LABORATORY TESTS 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 practice. During clinical trials, 2047 subjects with inflammatory lesions of rosacea received SOOLANTRA cream once daily. total of 1555 subjects were treated once daily for more than 12 weeks, and 519 for approximately one year. Adverse reactions, reported in <= 1% of subjects treated with SOOLANTRA cream for at least months in vehicle-controlled clinical trials, included skin burning sensation and skin irritation.

DESCRIPTION SECTION.

11 DESCRIPTION. SOOLANTRA (ivermectin) cream, 1% is white to pale yellow hydrophilic cream. Each gram of SOOLANTRA cream contains 10 mg of ivermectin. It is intended for topical use.Ivermectin is semi-synthetic derivative isolated from the fermentation of Streptomyces avermitilis that belongs to the avermectin family of macrocyclic lactones.Ivermectin is mixture containing not less than 95.0% and not more than 102.0% of 5-O-demethyl-22,23-dihydroavermectin A1a plus 5-O-demethyl-25-de(1-methylpropyl)-25-(1-methylethyl)-22,23-dihydroavermectin A1a, generally referred to as 22,23-dihydroavermectin B1a and B1b or H2B1a and H2B1b, respectively; and the ratio (calculated by area percentage) of component H2B1a/(H2B1a H2B1b) is not less than 90.0%. The respective empirical formulas of H2B1a and H2B1b are C48H74O14 and C47H72O14 with molecular weights of 875.10 and 861.07 respectively.The structural formulas are:Component H2B1a: = C2H5, Component H2B1b: = CH3.SOOLANTRA cream contains the following inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol.. ivermectin-chem-struct.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. In controlled clinical trials with SOOLANTRA the most common adverse reactions (incidence <= %) included skin burning sensation and skin irritation. (6)To report SUSPECTED ADVERSE REACTIONS, contact Galderma Laboratories, L.P. at 1-866-735-4137 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 practice. During clinical trials, 2047 subjects with inflammatory lesions of rosacea received SOOLANTRA cream once daily. total of 1555 subjects were treated once daily for more than 12 weeks, and 519 for approximately one year. Adverse reactions, reported in <= 1% of subjects treated with SOOLANTRA cream for at least months in vehicle-controlled clinical trials, included skin burning sensation and skin irritation. 6.2 Postmarketing Experience. Because adverse reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish casual relationship to drug exposure. Postmarketing reports for adverse reactions to SOOLANTRA Cream included: contact dermatitis and allergic dermatitis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The mechanism of action of SOOLANTRA cream in treating rosacea lesions is unknown.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt therapeutic doses, SOOLANTRA cream is not expected to prolong QTc interval.. 12.3 Pharmacokinetics. AbsorptionThe absorption of ivermectin from SOOLANTRA cream was evaluated in clinical trial in 15 adult male and female subjects with severe papulopustular rosacea applying g SOOLANTRA cream, 1% once daily. At steady state (after weeks of treatment), the highest mean +- standard deviation plasma concentrations of ivermectin peaked (Tmax) at 10 +- hours post dose, the maximum concentration (Cmax) was 2.10 +- 1.04 ng/mL (range: 0.69 4.02 ng/mL) and the area under the concentration curve (AUC0-24hr) was 36.14 +- 15.56 ng.hr/mL (range: 13.69-75.16 ng.hr/mL). In addition, systemic exposure assessment in longer treatment duration (Phase studies) showed that there was no plasma accumulation of ivermectin over the 52-week treatment period.DistributionAn in vitro study demonstrated that ivermectin is greater than 99% bound to plasma proteins and is bound primarily to human serum albumin. No significant binding of ivermectin to erythrocytes was observed.MetabolismIn vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. In vitro studies show that ivermectin at therapeutic concentrations does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 or 4A11, or induce 1A2, 2B6, 2C9 or 3A4.ExcretionThe apparent terminal half-life averaged 6.5 days (mean +- standard deviation: 155+- 40 hours, range 92-238 hours) in patients receiving once daily cutaneous application of SOOLANTRA cream for 28 days.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. SOOLANTRA cream applied once daily at bedtime was evaluated in the treatment of inflammatory lesions of rosacea in two randomized, double-blind, vehicle controlled clinical trials, which were identical in design. The trials were conducted in 1371 subjects aged 18 years and older who were treated once daily for 12 weeks with either SOOLANTRA cream or vehicle cream.Overall, 96% of subjects were Caucasian and 67% were female. Using the 5-point Investigator Global Assessment (IGA) scale (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe), 79% of subjects were scored as moderate (IGA=3) and 21% scored as severe (IGA= 4) at baseline.The co-primary efficacy endpoints in both pivotal trials were the success rate based on the IGA outcome (percentage of subjects clear and almost clear) and absolute change from baseline in inflammatory lesion counts at Week 12. Table presents the co-primary efficacy results at Week 12. SOOLANTRA cream was more effective than vehicle cream on the co-primary efficacy endpoints starting from weeks of treatment in both studies, see Figures through 4.Table 1: Co-Primary Efficacy Results at Week 12Study 1Study SOOLANTRA VehicleCream (N=451) Cream (N=232) SOOLANTRA VehicleCream (N=459) Cream (N=229)Investigator Global Assessment:Number (%) of Subjects Clear or Almost Clear173 (38.4%) 27 (11.6%)184 (40.1%) 43 (18.8%)Inflammatory Lesion Counts:Mean Absolute (%) Change from Baseline20.5 (64.9%) 12.0 (41.6%)22.2 (65.7%) 13.4 (43.4%)Figures and 2: IGA Success Rates Over TimeFigures and 4: Mean Absolute Change in Inflammatory Lesion Counts from Baseline Over Time. ivermectin-fig-1-fig-2. ivermectin-fig-3-fig-4.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2-year dermal mouse carcinogenicity study, ivermectin was administered to CD-1 mice at topical doses of 1, 3, and 10 mg/kg/day (0.1%, 0.3% and 1% ivermectin cream applied at ml/kg/day). No drug-related tumors were noted in this study up to the highest dose evaluated in this study of 10 mg/kg/day (747X maximum topical human dose [MTHD]).In 2-year oral rat carcinogenicity study, ivermectin was administered to Wistar rats at gavage doses of 1, 3, and mg/kg/day. statistically significant increase in the incidence of hepatocellular adenoma was noted in males treated with mg/kg/day (1766X MTHD) ivermectin. The clinical relevance of this finding is unknown. No drug-related tumors were noted in females up to the highest dose evaluated in this study of mg/kg/day (1959X MTHD). No drug-related tumors were noted in males at doses <= mg/kg/day (599X MTHD).Ivermectin revealed no evidence of genotoxic potential based on the results of two in vitro genotoxicity tests (the Ames test and the L5178Y/TK+/- mouse lymphoma assay) and one in vivo genotoxicity test (rat micronucleus assay).In fertility study, oral doses of 0.1, and mg/kg/day ivermectin were administered to male and female rats. Mortality occurred at mg/kg/day (1027X MTHD). The precoital period was generally prolonged at mg/kg/day. No treatment-related effects on fertility or mating performance were noted at doses <= mg/kg/day (68X MTHD).

OVERDOSAGE SECTION.

10 OVERDOSAGE. In accidental or significant exposure to unknown quantities of veterinary formulations of ivermectin in humans, either by ingestion, inhalation, injection, or exposure to body surfaces, the following adverse effects have been reported most frequently: rash, edema, headache, dizziness, asthenia, nausea, vomiting, and diarrhea. Other adverse effects that have been reported include: seizure, ataxia, dyspnea, abdominal pain, paresthesia, urticaria, and contact dermatitis.In case of accidental ingestion, supportive therapy, if indicated, should include parenteral fluids and electrolytes, respiratory support (oxygen and mechanical ventilation if necessary) and pressor agents if clinically significant hypotension is present. Induction of emesis and/or gastric lavage as soon as possible, followed by purgatives and other routine anti-poison measures, may be indicated if needed to prevent absorption of ingested material.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe absorption of ivermectin from SOOLANTRA cream was evaluated in clinical trial in 15 adult male and female subjects with severe papulopustular rosacea applying g SOOLANTRA cream, 1% once daily. At steady state (after weeks of treatment), the highest mean +- standard deviation plasma concentrations of ivermectin peaked (Tmax) at 10 +- hours post dose, the maximum concentration (Cmax) was 2.10 +- 1.04 ng/mL (range: 0.69 4.02 ng/mL) and the area under the concentration curve (AUC0-24hr) was 36.14 +- 15.56 ng.hr/mL (range: 13.69-75.16 ng.hr/mL). In addition, systemic exposure assessment in longer treatment duration (Phase studies) showed that there was no plasma accumulation of ivermectin over the 52-week treatment period.DistributionAn in vitro study demonstrated that ivermectin is greater than 99% bound to plasma proteins and is bound primarily to human serum albumin. No significant binding of ivermectin to erythrocytes was observed.MetabolismIn vitro studies using human hepatic microsomes and recombinant CYP450 enzymes have shown that ivermectin is primarily metabolized by CYP3A4. In vitro studies show that ivermectin at therapeutic concentrations does not inhibit the CYP450 isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4 or 4A11, or induce 1A2, 2B6, 2C9 or 3A4.ExcretionThe apparent terminal half-life averaged 6.5 days (mean +- standard deviation: 155+- 40 hours, range 92-238 hours) in patients receiving once daily cutaneous application of SOOLANTRA cream for 28 days.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women. SOOLANTRA cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Note: The animal multiples of human exposure calculations were based on AUC comparisons. The maximum topical human dose (MTHD) of SOOLANTRA cream is g applied once daily.Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1.5, 4, and 12 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 6-17) to pregnant female rats. Maternal death occurred at 12 mg/kg/day (1909X MTHD). Cleft palate occurred in the fetuses from the 12 mg/kg/day (1909X MTHD) group. No treatment related effects on embryofetal toxicity or teratogenicity were noted at mg/kg/day (708X MTHD). Oral doses of 0.5, 1.5, 2.5, 3.5 and 4.5 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 7-20) to pregnant female rabbits. Maternal death occurred at doses >2.5 mg/kg/day (72X MTHD). Carpal flexure occurred in the fetuses from the 4.5 mg/kg/day (354X MTHD) group. Fetal weight decrease was noted at 3.5 mg/kg/day (146X MTHD). No treatment related effects on embryofetal toxicity were noted at 2.5 mg/kg/day (72X MTHD) and no treatment related effects on teratogenicity were noted at 3.5 mg/kg/day (146X MTHD).A pre- and postnatal development study was conducted in rats. Oral doses of 1, and mg/kg/day ivermectin were administered to pregnant female rats during gestational days 6-20 and lactation days 2-20. Neonatal death occurred at doses >2 mg/kg/day. Behavior development of newborn rats was adversely affected at all doses.

SPL PATIENT PACKAGE INSERT SECTION.

Instructions for Use. SOOLANTRA (soo lan trah) (ivermectin) cream, 1%Important: SOOLANTRA(R) cream is for use on the face only. Do not use SOOLANTRA cream in your eyes, mouth or vagina.Read and follow the steps below so that you use SOOLANTRA cream correctly:1. Open the tube of SOOLANTRA cream by gently pressing down on the child resistant cap and twist in the direction of the arrow (counterclockwise) as shown below. See Figures and B. To avoid spilling, do not squeeze the tube while opening or closing.2. To apply SOOLANTRA cream to your face, squeeze pea-sized amount of SOOLANTRA cream from the tube onto your fingertip. See Figure C.3. Apply SOOLANTRA to the affected areas of your face once day. Use pea-sized amount of SOOLANTRA cream for each area of your face (forehead, chin, nose, each cheek) that is affected. Spread the cream smoothly and evenly in thin layer. Avoid contact with your eyes and lips.4. To close SOOLANTRA cream, gently press down on the child resistant cap and twist to the right (clockwise). See Figure D.How should store SOOLANTRA creamStore SOOLANTRA cream at room temperature between 68F to 77F (20C to 25C).Keep SOOLANTRA cream out of the reach of children.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Marketed by:GALDERMA LABORATORIES, L.P.Fort Worth, TX 76177 USAMade in Canada.Issued: July 2018P52476-2. ivermectin-fig-a-fig-b. ivermectin-fig-c. ivermectin-fig-d.

SPL UNCLASSIFIED SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In 2-year dermal mouse carcinogenicity study, ivermectin was administered to CD-1 mice at topical doses of 1, 3, and 10 mg/kg/day (0.1%, 0.3% and 1% ivermectin cream applied at ml/kg/day). No drug-related tumors were noted in this study up to the highest dose evaluated in this study of 10 mg/kg/day (747X maximum topical human dose [MTHD]).In 2-year oral rat carcinogenicity study, ivermectin was administered to Wistar rats at gavage doses of 1, 3, and mg/kg/day. statistically significant increase in the incidence of hepatocellular adenoma was noted in males treated with mg/kg/day (1766X MTHD) ivermectin. The clinical relevance of this finding is unknown. No drug-related tumors were noted in females up to the highest dose evaluated in this study of mg/kg/day (1959X MTHD). No drug-related tumors were noted in males at doses <= mg/kg/day (599X MTHD).Ivermectin revealed no evidence of genotoxic potential based on the results of two in vitro genotoxicity tests (the Ames test and the L5178Y/TK+/- mouse lymphoma assay) and one in vivo genotoxicity test (rat micronucleus assay).In fertility study, oral doses of 0.1, and mg/kg/day ivermectin were administered to male and female rats. Mortality occurred at mg/kg/day (1027X MTHD). The precoital period was generally prolonged at mg/kg/day. No treatment-related effects on fertility or mating performance were noted at doses <= mg/kg/day (68X MTHD).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Pregnancy Category C.There are no adequate and well-controlled studies in pregnant women. SOOLANTRA cream should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Note: The animal multiples of human exposure calculations were based on AUC comparisons. The maximum topical human dose (MTHD) of SOOLANTRA cream is g applied once daily.Systemic embryofetal development studies were conducted in rats and rabbits. Oral doses of 1.5, 4, and 12 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 6-17) to pregnant female rats. Maternal death occurred at 12 mg/kg/day (1909X MTHD). Cleft palate occurred in the fetuses from the 12 mg/kg/day (1909X MTHD) group. No treatment related effects on embryofetal toxicity or teratogenicity were noted at mg/kg/day (708X MTHD). Oral doses of 0.5, 1.5, 2.5, 3.5 and 4.5 mg/kg/day ivermectin were administered during the period of organogenesis (gestational days 7-20) to pregnant female rabbits. Maternal death occurred at doses >2.5 mg/kg/day (72X MTHD). Carpal flexure occurred in the fetuses from the 4.5 mg/kg/day (354X MTHD) group. Fetal weight decrease was noted at 3.5 mg/kg/day (146X MTHD). No treatment related effects on embryofetal toxicity were noted at 2.5 mg/kg/day (72X MTHD) and no treatment related effects on teratogenicity were noted at 3.5 mg/kg/day (146X MTHD).A pre- and postnatal development study was conducted in rats. Oral doses of 1, and mg/kg/day ivermectin were administered to pregnant female rats during gestational days 6-20 and lactation days 2-20. Neonatal death occurred at doses >2 mg/kg/day. Behavior development of newborn rats was adversely affected at all doses.. 8.3 Nursing Mothers. Following oral administration, ivermectin is excreted in human milk in low concentrations. Excretion in human milk following topical administration has not been evaluated. In oral studies in rats, ivermectin was excreted in the milk of nursing mothers and neonatal toxicity was observed in the litters. The blood-brain barrier in neonatal rats may not be fully developed at birth. Because of the potential for serious adverse reactions from SOOLANTRA cream in nursing infants, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. Safety and effectiveness of SOOLANTRA cream in pediatric patients have not been established.. 8.5 Geriatric Use. Of the 1371 subjects in the two pivotal clinical studies of SOOLANTRA cream, 170 (12.4%) were 65 and over, while 37 (2.7%) were 75 and over. 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.

PATIENT MEDICATION INFORMATION SECTION.

PATIENT INFORMATION. SOOLANTRA(R) (SOO-LAWN-TRAH) (ivermectin) creamImportant: SOOLANTRA cream is for use on the skin only (topical use). Do not use SOOLANTRA cream in your mouth, eyes, or vagina.What is SOOLANTRA creamSOOLANTRA cream is prescription medicine used on the skin (topical) to treat pimples and bumps (inflammatory lesions) caused by condition called rosacea. It is not known if SOOLANTRA cream is safe and effective in children.Before using SOOLANTRA cream, tell your healthcare provider about all your medical conditions, including if you:are pregnant or plan to become pregnant. It is not known if SOOLANTRA cream will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if SOOLANTRA cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use SOOLANTRA cream.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How should use SOOLANTRA cream See the detailed Instructions for Use that comes with SOOLANTRA cream for information on how to apply SOOLANTRA cream.Use SOOLANTRA cream exactly as your healthcare provider tells you to.Apply SOOLANTRA cream to the affected areas of your face time day.Avoid contact with your eyes and lips if SOOLANTRA cream is accidentally swallowed (ingested), call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of SOOLANTRA creamThe most common side effects of SOOLANTRA cream include skin burning sensation and skin irritation. These are not all of the possible side effects of SOOLANTRA cream. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Galderma Laboratories, L.P. at 1-866-735-4137.How should store SOOLANTRA creamStore SOOLANTRA cream at room temperature between 68F to 77F (20C to 25C).Keep SOOLANTRA cream and all medicines out of the reach of children.General information about the safe and effective use of SOOLANTRA cream.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use SOOLANTRA cream for condition for which it was not prescribed. Do not give SOOLANTRA cream to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about SOOLANTRA cream that is written for health professionals.What are the ingredients in SOOLANTRA creamActive ingredient: ivermectin Inactive ingredients: carbomer copolymer type B, cetyl alcohol, citric acid monohydrate, dimethicone, edetate disodium, glycerin, isopropyl palmitate, methylparaben, oleyl alcohol, phenoxyethanol, polyoxyl 20 cetostearyl ether, propylene glycol, propylparaben, purified water, sodium hydroxide, sorbitan monostearate, and stearyl alcohol.Marketed by: Galderma Laboratories, L.P., Dallas, Texas 75201 USA P52476-3Made in Canada For more information about SOOLANTRA cream, call 1-866-735-4137.This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 10/2022. are pregnant or plan to become pregnant. It is not known if SOOLANTRA cream will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if SOOLANTRA cream passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby if you use SOOLANTRA cream.. Use SOOLANTRA cream exactly as your healthcare provider tells you to.. Apply SOOLANTRA cream to the affected areas of your face time day.. Avoid contact with your eyes and lips if SOOLANTRA cream is accidentally swallowed (ingested), call your healthcare provider or go to the nearest hospital emergency room right away.. Store SOOLANTRA cream at room temperature between 68F to 77F (20C to 25C).