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Drugs and Renal
Transplant Recipient
Lou Huei-Xin
Department of Pharmacy
Drug Protocols Post Renal TX
Immunosuppressant Protocol
Prophylaxis Protocol
Treatment of CMV infection
Proteinuria Management
Hypertension Management
Lipid Management
Induction Agent
IL 2 receptor antagonist / CD 25 blocker
– Basilixmab (Simulcet®)
– Daclizumab (Zenapax®)
Anti-Thymocyte Globulin
– Thymoglobulin®
– ATG-Fresenius®
Immunosuppressant Protocol
Calcineurin inhibitor (CNI) based regimen
– CNI (cyclosporine or tacrolimus)
– Steroids
– Anti-proliferatives (mycophenolic acid
analogues or azathioprine
mammalian Target of Rapamycin (mTOR)
inhibitors based regimen
– mTOR (sirolimus or everolimus)
– Steroids
– Anti-proliferatives (mycophenolic acid
analogues or azathioprine
Immunosuppressant Protocol
CNI and mTOR based regimen
– Cyclosporin
– Sirolimus / Everolimus
– Steroid
Anti-proliferatives based regimen
– MPA analogue / Azathioprine
– Steroid
Basiliximab (Simulect®)
Chimeric monoclonal antibody
IV 20mg within 2 hours prior to surgery on
Day 0 and a second dose Day 4
Duration of effect : ~30 days
Daclizumab (Zenapax®)
Chimeric monoclonal antibody
IV 1mg/kg within 24 hour prior to
transplant, follow by another 4 doses
Duration of effect for 1 dose : ~ 2 weeks
IL 2 Receptor Antagonist
Adverse events
– Hypersensitivity, Bronchospasm
– Thrombocytopenia
– Infection
T Cells
Antibodies
Thymoglobulin®
Anti-Thymocyte Globulin
Eliminate T cells in peripheral blood
Indications
– As Quadruple immunosuppression in high risk
recipient (High PRA, Positive B cell cross
match, re-transplant)
– Treatment of delayed graft function (Sequential
immunosuppression)
– Treatment of acute rejection
For treatment of delayed graft function / as part of the quadruple therapy : 1.5 mg/kg/day
For treatment of acute rejection : 2.5 mg/kg/day
Each vial contains 25mg/5mL. Round up/down the daily dose to the nearest 25 mg
Pre-medications: IV promethazine 25 mg over 15 minutes and PO paracetamol 1 g half an hour before Thymoglobulin® administration
Thymoglobulin®
Dilute the dose in 100 to 250 mL normal saline and administer over 6 hours via central venous line through Mirafilter®
Half-hourly vital signs during infusion, subsequently hourly vital signs
Stop infusion for patient complaints of breathlessness, or bronchospasm or hypotension
Slow infusion rate if patient develops fever, rigors or chills and treat with paracetamol, promethazine
Thymoglobulin®
Thymoglobulin®
Do daily CD cell subsets (CD2, CD3, CD4, CD8) at start of ATG, daily during the course and for 3 days after completion of course
Aim for absolute CD3 counts between 50-100/uL
Reduce the dose should patient develops leucopenia and/or thrombocytopenia
Thymoglobulin®
Start pneumocytis carinii pnuemonia and cytomegalovirus prophylaxis
Monitor for sign and symptoms of infection
Check for cytomegalovirus infection
Ensure target level drugs are obtained before the end of therapy, ie increase to normal dose 3 days before the end of Thymo therapy
Immunoglobulin (IVIG)
Human immunoglobulin
Dose for high risk renal transplant
– 1 g/kg/day
Start with 0.5 mL/kg/hour, increase
to maximum rate of 4 mL/kg/hour
Side effects
– Flushing of face
– Tachycardia
– Hyper/hypotension
Calcineurin Inhibitor
Inhibit the synthesis of interleukin-2 (IL-2)
Bind to cyclophilin/FK binding protein,
cytosolic binding protein, to form an
active drug
Complex with calcineurin (CN), resulting
in reversible and non-competitive
inhibition of CN
Cyclosporin (Neoral®)
Neoral is the microemulsion formulation
of cyclosporin
Starting PO dose : 4 mg/kg bd
First dose to be served within 6 to 12 hour
post anastomosis
Titration of dose to cyclosporin peak level,
C2 hour level,
– 2 h + 15mins
Erratic absorption especially initially post
transplant
– Need to monitor C0 and C4 hour levels
Absorption improve with time post tx
– Need to tail down dose according to target C2 level
Half life of CyA ~ 8.4 hours
Steady state will be reached after 5 half life, ie C2 or C0 should be checked at least after 48 hours following any change in dose
Cyclosporin (Neoral®)
Cyclosporin (Neoral®)
Target C2 level
– Depending on risk for rejection
– Time post transplant
– Concurrent nephrotoxicity, liver dysfunction
– Concurrent immunosuppressant
Target C2 for RTX
– Day 0 to Month 1 : 1200 to 1600 ng/mL
– Month 1 to Month 6 : 1000 – 1200 ng/mL
– Month 6 to Year 1 : 800 – 1000 ng/mL
Cyclosporin (Neoral®)
Intravenous administration
– 1/3 of totally daily oral dose, given once
a day
– Must be diluted with 0.9% Sodium
Chloride in non-PVC bottle and infused
over 2 to 6 hours.
– Monitor C0, not C2
– Convert to oral as soon as patient can
take orally
Cyclosporin (Neoral®)
Patient who on tube feeding
– Convert to IV formulation if patient is on tube feeding only for a short period
– Use cyclosporin syrup if patient is on long term tube feeding
– Use only non-PVC nasogastric tube for tube feeding of cyclosporin syrup. Use non-PVC container whenever possible.
– Syrup should be diluted in water or any flavoured beverage before taking. Do not use hot fluid. Store the syrup in the refrigerator. Do not freeze.
Should be taken at the same time every day, 12 hour apart
Should be taken consistently with regard to food (ie with or without food)
Capsule must be swallowed whole. Do not break or pound the capsules. Capsules should not be removed from the blister pack until immediately before taking.
Do not take with grapefruit juice
Cyclosporin (Neoral®)
Tacrolimus (FK 506, Prograf®)
Starting PO dose : 0.1 to 0.15 mg/kg bd
First dose to be served within 6 to 12 hour post anastomosis
Titrate dose to blood trough tacrolimus
Erratic absorption especially initially post transplant
Concurrent administration with Diltiazem SR to increase FK level
Tacrolimus (FK 506, Prograf®)
Absorption improve with time post tx
– Need to tail down dose according to target trough level
Half life ~ 20 hours
Steady state will be reached after 5 half life, ie trough level should be checked at least after 72 hours following any change in dose
Target trough level
– Depending on risk for rejection
– Time post transplant
– Concurrent nephrotoxicity, liver dysfunction
– Concurrent immunosuppressant
Target trough level (General guide)
– Day 0 to Month 1 : 15 ng/mL
– Month 1 to Month 6 : 12 to 15 ng/mL
– Month 6 to Year 1 : 10 to 12 ng/mL
– After Year 1 : 8 to 10 ng/mL
Tacrolimus (FK 506, Prograf®)
Intravenous administration
– ~ 1/3 of totally daily oral dose, given
once a day or 0.03 mg/kg/day
– Must be diluted with 0.9% Sodium
Chloride in non-PVC bottle and infused
over 20 hours
– Final concentration between 0.004mg/mL
to 0.02 mg/mL
– Convert to oral as soon as patient can
take orally
Tacrolimus (FK 506, Prograf®)
Patient who on tube feeding
– No syrup formulation
– PVC nasogastric tube can be used
Tacrolimus (FK 506, Prograf®)
Tacrolimus (FK 506, Prograf®)
Tacrolimus should be taken at the same
time every day, 12 hour apart
Tacrolimus should be taken consistently
with regard to food (ie with or without
food) every day
Capsules can be served with water or any
fluid except grapefruit juice
Calcineurin Inhibitor Adverse
Events
Nephrotoxicity (acute versus chronic)
Hypertension
Neurotoxicity ~ tremor, headache,
insomina
Elevated serum alkaline phosphatase
Hyperkalaemia, hypomagnesemia
Diabetes mellitus
Hirsutism, alopecia, pruritus
Hyercholesteromia, hyperuricemia
Gingival hypertrophy
How much to increase or decrease a dose???
Formula
By 10% to 50%
Experience…
Steroid
IV steroid (1g hydrocortisone) at time of
anaesthesia induction
IV steroid (500mg hydrocortisone bd x 5
doses) immediate post op period, usually
Day 1 to Day 3
Oral steroid (prednisolone 30mg) once
daily
Taper down every 2 weeks by 2 to 3 mg
each time
Aim for 10mg/day about 3 months post Tx
Steroid
Prednisolone should be taken every
morning after food
Steroid Adverse Events
Increased appetite, weight gain
Central obesity, moon face
Acne
High blood glucose level
Gastric intolerance
Hypercholesterolemia
Hyperuricemia
Thinning of skin
Osteoporosis
Cataract
Azathioprine (Imuran®)
Prodrug, metabolise to 6-mercaptopurine
by the liver
Starting PO dose : 1 mg/kg/day
Titration of dose to side effect
Side effects:
– Leucopenia, thrombocytopenia, anemia
– Alopecia
– Elevated bilirubin, ALT, AST
– Infection
Azathioprine (Imuran®)
Azathioprine should be taken every
morning after food
Azathioprine (Imuran®)
Allopurinol increase marrow toxicity of
azathioprine
– Avoid allopurinol; use alternative anti-
uric acid agents
– Discontinue AZA and start MPA
analogues
Mycophenolic Acid (MPA)
Analogues
Designer immunosuppressive drug
Mycophenolate Mofetil (Cellcept®)
– Metabolise to active mycophenolic acid
in liver
Mycophenolate Sodium (Myfortic®)
– Enteric Coated
– Associated with a lower incidence of
gastric intolerance
IV formulation – Cellcept®
No syrup formulation in Singapore
Patient on tube feeding
– Review whether MPA can be omitted for
a couple of days
– Pound mycophenolate mofetil and feed
through the tube
MPA Analogues
MPA Analogues
International recommendation : mycophenolate mofetil 1 g bd / mycophenolate sodium 720 mg bd
SGH starting PO dose in CNI-treated renal transplant : 12 mg/kg bd – Measure trough MPA. High MPA trough
correlate to side effects but ? correlation to efficacy
For renal transplant on sirolimus, measure trough MPA level and reduce dose accordingly
MPA Analogues
Should be taken at the same time every
day, 12 hour apart
Should be taken consistently with regard
to food (ie with or without food) every day
MPA Adverse Events
Leucopenia
Thrombocytopenia
Elevated AST, ALT
Infections
Diarrhea, gastric discomfort
Teratogenic
Sirolimus (Rapamune®)
Bind to mammalian Target of Rapamycin (mTOR)
Long half life of 60 hours
Recommendation for use in combination with cyclosporin (PIL) : Load dose of 6mg, followed by maintenance dose of 2-4 mg once daily; administer 4 hours apart from cyclosporin
Sirolimus (Rapamune®)
SRL based regimen without CNI
– Loading dose 6mg follow by
maintenance dose of 1mg bd +
Diltiazem SR 90mg om
SRL / CyA regimen
– Load dose of 6mg, followed by
maintenance dose of 2 mg once daily;
administer SRL together with CyA
Sirolimus (Rapamune®)
Titrate dose to target trough level
Target trough level depends on
– Indication of sirolimus
– Concurrent immunosuppressant
General Guide (SRL based)
– BKV, EVB, Hepatitis : 5 to 8 ng/mL
– DGF, CNI vasculopathy, steroid
resistant rejection : 8 to 12 ng/mL
SRL / CNI based therapy : ~ 5 ng/mL
Sirolimus (Rapamune®)
No IV formulation
1mg tablet and 1mg/mL syrup
Alternate day dosing regimen
– 1mg bd (M, W, F)
– 1mg om (T, Th, Sat, Sun)
Sirolimus (Rapamune®) Should be taken at the same time every
day, 12 hour apart for bd dosing
Should be taken consistently with regard to food (ie with or without food) every day
Sirolimus solution should be diluted in at least 60 mL of water or any fluid in a glass or plastic container before taking immediately before taking. Rinse the container with another 120mL of the fluid and take the fluid immediately. Do not use hot fluid.
Everolimus (Certican®)
Bind to mammalian Target of Rapamycin
(mTOR)
Half life ~ 30 hours
Dosage: 0.75 mg to 1.5 mg bid
Use in combination with low dose CyA
Titrate to everolimus trough level
Everolimus (Certican®)
Should be taken at the same time every
day, 12 hour apart for bd dosing
Should be taken consistently with regard
to food (ie with or without food) every day
mTOR Adverse Events
Pneumonitis
Delayed wound healing
Cytopenia (decrease TW, Platelet)
Hypokalemia
Hyperlipidemia ( TG, LDL C)
Ulcers
Herpes infection
Teratogenic / Abortive effect
Diltiazem SR 90mg
Calcium channel blocker
Indications
– Hypertension
– Tachycardia
– Ischemia Heart Disease
Dose: 90mg once or twice daily
Side effects
– Bradycardia
Pharmacodynamic Drug
Interaction
Non-Steroidal Anti-inflammatory Drug including COX 2 inhibitor
Angiotensin Converting Enzyme Inhibitor / Angiotensin Receptor Blocker
Aminoglycoside, Amphotericin
Acyclovir
Co-trimoxazole
NO live vaccines to be given
Inactivated vaccine
Pharmacodynamics Drug
Interaction
Drug Interaction between
Immunosuppressive drugs
CyA inhibits enterohepatic
recirculation of MPA leading to a higher
dose requirement
FK and Sirolimus do not inhibit
enterohepatic recirculation
mycophenolic acid leading to a lower
dose requirement
Sirolimus inhibit MPA metabolism
further reduce the dose of MPA
Drugs that Decrease CNI/SRL
level
Barbiturate
– Phenobarbitone
– Primidone (Mysolin®)
Carbamazepine (Tergetrol®)
Phenytoin (Dilantin®)
Rifampicin
Need to increase the dose of CNI/SRL
upon initiation of rifampicin
Drugs that Increase CNI/SRL
level
Verampamil, Diltiazem^
Triazole Antifungal
– Fluconazole, itraconazole,
voriconazole
Macrolides
– Erythromycin/EES, Clarithromycin,
Azithromycin
Oral Contraceptive, Progesterones
Drug-Drug Interaction
To avoid drug interaction as much as possible
Co-administration or dose change of a drug that interacts with PK
– Reduced efficacy versus increased toxicity
– Increase frequency of monitoring
– Adjustment of dose
Prophylaxis of Infection
Pneumocystis carinii Pneumonia
– Co-trimoxazole 240mg tablet every
night for first 6 months post
transplant
– Inhalation pentamidine monthly for
G6PD deficiency patient or patient
allergy to sulpha
– Continue indefinitely in patients
treated with MPA, and/or SRL
Prophylaxis of Infection
Cytomegalovirus Infection
– D+/R- : Ganciclovir/Valganciclovir for
a minimum of 3 months
– Following antilymphocytes therapy :
1 month of Ganciclovir/Valganciclovir
+ 2 months of Valaciclovir
– Following pulse steroid in patient
treated with MPA analog : 1 month of
Valaciclovir Dose according to renal
function
Treatment of CMV Infection
Start treatment dose of IV ganciclovir or PO Valganciclovir
Reduce immunosuppressants
Do CMV antigen once to twice weekly
For CMV disease with organ involvement,
Start CMV IVIG (Megalotect®)
Calcium Carbonate
Calcium Supplement
Non-chew preparation, Calcium Carbonate
625mg om