INDICATIONS & USAGE SECTION.

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

SPL UNCLASSIFIED SECTION.

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.

STORAGE AND HANDLING SECTION.

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

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 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 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 to clinically typical, visible, and discrete AK lesions in 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 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 grading scale of = absent, = mild (slightly, barely perceptible), = moderate (distinct presence), and = 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 Investigator Assessment of Maximal Post-Baseline Local Skin Reactions Greater Than Baseline in the Treatment Area (face or scalp) Pooled Data from Controlled Clinical Phase TrialsKLISYRIN 353VehicleN 349Local Skin ReactionsMild (%)Moderaten (%)Severe (%)Mild (%)Moderaten (%)Severe (%)Erythema76 (22%)223 (63%)22 (6%)98 (28%)20 (6%)0Flaking/ Scaling92 (26%)166 (47%)31 (9%)86 (25%)33 (9%)1 (<1%)Crusting107 (30%)50 (14%)7 (2%)31 (9%)8 (2%)0Swelling102 (29%)32 (9%)2 (<1%)15 (4%)1 (<1%)0Vesiculation/ Pustulation25 (7%)2 (<1%)2 (<1%)3 (<1%)00Erosion/ Ulceration32 (9%)9 (3%)010 (3%)00Table 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 2Adverse Reactions Occurring in >=2% of Subjects in Controlled Clinical Trials- Pooled Safety Populationa Application site pain includes pain, tenderness, stinging, and burning sensation at the application site.Adverse Reaction System Organ ClassKLISYRIN 353VehicleN 349Number of Subjects (%) with any adverse reaction (possibly related to treatment)56 (16%)35 (10%) Application site pruritus32 (9%)21 (6%) Application site paina35 (10%)11 (3%)For the 51 subjects (45 KLISYRI, vehicle) who maintained complete clearance through the 12-month follow-up period, no additional local adverse reactions were reported.Dermal Safety StudiesClinical studies in healthy subjects demonstrated KLISYRI did not cause contact sensitization (261 subjects), phototoxic skin reactions (31 subjects), or photoallergic skin reactions (64 subjects).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 mg/kg/day (94 times the MRHD on an AUC comparison basis) in males and mg/kg/day (60 times the MRHD on an AUC comparison basis) in females. However, oral administration of 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 mg/kg/day (47 times the MRHD on an AUC comparison basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Tirbanibulin is 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. AbsorptionFollowing topical treatment of mean daily dose of 138 mg (range: 54 to 295 mg) of KLISYRI to 25 cm2 contiguous area of the face or balding scalp, once daily for consecutive days, the steady-state concentration of tirbanibulin was achieved by 72 hours with mean+-SD trough concentration (Ctrough) of 0.11+-0.08 ng/mL. On Day 5, systemic exposure to tirbanibulin was low with mean+-SD maximum plasma concentration (Cmax) of 0.34+-0.30 ng/mL and 0.18+-0.10 ng/mL, and mean+-SD area under the plasma concentration from time zero to 24 hours (AUC24) of 5.0+-3.9 hng/mL and 3.2+-1.9 hng/mL, in subjects who received the face and scalp topical treatment, respectively. The median time to reach Cmax (Tmax) was ~7 hours.DistributionPlasma protein binding of tirbanibulin is 88% and is independent of concentrations in the range of 0.01 to 10 ug/mL.EliminationMetabolismFollowing 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 or 10 uM tirbanibulin with human hepatocytes generated KX2-5036, KX-5163 and other unidentified metabolites.In vitro, tirbanibulin is mainly metabolized by CYP3A4, and to lesser extent, CYP2C8.ExcretionExcretion of tirbanibulin has not been fully characterized in humans.Drug InteractionsClinical StudiesNo clinical studies evaluating the drug interaction potential of KLISYRI have been conducted.In Vitro StudiesCYP 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 uM. Tirbanibulin up to uM (431.5 ng/mL) and the metabolite KX2-5036 up to uM (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 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 uM. 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Actinic Keratosis of the Face or ScalpTwo double-blind, vehicle-controlled clinical trials (NCT03285477 and NCT03285490) were conducted with 702 adult subjects with actinic keratosis on the face or scalp. Subjects were randomized 1:1 to KLISYRI or vehicle. Subjects enrolled had to clinically typical, visible, and discrete AK lesions in contiguous area of 25 cm2 on the face or scalp. Subjects had an average age of 70 years (range 45 to 96 years), were predominantly Caucasian (99%), male (87%), with Fitzpatrick skin types 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.Subjects received consecutive days of once daily treatment with either KLISYRI (353) or vehicle control (349) to the treatment field. Subjects with complete (100%) clearance of AK lesions in the treatment area at Day 57 returned to the clinic for recurrence assessment every months for total of 12 months post-Day 57.The primary efficacy endpoint was complete (100%) clearance of AK lesions in the treatment area, defined as the proportion of subjects at Day 57 with no clinically visible AK lesions in the treatment area and the secondary endpoint was partial (>=75%) clearance of AK lesions in the treatment area. Results from both studies are presented below.Table Complete (100%) AK Clearance Rates on Day 57 for the Two Phase Studies (Intent to Treat [ITT] Populationa. Based on Mantel-Haenszel methodStudy 1Study 2KLISYRIN 175n/N (%)VehicleN 176n/N (%)Treatment difference (KLISYRI-Vehicle)95% Confidence Interval for the Treatment differenceKLISYRIN 178n/N (%)VehicleN 173n/N (%)Treatment difference (KLISYRI-Vehicle)95% Confidence Interval for the Treatment differenceAll subjects77/175(44%)8/176(5%)40%a (31.6%, 47.5%)a 97/178(54%)22/173(13%)42%a (33.1%, 50.7%)a Face60/119(50%)7/121(6%)45%--73/119(61%)16/118(14%)48%--Scalp17/56(30%)1/55(2%)29%--24/59(41%)6/55(11%)30%--Table Partial (>= 75%) AK Clearance Rates on Day 57 for the Two Phase Studies (Intent to Treat [ITT] Population)a. Based on Mantel-Haenszel methodStudy 1Study 2KLISYRIN 175n/N (%)VehicleN 176n/N (%)Treatment difference (KLISYRI-Vehicle)95% Confidence Interval for the Treatment differenceKLISYRIN 178n/N (%)VehicleN 173n/N (%)Treatment difference (KLISYRI-Vehicle)95% Confidence Interval for the Treatment differenceAll subjects119/175(68%)29/176(16%)52%a (42.9%, 60.3%)a 136/178(76%)34/173(20%)57% (48.3%, 65.4%)a Face90/119(76%)23/121(19%)57%--95/119 (80%)26/118(22%)58%--Scalp29/56(52%)6/55(11%)41%--41/59(69%)8/55(15%)55%--Efficacy was consistent across sex and age (<65 and >=65 years) subgroups.Subjects who achieved 100% clearance of AK lesions in the treatment area at Day 57 continued to be followed for up to 12 months following Day 57 to determine the recurrence rate. Recurrence was defined as the proportion of subjects with any identified AK lesion (new or previous lesion) in the previously treated area who achieved 100% clearance at Day 57. Of the 174 subjects treated with KLISYRI who were followed, the recurrence rate at 12 months post Day 57 was 73%.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 to clinically typical, visible, and discrete AK lesions in 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 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 grading scale of = absent, = mild (slightly, barely perceptible), = moderate (distinct presence), and = 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 Investigator Assessment of Maximal Post-Baseline Local Skin Reactions Greater Than Baseline in the Treatment Area (face or scalp) Pooled Data from Controlled Clinical Phase TrialsKLISYRIN 353VehicleN 349Local Skin ReactionsMild (%)Moderaten (%)Severe (%)Mild (%)Moderaten (%)Severe (%)Erythema76 (22%)223 (63%)22 (6%)98 (28%)20 (6%)0Flaking/ Scaling92 (26%)166 (47%)31 (9%)86 (25%)33 (9%)1 (<1%)Crusting107 (30%)50 (14%)7 (2%)31 (9%)8 (2%)0Swelling102 (29%)32 (9%)2 (<1%)15 (4%)1 (<1%)0Vesiculation/ Pustulation25 (7%)2 (<1%)2 (<1%)3 (<1%)00Erosion/ Ulceration32 (9%)9 (3%)010 (3%)00Table 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 2Adverse Reactions Occurring in >=2% of Subjects in Controlled Clinical Trials- Pooled Safety Populationa Application site pain includes pain, tenderness, stinging, and burning sensation at the application site.Adverse Reaction System Organ ClassKLISYRIN 353VehicleN 349Number of Subjects (%) with any adverse reaction (possibly related to treatment)56 (16%)35 (10%) Application site pruritus32 (9%)21 (6%) Application site paina35 (10%)11 (3%)For the 51 subjects (45 KLISYRI, vehicle) who maintained complete clearance through the 12-month follow-up period, no additional local adverse reactions were reported.Dermal Safety StudiesClinical studies in healthy subjects demonstrated KLISYRI did not cause contact sensitization (261 subjects), phototoxic skin reactions (31 subjects), or photoallergic skin reactions (64 subjects).

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. KLISYRI (tirbanibulin) ointment is 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 C26H29N3O3. Tirbanibulins 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.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For topical use only; not for oral or ophthalmic use.Apply sufficient amount of KLISYRI to evenly cover up to 25 cm2 treatment field on the face or scalp once daily for consecutive days using single-dose packet per application.Wash hands immediately with soap and water after application.Avoid washing and touching the treated area for approximately hours after application of KLISYRI. Following this time, the area may be washed with 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 consecutive days using single-dose packet per application. (2). For topical use; not for oral or ophthalmic use. (2). Apply KLISYRI to the treatment field on the face or scalp once daily for consecutive days using single-dose packet per application. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Ointment: 1% white to off-white ointment in single-dose packet (2.5 mg tirbanibulin in 250 mg).. Ointment: 1% tirbanibulin, single-dose packets. (3).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the 353 subjects with AK treated with KLISYRI in the controlled Phase 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.

HOW SUPPLIED SECTION.

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

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Discard the packet after single use.Ophthalmic Adverse ReactionsAdvise 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 ReactionsInform patients that treatment with KLISYRI may lead to local skin reactions [see Warnings and Precautions (5.3)].Important Administration InstructionsAdvise 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 hours after treatment. Following this time, patients may wash the area with mild soap and water.Avoid inadvertent transfer of KLISYRI to other areas, or to another person.Manufactured for: Almirall, LLCMalvern, PA. 19355, USARevised: 08/2021. 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 hours after treatment. Following this time, patients may wash the area with mild soap and water.. Avoid inadvertent transfer of KLISYRI to other areas, or to another person.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for KLISYRI and any potential adverse effects on the breastfed child from tirbanibulin or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 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 mg/kg/day (94 times the MRHD on an AUC comparison basis) in males and mg/kg/day (60 times the MRHD on an AUC comparison basis) in females. However, oral administration of 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 mg/kg/day (47 times the MRHD on an AUC comparison basis).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdose of KLISYRI could cause an increase in incidence and severity of local skin reactions.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL NDC: 16110-391-05 Packet Label. Packet Label.

PEDIATRIC USE SECTION.

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 condition generally seen within the pediatric population.

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionFollowing topical treatment of mean daily dose of 138 mg (range: 54 to 295 mg) of KLISYRI to 25 cm2 contiguous area of the face or balding scalp, once daily for consecutive days, the steady-state concentration of tirbanibulin was achieved by 72 hours with mean+-SD trough concentration (Ctrough) of 0.11+-0.08 ng/mL. On Day 5, systemic exposure to tirbanibulin was low with mean+-SD maximum plasma concentration (Cmax) of 0.34+-0.30 ng/mL and 0.18+-0.10 ng/mL, and mean+-SD area under the plasma concentration from time zero to 24 hours (AUC24) of 5.0+-3.9 hng/mL and 3.2+-1.9 hng/mL, in subjects who received the face and scalp topical treatment, respectively. The median time to reach Cmax (Tmax) was ~7 hours.DistributionPlasma protein binding of tirbanibulin is 88% and is independent of concentrations in the range of 0.01 to 10 ug/mL.EliminationMetabolismFollowing 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 or 10 uM tirbanibulin with human hepatocytes generated KX2-5036, KX-5163 and other unidentified metabolites.In vitro, tirbanibulin is mainly metabolized by CYP3A4, and to lesser extent, CYP2C8.ExcretionExcretion of tirbanibulin has not been fully characterized in humans.Drug InteractionsClinical StudiesNo clinical studies evaluating the drug interaction potential of KLISYRI have been conducted.In Vitro StudiesCYP 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 uM. Tirbanibulin up to uM (431.5 ng/mL) and the metabolite KX2-5036 up to uM (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 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 uM. 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data with KLISYRI use in pregnant women to evaluate for 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 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 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 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 to 4% and 15 to 20%, respectively.DataAnimal DataTirbanibulin 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 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 dose of mg/kg/day, which resulted in 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 dose of 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 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued: 08/2021Patient InformationKLISYRI (klye si ree)(tirbanibulin)ointmentImportant: KLISYRI is for use on the skin only (topical). Do not use KLISYRI in, around, or near your eyes, mouth or lips.What is KLISYRIKLISYRI is prescription medicine used on the skin to treat actinic keratosis on the face or scalp.It is not known if KLISYRI is safe and effective in children less than 18 years of age.Before using KLISYRI, tell your healthcare provider about all of your medical conditions, including if you:are being treated or have been treated for actinic keratosis with any other medicine, procedure, or surgery. You should not use KLISYRI until your skin has healed from other treatments.have other skin problems in the treatment area.are pregnant or plan to become pregnant. It is not known if KLISYRI can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if KLISYRI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with KLISYRI.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins and herbal supplements.How should use KLISYRIUse KLISYRI as your healthcare provider tells you to. KLISYRI is for skin use only. Apply KLISYRI to evenly cover the treatment area(s) on the face or scalp time day for days in row (consecutive) using single dose packet with each application. Do not apply KLISYRI to other areas. Do not use more KLISYRI than you need to cover the treatment area. Using too much KLISYRI, or using it too often, or for too long can increase your chances of having severe skin reaction or other side effects.Do not cover the treatment area with dressing after application of KLISYRI. Irritation of the skin may happen if dressing is applied to the treatment area.Do not get KLISYRI in, around, or near your eyes. Do not touch your eyes while you are applying KLISYRI.Wash your hands right away with water and soap after applying KLISYRI. After applying KLISYRI, be careful to keep KLISYRI on the treated area from coming into contact with your eyes. Irritation may happen if you get KLISYRI in your eyes.If you accidently get KLISYRI in your eyes, flush them with water and get medical care as soon as possible. See, What are the possible side effects of KLISYRI Do not get KLISYRI in, around, or near your mouth or lips.Avoid washing and touching the treated area for approximately hours after application of KLISYRI. After hours, you may wash the area with mild soap and water.Avoid transferring the product to other areas after application.Throw away any open packet of KLISYRI after use even if there is medicine still left in it.What are the possible side effects of KLISYRIKLISYRI may cause serious side effects, including:Eye irritation can happen if KLISYRI gets into your eyes. If you accidently get KLISYRI into your eyes, flush them with water and get medical care as soon as possible.Local skin reactions are common but can also be severe during treatment with KLISYRI. Call your healthcare provider if you develop any local skin reactions including redness, flaking or scaling, crusting, or swelling that is more severe, or if you get blisters, peeling, pus, ulcers, or breakdown of your skin.The most common side effects of KLISYRI include: itching or pain in the treatment area.These are not all of the possible side effects of KLISYRI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store KLISYRIStore at room temperature between 68F to 77F (20C to 25C) .Do not refrigerate or freeze.Safely throw away used KLISYRI packets in household trash.Keep KLISYRI and all medicines out of the reach of children.General Information about the safe and effective use of KLISYRI.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use KLISYRI for condition for which it was not prescribed. Do not give KLISYRI to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KLISYRI that is written for health professionals.What are the ingredients of KLISYRIActive ingredient: TirbanibulinInactive ingredients: Mono- and di-glycerides and propylene glycol.Manufactured for: Almirall, LLC, Malvern, PA. 19355, USA.For more information, call 1-800-KLISYRI or visit www.KLISYRI.com.. are being treated or have been treated for actinic keratosis with any other medicine, procedure, or surgery. You should not use KLISYRI until your skin has healed from other treatments.. have other skin problems in the treatment area.. are pregnant or plan to become pregnant. It is not known if KLISYRI can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if KLISYRI passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with KLISYRI.. Use KLISYRI as your healthcare provider tells you to. KLISYRI is for skin use only. Apply KLISYRI to evenly cover the treatment area(s) on the face or scalp time day for days in row (consecutive) using single dose packet with each application. Do not apply KLISYRI to other areas. Do not use more KLISYRI than you need to cover the treatment area. Using too much KLISYRI, or using it too often, or for too long can increase your chances of having severe skin reaction or other side effects.. Do not cover the treatment area with dressing after application of KLISYRI. Irritation of the skin may happen if dressing is applied to the treatment area.. Do not get KLISYRI in, around, or near your eyes. Do not touch your eyes while you are applying KLISYRI.Wash your hands right away with water and soap after applying KLISYRI. After applying KLISYRI, be careful to keep KLISYRI on the treated area from coming into contact with your eyes. Irritation may happen if you get KLISYRI in your eyes.If you accidently get KLISYRI in your eyes, flush them with water and get medical care as soon as possible. See, What are the possible side effects of KLISYRI Wash your hands right away with water and soap after applying KLISYRI. After applying KLISYRI, be careful to keep KLISYRI on the treated area from coming into contact with your eyes. Irritation may happen if you get KLISYRI in your eyes.. If you accidently get KLISYRI in your eyes, flush them with water and get medical care as soon as possible. See, What are the possible side effects of KLISYRI Do not get KLISYRI in, around, or near your mouth or lips.. Avoid washing and touching the treated area for approximately hours after application of KLISYRI. After hours, you may wash the area with mild soap and water.. Avoid transferring the product to other areas after application.. Throw away any open packet of KLISYRI after use even if there is medicine still left in it.. Eye irritation can happen if KLISYRI gets into your eyes. If you accidently get KLISYRI into your eyes, flush them with water and get medical care as soon as possible.. Local skin reactions are common but can also be severe during treatment with KLISYRI. Call your healthcare provider if you develop any local skin reactions including redness, flaking or scaling, crusting, or swelling that is more severe, or if you get blisters, peeling, pus, ulcers, or breakdown of your skin.. Store at room temperature between 68F to 77F (20C to 25C) .. Do not refrigerate or freeze.. Safely throw away used KLISYRI packets in household trash.. Keep KLISYRI and all medicines out of the reach of children.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data with KLISYRI use in pregnant women to evaluate for 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 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 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 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 to 4% and 15 to 20%, respectively.DataAnimal DataTirbanibulin 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 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 dose of mg/kg/day, which resulted in 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 dose of 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 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 SummaryThere 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 mothers 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 condition generally seen within the pediatric population.. 8.5 Geriatric Use. Of the 353 subjects with AK treated with KLISYRI in the controlled Phase 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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 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). 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 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)]. 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.