIONS 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 )

7.1Disulfiram 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) ] .

7.2Alcoholic 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) ] .

7.3Warfarin 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.

7.4Lithium 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.

7.5Busulfan 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.

7.6Inhibitors 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.

7.7Inducers 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.

7.8Drugs 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.

7.9Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransfe… [Excerpted — this section continues on DailyMed.]