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)]. Avoid use until skin is healed from any previous drug, procedure, or surgical treatment. Occlusion after topical application of KLISYRI is more likely to result in irritation.

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 cm2 on the face or scalp. Subjects had an average age of 70 years (range 45 to 96 years) and were predominantly Caucasian (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 greater than baseline by treatment group are provided in Table 1. LSRs were mostly mild to moderate in degree (Table 1).

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.

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.

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).

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 74 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 159 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 74 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 18 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 159 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 53 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 74 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.

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.

12.2 Pharmacodynamics

The pharmacodynamics of tirbanibulin in the treatment of actinic keratosis is unknown.

12.3 Pharmacokinetics

Absorption

Following topical treatment of a mean daily dose of 138 mg (range: 54 to 295 mg) of KLISYRI to a 25 cm2 contiguous area of the face or balding scalp, once daily for 5 consecutive days, the steady-state concentration of tirbanibulin was achieved by 72 hours with a mean±SD trough concentration (Ctrough) of 0.11±0.08 ng/mL. On Day 5, systemic exposure to tirbanibulin was low with a mean±SD maximum plasma concentration (Cmax) of 0.34±0.30 ng/mL and 0.18±0.10 ng/mL, and a mean±SD area under the plasma concentration from time zero to 24 hours (AUC24) of 5.0±3.9 h*ng/mL and 3.2±1.9 h*ng/mL, in subjects who received the face and scalp topical treatment, respectively. The median time to reach Cmax (Tmax) was ~7 hours.

Distribution

Plasma protein binding of tirbanibulin is 88% and is independent of concentrations in the range of 0.01 to 10 µg/mL.

Elimination

Metabolism

Following topical treatment with KLISYRI to adult subjects with actinic keratosis, the plasma concentrations of KX2-5036 and KX2-5163, two pharmacologically inactive metabolites, were detectable with the highest plasma concentrations of 0.09 ng/mL and 0.12 ng/mL, respectively.

The in vitro study indicated that incubation of 1 or 10 µM tirbanibulin with human hepatocytes generated KX2-5036, KX-5163 and other unidentified metabolites.

In vitro, tirbanibulin is mainly metabolized by CYP3A4, and to a lesser extent, CYP2C8.

Excretion

Excretion of tirbanibulin has not been fully characterized in humans.

Drug Interactions

Clinical Studies

No clinical studies evaluating the drug interaction potential of KLISYRI have been conducted.

In Vitro Studies

CYP Enzymes: Tirbanibulin and the metabolite KX2-5036 directly or time-dependently inhibited CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 with an IC50 value of >17 µM. Tirbanibulin up to 1 µM (431.5 ng/mL) and the metabolite KX2-5036 up to 3 µM (1024 ng/mL) did not induce CYP 1A2, 2B6, or 3A4. These findings suggest that KLISYRI has no clinically meaningful effect on the PK of drugs metabolized by CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4.

Drug Transporters: Neither tirbanibulin nor the metabolite KX2-5036 was a substrate of MDR1, BCRP, BSEP, MRP2, MATE1, MATE2-K, OAT1, OAT3, OATP1B1, OATP1B3, OCT1 or OCT2. Tirbanibulin and the metabolite KX2-5036 inhibited MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1 and/or OCT2 with an IC50 value of >1 µM. The results suggest that KLISYRI has no clinically meaningful effect on the PK of drugs mediated by MATE1, MATE2-K, OATP1B1, OATP1B3, OCT1 and OCT2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to evaluate the potential of tirbanibulin to induce carcinogenesis.

Tirbanibulin was negative in an in vitro bacterial reverse mutation (Ames) assay. Tirbanibulin was positive in an in vitro chromosomal aberration assay with Chinese hamster ovary (CHO) cells, an in vitro mouse lymphoma assay with L5178/TK+/- cells, and an in vivo micronucleus assay in rats.

Tirbanibulin was assessed for effects on fertility or reproductive function in rats. Reproductive performance of rats was unaffected by oral doses of tirbanibulin up to 4 mg/kg/day (94 times the MRHD on an AUC comparison basis) in males and 1 mg/kg/day (60 times the MRHD on an AUC comparison basis) in females. However, oral administration of 4 mg/kg/day of tirbanibulin to male rats adversely affected spermatogenesis, including reduced sperm count and motility, and increased observations of morphologically abnormal sperm. No effects on sperm were observed in males treated at 2 mg/kg/day (47 times the MRHD on an AUC comparison basis).

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.