CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Terbinafine is an allylamine antifungal [see Clinical Pharmacology (12.4)] .

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 200-400 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 to50 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 vitrodata is unknown.

Terbinafine has been shown to be active against most strains of the following microorganisms both in vitroand in clinical infections:

Trichophyton mentagrophytes

Trichophyton rubrum

The following in vitrodata 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

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ADVERSE REACTIONS SECTION

Highlight: Common (greater than 2% of patients treated with Terbinafine tablets) reported adverse events include headache, diarrhea, rash, dyspepsia, liver enzyme abnormalities, pruritus, taste disturbance, nausea, abdominal pain, and flatulence. ( 6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Breckenridge Pharmaceutical, Inc. at 1-800-367-3395, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6. ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates 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 most frequently reported adverse events observed in the 3 US/Canadian placebo-controlled trials are listed in the Table 1. The adverse events reported encompass gastrointestinal symptoms (including diarrhea, dyspepsia, and abdominal pain), liver test abnormalities, rashes, urticaria, pruritus, and taste disturbances. Changes in the ocular lens and retina have been reported following the use of Terbinafine tablets in controlled trials. The clinical significance of these changes is unknown. In general, the adverse events were mild, transient, and did not lead to discontinuation from study participation.

Table 1. Most frequently reported adverse events observed in the 3 US/Canadian placebo-controlled trials

6.2 Postmarketing Experience

The following adverse events have been identified during post-approval use of Terbinafine tablets. Because these events 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.

Blood and lymphatic system disorders:Pancytopenia, agranulocytosis, severe neutropenia, thrombocytopenia, anemia, thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome [see Warnings and Precautions (5.5, 5.8)]

Immune system disorders:Serious hypersensitivity reactions e.g., angioedema and allergic reactions (including anaphylaxis), precipitation and exacerbation of cutaneous and systemic lupus erythematosus [see Warnings and Precautions (5.7)] , serum sickness-like reaction

Psychiatric disorders:Anxiety and depressive symptoms independent of taste disturbance have been reported with use of Terbinafine tablets. In some cases, depressive symptoms have been reported to subside with discontinuance of therapy and to recur with reinstitution of therapy [see Warnings and Precautions (5.4)] .

Nervous system disorders:Cases of taste disturbance, including taste loss, have 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. Cases of smell disturbance, including smell loss, have been reported with the use of Terbinafine tablets [see Warnings and Precautions (5.2, 5.3)] . Cases of paresthesia and hypoesthesia have been reported with the use of Terbinafine tablets.

Eye disorders:Visual field defects, reduced visual acuity

Ear and labyrinth disorders:Hearing impairment, vertigo, tinnitus

Vascular disorders:Vasculitis

Gastrointestinal disorders:Pancreatitis, vomiting

Hepatobiliary disorders:Cases of liver failure some leading to liver transplant or death [see Warnings and Precautions (5.1)] , idiosyncratic and symptomatic hepatic injury. Cases of hepatitis, cholestasis, and increased hepatic enzymes [see Warnings and Precautions (5.1)] have been seen with the use of Terbinafine tablets.

Skin and subcutaneous tissue disorders:Serious skin 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] [see Warnings and Precautions (5.6)] , acute generalized exanthematous pustulosis, psoriasiform eruptions or exacerbation of psoriasis, photosensitivity reactions, hair loss

Musculoskeletal and connective tissue disorders:Rhabdomyolysis, arthralgia, myalgia

General disorders and administration site conditions:Malaise, fatigue, influenza-like illness, pyrexia

Investigations:Altered prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin and increased blood creatine phosphokinase have been reported.

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