Regulatory Overview of Hydroxyethyl Starch

(HES) Solutions September 6, 2012

Laurence Landow MDMedical Officer, CBER

Overview

• 3 hydroxyethyl starch (HES) solutions — Hespan, Hextend, and Voluven — are licensed for treatment of hypovolemia

• HES solutions are associated with 3 toxicities of concern:– Pruritus– Bleeding– Acute Kidney Injury

FDA-Licensed HES Solutions

Hespan (B. Braun)Hextend (Biotime)

Voluven (Fresenius Kabi)

Licensed HES Solutions Hespan, Hextend, Voluven

• Derived from maize starch (amylopectin)• Vehicles

– Hespan: normal saline– Hextend: lactated electrolyte solution– Voluven: normal saline

• Different chemical structure – Molecular weight (MW) – C2/C6 ratio (number of hydroxyethyl (CH2CH2OH)

groups at C2 vs. C6 of glucose subunits)– Molar substitution (MS) (percent of glucose

subunits carrying hydroxyethyl groups)

Nomenclature

• Classification of HES depends on molar substitution– Hetastarch (0.7), e.g., Hespan, Hextend– Pentastarch (0.5), e.g., Pentaspan (not

US licensed for hypovolemia)– Tetrastarch (0.4), e.g., Voluven

Nomenclature

6% HES 130/0.4

Molecular weight (kD) Molar substitution (percent of hydroxyethyl groups per glucose subunit)

6% HES 130/0.4/9:1

C2/C6 Ratio (ratio of hydroxyethyl groups at C2 vs. C6)

Glucose

HES are Hydrolyzed by Plasma

α-Amylase

α-Amylase

Glucose

Higher Molar Substitution Values Slow Hydrolysis

Product MW (kD)

C2/C6 Ratio (Ratio of CH2CH2OH groups at C2 vs. C6)

Molar Substitution

(Number of CH2CH2OH groups per glucose

subunit)

Half-Life

(hours)

Hespan/Hextend

670 5:1 0.7 46.3

Voluven 130 9:1 0.4 12.1

Summary Basis for Approval

Hespan, Hextend, Voluven

Hespan (licensed 1972)

• US clinical studies– Study design

• 8 RCTs in different clinical settings (N=352): surgical, trauma, septic shock, burns, pump prime in open heart surgery

– Treatment regimen• Hespan vs. 5% human serum albumin (control) at a

rate of 20 mL/kg/h

– Outcomes• Total dose: no difference reported in safety and

efficacy from control with a range of 250 up to 2000 mL (specific numbers unavailable)

Hextend (licensed 1999)

• US clinical study– Study design

• Double-blind, 2-center, non-inferiority RCT in subjects undergoing elective non-cardiac surgery in patients with expected blood loss (EBL) > 500 mL

– Treatment regimen • Hextend vs. Hespan (control; albumin prohibited

intraoperatively) according to prespecified hemodynamic triggers (SBP + HR + U/O)

• Both arms received LR bolus (7 mL/kg) + infusion (5 mL/kg/h) for duration of anesthesia

– Sample size• 60 subjects/arm = 80% power to detect a 30% difference • Primary endpoint

– Total volume of Hextend or Hespan administered by end of surgery

Anesth Analg 1999;88:992-8

Hextend: Results

Hextend(N=59)

Hespan(N=58)

Received > 20 mL/kg (number (%) of subjects) Total dose administered (mL)

25 (42)1596±923

21 (36)1428±1094

Achieved prespecified hemodynamic targets (number (%) of subjects)

39 (66) 38 (66)

Received allogeneic transfusion (post hoc)

Number (%) of subjects Volume of pRBCs (mL)

EBL (mL)Number of subjects requiring Ca++

35 (59)642±1174

15601

34 (59)538±694

25166

Voluven (licensed 2007)

• Non-U.S. clinical studies (Europe)– Study design

• 12 double-blind RCTs in subjects undergoing noncardiac elective surgery expected to require volume replacement

– Treatment regimen• Voluven vs. 6% HES 200/0.5 (not US licensed)

– Aggregate sample size• N=705 (N=355 vs. 350)

– Primary endpoint• Total volume of synthetic starch solution

administered in the perioperative period

Voluven (cont’d)

– Results• Total dose administered: no difference

(1613 – 2913 mL vs. 1584-2884 mL)– > 40 mL/kg in 27% of subjects– 10-40 mL/kg in remaining 73%

• Severe bleeding: no difference • Acute Kidney Injury (elevated SCr or RRT):

no difference

Voluven (cont’d)

• U.S. clinical study– Design

• Double-blind RCT in subjects (N=100) undergoing major elective orthopedic surgery

– Treatment regimen• Voluven vs. Hespan (no other colloids allowed

intraoperatively)– Primary efficacy endpoint

• Total volume required for intraoperative volume replacement (hemodynamic triggers prespecified)

– Primary safety endpoints• Estimated blood loss over 48 h, nadir VIII activity,

nadir vWF concentration within 2 h after surgery, use of FFP

Anesthesiology 2007;106:1120-7

Voluven: Results Voluve

n(N=49)

Hespan(N=51)

Total dose in mL [mL/kg] 1613 [21.6 ] 1584 [25.5 ]

Volume of allogeneic blood transfused (mL/kg)

8.4±6.6 11.7± 9.9

FVIII activity <LLNEnd of surgery (number of subjects)

2h post surgery (number of subjects)5 0

13 7

Severe bleeding (number of subjects) 0 3

Elevated SCr (number of subjects) Peak SCr (mg/dL)

2 1.5, 3.3

1 2.7

RRT (number of subjects) 0 0

Voluven (cont’d)

• Two postmarketing RCTs to further evaluate safety – Adult patients with severe sepsis

(CRYSTMAS study: Crystalloids Morbidity Associated with severe Sepsis)

– Pediatric patients undergoing open heart surgery in association with CPB

Labeling

Dosage & Administration SectionWarnings Section

Dosage & Administration Section

(Highlights, Package Insert)

Hespan/Hextend

Recommended dose: 500-1000 mLUpper limit: 20 mL/kg/per day (~1500 mL/day for 70 kg patient

Voluven Upper limit: 50 mL/kg/per day (~3500 mL for a 70 kg patients

Warnings Section(Highlights, Package Insert)

Hespan Not recommended for use as a CPB pump prime while the patient is on CPB or in the immediate post-CPB period because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired (2003)

Hextend Increased bleeding has been associated in patients undergoing open heart surgery in association with CPB following use of 6% hetastarch in normal saline

Voluven At high dosages dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit

Overall Safety Review

Adverse Reactions

Adverse Reactions

1. Bleeding– Etiology incompletely understood

• Decreased availability of fibrinogen binding sites on platelets due to adherence of HES

• Impaired fibrin polymerization (Acta Anaesth Scand 2010;54:1241-1247)

• Decreased levels of Factor VIII, vWF, and XIII

(> hemodilution alone)– Bleeding reportedly greater with

higher molar substitution values

Adverse Reactions (cont’d)

2. Pruritus – Attributed to long-term deposition in

liver, skin, cutaneous nerves– Tissue uptake independent of MW and

substitution (Clin Pharmacokinet 2012;51:225-236)

– Rx: resistant to steroids, antihistamines, acetominophen and neuroleptic drugs

Adverse Reactions (cont’d)

3. Acute Kidney Injury – 2001: first clinical report of elevated

serum creatinine values with use of HES (6% HES 200/0.6 ) • Schortgen et al. Effects of HES and gelatin

on renal function in severe sepsis. Lancet 2001;157:911-916

Safety Information Received Since 2008

• 2008: VISEP study in ICU patients– 10% HES 200/0.5 vs. modified LR– Halted prematurely (excess RRT in HES

subjects)

• 2010: Cochrane review of HES effects on kidney function– No difference in risk except in septic shock

patients where risk is increased with 10% HES 200/0.5 or 6% HES 200/0.6

• Safety assessment of these studies confounded by use of HES formulations different from those approved in US

Safety Information Received Since 2008

2012: CRYSTMAS study in severe sepsis subjects comparing Voluven vs. normal saline (postmarketing study) •Methods

– Design: double-blind, multicenter, RCT – Treatment: Voluven (N=100) vs. normal

saline (N=96)– Primary endpoint: volume of study drug

required to achieve hemodynamic stabilization (HDS; criteria prespecified) over 4 days

– Safety endpoint: acute kidney failure prespecified as doubling of serum creatinine or need for RRT over study period, i.e., Schortgen criteria

CRYSTMAS Study

• Results– Baseline clinical characteristics: no difference– Efficacy: no difference

Voluven

(N=100)

Normal Saline(N=96)

Volume (mL) required to achieve HDS

1379 1709

Time to achieve HDS (h) 11.8 14.3

CRYSTMAS Study

Safety

Voluven

(N=100)

Normal Saline(N=96)

SARs (serious adverse reactions)

53 44

SARs leading to death 38 32

Doubling of SCr (number of subjects)

8 11

Required RRT Number of subjects

Duration of RRT (days)219.1

114.3

RIFLE Classification of AKI

RIFLE class is determined based on the worst of either GRF or U/O criteria

CRYSTMAS Study

Voluven(N=100)

NormalSaline(N=96)

Rifle Score (number of subjects)

None 77 73

Risk 13 11

Injury 4 5

Failure 5 7

Loss(>4 weeks) 1 0

ESKD (>3 months) 0 0

CRYSTMAS Study

P=0.063 log rank test

Normal saline

VoluvenProportion of subjects without RRT

Change in Voluven Package Insert

May 2012• Section 14 (Clinical Studies)

expanded to include a discussion of outcomes from CRYSTMAS trial

• Section 6 (Adverse Reactions) expanded to include increased frequency and duration of RRT in CRYSTMAS among Voluven patients

2012: S6 and CHEST Trials

• RCTs comparing Voluven vs. crystalloid in severe sepsis subjects and powered for death or dialysis-dependence at 90 days– S6 Trial (N=798)– CHEST (N=6999)

Thank you for your attention