Likmez Drug Information

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.

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.

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.

Recommended Dosage in Patients with Severe Hepatic Impairment For patients with severe

hepatic impairment (Child-Pugh C), reduce the dose of LIKMEZ by 50%.

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 . No adjustment in LIKMEZ dose is needed in patients undergoing continuous ambulatory peritoneal dialysis (CAPD) .

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.

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.

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) .

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 .

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) .

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.

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.

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.

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.

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.

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.

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.

Pregnancy Risk Summary While available studies cannot definitively establish the absence of risk, published data from case-control studies, cohort studies and meta-analyses have not established an association with metronidazole use during pregnancy and major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data There are published data from case-control studies, cohort studies, and 2 meta-analyses that include more than 5,000 pregnant women who used metronidazole during pregnancy. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero ; however, these findings were not confirmed.

In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5,000 pregnant women to assess the use of antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three studies conducted to assess the risk of infant cancer following metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Animal Data Metronidazole crosses the placental barrier. Reproduction studies have been performed in rats, rabbits, and mice at doses similar to the maximum recommended human dose based on body surface area comparisons. There was no evidence of harm to the fetus due to metronidazole.

Pediatric Use The safety and effectiveness of LIKMEZ for the treatment of amebiasis have been established in pediatric patients. The safety and effectiveness of LIKMEZ for the treatment of trichomoniasis and anaerobic bacterial infections have not been established in pediatric patients.

Hypersensitivity Reactions

LIKMEZ is contraindicated in patients with known hypersensitivity to metronidazole or other nitroimidazole derivatives .

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 .

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 .

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 .

General Single oral doses of metronidazole, up to 15 g (7.5 times the maximum recommended single dose), have been reported in suicide attempts and accidental overdoses. Symptoms reported include nausea, vomiting, and ataxia. Metronidazole is dialyzable.

Neurotoxic effects, including seizures and peripheral neuropathy, have been reported after 5 days to 7 days of doses of 6 g to 10.4 g every other day (3 times to 5.2 times the maximum recommended single dose). Treatment of Overdosage There is no specific antidote for metronidazole overdose; therefore, management of the patient should consist of symptomatic and supportive therapy.