Terbinafine

Terbinafine is an antifungal agent belonging to the pharmacological class of Allylamine.

Terbinafine has been approved to relieve symptoms and also for the treatment and maintenance of Onychomycosis, Sporotrichosis, and lymphocutaneous and cutaneous Tinea infections.

Terbinafine, when taken orally, is well absorbed with over 70% absorption, but only 40% of the drug is bioavailable due to first-pass metabolism. The drug undergoes multiple metabolic pathways, including deamination, hydroxylation, and N-demethylation, mediated by various cytochrome P450 enzymes. The elimination of terbinafine primarily occurs through urine (approximately 80%), with the remainder eliminated in faeces. The unmetabolized parent drug is not detected in urine.

The common side effects involved in using Terbinafine are Headache, Skin rash, Itching, Nausea, Diarrhea, Indigestion, Abdominal/stomach pain, Stomach upset.

Terbinafine is available in the form of Tablets, Oral granules.

Terbinafine is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Terbinafine belonging to the pharmacological class of Allyl Amine, acts as an antifungal agent.

Terbinafine acts as an inhibitor of the enzyme squalene monooxygenase, also known as squalene epoxidase, thereby hindering the conversion of squalene to 2,3-oxydosqualene, a critical step in the production of ergosterol. This disruption results in reduced levels of ergosterol, which is normally an essential component of the fungal cell wall, leading to an accumulation of squalene. Consequently, the cytoplasm generates numerous squalene-containing vesicles, which may cause the depletion of other lipids from the cell wall, further compromising its integrity.

Terbinafine has been approved to relieve symptoms and also for the treatment and maintenance of Onychomycosis, Sporotrichosis, and lymphocutaneous and cutaneous Tinea infections.

For oral terbinafine, the Cmax (maximum concentration) is 1µg/mL, and it is reached at a Tmax (time to reach maximum concentration) of 2 hours. The AUC (area under the concentration-time curve) is 4.56µg*h/mL.

For 1% topical terbinafine, the Cmax increases from 949 to 1049ng/cm2, and the AUC increases from 9694 to 13,492ng/cm2/h over the course of a week.

Terbinafine is found to be available in the form of Tablets, Oral granules.

Terbinafine can be used in the following treatment:

• Onychomycosis
• Sporotrichosis, lymphocutaneous and cutaneous
• Tinea infections

Terbinafine can help to relieve symptoms and also for the treatment and maintenance of Onychomycosis, Sporotrichosis, and lymphocutaneous and cutaneous Tinea infections.

Terbinafine is approved for use in the following clinical indications:

• Onychomycosis
• Sporotrichosis, lymphocutaneous and cutaneous
• Tinea infections

Onychomycosis:

• Continuous dosing: Take 250 mg orally once daily for 6 weeks (for fingernail) or 12 weeks (for toenail).
• Pulsed dosing (alternative dosing method) (off-label): Note that pulsed dosing is less effective than continuous dosing.
• Option 1: Take 250 mg orally once daily for 4 weeks, then stop for 4 weeks, and then resume with 250 mg orally once daily for 4 weeks .
• Option 2: Take 500 mg orally per day in 1 or 2 divided doses for 1 week, repeat every 4 weeks for 3 months .

Sporotrichosis, lymphocutaneous, and cutaneous (alternative agent for patients who do not respond to itraconazole) (off-label use):

• Take 500 mg orally twice daily . Treat for an additional 2 to 4 weeks after all lesions have resolved; the usual duration is 3 to 6 months.

Tinea infections:

• Dermatophyte folliculitis (tinea barbae, Majocchi granuloma) (off-label use): Take 250 mg orally once daily; duration is typically 2 to 6 weeks or until clinical resolution.
• Tinea capitis (off-label use): Take 250 mg orally once daily for 4 to 6 weeks .
• Tinea corporis/tinea cruris (alternative agent) (off-label use): Note: Consider this treatment if you have extensive skin involvement or if topical therapy failed .
• Take 250 mg orally once daily for 1 to 2 weeks.
• Tinea pedis/tinea manuum (alternative agent) (off-label use): Note: Consider this treatment if you have extensive skin involvement or if topical therapy fails.
• Take 250 mg orally once daily for 2 weeks.

Terbinafine is available in the following dosage forms and strengths:

• Tablet: Available in a strength of 250 mg.
• Oral Granules (Discontinued): Previously available in strengths of 125 mg and 187.5 mg.

Tablets, Oral granules.

• Dosage Adjustments in Kidney Patients:

For patients with a creatinine clearance (CrCl) of 50 mL/minute or higher, no dosage adjustment is needed.

For patients with a CrCl between 20 and less than 50 mL/minute, administer 50% of the usual dose.

For patients with a CrCl less than 20 mL/minute, using an alternative agent may be preferred (according to expert opinion) as it has not been adequately studied in this population. If necessary, administer 50% of the usual dose and closely monitor for adverse effects, such as gastrointestinal and hepatic issues.

· Dosage Adjustments in Pediatric Patients:

Tinea Capitis

Limited data is available for the treatment of Tinea capitis with terbinafine. It is important to note that for Microsporum spp. infections, griseofulvin is preferred over terbinafine. However, if terbinafine is used, higher-dose regimens are recommended. The standard-dose regimen for children and adolescents is as follows:

• Children weighing 10 to <20 kg: Take 62.5 mg orally once daily.
• Children weighing 20 to 40 kg: Take 125 mg orally once daily.
• Children weighing >40 kg: Take 250 mg orally once daily.
• The duration of therapy varies based on the species of the fungus. In general, the treatment lasts for 6 weeks. For Trichophyton tonsurans infections, the duration is 4 to 6 weeks, while for Microsporum canis infections, it is 6 to 12 weeks.

Onychomycosis

Limited data is available for the treatment of Onychomycosis with terbinafine in children and adolescents. The recommended dosages are as follows:

• Children weighing 10 to 20 kg: Take 62.5 mg orally once daily for 6 weeks (for fingernails) or 12 weeks (for toenails).
• Children weighing >20 to 40 kg: Take 125 mg orally once daily for 6 weeks (for fingernails) or 12 weeks (for toenails).
• Children weighing >40 kg: Take 250 mg orally once daily for 6 weeks (for fingernails) or 12 weeks (for toenails).

When taking Terbinafine, there are certain dietary restrictions that should be followed to ensure the medication's effectiveness and safety:

• Grapefruit and Grapefruit Juice: Avoid consuming grapefruit or grapefruit juice while taking terbinafine. Grapefruit can interfere with the metabolism of terbinafine, leading to increased drug levels in the bloodstream and a higher risk of side effects.
• Fatty Foods: Terbinafine is better absorbed when taken with food, but it is recommended to avoid consuming excessive amounts of fatty or high-fat foods. These foods may slow down the absorption of terbinafine, potentially reducing its effectiveness.
• Caffeine: While there is no specific interaction reported between terbinafine and caffeine, it is best to be cautious with excessive caffeine intake. Some individuals may experience increased nervousness or jitteriness when combining terbinafine with large amounts of caffeine.

The dietary restriction should be individualized as per patient requirements.

Terbinafine may be contraindicated under the following conditions:

• Individuals with a history of allergic reaction to oral terbinafine should not take Terbinafine Tablets due to the potential risk of anaphylaxis, making it contraindicated in such cases.

The treating physician must closely monitor the patient and keep pharmacovigilance as follows:

Hepatotoxicity

• Cases of liver failure, some resulting in liver transplant or death, have been reported with the use of Terbinafine Tablets in individuals with and without pre-existing liver disease. Patients with active or chronic liver conditions may experience more severe hepatic events. Treatment with Terbinafine Tablets should be discontinued if there is any evidence of liver injury, and the medication is not recommended for patients with chronic or active liver disease. Patients prescribed Terbinafine Tablets should be vigilant in reporting symptoms such as persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine, or pale stools, and their liver function should be immediately evaluated if any of these symptoms occur.

Taste Disturbance, Including Loss of Taste

• Terbinafine Tablets may cause taste disturbance, including taste loss, which can be severe enough to lead to decreased food intake, weight loss, and depressive symptoms. While taste disturbance may resolve within weeks after discontinuation of treatment, it could also be prolonged or permanent. If patients experience any taste-related symptoms, they should discontinue Terbinafine Tablets.

Smell Disturbance, Including Loss of Smell

• The use of Terbinafine Tablets has been associated with smell disturbance, which can include loss of smell. While discontinuing treatment may resolve the issue for some patients, in certain cases, it may persist for an extended period or become permanent. If any symptoms related to smell disturbance arise, patients should cease using the tablets.Terbinafine Tablets.

Depressive Symptoms

• Postmarketing use of terbinafine has been associated with depressive symptoms. Both prescribers and patients should be vigilant in recognizing and reporting depressive symptoms to the physician.

Hematologic Effects

• During clinical trials, there have been temporary drops in the number of lymphocytes in the blood of patients taking Terbinafine. It is recommended that doctors keep track of patients' blood counts if they have a weakened immune system and are taking Terbinafine for more than six weeks. There have also been reports of severe neutropenia, which was resolved after stopping Terbinafine.

Skin Reactions

• Postmarketing reports have linked Terbinafine Tablets to serious skin reactions, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis. If a progressive skin rash occurs, treatment with Terbinafine should be discontinued.

Lupus Erythematosus

• There have been reports of precipitation and worsening of cutaneous and systemic lupus erythematosus in patients who have taken Terbinafine Tablets during post-marketing experience. If such cases occur, it is recommended to discontinue the use of Terbinafine.

Laboratory Monitoring

• It is advisable to measure serum transaminases (ALT and AST) for all patients before starting Terbinafine Tablets. Regular monitoring of liver function is important throughout the course of treatment to identify any potential liver issues early on.

It is generally advisable to limit or avoid alcohol consumption while on terbinafine. Alcohol can strain the liver, and since terbinafine is metabolized in the liver, excessive alcohol consumption may increase the risk of liver damage.

Following oral intake, terbinafine can be detected in the breast milk of nursing mothers, with a milk-to-plasma ratio of 7:1. Therefore, the use of Terbinafine treatment is not advised for nursing mothers.

Pregnancy:

Pregnancy Category B

There have been no sufficient and conclusive studies conducted on pregnant women. As animal studies may not accurately predict human response, and considering that onychomycosis treatment can be deferred until after pregnancy, it is advised not to initiate Terbinafine treatment during pregnancy.

Studies on rabbits and rats have been conducted to examine the effects of terbinafine at doses up to 300 mg/kg/day. These doses were 12x to 23x higher than the recommended maximum human dose for rabbits and rats, respectively, based on body surface area. The results of these studies showed no negative impact on fertility or fetal development due to terbinafine.

There are certain food-related warnings and precautions to consider when using Terbinafine:

• Grapefruit and Grapefruit Juice: Avoid consuming grapefruit or grapefruit juice while taking terbinafine. Grapefruit can interfere with the metabolism of terbinafine, leading to increased drug levels in the bloodstream and a higher risk of side effects.
• Alcohol: It is generally advisable to limit or avoid alcohol consumption while on terbinafine. Alcohol can strain the liver, and since terbinafine is metabolized in the liver, excessive alcohol consumption may increase the risk of liver damage.
• Fatty Foods: Terbinafine is better absorbed when taken with food, but it is recommended to avoid consuming excessive amounts of fatty or high-fat foods. These foods may slow down the absorption of terbinafine, potentially reducing its effectiveness.
• Caffeine: While there is no specific interaction reported between terbinafine and caffeine, it is best to be cautious with excessive caffeine intake. Some individuals may experience increased nervousness or jitteriness when combining terbinafine with large amounts of caffeine.

The adverse reactions related to Terbinafine can be categorized as follows:

Common:

• Headache
• Nausea
• Vomiting
• Diarrhea
• Fatigue
• Sleepiness
• Stomach pain
• Gas
• Dry mouth
• Skin rash

Less Common :

• Difficulty with breathing
• Ear congestion
• General feeling of discomfort or illness
• Headache
• Joint pain
• Skin rash or itching
• Sneezing
• Body aches or pain
• Chills
• Cough
• Diarrhea
• Sore throat
• Sweating
• Trouble with sleeping
• Unusual tiredness or weakness
• Upper abdominal or stomach pain
• Vomiting
• Loss of appetite
• Loss of voice
• Nasal congestion
• Nausea
• Runny nose
• Shivering

Rare:

• Redness, blistering, peeling, or loosening of the skin
• Stomach pain
• Dark urine
• Difficulty with swallowing
• Pale skin
• Pale stools
• Unusual bleeding or bruising
• Yellow skin or eyes

The clinically relevant drug interactions of Terbinafine are briefly summarized here:

• CYP450 2D6 Inhibition: Terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs primarily metabolized by CYP450 2D6, such as tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics (class 1C), and monoamine oxidase inhibitors Type B, may require careful monitoring and potential dose reduction when co-administered with Terbinafine.
• A study conducted on healthy volunteers has shown that the use of terbinafine resulted in a 2-fold increase in Cmax and a 5-fold increase in AUC of desipramine, a drug that is metabolized by CYP450 2D6. Even after discontinuing the use of Terbinafine Tablets, these effects could last for up to 4 weeks. Additionally, terbinafine has the potential to convert extensive CYP2D6 metabolizers to poor metabolizer status.
• Dextromethorphan Interaction: In studies with healthy subjects characterized as extensive CYP2D6 metabolizers, terbinafine increased the dextromethorphan/dextrorphan metabolite ratio in urine by 16- to 97-fold on average, indicating potential CYP2D6 inhibition.
• Tolbutamide, Ethinylestradiol, and Cyclosporine: Terbinafine does not inhibit the metabolism of these drugs based on in vitro studies with human liver microsomes and in vivo drug-drug interaction studies in healthy volunteers.
• Antipyrine and Digoxin: Terbinafine does not affect the clearance of antipyrine or digoxin, as demonstrated in drug-drug interaction studies with healthy volunteers.
• Caffeine and Cyclosporine: Terbinafine increases the clearance of caffeine by 19% and the clearance of cyclosporine by 15% in healthy volunteers.
• When fluconazole is taken with terbinafine, terbinafine Cmax and AUC can increase by 52% and 69% respectively. Fluconazole inhibits CYP2C9 and CYP3A enzymes, so other inhibitors of these enzymes may also increase terbinafine exposure.
• Warfarin: There have been spontaneous reports of changes in prothrombin times in patients taking oral terbinafine and warfarin, but a causal relationship has not been established.
• Rifampin and Cimetidine: Terbinafine clearance is increased 100% by rifampin (CYP450 enzyme inducer) and decreased 33% by cimetidine (CYP450 enzyme inhibitor).
• Lack of Information on Drug Classes: There is no available information from adequate drug-drug interaction studies for certain drug classes, including oral contraceptives, hormone replacement therapies, hypoglycemics, phenytoins, thiazide diuretics, and calcium channel blockers, with terbinafine.

The following are the side effects involving Terbinafine:

• Headache
• Skin rash
• Itching
• Nausea
• Diarrhea
• Indigestion
• Abdominal/stomach pain
• Stomach upset
• Elevated liver function test results
• Visual disturbance
• Gas
• Dizziness
• Spinning sensation
• Temporary unusual or unpleasant taste or loss of taste in your mouth

The use of Terbinafine should be prudent in the following group of special populations:

Pregnancy:

Pregnancy Category C

There have been no sufficient and conclusive studies conducted on pregnant women. As animal studies may not accurately predict human response, and considering that onychomycosis treatment can be deferred until after pregnancy, it is advised not to initiate Terbinafine treatment during pregnancy.

Tests conducted on rabbits and rats have shown that doses up to 300 mg/kg/day (which is 12 to 23 times the recommended human dose, depending on the animal) of terbinafine do not cause any harm to fertility or fetal development.

Lactation:

Following oral intake, terbinafine can be detected in the breast milk of nursing mothers, with a milk-to-plasma ratio of 7:1. Therefore, the use of Terbinafine treatment is not advised for nursing mothers.

Pediatric:

The safety and effectiveness of Terbinafine Tablets have not been proven in pediatric patients with onychomycosis.

Geriatric Use:

Clinical trials evaluating Terbinafine Tablets did not include a significant number of participants aged 65 and above, making it challenging to determine if their response differs from younger individuals. However, based on other clinical observations, no significant differences in treatment responses have been noted between elderly and younger patients. Nevertheless, it is advisable to exercise caution when prescribing doses for elderly patients, typically commencing at the lower end of the dosage range. This approach takes into account the higher likelihood of reduced liver, kidney, or heart function, as well as the presence of concurrent medical conditions or other medication regimens.

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Terbinafine.

Clinical reports on overdose cases involving oral terbinafine are scarce. Instances of doses as high as 5 grams, which are 20 times the recommended therapeutic daily dose, have been reported without causing severe adverse reactions. Common symptoms observed in cases of overdose include nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache.

It is worth noting that Terbinafine is not eliminated from the body through hemodialysis.

Pharmacodynamics:

Terbinafine, an allylamine antifungal agent, exerts its antifungal activity by inhibiting squalene epoxidase, also known as squalene monooxygenase. This action prevents the formation of ergosterol, leading to the accumulation of squalene and weakening the cell wall of fungal cells. Due to its tissue distribution and long terminal elimination half-life, terbinafine exhibits a prolonged duration of action. Fortunately, cases of overdose with terbinafine are rare, even when exceeding the therapeutic dose, indicating a wide therapeutic index. However, patients receiving oral terbinafine treatment should undergo liver function tests before initiating therapy to minimize the risk of liver injury.

Pharmacokinetics:

Absorption

Oral terbinafine exhibits more than 70% absorption, but only 40% of the drug is bioavailable after undergoing first-pass metabolism. After administration, it reaches a peak concentration (Cmax) of 1µg/mL with a time to reach peak concentration (Tmax) of 2 hours and an area under the curve (AUC) of 4.56µg*h/mL. Over the course of a week, topical terbinafine at 1% concentration shows an increase in Cmax from 949-1049ng/cm2 and an increase in AUC from 9694-13,492ng/cm2/h.

Volume of Distribution

Following a single 250mg oral dose, terbinafine achieves a volume of distribution at steady state of 947.5L or 16.6L/kg.

Metabolism

Terbinafine undergoes various metabolic pathways involving several cytochrome P450 enzymes. It can be deaminated to 1-naphthaldehyde by CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19. 1-naphthaldehyde is further metabolized to 1-naphthoic acid or reduced to 1-naphthalenemethanol.

Another metabolic pathway involves the hydroxylation of terbinafine by CYP1A2, 2C9, 2C8, 2B6, and 2C19, leading to hydroxyterbinafine. Hydroxyterbinafine can be further oxidized to carboxyterbinafine or N-demethylated to desmethylhydroxyterbinafine by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19.

Furthermore, terbinafine can undergo N-demethylation to form desmethylterbinafine, which can be either dihydroxylated to a desmethyldihydrodiol or hydroxylated to desmethylhydroxyterbinafine.

Finally, terbinafine can be dihydroxylated to form a dihydrodiol, which is then N-demethylated to a desmethyldihydrodiol.

Route of Elimination

Approximately 80% of terbinafine is eliminated through urine, while the remaining portion is excreted in faeces. The unmetabolized parent drug is not present in urine.

1. https://www.webmd.com/drugs/2/drug-6188/terbinafine-hcl-oral/details
2. https://my.clevelandclinic.org/health/drugs/19379-terbinafine-tablets
3. https://www.drugs.com/mtm/terbinafine.html
4. https://go.drugbank.com/drugs/DB00857
5. https://reference.medscape.com/drug/Terbinafine-terbinafine-342595
6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020539s021lbl.pdf
7. https://www.medsafe.govt.nz/profs/PUArticles/December 2018/Spotlight on Terbinafine.htm
8. https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/pharmacare/prescribers/limited-coverage-drug-program/limited-coverage-drugs-terbinafine-tablets
9. https://www.tevacanada.com/en/canada/our-products/product-page/terbinafine-02254727
10. https://www.rxlist.com/terbinafine/generic-drug.htm