1.1       Fullness Associated with Submental Fat

KYBELLA® (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 KYBELLA® for the treatment of subcutaneous fat outside the submental region has not been established and is not recommended.

2.1       Dosage

KYBELLA® (deoxycholic acid) injection 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

KYBELLA® 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 KYBELLA® 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 KYBELLA® or to obtain the desired aesthetic result.

KYBELLA® is clear, colorless and free of particulate matter.  Visually inspect KYBELLA® 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 KYBELLA® depends on the use of the correct number and locations for injections, proper needle placement, and administration techniques.

Healthcare professionals administering KYBELLA® 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 [see Warnings and Precautions (5)].

Avoid injections near the area of the marginal mandibular nerve [see Warnings and Precautions (5.1)]

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 [see Warnings and Precautions (5.1)].

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 KYBELLA® only within the target submental fat treatment area (see Figures 1 and 3).

Figure 1. Avoid the Marginal Mandibular Nerve 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 KYBELLA® outside the defined parameters [see Warnings and Precautions (5.1, 5.4)].

• Using a large bore needle, draw 1 mL of KYBELLA® 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 KYBELLA® into the pre-platysmal fat (see Figure 2) 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 and necrosis. Do not withdraw the needle from the subcutaneous fat during injection as this could increase the risk of intradermal exposure and potential skin ulceration and necrosis.
  
• Avoid injecting into the post-platysmal fat by injecting KYBELLA® 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.

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, KYBELLA® (deoxycholic acid) injection 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 (dysphagia) 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 KYBELLA® 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 KYBELLA® experienced injection site hematoma/bruising [see Adverse Reactions (6.1)].

KYBELLA® 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, KYBELLA® should not be injected into or in close proximity (1-1.5 cm) to salivary glands, lymph nodes and muscles.

5.5       Injection site alopecia

Cases of injection site alopecia have been reported with the administration of KYBELLA®. The onset and duration of this adverse reaction may vary among individuals and may persist. Consider withholding subsequent treatments until resolution of the adverse reaction.

5.6       Injection site ulceration and necrosis

Injections that are too superficial (into the dermis) may result in skin ulceration and necrosis [see Injection Technique (2.3)]. Cases of injection site ulceration and necrosis have been reported with the administration of KYBELLA®. Do not administer KYBELLA® into the affected area until complete resolution of the adverse reaction.

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 KYBELLA® (deoxycholic acid) injection 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).

a Adverse reactions that occurred in ≥ 2% KYBELLA® treated subjects and at greater incidence than placebo
b Marginal mandibular nerve paresis

Other adverse reactions associated with the use of KYBELLA® 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%). 

6.2       Postmarketing Experience

The following adverse reactions have been identified during post-approval use of KYBELLA®.

Because these reactions are reported voluntarily from a population of uncertain size, it is not

always possible to reliably estimate their frequency or establish a causal relationship to

KYBELLA® exposure.

Administration site conditions: injection site ulceration, necrosis and alopecia.

8.1       Pregnancy

Risk Summary

There are no adequate and well-controlled studies of KYBELLA® (deoxycholic acid) injection 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 deoxycholic acid to rats during organogenesis at doses up to 5 times the maximum recommended human dose (MRHD) of 100 mg [see Data]. 

Data

Animal Data

Embryofetal development studies have been performed in rats and rabbits using subcutaneous doses of 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 KYBELLA® 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 KYBELLA® 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 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 KYBELLA® and any potential adverse effects on the breastfed child from KYBELLA® 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 KYBELLA® is not intended for use in children or adolescents.

8.5       Geriatric Use

The clinical trials of KYBELLA® 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.

12.1       Mechanism of Action

KYBELLA® (deoxycholic acid) injection is a cytolytic drug, which when injected into tissue physically destroys the cell membrane causing lysis.

12.2       Pharmacodynamics

Cardiac Electrophysiology

At therapeutic doses, KYBELLA® does not prolong the QTc interval.

12.3       Pharmacokinetics

Endogenous 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

Deoxycholic acid from KYBELLA® is rapidly absorbed following subcutaneous injection. After dosing with the maximum recommended single treatment dose with KYBELLA® (100 mg), maximum plasma concentrations (mean Cmax) were observed with a median Tmax of 18 minutes after injection.  The mean (±SD) Cmax value was 1024 ± 304 ng/mL and was 3.2-fold higher than average Cmax values observed during a 24-hour baseline endogenous period in the absence of KYBELLA®. After maximum recommended single treatment dose (100 mg), mean (±SD) deoxycholic acid exposure (AUC0-24) was 7896 ± 2269 ng.hr/mL and was 1.6-fold higher over endogenous exposure. Post-treatment deoxycholic acid plasma levels returned to the endogenous range within 24 hours. No accumulation is expected with the proposed treatment frequency.

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

Metabolism and Excretion

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

In Vitro Assessment of Drug Interactions

Results from in vitro studies indicate that deoxycholic acid does not inhibit or induce human cytochrome P450 (CYP) enzymes at clinically relevant concentrations.  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

KYBELLA® 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 deoxycholic acid levels, the pharmacokinetics of deoxycholic acid following KYBELLA® injection is unlikely to be influenced by hepatic impairment.

Pharmacokinetic Effects of Gender

Deoxycholic acid pharmacokinetics were not influenced by gender.

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of KYBELLA® (deoxycholic acid) injection. 

KYBELLA® 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 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.