Approval Date:
Terbinafine Hydrochloride Tablets InstructionsPlease read the instructions carefully and use under the guidance of your physician.
[Drug Name]
Generic Name: Terbinafine Hydrochloride Tablets
English name:Terbinafine Hydrochloride Tablets
Hanyu Pinyin:Yansuan Tebinaifen Pian
[Ingredients]
The main ingredients of this product areTebuprofen hydrochloride.
The chemical name is:(E)-N-(6,6-dimethyl-2-heptene-4-alkyne)-N-methyl-1-Naphthylmethylamine hydrochloride
Chemical structure formula:
Molecular Formula:C 21H25N-HCl
Molecular weight: 327.89
[Properties]
This product is a white or off-white tablet.
[Indications]
This product is used for the treatment of hand and foot nail fungal disease (onychomycosis) caused by fungal skin infection.
Pre-treatment should be performed by means of a finger/toenail specimens for laboratory testing [potassium hydroxide smear, fungal culture or finger//toenail specimens for laboratory testing [potassium hydroxide smear, fungal culture or finger span style=”font-family:Arial”>toenail biopsy] to confirm the diagnosis of onychomycosis.
[Specifications]
0.125g(based onC21H25N) )
[dosage]
Pre-use evaluation
Check patient for chronic or active liver disease [see Contraindications and Precautions] prior to use.
Dose
Nail fungus: each time0.25g(2tablets0.125g) daily1time daily6week.
Toenail fungus: each time0.25g(2tablets0.125g) daily1times a day12times a day =”font-family:Arial”>week.
A good clinical outcome is often seen after fungal cure and several months after cessation of treatment, which correlates with the time required for healthy nails to grow out.
[Adverse effects]
Clinical Trials
The incidence of adverse reactions observed in clinical trials of different drugs is not directly comparable due to the varying conditions of clinical trials. It also does not reflect the incidence of adverse reactions observed in clinical practice.
The following table shows the incidence of adverse reactions in the United States and Canada3 placebo-controlled clinical trials in which the most common adverse events were observed. Reported adverse events included gastrointestinal symptoms (including diarrhea, dyspepsia, and abdominal pain), abnormal liver function tests, rash, urticaria, skin pruritus, and taste disturbances. Ocular lens and retinal changes have been reported following administration of terbinafine hydrochloride tablets in controlled clinical trials. The clinical significance of these changes is unclear. Typically, the adverse events were mild, transient, and did not result in the subject being decompensated.
Adverse eventsTreatment Discontinued Tebuprofen hydrochloride tablets (%)
n=465placebo
(%)
n=137Tebuprofen Hydrochloride Tablets (%)
n=465placebo
(%)
n=137Headache12.99.5 0.20.0Gastrointestinal symptoms:Diarrhea5.62.90.60.0Indigestion4.32.90.40.0Abdominal pain2.41.50.40.0Nauseous2.62.90.20.0Gastrointestinal distention2.22.20.00.0Skin Symptoms:Rash5.62.20.90.7Itchy skin2.81.50.20.0Hives1.10.00.00.0 Liver enzyme abnormalities*3.31.40.20.0Taste Disorders2.80.70.20.0Visual impairment1.11.50.90.0*Hepatic enzyme abnormalities greater than or equal to the upper limit of normal2times.
Post-IPO experience
The following additional adverse events have been identified during the post-marketing approval use of terbinafine hydrochloride tablets. Because of spontaneous reporting and uncertainty regarding the number of reporting population sources, it is difficult to estimate with certainty the frequency of adverse events or their causal relationship with drug exposure.
Hematologic and lymphatic system disorders: complete hematocrit, granulocytopenia, severe neutropenia, thrombocytopenia anemia, thrombotic microangiopathy (TMA) (including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) [see precautions]. .
Immune system disorders: severe allergic reactions such as angioedema and allergic reactions (including anaphylaxis), skin and systemic lupus erythematosus immune precipitations and exacerbations [see Precautions] and serum sickness-like reactions.
Psychiatric disorders: The appearance of anxiety and depressive symptoms not triggered by taste disorders has been reported with terbinafine hydrochloride tablets. In some cases, reductions in depression after stopping treatment with terbinafine hydrochloride tablets and relapse after re-treatment have been reported [see PRECAUTIONS].
Neurological Disorders: Taste disturbances, including loss of taste, have been reported with terbinafine hydrochloride tablets. Severe cases may lead to decreased food intake, weight loss, anxiety, and symptoms of depression. Olfactory disturbances, including loss of sense of smell, have been reported with terbinafine hydrochloride tablets [see PRECAUTIONS]. Cases of abnormal sensation and hyperalgesia have been reported with terbinafine hydrochloride tablets.
Ocular disorders: Visual field defects, vision loss
Ear and inner ear disorders: Hearing impairment, vertigo, tinnitus
Vascular disease:Vasculitis
Gastrointestinal Disorders: Pancreatitis, Vomiting
Hepatobiliary disease: cases of liver failure and some resulting in patients requiring liver transplantation or death [see Precautions], atopic and symptomatic Hepatic injury. Cases of hepatitis, cholestasis, and elevated liver enzyme levels have been identified with terbinafine hydrochloride tablets [see PRECAUTIONS].
Dermal and subcutaneous tissue disorders:Severe skin reactions [for exampleStevens-Johnsonsyndrome, toxic epidermolysis bullosa, erythema multiforme, epidermolysis bullosa, dermatitis herpetiformis, eosinophilia due to drug reactions, and systemic symptoms (DRESS) syndrome)]][see PRECAUTIONS], acute generalized eruptive pustulosis, psoriasis-like rash and exacerbation of psoriasis, photosensitivity reactions, and hair loss.
Musculoskeletal and connective tissue disorders: rhabdomyolysis, arthralgia, myalgia.
Systemic disease and site of administration lesions: malaise, malaise, flu-like illness, fever.
Investigation: Concomitant warfarin use in patients results in altered prothrombin time in patients style=”font-family:Times New Roman”> (prolonged or shortened), and elevated blood creatine phosphokinase has been reported.
[Contraindicated]
This product is contraindicated in patients with the following conditions:
Patients with a history of oral terbinafine hypersensitivity are contraindicated because of the risk of hypersensitivity [see Adverse Reactions].
Contraindicated in patients with chronic or active liver disease [see Precautions].
[Caution]
Liver toxicity
This product is contraindicated in patients with chronic or active liver disease. All patients should undergo liver function testing prior to the use of this product because of the potential for hepatotoxicity regardless of whether the patient has underlying liver disease. Liver failure has been reported following the administration of terbinafine hydrochloride tablets regardless of whether the patient has underlying liver disease, and in some cases has resulted in the need for liver transplantation or death.
Most liver case reports associated with terbinafine hydrochloride tablets have patients with serious underlying systemic disorders. The severity of hepatic events and/ or outcomes may be worse in patients with active liver disease or chronic liver disease. Therefore, regular monitoring of liver function is recommended. If biochemical or clinical evidence of liver injury develops, the product should be discontinued.
Patients using this product or their caregivers should be informed that in the presence of persistent nausea, anorexia, malaise, vomiting, right upper abdominal pain or jaundice, dark urine or stool color If symptoms or signs of persistent nausea, anorexia, malaise, vomiting, right upper abdominal pain or jaundice, dark urine or light-colored stools occur, seek immediate medical attention. Patients experiencing these symptoms are advised to discontinue the product and have their liver function evaluated immediately.
Taste disorders include loss of taste
Taste disturbances, including loss of taste, have been reported with terbinafine hydrochloride tablets. Severe cases may result in decreased food intake, weight loss, anxiety, and depressive symptoms. Taste disturbances may return within a few weeks after discontinuation of the drug, but may persist for a long time (more than a year) or become permanent. If symptoms of taste disturbance occur, the product should be discontinued.
Sniffing disorders include loss of sense of smell
Sniffing disorders including loss of smell have been reported with terbinafine hydrochloride tablets. Olfactory disturbances will return after discontinuation of the drug, but may persist for a long time (more than a year) or become permanent. If olfactory disturbance occurs, the product should be discontinued.
Depressive symptoms
Depressive symptoms have been reported during post-marketing use of terbinafine hydrochloride tablets. Physicians should be alert for the development of depressive symptoms. Patients should be advised to report any depressive symptoms to their physician.
Hematologic effects
Absolute lymphocyte values have been observed in controlled clinical trials(ALCs)once-in-a-lifetime reduction. In the placebo-controlled trial,8/465 subjects taking terbinafine hydrochloride tablets (1.7%) and3/137 subjects taking placebo (2.2%) with two or more occurrences of ALC down to1000/mm3below. In patients with known or suspected immunodeficiency, physicians should consider monitoring the patient’s complete blood count if treatment continues for more than 6weeks. Cases of severe neutropenia have been reported. These reactions are reversible after discontinuation of terbinafine hydrochloride tablets, with or without supportive therapy. If clinical signs and symptoms suggest the development of secondary infection, a complete blood count test should be performed. If the neutrophil count≤1000 cells/mm3 is low, the product should be discontinued and supportive therapy.
Severe skin/hypersensitivity reactions
Terbinafine hydrochloride tablets have been marketed after severe skin/hypersensitivity reactions have been reported[for exampleStevens-Johnson syndrome , toxic epidermolysis bullosa, erythema multiforme, epidermolysis bullosa, dermatitis herpetiformis, drug reaction-induced eosinophilia, and systemic symptoms (DRESS) syndrome)]. The manifestations of DRESS syndrome include skin reactions (e.g., rash or exfoliative dermatitis), eosinophilia, and one or more organ complications (e.g., hepatitis, pneumonia, nephritis, myocarditis, and pericarditis). Discontinue this product if there are signs or symptoms of progressive rash or any of these drug reactions.
Lupus Erythematosus
Terbinafine hydrochloride tablets have been reported as immune precipitation and exacerbation of skin and SLE after administration of the drug after its launch. This product should be discontinued if the patient has clinical signs and symptoms suggestive of lupus erythematosus.
Thrombotic microangiopathy
There have been cases of thrombotic microangiopathy due to the use of terbinafine(TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, and even deaths have been reported. This product should be discontinued when clinical symptoms and laboratory findings are consistent with TMA. In case of unexplained thrombocytopenia and anemia, further evaluation and consideration of TMAdiagnosis should be performed.
Medication for patients with renal insufficiency
For patients with impaired renal function (creatinine clearance≤50 mL/min), there are no adequate studies with terbinafine hydrochloride tablets.
Medication for patients with hepatic insufficiency
This product is contraindicated in patients with chronic or active liver disease [see Contraindications and Precautions]. Liver failure has been reported following the administration of terbinafine hydrochloride tablets, regardless of whether the patient has underlying liver disease, and in some cases has resulted in the need for liver transplantation or death. The severity of hepatic events and/ or outcomes may be worse in patients with active liver disease or chronic liver disease.
[For pregnant and lactating women]
Type of pregnancyB
Adequate and rigorously controlled clinical studies have not been performed in pregnant women. Because animal reproduction studies are not always predictive of human response, and because treatment for onychomycosis can be delayed until the end of pregnancy, initiation of this product during pregnancy is not recommended.
Oral reproductive toxicity studies have been conducted in rabbits and rats, with maximum doses administered up to300 mg/kg/day ([based on body surface area (BSA)). /span>) were compared, the doses in rabbits and rats were equivalent to the maximum recommended human dose (MRHD), respectively =”font-family:Arial”>)12fold to23fold]), there is no evidence that terbinafine causes impaired fertility or harms the fetus.
Lactating women
Tebuprofen can be secreted into breast milk after oral administration in lactating women. The ratio of terbinafine in breast milk to plasma is 7:1. Therefore, this product is not recommended for use in breastfeeding women.
[Pediatric use]
The efficacy and safety of Terbinafine Hydrochloride Tablets in pediatric patients with onychomycosis is unclear.
[Geriatric use]
Tebuprofen Hydrochloride Tablets have not been used in a sufficient number of65years of age or older, so that differences in response from younger subjects could not be determined. Other reports of clinical experience have not found differences in response between older and younger patients. In conclusion, dose selection in elderly patients should be cautious. Treatment is generally started at the lower end of the dose range, taking into account that older patients are more likely to have hepatic, renal, or cardiac decompensation and often have comorbidities or other medications.
[Drug Interactions]
Effects of other drugs on terbinafine
Induction of cytochromeP450drug accelerates the plasma clearance of terbinafine and inhibits cytochromeP450 drugs can reduce their plasma clearance. When a combination of these drugs is required, the dose of this product must be adjusted accordingly.
The following drugs may increase the efficacy or plasma concentration of terbinafine:
Terbinafine clearance is decreased when terbinafine is coadministered with cimetidine30%, AUC =”font-family:Arial”>increased by34%.
Since fluconazole inhibits both CYP2C9andCYP3A4enzymes, so co-administration of fluconazole resulted in an increase in terbinafine’sCmaxandAUCincreased52%and69%and. When using other concurrent inhibitors of CYP2C9and and CYP3A4enzyme drugs, such as ketoconazole and amiodarone, cause similar effects.
The following drugs may reduce the efficacy or plasma concentration of terbinafine
Coadministration of rifampin may increase the clearance of terbinafine100%. AUCandCmaxdecreased to 50% of the control level, respectivelyand55%.
Effect of terbinafine on the pharmacokinetics of other drugs
Tebiprofen increases the clearance of cyclosporine15%(AUC =”font-family:Arial”>down13%).
Tebuprofen decreases the clearance of caffeine administered intravenously21%.
Mainly viaCYP2D6metabolized drugs
In vivo and in vitro studies have shown that terbinafine is able to inhibitCYP2D6mediated metabolism. These findings may have implications for compounds that are primarily metabolized by this enzyme such as tricyclic antidepressants (TCAs),beta-blockers, selective5-hydroxytryptamine reuptake inhibitors (SSRIs), and antiarrhythmic drugs (including1A, 1Band1C ) and monoamine oxidase inhibitors (MAO-Is)B types have an impact, especially when they also have a narrow treatment window.
Terbinafine reduces the clearance of desipramine by 82%, whileAUCincreased5fold.
In the presence of dextromethorphan (an analgesic andCYP2D6probe substrate) pan-metabolic profile in healthy subjects showed that terbinafine caused urinary dextromethorphan//meetabolic ratio of dextromethorphan increased on average16-97fold. Thus, terbinafine convertsCYP2D6pan-metabolizers to weak metabolizers.
Products of other metabolic pathways
Based on the results of in vitro and healthy volunteer studies of transcytokininP450system metabolism, terbinafine has very little potential to inhibit or enhance drug clearance (e.g., terfenadine, triazolam, methotrexate, or oral contraceptives). Except for drugs that are metabolized by CYP2D6.
In clinical studies, terbinafine had no relevant effect on the cotrimoxazole (meperidine and sulfamethoxazole), digoxin, fluconazole, antipyrine, theophylline, or zidovudine There was no relevant effect on pharmacokinetics.
The potential for interactions between terbinafine and commonly used anticoagulants has not been studied. In a warfarin study, no interaction was observed.
Drug-Food/drink interactions
Food has a moderate effect on the bioavailability of terbinafine (AUCincreased by 20%), but does not require dose adjustment.
[Drug overdose]
There is limited clinical experience regarding overdose of oral terbinafine. Doses up to5g (therapeutic daily dose of20 times the therapeutic daily dose) did not induce serious adverse reactions. Symptoms of overdose included nausea, vomiting, abdominal pain, dizziness, rash, urinary frequency, and headache.
[Pharmacology and Toxicology]
Pharmacological effects
Terbinafine is an arylamine antifungal drug that inhibits the biosynthesis of ergosterol, an essential component of fungal cell membranes, by inhibiting squalene epoxidase. The biosynthesis of ergosterol is inhibited by inhibition of squalene epoxidase, resulting in fungal cell death due to increased cell membrane permeability mediated by high levels of squalene aggregation (not due to ergosterol deficiency).
Terbinafine hydrochloride may have fungicidal activity based on data on drug concentrations and fungal species in in vitro assays. However, the clinical significance of its in vitro data is unclear.
Studies have shown that terbinafine has antifungal activity in in vitro tests and clinical infections against most strains of the following microorganisms:
Schizosaccharomyces pombe
Trichophyton rubrum
In in vitro trials, terbinafine has shown satisfactory minimal inhibitory concentrations against most strains of the following microorganisms, but has not been examined in adequate, Well-controlled clinical trials have examined the efficacy and safety of terbinafine in the treatment of clinical infections caused by these microorganisms.
Candida albicans
Flocculent Epidermophytes
Short-tailed Broomycetes
Toxicological studies
Repeated dosing toxicity:
Rats and dogs continuously1year oral administration of terbinafine hydrochloride at doses up to100mg/kg/day. Higher doses showed some hepatotoxicity and nephrotoxicity.
Genotoxicity:
In vitro (E. coli and Salmonella typhimurium mutations, rat hepatocytes “font-family:Times New Roman”>DNArepair, mutagenicity in Chinese hamster fibroblasts, chromosomal aberrations and sister chromatid exchange in Chinese hamster lung cells) and in vivo (Chinese hamster chromosomal aberrations, mouse micronucleus test) The results of genotoxicity tests all showed no potential mutagenic or chromosome-breaking effects of terbinafine.
Reproductive toxicity:
At a maximum transoral administration dose of300 mg/kg/day (converted to body surface area, which is approximately the maximum recommended human dose) MRHD12 times the maximum recommended human dose. ) in a reproductive toxicity test in rats, no specific effects on fertility or other reproductive parameters were seen. Terbinafine hydrochloride administered vaginally at 150 mg/day did not show an increased incidence of abortion or preterm delivery in pregnant rabbits, or effects on fetal parameters The effect on fetal parameters was not observed.
Carcinogenicity:
One transoral administration28months carcinogenicity test in rats at the highest dose69 mg/kg/day (as terbinafine prodrugAUCmeter, equivalent to MRHDof2fold), an increased incidence of liver tumors was observed in male rats. Although no dose-limiting toxicity was seen at these doses, higher doses were not tested.
Other:
Extensive in vivo studies in mice, rats, dogs and monkeys, and in vitro studies with rat, monkey and human liver cells . The results showed that the proliferation of peroxisomes in the liver was specific to rats. However, when given at steady-state concentrations (Css) ofMRHDunder concentration of 2 to 3fold of terbinafine, other responses occurred in dogs and monkeys, including liver weight andAPTTincreased. Not examined at higher doses.
At higher doses, abnormal eye refraction was seen in monkeys (no toxic reaction dose for 50 mg/kg), and these abnormalities were associated with the presence of terbinafine metabolites in the ocular tissues, which resolved upon discontinuation without histological changes.
Continuous in young rats 8weeks of oral administration of terbinafine hydrochloride without toxic effects at a dose close to100 mg/kg/day and only a slight increase in liver weight was seen. Doses in adult dogs≥100mg/kg/day[AUCare approximately children’s13 respectively =”font-family:Arial”> times
(Male)
and 6 times (females) (females)] at which central nervous system disturbances, including convulsions in individual animals, were seen. Similar results were observed in adult rats or monkeys given intravenous terbinafine at high doses.
[Pharmacokinetics]
Absorption
Tebrifen is well absorbed after oral administration (>70%), and the absolute bioavailability of terbinafine in this product after first-pass metabolism is about50%. A single oral dose of0.25gterbinafine in1.5hours after which mean peak plasma concentrations can reach1.3 μg/mL. span>. Concomitant intake of this product with a high-fat diet delays absorption and increases bioavailability by approximately20%.
Daily doses of terbinafine can be taken at28. Roman”>28days to achieve approximately70%steady state. Compared with single-dose administration, terbinafine steady-state peak concentrations were on average25% higher and plasmaAUCincreased to2.3fold.
Distribution
Terbinafine binds strongly to plasma proteins (99%), with a volume of distribution greater than2000L.
It is rapidly transdermally diffused (within minutes) and accumulates in the lipophilic stratum corneum. Terbinafine is also excreted via the sebaceous glands, such that high concentrations are reached in hair follicles, hairs, and sebum-rich skin. There is also evidence that terbinafine can be distributed to the nail plate within the first few weeks after initiation of treatment.
There are insufficient data on whether terbinafine penetrates the human placental barrier. Less than0.2% of the dose administered is excreted via breast milk.
Biotransformation/Metabolism
Tebrifen passes at least7speciesCYPisozymes, mainly includingCYP2C9, , CYP1A2,CYP3A4CYP3A4 span>,CYP2C8and. span>CYP2C19, are rapidly and extensively metabolized to inactive metabolites.
Clearance
Metabolites of terbinafine are excreted via urine (71%) and also in the feces (22%) ).
At steady state, the calculated clearance half-life is approximately30hours. However, the literature mentions a triphasic elimination pattern of this product in long-term therapy with a half-life of up to 16.5days.
Special Populations
Steady-state plasma concentrations of terbinafine are not clinically relevant to age.
On renal impairment (creatinine clearance<50 mL/min) and in patients with hepatic disease, single-dose pharmacokinetic studies have shown that terbinafine clearance is reduced by approximately50%.
[Storage]
Store under shade, sealed, at room temperature.
[Packaging]
Polyvinyl chloride solid pharmaceutical rigid tablets and pharmaceutical aluminum foil. 6tablets/Box
,12tablets/box
,14tablets. span>/box.
[Expiration date]
[Implementation Standard]
[approval number]
State PharmacopoeiaH10970218
[manufacturer]
Company Name: Qilu Pharmaceutical Co. family:Times New Roman”>
Location
Address: Xinro Street, High-tech Zone, Jinan317No.
Postal Code:250100
Tel:0531-83126000,83126111,83126333,83126548
Fax Number:0531-83126288,83126545
Net
Address:http://www.qilu-pharma.com