2.1       Recommended Dosage

Before injection, see General Considerations for Administration [see Dosage and Administration (2.2, 2.3)]. 

Inject KYBELLA into subcutaneous fat tissue in the submental area using an area-adjusted dose of 2 mg/cm2  (a single treatment of up to 100 mg (up to a total of 10 mL)) that consists of up to a maximum of 50 subcutaneous injections, (2 mg (0.2 mL)) each, spaced 1 cm apart.

Up to 6 treatments may be administered at intervals no less than 1 month apart.

2.2       Recommendations Prior to KYBELLA Treatment

KYBELLA should be administered by a healthcare provider.  

Prior to KYBELLA treatment:

• Screen patients for other potential causes of submental convexity/fullness (e.g., thyromegaly and cervical lymphadenopathy).
  
• Consider the risks of KYBELLA use 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.
  
• Visually inspect KYBELLA vials for particulate matter and/or discoloration, and discard the vial if the solution is discolored and/or contains particulate matter (KYBELLA is clear, colorless and free of particulate matter).  

Given that patients who have had prior surgical or aesthetic treatment of the submental area may have changes in anatomy/landmarks or scar tissue that may impact the ability of the health care provider to safely administer KYBELLA or to obtain the desired aesthetic result, use KYBELLA with caution in such patients.

2.3        Recommended Preparation and Administration Instructions

The safe and effective use of KYBELLA depends on the use of the correct number and locations of subcutaneous injections, proper needle placement, and administration technique. Prior to administration, 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 (5.1)].

Avoid Injections Near the Area of the Marginal Mandibular Nerve

To avoid injury to the marginal mandibular nerve:

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

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

Administration Instructions

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

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

Figure 3. Treatment Area and Injection Pattern

Do not inject KYBELLA outside the defined parameters [see Warnings and Precautions (5.1, 5.3, 5.4)] and follow these subcutaneous administration instructions:

• 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. 
  
• Do not withdraw the needle from the subcutaneous fat during injection; this could increase the risk of intradermal exposure and very superficial injections (into the dermis) may result in skin ulceration and necrosis [see Warnings and Precautions (5.3)].
  
• 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, withdraw the needle to an appropriate depth before the injection is administered.
  
• Avoid injecting into other tissues such as the muscle, salivary glands, lymph nodes; and artery or vein [see Warnings and Precautions (5.4)]. 
  
• Upon needle withdrawal, may apply pressure to each injection site as necessary to minimize bleeding; an adhesive dressing may be applied.

After use, discard any remaining solution in the vial. Do not dilute or mix KYBELLA with other compounds.

5.1       Marginal Mandibular Nerve Injury

Cases of marginal mandibular nerve injury, manifested as an asymmetric smile or facial muscle weakness (paresis), were reported in KYBELLA-treated patients during clinical trials.  All marginal mandibular nerve injuries reported from the trials resolved without additional treatment (range 1-298 days, median 44 days).

To avoid the potential for marginal mandibular nerve injury, do not inject KYBELLA into or in close proximity to the marginal mandibular branch of the facial nerve [see Dosage and Administration (2.3)].

5.2       Dysphagia

Difficulty swallowing (dysphagia) occurred in KYBELLA-treated patients in clinical trials in the setting of administration site reactions, e.g., pain, swelling, and induration of the submental area.  Cases of dysphagia resolved without additional treatment (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 patients with a current or prior history of dysphagia because KYBELLA use may exacerbate the condition. 

5.3       Injection Site Reactions 

Injection Site Hematoma or Bruising

In clinical trials, 72% of subjects treated with KYBELLA had an injection site hematoma or bruising [see Adverse Reactions (6.1)].

Use KYBELLA with caution in patients with bleeding abnormalities (e.g., taking antiplatelet or anticoagulant therapy) as excessive bleeding or bruising in the treatment area may occur.

Injection Site Alopecia

Cases of injection site alopecia have been reported with KYBELLA administration. The onset and duration of this adverse reaction may vary among individuals and may persist.

Consider withholding subsequent KYBELLA treatments until resolution of this adverse reaction.

Injection Site Ulceration, Necrosis, Nodule, Mass, and Infection

Very superficial injections (into the dermis) of KYBELLA may result in skin ulceration and necrosis [see Dosage and Administration (2.3)]. Cases of injection site ulceration, necrosis, nodule (≤ 3 cm in diameter), mass (> 3 cm in diameter), and infection have been reported with KYBELLA administration. Nodules or masses may occur following initial or subsequent KYBELLA administration. Some nodules and masses may not resolve and medical intervention may be required. Some cases of injection site infection have included cellulitis and abscess requiring intravenous antibiotic treatment and incision and drainage.

Discontinue KYBELLA if patients develop injection site ulceration, necrosis, nodule, mass, or infection after KYBELLA administration.

5.4       Risk of Injecting in Proximity to Vulnerable Anatomic Structures

To avoid potential tissue damage, do not inject KYBELLA into or in close proximity (1-1.5 cm) to salivary glands, lymph nodes and muscles.

Avoid inadvertent injection directly into an artery or a vein as it can result in vascular injury.

5.5       Serious Adverse Reactions Associated with Unapproved Use Outside the Submental Region

Serious adverse reactions have been reported following unapproved administration of KYBELLA outside the submental region (e.g., blurred or reduced vision with periorbital use, muscle or nerve injury including facial paresis and paresthesia). Cases of injection site nodules (≤ 3 cm in diameter) and masses (> 3 cm in diameter) have also been reported following initial or subsequent administration of KYBELLA outside the submental region. The nodules and masses may not resolve and medical intervention may be required.

KYBELLA is not approved for the treatment of subcutaneous fat outside the submental region [see Indications and Usage (1)].

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 and 506 subjects were treated with placebo [see Clinical Studies (14)]. 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 included 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 KYBELLA-treated 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, mass, infection, alopecia, and scarring.
  
• Immune System Disorders: Hypersensitivity reactions including rash, urticaria, and itching.
  
• Nervous System Disorders: Oral hypoaesthesia and oral paraesthesia.
  
• Procedural Complications: Vascular injury due to inadvertent intravascular injection. 

8.1       Pregnancy

Risk Summary

There are no adequate and well-controlled trials of KYBELLA in pregnant women to inform the drug-associated risk. 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]. 

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. 

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 of KYBELLA have not been established in pediatric patients and KYBELLA is not recommended 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 adult subjects.   

12.1       Mechanism of Action

KYBELLA is a cytolytic drug, which when injected into submental fat - in patients with moderate to severe convexity or fullness associated with submental fat - physically destroys the cell membrane causing lysis.

12.2       Pharmacodynamics

Cardiac Electrophysiology

At  the recommended deoxycholic acid dose, clinically significant QTc interval prolongation was not observed.

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

After KYBELLA subcutaneous injection, deoxycholic acid was rapidly absorbed. After dosing with the recommended single treatment KYBELLA dose (100 mg) 

• Maximum plasma concentrations of deoxycholic acid (mean Cmax) were observed with a median Tmax of 18 minutes after injection.  
  
• Mean (±SD) deoxycholic acid exposure (AUC0-24) was 7896 ± 2269 ng.hr/mL and was 1.6-fold higher over endogenous exposure.

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. 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.

Drug Interaction Studies

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

Patients with 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.

Male and Female Patients:  Deoxycholic acid pharmacokinetics were not influenced by sex.

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of deoxycholic acid. 

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 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.