Klisyri (tirbanibulin): Uses, Dosage, Side Effects & Warnings

Q: Who makes Klisyri?

Klisyri is listed by 1 labeler in the FDA NDC directory, including Almirall, LLC.

Uses

1 INDICATIONS AND USAGE KLISYRI is indicated for the topical field treatment of actinic keratosis on the face or scalp. KLISYRI is a microtubule inhibitor indicated for the topical treatment of actinic keratosis of the face or scalp. ( 1 )

Dosage and administration

For topical use only; not for oral or ophthalmic use. Apply KLISYRI evenly to cover up to 100 cm 2 treatment field on the face or balding scalp once daily for 5 consecutive days using 1 unit-dose packet per application. Wash hands immediately with soap and water after application. Avoid washing and touching the treated area for approximately 8 hours after application of KLISYRI. Following this time, the area may be washed with a mild soap. Avoid transfer of KLISYRI to the periocular area [see Warnings and Precautions ( 5.1 )] . Avoid application near and around the mouth and lips. For topical use; not for oral or ophthalmic use. ( 2 ) Apply KLISYRI to the treatment field on the face or scalp once daily for 5 consecutive days using 1 unit-dose packet per application. ( 2 )

Dosage forms and strengths

Ointment: 1% white to off-white ointment supplied in a unit-dose packet (2.5 mg tirbanibulin in 250 mg or 3.5 mg tirbanibulin in 350 mg). Ointment: 1% tirbanibulin supplied in unit-dose packets. ( 3 )

Contraindications

None. None. ( 4 )

Warnings and precautions

Ophthalmic Adverse Reactions: May cause eye irritation upon ocular exposure. Avoid transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, flush eyes with water and seek medical care. ( 5.1 ) Local Skin Reactions: Local skin reactions can occur including severe reactions (e.g., vesiculation/pustulation, erosion/ulceration) in the treated area. Avoid use until skin is healed from any previous drug or surgical treatment. ( 5.2 ) 5.1 Ophthalmic Adverse Reactions KLISYRI may cause eye irritation. Avoid transfer of the drug into the eyes and to the periocular area during and after application. Wash hands immediately after application. If accidental exposure occurs, instruct patient to flush eyes with water and seek medical care as soon as possible. 5.2 Local Skin Reactions Local skin reactions, including severe reactions (erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation and erosion/ulceration) in the treated area can occur after topical application of KLISYRI [see Adverse Reactions ( 6.1 )] . Occlusion after topical application of KLISYRI is more likely to result in irritation. Avoid use until skin is healed from any previous drug, procedure, or surgical treatment.

Side effects

Most common adverse reactions (incidence ≥2%) are local skin reactions, application site pruritus, and application site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almirall, at 1-866-665-2782 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed 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 clinical practice. Two double-blind, vehicle-controlled clinical trials were conducted in 702 adult subjects with actinic keratosis on the face or scalp. Subjects were randomized 1:1 to KLISYRI or vehicle. Subjects enrolled in the trials had 4 to 8 clinically typical, visible, and discrete AK lesions in a contiguous area of 25 cm 2 on the face or scalp. Subjects’ average age was 70 years (range 45 to 96 years) and they were predominantly White (99%), male (87%), with Fitzpatrick skin types I or II (72%) and actinic keratosis on the face (68%) or scalp (32%). Treatment groups were comparable across all demographics and baseline characteristics, including AK lesion count and distribution on the face or scalp. In the controlled trials, local skin reactions (LSRs) were collected independent of adverse events. Local skin reactions including erythema, flaking/scaling, crusting, swelling, vesiculation/pustulation, erosions/ulcerations were assessed by the investigators using a grading scale of 0 = absent, 1 = mild (slightly, barely perceptible), 2 = moderate (distinct presence), and 3 = severe (marked, intense). The percentages of subjects with the maximal post-baseline grades for each local skin reaction (LSR) greater than baseline by treatment group are provided in Table 1 . LSRs were mostly mild to moderate in severity ( Table 1 ). Table 1 Post-Baseline Local Skin Reactions in the Treatment Area (face or scalp) - Pooled Data from 2 Controlled Clinical Phase 3 Trials KLISYRI N = 353 Vehicle N = 349 Local Skin Reactions Mild n (%) Moderate n (%) Severe n (%) Mild n (%) Moderate n (%) Severe n (%) Erythema 76 (22%) 223 (63%) 22 (6%) 98 (28%) 20 (6%) 0 Flaking/ Scaling 92 (26%) 166 (47%) 31 (9%) 86 (25%) 33 (9%) 1 (<1%) Crusting 107 (30%) 50 (14%) 7 (2%) 31 (9%) 8 (2%) 0 Swelling 102 (29%) 32 (9%) 2 (<1%) 15 (4%) 1 (<1%) 0 Vesiculation/ Pustulation 25 (7%) 2 (<1%) 2 (<1%) 3 (<1%) 0 0 Erosion/ Ulceration 32 (9%) 9 (3%) 0 10 (3%) 0 0 Table 2 presents the adverse reactions experienced in ≥2% of subjects participating in the controlled clinical trials with KLISYRI. No subject withdrew from the trials due to adverse reactions. Table 2 Adverse Reactions Occurring in ≥2% of Subjects in 2 Controlled Clinical Trials– Pooled Safety Population a Application site pain includes pain, tenderness, stinging, and burning sensation at the application site. Adverse Reaction System Organ Class KLISYRI N = 353 Vehicle N = 349 Number of Subjects (%) with any adverse reaction (possibly related to treatment) 56 (16%) 35 (10%) Application site pruritus 32 (9%) 21 (6%) Application site paina 35 (10%) 11 (3%) For the 51 subjects (45 KLISYRI, 6 vehicle) who maintained complete clearance through the 12-month follow-up period, no additional local adverse reactions were reported. In a multicenter, open-label safety trial of 105 subjects where KLISYRI was applied to a treatment field of 100 cm 2 on the face or balding scalp, the results were comparable to the safety profile established by the controlled trials in subjects with a 25 cm 2 treatment area. Dermal Safety Studies Clinical studies in healthy subjects demonstrated KLISYRI did not cause contact sensitization (261 subjects), phototoxic skin reactions (31 subjects), or photoallergic skin reactions (64 subjects).

Use in specific populations

8.1 Pregnancy Risk Summary There are no available data with KLISYRI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of tirbanibulin to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal deaths and malformations at a systemic exposure that was at least 19 times the exposure associated with the maximum recommended human dose (MRHD). Oral administration of tirbanibulin to pregnant rabbits during the period of organogenesis resulted in reduced mean fetal weight and size at a systemic exposure that was 41 times the exposure associated with the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day, which resulted in systemic exposures at least 19 times the exposure associated with the MRHD on an Area Under the Curve (AUC) comparison basis. Tirbanibulin had no apparent effects on fetal development in rats at a dose of 0.5 mg/kg/day, which resulted in systemic exposures 5 times the exposure associated with the MRHD. Tirbanibulin reduced mean fetal weight and size (crown-rump length) when administered orally to pregnant rabbits during the period of organogenesis at a dose of 3 mg/kg/day, which resulted in a systemic exposure 41 times the exposure associated with the MRHD on an AUC comparison basis. Tirbanibulin had no apparent effects on fetal development in rabbits at a dose of 1 mg/kg/day, which resulted in systemic exposures 14 times the exposure associated with the MRHD. Tirbanibulin was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at dosages up to 1.25 mg/kg/day. These dosages resulted in systemic exposures up to 19 times the exposure associated with the MRHD on an AUC comparison basis. No adverse effects on maternal function or developmental, neurobehavioral, or reproductive performance of offspring were observed. 8.2 Lactation Risk Summary There are no data on lactational transfer of KLISYRI to human or animal milk. The effects of KLISYRI on the breastfed infant, or its effects on milk production, are unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KLISYRI and any potential adverse effects on the breastfed child from tirbanibulin or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of KLISYRI for actinic keratosis in subjects less than 18 years of age have not been established. Actinic keratosis is not a condition generally seen within the pediatric population. 8.5 Geriatric Use Of the 353 subjects with AK treated with KLISYRI in the 2 controlled Phase 3 trials, 246 (70%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Pregnancy

8.1 Pregnancy Risk Summary There are no available data with KLISYRI use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, oral administration of tirbanibulin to pregnant rats during the period of organogenesis resulted in an increased incidence of fetal deaths and malformations at a systemic exposure that was at least 19 times the exposure associated with the maximum recommended human dose (MRHD). Oral administration of tirbanibulin to pregnant rabbits during the period of organogenesis resulted in reduced mean fetal weight and size at a systemic exposure that was 41 times the exposure associated with the MRHD ( see Data ). The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Tirbanibulin induced fetal deaths and external, visceral, and skeletal malformations when administered orally to pregnant rats during the period of organogenesis at doses greater than or equal to 1.25 mg/kg/day, which resulted in systemic exposures at least 19 times the exposure associated with the MRHD on an Area Under the Curve (AUC) comparison basis. Tirbanibulin had no apparent effects on fetal development in rats at a dose of 0.5 mg/kg/day, which resulted in systemic exposures 5 times the exposure associated with the MRHD. Tirbanibulin reduced mean fetal weight and size (crown-rump length) when administered orally to pregnant rabbits during the period of organogenesis at a dose of 3 mg/kg/day, which resulted in a systemic exposure 41 times the exposure associated with the MRHD on an AUC comparison basis. Tirbanibulin had no apparent effects on fetal development in rabbits at a dose of 1 mg/kg/day, which resulted in systemic exposures 14 times the exposure associated with the MRHD. Tirbanibulin was assessed for effects on peri- and post-natal development of rats in a study that involved oral administration to pregnant rats during the period of organogenesis through lactation at dosages up to 1.25 mg/kg/day. These dosages resulted in systemic exposures up to 19 times the exposure associated with the MRHD on an AUC comparison basis. No adverse effects on maternal function or developmental, neurobehavioral, or reproductive performance of offspring were observed.

Pediatric use

8.4 Pediatric Use The safety and effectiveness of KLISYRI for actinic keratosis in subjects less than 18 years of age have not been established. Actinic keratosis is not a condition generally seen within the pediatric population.

Geriatric use

8.5 Geriatric Use Of the 353 subjects with AK treated with KLISYRI in the 2 controlled Phase 3 trials, 246 (70%) were 65 years of age or older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Description

(tirbanibulin) ointment is a microtubule inhibitor for topical use. The chemical name of tirbanibulin is N -benzyl-2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl) acetamide. The molecular weight is 431.4 and the molecular formula is C 26 H 29 N 3 O 3 . Tirbanibulin’s structural formula is: Tirbanibulin ointment 1% contains 10 mg tirbanibulin per gram of white to off-white ointment containing mono- and di-glycerides and propylene glycol. Chemical Structure

Mechanism of action

12.1 Mechanism of Action Tirbanibulin is a microtubule inhibitor. The mechanism of action of KLISYRI for the topical treatment of actinic keratosis is unknown.

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING KLISYRI is a white to off-white ointment and is supplied in unit-dose packets containing either 250 mg or 350 mg of tirbanibulin ointment 1%. Discard each unit-dose packet after use. NDC 16110-391-05 (5 unit-dose packets each containing 250 mg of ointment) NDC 16110-391-55 (5 unit-dose packets each containing 350 mg of ointment) Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.

Storage

Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze.

Patient information

Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use). Ophthalmic Adverse Reactions Advise patients that KLISYRI is not for ophthalmic use. Advise patients to avoid application around the eyes, and transfer of the drug into the eyes and to the periocular area. If accidental exposure occurs, advise patients to flush eyes with water and seek medical care [see Warnings and Precautions ( 5.1 )] . Local Skin Reactions Inform patients that treatment with KLISYRI may lead to local skin reactions [see Warnings and Precautions ( 5.2 )] . Important Administration Instructions Advise patients that KLISYRI is for topical use only. Advise patients to avoid application near and around the eyes, mouth and lips. Instruct patients to: Wash hands well after applying KLISYRI to avoid transfer of the drug into the eyes and to the periocular area after application. Avoid washing and touching the treated area for 8 hours after treatment. Following this time, patients may wash the area with a mild soap and water [see Dosage and Administration ( 2 )]. Avoid inadvertent transfer of KLISYRI to other areas, or to another person. Manufactured for: Almirall, LLC Malvern, PA. 19355, USA

Active ingredients

Tirbanibulin in 1 product

Klisyri NDC products (1)

NDC	Strength & form	Labeler	Type
16110-391	Tirbanibulin 10 mg/g Ointment	Almirall, LLC	NDA

Frequently asked questions

What is Klisyri used for?

1 INDICATIONS AND USAGE KLISYRI is indicated for the topical field treatment of actinic keratosis on the face or scalp. KLISYRI is a microtubule inhibitor indicated for the topical treatment of actinic keratosis of the face or scalp. ( 1 )

What are the side effects of Klisyri?

Most common adverse reactions (incidence ≥2%) are local skin reactions, application site pruritus, and application site pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Almirall, at 1-866-665-2782 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in… See the full label for the complete list.

Who makes Klisyri?

Klisyri is listed by 1 labeler in the FDA NDC directory, including Almirall, LLC.