Metronidazole 500 mg/100mL Injection, Solution — NDC 0338-1055-48 (Billing 00338-1055-48)

WARNINGS Severe Cutaneous Adverse Reactions Severe cutaneous adverse reactions (SCARs) including toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported with the use of metronidazole. Symptoms can be serious and potentially life threatening. If symptoms or signs of SCARs develop, discontinue Metronidazole injection immediately and institute appropriate therapy.

Central and Peripheral Nervous System Effects Severe neurological disturbances, including encephalopathy, cerebellar symptoms, convulsive seizures, peripheral neuropathy, optic neuropathy, and aseptic meningitis, have been reported in patients treated with metronidazole. Encephalopathy associated with metronidazole may manifest as confusion or decreased level of consciousness, and is associated with widespread lesions on magnetic resonance imaging (MRI) of the brain. Cerebellar toxicity associated with metronidazole may manifest as ataxia, dizziness, dysarthria, nystagmus and saccadic pursuit and is accompanied by T2 flair lesions within the dentate nuclei seen on MRI.

Cerebellar toxicity may concurrently occur with encephalopathy, peripheral neuropathy or seizures. CNS symptoms and CNS lesions are generally reversible within days to weeks upon discontinuation of Metronidazole Injection. Peripheral neuropathy, usually symmetric and mainly of sensory type is characterized by numbness or paresthesia of an extremity.

Symptoms may be prolonged after drug discontinuation. Aseptic meningitis may occur within hours of dose administration and generally resolve after metronidazole therapy is discontinued (see ADVERSE REACTIONS ). Advise patients to report neurologic symptoms that occur during metronidazole administration.

Discontinue metronidazole treatment if any abnormal neurologic symptoms occur such as ataxia, dizziness, confusion or any other CNS adverse reaction (see ADVERSE REACTIONS ).

ADVERSE REACTIONS The following reactions have been reported during treatment with metronidazole formulations: INFECTIONS AND INFESTATIONS: Vaginal candidiasis BLOOD AND LYMPHATIC SYSTEM DISORDERS: Agranulocytosis, Leukopenia, Neutropenia, Thrombocytopenia, Eosinophilia IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity METABOLISM AND NUTRITION DISORDERS: Decreased appetite PSYCHIATRIC DISORDERS: Confusional state, Depression, Insomnia, Decreased libido NERVOUS SYSTEM DISORDERS: Encephalopathy, Seizure, Neuropathy peripheral, Ataxia, Dizziness, Hypoesthesia, Paresthesia, Dysgeusia, Headache, Nystagmus, Aseptic meningitis, Somnolence, Dysarthria, Numbness, Syncope EYE DISORDERS: Optic neuropathy, Saccadic eye movement EAR AND LABYRINTH DISORDERS: Vertigo, tinnitus, hearing impairment, hearing loss CARDIAC DISORDERS: 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, Tachycardia, Palpitation RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea GASTROINTESTINAL DISORDERS: Pancreatitis, Abdominal pain, Diarrhea, Nausea, Vomiting, Asthenia, Proctitis HEPATOBILIARY DISORDERS: Hepatotoxicity/Liver Failure in patients with Cockayne syndrome (see CONTRAINDICATIONS ), Jaundice SKIN AND SUBCUTANEOUS DISORDERS: Toxic epidermal necrolysis, Swelling face, Pruritus, Urticaria, Hyperhidrosis, Erythema, Rash; Stevens-Johnson syndrome, Fixed drug eruption, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP) (see WARNINGS ) MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: Muscle spasms, Arthralgia, Myalgia RENAL AND URINARY DISORDERS: Chromaturia, Dysuria Hepatic: 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 ) REPRODUCTIVE: Dyspareunia GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Injection site reaction, Malaise, Face edema, Edema peripheral, Chest pain, Chills, INVESTIGATIONS: Hepatic enzyme increased.

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 Metronidazole Injection.

Drug Interactions • Disulfiram Psychotic reactions and confusion have been reported in alcoholic patients who are using metronidazole and disulfiram concurrently. Do not administer Metronidazole Injection to patients who have taken disulfiram within the last two weeks (see CONTRAINDICATIONS ). • Alcoholic Beverages Abdominal cramps, nausea, vomiting, headaches, tachycardia and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following metronidazole therapy. Discontinue consumption of alcohol or products containing propylene glycol before, during and up to 72 hours after therapy with Metronidazole Injection (see CONTRAINDICATIONS ). • 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 and increased risk of hemorrhages.

When Metronidazole Injection is prescribed for patients on this type of anticoagulant therapy, prothrombin time and international normalized ratio (INR) should be carefully monitored and their anticoagulant dose adjusted accordingly. Monitor patients for signs and symptoms of bleeding. • Lithium In patients stabilized on relatively high doses of lithium, short-term metronidazole therapy has been associated with elevation of serum lithium and, in a few cases, signs of lithium toxicity. Lithium toxicity may lead to renal damage.

Frequent monitoring of serum lithium and serum creatinine levels is necessary. • Busulfan Metronidazole has been reported to increase plasma concentrations of busulfan, which can result in an increased risk for serious busulfan toxicity such as sinusoidal obstruction syndrome, gastrointestinal mucositis, and hepatic veno-occlusive disease. Metronidazole Injection should not be administered concomitantly with busulfan unless the benefit outweighs the risk. If no therapeutic alternatives to metronidazole are available, and concomitant administration with busulfan is medically needed, frequent monitoring of busulfan plasma concentration should be performed and the busulfan dose should be adjusted accordingly. • Drugs that Inhibit CYP450 Enzymes The simultaneous administration of drugs that decrease microsomal liver enzyme activity, such as cimetidine, may decrease metabolism and reduce plasma clearance of metronidazole which may result in metronidazole toxicity. • Drugs that Induce CYP450 Enzymes The simultaneous administration of drugs that induce microsomal liver enzyme activity, such as phenytoin or phenobarbital, may accelerate the elimination of metronidazole and therefore decrease its efficacy. • Cytochrome P450 3A4 (CYP3A4) substrates Concomitant use of Metronidazole Injection and CYP3A4 substrates (e.g., amiodarone, tacrolimus, cyclosporine, carbamazepine, phenytoin, and quinidine) may increase respective CYP3A4-substrate plasma levels.

Monitoring of plasma concentrations of CYP3A4 substrates may be necessary. • 5-Fluorouracil Metronidazole Injection decreases the clearance of 5-fluorouracil and may therefore cause 5-fluorouracil toxicity. • Vecuronium Metronidazole Injection may potentiate the effects of vecuronium. • 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.

Metronidazole causes an increase in ultraviolet absorbance at 340 nm resulting in falsely decreased values.

PRECAUTIONS General Hepatic Impairment Patients with hepatic impairment metabolize metronidazole slowly, with resultant accumulation of metronidazole and increase the plasma concentrations. Reduce the dose of Metronidazole Injection by 50% in patients with severe hepatic impairment (Child-Pugh C). For patients with mild to moderate hepatic impairment, no dosage adjustment is needed but these patients should be monitored for metronidazole associated adverse events (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION ).

Patients with severe hepatic encephalopathy metabolize metronidazole slowly, with resultant accumulation of metronidazole. This may cause exacerbation of CNS adverse effects. Reduce the dose of Metronidazole Injection as necessary.

Renal Impairment For patients with mild to moderate renal impairment dose adjustment is not considered necessary as elimination half-life is not significantly altered. In patients with severe renal impairment or end stage of renal disease, metronidazole and metronidazole metabolites may accumulate significantly because of reduced urinary excretion in those patients. Monitoring for metronidazole associated adverse events is recommended when metronidazole is administered in patients with severe renal impairment or end stage of renal disease who are not undergoing hemodialysis (see CLINICAL PHARMACOLOGY ).

Hemodialysis removes significant amounts of metronidazole and its metabolites from systemic circulation. Therefore, supplementation of metronidazole following a hemodialysis session may be necessary. Patients receiving peritoneal dialysis should be monitored for signs of toxicity due to the potential accumulation of metronidazole metabolites.

Fungal Superinfections Known or previously unrecognized candidiasis may present more prominent symptoms during therapy with Metronidazole Injection and requires treatment with a candicidal agent. Use in Patients with Blood Dyscrasias Metronidazole is a nitroimidazole, and should be used with care in patients with evidence of or history of blood dyscrasia. Agranulocytosis, leukopenia and neutropenia have been associated with metronidazole administration.

Monitor complete blood count in these patients. Monitoring for Leukopenia Monitoring of complete blood count (CBC) is recommended before, during, and after prolonged or repeated courses of metronidazole therapy. Sodium Retention Metronidazole Injection contains 790 mg of sodium per 100 mL.

Care should be taken when administering Metronidazole Injection to patients receiving a controlled sodium diet or corticosteroids or to patients predisposed to edema. Drug-Resistant Bacteria Prescribing Metronidazole Injection 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. Information for Patients • Interaction with Alcohol Discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Metronidazole Injection and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur (see CONTRAINDICATIONS , PRECAUTIONS-Drug Interactions ). • Treatment of Bacterial Infections Patients should be counseled that antibacterial drugs including Metronidazole Injection should only be used to treat bacterial infections.

They do not treat viral infections ( e.g., the common cold). When Metronidazole Injection 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 Metronidazole Injection or other antibacterial drugs in the fu… [Excerpted — this section continues on DailyMed.]