Taclonex (Page 2 of 5)

6.2 Postmarketing Experience

The following adverse reactions associated with the use of Taclonex® Ointment have been identified post-approval: pustular psoriasis and rebound effect.

Because these reactions 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.

Postmarketing reports for local adverse reactions to topical corticosteroids may also include: striae, dryness, acneiform eruptions, perioral dermatitis, secondary infection and miliaria.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Taclonex® Ointment contains calcipotriene and betamethasone dipropionate. The limited data with Taclonex® Ointment and calcipotriene use in pregnant women are not sufficient to evaluate a Taclonex® Ointment-associated or calcipotriene-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes.

Observational studies suggest an increased risk of having low birthweight infants with the maternal use of potent or very potent topical corticosteroids (see Data). Advise pregnant women that Taclonex® Ointment may increase the potential risk of having a low birth weight infant and to use Taclonex® Ointment on the smallest area of skin and for the shortest duration possible.

In animal reproduction studies, oral administration of calcipotriene to pregnant rats during the period of organogenesis resulted in an increased incidence of minor skeletal abnormalities, including enlarged fontanelles and extra ribs (see Data). Oral administration of calcipotriene to pregnant rabbits during the period of organogenesis had no apparent effects on embryo-fetal development. Subcutaneous administration of betamethasone dipropionate to pregnant rats and rabbits during the period of organogenesis resulted in fetal toxicity, including fetal deaths, reduced fetal weight, and fetal malformations (cleft palate and crooked or short tail) (see Data). The available data do not allow the calculation of relevant comparisons between the systemic exposures of calcipotriene and betamethasone diproprionate observed in animal studies to the systemic exposures that would be expected in humans after topical use of Taclonex® Ointment.

The estimated background risk of major birth defects and miscarriage of the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

​Data

Human Data

Available observational studies in pregnant women did not identify a drug-associated risk of major birth defects, preterm delivery, or fetal mortality with the use of topical corticosteroids of any potency. However, when the dispensed amount of potent or very potent topical corticosteroids exceeded 300 g during the entire pregnancy, maternal use was associated with an increased risk of low birth weight in infants.

Animal Data

Embryo-fetal development studies with calcipotriene were performed by the oral route in rats and rabbits. Pregnant rats received dosages of 0, 6, 18, or 54 mcg/kg/day (0, 36, 108, and 324 mcg/m2 /day, respectively) on days 6-15 of gestation (the period of organogenesis). There were no apparent effects on maternal survival, behavior, or body weight gain, no effects on litter parameters, and no effects on the incidence of major malformations in fetuses. Fetuses from dams dosed at 54 mcg/kg/day exhibited a significantly increased incidence of minor skeletal abnormalities, including enlarged fontanelles and extra ribs.

Pregnant rabbits were dosed daily with calcipotriene at exposures of 0, 4, 12, or 36 mcg/kg/day (0, 48, 144, and 432 mcg/m2 /day, respectively) on days 6-18 of gestation (the period of organogenesis). Mean maternal body weight gain was reduced in animals dosed at 12 or 36 mcg/kg/day. The incidence of fetal deaths was increased in the group dosed at 36 mcg/kg/day; reduced fetal weight was also observed in this group. The incidence of major malformations among fetuses was not affected. An increase in the incidence of minor skeletal abnormalities, including incomplete ossification of sternebrae, pubic bones, and forelimb phalanges, was observed in the group dosed at 36 mcg/kg/day.

Embryo-fetal development studies with betamethasone dipropionate were performed via subcutaneous injection in mice and rabbits. Pregnant mice were administered doses of 0, 156, 625, or 2500 mcg/kg/day (0, 468, 1875, and 7500 mcg/m2 /day, respectively) on days 7 through 13 of gestation (the period of organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal deaths, reduced fetal weight, malformations (increased incidence of the cleft palate and crooked or short tail), and minor skeletal abnormalities (delayed ossification of vertebra and sternebrae). Fetal toxicity was observed at the lowest exposure that was evaluated (156 mcg/kg/day).

Pregnant rabbits were injected subcutaneously at dosages of 0, 0.625, 2.5, and 10 mcg/kg/day (0, 7.5, 30, and 120 mcg/m2 /day, respectively) on days 6 through 18 of gestation (the period of organogenesis). Betamethasone dipropionate induced fetal toxicity, including fetal deaths, reduced fetal weight, external malformations (including malformed ears, cleft palate, umbilical hernia, kinked tail, club foot, and club hand), and skeletal malformations (including absence of phalanges of the first digit and cranial dysplasia) at dosages of 2.5 mcg/kg/day and above.

Calcipotriene was evaluated for effects on peri- and post-natal development when orally administered to pregnant rats at dosages of 0, 6, 18 or 54 mcg/kg/day (0, 36, 108, and 324 mcg/m2 /day, respectively) from gestation day 15 through day 20 postpartum. No remarkable effects were observed on any parameter, including survival, behavior, body weight, litter parameters, or the ability to nurse or rear pups.

Betamethasone dipropionate was evaluated for effects on peri- and post-natal development when orally administered to pregnant rats at dosages of 0, 100, 300, and 1000 mcg/kg/day (0, 600, 1800, and 6000 mcg/m2 /day, respectively) from gestation day 6 through day 20 postpartum. Mean maternal body weight was significantly reduced on gestation day 20 in animals dosed at 300 and 1000 mcg/kg/day. The mean duration of gestation was slightly, but statistically significantly, increased at 100, 300, and 1000 mcg/kg/day. The mean percentage of pups that survived to day 4 was reduced in relation to dosage. On lactation day 5, the percentage of pups with a reflex to right themselves when placed on their back was significantly reduced at 1000 mcg/ kg/day. No effects on the ability of pups to learn were observed, and the ability of the offspring of treated rats to reproduce was not affected.

8.2 Lactation

Risk Summary

There is no information regarding the presence of topically administered calcipotriene and betamethasone dipropionate in human milk, the effects on the breastfed infant, or the effects on milk production. It is not known whether topically administered calcipotriene or corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Taclonex® Ointment and any potential adverse effects on the breastfed child from Taclonex® Ointment or from the underlying maternal condition.

Clinical Considerations

To minimize potential exposure to the breastfed infant via breast milk, use Taclonex® Ointment on the smallest area of skin and for the shortest duration possible while breastfeeding. Advise breastfeeding women not to apply Taclonex® Ointment directly to the nipple and areola to avoid direct infant exposure [see Use in Specific Populations (8.4)].

8.4 Pediatric Use

Safety and effectiveness of the use of Taclonex® Ointment in pediatric patients under the age of 12 years have not been established.

The safety and effectiveness of Taclonex® Ointment for the treatment of plaque psoriasis have been established in the age group 12 to 17 years. In a prospective, uncontrolled trial, 33 pediatric subjects ages 12-17 years with plaque psoriasis on the body were treated with Taclonex® Ointment for 4 weeks up to a maximum of 55.8 g per week. Subjects were assessed for HPA axis suppression and effects on calcium metabolism. No adverse effects on adrenal suppression were observed. No hypercalcemia was observed but one subject had a possible treatment-related increase in urinary calcium [see Clinical Pharmacology (12.2)].

Because of a higher ratio of skin surface area to body mass, pediatric patients are at a greater risk than adults of systemic toxicity when treated with topical drugs. They are, therefore, also at greater risk of HPA axis suppression and adrenal insufficiency upon the use of topical corticosteroids [see Warnings and Precautions (5.2)].

Rare systemic toxicities such as Cushing’s syndrome, linear growth retardation, delayed weight gain, and intracranial hypertension have been reported in pediatric patients, especially those with prolonged exposure to large doses of high potency topical corticosteroids.

Local adverse reactions including striae have also been reported with use of topical corticosteroids in pediatric patients.

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