AFSTYLA Dailymed

The most common adverse reactions (>0.5% of subjects) reported in clinical trials were Factor VIII inhibition in previously untreated patients (PUPs), dizziness and hypersensitivity.

• The most common adverse reactions reported in clinical trials (>0.5% of subjects) were Factor VIII inhibition in previously untreated patients (PUPs), dizziness and hypersensitivity. (6)

To report SUSPECTED ADVERSE REACTIONS, contact the CSL Behring Pharmacovigilance Department at 1-866-915-6958 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 one drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice.

The safety, efficacy and pharmacokinetics of AFSTYLA have been evaluated in 258 previously treated patients (PTPs) and 24 previously untreated patients (PUPs) with severe hemophilia A (<1% endogenous Factor VIII activity) who received at least one dose of AFSTYLA as part of either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management in two completed clinical trials (an adult/adolescent study [≥12 to 65 years of age] and a pediatric study [<12 years of age]), and an extension study (0 to ≤65 years of age PTPs and 0 to ≤5 years old PUPs). Patients with a history of, or current FVIII inhibitors, or any first order family history of FVIII inhibitors, patients with known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, and patients with evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months prior to Day 1 of the study were excluded from study participation.

One hundred eight (38.3%) subjects were children <12 years of age (59 [20.9%] 0 to <6 years and 49 [17.4%] ≥6 to <12 years), 14 (5.0%) were adolescents (≥12 to <18 years), and 160 (56.7%) were adults (≥18 to ≤65 years). In PTPs there have been a total of 28,418 exposure days (EDs), with at least 28,492 injections of AFSTYLA administered. In the completed studies, a total of 185 subjects achieved at least 50 EDs, of whom 60 subjects achieved ≥100 EDs. In PUPs there have been a total number of 5909 EDs, with 5914 injections, 21 subjects achieved ≥50 EDs.

Adverse reactions (ARs) (summarized in Table 3) were reported for 14 of 258 (5.4%) subjects in all studies. An adverse reaction of hypersensitivity resulted in the withdrawal of one subject. Among PTPs no subject developed neutralizing antibodies (inhibitors) to Factor VIII. No PTPs and PUPs developed antibodies to host cell proteins. No events of anaphylaxis or thrombosis were reported.

Table 3. Adverse Reactions Reported for AFSTYLA (N=258)Adverse reactions reported in adult/adolescent and pediatric studies in previously treated patients

MedDRA System Organ Class	Adverse Reactions	Number of Subjectsn (%)
Immune system disorders	Hypersensitivity	4 (1.6)
Nervous system disorders	Dizziness	2 (0.8)
	Paresthesia	1 (0.4)
Skin and subcutaneous tissue disorders	Rash	1 (0.4)
	Erythema	1 (0.4)
	Pruritus	1 (0.4)
General disorders and administration site conditions	Pyrexia	1 (0.4)
	Injection-site pain	1 (0.4)
	Chills	1 (0.4)
	Feeling hot	1 (0.4)

6.2 Immunogenicity

All subjects were monitored for inhibitory and binding antibodies to AFSTYLA, and binding antibodies to chinese hamster ovary (CHO) host cell proteins prior to the first infusion of AFSTYLA, at defined intervals during the studies and at the end of study visit.

Data from a completed clinical trial in previously untreated patients (PUPs) aged ≤5 years indicate that:

• 12 (50%; 95% CI: [29.1%, 70.9%]) of 24 treated subjects developed an inhibitor to Factor VIII.
• Of 22 subjects with at least 50 EDs or who developed inhibitor at any time, 6 (27.3%) developed high titer inhibitors (≥ 5BU) and 6 (27.3%) developed low titer inhibitors (<5BU).

The overall median EDs until initial inhibitor development was 10 EDs (range: 4 to 23). Of the 12 subjects who tested positive for inhibitors, 11 subjects have remained in the trial; 9 experienced successful eradication of the inhibitor. The median (range) EDs to inhibitor eradication was 37 (16 to 194). The median (range) time to inhibitor eradication was 14.3 (7.7 to 64.4) weeks. Two subjects with high titer inhibitors remain inhibitor positive: one subject was withdrawn from the immune tolerance induction (ITI) substudy after approximately 12 months, another subject completed ITI substudy after approximately 24 months.

No PTPs developed neutralizing antibodies (inhibitors) to Factor VIII or antibodies against CHO host cell proteins at any time during the completed clinical studies. Four subjects in the adult/adolescent study and 10 subjects in the pediatric study were negative for non-neutralizing anti-drug antibodies (ADAs) at screening and turned positive during the clinical study. Two of the adult/adolescent subjects and three of the pediatric subjects who developed ADAs were negative at end of study visit. No adverse events were associated with the development of ADAs. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to AFSTYLA with the incidence of antibodies to other products.

6.3Postmarketing Experience

The following adverse reaction has been identified during post-approval use of AFSTYLA. 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 drug exposure.

Blood and lymphatic systems disorders: Factor VIII inhibitor development

8 Use In Specific Populations

• Pediatric: Clearance (based on per kg body weight) is higher in pediatric patients 0 to <12 years of age. Higher and/or more frequent dosing may be needed. (8.4)

8.1 Pregnancy

Risk Summary

There are no data with AFSTYLA use in pregnant women to inform on drug-associated risk. No developmental or animal reproduction toxicity studies were conducted with AFSTYLA. Thus, the risk of developmental toxicity including, structural abnormalities, embryo-fetal and/or infant mortality, functional impairment, and alterations to growth is not known. In the US general population, the estimated background risk of major birth defects occurs in 2-4% of the general population and miscarriage occurs in 15-20% of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

There is no information regarding the excretion of AFSTYLA in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for AFSTYLA and any potential adverse effects on the breastfed infant from AFSTYLA or from the underlying maternal condition.

8.4 Pediatric Use

Safety and efficacy studies with AFSTYLA have been performed in 98 PTPs <18 years of age and in 24 PUPs ≤5 years. Fourteen adolescent subjects ≥12 to <18 years were enrolled in the adult/adolescent safety and efficacy study. Thirty-five subjects 0 to <6 years and 49 subjects ≥6 to <12 years were enrolled in a pediatric safety and efficacy study [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)]. Because clearance (based on per kg body weight) has been shown to be higher in the pediatric population 0 to <12 years, more frequent or higher doses of AFSTYLA based on body weight may be needed [see Clinical Pharmacology (12.3)].

8.5 Geriatric Use

Clinical studies of AFSTYLA did not include subjects over 65 years to determine whether or not they respond differently from younger subjects.

11 Description

AFSTYLA is a single-chain recombinant Factor VIII produced in chinese hamster ovary (CHO) cells. It is a construct where the B-domain occurring in wild type full-length Factor VIII has been truncated and 4 amino acids of the adjacent acidic a3 domain were removed (amino acids 765 to 1652 of full-length Factor VIII). AFSTYLA is expressed as a single-chain Factor VIII molecule with covalent linkage between heavy and light chains; thereby keeping the molecule in the single-chain form resulting in increased stability and increased von Willebrand Factor (VWF) affinity. Except for a new N-glycosylation site at the junction between heavy and light chains, the post-translational modifications are comparable to endogenous Factor VIII.

AFSTYLA is purified by a controlled multi-step process including two virus reduction steps complementing each other in their mode of action. No human or animal derived proteins are used in the purification or formulation processes.

AFSTYLA is a preservative-free, sterile, non-pyrogenic, lyophilized powder to be reconstituted with sterile water for injection (sWFI) for intravenous injection. AFSTYLA is available in single-dose vials containing the labeled amount of Factor VIII activity, expressed in IU. Each vial contains nominally 250, 500, 1000, 1500, 2000, 2500, or 3000 IU of AFSTYLA. The actual potency is labeled on each AFSTYLA vial and carton. After reconstitution of the lyophilized powder, all dosage strengths yield an almost colorless to slightly opalescent solution. The concentrations of excipients based on the vial size, as well as the amount of sWFI for reconstitution are provided in Table 4 below.

Table 4. Nominal Composition after Reconstitution with sWFI

Ingredient	250 IU vial	500 IU vial	1000 IU vial	1500 IU vial	2000 IU vial	2500 IU vial	3000 IU vial
rVIII-Single Chain	100 IU/mL	200 IU/mL	400 IU/mL	300 IU/mL	400 IU/mL	500 IU/mL	600 IU/mL
L-Histidine	3.1 mg/mL	3.1 mg/mL	3.1 mg/mL	3.1 mg/mL	3.1 mg/mL	3.1 mg/mL	3.1 mg/mL
Polysorbate 80	0.2 mg/mL	0.2 mg/mL	0.2 mg/mL	0.2 mg/mL	0.2 mg/mL	0.2 mg/mL	0.2 mg/mL
Calcium chloride	0.4 mg/mL	0.4 mg/mL	0.4 mg/mL	0.4 mg/mL	0.4 mg/mL	0.4 mg/mL	0.4 mg/mL
Sodium chloride	16.4 mg/mL	16.4 mg/mL	16.4 mg/mL	16.4 mg/mL	16.4 mg/mL	16.4 mg/mL	16.4 mg/mL
Sucrose	6 mg/mL	6 mg/mL	6 mg/mL	6 mg/mL	6 mg/mL	6 mg/mL	6 mg/mL
Water for Injection	2.5 mL	2.5 mL	2.5 mL	5 mL	5 mL	5 mL	5 mL

The number of units of Factor VIII administered is expressed in IU, which are related to the current WHO standard for Factor VIII products. One IU of Factor VIII activity in plasma is equivalent to that quantity of Factor VIII in 1 mL of normal plasma. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for Factor VIII in plasma).

12 Clinical Pharmacology

12.1 Mechanism of Action

AFSTYLA is a recombinant protein that replaces the missing Coagulation Factor VIII needed for effective hemostasis. AFSTYLA is a single polypeptide chain with a truncated B-domain that allows for a covalent bridge to link the Factor VIII heavy and light chains. AFSTYLA has demonstrated a higher VWF affinity relative to full-length rFVIII.¹ VWF stabilizes Factor VIII and protects it from degradation. Activated AFSTYLA has an amino acid sequence identical to endogenous FVIIIa.

12.2 Pharmacodynamics

Hemophilia A is an X-linked hereditary disorder of blood coagulation due to decreased levels of Factor VIII and results in bleeding into joints, muscles or internal organs, either spontaneously or as result of accidental or surgical trauma. Replacement therapy increases the plasma levels of Factor VIII enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.

12.3 Pharmacokinetics

Subjects ≥12 years

The pharmacokinetics (PK) of AFSTYLA were evaluated in 91 (81 adults ≥18 years and 10 adolescents ≥12 to <18 years) previously treated subjects following an intravenous injection of a single dose of 50 IU/kg.

The PK parameters (Table 5) were based on plasma Factor VIII activity measured by the chromogenic assay after the first dose (initial PK assessment). The PK profile obtained 3 to 6 months after the initial PK assessment was comparable with the PK profile obtained after the first dose.

Table 5. Pharmacokinetic Parameters (Arithmetic Mean, Coefficient of Variation [CV%]) in Adults and Adolescents Following a Single Injection of 50 IU/kg of AFSTYLA - Chromogenic Assay

PK Parameters	≥18 years(N=81)	≥12 to <18 years(N=10)
IR = incremental recovery recorded at 30 minutes after injection; Cmax = observed maximum plasma concentration; AUC0-inf = area under the Factor VIII activity time curve extrapolated to infinity; t1/2 = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state.
IR (IU/dL)/(IU/kg)	2.00 (20.8)	1.69 (24.8)
Cmax (IU/dL)	106 (18.1)	89.7 (24.8)
AUC0-inf (IU*h/dL)	1960 (33.1)	1540 (36.5)
t1/2 (h)	14.2 (26.0)	14.3 (33.3)
MRT (h)	20.4 (25.8)	20.0 (32.2)
CL (mL/h/kg)	2.90 (34.4)	3.80 (46.9)
Vss (mL/kg)	55.2 (20.8)	68.5 (29.9)

Children <12 years

Pharmacokinetic parameters of AFSTYLA were evaluated in 39 previously treated children (0 to <12 years) in open-label, multicenter studies following a 50 IU/kg intravenous injection of AFSTYLA.

Table 6 summarizes the PK parameters calculated from the pediatric data. These parameters were estimated based on the plasma Factor VIII activity over time profile.

Table 6. Comparison of Pharmacokinetic Parameters in Children by Age Category (Arithmetic Mean, Coefficient of Variation [CV%]) Following a Single Injection of 50 IU/kg of AFSTYLA - Chromogenic Assay

PK Parameters	0 to <6 years(N=20)	≥6 to <12 years(N=19)
IR = incremental recovery recorded at 30 minutes after injection for subjects 12 to <18 years and at 60 minutes after injection for subjects 1 to <12 years; Cmax = observed maximum plasma concentration; AUC = area under the Factor VIII activity time curve extrapolated to infinity; t1/2 = half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state.
IR (IU/dL)/(IU/kg)	1.60 (21.1)	1.66 (19.7)
Cmax (IU/dL)	80.2 (20.6)	83.5 (19.5)
AUC0-inf (IU*h/dL)	1080 (31.0)	1170 (26.3)
t1/2 (h)	10.4 (28.7)	10.2 (19.4)
MRT (h)	12.4 (25.0)	12.3 (16.8)
CL (mL/h/kg)	5.07 (29.6)	4.63 (29.5)
Vss (mL/kg)	71.0 (11.8)	67.1 (22.3)

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies investigating the carcinogenic effects of AFSTYLA have not been conducted. In vitro and in vivo testing of AFSTYLA for mutagenicity or effects on fertility were not performed.

14 Clinical Studies

The safety and efficacy of AFSTYLA were evaluated in two studies in PTPs: an open-label, multicenter, crossover safety, efficacy and pharmacokinetic study in adults/adolescents as well as in an open-label pharmacokinetic, efficacy and safety study in children. The safety and efficacy of AFSTYLA was also evaluated in previously untreated patients (PUPs) in an open-label, multicenter pharmacokinetic, efficacy and safety study. These studies characterized the PK of AFSTYLA and determined hemostatic efficacy in the control of bleeding events, the prevention of bleeding events in prophylaxis and in the adult/adolescent study determined hemostatic efficacy during perioperative management of bleeding in subjects undergoing surgical procedures.

The adult/adolescent study enrolled a total of 175 previously treated male subjects with severe hemophilia A (<1% endogenous Factor VIII activity). Subjects ranged in age from 12 to 65 years, including 14 adolescent subjects (≥12 to <18 years). Of the 175 enrolled subjects, 174 received at least one dose of AFSTYLA and 173 (99%) were evaluable for efficacy. A total of 161 subjects (92.5%) completed the study. A total of 120 (69.0%) subjects were treated for at least 50 EDs and 52 (29.9%) of those subjects were treated for at least 100 EDs. Subjects received a total of 14,592 injections with a median of 67.0 (range 1 to 395) injections per subject.

The pediatric study enrolled 84 previously treated male subjects with severe hemophilia A (35 subjects 0 to <6 years and 49 subjects ≥6 to <12 years). Of the 84 enrolled subjects, all received at least one dose of AFSTYLA and 83 (99%) were evaluable for efficacy. A total of 65 (77.4%) subjects were treated for at least 50 EDs and 8 (9.5%) of those subjects were treated for at least 100 EDs. Subjects received a total of 5,313 injections with a median of 59 (range 4 to 145) injections per subject.

On-demand Treatment and Control of Bleeding Episodes

In the adult/adolescent study a total of 848 bleeding episodes were treated with AFSTYLA and 835 received an efficacy assessment by the investigator. The majority of the bleeding episodes occurred in joints. The median dose per injection used to treat a bleeding episode was 31.7 IU/kg (range 6 to 84 IU/kg). Of the 848 bleeding episodes, 686 (81%) were controlled with a single AFSTYLA injection and another 107 (13%) were controlled with 2 injections. Fifty-five (6%) of the 848 bleeding episodes required 3 or more injections. For 94% of bleeding episodes the hemostatic efficacy rating by the investigator was either excellent or good.

In the pediatric study a total of 347 bleeding episodes were treated with AFSTYLA all of which received an efficacy assessment by the investigator. The majority of the bleeding episodes occurred in joints. The median dose per injection used to treat a bleeding episode was 27.3 IU/kg (range 16 to 76 IU/kg). Of the 347 bleeding episodes, 298 (86%) were controlled with a single AFSTYLA injection and another 34 (10%) were controlled with 2 injections. Fifteen (4%) of the 347 bleeding episodes required 3 or more injections. For 96% of bleeding episodes the hemostatic efficacy rating by the investigator was either excellent or good.

Assessment of response to treatment of bleeds by the investigator was as follows:

Excellent: Pain relief and/or improvement in signs of bleeding (i.e., swelling, tenderness, and/or increased range of motion in the case of musculoskeletal hemorrhage) within approximately 8 hours after the first infusion

Good: Pain relief and/or improvement in signs of bleeding at approximately 8 hours after the first infusion, but requires two infusions for complete resolution

Moderate: Probable or slight beneficial effect within approximately 8 hours after the first infusion; requires more than two infusions for complete resolution

No response: No improvement at all or condition worsens (i.e., signs of bleeding) after the first infusion and additional hemostatic intervention is required with another FVIII product, cryoprecipitate, or plasma for complete resolution.

Efficacy in control of bleeding episodes in both studies is summarized in Table 7.

Table 7. Efficacy of AFSTYLA in Control of Bleeding

Bleeding Episodes Treated	Adult and Adolescent(≥12 to 65 years of age)(N=848)	Pediatric(0 to <12 years of age)(N=347)
Number of injections
1 injection, n (%)	686 (81%)	298 (85.9%)
2 injections, n (%)	107 (13%)	34 (9.8%)
3 injections, n (%)	29 (3%)	8 (2.3%)
>3 injections, n (%)	26 (3%)	7 (2.0%)
Efficacy evaluation by investigator	(N=835)	(N=347)
Excellent or Good, n (%)	783 (94%)	334 (96.3%)
Moderate, n (%)	52 (6%)	12 (3.5%)
No response, n (%)	0	1 (0.3%)

Routine Prophylaxis

Adult and Adolescent Study

In the adult/adolescent and pediatric studies, subjects received prophylaxis in a regimen that was determined by the investigator, taking into account the subject's Factor VIII treatment regimen used prior to enrollment and the subject's bleeding phenotype.

In the adult/adolescent study, 54% of the 146 subjects on prophylaxis received AFSTYLA 3 times weekly; 32% of subjects received AFSTYLA 2 times weekly; 6% received AFSTYLA every other day, and 8% of subjects received other regimens.

The annualized bleeding rate (ABR) was comparable between subjects on a 3 times weekly regimen (median ABR of 1.53) and those on a 2 times weekly regimen (median ABR of 0.00). The annualized spontaneous bleeding rate (AsBR) was also comparable between subjects on a 3 times weekly regimen (median AsBR of 0.0) and those on a 2 times weekly regimen (median AsBR of 0.0). The number of subjects who needed dose adjustments was comparable between the two groups (34.2% [27 subjects] for 3 times weekly and 27.7% [13 subjects] for twice weekly).

The median prescribed dose for subjects on a 3 times weekly prophylaxis regimen was 30 IU/kg (12 to 50 IU/kg). The median prescribed dose for subjects on a 2 times weekly regimen was 35 IU/kg (17 to 50 IU/kg).

The ABR in prophylaxis (median of 1.14) was significantly lower (p <0.0001) than the ABR that was observed in subjects treated on-demand (median of 19.64). Sixty-three of 146 subjects (43%) experienced no bleeding episodes while on prophylaxis. There were no severe or life-threatening bleeds (e.g., intracranial hemorrhage) in subjects receiving prophylaxis.

Pediatric Study

In the pediatric study, 54% of the 80 subjects on prophylaxis received AFSTYLA 2 times a week; 30% of subjects received AFSTYLA 3 times a week; 4% received AFSTYLA every other day; and 12% of subjects received other regimens.

Twenty-one of 80 subjects (26%) experienced no bleeding episodes while on prophylaxis. There was one severe bleed (hip joint hemorrhage) in the pediatric study that was successfully treated.

For subjects on prophylaxis the overall ABR was 3.69, with a median ABR of 2.30 for subjects on a 3 times a week regimen and 4.37 for subjects on a 2 times a week regimen. The median AsBR (0.00) was identical between subjects on the 3 times a week and 2 times a week regimens.

The median prescribed dose for subjects on a 3 times a week regimen was 32 IU/kg (19 to 50 IU/kg) and for subjects on a 2 times a week regimen was 35 IU/kg (20 to 57 IU/kg).

The ABRs for prophylaxis and on-demand in both studies are summarized in Table 8.

Table 8. Summary of Annualized Bleeding Rate (ABR) by AFSTYLA Treatment Regimen

	Phase I/III Adult/Adolescent Study		Phase III Pediatric Study
	Prophylaxis(N=146)	On-demand(N=27)	Prophylaxis(N=80)	On-demand(N=3)
Overall ABR  Median (IQRIQR = interquartile range, 25th percentile to 75th percentile)	1.14 (0–4.2)	19.64 (6.2–46.5)	3.69 (0–7.2)	78.56 (35.1–86.6)
Annualized Spontaneous Bleeding Rate (AsBR)Median (IQR)	0 (0–2.4)	11.73 (2.8–36.5)	0 (0–2.2)	31.76 (0–42.7)
Number of subjects with zero bleeding episodes	63 (43.2%)	1 (3.7%)	21 (26.3%)	0

Perioperative Management of Bleeding

Thirteen subjects in the adult/adolescent study underwent a total of 16 surgical procedures. Overall, investigators assessed hemostatic efficacy of AFSTYLA in perioperative management of bleeding as excellent in 15 of 16 surgeries and as good in 1 of 16 surgeries (see Table 9). Median factor consumption pre- and intra-operatively was 89.4 IU/kg (range 40.5 to 108.6 IU/kg).

Assessment of hemostasis during surgical procedures by the investigator was as follows:

Excellent: Hemostasis clinically not significantly different from normal (e.g., achieved hemostasis comparable to that expected during similar surgery in a non-factor deficient patient) in the absence of other hemostatic intervention and estimated blood loss during surgery is not more than 20% higher than the predicted blood loss for the intended surgery

Good: Normal or mildly abnormal hemostasis in terms of quantity and/or quality (e.g., slight oozing, prolonged time to hemostasis with somewhat increased bleeding compared to a non-factor deficient patient in the absence of other hemostatic intervention) or estimated blood loss is >20%, but ≤30% higher than the predicted blood loss for intended surgery

Moderate: Moderately abnormal hemostasis in terms of quantity and/or quality (e.g., moderate hemorrhage that is difficult to control) with estimated blood loss greater than what is defined as good

Poor/No Response: Severely abnormal hemostasis in terms of quantity and/or quality (e.g., severe hemorrhage that is difficult to control) and/or additional hemostatic intervention required with another FVIII product, cryoprecipitate, or plasma for complete resolution.

Table 9. Efficacy of AFSTYLA in Perioperative Management of Bleeding

Procedure	Efficacy Evaluation	Factor Consumption (IU/kg)(pre- and intra-operatively)
Extraction of wisdom teeth	Excellent	51.09
Abdominal hernia repair	Excellent	47.89
Elbow replacement	Excellent	108.58
Ankle arthroplasty	Excellent	76.83
Knee replacement (5)	Excellent (4), Good (1)	92.49100.967.26105.7986.09
CholecystectomyandLengthening of the Achilles tendon combined with: Straightening of the right toes	Excellent Excellent	105.95
Circumcision (3)	Excellent (3)	99.0492.7481.5
Open reduction internal fixation (ORIF) right ankle	Excellent	89.36
Hardware removal, Right ankle	Excellent	40.45