Approval Date.
Cloriboro Ointment Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Clifeboro Ointment
Trade name: Sutemin®/Staquis®
English Name: Crisaborole Ointment
Hanyu Pinyin: Kelipengluo Ruangao
Ingredients
The main ingredient of this product is: Crisaborole
Chemical name: 5-(4-cyanophenoxy)-1,3-dihydro-1-hydroxy-[2,1]-benzoxaborole
Chemical structure formula.
Molecular formula: C14H10BNO3
Molecular weight: 251.1
Excipient name: white petroleum jelly, propylene glycol, glycerol monodistearate, paraffin, dibutyl hydroxytoluene and disodium calcium ethylenediaminetetraacetate.
Properties
This product is a white or off-white ointment.
Indications】
Sultamax® is indicated for the topical treatment of mild to moderate atopic dermatitis in patients aged 2 years and above.
Specification
Each gram of this product contains 20 mg of Clitabroid (2%).
Dosage]
Apply a thin layer of Sultamax® to the affected area twice daily. Sultamax® is for external use only and should not be taken orally, used intraocularly or administered intravaginally.
[Adverse Reactions].
Clinical trial experience
Because clinical trials are completed under different conditions, the rate of adverse reactions observed in clinical trials of one drug cannot be directly compared to the rate of adverse reactions in clinical trials of other drugs and does not necessarily reflect the rate of adverse reactions in actual application.
In two double-blind, fugitive agent-controlled clinical trials (Trials 1 and 2), 1012 subjects aged 2 to 79 years with mild to moderate atopic dermatitis were treated with Sultamax® twice daily for four weeks. Adverse reactions reported by ≥1% of subjects treated with Sultamax® are listed in Table 1.
Table 1: Adverse reactions in ≥1% of subjects in the 4-week atopic dermatitis trial
Adverse reactions Sultamax®
N=1012
n (%) excipients
N=499
n (%) Pain at the site of administrationa45(4)6(1)a Refers to skin sensations such as burning or tingling sensations.
Less common (<1%) adverse reactions in subjects treated with Sultamax® included contact urticaria (see [Precautions]).
[Contraindications].
Sultamax® is contraindicated in patients with known hypersensitivity to clitabroid or any component of the formulation.
[Precautions].
Allergic reactions
Allergic reactions, including contact urticaria, have been reported in patients treated with sultamifene®. Allergy should be suspected when severe itching, swelling and erythema occur at the site of administration or distant sites. If signs and symptoms of an allergic reaction develop, Sultamax® should be discontinued immediately and treated appropriately.
[For pregnant and lactating women].
Pregnancy
Summary of risks
No data are available on the use of Sultamax® in pregnant women to provide information on the risk of major birth defects and miscarriage associated with the drug. In animal reproduction studies, no adverse developmental effects were observed in pregnant rats and rabbits given orally during organogenesis at doses equivalent to three and two times the maximum recommended human dose (MRHD), respectively (see data).
Data
Animal data (see [Pharmacology and Toxicology])
Lactation
Risk Summary
There is no information available on the presence of sultamicin® in human milk for breastfed infants or on the effect of topical application of the drug on milk production in lactating women. Sultamarin® is absorbed systemically.
There is a lack of clinical data on lactation, so it is not possible to determine the risk of sultamifene® on breastfed infants. Therefore, the developmental and health benefits of breastfeeding should be considered, as well as the clinical need for sultamifene® in the mother and any potential adverse effects of sultamifene® or maternal underlying disease on the breastfed infant.
[Pediatric Dosage].
The safety and efficacy of Sultamax® for the topical treatment of mild to moderate atopic dermatitis has been demonstrated in pediatric patients aged 2 years and older in foreign countries. Evidence from two multicenter, randomized, double-blind, parallel-group, excipient-controlled 28-day trials (including 1313 pediatric subjects aged 2 years and older) supports the use of Sultamax® in this age group (see [Adverse Reactions] and [Clinical Studies]).
[Geriatric Use].
Clinical studies of Sultamax® did not include a sufficient number of elderly patients (65 years of age or older) to determine whether they respond differently to this product than younger patients.
[Drug Interactions].
Drug-Drug Interaction Studies
In vitro studies using human liver microsomes have shown that clenbuterol and metabolite 1 are not expected to inhibit cytochrome P450 (CYP) 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 under clinical conditions of use.
In vitro human liver microsomal studies of metabolite 2 showed that it did not inhibit CYP2C19, 2D6, and 3A4; was a weak inhibitor of CYP1A2 and 2B6; and a moderate inhibitor of CYP2C8 and 2C9. The most sensitive enzyme was CYP2C9, which was further investigated in clinical trials using warfarin as a substrate for CYP2C9. The results of this study did not show the potential for drug-drug interactions.
In vitro studies in human hepatocytes showed that clenbuterol and metabolites 1 and 2 are not expected to induce CYP enzymes under clinical conditions of use.
Drug Overdose]
No drug overdose has been reported.
Clinical trials
Two foreign multicenter, randomized, double-blind, parallel-group, fugitive agent-controlled trials (Trials 1 and 2) enrolled a total of 1522 subjects, aged 2 to 79 years (86.3% of subjects were between 2 and 17 years), with treatable body surface area ranging from 5% to 95%. Subjects were evaluated for atopic dermatitis (erythema, nodules/papules, exudate/crusting) using the Investigator’s Static Global Assessment Scale (ISGA, which rates severity on a scale of 0-4), and at baseline, 38.5% of subjects had an ISGA score of 2 (mild) and 61.5% had an ISGA score of 3 (moderate).
In both trials, subjects were randomly assigned in a 2:1 ratio to receive sultamicin® or fugax twice daily for 28 days. The primary efficacy endpoint was a comparison of the proportion of subjects in the sultamarin®-treated and fugax-treated groups who achieved treatment success on day 29, defined as an ISGA rating of clear (score of 0) or almost clear (score of 1) with a grade 2 or higher improvement from baseline.
The efficacy results of the two trials are shown in Table 2.
Table 2: Primary efficacy results for subjects with mild to moderate atopic dermatitis at day 29
Trial 1 Trial 2 Sultamax®
(N=503) Excipients
(N=256) Sultamax®
(N=513)excipient
(N=250) ISGA successa32.8%25.4%31.4%18.0%a Defined as an ISGA score of clear (0) or almost clear (1) with at least 2 levels of improvement relative to baseline.
The change in success rate over time is shown in Figure 1.
Figure 1: Proportion of patients with mild to moderate atopic dermatitis who achieved ISGA successa over time
Trial 1 Trial 2a Success was defined as an ISGA score of clear [0] or almost clear [1] with at least 2 grades of improvement relative to baseline.
[Pharmacology and Toxicology].
Pharmacological effects
Clitoriborol is a phosphodiesterase 4 (PDE-4) inhibitor. inhibition of PDE-4 leads to an increase in intracellular cyclic adenosine monophosphate (cAMP) levels. The specific mechanism of action of clenbuterol in the treatment of atopic dermatitis is not known.
Toxicological studies
Genotoxicity
Clenbuterol was negative in the Ames test, in vitro chromosomal aberration test in human lymphocytes and in vivo micronucleus test in rats.
Reproductive toxicity
In the rat fertility and early embryonic developmental assay, oral administration of clenbuterol up to 600 mg/kg/day (approximately 13 times the maximum recommended clinical dose [MRHD] in terms of AUC) showed no effect on fertility in female and male rats.
In a rat embryo-fetus developmental toxicity assay, no adverse effects on fetuses were observed in pregnant rats given orally 300 mg/kg/day (approximately 3 times the MRHD in terms of AUC) during the organogenesis phase, and no adverse effects on fetuses were observed in rats given orally 600 mg/kg/day (approximately 13 times the MRHD in terms of AUC), with decreased fetal body weight and delayed skeletal No fetal malformations associated with clenbuterol administration were observed. No adverse effects on fetuses were observed in pregnant rabbits given orally up to 100 mg/kg/day (approximately twice the AUC of MRHD) during organogenesis.
In a perinatal toxicity test, oral administration of 150, 300 and 600 mg/kg/day of clitorazepam from day 7 of gestation to day 20 of lactation in rats showed no significant effects on fetal development at doses ≤300 mg/kg/day (approximately 3 times the MRHD in terms of AUC); at 600 mg/kg/day, stillbirth, pup mortality and pup weight loss associated with maternal toxicity were observed. At 600 mg/kg/day, stillbirth, pup mortality and pup weight loss associated with maternal toxicity were observed.
Carcinogenicity
In a carcinogenicity study in SD rats administered orally once daily at 30, 100 and 300 mg/kg/day, an increased incidence of benign granulosa cell tumors of the uterus (including the cervix) and vagina (combined) associated with clitoral administration was seen in female rats at 300 mg/kg/day (approximately twice the AUC of MRHD). The clinical relevance of the results of this study is unclear.
In the CD-1 mouse dermal administration carcinogenicity assay, no administration-related tumors were seen with once-daily topical application of 2%, 5%, and 7% clenbuterol ointment (at a maximum dose of approximately one times the MRHD in terms of AUC).
[Pharmacokinetics].
Absorption
The pharmacokinetics (PK) of Sultamax® Ointment was studied in 33 pediatric subjects between 2 and 17 years of age with mild to moderate atopic dermatitis and body surface area (BSA) involvement (mean ± standard deviation (SD)) of 49% ± 20% (range 27% to 92%). In this study, subjects were administered approximately 3 mg/cm2 of Sultamax® Ointment (dose range approximately 6 g to 30 g per application) twice daily for 8 days.
Blood levels were quantifiable in all subjects. On day 8, the maximum plasma concentration (Cmax) and the area under the concentration time curve (AUC0-12) from 0 to 12 hours after administration (mean ± SD) of clitoriborol were 127 ± 196 ng/mL and 949 ± 1240 ng*h/mL, respectively. by day 8, systemic concentrations of clitoriborol reached steady state. Based on the ratio of AUC0-12 between day 8 and day 1, the mean accumulation factor of clitoriborolol was 1.9.
Distribution
Based on in vitro studies, 97% of clenbuterol was bound to human hemoglobin.
Elimination
Metabolism
Clitoriboro is largely metabolized to inactive metabolites. The major metabolite, 5-(4-cyanophenoxy)-2-hydroxybenzyl alcohol (metabolite 1), is formed by hydrolysis; this metabolite is further metabolized to downstream metabolites, of which 5-(4-cyanophenoxy)2-hydroxybenzoic acid (metabolite 2), formed by oxidation, is also the major metabolite.
The PK of metabolites 1 and 2 was evaluated in the PK study described above, and systemic concentrations reached steady state or near steady state by day 8. Based on the ratio of AUC0-12 between day 8 and day 1, the mean accumulation factors for metabolites 1 and 2 were 1.7 and 6.3, respectively.
Excretion
The metabolites are mainly eliminated by renal excretion.
[Storage].
Seal, store below 25℃, do not freeze.
Package
Laminated tube. 30g/stem, 60g/stem.
Expiration date
24 months
【Execution standard
【Approval number】
[Drug Marketing Licensee
Name: Anacor Pharmaceuticals, Inc.
Registered address: 270 Littlefield Avenue, South San Francisco, CA 94080 United States of America
Manufacturer
Company Name
Pharmacia and Upjohn Company LLC
Production Address
7000 Portage Road, Kalamazoo, MI 49001 United States of America
Domestic Affiliations
Name: Pfizer Investment Co.
Address: 8-13F, Block B, Minmetals Plaza, 3-7 Chaoyangmen North Street, Dongcheng District, Beijing, China Zip Code: 100010
Contact：010-85167000
Product Hotline：400 910 0055