Terbinafine: Package Insert and Label Information

TERBINAFINE- terbinafine hydrochloride tablet
REMEDYREPACK INC.

1 INDICATIONS AND USAGE

Terbinafine tablets 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.

2 DOSAGE AND ADMINISTRATION

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.

3 DOSAGE FORMS AND STRENGTHS

Tablet, 250 mg white to off-white, round uncoated, biconvex beveled edge tablets having ‘D’ debossed on one side and ‘74’ on the other side.

4 CONTRAINDICATIONS

Terbinafine tablets are contraindicated in patients with:

5 WARNINGS AND PRECAUTIONS

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. 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.

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 U.S./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 U.S./Canadian placebo-controlled trials

Adverse Event Discontinuation
Terbinafine Tablets (%) n=465 Placebo (%) n=137 Terbinafine Tablets (%) n=465 Placebo (%) n=137
* Liver enzyme abnormalities greater than or equal to 2 times the upper limit of normal range.
Headache 12.9 9.5 0.2 0
Gastrointestinal Symptoms: Diarrhea Dyspepsia Abdominal Pain Nausea Flatulence 5.6 4.3 2.4 2.6 2.2 2.9 2.9 1.5 2.9 2.2 0.6 0.4 0.4 0.2 0 0 0 0 0 0
Dermatological Symptoms: Rash Pruritus Urticaria 5.6 2.8 1.1 2.2 1.5 0 0.9 0.2 0 0.7 0 0
Liver Enzyme Abnormalities* 3.3 1.4 0.2 0
Taste Disturbance 2.8 0.7 0.2 0
Visual Disturbance 1.1 1.5 0.9 0

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

7 DRUG INTERACTIONS

7.1 Drug-Drug Interactions

In vivo studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs predominantly metabolized by the CYP450 2D6 isozyme include the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C (e.g., flecainide and propafenone) and monoamine oxidase inhibitors Type B. Coadministration of terbinafine tablets should be done with careful monitoring and may require a reduction in dose of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2-fold increase in C max and a 5-fold increase in area under the curve (AUC). In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of terbinafine tablets. In studies in healthy subjects characterized as extensive metabolizers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increases the dextromethorphan/dextrorphan metabolite ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolizers to poor metabolizer status.

In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, cyclosporine, cisapride and fluvastatin. In vivo drug-drug interaction studies conducted in healthy volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%.
The influence of terbinafine on the pharmacokinetics of fluconazole, cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline was not considered to be clinically significant.
Coadministration of a single dose of fluconazole (100 mg) with a single dose of terbinafine resulted in a 52% and 69% increase in terbinafine C max and AUC, respectively. Fluconazole is an inhibitor of CYP2C9 and CYP3A enzymes. Based on this finding, it is likely that other inhibitors of both CYP2C9 and CYP3A4 (e.g., ketoconazole, amiodarone) may also lead to a substantial increase in the systemic exposure (C max and AUC) of terbinafine when concomitantly administered.
There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between terbinafine tablets and these changes has not been established.
Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, phenytoins, thiazide diuretics, and calcium channel blockers.

Page 1 of 2 1 2

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2020. All Rights Reserved.