Terbinafine Generis: uses, side effects, interactions, dose/pill (2023)

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Lamisil (terbinafine hydrochloride) tablets are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium).

Before starting treatment, nail samples suitable for laboratory testing [potassium hydroxide (KOH) preparation, fungal culture, or nail biopsy] should be collected to confirm the diagnosis of onychomycosis.

onychomycosis nail: One 250 mg tablet once a day for 6 weeks.

an onychomycosis: One 250 mg tablet once a day for 12 weeks.

The ideal clinical effect is observed a few months after mycological cure and discontinuation of treatment. This is related to the time required for healthy nail growth.

TIPS

Included as part ofPRECAUTIONSSection.

PRECAUTIONS

hepatotoxicity

Cases of liver failure, some of which have resulted in death or liver transplantation, have occurred with the use of oral terbinafine in postmarketing experience in patients with and without pre-existing liver disease. In the majority of reported liver cases, patients had severe underlying systemic diseases. The severity of hepatic events and/or their outcome may be worse in patients with active or chronic liver disease. Treatment with Terbinafine Generis (terbinafine hydrochloride) should be discontinued if there are biochemical or clinical signs of liver damage.

Terbinafine Generis (terbinafine hydrochloride) is not recommended for patients with chronic or active liver disease. Pre-existing liver disease should be evaluated before prescribing Terbinafine Generis (terbinafine hydrochloride). Hepatotoxicity can occur in patients with and without pre-existing liver disease. Pretreatment testing of serum transaminases (ALT and AST) is recommended for all patients before taking Terbinafine Generis (terbinafine hydrochloride). Patients prescribed Terbinafine Generis (terbinafine hydrochloride) and/or their legal guardians should be instructed to immediately report to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, upper abdominal pain, or jaundice, dark urine or light-colored stools. Patients who develop these symptoms should discontinue the use of Terbinafine Generis (terbinafine hydrochloride) and immediately monitor the patient's liver function.

Follow-up of laboratory tests

Pretreatment testing of serum transaminases (ALT and AST) is recommended for all patients before taking Terbinafine Generis (terbinafine hydrochloride).

hematological

A transient decrease in absolute lymphocyte count (ALC) was observed in clinical studies. In placebo-controlled studies, 8/465 patients receiving Lamisil tablets (1.7%) and 3/137 patients receiving placebo (2.2%) had reductions in ALC below 1000/mm³on two or more occasions. In patients with known or suspected immunodeficiency, clinicians should consider monitoring complete blood counts if treatment exceeds 6 weeks. Cases of severe neutropenia have been reported; these were reversible on discontinuation of terbinafine with or without supportive therapy. If clinical signs and symptoms suggestive of a secondary infection develop, a complete blood count should be performed. When the neutrophil count is ≤ 1000 cells/mm³, Terbinafine Generis (terbinafine hydrochloride) should be discontinued and supportive care instituted.

skin reactions

There have been postmarketing reports of serious skin reactions (eg, Stevens-Johnson syndrome and toxic epidermal necrolysis) with oral terbinafine. If a progressive skin rash occurs, treatment with Terbinafine Generis (terbinafine hydrochloride) should be discontinued.

kidney function

The use of terbinafine in patients with renal impairment (creatinine clearance < 50 ml/min) has not been adequately studied.

A wolf with red hair

Postmarketing reports of cutaneous and systemic lupus erythematosus have been reported in patients taking oral terbinafine. Therapy should be discontinued in patients with clinical signs and symptoms suggestive of lupus erythematosus.

non-clinical toxicology

Carcinogenesis, mutagenesis, impaired fertility

In a 28-month oral carcinogenicity study in rats, an increased incidence of liver tumors was observed in males at the highest dose tested, 69 mg/kg/day (twice the MRHD based on AUC comparisons of parent terbinafine ); although dose-limiting toxicity was not achieved at the highest dose tested, higher doses were not tested.

The results of a variety ofin vitro(mutations in>E. colimiS. typhimurium, DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchange in Chinese hamster lung cells) andlive(Chinese hamster chromosome aberration, mouse micronucleus test) Genotoxicity tests showed no mutagenic or clastogenic potential. Oral reproductive studies in rats at doses up to 300 mg/kg/day (approximately 12 times the MRHD based on BSA comparisons) revealed no specific effects on fertility or other reproductive parameters. Intravaginal administration of terbinafine hydrochloride at a dose of 150 mg/day to pregnant rabbits did not increase the incidence of spontaneous abortion or preterm delivery and did not affect fetal parameters.

Use in certain population groups

the pregnancy

Pregnancy category B

Oral reproductive studies were conducted in rabbits and rats at doses up to 300 mg/kg/day [12 to 23 times the maximum recommended human dose (MRHD) in rabbits and rats, respectively, based on body surface area (BSA) comparisons. )]. There was no evidence of impaired fertility or harm to the fetus from terbinafine. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproductive studies are not always predictive of human response, and because treatment of onychomycosis may be postponed later in pregnancy, it is recommended that Lamisil (terbinafine hydrochloride) oral granules not be started. During pregnancy.

lactating mothers

After oral administration, terbinafine is present in the breast milk of lactating mothers. The ratio of terbinafine in milk to plasma is 7:1. Treatment with Terbinafine Generis (terbinafine hydrochloride) in nursing mothers is not recommended.

pediatric use

Terbinafine (terbinafine hydrochloride) tablets were evaluated in two randomized, active-controlled studies in which 1021 patients with a clinical diagnosis of tinea capitis, confirmed by KOH microscopy, received terbinafine (terbinafine hydrochloride) tablets at the indicated dose for a maximum of 6 weeks. The most common side effects were nasopharyngitis, headache, fever, cough, vomiting, and upper respiratory tract infection.

geriatric use

Terbinafine Generis (terbinafine hydrochloride) has not been studied in geriatric patients.

Experience in clinical trials

Because clinical trials are conducted under a wide variety of conditions, adverse reaction rates in clinical trials for one drug cannot be directly compared with rates in clinical trials for another drug and may not reflect the rates observed in real world settings.

Lamisil (terbinafine hydrochloride) granules for oral use

Data described below reflect exposure to terbinafine, including 1042 subjects exposed for a median of 42 days. Terbinafine Generis (terbinafine hydrochloride) was evaluated in 2 active controlled studies (n=1042). The population consisted of children ages 4-12, 64% male and 36% female, 21% Caucasian, 47% Black, 32% Other. Baseline disease characteristics (dermatophytes) of included subjects 49%t. scher, 15%T. violaceum, 15%canis, 2%M audiences, and 1% others. Subjects received once daily oral doses of Terbinafine Generis (terbinafine hydrochloride) based on body weight for 6 weeks: < 25 kg 125 mg/day, 25-35 kg 187.5 mg/day and > 35 kg 250 mg/day. day. Adverse events reported in the 2 studies are listed in the table below.

Table 2 Adverse reactions (≥ 1%) in tinea capitis studies

In the pooled pivotal studies, 2% (17/1042) of patients in the terbinafine group and 2% (6/507) in the griseofulvin group discontinued study drug due to adverse events. The most common adverse event categories leading to discontinuation in subjects exposed to terbinafine were gastrointestinal disorders, skin and subcutaneous disorders, and infections and infestations.

No ophthalmic safety signals were identified in the pooled pivotal studies. Ophthalmological examinations included dilated fundoscopy to evaluate refractory bodies in the retina, evaluation of visual acuity, and color vision tests. Of the 940 subjects in the terbinafine group and 471 subjects in the griseofulvin group who underwent dilated fundoscopy at follow-up visits, none of the subjects had retinal bodies at baseline or end of treatment. Regarding visual acuity, 1% (11/837) of terbinafine-treated subjects and 2% (7/426) of griseofulvin-treated subjects demonstrated a doubling of visual angle after 6 weeks of treatment, while that 2% (15/837) experienced a doubling of the viewing angle of the visual angle was shown. patients treated with terbinafine and 3% (12/426) with griseofulvin had a visual angle halved after 6 weeks of treatment. Of subjects who completed a yellow-blue color vision test for acquired defects, 5% (13/262) of terbinafine-treated subjects and 6% (8/129) of griseofulvin-treated subjects had color confusion. by more than one symbol per week 6 than baseline, whereas 13% (33/262) of terbinafine-treated patients and 13% (17/129) of griseofulvin-treated patients correctly identified more symbols in week 6 than at the beginning.

Lamisil (terbinafine hydrochloride) tablets

Adverse reactions reported in three placebo-controlled studies in the US/Canada included diarrhea (6%), rash (6%), dyspepsia (4%), nausea (3%), liver abnormalities (3%), pruritus (3%), taste disturbances (3%), abdominal pain (2%) and urticaria (1%).

Changes in the lens and retina have been reported after the use of Lamisil tablets in clinical trials in adult subjects with onychomycosis. The clinical significance of these changes is unknown.

Post-Marketing Experience

The following adverse events have been reported during post-marketing use of Lamisil. Because these events are voluntarily reported by a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship with drug exposure.

Adverse reactions reported with oral terbinafine include: idiosyncratic and symptomatic liver injury and cases of liver failure, some resulting in death or liver transplantation, severe skin reactions, severe neutropenia, thrombocytopenia, agranulocytosis, pancytopenia, anemia, angioedema, and allergic reactions ( including anaphylaxis). ).

Rashes or exacerbations of psoriasis, acute generalized exanthematous pustulosis, and precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported. Oral terbinafine can cause taste disturbances (including loss of taste), which usually resolve within a few weeks of stopping the drug. There have been reports of persistent taste disturbances (more than one year). Taste disturbances have been reported to be severe enough to reduce food intake, leading to significant and undesirable weight loss.

Other reported side effects include malaise, fatigue, arthralgia, myalgia, vomiting, acute pancreatitis, rhabdomyolysis, decreased visual acuity, visual field defects, and hair loss. Postmarketing spontaneously reported side effects include altered prothrombin time (increased and decreased) in patients co-treated with warfarin.

Clinical experience of overdose with oral terbinafine is limited. Doses of up to 5 grams in adults (20 times the adult therapeutic daily dose) have been reported without causing serious side effects. Overdose symptoms included nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache.

The pharmacokinetics in children 4 to 8 years of age with tinea capitis were evaluated in a pharmacokinetic study after single and repeated (for 42 days) oral administration of Terbinafine Generis (terbinafine hydrochloride) (N=16) once daily using the body weight groups and doses described. in Section 2.2. Systemic exposure (Cmax and AUC_0-24) of terbinafine in children showed relatively high inter-individual variability (ranging from 36% to 64%). At steady state, the AUC is_0-24between doses it increased by a mean factor of 1.9 to 2.1. The median effective half-life (SD) derived from the observed accumulation was 26.7 (13.8) hours and 30.5 (9.3) hours for the 125 mg and 187.5 mg doses, respectively.

Systemic exposure to terbinafine in children did not exceed the highest systemic exposure values ​​in adults receiving repeated daily doses of Lamisil (terbinafine) 250 mg tablets. A population pharmacokinetic evaluation of oral terbinafine, including children 4 to 12 years of age and adults 18 to 45 years of age (N=113), revealed that the clearance (CL/F) of terbinafine is not linear with body weight. CL/F was predicted to be 19 L/h for a typical 25-kg child and 27 L/h for a typical 70-kg adult. In the weight range of the pediatric patients included in the analysis (14.1 kg to 68 kg), the predicted CL/F ranged from 15.6 to 26.7 L/h. In plasma, terbinafine is >99% bound to plasma proteins. Prior to elimination, terbinafine is rapidly and extensively metabolized by at least seven CYP isoenzymes, with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8, and CYP2C19. No metabolites with antifungal activity similar to terbinafine have been identified. Approximately 70% of the administered dose is excreted in the urine. In adult patients with renal impairment (creatinine clearance ≤ 50 mL/min) or liver cirrhosis, terbinafine clearance is reduced by approximately 50% compared to healthy subjects.

In long-term studies (up to 1 year) in rats and dogs, no significant toxic effects were observed in any species up to oral doses of approximately 100 mg/kg per day. In high oral doses, the liver and possibly also the kidneys have been identified as possible target organs.

In a two-year oral carcinogenicity study in mice, no neoplastic or other abnormal findings were found that were attributable to treatment with doses of 130 (males) and 156 (females) mg/kg per day. In a two-year oral carcinogenicity study in rats, an increased incidence of liver tumors was observed in male animals at the highest dose of 69 mg/kg per day. Changes that may be associated with peroxisome proliferation have been shown to be species-specific, as they were not observed in the mouse carcinogenicity study or other studies in mice, dogs, or monkeys.

During high-dose studies of oral terbinafine in monkeys, refractive retinal irregularities were observed at the highest doses (non-toxic potency was 50 mg/kg). These irregularities were associated with the presence of a terbinafine metabolite in the ocular tissue and disappeared after stopping the drug. They were not associated with histological changes.

A standard battery of in vitro and in vivo genotoxicity tests revealed no evidence of mutagenic or clastogenic potential of the drug.

No adverse effects on fertility or other reproductive parameters were observed in studies in rats or rabbits.

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