Regubil

Deoxycholic Acid:

• Indications and usage
• Dosage and administration
• Dosage forms and strengths
• Contraindications
• Warnings and precautions
• Adverse reactions
• Use in specific populations
• Overdosage
• Description
• Clinical pharmacology
• Nonclinical toxicology
• Clinical studies
• How supplied/storage and handling
• Patient counseling information
• Regubil (Deoxycholic Acid) reviews

1 INDICATIONS AND USAGE

Regubil is a cytolytic drug indicated for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat in adults. (1.1)

Limitation of use: The safe and effective use of Regubil (Deoxycholic Acid) for the treatment of subcutaneous fat outside the submental region has not been established and is not recommended. (1.2)

1.1 Fullness Associated with Submental Fat

Regubil (Deoxycholic Acid) (deoxycholic acid) injection is indicated for improvement in the appearance of moderate to severe convexity or fullness associated with submental fat in adults.

1.2 Limitation of use

The safe and effective use of Regubil (Deoxycholic Acid) for the treatment of subcutaneous fat outside the submental region has not been established and is not recommended.

2 DOSAGE AND ADMINISTRATION

• 0.2 mL injections spaced 1 cm apart until all sites in the planned treatment area have been injected.
• Up to 50 injections or 10 mL may be injected in a single treatment. (2.1)
• Up to 6 single treatments may be administered at intervals no less than 1-month apart. (2.1)
• See General Considerations for Administration and Injection Technique before injection. (2.2, 2.3)

2.1 Dosage

Regubil (Deoxycholic Acid) is injected into subcutaneous fat tissue in the submental area using an area-adjusted dose of 2 mg/cm².

• A single treatment consists of up to a maximum of 50 injections, 0.2 mL each (up to a total of 10 mL), spaced 1 cm apart.
• Up to 6 single treatments may be administered at intervals no less than 1 month apart.

See General Considerations for Administration (2.2) and Injection Technique (2.3) before injection.

2.2 General Considerations for Administration

Regubil should be administered by a healthcare professional.

Screen patients for other potential causes of submental convexity/fullness (e.g., thyromegaly and cervical lymphadenopathy).

Give careful consideration to the use of Regubil (Deoxycholic Acid) in patients with excessive skin laxity, prominent platysmal bands or other conditions for which reduction of submental fat may result in an aesthetically undesirable outcome.

Use caution in patients who have had prior surgical or aesthetic treatment of the submental area. Changes in anatomy/landmarks or the presence of scar tissue may impact the ability to safely administer Regubil (Deoxycholic Acid) or to obtain the desired aesthetic result.

Regubil (Deoxycholic Acid) is clear, colorless and free of particulate matter. Visually inspect Regubil (Deoxycholic Acid) vials for particulate matter and/or discoloration, and discard the vial if the solution is discolored and/or contains particulate matter.

After use, discard any remaining solution in the vial.

2.3 Injection Technique

The safe and effective use of Regubil (Deoxycholic Acid) depends on the use of the correct number and locations for injections, proper needle placement, and administration techniques.

Health care professionals administering Regubil (Deoxycholic Acid) must understand the relevant submental anatomy and associated neuromuscular structures in the area involved and any alterations to the anatomy due to prior surgical or aesthetic procedures .

Avoid injections near the area of the marginal mandibular nerve

Needle placement with respect to the mandible is very important as it reduces the potential for injury to the marginal mandibular nerve, a motor branch of the facial nerve. Injury to the nerve presents as an asymmetrical smile due to paresis of lip depressor muscles .

To avoid injury to the marginal mandibular nerve:

• Do not inject above the inferior border of the mandible.
• Do not inject within a region defined by a 1-1.5 cm line below the inferior border (from the angle of the mandible to the mentum).
• Inject Regubil (Deoxycholic Acid) only within the target submental fat treatment area.

Avoid injection into the platysma

Prior to each treatment session, palpate the submental area to ensure sufficient submental fat and to identify subcutaneous fat between the dermis and platysma (pre-platysmal fat) within the target treatment area (Figure 2). The number of injections and the number of treatments should be tailored to the individual patient's submental fat distribution and treatment goals.

Figure 2. Sagittal View of Platysma Area

Injecting into the treatment area

Use of ice/cold packs, topical and/or injectable local anesthesia (e.g., lidocaine) may enhance patient comfort.

Outline the planned treatment area with a surgical pen and apply a 1 cm injection grid to mark the injection sites (Figures 2 and 3).

Figure 3. Treatment Area and Injection Pattern

Do not inject Regubil (Deoxycholic Acid) outside the defined parameters .

• Using a large bore needle, draw 1 mL of Regubil (Deoxycholic Acid) into a sterile 1 mL syringe and expel any air bubbles in the syringe barrel.
• Have the patient tense the platysma. Pinch the submental fat and, using a 30 gauge (or smaller) 0.5 inch needle, inject 0.2 mL of Regubil (Deoxycholic Acid) into the pre-platysmal fat next to each of the marked injection sites by advancing the needle perpendicular to the skin.
• Injections that are too superficial (into the dermis) may result in skin ulceration. Do not withdraw the needle from the subcutaneous fat during injection as this could increase the risk of intradermal exposure and potential skin ulceration.
• Avoid injecting into the post-platysmal fat by injecting Regubil (Deoxycholic Acid) into fat tissue at the depth of approximately mid-way into the subcutaneous fat layer (Figure 2).
• If at any time resistance is met as the needle is inserted, indicating the possibility of contact with fascial or nonfat tissue, the needle must be withdrawn to an appropriate depth before the injection is administered.
• Avoid injecting into other tissues such as the muscle, salivary glands and lymph nodes.
• Upon needle withdrawal, pressure may be applied to each injection site as necessary to minimize bleeding; an adhesive dressing may be applied.

3 DOSAGE FORMS AND STRENGTHS

Injection: 10 mg/mL. Regubil (Deoxycholic Acid) injection is a clear, colorless, sterile solution supplied in 2 mL vials intended for single patient use. Each milliliter of the solution contains 10 mg of Regubil (Deoxycholic Acid).

• Injection: 10 mg/mL sterile solution, supplied in 2 mL vials. Each vial is for single patient use. (3)
• Dilution or admixture with other compounds is not recommended. (3)

4 CONTRAINDICATIONS

Regubil (Deoxycholic Acid) is contraindicated in the presence of infection at the injection sites.

Regubil (Deoxycholic Acid) is contraindicated in the presence of infection at the injection sites. (4)

5 WARNINGS AND PRECAUTIONS

• Marginal mandibular nerve injury: Follow injection technique to avoid this injury. (2.3, 5.1)
• Dysphagia may occur with Regubil (Deoxycholic Acid) use. Use in patients with pre-existing dysphagia may exacerbate the condition. (5.2)
• Submental hematoma/bruising occurs frequently after Regubil (Deoxycholic Acid) administration. Use with caution in patients who are being treated with antiplatelet or anticoagulant therapy or have coagulation abnormalities. (5.3)
• Avoid injecting in proximity to vulnerable anatomic structures due to the increased risk of tissue damage. (2.3, 5.4)

5.1 Marginal mandibular nerve injury

Cases of marginal mandibular nerve injury, manifested as an asymmetric smile or facial muscle weakness (paresis), were reported during clinical trials. To avoid the potential for nerve injury, Regubil (Deoxycholic Acid) should not be injected into or in close proximity to the marginal mandibular branch of the facial nerve. All marginal mandibular nerve injuries reported from the trials resolved spontaneously (range 1-298 days, median 44 days).

5.2 Dysphagia

Difficulty swallowing occurred in clinical trials in the setting of administration site reactions, e.g., pain, swelling, and induration of the submental area. Cases of dysphagia spontaneously resolved (range 1-81 days, median 3 days).

Subjects with current or prior history of dysphagia were excluded from clinical trials. Avoid use of Regubil (Deoxycholic Acid) in these patients as current or prior history of dysphagia may exacerbate the condition.

5.3 Injection site hematoma/bruising

In clinical trials, 72% of subjects treated with Regubil (Deoxycholic Acid) experienced injection site hematoma/bruising .

Regubil (Deoxycholic Acid) should be used with caution in patients with bleeding abnormalities or who are currently being treated with antiplatelet or anticoagulant therapy as excessive bleeding or bruising in the treatment area may occur.

5.4 Risk of injecting in proximity to vulnerable anatomic structures

To avoid potential tissue damage, Regubil (Deoxycholic Acid) should not be injected into or in close proximity (1-1.5 cm) to salivary glands, lymph nodes and muscles.

6 ADVERSE REACTIONS

• The most common adverse reactions include injection site edema/swelling, hematoma, pain, numbness, erythema and induration. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Kythera Biopharmaceuticals, Inc. at 1-844-KYTHERA (1-844-598-4372) 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, the 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 practice.

In two double-blind, placebo-controlled clinical trials 513 subjects were treated with Regubil (Deoxycholic Acid) and 506 subjects were treated with placebo. The population was 19-65 years old, 85% were women, 87% Caucasian, 8% African American. At baseline the population had a mean BMI of 29 kg/m², moderate to severe submental convexity (graded as 2 or 3 on a 0 to 4 scale) and without excessive skin laxity. Subjects received up to 6 treatments at least 1 month apart and were followed for up to 6 months after the last received treatment.

The most commonly reported adverse reactions are listed below (Table 1).

Other adverse reactions associated with the use of Regubil (Deoxycholic Acid) include: injection site hemorrhage, injection site discoloration, pre-syncope/syncope, lymphadenopathy, injection site urticaria and neck pain.

Adverse reactions that lasted more than 30 days and occurred in more than 10% of subjects were injection site numbness (42%), injection site edema/swelling (20%), injection site pain (16%), and injection site induration (13%).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

There are no adequate and well-controlled studies of Regubil in pregnant women to inform the drug-associated risk. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk of major birth defects in the U.S. general population is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. In animal reproduction studies, no fetal harm was observed with the subcutaneous administration of Regubil (Deoxycholic Acid) to rats during organogenesis at doses up to 5 times the maximum recommended human dose (MRHD) of 100 mg .

Data

Animal Data

Embryofetal development studies have been performed in rats and rabbits using subcutaneous doses of Regubil (Deoxycholic Acid) administered during the period of organogenesis. For the basis of comparing animal to human doses, the MRHD is 1.7 mg/kg (100 mg/60 kg). No evidence of fetal harm was observed in rats at up to the highest dose tested (50 mg/kg) which is 5-fold higher than the MRHD of Regubil (Deoxycholic Acid) based on a mg/m² comparison. However, missing intermediate lung lobe was noted in rabbits at all dose levels tested including the lowest dose (10 mg/kg) which is 2-fold higher than the MRHD of Regubil (Deoxycholic Acid) based on a mg/m² comparison. These effects may be related to maternal toxicity, which was also seen at all dose levels tested.

8.2 Lactation

Risk Summary

There is no information available on the presence of synthetic Regubil (Deoxycholic Acid) in human milk, the effects of the drug on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Regubil (Deoxycholic Acid) and any potential adverse effects on the breastfed child from Regubil (Deoxycholic Acid) or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in patients below the age of 18 years have not been established and Regubil is not intended for use in children or adolescents.

8.5 Geriatric Use

The clinical trials of Regubil (Deoxycholic Acid) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

10 OVERDOSAGE

Injection of excessive doses/volumes of Regubil (Deoxycholic Acid) may increase the risk of adverse reactions.

11 DESCRIPTION

Regubil (Deoxycholic Acid) (deoxycholic acid) injection, 10 mg/mL is a clear colorless, sterile solution for subcutaneous use. It contains a cytolytic agent, Regubil (Deoxycholic Acid), as the active ingredient. The chemical name of Regubil (Deoxycholic Acid) is 3α,12α-dihydroxy-5β-cholan-24-oic acid, and its molecular formula is C₂₄H₄₀O₄, and its molecular weight is 392.57 g/mol. The chemical structure of Regubil (Deoxycholic Acid) is:

Each 2 mL vial of Regubil (Deoxycholic Acid) (deoxycholic acid) injection contains 20 mg synthetic Regubil (Deoxycholic Acid) as the active ingredient and the following inactive ingredients: benzyl alcohol (18 mg), dibasic sodium phosphate (2.84 mg), sodium chloride (8.76 mg), sodium hydroxide (2.86 mg) in water for injection, USP. Hydrochloric acid and additional sodium hydroxide are added as necessary to adjust the formulation to pH 8.3. Each vial is for single patient use.

Chemical Structure

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Regubil is a cytolytic drug, which when injected into tissue physically destroys the cell membrane causing lysis.

12.2 Pharmacodynamics

Cardiac Electrophysiology

At therapeutic doses, Regubil (Deoxycholic Acid) does not prolong the QTc interval.

12.3 Pharmacokinetics

Endogenous Regubil (Deoxycholic Acid) plasma levels are highly variable within and between individuals; most of this natural bile component is sequestered in the enterohepatic circulation loop.

Absorption and Distribution

Regubil (Deoxycholic Acid) from Regubil (Deoxycholic Acid) is rapidly absorbed following subcutaneous injection. After dosing with the maximum recommended single treatment dose with Regubil (Deoxycholic Acid) (100 mg), maximum plasma concentrations (mean C_max) were observed with a median T_max of 18 minutes after injection. The mean (±SD) C_max value was 1024 ± 304 ng/mL and was 3.2-fold higher than average C_max values observed during a 24-hour baseline endogenous period in the absence of Regubil (Deoxycholic Acid). After maximum recommended single treatment dose (100 mg), mean (±SD) Regubil (Deoxycholic Acid) exposure (AUC_0-24) was 7896 ± 2269 ng.hr/mL and was 1.6-fold higher over endogenous exposure. Post-treatment Regubil (Deoxycholic Acid) plasma levels returned to the endogenous range within 24 hours. No accumulation is expected with the proposed treatment frequency.

Regubil (Deoxycholic Acid) is extensively bound to proteins in plasma (98%).

Metabolism and Excretion

Endogenous Regubil (Deoxycholic Acid) is a product of cholesterol metabolism and is excreted intact in feces. Regubil (Deoxycholic Acid) is not metabolized to any significant extent under normal conditions. Regubil (Deoxycholic Acid) from Regubil (Deoxycholic Acid) joins the endogenous bile acid pool in the enterohepatic circulation and is excreted along with the endogenous Regubil (Deoxycholic Acid).

In Vitro Assessment of Drug Interactions

Results from in vitro studies indicate that Regubil (Deoxycholic Acid) does not inhibit or induce human cytochrome P450 (CYP) enzymes at clinically relevant concentrations. Regubil (Deoxycholic Acid) does not inhibit the following transporters: P-gp, BCRP, MRP4, MRP2, OATP1B1, OATP2B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, NTCP, and ASBT.

Specific Populations

Hepatic Impairment

Regubil (Deoxycholic Acid) has not been studied in subjects with hepatic impairment. Considering the intermittent dose frequency, the small dose administered that represents approximately 3% of the total bile acid pool, and the highly variable endogenous Regubil (Deoxycholic Acid) levels, the pharmacokinetics of Regubil (Deoxycholic Acid) following Regubil (Deoxycholic Acid) injection is unlikely to be influenced by hepatic impairment.

Pharmacokinetic Effects of Gender

Regubil (Deoxycholic Acid) pharmacokinetics were not influenced by gender.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of Regubil (Deoxycholic Acid).

Regubil (Deoxycholic Acid) was negative in a battery of in vitro (Ames test and chromosomal aberration assay in human lymphocytes) and in vivo (rat erythrocyte micronucleus assay) genetic toxicology assays.

No effects on fertility were observed in male and female rats administered Regubil (Deoxycholic Acid) at subcutaneous doses up to 50 mg/kg (5 times the MRHD based on a mg/m² comparison) once weekly prior to and during the mating period and through gestation day 7 in female rats.

14 CLINICAL STUDIES

Two randomized, multi-center, double-blind, placebo-controlled trials of identical design were conducted to evaluate Regubil (Deoxycholic Acid) for use in improvement in the appearance of convexity or fullness associated with submental fat. The trials enrolled healthy adults (ages 19 to 65, BMI ≤ 40 kg/m²) with moderate or severe convexity or fullness associated with submental fat (i.e., grade 2 or 3 on 5-point grading scales, where 0 = none and 4 = extreme), as judged by both clinician and subject ratings. Subjects received up to 6 treatments with Regubil (Deoxycholic Acid) (N=514, combined trials) or placebo (N=508, combined trials) at no less than 1 month intervals. Use of ice/cold packs, topical and/or injectable local anesthesia was allowed during the clinical trials. Injection volume was 0.2 mL per injection site, spaced 1 cm apart into the submental fat tissue, which is also expressed in dose per area as 2 mg/cm². For each treatment session a maximum of 100 mg (10 mL) was permitted over the entire treatment area. Subjects were administered an average of 6.4 mL at the first treatment session, and subjects who received all six treatments were administered an average of 4.4 mL at the sixth treatment session. Fifty-nine percent of subjects received all six treatments.

In these trials, the mean age was 49 years and the mean BMI was 29 kg/m². Most of the subjects were women (85%) and Caucasian (87%). At baseline, 51% of the subjects had a clinician-rated submental fat severity rating of moderate and 49% had a severe submental fat rating.

The co-primary efficacy assessments were based on at least 2-grade and at least 1-grade improvements in submental convexity or fullness on the composite of clinician-reported and patient-reported ratings of submental fat 12 weeks after final treatment. Additionally, changes in submental fat volume were evaluated in a subset of subjects (N=449, combined trials) using magnetic resonance imaging (MRI). Visual and emotional impacts of submental fat (happy, bothered, self-conscious, embarrassed, looking older or overweight) were also evaluated using a 6-question survey, with each question rated from 0 (not at all) to 10 (extremely/very much).

Reductions in submental fat volume were observed more frequently in the Regubil (Deoxycholic Acid) group compared to the placebo group as measured by the composite clinician and patient ratings (Table 2). The composite response rates by visit are presented in Figure 4.

Note: Subjects were followed up 4, 12 and 24 weeks after the last treatment. Forty-one percent of subjects received fewer than 6 treatments and entered the post-treatment period earlier than Week 24.

A greater proportion of KYBELLA-treated subjects had at least a 10% reduction in submental fat volume as compared to placebo-treated subjects when evaluated by MRI (43% vs 5%, respectively).

The overall patient-reported satisfaction and self-perceived visual attributes showed greater improvement in the Regubil (Deoxycholic Acid) group than in the placebo group.

Figure 4

16 HOW SUPPLIED/STORAGE AND HANDLING

Regubil (Deoxycholic Acid) (deoxycholic acid) injection, 10 mg/mL is a clear, colorless, sterile solution supplied in 2 mL, single patient use vials in the following dispensing pack:

4 vials, NDC 61168-101-04

Store at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F).

Regubil (Deoxycholic Acid) has a unique hologram on the vial label. If you do not see a hologram, do not use the product and call 1-844-KYTHERA (1-844-598-4372).

Each vial is for a single patient use. Do not dilute. Discard unused portion.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advise patients to inform their healthcare professional if they develop signs of marginal mandibular nerve paresis (e.g., asymmetric smile, facial muscle weakness), difficulty swallowing, or if any existing symptom worsens.

Manufactured for Kythera Biopharmaceuticals, Inc., Westlake Village, CA 91362

© 2015 Kythera Biopharmaceuticals, Inc.

Trademarks owned by Kythera Biopharmaceuticals, Inc.

U.S. Patents 8,298,556; 7,622,130; 7,754,230; 8,242,294; 8,101,593; 8,367,649; 8,653,058, 8,461,140; 8,846,066; other patents pending

NDC 61168-101-04

Regubil (Deoxycholic Acid)

(deoxycholic acid) injection

20 mg/2mL

(10 mg/mL)

for subcutaneous use only

Single use vials. Discard unused portion.

Four ready-to-use vials. Do not dilute.

Rx ONLY

KYTHERA Biopharmaceuticals, Inc.