Creatinine (mg/dL)
Cyclosporine/tacrolimus dose
1.5–1.75 (or 1–1.5 × baseline)
50–75 % of current dose
1.76–2 (or 1.6–1.9 × baseline)
25–50 % of current dose
> 2 (or > 1.9 × baseline)
Hold until creatinine < 2 then resume at 50–75 % of prior dose
The risk of creatinine > 2 × baseline increases by 94 % when the mean concentration of cyclosporine is > 300 for 7–14 days.
The risk of creatinine > 2 × baseline increases by 41 % when the mean concentration of tacrolimus is > 20 for 7–14 days.
iv.
Dose adjust for drug interactions with CYP 3A4 inhibitors such as amiodarone, azole antifungals, calcium channel blockers, nicardipine, macrolide antibiotics, protease inhibitors, and some tyrosine kinase inhibitors:
Depending on the strength of azole antifungal as an inhibitor, cyclosporine doses may need to be reduced as much as 60 % when given concomitantly with the azole.
Adjust doses by up to 20 % each time.
v.
Dose adjust for drug interactions with CYP 3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin.
e.
Adverse effects (Note: There is no strict correlation between toxicity and level):
i.
Adverse effects common to cyclosporine and tacrolimus:
Hypertension:
◦ Treat with a calcium blocker, such as nifedepine ER or amlodipine.
◦ Avoid angiotensin converting enzyme (ACE) inhibitors and diuretics with cyclosporine. They can exacerbate the already reduced renal blood flow caused by cyclosporine due to afferent arteriole vasoconstriction.
◦ It is critically important to maintain DBP < 90.
Renal impairment:
◦ Decrease dose to avoid continued damage to kidneys. See dose adjustments listed above.
Electrolyte abnormalities: hypomagnesemia, hyperkalemia
Neurotoxicity : tremors, ataxia, headache, seizures
◦ Obtain MRI. If posterior leukoencephalopathy is evidenced by MRI, hold doses. The condition is reversible.
◦ Treat seizures with antiepileptic agents such as phenytoin or levetiracetam.
◦ Reduce tremors with propranolol 10 mg PO every 6 hours.
Hepatic impairment: hyperbilirubinemia:
◦ Cyclosporine and tacrolimus are excreted through the bile in feces.
◦ Monitor levels closely and decrease dose.
Hemolytic uremic syndrome /microangiopathic hemolytic anemia (MAHA)/transplant-associated thrombotic microangiopathy (TATMA)
Diabetes
ii.
Adverse effects specific to cyclosporine:
Infusion reaction: burning hands and feet, whole body flushing, and/or muscle cramping:
◦ May be reaction to the cremaphor diluent.
◦ Slow the every 12 hours infusion or give the daily dose as a continuous infusion.
◦ Premedication or oral administration of cyclosporine may be required.
Hypertrichosis/hirsutism
Gingival hyperplasia
Arthralgias and myalgias:
◦ Can be seen with first dose. Treat with narcotic analgesics.
iii.
Adverse effects specific to tacrolimus:
Neurotoxicity : hallucinations, nightmares
Infusion reaction:
◦ May be reaction to the castor oil and dehydrated alcohol in the formulation.
◦ Use premedication and give tacrolimus orally if possible.
2.
Methotrexate
a.
Mechanism of action/place in therapy:
i.
Inhibits dihydrofolate reductase, resulting in a lack of reduced folates available for thymidylate and purine synthesis. As a result, lymphocytes are unable to proliferate .
ii.
Used in conjunction with cyclosporine, tacrolimus, or sirolimus for prevention of GVHD in myeloablative transplants.
b.
Dose and administration:
i.
Standard regimen:
15 mg/m2 IV push on day + 1. Administer at least 24 hours after infusion of stem cells.
10 mg/m2 IV push on day + 3, + 6 (+/– day + 11)
Patients receiving peripheral blood stem cells (PBSCs) have an increased disease-free and overall survival when given day + 11 methotrexate versus those receiving BM and day + 11 methotrexate.
ii.
Mini dose:
5 mg/m2 IV push on day + 1, + 3, + 6, + 11
iii.
Assess patient prior to each dose and consider holding the dose for third spacing (pleural or pericardial effusions, ascites), liver insufficiency, or renal failure.
c.
Monitoring:
i.
High serum methotrexate levels can be toxic to an early graft
ii.
Check serum methotrexate level 24 hours after the dose is given if suspect toxicity.
iii.
May use folinic acid rescue if serum levels are > 0.05 µmol/L.
d.
Dose adjustments (see Table 11.2):
Table 11.2.
Methotrexate dosing in liver insufficiency
Bilirubin (mg/dL) | Methotrexate dose |
|---|---|
< 3.0 | 100 % |
3.1–6.0 | 50 % |
> 6.0 | Hold |
i.
Dose adjust for liver insufficiency
ii.
Check with provider if patient has renal failure/compromise
e.
Adverse effects:
i.
Minimal toxicity at low doses
ii.
Mucositis:
May hold the dose or decrease to 5 mg/m2 if grade IV mucositis is present .
May use folinic acid rescue 10 mg IV every 6 hours × 6–8 doses to prevent exacerbation of existing mucositis. Begin 24 hours after administration of methotrexate dose.
Use of folinic acid does not affect aGVHD outcomes.
iii.
Hyperbilirubinemia
iv.
Delayed neutrophil and platelet recovery
3.
Corticosteroids:
a.
Mechanism of action/place in therapy:
i.
Suppresses immune response to stimuli
ii.
Used in conjunction with cyclosporine or tacrolimus and methotrexate for prevention of GVHD in myeloablative transplants
b.
Dose and administration:
i.
Methylprednisolone (Solumedrol®, Medrol®):
0.25 mg/kg/dose IV every 12 hours beginning day + 7 or day + 12
May increase dose to 0.5 mg/kg/dose IV every 12 hours during weeks 2 and 3 after initiation
ii.
Conversion from IV to PO:
Convert to PO prednisone using an IV:PO conversion factor of 1:1.
Standard conversion factor is 4:5; however, no loss of efficacy has been observed in practice using 1:1.
iii.
Tapering doses:
Tapering schedule varies based on protocol and institutional standards. Day of taper initiation and duration of therapy vary from center to center.
General rules:
◦ Taper dose approximately 5 % each week if no GVHD
◦ Begin taper at approximately day + 30 with the goal of reaching 10 mg PO daily by day + 84
◦ Hold prednisone dose at 10 mg PO daily when beginning to taper calcineurin inhibitor at approximately day + 100 .
c.
Monitoring/adverse effects:
i.
Diabetes:
Monitor blood glucose levels on a regular basis and supplement patient with insulin and short-acting insulin on an as-needed basis and intermediate-acting insulin on a scheduled basis
ii.
Infection:
Patients should receive antifungal prophylaxis when taking > 30 mg/day of prednisone
d.
Additional information:
i.
The addition of corticosteroids to a prophylaxis regimen will significantly reduce the patient’s risk for grade I–IV aGVHD but does not decrease the incidence of grade III–IV aGVHD or cGVHD.
4.
Mycophenolate mofetil (Cellcept®):
a.
Mechanism of action/place in therapy:
i.
Inhibits both T and B lymphocyte proliferation via inhibition of inosine monophosphate dehydrogenase (IMPDH).
ii.
Used in conjunction with cyclosporine and tacrolimus for prevention of GVHD in nonmyeloablative transplants. Replaces methotrexate in two- to three-drug combinations.
b.
Dose and administration:
i.
Myeloablative transplants:
500–1500 mg PO/IV two to three times daily or 15 mg/kg/dose PO/IV two to three times daily beginning day 0 or + 1
Administration of 15 mg/kg/dose three times daily will provide serum concentrations of mycophenolate similar to those seen in the solid organ transplant setting
ii.
Nonmyeloablative transplants:
1000 mg PO/IV two to three times daily or 15 mg/kg/dose PO/IV two to three times daily
First dose should be at least 4–6 hours after the infusion of stem cells
Related donor transplant recipients can receive twice daily dosing, while unrelated donor transplants recipients should receive three times daily dosing
iii.
Conversion from IV to PO:
Do not crush/open capsules and administer on an empty stomach if possible.
Dose can be given as an IV infusion over 2 hours if necessary.The IV:PO conversion is 1:1.
iv.
Tapering doses:
Tapering schedule varies based on protocol and institutional standards. Day of taper initiation and duration of therapy varies from center to center.
General rules:
◦ Related donor transplants: stop mycophenolate at day + 28
◦ Unrelated donor transplants: begin taper at approximately day + 29 with the goal of discontinuing therapy by day + 56.
c.
Monitoring/adverse effects:
i.
Cardiovascular:
Hypertension
Edema
ii.
Gastrointestinal:
Diarrhea
Nausea/vomiting
iii.
Infection:
Mycophenolate has been shown to be an independent risk factor for the development of cytomegalovirus (CMV) infections.
Preemptive treatment of positive CMV antigenemia is required to prevent active CMV infection.
5.
Sirolimus:
a.
Mechanism of action/place in therapy:
i.
Inhibits both T and B lymphocyte proliferation by binding to FK binding protein 12, resulting in a complex that directly affects the function of mammalian target of rapamycin (mTOR), an enzyme responsible for growth of cells in the G phase
ii.
Thought to have synergy with calcineurin inhibitors , sirolimus is used in conjunction with tacrolimus +/– methotrexate for myeloablative and nonmyeloablative transplants
b.
Dose and administration:
i.
Myeloablative and nonmyeloablative transplants:
Load with 12 mg PO × 1 beginning day − 3 followed by 4 mg PO daily
If body surface area (BSA) is < 1.5 m2, load with 6 mg/ m2 PO × 1 followed by 2 mg/m2 PO daily
ii.
Other information:
There is no IV formulation.
Consistently taking medication with or without meals will help with monitoring of levels and dose adjustments.
Repeat dose if patient vomits within 15 min of administration. However, t-1/2 life is very long (60 hours) so missing a dose is not likely to affect serum levels.
c.
Monitoring:
i.
Goal trough concentration is 3–12 ng/mL
ii.
Checking levels:
Levels are to be checked no sooner than 5 days following a change in dose or schedule.
Routine monitoring of levels should occur once a week.
d.
Dose adjustments:
i.
Dose adjust for drug interactions with CYP 3A4 inhibitors such as amiodarone, azole antifungals, calcium channel blockers, nicardipine, macrolide antibiotics, protease inhibitors, and some tyrosine kinase inhibitors:
Depending on the strength of azole antifungal as an inhibitor, sirolimus doses may need to be reduced as much as 60 % when given concomitantly with the azole.
Concomitant administration with voriconazole may require sirolimus to be taken every other day. Inhibition of 3A4 in the gut wall by voriconazole can result in a 100-fold increase in sirolimus concentration.
ii.
Dose adjust for drug interactions with CYP 3A4 inducers such as carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin
e.
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Common toxicities:
i.
Cardiovascular:
Hypertension
Edema
ii.
Pulmonary:
Epistaxis
Interstitial pneumonitisRelated posts:
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