Version May 2024
| Drug* | Mechanism of action | Suggested dose* | Drug monitoring | Metabolism/transporter effects with selected drug interactions¶ | Common major adverse effects | Comments |
| Glucocorticoids | ||||||
| Methylprednisolone, prednisone | Inhibits humoral and cell-mediated immunity Binds with DNA sequences (+/– nuclear factor-kB) to inhibit production of inflammatory cytokines | At time of transplant: 500 to 1000 mg methylprednisolone intravenously Maintenance oral prednisone dose: 0.5 to 1 mg/kg per day initially after transplant with taper to a goal of 5 to 10 mg per day over several months to one year Protocols may vary by institution | N/A | Cytochrome P450 3A4 substrate Numerous clinically relevant interactions in transplant patientsΔ | Diabetes GERD, PUD Osteoporosis Skeletal muscle wasting Hypertension Hypercholesterolemia Change in appetite Weight gain | Do not stop abruptly; may be taken with food to reduce dyspepsia |
| Calcineurin inhibitors | ||||||
| Cyclosporine◊ | Prevents T cell activation and proliferation by inhibiting the production of interleukins and other cytokines | 2 to 3 mg/kg per day intravenously at time of transplantation given in a 24 hour infusion or 1 to 1.5 mg/kg in two or more four hour infusions and until patient can tolerate oral intake. Adjust dose to target trough concentration of 250 to 350 ng/mL and two hour post dose (C2) concentration of 900 to 1200 ng/mL. Maintenance oral dose: 3 to 5 mg/kg twice per day 12 hours apart at a consistent time each day in relation to meals and adjusted according to trough or C2 concentration as above. | Monitor BUN, Cr, magnesium, potassium Trough levels typically used but levels drawn two hours post dose (C2) are most accurate | Metabolized by cytochrome P450 enzyme system Cytochrome P450 3A4 substrate/inhibitor, P-glycoprotein substrate/inhibitor Marked increase in levels of statin drugs when co-administered Numerous clinically relevant interactions in transplant patientsΔ | Renal dysfunction including acute nephrotoxicity Hypertension Hypercholesterolemia Gingival hyperplasia Neurotoxicity (tremor, headache, encephalopathy, focal deficits) Hirsutism | High inter- and intra-individual absorption variability. Blood concentration monitoring is necessary for any change in formulation (including switch between generics or brands) to determine need for dose alteration. The microemulsion form, which is also known as "modified" (Neoral) is generally better absorbed than the non-modified form (Sandimmune). |
| Tacrolimus◊ | Prevents T cell activation and proliferation by inhibiting the production of interleukins and other cytokines | Initial dose sublingually: 0.04 to 0.05 mg/kg per day in two divided doses (eg, 1 to 2 mg sublingually every 12 hours)[1,2]§; OR Initial dose intravenously: 0.03 to 0.05 mg/kg per day by continuous infusion over 24 hours; risk of infusion reactions and other toxicities (refer to accompanying text) Maintenance oral dose: 0.05 mg/kg twice daily taken 12 hours apart at a consistent time each day in relation to meals Initial and maintenance: Adjust dose to target trough level of 10 to 15 ng/mL for months 1 to 3; 8 to 13 ng/mL for months 4 to 12; and 6 to 8 ng/mL after the first 12 months, although target levels vary based on center practice and clinical circumstances | Monitor glucose, LFTs, BUN, Cr, calcium, magnesium, potassium Monitor trough levels | Metabolized by cytochrome P450 enzyme system Cytochrome P450 3A4 substrate, P-glycoprotein substrate Numerous clinically relevant interactions in transplant patientsΔ | Renal dysfunction Diabetes Hypertension (less than cyclosporine) Hypercholesterolemia Altered mental status Headache Focal neurological deficits | High inter- and intra-individual absorption variability Blood concentration monitoring is necessary for change in formulation (including switch between generics or brands) and between methods of administration (eg, sublingual, oral, and IV administration) to determine need for dose alteration |
| Antimetabolites | ||||||
| Mycophenolate mofetil (CellCept) | Nucleotide blocking agent Inhibits T cell proliferation by blocking nucleotide synthesis | IV equivalent to oral Starting dose: 1000 to 1500 mg twice daily within 72 hours after transplantation Oral doses should be taken on an empty stomach or at a consistent time each day in relation to meals if taken with food to improve tolerability Giving total daily dose in three or four equally divided doses might improve GI tolerability | Monitor WBC Dose adjusted for leukopenia Serum concentration monitoring not routinely performed¥ | Levels decreased by:¥
Levels increased by:¥
May inactivate protein bound drugs, especially hormonal contraceptives (use nonhormonal method of contraception) | Nausea, vomiting, diarrhea, abdominal pain Diarrhea may occur after months of treatment GI tolerability may improve with more frequent dosing (same total daily dose) or by changing to enteric-coated mycophenolate sodium (below) Myelosuppression, anemia Increased risk of CMV disease | Serum concentration monitoring is not routinely performed¥ |
| Mycophenolate sodium, enteric coated (Myfortic) | Nucleotide blocking agent Inhibits T cell proliferation by blocking nucleotide synthesis | Starting dose: 720 to 1080 mg orally twice daily on an empty stomach To convert from mycophenolate mofetil 1000 mg every 12 hours, switch to mycophenolate sodium enteric coated 720 mg every 12 hours | Monitor WBC Dose adjusted for leukopenia Serum concentration monitoring not routinely performed¥ | Levels decreased by:¥
Levels increased by:¥
May inactivate protein bound drugs, especially hormonal contraceptives (use nonhormonal method of contraception) | Nausea, vomiting Diarrhea Myelosuppression, anemia Increased risk of CMV disease | Serum concentration monitoring is not routinely performed¥ |
| Azathioprine | Nucleotide blocking agent Inhibits T and B cell proliferation by blocking nucleotide synthesis | IV equivalent to oral Starting dose: 1 to 2 mg/kg daily and adjusted to prevent development of leukopenia | Monitor WBC Dose adjusted for leukopenia Monitor LFTs | Levels increased by:
Use with febuxostat is contraindicated May diminish anticoagulant effects of warfarin | Nausea, vomiting Diarrhea Bone marrow suppression Liver abnormality | Requires TPMT enzyme for metabolism. Individuals with profound initial side effects may be deficient in this enzyme. |
| mTOR inhibitors | ||||||
| Sirolimus | Inhibits T cell proliferation by cell cycle arrest in G1 phase | Sirolimus is initiated at least three months post-transplantation, due to effects on wound healing. Liquid and tablet form. Starting dose: 2 mg orally per day. Adjusted to maintain a trough target between 8 and 12 ng/mL when used without calcineurin inhibitor. Adjust to maintain trough level between 4 and 8 ng/mL when used with calcineurin inhibitor. | Monitor CBC, LFTs Obtain trough level three to four days after initiation and seven days after any change in dose | Metabolized by cytochrome P450 3A enzyme system Cytochrome P450 3A4 substrate, P-glycoprotein substrate Cyclosporine dose should be decreased by one-half to two-thirds when co-administered with sirolimus[3] Numerous clinically relevant interactions in transplant patientsΔ | Delayed wound healing Fatal airway anastomotic dehiscence if administered early after lung transplantation Myelosuppression Hypercholesterolemia Pulmonary toxicity LFT abnormalities Diarrhea Nausea | Associated with increased incidence of deep venous thrombosis[4] |
| Everolimus | Inhibits T cell proliferation by cell cycle arrest in G1 phase | Everolimus is initiated at least three months post-transplantation, due to effects on wound healing Starting dose: 1.5 mg orally every 12 hours and adjusted to maintain a trough target between 3 and 12 ng/mL in combination with cyclosporine and a glucocorticoid In combination with tacrolimus, higher doses of everolimus may be needed to maintain trough levels within target range compared to doses when used with cyclosporine | Monitor CBC, LFTs, BUN, Cr, glucose Monitor trough levels; steady state levels are reached four to five days after a dose change | Metabolized by cytochrome P450 3A enzyme system Cytochrome P450 3A4 substrate, P-glycoprotein substrate Cyclosporine dose should be decreased by one-half to two-thirds when co-administered with everolimus Numerous clinically relevant interactions in transplant patientsΔ | Delayed wound healing Bone marrow suppression Hypercholesterolemia Pulmonary toxicity Diarrhea Nausea | |
GERD: gastroesophageal reflux disease; PUD: peptic ulcer disease; Cr: creatinine; LFT: liver function tests; BUN: blood urea nitrogen; ECG: electrocardiogram; WBC: white blood cell count; CMV: cytomegalovirus; MPA: mycophenolic acid (active metabolite of mycophenolate); TPMT: thiopurine methyltransferase; mTOR: mechanistic target of rapamycin; CBC: complete blood count.
* Initial immunosuppressant doses shown should be adjusted based upon patient-specific factors including organ function and potential drug interactions. Drug therapy should be managed by transplant specialists with expertise in therapeutic drug monitoring and doses should be adjusted based upon measurement of immunosuppressant concentrations. The US Food and Drug Administration has approved tacrolimus for use in lung transplantation, but other medications have not been approved. The doses are suggested based on the experience of large lung transplantation centers. Dosing protocols vary by institution.
¶ Immunosuppressants are subject to numerous drug interactions, particularly with drugs or foods that inhibit or induce cytochrome CYP 450 3A4 and/or P-glycoprotein transporters (P-gp). Drug therapy should be managed by transplant specialists with expertise in therapeutic drug monitoring and doses adjusted based upon measurement of immunosuppressant concentrations, particularly whenever drug therapy is altered. The table is NOT a complete list of all possible interactions. To determine specific drug interactions and suggestions for management, consult a drug interactions database such as Lexicomp drug interactions included with UpToDate.
Δ For additional information, refer to UpToDate table on major drug interactions with immunosuppressants: cyclosporine, tacrolimus, sirolimus, or everolimus.
◊ For additional information, refer to UpToDate topic on pharmacology and side effects of cyclosporine and tacrolimus.
§ Sublingual administration of tacrolimus may be an alternative for lung transplant recipients who are unable to swallow capsules[1,2].
¥ Serum levels of mycophenolate active metabolite (MPA) can be altered by some drug interactions. However, adjustment of mycophenolate dose may not be necessary depending upon the expected effect of the interaction and patient factors (eg, rejection risk); single MPA serum levels are not reliable for determining mycophenolate exposure or predicting efficacy and are not routinely performed (refer to accompanying text).Prepared with data from:
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