Drug Protocol Rx Tx_Nurse Teaching

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®


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


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



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


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


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


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


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


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


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


Patient who on tube feeding

– No syrup formulation

– PVC nasogastric tube can be used



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 should be taken every

morning after food


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


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


Titrate dose to target trough level

Target trough level depends on

– Indication of sirolimus


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


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

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Drug Protocol Rx Tx_Nurse Teaching