Terbinafine Hydrochloride

1 INDICATIONS AND USAGE Terbinafine tablets are indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium). Prior to initiating treatment, appropriate nail specimens for laboratory testing (KOH preparation, fungal culture, or nail biopsy) should be obtained to confirm the diagnosis of onychomycosis. Terbinafine tablets are an allylamine antifungal indicated for the treatment of onychomycosis of the toenail or fingernail due to dermatophytes (tinea unguium)

6 ADVERSE REACTIONS Common (>2% in patients treated with terbinafine tablets) reported adverse events include headache, diarrhea, rash, dyspepsia, liver enzyme abnormalities, pruritus, taste disturbance, nausea, abdominal pain, and flatulence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse events observed in the three US/Canadian placebo-controlled trials are listed in the table below. The adverse events reported encompass gastrointestinal symptoms (including diarrhea, dyspepsia, and abdominal pain), liver test abnormalities, rashes, urticaria, pruritus, and taste disturbances. Changes in the ocular lens and retina have been reported following the use of terbinafine tablets in controlled trials. The clinical significance of these changes is unknown. In general, the adverse events were mild, transient, and did not lead to discontinuation from study participation. Adverse Event Discontinuation Terbinafine tablet Placebo Terbinafine tablet Placebo (%) (%) (%) (%) n=465 n=137 n=465 n=137 Headache 12.9 9.5 0.2 0.0 Gastrointestinal Symptoms: Diarrhea 5.6 2.9 0.6 0.0 Dyspepsia 4.3 2.9 0.4 0.0 Abdominal Pain 2.4 1.5 0.4 0.0 Nausea 2.6 2.9 0.2 0.0 Flatulence 2.2 2.2 0.0 0.0 Dermatological Symptoms: Rash 5.6 2.2 0.9 0.7 Pruritus 2.8 1.5 0.2 0.0 Urticaria 1.1 0.0 0.0 0.0 Liver Enzyme Abnormalities* 3.3 1.4 0.2 0.0 Taste Disturbance 2.8 0.7 0.2 0.0 Visual Disturbance 1.1 1.5 0.9 0.0 * Liver enzyme abnormalities ≥ 2x the upper limit of normal range. 6.2 Postmarketing Experience The following adverse events have been identified during post-approval use of terbinafine hydrochloride. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse events, based on worldwide experience with terbinafine tablets use, include: idiosyncratic and symptomatic hepatic injury and more rarely, cases of liver failure, some leading to death or liver transplant, serious skin reactions (e.g., Stevens-Johnson Syndrome and toxic epidermal necrolysis), severe neutropenia, thrombocytopenia, agranulocytosis, pancytopenia, anemia, angioedema, and allergic reactions (including anaphylaxis) [see Warnings and Precautions ( 5.1 , 5.5 , and 5.6 )]. Psoriasiform eruptions or exacerbation of psoriasis, acute generalized exanthematous pustulosis and precipitation and exacerbation of cutaneous and systemic lupus erythematosus have been reported in patients taking terbinafine hydrochloride [see Warnings and Precautions ( 5.7 )]. Cases of taste disturbance, including taste loss, have been reported with the use of terbinafine tablets. It can be severe enough to result in decreased food intake, weight loss, and depressive symptoms [see Warnings and Precautions ( 5.2) ]. Depressive symptoms independent of taste disturbance have been reported with use of terbinafine tablets. In some cases, depressive symptoms have been reported to subside with discontinuance of therapy and to recur with reinstitution of therapy [see Warnings and Precautions ( 5.4) ]. Cases of smell disturbance, including smell loss, have been reported with the use of terbinafine tablets [see Warnings and Precautions ( 5.3 )]. Other adverse reactions which have been reported include malaise, fatigue, vomiting, arthralgia, myalgia, rhabdomyolysis, reduced visual acuity, visual field defect, hair loss, serum sickness-like reaction, vasculitis, pancreatitis, influenza-like illness, pyrexia, increased blood creatine phosphokinase, photosensitivity reactions, tinnitus, hearing impairment and vertigo. Altered prothrombin time (prolongation and reduction) in patients concomitantly treated with warfarin has been reported.

4 CONTRAINDICATIONS Terbinafine tablets are contraindicated in individuals with a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis. Terbinafine tablets are contraindicated in individuals with a history of allergic reaction to oral terbinafine because of the risk of anaphylaxis. ( 4 )

11 DESCRIPTION Terbinafine tablets contain the synthetic allylamine antifungal compound terbinafine hydrochloride. Chemically, terbinafine hydrochloride is (E)- N -(6,6-dimethyl-2-hepten-4-ynyl)- N -methyl-1-naphthalenemethanamine hydrochloride. The molecular formula C 21 H 26 CIN with a molecular weight of 327.90, and the following structural formula: Terbinafine hydrochloride is a white to off-white fine crystalline powder. It is freely soluble in methanol and methylene chloride, soluble in ethanol, and slightly soluble in water. Each tablet contains: Active Ingredients: terbinafine hydrochloride (equivalent to 250 mg of terbinafine) Inactive Ingredients: colloidal silicon dioxide, NF; croscarmellose sodium, NF; hypromellose, NF; magnesium stearate, NF; microcrystalline cellulose, NF.

2 DOSAGE AND ADMINISTRATION Fingernail onychomycosis: One 250 mg tablet once daily for 6 weeks. Toenail onychomycosis: One 250 mg tablet once daily for 12 weeks. The optimal clinical effect is seen some months after mycological cure and cessation of treatment. This is related to the period required for outgrowth of healthy nail. Fingernail onychomycosis: One 250 mg tablet, once daily for 6 weeks. Toenail onychomycosis: One 250 mg tablet, once daily for 12 weeks.

10 OVERDOSAGE Clinical experience regarding overdose with oral terbinafine is limited. Doses up to 5 grams (20 times the therapeutic daily dose) have been taken without inducing serious adverse reactions. The symptoms of overdose included nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache.

7 DRUG INTERACTIONS Terbinafine is an inhibitor of CYP4502D6 isozyme and has an effect on metabolism of desipramine, cimetidine, fluconazole, cyclosporine, rifampin, and caffeine. ( 7.1) 7.1 Drug-Drug Interactions In vivo studies have shown that terbinafine is an inhibitor of the CYP450 2D6 isozyme. Drugs predominantly metabolized by the CYP450 2D6 isozyme include the following drug classes: tricyclic antidepressants, selective serotonin reuptake inhibitors, beta-blockers, antiarrhythmics class 1C (e.g., flecainide and propafenone) and monoamine oxidase inhibitors Type B. Coadministration of terbinafine hydrochloride should be done with careful monitoring and may require a reduction in dose of the 2D6-metabolized drug. In a study to assess the effects of terbinafine on desipramine in healthy volunteers characterized as normal metabolizers, the administration of terbinafine resulted in a 2-fold increase in C max and a 5-fold increase in AUC. In this study, these effects were shown to persist at the last observation at 4 weeks after discontinuation of terbinafine tablets. In studies in healthy subjects characterized as extensive metabolizers of dextromethorphan (antitussive drug and CYP2D6 probe substrate), terbinafine increases the dextromethorphan/dextrorphan metabolite ratio in urine by 16- to 97-fold on average. Thus, terbinafine may convert extensive CYP2D6 metabolizers to poor metabolizer status. In vitro studies with human liver microsomes showed that terbinafine does not inhibit the metabolism of tolbutamide, ethinylestradiol, ethoxycoumarin, cyclosporine, cisapride and fluvastatin. In vivo drug-drug interaction studies conducted in healthy volunteer subjects showed that terbinafine does not affect the clearance of antipyrine or digoxin. Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%. The influence of terbinafine on the pharmacokinetics of fluconazole, cotrimoxazole (trimethoprim and sulfamethoxazole), zidovudine or theophylline was not considered to be clinically significant. Co-administration of a single dose of fluconazole (100mg) with a single dose of terbinafine resulted in a 52% and 69% increase in terbinafine C max and AUC, respectively. Fluconazole is an inhibitor of CYP2C9 and CYP3A enzymes. Based on this finding, it is likely that other inhibitors of both CYP2C9 and CYP3A4 (e.g., ketoconazole, amiodarone) may also lead to a substantial increase in the systemic exposure (C max and AUC) of terbinafine when concomitantly administered. There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between terbinafine tablets and these changes has not been established. Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine. There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, phenytoins, thiazide diuretics, and calcium channel blockers. 7.2 Food Interactions An evaluation of the effect of food on terbinafine tablets was conducted. An increase of less than 20% of the AUC (i.e. area under the curve) of terbinafine was observed when terbinafine tablets were administered with food. Terbinafine tablets can be taken with or without food.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Terbinafine is an allylamine antifungal [see Clinical Pharmacology ( 12.4 )]. 12.2 Pharmacodynamics The pharmacodynamics of terbinafine hydrochloride is unknown. 12.3 Pharmacokinetics Following oral administration, terbinafine is well absorbed (>70%) and the bioavailability of terbinafine tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 μg/mL appear within 2 hours after a single 250 mg dose; the AUC (area under the curve) is approximately 4.56 μg.h/mL. An increase in the AUC of terbinafine of less than 20% is observed when terbinafine tablets are administered with food. In plasma, terbinafine is >99% bound to plasma proteins and there are no specific binding sites. At steady-state, in comparison to a single dose, the peak concentration of terbinafine is 25% higher and plasma AUC increases by a factor of 2.5; the increase in plasma AUC is consistent with an effective half-life of ~36 hours. Terbinafine is distributed to the sebum and skin. A terminal half-life of 200-400 hours may represent the slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is extensively metabolized by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine. In patients with renal impairment (creatinine clearance <50 mL/min) or hepatic cirrhosis, the clearance of terbinafine is decreased by approximately 50% compared to normal volunteers. No effect of gender on the blood levels of terbinafine was detected in clinical trials. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been reported. 12.4 Microbiology Terbinafine, an allylamine antifungal, inhibits biosynthesis of ergosterol, an essential component of fungal cell membrane, via inhibition of squalene epoxidase enzyme. This results in fungal cell death primarily due to the increased membrane permeability mediated by the accumulation of high concentrations of squalene but not due to ergosterol deficiency. Depending on the concentration of the drug and the fungal species test in vitro , terbinafine hydrochloride may be fungicidal. However, the clinical significance of in vitro data is unknown. Terbinafine has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections: Trichophyton mentagrophytes Trichophyton rubrum The following in vitro data are available, but their clinical significance is unknown. In vitro , terbinafine exhibits satisfactory MIC’s against most strains of the following microorganisms; however, the safety and efficacy of terbinafine in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials: Candida albicans Epidermophyton floccosum Scopulariopsis brevicaulis

12.1 Mechanism of Action Terbinafine is an allylamine antifungal [see Clinical Pharmacology ( 12.4 )].

12.2 Pharmacodynamics The pharmacodynamics of terbinafine hydrochloride is unknown.

12.3 Pharmacokinetics Following oral administration, terbinafine is well absorbed (>70%) and the bioavailability of terbinafine tablets as a result of first-pass metabolism is approximately 40%. Peak plasma concentrations of 1 μg/mL appear within 2 hours after a single 250 mg dose; the AUC (area under the curve) is approximately 4.56 μg.h/mL. An increase in the AUC of terbinafine of less than 20% is observed when terbinafine tablets are administered with food. In plasma, terbinafine is >99% bound to plasma proteins and there are no specific binding sites. At steady-state, in comparison to a single dose, the peak concentration of terbinafine is 25% higher and plasma AUC increases by a factor of 2.5; the increase in plasma AUC is consistent with an effective half-life of ~36 hours. Terbinafine is distributed to the sebum and skin. A terminal half-life of 200-400 hours may represent the slow elimination of terbinafine from tissues such as skin and adipose. Prior to excretion, terbinafine is extensively metabolized by at least seven CYP isoenzymes with major contributions from CYP2C9, CYP1A2, CYP3A4, CYP2C8 and CYP2C19. No metabolites have been identified that have antifungal activity similar to terbinafine. Approximately 70% of the administered dose is eliminated in the urine. In patients with renal impairment (creatinine clearance <50 mL/min) or hepatic cirrhosis, the clearance of terbinafine is decreased by approximately 50% compared to normal volunteers. No effect of gender on the blood levels of terbinafine was detected in clinical trials. No clinically relevant age-dependent changes in steady-state plasma concentrations of terbinafine have been reported.

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3 DOSAGE FORMS AND STRENGTHS Tablet, 250 mg are white, round, flat, beveled edged tablets embossed ‘250’ on one side and ‘RDY’ on other side Tablet, 250 mg

Terbinafine Hydrochloride Terbinafine Hydrochloride TERBINAFINE HYDROCHLORIDE TERBINAFINE SILICON DIOXIDE CROSCARMELLOSE SODIUM HYPROMELLOSES magnesium stearate CELLULOSE, MICROCRYSTALLINE 250;RDY structure container

13.2 Animal Pharmacology and/or Toxicology A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies using rat, monkey, and human hepatocytes suggest that peroxisome proliferation in the liver is a rat-specific finding. However, other effects, including increased liver weights and APTT, occurred in dogs and monkeys at doses giving Css trough levels of the parent terbinafine 2-3x those seen in humans at the MRHD. Higher doses were not tested.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 28-month oral carcinogenicity study in rats, an increase in the incidence of liver tumors was observed in males at the highest dose tested, 69 mg/kg/day [2x the Maximum Recommended Human Dose (MRHD) based on AUC comparisons of the parent terbinafine]; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested. The results of a variety of in vitro (mutations in E. coli and S. typhimurium , DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential. Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12x the MRHD based on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal parameters.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility In a 28-month oral carcinogenicity study in rats, an increase in the incidence of liver tumors was observed in males at the highest dose tested, 69 mg/kg/day [2x the Maximum Recommended Human Dose (MRHD) based on AUC comparisons of the parent terbinafine]; however, even though dose-limiting toxicity was not achieved at the highest tested dose, higher doses were not tested. The results of a variety of in vitro (mutations in E. coli and S. typhimurium , DNA repair in rat hepatocytes, mutagenicity in Chinese hamster fibroblasts, chromosome aberration and sister chromatid exchanges in Chinese hamster lung cells), and in vivo (chromosome aberration in Chinese hamsters, micronucleus test in mice) genotoxicity tests gave no evidence of a mutagenic or clastogenic potential. Oral reproduction studies in rats at doses up to 300 mg/kg/day (approximately 12x the MRHD based on body surface area comparisons, BSA) did not reveal any specific effects on fertility or other reproductive parameters. Intravaginal application of terbinafine hydrochloride at 150 mg/day in pregnant rabbits did not increase the incidence of abortions or premature deliveries nor affect fetal parameters. 13.2 Animal Pharmacology and/or Toxicology A wide range of in vivo studies in mice, rats, dogs, and monkeys, and in vitro studies using rat, monkey, and human hepatocytes suggest that peroxisome proliferation in the liver is a rat-specific finding. However, other effects, including increased liver weights and APTT, occurred in dogs and monkeys at doses giving Css trough levels of the parent terbinafine 2-3x those seen in humans at the MRHD. Higher doses were not tested.

ANDA076390

Terbinafine Hydrochloride

Terbinafine Hydrochloride

55111-250

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION Container label

17 PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling (Patient Information)] Patients taking terbinafine tablets should receive the following information and instructions: Patients should take one 250 mg tablet once daily for 6 weeks for treatment of fingernail onychomycosis or once daily for 12 weeks for treatment of toenail onychomycosis. The optimal clinical effect is seen some months after mycological cure and cessation of treatment due to the time period required for outgrowth of healthy nail. Patients should be advised to immediately report to their physician any symptoms of persistent nausea, anorexia, fatigue, vomiting, right upper abdominal pain, jaundice, dark urine or pale stools. Terbinafine tablets treatment should be discontinued. Patients should be advised to report to their physician any signs of taste disturbance, smell disturbance and/or depressive symptoms. Terbinafine tablets treatment should be discontinued. Patients should be advised to immediately report to their physician or get emergency help if they experience any of the following symptoms: hives, mouth sores, blistering and peeling of skin, swelling of face, lips, tongue, or throat, difficulty swallowing or breathing. Terbinafine tablets treatment should be discontinued. Patients should be advised to report to their physician any symptoms of new onset or worsening lupus erythematosus. Symptoms can include erythema, scaling, loss of pigment, and unusual photosensitivity that can result in a rash. Terbinafine hydrochloride treatment should be discontinued. Photosensitivity reactions have been reported with the use of Terbinafine hydrochloride. Patients should be advised to minimize exposure to natural and artificial sunlight (tanning beds or UVA/B treatment) while using Terbinafine hydrochloride. Measurement of serum transaminases (ALT and AST) is advised for all patients before taking terbinafine tablets. Patients should be advised that if they forget to take terbinafine tablets, to take their tablets as soon as they remember, unless it is less than four hours before the next dose is due. Patients should also be advised that if they take too many terbinafine tablets they should call their physician.

14 CLINICAL STUDIES The efficacy of terbinafine tablets in the treatment of onychomycosis is illustrated by the response of patients with toenail and/or fingernail infections who participated in three US/Canadian placebo-controlled clinical trials. Results of the first toenail study, as assessed at week 48 (12 weeks of treatment with 36 weeks follow-up after completion of therapy), demonstrated mycological cure, defined as simultaneous occurrence of negative KOH plus negative culture, in 70% of patients. Fifty-nine percent (59%) of patients experienced effective treatment (mycological cure plus 0% nail involvement or >5mm of new unaffected nail growth); 38% of patients demonstrated mycological cure plus clinical cure (0% nail involvement). In a second toenail study of dermatophytic onychomycosis, in which non-dermatophytes were also cultured, similar efficacy against the dermatophytes was demonstrated. The pathogenic role of the non-dermatophytes cultured in the presence of dermatophytic onychomycosis has not been established. The clinical significance of this association is unknown. Results of the fingernail study, as assessed at week 24 (6 weeks of treatment with 18 weeks follow-up after completion of therapy), demonstrated mycological cure in 79% of patients, effective treatment in 75% of the patients, and mycological cure plus clinical cure in 59% of the patients. The mean time to overall success was approximately 10 months for the first toenail study and 4 months for the fingernail study. In the first toenail study, for patients evaluated at least six months after achieving clinical cure and at least one year after completing terbinafine hydrochloride therapy, the clinical relapse rate was approximately 15%.

8.5 Geriatric Use Clinical studies of terbinafine tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.3 Nursing Mothers After oral administration, terbinafine is present in breast milk of nursing mothers. The ratio of terbinafine in milk to plasma is 7:1. Treatment with terbinafine hydrochloride is not recommended in nursing mothers.

8.4 Pediatric Use The safety and efficacy of terbinafine tablets have not been established in pediatric patients with onychomycosis.

8.1 Pregnancy Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because treatment of onychomycosis can be postponed until after pregnancy is completed, it is recommended that terbinafine hydrochloride not be initiated during pregnancy. Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (12x to 23x the MRHD, in rabbits and rats, respectively, based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to terbinafine.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B: There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, and because treatment of onychomycosis can be postponed until after pregnancy is completed, it is recommended that terbinafine hydrochloride not be initiated during pregnancy. Oral reproduction studies have been performed in rabbits and rats at doses up to 300 mg/kg/day (12x to 23x the MRHD, in rabbits and rats, respectively, based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to terbinafine. 8.3 Nursing Mothers After oral administration, terbinafine is present in breast milk of nursing mothers. The ratio of terbinafine in milk to plasma is 7:1. Treatment with terbinafine hydrochloride is not recommended in nursing mothers. 8.4 Pediatric Use The safety and efficacy of terbinafine tablets have not been established in pediatric patients with onychomycosis. 8.5 Geriatric Use Clinical studies of terbinafine tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

16 HOW SUPPLIED/STORAGE AND HANDLING Terbinafine tablets USP, 250 mg are white, round, flat, beveled edged tablets embossed ‘250’ on one side and ‘RDY’ on other side and are supplied in bottles of 30, 90,100, 500 and unit dose packages of 100 (10 x 10). Bottles of 30 NDC 55111-250-30 Bottles of 90 NDC 55111-250-90 Bottles of 100 NDC 55111-250-01 Bottles of 500 NDC 55111-250-05 Unit dose packages of 100 (10 x 10) NDC 55111-250-78 Store at 20°-25°C (68°-77°F) [see USP Controlled Room Temperature]; in a tight container. Protect from light.