terbinafine 0.01 MG/MG Topical Gel

INDICATIONS AND USAGE Terbinafine tablets, USP are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing [potassium hydroxide (KOH) preparation, fungal culture, or nail biopsy] should be obtained to confirm the diagnosis of onychomycosis. Terbinafine tablets are an allylamine antifungal indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium). ( 1 )

2. DOSAGE AND ADMINISTRATION • Prior to administering, evaluate patients for evidence of chronic or active liver disease. ( 2.1 ) • Fingernail onychomycosis: One 250 mg tablet, once daily for 6 weeks. ( 2.2 ) • Toenail onychomycosis: One 250 mg tablet, once daily for 12 weeks. ( 2.2 ) 2.1 Assessment Prior to Initiation Before administering Terbinafine tablets, evaluate patients for evidence of chronic or active liver disease [see Contraindications (4) and Warnings and Precautions (5.1) ] . 2.2 Dosage Fingernail onychomycosis: One 250 mg tablet once daily for 6 weeks. Toenail onychomycosis: One 250 mg tablet once daily for 12 weeks. The optimal clinical effect is seen some months after mycological cure and cessation of treatment. This is related to the period required for outgrowth of healthy nail.

5. WARNINGS AND PRECAUTIONS Liver failure, sometimes leading to liver transplant or death, has occurred with the use of oral terbinafine. Obtain pretreatment serum transaminases. Prior to initiating treatment and periodically during therapy, assess liver function tests. Discontinue Terbinafine tablets if liver injury develops. ( 5.1 ) Taste disturbance, including taste loss, has been reported with the use of Terbinafine tablets. Taste disturbance can be severe, may be prolonged, or may be permanent. Discontinue Terbinafine tablets if taste disturbance occurs. ( 5.2 ) Smell disturbance, including loss of smell, has been reported with the use of Terbinafine tablets. Smell disturbance may be prolonged, or may be permanent. Discontinue Terbinafine tablets if smell disturbance occurs. ( 5.3 ) Depressive symptoms have been reported with terbinafine use. Prescribers should be alert to the development of depressive symptoms. ( 5.4 ) Severe neutropenia has been reported. If the neutrophil count is less than or equal to 1000 cells/mm 3 , Terbinafine tablets should be discontinued. ( 5.5 ) Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, bullous dermatitis, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome have been reported with oral terbinafine use. If signs or symptoms of drug reaction occur, treatment with Terbinafine tablets should be discontinued. ( 5.6 ) 5.1 Hepatotoxicity Terbinafine tablets are contraindicated for patients with chronic or active liver disease. Before prescribing Terbinafine tablets, perform liver function tests because hepatotoxicity may occur in patients with and without preexisting liver disease. Cases of liver failure, some leading to liver transplant or death, have occurred with the use of Terbinafine tablets in individuals with and without preexisting liver disease. In the majority of liver cases reported in association with use of Terbinafine tablets, the patients had serious underlying systemic conditions. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease. Periodic monitoring of liver function tests is recommended. Discontinue Terbinafine tablets if biochemical or clinical evidence of liver injury develops.In the majority of liver cases reported in association with use of Terbinafine tablets, the patients had serious underlying systemic conditions. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease. Periodic monitoring of liver function tests is recommended. Discontinue Terbinafine tablets if biochemical or clinical evidence of liver injury develops. Warn patients prescribed Terbinafine tablets and/or their caregivers to report immediately to their healthcare providers any symptoms or signs of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, or pale stools. Advise patients with these symptoms to discontinue taking oral terbinafine, and immediately evaluate the patient's liver function.Warn patients prescribed Terbinafine tablets and/or their caregivers to report immediately to their healthcare providers any symptoms or signs of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain or jaundice, dark urine, or pale stools. Advise patients with these symptoms to discontinue taking oral terbinafine, and immediately evaluate the patient's liver function. 5.2 Taste Disturbance Including Loss of Taste Taste disturbance, including taste loss, has been reported with the use of Terbinafine tablets. It can be severe enough to result in decreased food intake, weight loss, anxiety, and depressive symptoms. Taste disturbance may resolve within several weeks after discontinuation of treatment, but may be prolonged (greater than 1 year), or may be permanent. If symptoms of a taste disturbance occur, Terbinafine tablets should be discontinued. 5.3 Smell Disturbance Including Loss of Smell Smell disturbance, including loss of smell, has been reported with the use of Terbinafine tablets. Smell disturbance may resolve after discontinuation of treatment, but may be prolonged (greater than 1 year), or may be permanent. If symptoms of a smell disturbance occur, Terbinafine tablets should be discontinued. 5.4 Depressive Symptoms Depressive symptoms have occurred during postmarketing use of Terbinafine tablets. Prescribers should be alert to the development of depressive symptoms, and patients should be instructed to report depressive symptoms to their physician. 5.5 Hematologic Effects Transient decreases in absolute lymphocyte counts (ALCs) have been observed in controlled clinical trials. In placebo-controlled trials, 8/465 subjects receiving Terbinafine tablets (1.7%) and 3/137 subjects receiving placebo (2.2%) had decreases in ALC to below 1000/mm 3 on 2 or more occasions. In patients with known or suspected immunodeficiency, physicians should consider monitoring complete blood counts if treatment continues for more than 6 weeks. Cases of severe neutropenia have been reported. These were reversible upon discontinuation of Terbinafine tablets, with or without supportive therapy. If clinical signs and symptoms suggestive of secondary infection occur, a complete blood count should be obtained. If the neutrophil count is less than or equal to 1000 cells/mm 3 , Terbinafine tablets should be discontinued and supportive management started. 5.6 Serious Skin/Hypersensitivity Reactions There have been postmarketing reports of serious skin/hypersensitivity reactions [e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, bullous dermatitis, and drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome]. Manifestations of DRESS syndrome may include cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, and one or more organ complications such as hepatitis, pneumonitis, nephritis, myocarditis, and pericarditis. If progressive skin rash or signs/symptoms of the above drug reactions occur, treatment with Terbinafine tablets should be discontinued. 5.7 Lupus Erythematosus During postmarketing experience, precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported in patients taking Terbinafine tablets. Terbinafine tablets should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus. 5.8 Thrombotic Microangiopathy Cases of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, some fatal, have been reported with terbinafine. Discontinue terbinafine if clinical symptoms and laboratory findings consistent with TMA occur. The findings of unexplained thrombocytopenia and anemia should prompt further evaluation and consideration of diagnosis of TMA.

4. CONTRAINDICATIONS Terbinafine tablets are contraindicated in patients with: • History of allergic reaction to oral terbinafine because of the risk of anaphylaxis [see Adverse Reactions (6.2) ] • Chronic or active liver disease [see Warnings and Precautions (5.1) ] • History of allergic reaction to oral terbinafine because of the risk of anaphylaxis. ( 4 ) • Chronic or active liver disease. ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Terbinafine is an allylamine antifungal [see Clinical Pharmacology ( Error! Hyperlink reference not valid. ) ]. 12.2 Pharmacodynamics The pharmacodynamics of terbinafine tablets is unknown. 12.3 Pharmacokinetics Following oral administration, terbinafine is well absorbed (greater than 70%) and the bioavailability of terbinafine tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 mcg/mL appear within 2 hours after a single 250 mg dose; the AUC is approximately 4.56 mcg.h/mL. An increase in the AUC of terbinafine of less than 20% is observed when terbinafine tablets are administered with food. In plasma, terbinafine is greater than 99% bound to plasma proteins and there are no specific binding sites. At steady-state, in comparison to a single dose, the peak concentration of terbinafine is 25% higher and plasma AUC increases by a factor of 2.5; the increase in plasma AUC is consistent with an effective half-life of ~36 hours. Terbinafine is distributed to the sebum and skin. A terminal half-life of 200 to 400 hours may represent the slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is extensively metabolized by at least 7 CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine. In patients with renal impairment (creatinine clearance less than or equal to 50 mL/min) or hepatic cirrhosis, the clearance of terbinafine is decreased by approximately 50% compared to normal volunteers. No effect of gender on the blood levels of terbinafine was detected in clinical trials. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been reported. 12.4 Microbiology Terbinafine, an allylamine antifungal, inhibits biosynthesis of ergosterol, an essential component of fungal cell membrane, via inhibition of squalene epoxidase enzyme. This results in fungal cell death primarily due to the increased membrane permeability mediated by the accumulation of high concentrations of squalene but not due to ergosterol deficiency. Depending on the concentration of the drug and the fungal species test in vitro , terbinafine hydrochloride may be fungicidal. However, the clinical significance of in vitro data is unknown. Terbinafine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections: Trichophyton mentagrophytes Trichophyton rubrum The following in vitro data are available, but their clinical significance is unknown. In vitro , terbinafine exhibits satisfactory MIC’s against most strains of the following microorganisms; however, the safety and efficacy of terbinafine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials: Candida albicans Epidermophyton floccosum Scopulariopsis brevicaulis