Composition:
Utilisé dans le traitement:
Examiné médicalement par Militian Inessa Mesropovna, Pharmacie Dernière mise à jour le 05.04.2022
Attention! Information sur la page est réservée aux professionnels de la santé! Les informations sont collectées dans des sources ouvertes et peuvent contenir des erreurs significatives! Soyez prudent et revérifiez toutes les informations de cette page!
Top 20 des médicaments avec les mêmes ingrédients:
Top 20 des médicaments avec le même usage:
FABIOR® (tazarotène) Mousse, 0,1% est indiqué pour le traitement topique de l'acné vulgaire chez les patients de 12 ans ou plus.
Le gel Karac® (tazarotène) 0,05% et 0,1% sont indiqués pour le traitement topique des patients atteints de psoriasis en plaques stable jusqu'à 20% d'atteinte de la surface corporelle.
Le gel Karac® (tazarotène) 0,1% est également indiqué pour le traitement topique des patients atteints d'acné faciale vulgaris de gravité légère à modérée.
L'efficacité du gel de Karac® (gel de tazarotène) dans le traitement de l'acné précédemment traité avec d'autres rétinoïdes ou résistant aux antibiotiques oraux n'a pas été établie.
Karac® (tazarotène) Mousse, 0,1% est indiqué pour le traitement topique de l'acné vulgaire chez les patients de 12 ans ou plus.
FABIOR Foam est à usage topique uniquement. FABIOR Foam n'est pas destiné à un usage oral, ophtalmique ou intravaginal.
FABIOR Foam doit être appliqué une fois par jour le soir après le lavage avec un nettoyant doux et séchage complet de la zone affectée. Distribuez une petite quantité de mousse dans la paume de la main. À l'aide du bout des doigts, appliquez uniquement suffisamment de mousse pour couvrir légèrement toutes les zones affectées du visage et / ou du tronc supérieur avec une couche mince; masser doucement la mousse dans la peau jusqu'à ce que la mousse disparaisse. Évitez les yeux, les lèvres et les muqueuses. Se laver les mains après l'application.
Les patients peuvent utiliser une crème hydratante au besoin.
En cas d'irritation excessive (rougeur, desquamation ou inconfort), les patients doivent réduire la fréquence d'application ou interrompre temporairement le traitement. Le traitement peut être repris une fois l'irritation disparue. Le traitement doit être interrompu si l'irritation persiste.
Général
L'application peut provoquer une irritation excessive de la peau de certaines personnes sensibles. Dans les cas où il a été nécessaire d'arrêter temporairement le traitement, ou le dosage a été réduit à une concentration inférieure (chez les patients atteints de psoriasis) ou à un intervalle que le patient peut tolérer, la thérapie peut reprendre, ou la concentration ou la fréquence d'application du médicament peut être augmentée à mesure que le patient devient capable de tolérer le traitement. La fréquence d'application doit être étroitement surveillée par une observation attentive de la réponse thérapeutique clinique et de la tolérance cutanée. L'efficacité n'a pas été établie pour moins d'une fois les fréquences de dosage quotidiennes.
Pour le psoriasis: Il est recommandé de commencer le traitement avec du Karac® (gel de tazarotène) 0,05% Gel, avec une résistance augmentée à 0,1% si elle est tolérée et médicalement indiquée. Appliquer le gel Karac® (gel de tazarotène) une fois par jour, le soir, sur les lésions psoriasiques, en utilisant suffisamment (2 mg / cm²) pour couvrir uniquement la lésion avec un film mince à pas plus de 20% de la surface corporelle. Si un bain ou une douche est pris avant l'application, la peau doit être sèche avant d'appliquer le gel. Si des émollients sont utilisés, ils doivent être appliqués au moins une heure avant l'application du gel Karac® (gel de tazarotène). Étant donné que la peau non affectée peut être plus sensible à l'irritation, l'application de tazarotène dans ces zones doit être soigneusement évitée. Le gel de karac® (gel de tazarotène) a été étudié jusqu'à 12 mois au cours des essais cliniques sur le psoriasis.
Pour l'acné: Nettoyez doucement le visage. Une fois la peau sèche, appliquez une fine pellicule de Karac® (gel de tazarotène) Gel 0,1% (2 mg / cm²) une fois par jour, le soir, sur la peau où apparaissent les lésions d'acné. Utilisez suffisamment pour couvrir toute la zone affectée. Le gel de karac® (gel de tazarotène) a été étudié jusqu'à 12 semaines au cours des essais cliniques sur l'acné.
La mousse de karaon est à usage topique uniquement. La mousse de karac n'est pas à usage oral, ophtalmique ou intravaginal.
La mousse de karac doit être appliquée une fois par jour le soir après le lavage avec un nettoyant doux et un séchage complet de la zone affectée. Distribuez une petite quantité de mousse dans la paume de la main. À l'aide du bout des doigts, appliquez uniquement suffisamment de mousse pour couvrir légèrement toutes les zones affectées du visage et / ou du tronc supérieur avec une couche mince; masser doucement la mousse dans la peau jusqu'à ce que la mousse disparaisse. Évitez les yeux, les lèvres et les muqueuses. Se laver les mains après l'application.
Les patients peuvent utiliser une crème hydratante au besoin.
En cas d'irritation excessive (rougeur, desquamation ou inconfort), les patients doivent réduire la fréquence d'application ou interrompre temporairement le traitement. Le traitement peut être repris une fois l'irritation disparue. Le traitement doit être interrompu si l'irritation persiste.
FABIOR Foam is contraindicated in pregnancy.
FABIOR Foam may cause fetal harm when administered to a pregnant woman. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient apprised of the potential hazard to the fetus.
Retinoids may cause fetal harm when administered to a pregnant woman.
In rats, tazarotene 0.05% gel, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day (1.5 mg/m²/day) resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day (2.75 mg/m² total body surface area/day) tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. Systemic daily-exposure (AUCde) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 0.62 and 6.7 times, respectively, the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.78 and 8.4 times, respectively, the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
As with other retinoids, when tazarotene was given orally to experimental animals, developmental delays were seen in rats, and teratogenic effects and post-implantation loss were observed in rats and rabbits at AUCde values that were 0.55 and 13.2 times, respectively, the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.68 and 16.4 times, respectively, the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
In a study of the effect of oral tazarotene on fertility and early embryonic development in rats, decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights, all classic developmental effects of retinoids, were observed when female rats were administered 2 mg/kg/day from 15 days before mating through gestation day 7. A low incidence of retinoid-related malformations at that dose was reported to be related to treatment. This dose produced an AUCde that was 1.7 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area) and 2.1 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
SYSTEMIC EXPOSURE TO TAZAROTENIC ACID IS DEPENDENT UPON THE EXTENT OF THE BODY SURFACE AREA TREATED. IN PATIENTS TREATED TOPICALLY OVER SUFFICIENT BODY SURFACE AREA, EXPOSURE COULD BE IN THE SAME ORDER OF MAGNITUDE AS IN THESE ORALLY TREATED ANIMALS. ALTHOUGH THERE MAY BE LESS SYSTEMIC EXPOSURE IN THE TREATMENT OF ACNE OF THE FACE ALONE DUE TO LESS SURFACE AREA FOR APPLICATION, TAZAROTENE IS A TERATOGENIC SUBSTANCE, AND IT IS NOT KNOWN WHAT LEVEL OF EXPOSURE IS REQUIRED FOR TERATOGENICITY IN HUMANS (SEE
Karac Foam is contraindicated in pregnancy.
Karac Foam may cause fetal harm when administered to a pregnant woman. Tazarotene elicits teratogenic and developmental effects associated with retinoids after topical or systemic administration in rats and rabbits.
If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient apprised of the potential hazard to the fetus.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Fetal Risk
Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In patients treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans.
There were 5 reported pregnancies in subjects who participated in clinical trials for topical tazarotene foam. One of the subjects was found to have been treated with topical tazarotene for 25 days, 2 were treated with vehicle foam, and the other 2 did not receive either tazarotene foam or vehicle foam. The subjects were discontinued from the trials when their pregnancy was reported. The one pregnant woman who was inadvertently exposed to topical tazarotene during the clinical trial delivered a full-term healthy infant.
Females Of Childbearing Potential
Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when tazarotene foam is used. The possibility of pregnancy should be considered in females of child-bearing potential at the time of institution of therapy.
A negative serum or urine result for pregnancy test having a sensitivity down to at least 25 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within 2 weeks prior to therapy with FABIOR Foam, which should begin during a normal menstrual period for females of childbearing potential. Advise patients of the need to use an effective method of contraception to avoid pregnancy.
Local Irritation
FABIOR Foam should be used with caution in patients with a history of local tolerability reactions or local hypersensitivity. Retinoids should not be used on abraded or eczematous skin, as they may cause severe irritation. Contact with the mouth, eyes, and mucous membranes should be avoided. In case of accidental contact, rinse well with water.
Some individuals may experience skin redness, peeling, burning or excessive pruritus. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established.
Weather extremes, such as wind or cold, may be more irritating to patients using FABIOR Foam.
Potential Irritant Effect With Concomitant Topical Medications
Concomitant topical acne therapy should be used with caution because a cumulative irritant effect may occur. If irritancy or dermatitis occurs, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists.
Photosensitivity And Risk For Sunburn
Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided. Patients must be warned to use sunscreens and protective clothing when using FABIOR Foam. Patients with sunburn should be advised not to use FABIOR Foam until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using FABIOR Foam and ensure that the precautions are observed. Due to the potential for photosensitivity resulting in greater risk for sunburn, FABIOR Foam should be used with caution in patients with a personal or family history of skin cancer.
FABIOR Foam should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity.
Flammability
The propellant in FABIOR Foam is flammable. Instruct the patient to avoid fire, flame, and/or smoking during and immediately following application.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
Inform the patient of the following:
- Fetal risk associated with FABIOR Foam for females of childbearing potential. Advise patients to use an effective method of contraception during treatment to avoid pregnancy. Advise the patient to stop medication if she becomes pregnant and call her doctor.
- If undue irritation (redness, peeling, or discomfort) occurs, reduce frequency of application or temporarily interrupt treatment. Treatment may be resumed once irritation subsides.
- Do not place FABIOR Foam in the freezer.
- Avoid exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps.
- Avoid contact with the eyes. If FABIOR Foam gets in or near their eyes, to rinse thoroughly with water.
- Wash their hands after applying FABIOR Foam.
- Avoid fire, flame, or smoking during and immediately following application since FABIOR Foam is flammable.
- Keep out of the reach of children.
- Not for ophthalmic, oral, or intravaginal use.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risk. Based on pharmacokinetic data from a shorter-term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in rats approximately 2 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
A long-term topical application study of up to 0.1% tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared with vehicle control animals. AUC at the highest dose in mice was 49 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
In evaluation of photocarcinogenicity, median time to onset of tumors was decreased and the number of tumors increased in hairless mice following chronic topical dosing with exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks.
Mutagenesis
Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test.
Impairment Of Fertility
No impairment of fertility was observed in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure at the 0.125 mg/kg/day dose in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. AUC at the highest dose in rats was 23 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
No effect on parameters of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose. AUC at the highest dose in rats was 42 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the AUC in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
Use In Specific Populations
Pregnancy
Pregnancy Category X.
FABIOR Foam is contraindicated in pregnancy.
There are no adequate and well-controlled studies with FABIOR Foam in pregnant women. FABIOR Foam is contraindicated in females who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when FABIOR Foam is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative serum or urine result for pregnancy test having a sensitivity down to at least 25 mIU/mL for hCG should be obtained within 2 weeks prior to therapy with FABIOR Foam, which should begin during a normal menstrual period for females of childbearing potential.
In rats, tazarotene 0.05% gel administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies.
Systemic exposure (AUC) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits were 15 and 166 times, respectively, the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
As with other retinoids, when tazarotene was administered orally to experimental animals, developmental delays were seen in rats, and teratogenic effects and post-implantation loss were observed in rats and rabbits at doses 13 and 325 times, respectively, the AUC to tazarotenic acid in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
In female rats orally administered 2 mg/kg/day tazarotene from 15 days before mating through gestation day 7, a number of classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations was also observed. AUC in rats was 42 times the AUC in acne patients treated with 2 mg/cm² of FABIOR Foam 0.1% over a 15% body surface area.
Nursing Mothers
After single topical doses of 14C-tazarotene to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. The safe use of FABIOR Foam during lactation has not been established. A decision should be made whether to discontinue breastfeeding or to discontinue therapy with FABIOR Foam taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Pediatric Use
The safety and effectiveness of FABIOR Foam in pediatric patients younger than 12 years have not been established. Clinical studies of FABIOR Foam included 860 patients aged 12 to 17 years with acne vulgaris.
Geriatric Use
FABIOR Foam for the treatment of acne has not been clinically evaluated in persons over the age of 65.
WARNINGS
Pregnancy Category X
See CONTRAINDICATIONS section. Women of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when Karac® (tazarotene gel) Gel is used. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test having a sensitivity down to at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to Karac® (tazarotene gel) Gel therapy, which should begin during a normal menstrual period.
PRECAUTIONS
General
Karac® (tazarotene gel) Gel should be applied only to the affected areas. For external use only. Avoid contact with eyes, eyelids, and mouth. If contact with eyes occurs, rinse thoroughly with water. The safety of use of Karac® (tazarotene gel) Gel over more than 20% of body surface area has not been established in psoriasis or acne.
Retinoids should not be used on eczematous skin, as they may cause severe irritation.
Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided unless deemed medically necessary, and in such cases, exposure should be minimized during the use of Karac® (tazarotene gel) Gel. Patients must be warned to use sunscreens (minimum SPF of 15) and protective clothing when using Karac® (tazarotene gel) Gel. Patients with sunburn should be advised not to use Karac® (tazarotene gel) Gel until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using Karac® (tazarotene gel) Gel and ensure that the precautions outlined in the Information for Patients subsection are observed.
Karac® (tazarotene gel) Gel should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity.
Some individuals may experience excessive pruritus, burning, skin redness or peeling. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established. Alternatively, patients with psoriasis who are being treated with the 0.1% concentration can be switched to the lower concentration.
Weather extremes, such as wind or cold, may be more irritating to patients using Karac® (tazarotene gel) Gel.
Information for Patients
See Patient Package Insert.
Carcinogenesis, Mutagenesis, Impairment of Fertility
A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risks. Based on pharmacokinetic data from a shorter-term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure (AUCde) in the rat equivalent to 0.32 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.38 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
In evaluation of photo co-carcinogenicity, median time to onset of tumors was decreased, and the number of tumors increased in hairless mice following chronic topical dosing with intercurrent exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks.
A long-term topical application study of up to 0.1% tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared to vehicle control animals; untreated control animals were not completely evaluated. Systemic exposure (AUC0-12h) at the highest dose was 2 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 2.5 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
Tazarotene was found to be non-mutagenic in the Ames assay using Salmonella and E. coli and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was also non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test.
No impairment of fertility occurred in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure (AUCde) in the rat would be equivalent to 0.31 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.38 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene, which produced an AUCde that was 0.95 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 1.2 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
No effect on parameters of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through day 7 of gestation with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at 2 mg/kg/day (see CONTRAINDICATIONS). This dose produced an AUC0-24h which was 1.7 times that observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 2.1 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure (AUCde) in the rat would be equivalent to 0.31 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.38 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
Pregnancy
Teratogenic Effects - Pregnancy Category X
See CONTRAINDICATIONS section. Women of childbearing potential should use adequate birth-control measures when Karac® (tazarotene gel) Gel is used. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test having a sensitivity down to at least 50 mIU/mL for hCG should be obtained within 2 weeks prior to Karac® (tazarotene gel) Gel therapy, which should begin during a normal menstrual period. There are no adequate, well-controlled studies in pregnant women. Although there may be less systemic exposure in the treatment of acne of the face alone due to less surface area for application, tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans (see CLINICAL PHARMACOLOGY: Pharmacokinetics).
Nursing Mothers
After single topical doses of 14
Pediatric Use
The safety and efficacy of tazarotene have not been established in pediatric patients under the age of 12 years.
Geriatric Use
Of the total number of subjects in clinical studies of tazarotene gels, 0.05% and 0.1% for plaque psoriasis, 163 were over the age of 65. Subjects over 65 years of age experienced more adverse events and lower treatment success rates after 12 weeks of use of Karac® (tazarotene gel) Gel compared with those 65 years of age and younger. Currently there is no other reliable clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals can not be ruled out. Tazarotene gel for the treatment of acne has not been clinically evaluated in persons over the age of 65.
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Fetal Risk
Systemic exposure to tazarotenic acid is dependent upon the extent of the body surface area treated. In patients treated topically over sufficient body surface area, exposure could be in the same order of magnitude as in orally treated animals. Tazarotene is a teratogenic substance, and it is not known what level of exposure is required for teratogenicity in humans.
There were 5 reported pregnancies in subjects who participated in clinical trials for topical tazarotene foam. One of the subjects was found to have been treated with topical tazarotene for 25 days, 2 were treated with vehicle foam, and the other 2 did not receive either tazarotene foam or vehicle foam. The subjects were discontinued from the trials when their pregnancy was reported. The one pregnant woman who was inadvertently exposed to topical tazarotene during the clinical trial delivered a full-term healthy infant.
Females Of Childbearing Potential
Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when tazarotene foam is used. The possibility of pregnancy should be considered in females of child-bearing potential at the time of institution of therapy.
A negative serum or urine result for pregnancy test having a sensitivity down to at least 25 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within 2 weeks prior to therapy with Karac Foam, which should begin during a normal menstrual period for females of childbearing potential. Advise patients of the need to use an effective method of contraception to avoid pregnancy.
Local Irritation
Karac Foam should be used with caution in patients with a history of local tolerability reactions or local hypersensitivity. Retinoids should not be used on abraded or eczematous skin, as they may cause severe irritation. Contact with the mouth, eyes, and mucous membranes should be avoided. In case of accidental contact, rinse well with water.
Some individuals may experience skin redness, peeling, burning or excessive pruritus. If these effects occur, the medication should either be discontinued until the integrity of the skin is restored, or the dosing should be reduced to an interval the patient can tolerate. However, efficacy at reduced frequency of application has not been established.
Weather extremes, such as wind or cold, may be more irritating to patients using Karac Foam.
Potential Irritant Effect With Concomitant Topical Medications
Concomitant topical acne therapy should be used with caution because a cumulative irritant effect may occur. If irritancy or dermatitis occurs, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists.
Photosensitivity And Risk For Sunburn
Because of heightened burning susceptibility, exposure to sunlight (including sunlamps) should be avoided. Patients must be warned to use sunscreens and protective clothing when using Karac Foam. Patients with sunburn should be advised not to use Karac Foam until fully recovered. Patients who may have considerable sun exposure due to their occupation and those patients with inherent sensitivity to sunlight should exercise particular caution when using Karac Foam and ensure that the precautions are observed. Due to the potential for photosensitivity resulting in greater risk for sunburn, Karac Foam should be used with caution in patients with a personal or family history of skin cancer.
Karac Foam should be administered with caution if the patient is also taking drugs known to be photosensitizers (e.g., thiazides, tetracyclines, fluoroquinolones, phenothiazines, sulfonamides) because of the increased possibility of augmented photosensitivity.
Flammability
The propellant in Karac Foam is flammable. Instruct the patient to avoid fire, flame, and/or smoking during and immediately following application.
Patient Counseling Information
See FDA-approved patient labeling (PATIENT INFORMATION).
Inform the patient of the following:
- Fetal risk associated with Karac Foam for females of childbearing potential. Advise patients to use an effective method of contraception during treatment to avoid pregnancy. Advise the patient to stop medication if she becomes pregnant and call her doctor.
- If undue irritation (redness, peeling, or discomfort) occurs, reduce frequency of application or temporarily interrupt treatment. Treatment may be resumed once irritation subsides.
- Do not place Karac Foam in the freezer.
- Avoid exposure of the treated areas to either natural or artificial sunlight, including tanning beds and sun lamps.
- Avoid contact with the eyes. If Karac Foam gets in or near their eyes, to rinse thoroughly with water.
- Wash their hands after applying Karac Foam.
- Avoid fire, flame, or smoking during and immediately following application since Karac Foam is flammable.
- Keep out of the reach of children.
- Not for ophthalmic, oral, or intravaginal use.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Carcinogenesis
A long-term study of tazarotene following oral administration of 0.025, 0.050, and 0.125 mg/kg/day to rats showed no indications of increased carcinogenic risk. Based on pharmacokinetic data from a shorter-term study in rats, the highest dose of 0.125 mg/kg/day was anticipated to give systemic exposure in rats approximately 2 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
A long-term topical application study of up to 0.1% tazarotene in a gel formulation in mice terminated at 88 weeks showed that dose levels of 0.05, 0.125, 0.25, and 1 mg/kg/day (reduced to 0.5 mg/kg/day for males after 41 weeks due to severe dermal irritation) revealed no apparent carcinogenic effects when compared with vehicle control animals. AUC at the highest dose in mice was 49 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
In evaluation of photocarcinogenicity, median time to onset of tumors was decreased and the number of tumors increased in hairless mice following chronic topical dosing with exposure to ultraviolet radiation at tazarotene concentrations of 0.001%, 0.005%, and 0.01% in a gel formulation for up to 40 weeks.
Mutagenesis
Tazarotene was non-mutagenic in the Ames assay and did not produce structural chromosomal aberrations in a human lymphocyte assay. Tazarotene was non-mutagenic in the CHO/HGPRT mammalian cell forward gene mutation assay and was non-clastogenic in the in vivo mouse micronucleus test.
Impairment Of Fertility
No impairment of fertility was observed in rats when male animals were treated for 70 days prior to mating and female animals were treated for 14 days prior to mating and continuing through gestation and lactation with topical doses of tazarotene gel up to 0.125 mg/kg/day. Based on data from another study, the systemic drug exposure at the 0.125 mg/kg/day dose in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
No impairment of mating performance or fertility was observed in male rats treated for 70 days prior to mating with oral doses of up to 1 mg/kg/day tazarotene. AUC at the highest dose in rats was 23 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
No effect on parameters of mating performance or fertility was observed in female rats treated for 15 days prior to mating and continuing through gestation day 7 with oral doses of tazarotene up to 2 mg/kg/day. However, there was a significant decrease in the number of estrous stages and an increase in developmental effects at that dose. AUC at the highest dose in rats was 42 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
Reproductive capabilities of F1 animals, including F2 survival and development, were not affected by topical administration of tazarotene gel to female F0 parental rats from gestation day 16 through lactation day 20 at the maximum tolerated dose of 0.125 mg/kg/day. Based on data from another study, the AUC in rats would be equivalent to 7.6 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
Use In Specific Populations
Pregnancy
Pregnancy Category X.
Karac Foam is contraindicated in pregnancy.
There are no adequate and well-controlled studies with Karac Foam in pregnant women. Karac Foam is contraindicated in females who are or may become pregnant. Females of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when Karac Foam is used. The possibility that a female of child-bearing potential is pregnant at the time of institution of therapy should be considered. A negative serum or urine result for pregnancy test having a sensitivity down to at least 25 mIU/mL for hCG should be obtained within 2 weeks prior to therapy with Karac Foam, which should begin during a normal menstrual period for females of childbearing potential.
In rats, tazarotene 0.05% gel administered topically during gestation days 6 through 17 at 0.25 mg/kg/day resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies.
Systemic exposure (AUC) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits were 15 and 166 times, respectively, the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
As with other retinoids, when tazarotene was administered orally to experimental animals, developmental delays were seen in rats, and teratogenic effects and post-implantation loss were observed in rats and rabbits at doses 13 and 325 times, respectively, the AUC to tazarotenic acid in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
In female rats orally administered 2 mg/kg/day tazarotene from 15 days before mating through gestation day 7, a number of classic developmental effects of retinoids were observed including decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights. A low incidence of retinoid-related malformations was also observed. AUC in rats was 42 times the AUC in acne patients treated with 2 mg/cm² of Karac Foam 0.1% over a 15% body surface area.
Nursing Mothers
After single topical doses of 14C-tazarotene to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. The safe use of Karac Foam during lactation has not been established. A decision should be made whether to discontinue breastfeeding or to discontinue therapy with Karac Foam taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
Pediatric Use
The safety and effectiveness of Karac Foam in pediatric patients younger than 12 years have not been established. Clinical studies of Karac Foam included 860 patients aged 12 to 17 years with acne vulgaris.
Geriatric Use
Karac Foam for the treatment of acne has not been clinically evaluated in persons over the age of 65.
Expérience des essais cliniques
Étant donné que les essais cliniques sont menés dans des conditions très variables, les taux d'effets indésirables observés dans les essais cliniques d'un médicament ne peuvent pas être directement comparés aux taux dans les essais cliniques d'un autre médicament et peuvent ne pas refléter les taux observés dans la pratique.
Les données de sécurité reflètent l'exposition à la mousse FABIOR chez 744 sujets atteints d'acné vulgaire. Les sujets étaient âgés de 12 à 45 ans et ont été traités une fois par jour le soir pendant 12 semaines. Les effets indésirables rapportés chez ≥ 1% des sujets traités par FABIOR Foam sont présentés dans le tableau 1. La plupart des effets indésirables étaient d'intensité légère à modérée. Les effets indésirables graves représentaient 3,0% des sujets traités. Dans l'ensemble, 2,7% (20/744) des sujets ont abandonné la mousse FABIOR en raison de réactions cutanées locales.
Tableau 1: Incidence des effets indésirables chez ≥ 1% des sujets traités avec de la mousse FABIOR
FABIOR Foam N = 744 | Mousse de véhicule N = 741 | |
Patients présentant un effet indésirable, n (%) | 163 (22) | 19 (3) |
Irritation du site d'application | 107 (14) | 9 (1) |
Sécheresse au site d'application | 50 (7) | 8 (1) |
Érythème du site d'application | 48 (6) | 3 (<1) |
Exfoliation du site d'application | 44 (6) | 3 (<1) |
Douleur au site d'application | 9 (1) | 0 |
Photosensibilité au site d'application (y compris les coups de soleil) | 8 (1) | 3 (<1) |
Prurit du site d'application | 7 (1) | 3 (<1) |
Dermatite au site d'application | 6 (1) | 1 (<1) |
Les effets indésirables supplémentaires signalés chez <1% des sujets traités par FABIOR Foam comprenaient des réactions au site d'application (y compris décoloration, inconfort, œdème, éruption cutanée et gonflement), une dermatite, un impétigo et un prurit.
Les réactions cutanées locales, la sécheresse, l'érythème et le pelage activement évalués par l'investigateur et les brûlures / picotements et démangeaisons signalés par le sujet ont été évalués au départ, pendant le traitement et à la fin du traitement. Pendant les 12 semaines de traitement, chaque réaction cutanée locale a culminé à la semaine 2 et s'est progressivement réduite par la suite avec l'utilisation continue de FABIOR Foam.
Dans les études de sécurité cutanée humaine, le tazarotène 0,05% et 0,1% gels n'ont pas induit de sensibilisation au contact allergique, de phototoxicité ou de photoallergie.
Psoriasis
Les événements indésirables les plus fréquemment rapportés avec le gel de Karac® (gel de tazarotène) à 0,05% et 0,1% étaient limités à la peau. Ceux qui se produisent chez 10 à 30% des patients, par ordre décroissant, comprenaient le prurit, les brûlures / picotements, l'érythème, l'aggravation du psoriasis, l'irritation et les douleurs cutanées. Les événements survenus chez 1 à 10% des patients comprenaient une éruption cutanée, une desquamation, une dermatite de contact irritante, une inflammation cutanée, des fissures, des saignements et une peau sèche. Des augmentations de «l'aggravation de la psoriasis» et de «l'érythème induit par le soleil» ont été notées chez certains patients au cours des 4e à 12e mois par rapport aux trois premiers mois d'une étude d'un an. En général, l'incidence des événements indésirables avec le gel de Karac® (gel de tazarotène) 0,05% était de 2 à 5% inférieure à celle observée avec le gel de Karac® (gel de tazarotène) 0,1%.
Acné
Les événements indésirables les plus fréquents rapportés avec le gel de Karac® (gel de tazarotène) 0,1% dans le traitement de l'acné survenant chez 10 à 30% des patients, par ordre décroissant, comprenaient la desquamation, les brûlures / picotements, la peau sèche, l'érythème et le prurit. Les événements survenus chez 1 à 10% des patients comprenaient une irritation, des douleurs cutanées, des fissures, un œdème localisé et une décoloration de la peau.
Expérience post-commercialisation
Les effets indésirables suivants ont été identifiés lors de l'utilisation post-commercialisation du gel Karac® (gel de tazarotène) à 0,05% et 0,1% en pratique clinique. Parce qu'ils sont signalés volontairement par une population de taille inconnue, il n'est pas toujours possible d'estimer de manière fiable leur fréquence ou d'établir une relation causale avec le gel Karac® (gel de tazarotène). Les réactions comprennent: cloques, éruptions cutanées, décoloration de la peau (y compris hyperpigmentation cutanée ou hypopigmentation cutanée) et douleur.
Expérience des essais cliniques
Étant donné que les essais cliniques sont menés dans des conditions très variables, les taux d'effets indésirables observés dans les essais cliniques d'un médicament ne peuvent pas être directement comparés aux taux dans les essais cliniques d'un autre médicament et peuvent ne pas refléter les taux observés dans la pratique.
Les données de sécurité reflètent l'exposition à la mousse de karac chez 744 sujets atteints d'acné vulgaire. Les sujets étaient âgés de 12 à 45 ans et ont été traités une fois par jour le soir pendant 12 semaines. Les effets indésirables rapportés chez ≥ 1% des sujets traités par de la mousse de karac sont présentés dans le tableau 1. La plupart des effets indésirables étaient d'intensité légère à modérée. Les effets indésirables graves représentaient 3,0% des sujets traités. Dans l'ensemble, 2,7% (20/744) des sujets ont arrêté la mousse de karac en raison de réactions cutanées locales.
Tableau 1: Incidence des effets indésirables chez ≥ 1% des sujets traités avec de la mousse de karac
Mousse de karac N = 744 | Mousse de véhicule N = 741 | |
Patients présentant un effet indésirable, n (%) | 163 (22) | 19 (3) |
Irritation du site d'application | 107 (14) | 9 (1) |
Sécheresse au site d'application | 50 (7) | 8 (1) |
Érythème du site d'application | 48 (6) | 3 (<1) |
Exfoliation du site d'application | 44 (6) | 3 (<1) |
Douleur au site d'application | 9 (1) | 0 |
Photosensibilité au site d'application (y compris les coups de soleil) | 8 (1) | 3 (<1) |
Prurit du site d'application | 7 (1) | 3 (<1) |
Dermatite au site d'application | 6 (1) | 1 (<1) |
Les effets indésirables supplémentaires signalés chez <1% des sujets traités par Karac Foam comprenaient des réactions au site d'application (y compris décoloration, inconfort, œdème, éruption cutanée et gonflement), une dermatite, un impétigo et un prurit.
Les réactions cutanées locales, la sécheresse, l'érythème et le pelage activement évalués par l'investigateur et les brûlures / picotements et démangeaisons signalés par le sujet ont été évalués au départ, pendant le traitement et à la fin du traitement. Pendant les 12 semaines de traitement, chaque réaction cutanée locale a culminé à la semaine 2 et s'est progressivement réduite par la suite avec l'utilisation continue de mousse de karac.
Une application topique excessive de mousse FABIOR peut entraîner une rougeur, un peeling ou une gêne marqués.. La prise en charge de l'ingestion accidentelle ou d'une application excessive sur la peau doit être la mention clinique.
Une utilisation topique excessive du gel Karac® (gel de tazarotène) peut entraîner une rougeur, un peeling ou une gêne marqués (voir PRÉCAUTIONS: Général).
Les gels de karac® (gel de tazarotène) 0,05% et 0,1% ne sont pas destinés à un usage oral. L'ingestion orale du médicament peut entraîner les mêmes effets indésirables que ceux associés à un apport oral excessif en vitamine A (hypervitaminose A) ou d'autres rétinoïdes. En cas d'ingestion orale, le patient doit être surveillé et des mesures de soutien appropriées doivent être administrées si nécessaire.
Une application topique excessive de mousse de Karac peut entraîner une rougeur, un peeling ou une gêne marqués.. La prise en charge de l'ingestion accidentelle ou d'une application excessive sur la peau doit être la mention clinique.
La pharmacodynamique de FABIOR Foam est inconnue.
La pharmacodynamique de la mousse de Karac est inconnue.
Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones, and other polar metabolites which were eliminated through urinary and fecal pathways.
Systemic exposure following topical application of FABIOR Foam 0.1% was evaluated in one trial. Patients aged 15 years and older with moderate-to-severe acne applied approximately 3.7 grams of FABIOR Foam 0.1% (N = 13) to approximately 15% body surface area (face, upper chest, upper back, and shoulders) once daily for 22 days. On Day 22, the mean (±SD) tazarotenic acid Cmax was 0.43 (±0.19) ng/mL, the AUC0-24h - was 6.98 (±3.56) ng·h/mL, and the half-life was 21.7 (±15.7) hours. The median Tmax was 6 hours (range: 4.4 to 12 hours). The AUC0-24h for tazarotenic acid was approximately 50-fold higher compared with the parent compound tazarotene. The mean (±SD) half-life of tazarotene was 8.1 (±3.7) hours.
Accumulation was observed upon repeated once-daily dosing as the tazarotenic acid predose concentrations were measurable in the majority of subjects. Steady state was attained within 22 days of daily application. Once-daily dosing resulted in little to no accumulation of tazarotene as predose concentrations were mostly below the quantitation limit throughout the study.
Nursing Mothers
After single topical doses of 14C-tazarotene to the skin of lactating rats, radioactivity was detected in milk, suggesting that there would be transfer of drug-related material to the offspring via milk. It is not known whether this drug is excreted in human milk. Caution should be exercised when tazarotene is administered to a nursing woman.
Pediatric Use
The safety and efficacy of tazarotene have not been established in pediatric patients under the age of 12 years.
Geriatric Use
Of the total number of subjects in clinical studies of tazarotene gels, 0.05% and 0.1% for plaque psoriasis, 163 were over the age of 65. Subjects over 65 years of age experienced more adverse events and lower treatment success rates after 12 weeks of use of Karac® (tazarotene gel) Gel compared with those 65 years of age and younger. Currently there is no other reliable clinical experience on the differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals can not be ruled out. Tazarotene gel for the treatment of acne has not been clinically evaluated in persons over the age of 65.
Overdosage & ContraindicationsOVERDOSE
Excessive topical use of Karac® (tazarotene gel) Gel may lead to marked redness, peeling, or discomfort (see PRECAUTIONS: General).
Karac® (tazarotene gel) Gels 0.05% and 0.1% are not for oral use. Oral ingestion of the drug may lead to the same adverse effects as those associated with excessive oral intake of Vitamin A (hypervitaminosis A) or other retinoids. If oral ingestion occurs, the patient should be monitored, and appropriate supportive measures should be administered as necessary.
CONTRAINDICATIONS
Retinoids may cause fetal harm when administered to a pregnant woman.
In rats, tazarotene 0.05% gel, administered topically during gestation days 6 through 17 at 0.25 mg/kg/day (1.5 mg/m²/day) resulted in reduced fetal body weights and reduced skeletal ossification. Rabbits dosed topically with 0.25 mg/kg/day (2.75 mg/m² total body surface area/day) tazarotene gel during gestation days 6 through 18 were noted with single incidences of known retinoid malformations, including spina bifida, hydrocephaly, and heart anomalies. Systemic daily-exposure (AUCde) to tazarotenic acid at topical doses of 0.25 mg/kg/day tazarotene in a gel formulation in rats and rabbits represented 0.62 and 6.7 times, respectively, the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.78 and 8.4 times, respectively, the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
As with other retinoids, when tazarotene was given orally to experimental animals, developmental delays were seen in rats, and teratogenic effects and post-implantation loss were observed in rats and rabbits at AUCde values that were 0.55 and 13.2 times, respectively, the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² of tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area), and 0.68 and 16.4 times, respectively, the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
In a study of the effect of oral tazarotene on fertility and early embryonic development in rats, decreased number of implantation sites, decreased litter size, decreased numbers of live fetuses, and decreased fetal body weights, all classic developmental effects of retinoids, were observed when female rats were administered 2 mg/kg/day from 15 days before mating through gestation day 7. A low incidence of retinoid-related malformations at that dose was reported to be related to treatment. This dose produced an AUCde that was 1.7 times the AUC0-24h observed in psoriatic patients treated with 2 mg/cm² tazarotene gel 0.1% (extrapolated for topical application over 20% body surface area) and 2.1 times the maximum AUC0-24h in acne patients treated with 2 mg/cm² of tazarotene gel 0.1% over 15% (targeted) body surface area.
SYSTEMIC EXPOSURE TO TAZAROTENIC ACID IS DEPENDENT UPON THE EXTENT OF THE BODY SURFACE AREA TREATED. IN PATIENTS TREATED TOPICALLY OVER SUFFICIENT BODY SURFACE AREA, EXPOSURE COULD BE IN THE SAME ORDER OF MAGNITUDE AS IN THESE ORALLY TREATED ANIMALS. ALTHOUGH THERE MAY BE LESS SYSTEMIC EXPOSURE IN THE TREATMENT OF ACNE OF THE FACE ALONE DUE TO LESS SURFACE AREA FOR APPLICATION, TAZAROTENE IS A TERATOGENIC SUBSTANCE, AND IT IS NOT KNOWN WHAT LEVEL OF EXPOSURE IS REQUIRED FOR TERATOGENICITY IN HUMANS (SEE CLINICAL PHARMACOLOGY: Pharmacokinetics).
There were thirteen reported pregnancies in patients who participated in clinical trials for topical tazarotene. Nine of the patients were found to have been treated with topical tazarotene, and the other four had been treated with vehicle. One of the patients who was treated with tazarotene cream elected to terminate the pregnancy for non-medical reasons unrelated to treatment. The other eight pregnant women who were inadvertently exposed to topical tazarotene during clinical trials subsequently delivered apparently healthy babies. As the exact timing and extent of exposure in relation to the gestation times are not certain, the significance of these findings is unknown.
Karac® (tazarotene gel) Gel is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, treatment should be discontinued and the patient apprised of the potential hazard to the fetus. Women of child-bearing potential should be warned of the potential risk and use adequate birth-control measures when Karac® (tazarotene gel) Gel is used. The possibility that a woman of childbearing potential is pregnant at the time of institution of therapy should be considered. A negative result for pregnancy test having a sensitivity down to at least 50 mIU/mL for human chorionic gonadotropin (hCG) should be obtained within 2 weeks prior to Karac® (tazarotene gel) Gel therapy, which should begin during a normal menstrual period (see also PRECAUTIONS: Pregnancy: Teratogenic Effects).
Karac® (tazarotene gel) Gel is contraindicated in individuals who have shown hypersensitivity to any of its components.
Clinical PharmacologyCLINICAL PHARMACOLOGY
Tazarotene is a retinoid prodrug which is converted to its active form, the cognate carboxylic acid of tazarotene (AGN 190299), by rapid deesterification in animals and man. AGN 190299 (“tazarotenic acid”) binds to all three members of the retinoic acid receptor (RAR) family: RARα, RARβ, and RARγ but shows relative selectivity for RARβ, and RARγ and may modify gene expression. The clinical significance of these findings is unknown.
Psoriasis
The mechanism of tazarotene action in psoriasis is not defined. Topical tazarotene blocks induction of mouse epidermal ornithine decarboxylase (ODC) activity, which is associated with cell proliferation and hyperplasia. In cell culture and in vitro models of skin, tazarotene suppresses expression of MRP8, a marker of inflammation present in the epidermis of psoriasis patients at high levels. In human keratinocyte cultures, it inhibits cornified envelope formation, whose build-up is an element of the psoriatic scale. Tazarotene also induces the expression of a gene which may be a growth suppressor in human keratinocytes and which may inhibit epidermal hyperproliferation in treated plaques. However, the clinical significance of these findings is unknown.
Acne
The mechanism of tazarotene action in acne vulgaris is not defined. However, the basis of tazarotene's therapeutic effect in acne may be due to its anti-hyperproliferative, normalizing-of-differentiation and antiinflammatory effects. Tazarotene inhibited corneocyte accumulation in rhino mouse skin and cross-linked envelope formation in cultured human keratinocytes. The clinical significance of these findings is unknown.
Pharmacokinetics
Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Little parent compound could be detected in the plasma. Tazarotenic acid was highly bound to plasma proteins ( ≥ greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. The half-life of tazarotenic acid was approximately 18 hours, following topical application of tazarotene to normal, acne or psoriatic skin.
The human in vivo studies described below were conducted with tazarotene gel applied topically at approximately 2 mg/cm² and left on the skin for 10 to 12 hours. Both the peak plasma concentration (Cmax) and area under the plasma concentration time curve (AUC) refer to the active metabolite only.
Two single, topical dose studies were conducted using 14C-tazarotene gel. Systemic absorption, as determined from radioactivity in the excreta, was less than 1% of the applied dose (without occlusion) in six psoriatic patients and approximately 5% of the applied dose (under occlusion) in six healthy subjects. One non-radiolabeled single-dose study comparing the 0.05% gel to the 0.1% gel in healthy subjects indicated that the Cmax and AUC were 40% higher for the 0.1% gel.
After 7 days of topical dosing with measured doses of tazarotene 0.1% gel on 20% of the total body surface without occlusion in 24 healthy subjects, the Cmax for tazarotenic acid was 0.72 RMG 0.58 ng/mL (mean RMG SD) occurring 9 hours after the last dose, and the AUC0-24hr for tazarotenic acid was 10.1 RMG 7.2 ng·hr/mL. Systemic absorption was 0.91 RMG 0.67% of the applied dose.
In a 14-day study in five psoriatic patients, measured doses of tazarotene 0.1% gel were applied daily by nursing staff to involved skin without occlusion (8 to 18% of total body surface area; mean RMG SD: 13 RMG 5%). The Cmax for tazarotenic acid was 12.0 RMG 7.6 ng/mL occurring 6 hours after the final dose, and the AUC0-24hr for tazarotenic acid was 105 RMG 55 ng·hr/mL. Systemic absorption was 14.8 RMG 7.6% of the applied dose. Extrapolation of these results to represent dosing on 20% of total body surface yielded estimates for tazarotenic acid with Cmax of 18.9 RMG 10.6 ng/mL and AUC0-24hr of 172 RMG 88 ng·hr/mL.
An in vitro percutaneous absorption study, using radiolabeled drug and freshly excised human skin or human cadaver skin, indicated that approximately 4 to 5% of the applied dose was in the stratum corneum (tazarotene: tazarotenic acid = 5:1) and 2 to 4% was in the viable epidermis-dermis layer (tazarotene:tazarotenic acid = 2:1) 24 hours after topical application of the gel.
Clinical Studies
Psoriasis
In two large vehicle-controlled clinical studies, tazarotene 0.05% and 0.1% gels applied once daily for 12 weeks were significantly more effective than vehicle in reducing the severity of the clinical signs of stable plaque psoriasis covering up to 20% of body surface area. In one of the studies, patients were followed up for an additional 12 weeks following cessation of therapy with Karac® (tazarotene gel) Gel. Mean baseline scores and changes from baseline (reductions) after treatment in these two studies are shown in the following table:
Plaque Elevation, Scaling and Erythema in Two Controlled Clinical Trials for Psoriasis
Karac® 0.05% Gel | Karac® 0.1% Gel | Vehicle | Gel | ||||||||||
Trunk/Arm/Leg Lesions | Knee/Elbow Lesions | Trunk/Arm/Leg Lesions | Knee/Elbow Lesions | Trunk/Arm/Leg Lesions | Knee/Elbow Lesions | ||||||||
N=108 | N=111 | N=108 | N=111 | N=108 | N=112 | N=108 | N=112 | N=108 | N=113 | N=108 | N=113 | ||
Plaque | B* | 2.5 | 2.6 | 2.6 | 2.6 | 2.5 | 2.6 | 2.6 | 2.6 | 2.4 | 2.6 | 2.6 | 2.6 |
Elevation | C-12* | -1.4 | -1.3 | -1.3 | -1.1 | -1.4 | -1.4 | -1.5 | -1.3 | -0.8 | -0.7 | -0.7 | -0.6 |
C-24* | -1.2 | -1.1 | -1.1 | -1.0 | -0.9 | -0.7 | |||||||
Scaling | B* | 2.4 | 2.5 | 2.5 | 2.6 | 2.4 | 2.6 | 2.5 | 2.7 | 2.4 | 2.6 | 2.5 | 2.7 |
C-12* | -1.1 | -1.1 | -1.1 | -0.9 | -1.3 | -1.3 | -1.2 | -1.2 | -0.7 | -0.7 | -0.6 | -0.6 | |
C-24* | -0.9 | -0.8 | -1.0 | -0.8 | -0.8 | -0.7 | |||||||
Erythema | B* | 2.4 | 2.7 | 2.2 | 2.5 | 2.4 | 2.8 | 2.3 | 2.5 | 2.3 | 2.7 | 2.2 | 2.5 |
C-12* | -1.0 | -0.8 | -0.9 | -0.8 | -1.0 | -1.1 | -1.0 | -0.8 | -0.6 | -0.5 | -0.5 | -0.5 | |
C-24* | -1.1 | -0.7 | -0.9 | -0.8 | -0.7 | -0.6 | |||||||
Plaque elevation, scaling and erythema scored on a 0-4 scale with 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe. B*=Mean Baseline Severity: C-12*=Mean Change from Baseline at end of 12 weeks of therapy: C-24*=Mean Change from Baseline at week 24 (12 weeks after the end of therapy). |
Global improvement over baseline at the end of 12 weeks of treatment in these two studies is shown in the following table:
Karac® 0.05% Gel | Karac® 0.1% Gel | Vehicle Gel | ||||
N=81 | N-93 | N=79 | N=69 | N=84 | N=91 | |
100% improvement | 2 (2%) | 1 (1%) | 0 | 0 | 1 (1%) | 0 |
≥ 75% improvement | 23 (28%) | 17 (18%) | 30 (38%) | 17 (25%) | 10 (12%) | 9 (10%) |
≥ 50% improvement | 42 (52%) | 39 (42%) | 51 (65%) | 36 (52%) | 28 (33%) | 21 (23%) |
1-49% improvement | 21 (26%) | 32 (34%) | 18 (23%) | 23 (33%) | 27 (32%) | 32 (35%) |
No change or worse | 18 (22%) | 22 (24%) | 10 (13%) | 10 (14%) | 29 (35%) | 38 (42%) |
The 0.1% gel was more effective than the 0.05% gel, but the 0.05% gel was associated with less local irritation than the 0.1% gel (see ADVERSE REACTIONS section).
Acne
In two large vehicle-controlled studies, tazarotene 0.1% gel applied once daily was significantly more effective than vehicle in the treatment of facial acne vulgaris of mild to moderate severity. Percent reductions in lesion counts after treatment for 12 weeks in these two studies are shown in the following table:
Reduction in Lesion Counts after Twelve Weeks of Treatment in Two Controlled Clinical Trials for Acne
Karac® 0.1% Gel | Vehicle Gel | |||
N=150 | N=149 | N=148 | N=149 | |
Noninflammatory lesions | 55% | 43% | 35% | 27% |
Inflammatory lesions | 42% | 47% | 30% | 28% |
Total lesions | 52% | 45% | 33% | 27% |
Global improvement over baseline at the end of 12 weeks of treatment in these two studies is shown in the following table:
Karac® 0.1% Gel | Vehicle Gel | |||
N=105 | N=117 | N=117 | N=110 | |
100% improvement | 1 (1%) | 0 | 0 | 0 |
≥ 75% improvement | 40(38%) | 21(18%) | 23(20%) | 11(10%) |
≥ 50% improvement | 71(68%) | 56(48%) | 47(40%) | 32(29%) |
1-49% improvement | 23(22%) | 49(42%) | 48(41%) | 46(42%) |
No change or worse | 11(10%) | 12(10%) | 22(19%) | 32(29%) |
Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. Tazarotenic acid was highly bound to plasma proteins (greater than 99%). Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones, and other polar metabolites which were eliminated through urinary and fecal pathways.
Systemic exposure following topical application of Karac Foam 0.1% was evaluated in one trial. Patients aged 15 years and older with moderate-to-severe acne applied approximately 3.7 grams of Karac Foam 0.1% (N = 13) to approximately 15% body surface area (face, upper chest, upper back, and shoulders) once daily for 22 days. On Day 22, the mean (±SD) tazarotenic acid Cmax was 0.43 (±0.19) ng/mL, the AUC0-24h - was 6.98 (±3.56) ng·h/mL, and the half-life was 21.7 (±15.7) hours. The median Tmax was 6 hours (range: 4.4 to 12 hours). The AUC0-24h for tazarotenic acid was approximately 50-fold higher compared with the parent compound tazarotene. The mean (±SD) half-life of tazarotene was 8.1 (±3.7) hours.
Accumulation was observed upon repeated once-daily dosing as the tazarotenic acid predose concentrations were measurable in the majority of subjects. Steady state was attained within 22 days of daily application. Once-daily dosing resulted in little to no accumulation of tazarotene as predose concentrations were mostly below the quantitation limit throughout the study.
However, we will provide data for each active ingredient