Fosrenol®

Contents

• Fosrenol® Indication and MoA

• Fosrenol® Efficacy and Safety
• Other Benefits
• How to Take Fosrenol®
• Q & As
Fosrenol®
Indications and
MoA
 FOSRENOL® Indications

FOSRENOL is a non-Ca based PB, does not promote HPCM or

excess Pi load1

• FOSRENOL is indicated as a phosphate binding agent for use in

control of HPTM in CKD patients on HD/CAPD

• FOSRENOL is also indicated in adult patients with CKD not on

dialysis with sPi levels ≥1.78mmol/L (≥5.6 mg/dL) in whom a low
Pi diet alone is insufficient to control sPi levels

(1) De Broe ME et al. Nephrol Dial Transplant 2004; 19(Suppl 1): 14-18 (2) Shire Pharmaceuticals Limited. FOSRENOL Summary of Product Characteristics.
United Kingdom, October 2011.
 Mechanism of Action

FOSRENOL acts locally in the intestine to bind ingested Pi to form insoluble complexes
which are excreted in the Faeces1

(1) Shire Pharmaceuticals Limited. FOSRENOL Summary of Product Characteristics. United Kingdom, October 2011
Fosrenol®
Pharmacokinetics
 Absorption, Distribution, Metabolism,
Excretion
• Absorption: La is poorly absorbed (absolute oral bioavailability <
0.002%)

• Distribution: Systemic tissue exposure is greatly limited at very low

levels. When given orally, the La in FOSRENOL is distributed
predominantly within the GI tract, bone and liver.1

• Metabolism: La is not metabolised.1

• Excretion: The majority of LC from a dose of FOSRENOL is

excreted unabsorbed in the faeces.1Excretion in urine is
minimal.1(0.000031% in humans)

Removal of Fosrenol is not dependent on renal function, so patients with CKD, are
unlikely to have increased risk of accumulation of La 2
(1) Shire Parmaceuticals Ltd. Fosrenol 250mg, 500mg, 750mg & 1000mg chewable tablets. Summary of Product Characteristics. United Kingdom, June
2013. (2) Pennick M et al. Absolute Bioavailability and Disposition of Lanthanum in Healthy Human Subjects Administered Lanthanum Carbonate J Clin
Pharmacol 2006; 46(7): 738–746 (3) Spasovski GB et al. Evolution of bone and plasma concentration of lanthanum in dialysis patients before, during 1 year
of treatment with lanthanum carbonate and after 2 years of follow-up. Nephrol Dial Transplant 2006;21(8):2217–2224.
Fosrenol®
Clinical Efficacy
and Safety Data
 Effective Binder Across pH Ranges

Binding Affinity was unaffected across pH 3-7

Binding Affinity was poor at an acidic pH

*Data relating to in vitro binding capacity may not correlate with clinical response

In vitro, FOSRENOL was shown to bind Pi more effectively than SH across the pH range
encountered within the GI tract1

(1) Autissier V et al. . Relative in vitro efficacy of the phosphate binders lanthanum carbonate and sevelamer hydrochloride J Pharm Sci 2007;96:2818–2827
(2) Stuart M. Sprague ; A Comparative Review of the Efficacy and Safety of Established PBs ; Ca, SV and LC, Current Medical Research and Opinion, Vol. 23,
No. 12, 2007, 3167-3175
 High Binding Affinity
A randomized, open-label, crossover study; comparison dietary Pi absorption after single
dose of LC vs SC in 18 healthy volunteers. 1

21
45 %
%

*Data relating to binding capacity and dosing in healthy volunteers may not translate to end-stage renal disease patients

Fosrenol binds significantly more Pi. Per tablet, LC bound with P 135 mg versus SV bound
with P 21 mg
(1) Martin P, Wang P, Robinson A, et al. Comparison of dietary phosphate absorption after single doses of lanthanum carbonate and sevelamer carbonate
in healthy volunteers: A balance study. Am J Kidney Dis. 2011;57(5):700-6
 High Phosphate Binder Equivalent Dose

Fosrenol 500 mg 1 tab

SC 800 mg ~2 tabs

(1) Daugirdas JT, Finn WF, Emmett M, et al. The phosphate binder equivalent dose. Seminars in Dialysis 2011;24(1):41-49.
 Low Pill Burden
An open-label, phase IV, multicenter study; Conversion to LC monotherapy effective control
sPi with a reduced tablet burden.

sPi levels were effectively maintained in patients converted from other PBs to Fosrenol, with
reduced tablet burden (2.2 -8.4 pills/day).
(1) Chiu YW et al. Pill burden, adherence, hyperphosphatemia, and quality of life in maintenance dialysis patients. Clin J Am Soc Nephrol 2009;4(6):1089-1096.
(2) Hutchison AJ et al. Switching to lanthanum carbonate monotherapy provides effective phosphate control with a low tablet burden Nephrol Dial Transplant
2008;23(11):3677–84.
 Rapid Phosphate Binding Onset

Significantly reductions in sPi vs placebo, occurred in Fosrenol 1,350 mg/day group from the
2nd week and in the 2,250 mg/day group from the 1st week of treatment.

(1) W.F.Finn et al; Efficacy and Safety of LC for Reduction of sPi in Patients with CRF receiving HD, Clinical Nephrology, Vol. 62, No. 3/2004, 193-201
 Long-term Efficacy up to 6 Years

Open-label extension study to assess the safety and efficacy of FOSRENOL in 93 patients for
up to 6 years.

FOSRENOL
FOSRENOL delivers
delivers sustained
sustained Pi
Pi control
control for
for up
up to
to 6
6 years.
years.
(1) Hutchison AJ et al. Long-term efficacy and safety profile of lanthanum carbonate:results for up to 6 years of treatment. Nephron Clin Pract
2008;110:c15–c23
 Long-term Safety up to 6 Years

Levels of liver enzymes (aspartate aminotransferase (AST), alanine aminotransferase (ALT),

and billi-rubin in patients receiving lanthanum carbonate for up to 6 years )

No
No clinically
clinically relevant
relevant changes
changes in
in liver
liver enzymes
enzymes and
and bilirubin
bilirubin levels
levels
(1) Hutchison AJ et al. Long-term efficacy and safety profile of lanthanum carbonate:results for up to 6 years of treatment. Nephron Clin Pract
2008;110:c15–c23
 Long-term Safety up to 6 Years

Serum levels of calcium, PTH, bone-specific alkaline phosphatase and osteocalcin patients
receiving lanthanum carbonate for up to 6 years )

Serum
Serum levels
levels of
of calcium,
calcium, PTH,
PTH, bone-specific
bone-specific alkaline
alkaline phosphatase
phosphatase and
and osteocalcin
osteocalcin generally
generally
remained
remained STABLE.
STABLE.
(1) Hutchison AJ et al. Long-term efficacy and safety profile of lanthanum carbonate:results for up to 6 years of treatment. Nephron Clin Pract
2008;110:c15–c23
 Lanthanum carbonate: Safety
data after 10 years

Background
• Phase 4, observational database ESRD USA patients. The primary objectives of the SPD405-
404 study are to compare all-cause mortality and bone fractures requiring hospitalisation in
patients who received LaC with patients who received other phosphate binders.
• The interim analysis presented was based on USRDS data through 2014, which was
downloaded in May 2015.

Patients
• The control arms (historical and concomitant), which included adult patients with ESRD
receiving dialysis
• The historical control group comprised individuals whose data is 5 years before LaC became
available in the USA, and as such the comparison has limitations due to changes in standards
of care.
• The concomitant therapy control group instead comprised patients who were treated for
hyperphosphatemia with any phosphate binder other than LaC (same era as the test group).

Hutchison AJ et al. Lanthanum carbonate: safety data after 10 years. Nephrology (Carlton) 2016 Dec;21(12):987-994
 Kaplan–Meier analysis of time to
all-cause mortality
• The median 5-year survival
was:
• 51.6 months (95% CI: 49.1,
54.2) in patients who
received lanthanum
carbonate (test group),
• 48.9 months (95% CI: 47.3,
50.5) in patients treated with
other phosphate binders
(concomitant therapy control
group) and
• 40.3 months (95% CI: 38.9,
41.5) in patients before the
availability of lanthanum
carbonate (historical control
group).

Hutchison AJ et al. Lanthanum carbonate: safety data after 10 years. Nephrology (Carlton) 2016 Dec;21(12):987-994
 Bone fracture requiring
hospitalisation 

Bone
Bone fracture
fracture rates
rates were
were 5.9%,
5.9%, 6.7%
6.7% and
and 6.4%,
6.4%, respectively.
respectively.
• After more than 850 000 person-years of worldwide patient exposure, there is no evidence
that lanthanum carbonate is associated with adverse safety outcomes in patients with end-
stage renal disease.

Hutchison AJ et al. Lanthanum carbonate: safety data after 10 years. Nephrology (Carlton) 2016 Dec;21(12):987-994
 Distribution of La in the Body: Brain

In a 2 year, multi-center, comparative study in 360 DIA patients; LC vs STD therapy in 5

aspects of cognitive function.3

FOSRENOL does not adversely affect Cognitive Function compared with standard PBs
therapy.3
(1) Alfrey AC et al. The Dialysis Encephalopathy Syndrome-Possible Aluminum Intoxication. N Engl J Med 1976;294:184–188. (2) McLeod C et al. The
need for contamination control in studies on lanthanum biodisposition. Kidney Int 2005; 68:2906–2906. (3) Altmann P et al. Cognitive Function in Stage 5
Chronic Kidney Disease Patients on Hemodialysis: No Adverse Effects of Lanthanum Carbonate Compared with Standard Phosphate-Binder Therapy.
Kidney Int 2007; 71(3):252–259
 Not Alter Absorption and Serum Levels
of Fat-soluble Vitamins
A randomized crossover, open-label, drug interaction study; 41 healthy volunteers. 2

No significant
effect
In
AUC0-48 & Cmax
of Calcitriol.

Significant
reduction
In
AUC0-48 (57%)
& Cmax (19%) of
Calcitriol.

FOSRENOL is a non-resin binder which does not alter bioavailability parameters for
Calcitriol
(1) Finn W et al. Poster presented at the XLV ERA–EDTA Congress, Stockholm, Sweden, 10–13 May 2008 (2) Pierce D, Hossack S, Poole L, et al. The effect of
sevelamer carbonate and lanthanum carbonate on the pharmacokinetics of oral calcitriol. Nephrol Dial Transplant 2011;26(5):1615-1621 (3) Shire
Parmaceuticals Ltd. Fosrenol 250mg, 500mg, 750mg & 1000mg chewable tablets. Summary of Product Characteristics. United Kingdom, June 2013
 Well-tolerability and Safety Profile

• LC taken with meals appears to be generally well tolerated.

• GI effects are the most common AEs and are typically mild to moderate. No new or
unexpected AEs, or any increase in the incidence of AEs with increasing exposure to LC over
LT treatment.

• No significant inhibition of CYP450 isoforms and no clinically relevant changes in liver

enzymes and bilirubin levels.

• Serum levels of Ca, PTH, bone-specific alkaline phosphatase and osteocalcin generally
remained STABLE.

• The incidence of HPCM was greatly reduced by LC compared with CC.

• After 10 years of continuous post‐marketing safety monitoring and more than 850 000
person‐years of worldwide patient exposure to LaC, there is no evidence that LaC is
associated with adverse safety outcomes in patients with ESRD.

(1) Hutchison AJ et al. Long-term efficacy and safety profile of lanthanum carbonate:results for up to 6 years of treatment. Nephron Clin Pract
2008;110:c15–c23
Other Benefits of
Fosrenol® Beyond
HPTM to CKD-MBD
 Delay Progression of CAC (Pilot Study)

A prospective, randomized trial; LC vs CC in delay progression of CAC in patients on HD.

Intervention Period

Lead-in Period

Switching PB from CC to Fosrenol delayed the progression of CAC in patients on HD.

(1) Takayasu Ohtake wt al; LC Delays aprogression of CAC Compared with Ca-based PBs in Patients on HD: A Pilot Study, J. of Cardiovascular
Pharmacology and Therapeutics.
 Low Risk of Mortality
(COSMOS Study)
COSMOS: a multicenter, open-cohort, observational prospective study; the use of single &
combined PBs vs survival in DIA patients.

All-cause mortality were statistically significant reduced with PBAs (except Al), HR ranging
from 0.28 to 0.73. (Excluding those grouped as ‘others’)
(1) Jorge B. Canata Andia et al; Use of Phosphate-binding Agents is Associated with a Low Risk of Mortality, Kidney International

(1) Jorge B. Canata et al; Use of Phosphate-binding Agents is Associated with a Lower Risk of Mortality, Kidney International advance online publication, 3
July 2013
 Low Bone Abnormalities

A comparative bone biopsy study; LC vs CC in 98 HD & CAPD patients

6 7 5 3

9 3
7 7

Fosrenol show almost no evolution toward low bone turnover over 1 year, nor do any
aluminum-like effects on Bone

(1) D’Haese PC et al. A multicenter study on the effects of lanthanum carbonate (Fosrenol™) and calcium carbonate on renal bone disease in dialysis
patients. Kidney Int 2003;63 (Suppl 85):S73-S78
How to Take
Fosrenol®
 Dosing and Administration

• Available as 500, 750 mg chewable tablets.*1

• The tablet should be chewed completely before swallowing and
not swallowed whole.1
• To aid with chewing, FOSRENOL tablets may be crushed.1
• FOSRENOL should be taken with or immediately after food, with
the daily dose divided between meals.1

(1) Fosrenol tablet international prescribing information, June 2013..

 Dose and Cost/day
Fosrenol 500 mg Chewable Tablet
sPi level Fosrenol Pills/day Cost /day Sevelamer Pills/day Cost /day
Recommend (500 mg) (THB) Recommend (800 mg) (THB)
ed Initial ed Initial
Daily Dose Daily Dose

5.6 – 7.4 750 mg ½ tab x 3 109.5 2400 mg 1 tab x 3 174

mg/dl
(1.8 – 2.4
mMol/L)

>7.4 – 9.0 1500 mg 1 tab x 3 219 4800 mg 2 tab x 3 348

mg/dl
(>2.4 – 2.9
mMol/L)

> 9 mg/dl 2250 mg 1 ½ tab x 3 331.7 N/A N/A N/A

(> 2.9
mMol/L)

As with other PBs, FOSRENOL is cheaper than Sevelamer ~ 59%

Price /tab : Fosrenol = 73 THB , Sevelamer = 58 THB

Defined Daily Dose WHO Drug Information
(http://www.whocc.no/atc_ddd_index/)
 Summary

• HPTM has many negative health effects such as secondary

hyperparathyroidism, mineral-bone disorder and vascular
calcification.
• Adequate management often involves dialysis, a low phosphate diet
and phosphate binders.
• FOSRENOL® is a non-calcium phosphate binder, can be used in
patients on HD or CAPD, and also in patients with CKD not on
dialysis with serum phosphae levels ≥1.78 mmol/L, in whom a
phosphate diet alone is insufficient.
 Fosrenol®
High Efficacy Fast Action

Well Tolerate
Thank You Very
Much for Your
Attention
 Distribution of La in the Body: Brain

In a 2 year, multicenter, comparative study in 360 DIA patients; LC vs STD therapy in 5

aspects of cognitive function.3

FOSRENOL does not adversely affect Cognitive Function compared with standard PBs
therapy.3
(1) Alfrey AC et al. The Dialysis Encephalopathy Syndrome-Possible Aluminum Intoxication. N Engl J Med 1976;294:184–188. (2) McLeod C et al. The
need for contamination control in studies on lanthanum biodisposition. Kidney Int 2005; 68:2906–2906. (3) Altmann P et al. Cognitive Function in Stage 5
Chronic Kidney Disease Patients on Hemodialysis: No Adverse Effects of Lanthanum Carbonate Compared with Standard Phosphate-Binder Therapy.
Kidney Int 2007; 71(3):252–259
CDR Assessments