Drugs and Dialysis:
Commonly Used Medications
Karen Shalansky, Pharm.D.
Elaine Cheng, Pharm.D.
Vancouver General Hospital
August 12, 2014
Typical Medication List
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Darbepoetin (Aranesp) 20 mcg IV once weekly
Iron gluconate (Ferrlecit) 125 mg IV monthly
Alfacalcidol 0.25 mcg PO 3X weekly
TUMS Regular 2 tablets PO TID with meals
Ramipril 10 mg PO once daily
Metoprolol 25 mg PO twice daily
Amlodipine 10 mg PO once daily
Renavite 1 tablet PO once daily
Docusate 200 mg PO BID
Lactulose 30 mL PO HS prn
Hydroxyzine (Atarax) 10 mg po HS prn
Session Outline
1.
2.
Darbepoetin 20 mcg IV once weekly
Iron gluconate 125 mg IV monthly
Anemia
3.
4.
Alfacalcidol 0.25 mcg PO 3X weekly
TUMS Regular 2 tablets PO TID CC
CKD-MBD
5.
6.
7.
Ramipril 10 mg PO once daily
Metoprolol 25 mg PO BID
Amlodipine 10 mg PO once daily
Blood pressure
8.
Renavite 1 tablet PO once daily
Vitamins
9.
10.
Docusate 200 mg PO BID
Lactulose 30 mL PO HS prn
Bowels
11.
Hydroxyzine 10 mg PO HS prn
Itch
BC Provincial Renal Agency

BC PRA provides 100% coverage of medications essential
in the care and treatment of CKD patients

Separate formulary for CKD Patients Not on Dialysis and
Dialysis Patients

Billing goes through PharmaCare first, then BC PRA picks
up remainder of cost

Must use a community pharmacy that has a contract with
BC PRA, otherwise patient pays as per usual Pharmacare
rules or non-prescription items paid in full by patient
 e.g. Macdonald’s Pharmacy on West 6th Avenue
Anemia Management
Role of Erythropoietin
Decreased oxygen
delivery to kidneys
Renal interstitial peritubular cells
detect low blood oxygen levels
Erythropoietin (EPO)
secreted into blood
Increased oxygen
delivery to tissues
EPO stimulates proliferation
and differentiation of erythroid
progenitors into reticulocytes
and prevents apoptosis
More
reticulocytes
enter
circulating
blood
Reticulocytes
differentiate into
erythrocytes (RBCs)
www.anemia.org/professionals/resources/slides/ckd.ppt
Anemia Target Values
HEMOGLOBIN TARGET: BC = 100 to 120 g/L
Hemoglobin
KDOQI 2007: 110-120 g/L
(Do not exceed 130 g/L)
KDIGO 2012: 100-115 g/L
CSN 2013:
95-115 g/L
Monitor Q4-6 weeks
(Minimum 2-3 weeks
post dose change)
Initiate ESA (erythropoiesis-stimulating agent) when Hgb < 90 g/L in CKD patients
(TREAT 2009) and Hgb < 100 g/L in dialysis patients (KDIGO 2012)
IRON TARGET
Serum
Ferritin
100-1000 mcg/L (PD/CKD)
Monitor Q3months
200-1000 mcg/L (HD)
(upper limit controversial)
TSAT
20-50% (Same for all 3 groups)
Monitor Q3months
Anemia Target Values
Why not higher Hgb levels?
Hypertension
 ↑ thrombosis from altered blood viscosity
 No cardiovascular benefit; some
improvement in QOL (CREATE 2006)
 ↑ mortality, non-fatal MI and hospitalization
with Hgb > 130 g/L; no improvement in QOL
(CHOIR 2006, NEJM 1998)
  stroke (TREAT 2009)

Comparison of ESAs
Endogenous human EPO composed of 165 amino acids, 4 carbohydrate
groups and 2 disulfide bonds that maintain the shape of the molecule

Epoetin alfa (Eprex®)
identical to human EPO

Darbepoetin alfa
(Aranesp®) different
from human EPO




165 amino acids but
with 5 substitutions
5 vs. 3 N-linked
carbohydrate chains
< 22 vs. < 14 sialic
acid residues
51% vs. 40%
carbohydrate
Comparison of ESAs
Epoetin alfa
(Eprex®)
Darbepoetin alfa
(Aranesp®)
t1/2 SC
18-24 hrs
48 hrs
t1/2 IV
8.5 hrs
25.3 hrs
Starting
dose
100 IU/kg weekly divided
into 1-3x/week
0.45 mcg/kg qweekly
IV and SC
IV dose 30% more than SC
dose
IV dose = SC dose
Monitoring
Min 2 weeks post change
Min 3 weeks post change
Max Hgb 
20 g/L in 4-week period
20 g/L in 4-week period
Adjustment
 or  by 25%
 or  by 25%*
*If Hgb >130 g/L - Hold Aranesp, check CBC q2weeks, restart when Hgb 125 g/L
ESA Resistance

EPO (Eprex®): > 300 units/kg SC or > 450 units/kg IV

Darbepoetin (Aranesp®): > 1.5 mcg/kg IV/SC

Causes:







Blood loss
Infection
Iron deficiency
High iPTH (> 100 pmol/L)
MDS
PRCA (Pure Red Cell Aplasia)
Thalassemia
Iron Therapy
Oral Iron Products
Iron Salt
% Elemental
Iron
Elemental Iron (mg)
in 300 mg Tablet
Ferrous gluconate
12
36
Ferrous sulfate
20
60
Ferrous fumarate
33
99


Goal: 150-200 mg elemental iron/day
Give HS to prevent interaction with calcium products
Iron Therapy
Intravenous Iron Products
Test
Dose
Infusion
Rate
Cost
Per 500 mg
Dose
Iron dextran (Dexiron®)
Yes
100 mg/hr
$84.15
Iron sucrose (Venofer®)*
No
100 mg/hr
$185.00
Iron Product
Iron*Lower
gluconate
(Ferrlecit®)*
No to iron 125
mg/hr
$96.00
incidence
of side effects compared
dextran,
e.g. anaphylaxis,
back pain, hypotension, pruritus
Ferumoxytol
(Feraheme®)*
(Superparamagnetic iron)
No
510 mg IV
over 1 min
$186.00
*Lower incidence of side effects compared to iron dextran, e.g. anaphylaxis, back
pain, hypotension, pruritus
IV Iron Dosing
Hemodialysis Patients:
TSAT
(%)
Ferritin
(mcg/L)
Dose
< 20
< 200
100-125 mg IV qHD x 8-10 runs (Total dose
= 1 g), then 100-125 mg IV qweekly
20-34
200 – 800
100-125 mg IV qweekly or q2weeks
35-50
200 – 800
100-125 mg IV q4weeks
> 50
Any value
Stop iron and reassess after 3 months
< 20
> 800
Depends on Hgb
CKD or PD Patients:
Iron sucrose (Venofer) 300 mg IV qweekly x 1-3 doses or
Ferumoxytol (Feraheme) 510 mg IV q2-7days x 1-2 doses
Case #1: Anemia

SK 68 yo female
 New HD patient
 Wt = 58.2 kg
 Labs:
Hgb
TSAT
Ferritin
Sept/10
122
0.18
158
Current Meds:
- Aranesp 30 mcg IV qweekly
- Ferrous sulfate 600 mg po qhs
What to do?
Case #1: Anemia

Later…
Hgb
TSAT
Ferritin
Sept/10
Dec/10
122
0.18
158
140
0.26
412
What to do?
Chronic Kidney Disease –
Mineral and Bone Disorder
Pathophysiology
 Pi,  Ca
Renal Osteodystrophy

Disorder of bone remodelling



high turnover -  iPTH (Osteitis Fibrosa)
low turnover -  iPTH (adynamic),aluminum (osteomalacia)
mixed - hyperparathyroidism + defective mineralization

Starts when GFR declines below 60mL/min (Stage 3)

Consequences:




Parathyroid gland hypertrophy ( iPTH,  Ca and Pi)
Metastatic calcification (Ca x PO4 precipitate)
Bone pain, fractures, itching, resistance to EPO
May require parathyroidectomy (iPTH > 100)
CKD-MBD Targets: Stage 5 Dialysis
KDOQI 2003
CSN 2006
KDIGO 2009
Calcium
(N=2.1-2.55)
Low normal range
(preferably
< 2.4 mmol/L)
Normal range
Normal range
Avoid hypercalcemica
Phosphate
(N=0.8-1.45)
1.1-1.8 mmol/L
Normal range
Normal range
iPTH
(N=1.5-7.6)
16.5-33 pmol/L
10.6-53 pmol/L
2-9 times the
upper limit of
normal
(15.2-68.4 pmol/L)
Treatment Options
Goals: PO4, Ca, iPTH

Dietary phosphate restriction
 Phosphate Binders





Vitamin D Analogues



Calcium Salts
Sevelamer hydrochloride (Renagel®)
Lanthanum carbonate (Fosrenol®)
Aluminum products – anemia, dementia, osteomalacia
Alfacalcidol (One-Alpha®), Calcitriol (Rocaltrol®)
Calcimimetic – Cinacalcet (Sensipar®)
Parathyroidectomy
Phosphate Binders: Calcium Salts
Strength
Elemental
Ca++
Cost/tab
TUMS Regular®
500 mg
200 mg
$0.04
TUMS Extra Strength®
750 mg
300 mg
$0.05
TUMS Ultra Strength®
1000 mg
400 mg
$0.07
Apo-Cal®
625 mg
1250 mg
250 mg
500 mg
$0.03
$0.04
Calcium acetate*
667 mg
169 mg
$0.11
Calcium Salt
Calcium carbonate
*Calcium acetate better binder and less absorption


Adverse effects: constipation,  Ca,  PO4
Max: 1500 mg elemental calcium/day (soft guideline)
Factors Associated with Cardiac Calcification
• Survey of 39 dialysis pts < 30 yrs vs. 60 normals
• 36% calcification (EBT) in dialysis vs. 5% controls
Ca++ Intake from
Binders, mg/day
Serum P, mmol/L
Ca x P product,
mmol2/L2
Age, years
Mean Duration of
Dialysis, years
Coronary
Calcification
(N = 14)
No
Calcification
(N=25)
P value
2582
1330
0.02
2.21
2.02
0.06
5.4
4.7
0.04
26
15
< 0.001
14
4
< 0.001
New Engl J Med 2000;342:1478-83
Phosphate Binders: Sevelamer (Renagel®)
Mechanism of Action


Non-calcium/aluminum based
Non-absorbed phosphate binder
Indication (need to fill out form)


Failure on calcium therapy
Ca >2.6 mmol/L and PO4 >1.8 mmol/L
Adverse Effects


Bloating, diarrhea, pill burden
Acidosis, esp if not combined with CaCO3 or calcium acetate
Dose

800 mg tabs 1-5 tabs po tid (Max: 12 g/day); $1.61/800 mg
Phosphate Binders: Lanthanum (Fosrenol®)
Mechanism of Action



Non-calcium/aluminum based
Earth metal on periodic table (similar to aluminum)
Minimal absorption <0.1% but some accumulation in rat bone
Indication

Same as for Sevelamer (Renagel®)
Adverse Effects

Large chewable tablet, nausea/vomiting
Dose

500-1000 mg po tid (Max: 3 g/day); $3.00/750 mg
Relative Potency of PO4 Binders:
Aluminum/Lanthanum > Calcium acetate > CaCO3 > Sevelamer
Calcium vs. Non-Calcium Based Binders
Is there a mortality benefit?

Cochrane Review 2011




10 RCTs: Sevelamer vs. Calcium binders
No reduction in all-cause mortality
(RR 0.73, 95% CI 0.46-1.16)
No difference in coronary artery calcification
Lancet Meta-Analysis 2013



11 RCTs: Sevelamer x 10; Lanthanum x 1
Significant reduction in all-cause mortality
(RR 0.78, 95% CI 0.61-0.98)
Significant reduction in coronary artery calcification
at 12 months
VITAMIN D
METABOLISM
Commercially available:
Vitamin D3 (cholecalciferol)
Vitamin D2 (ergocalciferol - plant)
One Alpha® (alfacalcidol)
- 1- cholecalciferol
Rocaltrol® (calcitriol)
- 1-,25 cholecalciferol
Vitamin D Analogues: Alfacalcidol (One-Alpha®)
and Calcitriol (Rocaltrol®)
Mechanism of Action



↑ absorption of calcium
Direct inhibition of iPTH release
Negative feedback inhibition of parathyroid gland
Indication

iPTH > 65 pmol/L (Ca <2.6 mmol/L and PO4 <1.8 mmol/L)
Adverse Effects

↑ Ca and ↑ PO4
Dose

0.25 mcg po 3X/week up to 1-1.5 mcg/day
Calcimimetic: Cinacalcet (Sensipar®)
Mechanism of Action


↑ sensitivity of iPTH gland to calcium
↓ iPTH, Ca, PO4 levels
Indication (need to fill out form)




Failure on vitamin D therapy (alfacalcidol)
iPTH >88 pmol/L x 2 readings
Not a candidate for parathyroidectomy or waiting for one
Note: clinical endpoints not assessed long-term
Adverse Effects

Hypocalcemia, GI upset
Dose



30 mg po daily ($10/30 mg)
↑ dose q4-6weeks by 30 mg/day to max 120 mg/day
Onset: hours (vs. hours to day with vitamin D)
Case #2: CKD-MBD

66 yo, 100 kg female on HD x 5 years


AVR 2° aortic stenosis 2006


CRF 2° diabetic nephropathy
Echo Oct 2010 showed Ca deposits on aortic valve
Labs (May-Oct 2010)


Ca 2.1-2.33, PO4 1.39-1.81, iPTH 10.9-12
Meds: Calcium carbonate 1500 mg po tid and
Alfacalcidol 0.25 mcg po daily
What to do?
Chronic Opioids in Renal Failure
Opioids
Reason
Appears Safe
Fentanyl
Methadone
No active metabolites
Use Carefully
Hydromorphone
 accumulation of active metabolite
(HM-3-glucuronide)
Oxycodone
<10% excreted unchanged in urine
Codeine
Morphine
- 10% metabolized to morphine
- Active metabolite (M-6 glucuronide)
can be neurotoxic
(myoclonus,sedation)
- Active metabolite (normeperidine)
can cause seizures
Best to Avoid
Meperidine
J Pain Symptom Management 2004;28:497-504
Bowel Regulation
Constipation




Low fibre diet – fruit and vegetable restriction
Limited fluid intake
Limited exercise
Medications – calcium and iron
Treatment




Stool softener – docusate 200 mg po bid
Stimulant laxative – sennosides 24 mg po hs prn
Osmotic laxative – lactulose 30 mL po bid prn or polyethylene
glycol (PegLyte 1-4 L or Lax-A-Day 17 g/dose)
AVOID: Fleet Enema (sodium phosphate), Milk of Magnesia
(magnesium hydroxide), Fruitlax (High in K+ = 45 mg/15 g)
Vitamins
Nutritional Deficiencies

Water soluble vitamins, e.g. B vitamins, vitamin C, and
folic acid, are dialyzable


Avoid multivitamins (fat soluble vitamins)



Renavite or Replavite 1 tab po daily
(B vitamins, vitamin C 100 mg, folic acid 1 mg)
Vit A accumulates - associated with renal osteodystrophy
Vit D ineffective – needs to be hydroxylated
Zinc 10-20 mg/day x 3 months

Impaired taste, impaired wound healing, hair loss
Anticoagulation in Dialysis Pts
Anticoagulation in Dialysis Pts
Prophylaxis


Heparin 5000 units SC Q12h
Dalteparin 5000 units SC daily


Data up to 10-30 days safe in eGFR < 30mL/min
Enoxaparin 30 mg SC daily (i.e. half dose)

Will accumulate with full dosing
Treatment


Unfractionated heparin preferred as inpatient
Outpatient bridge therapy:


Tinzaparin 175 units/kg SC daily (preferred over other LMWH)
Target peak anti-Xa 0.6-1.5 units/mL (> 7-10 days)
Antibiotic Dosing and Dialysis
VA Anti-infective Comparison Card
Cephalosporin Dosing in HD

1st generation

Cefazolin 2 g IV qHD for MSSA




Superior to vancomycin for MSSA (CID 2007)
Long half-life – primarily renally eliminated
Post-antibiotic effect
3rd generation

Cefotaxime 2 g IV qHD



Active metabolite has long half-life
Alternative to Ceftriaxone, which must be dosed Q24H
as primarily eliminated by liver
Ceftazidime 2 g IV qHD

Pseudomonas and other Gram negative organisms
Vancomycin Dosing in HD

~30% vancomycin is dialyzed out

Loading Dose:


Maintenance Dose:



25 mg/kg if dialyzing; 20 mg/kg if no dialysis
**Use goal weight**
< 70 kg – 500 mg qHD; > 70 kg – 750 mg qHD
Adjust dosage in increments of 250 mg
Target pre-HD trough of 15-20mg/L
Vancomycin Case

80 kg male on HD with MRSA CVC line infection
 Vancomycin dose:
 Duration of treatment:
 When to check a level:

Pre-HD trough level prior to 2nd vancomycin
maintenance dose is:
 12 mg/L – What to do?
 24 mg/L – What to do?
Aminoglycoside Dosing in HD

Gentamicin and Tobramycin
 Loading dose: 2 mg/kg
**Use goal weight (round down if obese)**
 Treatment: 1.5 mg/kg post HD
 Target pre-HD trough < 3.5 mg/L
 Synergy or UTI: 1 mg/kg post HD
 Target pre-HD trough < 2 mg/L
 Adjust dosage in increments of 10 mg
e.g. 78 kg male on HD with gram (-) bacteremia
On-line References
Dialysis of Drugs Handbook

http://renalpharmacyconsultants.com/ass
ets/2013dodbooklet.pdf
Drug Prescribing in Renal Failure

www.kdp-baptist.louisville.edu/renalbook/
Dialyze IHD

www.dialyzeihd.com/