Active ingredients: Terbinafine
LAMISIL 250 mg Tablets
LAMISIL 125 mg Tablets
Lamisil package inserts are available for pack sizes: - LAMISIL 250 mg Tablets, LAMISIL 125 mg Tablets
- LAMISIL 1% cream
- Lamisil DermGel 1%, gel
- Lamisil 1% cutaneous solution
- Lamisil 1% cutaneous spray, solution
Why is Lamisil used? What is it for?
PHARMACOTHERAPEUTIC CATEGORY
Antifungal for systemic use.
THERAPEUTIC INDICATIONS
- Onychomycosis (fungal nail infections) caused by dermatophyte fungi.
- Tinea capitis.
- Dermatophyte fungal skin infections (Tinea corporis, Tinea cruris, Tinea pedis), and skin yeast infections, caused by the Candida genus (e.g. Candida albicans) for which oral therapy is considered appropriate due to their location, severity or extent of the infection.
Note: Unlike topical formulations of Lamisil, orally administered terbinafine tablets are not effective against Pityriasis versicolor.
Contraindications When Lamisil should not be used
- Known hypersensitivity to terbinafine or to any of the excipients of Lamisil tablets.
- Do not administer under 2 years of age.
- Generally contraindicated in pregnancy and lactation (see "Special Warnings").
Precautions for use What you need to know before taking Lamisil
Liver function
Lamisil tablets are not recommended in patients with active or chronic liver disease. A liver function test is required before taking Lamisil tablets. Liver toxicity may occur in patients with and without pre-existing liver disease, therefore periodic monitoring (after 4-6 weeks of treatment) with a liver function test is recommended. Terbinafine should be discontinued immediately in the event of an increase in liver function parameters. Very rare cases of severe liver failure (some with fatal outcome or requiring liver transplantation) have been reported in patients treated with Lamisil tablets. In most cases of hepatic insufficiency, the patients had previous serious systemic diseases and the causal relationship to taking Lamisil tablets was not certain (see "Undesirable effects"). Patients taking Lamisil tablets should report promptly to your doctor for any signs and symptoms of persistent nausea with no apparent cause, decreased appetite, fatigue, vomiting, right upper quadrant abdominal pain, jaundice, dark urine, or pale stools. Patients presenting with these symptoms should discontinue oral terbinafine therapy and their liver function evaluated immediately.
Dermatological effects
Very rare cases of severe dermatological reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms) have been reported in patients treated with Lamisil tablets. Should progressively worsening skin rash occur, treatment with Lamisil tablets should be discontinued. Terbinafine should be administered with caution to patients with pre-existing psoriasis or lupus erythematosus, as cases of drastic worsening and exacerbation of psoriasis and cutaneous and systemic lupus erythematosus have been reported in post-marketing experience.
Hematological effects
Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Lamisil tablets. The etiology of any blood disorders that may occur in patients receiving Lamisil tablets should be considered and possible changes in the treatment regimen, including discontinuation of Lamisil tablets, should be considered.
Renal function
The use of Lamisil tablets in patients with impaired renal function (creatinine clearance less than 50 ml / min or serum creatinine greater than 300 micromol / l) has not been adequately studied and is therefore not recommended.
Interactions with other medicines
Patients receiving concomitant treatments with certain drugs belonging to the following classes should be monitored: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including those of class IA, IB and IC), monoamine inhibitors type B oxidase (see "Interactions").
Interactions Which drugs or foods can modify the effect of Lamisil
Tell your doctor or pharmacist if you have recently taken any other medicines, even those without a prescription.
Use caution when Lamisil tablets are taken with medications such as:
- cimetidine;
- fluconazole, ketoconazole, amiodarone;
- rifampicin;
- tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including those of class IA, IB and IC), monoamine oxidase type B inhibitors (see "Precautions for use");
- desipramine;
- dextromethorphan;
- caffeine (when administered intravenously);
- cyclosporine
as there may be interference in the action of individual drugs.
Lamisil tablets negligibly interfere with drugs containing terfenadine, triazolam, tolbutamide or oral contraceptives; some cases of irregular menstruation have been reported in patients who have taken Lamisil tablets concomitantly with oral contraceptives, although the incidence of these disorders is in the same range as in patients taking oral contraceptives alone.
Food / Drink Interactions: Lamisil can be taken on an empty stomach or after meals.
Warnings It is important to know that:
Ask your doctor or pharmacist for advice before taking any medicine.
The 125 mg tablets contain lactose. Therefore, in case of ascertained intolerance to sugars, contact your doctor before taking the medicine.
Women of childbearing age
Some cases of irregular menstruation have been reported in patients who have taken Lamisil tablets concomitantly with oral contraceptives, although the incidence of these disorders is in the same range as in patients taking oral contraceptives alone.
There are no data to support special recommendations for women of childbearing age.
Pregnancy
Since the clinical experience in pregnant women is very limited, Lamisil tablets should not be used during pregnancy unless the clinical condition of the woman requires treatment with oral terbinafine and the potential benefits for the mother do not outweigh the potential. risks to the fetus.
Feeding time
Terbinafine is excreted in breast milk; therefore patients treated with oral Lamisil should not breastfeed. Fertility Toxicity and fertility studies in animals did not reveal any adverse effects.
Effects on ability to drive and use machines
Patients who experience dizziness as an undesirable effect should avoid driving or using machines.
Dose, Method and Time of Administration How to use Lamisil: Posology
Dosage
The duration of oral treatment varies according to the type and severity of the infection and may possibly be increased in the judgment of the physician.
Adults
1 tablet of 250 mg once daily or 1 tablet of 125 mg twice daily.
Children over 2 years of age weighing more than 12 kg
There are no data available on use in children below 2 years of age (usually weighing <12 kg).
* 250 mg tablets do not allow the treatment of children weighing <20 kg.
Skin infections
Recommended duration of treatment
- Tinea pedis (interdigital, plantar and / or moccasin type): 2 - 6 weeks
- Tinea corporis, cruris: 2 - 4 weeks
- Skin candidiasis: 2 - 4 weeks
Complete resolution of the signs and symptoms of the infection may occur several weeks after healing from the mycosis.
Scalp infections
Recommended duration of treatment:
- Tinea capitis: 2 - 4 weeks
Note: Tinea capitis is mainly found in children.
Onychomycosis
For most patients the duration of treatment is between 6 and 12 weeks:
- Finger onychomycosis: 6 weeks
- Onychomycosis toes: 12 weeks
Some patients with impaired nail growth may require prolongation of therapy. A complete resolution of the signs and symptoms of the infection takes several months from the suspension of treatment (ie until the growth of the nail plate has determined the complete replacement of the plate itself).
Additional information on special patient populations
Patients with hepatic impairment
Lamisil tablets are not recommended in patients with chronic or active liver disease (see "Precautions for use")
Patients with renal impairment
The use of Lamisil tablets has not been adequately studied in patients with renal insufficiency and is therefore not recommended in this patient population (see "Precautions for use").
Elderly patients
There is no evidence to suggest that elderly patients require a different dosage or that they experience different side effects than those seen in younger patients. When prescribing Lamisil tablets to patients in this age group, the possibility of pre-existing impaired liver or kidney function should be considered (see "Precautions for use").
Method of administration
The scored tablets should be taken orally with water. They should preferably be taken at the same time each day, on an empty stomach or after meals.
The tablets are divisible to allow dosing in children according to their body weight.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Lamisil
In case of accidental ingestion / intake of an excessive dose of Lamisil, notify your doctor immediately or go to the nearest hospital
A few cases of overdose (up to 5 g) have been reported, with headache, nausea, pain in the upper abdomen and dizziness. In case of overdose it is recommended to eliminate the drug by administration of activated charcoal accompanied. if necessary, give symptomatic treatment.
Side Effects What are the side effects of Lamisil
Like all medicines, Lamisil can cause side effects, although not everybody gets them.
Adverse drug reactions observed during clinical trials or pharmacovigilance (table 1) are listed by MedDRA system organ class. Within each frequency group, adverse reactions are listed in order of decreasing severity. In addition, the corresponding frequency category for each adverse reaction is defined according to the following convention (CIOMS III): very common (≥ 1/10 ); common (≥ 1/100 e
Hypogeusia, including ageusia, which usually resolves within a few weeks after stopping treatment. There have been isolated reports of prolonged hypogeusia.
** Weight loss secondary to dysgeusia.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please inform your doctor or pharmacist.
Expiry and Retention
Expiry: see the expiry date indicated on the package.
The expiry date indicated refers to the product in intact packaging, correctly stored.
Warning: do not use the medicine after the expiry date indicated on the package.
Keep the blister in the outer carton to protect from light. Keep the medicine out of the reach and sight of children.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.
COMPOSITION
LAMISIL 250 mg Tablets
Each tablet contains:
Active principle:
terbinafine hydrochloride ................................................ .................. 281,250 mg
equal to 250 mg of terbinafine base
Excipients:
Magnesium stearate, anhydrous colloidal silica, hypromellose, sodium starch carboxymethyl A, microcrystalline cellulose.
LAMISIL 125 mg Tablets
Each tablet contains:
Active principle:
terbinafine hydrochloride ................................................ .................. 140.625 mg
equal to 125 mg of terbinafine base
Excipients:
Magnesium stearate, hypromellose, microcrystalline cellulose, lactose monohydrate, sodium starch carboxymethyl A.
PHARMACEUTICAL FORM AND CONTENT
LAMISIL 250 mg Tablets 8 tablets of 250 mg for oral use
14 tablets of 250 mg for oral use
LAMISIL 125 mg Tablets 16 tablets of 125 mg for oral use
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
LAMISIL TABLETS
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
LAMISIL 250 mg Tablets
Each tablet contains:
Active ingredient: terbinafine hydrochloride 281,250 mg (equal to 250 mg of terbinafine base).
LAMISIL 125 mg Tablets
Each tablet contains:
Active ingredient: terbinafine hydrochloride 140.625 mg (equal to 125 mg of terbinafine base).
For the full list of excipients see section 6.1.
03.0 PHARMACEUTICAL FORM
Tablets. The tablets can be divided into equal halves.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
• Onychomycosis (fungal nail infections) caused by dermatophyte fungi.
• Tinea capitis.
• Dermatophyte fungal skin infections (Tinea corporis, Tinea cruris, Tinea pedis) and skin yeast infections, caused by the Candida genus (eg Candida albicans) for which oral therapy is considered appropriate due to their location, severity or extent of the infection.
Note: Unlike topical formulations of Lamisil, orally administered terbinafine tablets are not effective against Pityriasis versicolor.
04.2 Posology and method of administration
Dosage
The duration of oral treatment varies according to the type and severity of the infection and may possibly be increased in the judgment of the physician.
Adults
1 tablet of 250 mg once daily or 1 tablet of 125 mg twice daily.
Children over 2 years of age weighing more than 12 kg
There are no data available on use in children under 2 years of age (generally weighing
* 250 mg tablets do not allow the treatment of children of weight
Skin infections
Recommended duration of treatment:
• Tinea pedis (interdigital, plantar and / or moccasin type): 2 - 6 weeks
• Tinea corporis, cruris: 2 - 4 weeks
• Skin candidiasis: 2 - 4 weeks
Complete resolution of the signs and symptoms of the infection may occur several weeks after healing from the mycosis.
Scalp infections
Recommended duration of treatment:
• Tinea capitis: 2 - 4 weeks
Note: Tinea capitis is mainly found in children.
Onychomycosis
For most patients the duration of treatment is between 6 and 12 weeks:
• Onychomycosis of fingers: 6 weeks
• Onychomycosis toes: 12 weeks
Some patients with impaired nail growth may require prolongation of therapy. A complete resolution of the signs and symptoms of the infection takes several months from the suspension of treatment (ie until the growth of the nail plate has determined the complete replacement of the plate itself).
Additional information on special patient populations
Patients with hepatic impairment
Lamisil tablets are not recommended for patients with chronic or active liver disease (see section 4.4 Special warnings and precautions for use).
Patients with renal impairment
The use of Lamisil tablets has not been adequately studied in patients with renal impairment and is therefore not recommended in this patient population (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties).
Elderly patients
There is no evidence to suggest that elderly patients require a different dosage or that they experience side effects other than those seen in younger patients. When prescribing Lamisil tablets to patients in this age group, the possibility of pre-existing impaired hepatic or renal function should be considered (see section 4.4 Special warnings and precautions for use).
Method of administration
The scored tablets should be taken orally with water. They should preferably be taken at the same time each day, on an empty stomach or after meals.
The tablets are divisible to allow dosing in children according to their body weight.
04.3 Contraindications
• Known hypersensitivity to terbinafine or to any of the other ingredients of Lamisil tablets.
• Do not administer under 2 years of age.
• Generally contraindicated during pregnancy and lactation (see section 4.6).
04.4 Special warnings and appropriate precautions for use
Liver function
Lamisil tablets are not recommended in patients with active or chronic liver disease. Before prescribing Lamisil tablets, a liver function test is required. Liver toxicity may occur in patients with and without pre-existing liver disease, therefore periodic monitoring (after 4-6 weeks of treatment) with a liver function test is recommended. Terbinafine should be discontinued immediately in the event of an increase in liver function parameters. Very rare cases of severe liver failure (some with fatal outcome or requiring liver transplantation) have been reported in patients treated with Lamisil tablets. In most cases of hepatic insufficiency, the patients presented with previous serious systemic diseases and the causal correlation with the intake of Lamisil
tablets was not certain (see section 4.8 Undesirable effects). Patients being treated with Lamisil tablets should be advised to promptly report any signs and symptoms of persistent nausea with no apparent cause, decreased appetite, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine to their doctor. or pale stools Patients presenting with these symptoms should discontinue oral terbinafine therapy and their liver function evaluated immediately.
Dermatological effects
Very rare cases of severe dermatological reactions (e.g. Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash with eosinophilia and systemic symptoms) have been reported in patients treated with Lamisil tablets. Should progressively worsening skin rash occur, treatment with Lamisil tablets should be discontinued.
Terbinafine should be administered with caution to patients with pre-existing psoriasis or lupus erythematosus, as cases of drastic worsening and exacerbation of psoriasis and cutaneous and systemic lupus erythematosus have been reported in post-marketing experience.
Hematological effects
Very rare cases of blood dyscrasias (neutropenia, agranulocytosis, thrombocytopenia, pancytopenia) have been reported in patients treated with Lamisil tablets. The etiology of any blood disorders that may occur in patients receiving Lamisil tablets should be considered and possible changes in the treatment regimen, including discontinuation of Lamisil tablets, should be considered.
Renal function
The use of Lamisil tablets in patients with impaired renal function (creatinine clearance less than 50 ml / min or serum creatinine greater than 300 micromol / l) has not been adequately studied and is therefore not recommended (see section 5.2 Pharmacokinetic properties).
Interactions with other medicines
Education in vitro And in vivo showed that terbinafine inhibits CYP2D6 enzyme-mediated metabolism. Therefore patients should be monitored in case of concomitant treatment with drugs mainly metabolised by CYP2D6 (eg some drugs belonging to the following classes: tricyclic antidepressants, beta-blockers, selective serotonin reuptake inhibitors, antiarrhythmics (including those of class IA, IB and IC), monoamine oxidase type B inhibitors), especially if the concomitantly administered drug has a narrow therapeutic window (see section 4.5).
Other
The 125 mg tablets contain lactose (21 mg / tablet). Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take terbinafine 125 mg tablets.
04.5 Interactions with other medicinal products and other forms of interaction
Observed interactions to be considered
Effects of other drugs on terbinafine
Plasma clearance of terbinafine can be accelerated by drugs that induce metabolism and can be inhibited by drugs that inhibit cytochrome P450. In cases where concomitant administration of these drugs is necessary, an adjustment of the dosage of terbinafine tablets may be necessary.
The following drugs may increase the effect or plasma concentration of terbinafine:
Cimetidine decreased the clearance of terbinafine by 33%.
Fluconazole increased the Cmax and AUC of terbinafine by 52% and 69%, respectively, following inhibition of both CYP2C9 and CYP3A4 enzymes. A similar increase in exposure may occur when other drugs that inhibit both CYP2C9 and CYP3A4, such as ketoconazole and amiodarone, are co-administered with terbinafine.
The following drugs may decrease the effect or plasma concentration of terbinafine:
Rifampicin increased the clearance of terbinafine by 100%.
Effects of terbinafine on other drugs
Terbinafine may increase the effect or plasma concentration of the following drugs
Drugs metabolised predominantly by CYP2D6
Education in vitro And in vivo showed that terbinafine inhibits CYP2D6 enzyme-mediated metabolism. This result may be clinically significant for drugs metabolised primarily by CYP2D6, eg some drugs belonging to the following classes: tricyclic antidepressants, beta-blockers, selective reuptake inhibitors serotonin, antiarrhythmics (including those of class IA, IB and IC) and monoamine oxidase type B inhibitors, especially if they also have a narrow therapeutic window (see section 4.4 Special warnings and precautions for use).
Terbinafine decreased the clearance of desipramine by 82% (see section 4.4 Special warnings and precautions for use).
In studies conducted in healthy subjects classified as extensive metabolisers of dextromethorphan (antitussive drug and substrate used to investigate CYP2D6 activity), terbinafine increased the dextromethorphan / dextrorphan metabolic ratio in urine by 16 to 97 times on average. Thus terbinafine it can convert extensive metabolisers (as a genotype) to the phenotypic state characteristic of poor metabolisers (regarding CYP2D6 activity).
Caffeine
Terbinafine decreased the clearance of intravenous caffeine by 19%.
Information on other drugs whose concomitant use with Lamisil induces no interaction or induces a negligible "interaction
Based on the results of studies conducted in vitro and in healthy volunteers it appears that terbinafine negatively affects the plasma clearance of most drugs that are metabolized via the cytochrome P450 enzyme system (e.g. terfenadine, triazolam, tolbutamide or oral contraceptives), with the exception of those metabolized through the CYP2D6 (see above).
Terbinafine does not interfere with the clearance of antipyrine or digoxin.
There was no effect of terbinafine on the pharmacokinetics of fluconazole. Furthermore, no clinically significant interaction was shown between terbinafine and the potential concomitant drugs cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline.
Some cases of irregular menstruation have been reported in patients who have taken Lamisil tablets concomitantly with oral contraceptives, although the incidence of these disorders is in the same range as in patients taking oral contraceptives alone.
Terbinafine may decrease the effect or plasma concentration of the following drugs:
Terbinafine increased the clearance of cyclosporine by 15%.
Interactions with food / beverages
The bioavailability of terbinafine is slightly influenced by food intake (increase in AUC of just under 20%), but not to levels that require dose adjustment.
04.6 Pregnancy and lactation
Women of childbearing age
Some cases of irregular menstruation have been reported in patients who have taken Lamisil tablets concomitantly with oral contraceptives, although the incidence of these disorders is in the same range as in patients taking oral contraceptives alone.
There are no data to support special recommendations for women of childbearing age.
Pregnancy
Fetal toxicity studies with terbinafine in animals have not shown any adverse effects. Since the documented clinical experience in pregnant women is very limited, Lamisil tablets should not be used during pregnancy unless the clinical condition of the woman require oral treatment with terbinafine and the potential benefits to the mother do not outweigh the potential risks to the fetus (see section 4.3).
Feeding time
Terbinafine is excreted in breast milk; therefore patients treated with oral terbinafine should not breastfeed (see section 4.3).
Fertility
Animal toxicity and fertility studies did not reveal any adverse effects (see section 5.3).
04.7 Effects on ability to drive and use machines
No studies on the effects of Lamisil tablets on the ability to drive and use machines have been performed. Patients who experience dizziness as an undesirable effect should avoid driving or using machines.
04.8 Undesirable effects
Adverse drug reactions observed in clinical trials or post-marketing experience (Table 1) are listed by MedDRA system organ class. Within each frequency group, adverse reactions are listed in descending order of severity. In addition, the corresponding frequency category for each adverse reaction is defined according to the following convention (CIOMS III): very common (≥1 / 10); common (≥ 1/100 e
Table 1
* Hypogeusia, including ageusia, which usually resolves within a few weeks after stopping treatment. There have been isolated reports of prolonged hypogeusia.
** Weight loss secondary to dysgeusia.
04.9 Overdose
A few cases of overdose (up to 5 g), with onset of headache, nausea, pain in the upper abdomen and dizziness have been reported.
In case of overdose it is recommended to eliminate the drug by administering activated charcoal accompanied, if necessary, by symptomatic treatment.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: systemic antifungal. ATC code: D01B A02.
Terbinafine is a drug belonging to the class of allylamines, with broad-spectrum activity against pathogenic fungi of the skin, hair and nails, such as the genus Tricophyton (eg T. rubrum, T. mentagrophytes, T. verrucosum, T tonsurans, T. violaceum), Microsporum (eg M. Canis), Epidermophyton floccosum, and yeasts of the genus Candida (eg C. albicans) and Pityrosporum. At low concentrations terbinafine is fungicide against dermatophytes, molds and some dimorphic fungi. The activity on yeasts is species-dependent: on some species it is fungicidal, on others it is fungistatic.
Terbinafine specifically interferes with an early step in the biosynthesis of fungal sterols. This causes a decrease in ergosterol (the main component of the cell membrane of fungi) and an intracellular accumulation of squalene, resulting in the death of fungal cells. Terbinafine acts by inhibiting the enzyme squalene-epoxidase in the cell membrane of fungi. L "Squalene-epoxidase enzyme is not bound to the cytochrome P450 enzyme system.
After oral administration, terbinafine concentrates in the skin, hair and nails with fungicidal activity.
Clinical studies
The efficacy of Lamisil tablets in the treatment of onychomycosis was demonstrated in three placebo-controlled clinical trials in patients with toenail and / or hand nail infections.
Three comparative efficacy studies were conducted for the indication of terbinafine versus Tinea Capitis, in which oral Lamisil (62.5 - 250 mg per day) was administered to a total of 117 patients.
Two phase II studies were also completed to identify the duration of treatment, for a total of 342 patients (mainly children) with T. capitis.
The analysis of the efficacy data showed that both the 2-week and the 4-week treatment ensured good efficacy against T. capitis caused by Trichophyton.
Three multicentre, controlled, double-blind, randomized studies demonstrated the efficacy and safety of Lamisil tablets in the treatment of Tinea corporis and cruris.
In a four-week, double-blind study, Lamisil 125 mg b.i.d. it was compared with placebo in patients with cutaneous candidiasis, demonstrating good efficacy for a treatment period of at least 2 weeks.
Two double-blind, controlled studies compared Lamisil 125 mg b.i.d. to placebo and griseofulvin 250 mg b.i.d. in the treatment of Tinea pedis. Both studies enrolled patients with chronic and recurrent disease and showed that Lamisil was more effective than placebo in the treatment of mycosis.
05.2 Pharmacokinetic properties
Absorption
After oral administration, terbinafine is well absorbed (> 70%). After a single oral dose of 250 mg terbinafine the mean peak plasma concentration was reached in 1.5 hours and was 1.3 mcg / ml. At steady-state, the peak concentration of terbinafine was on average 25% higher and the plasma AUC (area under the curve) 2.3 times higher than with single dose administration.
Distribution
Terbinafine is strongly bound to plasma proteins (99%). It spreads rapidly through the dermis and accumulates in the lipophilic stratum corneum. It is secreted with the sebum and therefore reaches high concentrations in the hair bulbs and skin areas rich in hair and sebum. It has also been shown that terbinafine is distributed in the nail plates within the first few weeks of treatment.
Biotransformation / Metabolism
Terbinafine is rapidly and extensively metabolised by at least seven isoenzymes of the CYP group, with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. Biotransformation leads to metabolites lacking antifungal activity.
Elimination
The metabolites are mainly excreted in the urine. Considering the increase in plasma AUC, an effective half-life of approximately 30 hours can be calculated. Multiple dose administration, followed by extensive blood sampling, revealed a "triphasic elimination with a" terminal half-life of approximately 16.5 days.
Bioavailability
The absolute bioavailability of terbinafine, due to first pass metabolism, is approximately 50%.
Special populations
No clinically significant age-related changes in steady-state plasma levels were observed.
Single dose pharmacokinetic studies conducted in patients with impaired renal function (creatinine clearance pre-existing liver disorders have shown that the elimination of Lamisil tablets can be reduced by approximately 50%.
05.3 Preclinical safety data
Long-term oral studies (up to 1 year) in rats and dogs have not shown marked toxic effects in any species up to doses of approximately 100 mg / kg / day. At high dosages, administered orally, the liver and possibly the kidney as well have been identified as potential target organs.
In a carcinogenicity study in orally treated mice for 2 years, there was no evidence of neoplasms or other abnormalities attributable to treatment with doses up to 130 mg / kg / day (males) and 156 mg / kg / day (females). In rats treated orally for 2 years, an increase in the incidence of liver tumors was observed in males at the highest dose of 69 mg / kg / day. These alterations, which could be related to peroxisome proliferation, were found to be species -specific in that they were not found in mouse carcinogenicity studies or in other studies in mice, dogs and monkeys.
In monkeys, administration of terbinafine resulted in changes in ocular refraction at higher doses (non-toxic dose level: 50 mg / kg). These changes were associated with the presence of a terbinafine metabolite in ocular tissue and disappeared after discontinuation of treatment. They were not accompanied by histological changes.
A study in juvenile rats treated orally for 8 weeks identified a no-toxic-effect level (NTEL) of approximately 100 mg / kg / day, with a slight increase in liver weight as the only observed effect, while in developing dogs at doses> 100 mg / kg / day (AUC values in males and females approximately 13 and 6 times higher than the values found in children), signs of central nervous system alteration, including single episodes, were observed of convulsions in some animals. Similar effects were observed in adult rats or monkeys following exposure to high systemic doses of intravenously administered terbinafine.
A standard battery of "in vitro" and "in vivo" genotoxicity tests did not reveal any mutagenic or clastogenic potential of the drug.
In studies conducted in rats and rabbits, no effects on fertility or other reproductive parameters were observed.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
LAMISIL 250 mg Tablets
Magnesium stearate, anhydrous colloidal silica, hypromellose, sodium starch carboxymethyl A, microcrystalline cellulose.
LAMISIL 125 mg Tablets
Magnesium stearate, hypromellose, microcrystalline cellulose, lactose monohydrate, sodium starch carboxymethyl A.
06.2 Incompatibility
None known.
06.3 Period of validity
250 mg tablets: 3 years
125 mg tablets: 4 years
06.4 Special precautions for storage
Keep the blister in the outer carton in order to protect it from light.
06.5 Nature of the immediate packaging and contents of the package
LAMISIL 250 mg Tablets
Packs of 8 and 14 tablets of 250 mg in PVC / Al blisters
LAMISIL 125 mg Tablets
Pack of 16 tablets of 125 mg in PVC / Al blisters
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Novartis Farma S.p.A.
Largo Umberto Boccioni, 1 - 21040 Origgio (VA)
08.0 MARKETING AUTHORIZATION NUMBER
LAMISIL 250 mg Tablets
8 tablets of 250 mg A.I.C. n. 028176028
14 tablets of 250 mg A.I.C. n. 028176105
LAMISIL 125 mg Tablets
16 tablets of 125 mg A.I.C. n. 028176016
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
LAMISIL 250 mg Tablets - 8 tablets of 250 mg
First authorization: 12.12.1992
Renewal: 16.12.2007
LAMISIL 250 mg Tablets - 14 tablets of 250 mg
First authorization: 27.07.2000
Renewal: 16.12.2007
LAMISIL 125 mg Tablets - 16 tablets of 125 mg
First authorization: 12.12.1992
Renewal: 16.12.2007
10.0 DATE OF REVISION OF THE TEXT
AIFA Resolution of 3 July 2013.
