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Pharmacology of cyclosporine and tacrolimus

Authors: Karen Hardinger, PharmD, BCPS, Colm C Magee, MD, MPH, FRCPI
Section Editors: Daniel E Furst, MD, Daniel C Brennan, MD, FACP
Deputy Editor: Albert Q Lam, MD

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2017. | This topic last updated: Mar 31, 2017.

INTRODUCTION — Cyclosporine and tacrolimus selectively inhibit calcineurin, thereby impairing the transcription of
interleukin (IL)-2 and several other cytokines in T lymphocytes. Calcineurin inhibit
ors have been mainstays of
immunosuppression in solid organ transplantation for over three decades.

Cyclosporine and tacrolimus are occasionally used in the treatment of various immune-mediated diseases.
However, concerns about their long-term ot xicity (especially renal dysfunction and hypertension) and the availability
of newer biologic agents have restricted the use of cyclosporine and tacrolimus to patients who have not responded
to conventional treatment. The renal toxicity of these agents is reviewed in detail separately. (See "Cyclosporine and
tacrolimus nephrotoxicity".)

The pharmacology ofcyclosporine and tacrolimus is reviewed here. The efficacy and use of these agents in specific
conditions, including organ transplantation and immune-mediated diseases, ar e discussed separately in the topic
reviews addressing the treatment of each disorder. (See appropriate topic reviews.)

MECHANISM OF ACTION — Cyclosporine is a lipophilic cyclic peptide of 11 amino acids, whiletacrolimus is a

macrolide antibiotic. Both drugs have been isolated from fungi and possess similar suppressive effects on cell-
mediated and humoral immune responses.

Both drugs bind with high affinity ot a family of cytoplasmic proteins present in most cells: cyclophilins for
cyclosporine, and FK-binding proteins for tacrolimus. The drug-receptor complex specifically and competitively
binds to and inhibits calcineurin, a calcium- and calmodulin-dependent phosphatase1-4]. [ This process inhibits the
translocation of a family of transcription factors (NF-AT), leading to reduced transcriptional activation of cytokine
genes for interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, IL-3, IL-4, CD40L, granulocyte-macrophage colony-
stimulating factor, and interferon-gamma [1,2,5,6]. Ultimately, proliferation of T lymphocytes is reduced.

Cyclosporine and tacrolimus act primarily on T-helper cells, although some inhibition of -Tsuppressor and T-cytotoxic
cells may also occur. Cyclosporine also increases the expression of transforming growth factor (TGF)-beta, which
may be an important mechanism by which it causes renal fibrosis [7,8]. Unlike some other immunosuppressive
agents, such as azathioprine and the alkylating agents, cyclosporine and tacrolimus lack clinically significant
myelosuppressive activity [9].

FORMULATIONS — Oral, intravenous, and ophthalmic formulations ofcyclosporine are available (table 1). Oral,
intravenous, and topical formulations oftacrolimus are available. The intravenous forms of both drugs should be
used only if enteral administration is not possible, because there is the potential for greater toxicity with intravenous
administration. Generic forms of cyclosporine and tacrolimus are available in many countries, including the United
States. In general, patients stabilized on one preparation should not be switched o t another, because there are
concerns about differences in pharmacokinetics. If a conversion between preparations is necessary, monitoring
trough concentrations should be performed until the results are stable [10]. (See 'Switching formulations'below.)

Cyclosporine — Oral, intravenous, and ophthalmic formulations ofcyclosporine are available.

Cyclosporine is available in nonmodified and modified formulations. Nonmodified or al cyclosporine depends upon
bile for absorption and has erratic gastrointestinal absorption patterns. Modified cy
closporine, a microemulsion
formulation, does not depend upon bile salts for absorption and exhibits increased bioavailability and more
consistent absorption.

Nonmodified — Liquid cyclosporine is available in capsules, oral solution, and concentrate for injection:

● Liquid-filled capsules of 25 mg and 100 mg ar

e stored at less than 86ºF (30ºC) but not frozen.

● The oral solution of 100mg/mL in 50 mL bottles remains stable for two months after opening if stored in the
original container at less than 86ºF (30ºC
) but does not require refrigeration and should not be frozen.

● Concentrate for injection of 50mg/mL in 5 mL ampules should be stored at less than 86ºF (30ºC) and
protected from light and freezing. Dilutions in 5 percent glucose or normal saline are stable for 24 hours.
Substantial amounts ofcyclosporine may be lost during intravenous administration through plastic tubing.
Polyoxyethylated castor oil that is contained in the concentration for intravenous cyclosporine infusion can
cause phthalate stripping from polyvinyl chloride (PVC)-containing intravenous tubing. Thus, when intravenous
nonmodified cyclosporine is administered, PVC-free intravenous fluid containers and tubing should be used.

Modified — Capsules and solution are for oral use; no parenteral formulation is available. Patients who need an
intravenous formulation should be prescribed cyclosporine nonmodified concentrate for injection. Cyclosporine
modified capsules or the equivalent generic product are preferred due to superior pharmacokinetic profile compared
with the nonmodified formulation:

● Capsules of 25 mg and 100 mg should be st

ored at 68 to 77ºF (20 to 25ºC); some generic formulations are
available in a 50 mg capsule.

● The oral solution of 100mg/mL is available in 50 mL bottles, which er mains stable for two months after
opening if stored in the original container at 68 ot 77ºF (20 to 25ºC).

Ophthalmic emulsion — An ophthalmic emulsion of 0.05 percent is available in single vials of 0.4 mL and stored
at 59 to 77ºF (15 to 25ºC).

Tacrolimus — Oral, intravenous, and topical formulationsof tacrolimus are available.

● Tacrolimus immediate-release capsules of 0.5 mg, 1mg, and 5 mg are stored at 59 to 86ºF (15 to 30ºC).

● Extended-release capsules (Astagraf XL) of 0.5 mg, 1 mg, and 5 mg are stored at 59 to 86ºF (15 to 30ºC). They
should not be crushed or chewed.

● Extended-release tablets (Envarsus XR) of 0.75 mg, 1 mg, and 4 mg are stored at 59 to 86ºF (15 to 30ºC). They
should not be crushed or chewed.

● Tacrolimus concentrate for injection of 5mg/mL in 1 mL ampules is stored at 41 to 77ºF (5 to 25ºC) and is
stable for 24 hours in plastic syringes at 75ºF (24ºC
). When diluted in glucose or saline solutions, itemains
r
stable for 24 hours in glass, but not PVC containers.

● Tacrolimus ointment of 0.03 and 0.1 percent in 30 g and 60 g tubes are stored at 41 to 77ºF (5 to 25ºC).
There are two extended-release formulations of tacrolimus designed for once-daily administration. Their
mechanisms of prolonged release and pharmacokinetic profiles differ; therefore, the two are not interchangeable.
The extended-release tacrolimus capsule (Astagraf XL) is a modified-release formulation that allows slow elease
r of
the drug by controlling water penetration and forming a protective polymer gel layer around tacrolimus [11]. The
extended-release tacrolimus tablet (Envarsus XR) uses a drug-delivery technology that improves the bioavailability
of drugs with low water solubility 12].
[

Extended-release tacrolimus capsules are not approved in liver transplantation due to an increase in mortality in
female liver transplant recipients [13]. Extended-release tacrolimus tablets are only approved in kidney transplant
patients converted from immediate-release tacrolimus.

Short courses of sublingualtacrolimus have been used as an alternative to intravenous tacrolimus when enteral
administration is not possible [14].

DOSE AND ADMINISTRATION

Administration

● Cyclosporine – Cyclosporine should be administered at a consistent time of the day (at 12-hour intervals), and
with a consistent relation to meals, in order to decrease the intra-individual blood concentration variations.

Cyclosporine nonmodified oral solution should be mixed with milk, chocolate milk, or orange juice at room
temperature. Cyclosporine modified oral solution should be mixed with water, orange juice, or apple juice.

Both cyclosporine solutions may adhere to plastic and therefore should not be mixed in a plastic cup or with
plastic utensils. If a dose is missed, patients should tak
e it as soon as possible, ideally within four hours. The
y
should not double the next dose.

● Tacrolimus – Tacrolimus immediate-release should be administered at a consistent time of the day (at 12-hour
intervals) and preferably on an empty stomach. The extended-release products should be taken at the same
time of the day, preferably in the morning. Patients should not chew, divide, or crush the tablets.

If an immediate-release tacrolimus dose is missed, patients should take it as soon as possible, ideally within
four hours.

For the extended-release product, if a dose is missed, patients should take it as soon as possible within 14 ot
15 hours after missing the dose. After the 14-ot 15-hour timeframe, patients should wait until the usual
scheduled time to take the next daily dose. Patients should not double the next dose. P atients should avoid
alcoholic beverages while taking the extended-release product. Consumption of alcohol may increase the
release rate of tacrolimus and/or adversely alter the pharmacokinetic properties and the effectiveness and
safety of the extended-release product [15].

Dose — The dose and target concentrations of cyclosporine and tacrolimus vary with the disease being treated. The
doses used in patients with solid organ transplants are discussed below. Other diseases are discussed elsewhere in
the appropriate topic reviews.

Initial doses of calcineurin inhibitors should be determined by taking into account drug interactions, diet, time after
transplantation, pharmacokinetics, presence of infection, drug toxicity, and/or rejection. Drug concentration
monitoring should occur after the initial doses are given. (See 'Drug monitoring' below.)

We initiate calcineurin inhibitor therapy in transplant recipients on the first postoperative day (see "Induction
immunosuppressive therapy in renal transplantation in adults"). Some centers delay the introduction of a calcineurin
inhibitor until the serum creatinine has decreased by 50 percent from the pretransplant value or the patient has
significant urine output. However, there is little evidence that delayed, rather than immediate, initiation of a
calcineurin inhibitor results in lower rates of delayed graft function [16,17].

In addition, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines ecommend
r that administration of
calcineurin inhibitors should not be delayed until the onset of graft function [18].

● Cyclosporine modified – For non-autoimmune disease, cyclosporine modified is initially dosed at 4 ot 10

mg/kg/day orally in two divided doses. Most clinicians start at the lower end of the dosing ar nge and make
adjustments based upon drug concentrations. The first dose may be administered within 24 hours of
transplantation. In newly transplanted patients, the initial dose of cy
closporine modified is the same as the
initial dose of cyclosporine nonmodified, although cyclosporine modified is preferred.

● Tacrolimus – Tacrolimus is typically dosed at 0.1 ot 0.2 mg/kg/day orally in two divided doses. Most clinicians
start at the lower end of the dosing ar nge and make adjustments based upon drug concentr ations. The product
information recommends the following for tacrolimus initiation [19]:

• At 0.1 mg/kg/day in kidney transplant recipients who also receive mycophenolate mofetil plus an
interleukin-2 (IL-2) receptor antagonist

• At 0.2 mg/kg/day in kidney transplant recipients treated with azathioprine rather than mycophenolate
mofetil

• At 0.1 to 0.15 mg/kg/day in adult liver transplant recipients

• At 0.075 mg/kg/day in adult heart transplant recipients

● Extended-release tacrolimus products – In patients receiving mycophenolate mofetil, steroids, and basiliximab
induction, extended-release tacrolimus capsules (Astagraf XL) should be given at a dose of 0.15 to 0.2
mg/kg/day prior to reperfusion or within 48 hours of the completion of the tr ansplant procedure. In patients
treated with mycophenolate mofetil and steroids without basiliximab induction, extended-r elease tacrolimus
capsules should be given as a single dose of 0.1mg/kg within 12 hours prior to reperfusion, then 0.2 mg/kg at
least four hours after the preoperative dose, and within 12 hours after er perfusion, then 0.2 mg/kg daily [13].

Drug monitoring — Therapeutic monitoring of cyclosporine and tacrolimus is complicated by the narrow margin
between adequate immunosuppression and toxicity. Whole blood should be used as a sample for both drugs. A
variety of assays are available, and clinicians should become familiar with the one used in their local labor
atory.

Cyclosporine should be monitored using 12-hour trough (C0), two-hour post-dose (C2), or abbreviated area under
the time concentration curve (AUC) [18]. Although monitoring of C0 is common practice, there is a poor correlation
with safety, efficacy, and drug exposure using this strategy. Some centers use C2 monitoring among kidney
transplant recipients since these concentrations may correlate more closely with exposure, and higher C2
concentrations have been associated withdecreased acute rejection rates in the first year [20-22]. In one study of
liver transplant patients, C2 was more closely associated with the first four-hour post-dose cyclosporine exposure
(AUC0-4) than C0 [23]. C2 monitoring may be more accurate but is often more difficult and less convenient for the
patient. Most centers monitor either C0 or C2 concentrations but not both. In rare circumstances, assessing both
may be beneficial in a patient with absorption issues.

Tacrolimus should be monitored using 12- and 24-hour trough (C0) concentrations for the immediate-release and
extended-release preparations, respectively [18].

Blood concentrations should be checked two to three days after starting cyclosporine or tacrolimus and after any
dose change. Typically, after transplant, concentrations are measured every one or two days while hospitalized.
After discharge, levels should be measured once or twice weekly for the first month , then weekly until three months
posttransplantation, then every two weeks until six months posttransplant, and then monthly. Some stable, low-risk
patients may have concentrations monitored every two to three months. However, if drugs that affect cyclosporine
or tacrolimus metabolism are added or withdrawn, more frequent measurement of trough concentrations will be
required (see 'Food and drug interactions' below). Tacrolimus and cyclosporine reach steady-state concentrations
after four to six doses.

Target concentrations — Target concentrations for cyclosporine and tacrolimus vary depending upon which disease
is being treated. These recommendations are presented elsewhere:

● In kidney transplant recipients (see "Maintenance immunosuppressive therapy in renal transplantation in

adults")

● In lung transplant recipients (see "Maintenance immunosuppression following lung transplantation", section on
'Calcineurin inhibitors')

● In liver transplant recipients (see "Liver transplantation in adults: Overview of immunosuppression", section on
'Calcineurin inhibitors')

● In heart transplant recipients (see "Induction and maintenance of immunosuppr

essive therapy in cardiac
transplantation", section on 'Calcineurin-inhibitors')

● In hematopoietic cell transplant recipients (see "Prevention of acute graft-versus-host disease", section on
'Calcineurin inhibitor-based therapy' and "Treatment of acute graft-versus-host disease")

● In glomerular diseases (see"Treatment of minimal change disease in adults", section on 'Calcineurin inhibit ors'
and "Treatment of idiopathic membranous nephropathy", section on 'Calcineurin inhibitors' and "Treatment of
primary focal segmental glomerulosclerosis", section on 'Calcineurin inhibitors' and "Treatment of idiopathic
nephrotic syndrome in children", section on 'Calcineurin inhibitors' and "Steroid-resistant idiopathic nephrotic
syndrome in children", section on 'Calcineurin inhibitors')

● In inflammatory bowel diseases (see"Approach to adults with steroid-refractory and steroid-dependent

ulcerative colitis", section on Adding
' a fast-acting second medication' and "Immunomodulator therapy in Crohn
disease", section on 'Cyclosporine' and "Immunomodulator therapy in Crohn disease", section on 'Tacrolimus')

● In autoimmune diseases (see"Chronic immunomodulating therapies for myasthenia gravis", section on

'Glucocorticoid-sparing agents')

Dose adjustments — In clinical practice, dose adjustments are made in small increments with subsequent drug
concentration monitoring. If a cyclosporine concentration is high, then the dose of cyclosporine may be lowered by
25 to 50 mg per dose. If the concentration is low, then the dose may be increased by 25 to 50 mg per dose. For
tacrolimus, dose adjustments are typically 0.5 to 1 mg per dose. If a drug concentration is supratherapeutic (>400
ng/mL for cyclosporine or >30ng/mL for tacrolimus), then the dose may be held until the concentration returns to
the therapeutic range. It is important to determine whether the concentration was obtained correctly before making
any dose adjustments. Tacrolimus and cyclosporine reach steady-state concentrations after four to six doses, and
therefore, dose adjustments can be assessed via drug concentr ation monitoring two to three days after an
adjustment. In addition, safety and efficacy should be monitored after adjustments.

Optimal dosing and concentrations may be affected by several factors including pharmacokinetic factors, presence
of infection, drug toxicity, and/or rejection (table 2) (see "Maintenance immunosuppressive therapy in renal
transplantation in adults"and "Treatment of acute T cell-mediated (cellular) ejection
r of the renal allograft"). Testing
for polymorphisms of the multidrug esistance-1
r (P-glycoprotein) and CYP3A5 genes may aid in the dosing of
calcineurin inhibitors [24-29], but large, well-designed trials are needed to determine if testing improves outcomes
and is cost effective.

Switching formulations — When switching formulations of products, drug concentrations should be closely

monitored for several weeks. The frequency of monitoring should depend upon several factors (table 2), as well as
how far the patient is from transplant. In a stable patient who is more than six months posttransplant, we monitor
drug concentrations weekly for two to three weeks. The dose should subsequently be adjustedot attain the
preconversion blood concentration. In addition, safety and efficacy should be monitored after conversion.

● Cyclosporine

• Oral to intravenous administration – For patients unable to take oral cyclosporine, the intravenous dose
should be equal to one-third of the oral dose. Intravenous administration should occur over at least two to
six hours twice daily in a well-hydrated patient to avoid nephrotoxicity.

• Nonmodified to modified formulation – Ingeneral, modified formulations ofcyclosporine lead to higher

area under the time concentration curve (AUC) than nonmodified preparations. Thus, patients stabilized on
either form should generally not be switched from one to the other. If patients are switched, a 1:1 ratio is
recommended when converting from the nonmodified to the modified formulation.

• Cyclosporine to tacrolimus – Clinicians use a 40:1 ratio when converting from cyclosporine to tacrolimus.
As an example, if a patient takes 125 mg of modified cyclosporine twice daily (250mg/day), then a
tacrolimus dose of 3 mg twice daily (6mg/day) would be appropriate.

● Tacrolimus

• Oral to intravenous administration – For patients unable to take oral tacrolimus, the intravenous dose
should be equal to one-third to one-fifth of the oral daily dose and should be given as a continuous 24-hour
infusion.

• Immediate-release to extended-release capsules – A 1:1 conversion from immediate-release tacrolimus to

extended-release tacrolimus capsules (Astagraf XL) has been proven equivalent. The ratio of exposure
(AUC0-24) of extended-release tacrolimus capsules to immediate-release tacrolimus twice daily is
approximately 90 percent across various conversion studies in kidney, liver, and heart transplant recipients;
however, in liver transplant patients, the extended-release tacrolimus capsule AUC was significantly lower
in the early posttransplant period compared with that of tacrolimus twice daily [28,30-35].

• Immediate-release to extended-release tablets – Eighty percent of the total daily dose of immediate-
release tacrolimus should be used when converting to extended-release tablets (Envarsus XR) [36].

• Oral immediate-release to sublingual immediate-release tacrolimus – To convert from oral tacrolimus to

sublingual tacrolimus, the oral tacrolimus dose should be decreased by 50 percent [14,37].

PHARMACOKINETICS

Absorption — Oral cyclosporine and tacrolimus are only partially absorbed with large inter- and intra-individual
variability. Cyclosporine and tacrolimus are absorbed in the small intestine, and plasma peak concentr ations occur
after one to eight hours. The oral bioavailability is limited for both drugs (roughly 20 percent for tacrolimus) as a
result of poor absorption, partial metabolism by enzymes in the bowel mucosa, and first-pass hepatic metabolism
[38,39]. In general, modified formulations of cyclosporine lead to higher area under the time concentration curve
(AUC) than the nonmodified preparations.
In healthy volunteers, the oral bioavailability of extended-release tacrolimus tablets was approximately 50 percent
higher as compared with tacrolimus immediate-release at steady state 3 [ 6]. Both extended-release tacrolimus
products exhibit chronopharmacokinetic effects; evening administration, compared with morning dosing, results in
a 15 percent lower AUC for extended-release tacrolimus tablets and a 35 percent lower AUC for extended-release
tacrolimus capsules [13,36]. Thus, both products should be taken consistently every morning.

Pharmacokinetic trials comparing extended-r elease tacrolimus formulations with immediate-release tacrolimus
have demonstrated a decreased maximum concentration (Cmax) and delayed time to maximum concentration with
extended-release formulations. However, extended-release tacrolimus tablets have an AUC0-24 (area under the time
concentration curve from 0 to 24 hours) that is comparable to that of immediate-release tacrolimus; extended-
release tacrolimus capsules have an AUC0-24 that is higher than that of immediate -release tacrolimus [13,36].

The absorption and metabolism of calcineurin inhibit ors may vary with race and ethnicity. As an example, the mean
tacrolimus exposure after a single 5 mg oral dose in healthy Hispanic and African-A merican subjects was 18 and 39
percent less, respectively, than in Caucasians [40]. Similar results have been seen with theextended-release
products [13,36]. Such variation may be related to differences in the frequency of polymorphisms in theCYP3A5
gene among African-American, Hispanic, and Caucasian transplant recipients [41-43].

The absorption ofcyclosporine, but not tacrolimus, is dependent upon bile salts. Thus, cyclosporine modified or
tacrolimus may be preferable in patients with biliary diversion or cholestasis. Cyclosporine modified absorption is
decreased modestly when ingested with afatty meal (table 3). Similarly, tacrolimus absorption is decreased if
administered after a fatty meal and shouldbe taken on an empty stomach, if possible [44].

Patients receiving long-termcyclosporine ophthalmic emulsion of 0.05 percent had no detectable blood
cyclosporine concentrations, indicating nosignificant systemic absorption 45].
[

Topical tacrolimus is minimally absorbed in patients with normal skin, but clinically significant absorption has been
reported when used in patients with skin disease [46].

Distribution — Cyclosporine and tacrolimus are lipophilic and undergo extensive body distribution. In the blood,
most of the absorbed amount of each drug is tak en up by erythrocytes. In the plasma, cyclosporine binds mainly to
lipoproteins, whereas tacrolimus binds to proteins, primarily albumin and alpha-1-acid gly
coprotein. The plasma
protein binding of tacrolimus is approximately 99 percent and is independent of concentration over a range of 5 to
50 ng/mL.

The highest tissuecyclosporine concentration is achieved in the thymus, spleen, lymph nodes, bone marrow, liver,
pancreas, kidney, adrenal glands, lung, andskin. Tacrolimus accumulates mainly in the lung, spleen, hear
t, kidney,
and pancreas.

Cyclosporine penetrates well into synovial fluid but does not cross the blood-brain barrier. Both drugs cross the
placenta and appear to some extent in breast milk, but actual toxicity in breastfed infants appears to be rare [47].
Some centers measure cyclosporine and/or tacrolimus blood concentrations in breastfed infants to confirm that
these are low.

Metabolism — Cyclosporine and tacrolimus are extensively metabolized by cytochrome P-450 CYP3A enzymes in
the liver. There is also some metabolism ni the gut mucosa. The most active cyclosporine metabolites have only 10
to 20 percent of the drug's immunosuppressive activity. By comparison, one of the metabolites of tacr
olimus
possesses equal immunosuppressive potency to the parent drug.

Elimination — Cyclosporine and tacrolimus are excreted in the bile. The elimination half-life can vary significantly
among patients, especially with cyclosporine nonmodified, but is approximately 19 hours for cyclosporine modified
and 12 hours for immediate-release tacrolimus. The elimination half-life of extended-release tacrolimus tablets after
oral administration of 2 mg once daily for 10 days was 31±8 hours in healthy subjects [36]. The elimination half-life
of extended-release tacrolimus capsules after oral administration of 4 mg capsules daily for 10 days was 38±3
hours in healthy subjects 1
[ 3]. Cyclosporine metabolism is age dependent, with a 1.5-ot 2.5-fold increase in half-life
in adults compared with children. Liver dysfunction prolongs the half-life of both cyclosporine and tacrolimus
[48,49].

Food and drug interactions

● Food interactions – The presence, composition, and timingof food may affect the absorption of many of the
immunosuppressive drugs (table 3). Because the avoidance of food at the time of medication administration is
not always practical, many clinicians recommend that patients be consistent and alwa
ys take their medication
in the same manner, whether it is with or without food.

A group of active chemical compounds ingrapefruit, known as the furanocoumarins, are potent inhibitors of
cytochrome P-450 3A4 enzyme. Grapefruit or grapefruit juice can result in an increase in systemic exposure to
cyclosporine or tacrolimus. It is important to educate patients aboutthe interaction between
grapefruit/grapefruit juice and their immunosuppressive agents. Patients should be counseled o t completely
avoid grapefruit and grapefruit juice when being treated with cyclosporine or tacrolimus. In patients who refuse
to avoid grapefruit and grapefruit juice, more frequent monitoring of blood cyclosporine or tacrolimus
concentrations is required.

● Drug interactions – There are multiple interactions between calcineurin inhibitors and commonly used
medications. General principles of these drug interactions are reviewed here. More detailed discussions of drug
interactions are found elsewhere.

• Since cyclosporine and tacrolimus are substrates for cytochrome P-450 3A4/5 (CYP3A4/5) enzymes, any
drug that is metabolized by these enzymes or that affects metabolism by these enzymes can potentially
interact with calcineurin inhibitors. These interactions are discussed in detail separately on the drug
information topics for cyclosporine and tacrolimus (table 4 and table 5 and table 6). (See "Maintenance
immunosuppressive therapy in renal transplantation in adults".)

If a patient cannot avoid a strong inhibitor/inducer of CYP3A4/5, then drug concentrations and toxicities
must be closely monitored. Limited data are available regarding precise dose adjustments when inhibitors
of CYP3A4/5 are coadministered with cyclosporine and tacrolimus.

• Clinicians may take advantage of cytochrome drug interaction to lower the dose of the calcineurin inhibitor
or enhance the drug concentration. The effects of diltiazem and ketoconazole on cyclosporine metabolism
have led to their use in transplant recipients as a method of lowering the ot tal cyclosporine dose and,
therefore, the cost of cyclosporine therapy. (See "Maintenance immunosuppressive therapy in renal
transplantation in adults".)

• Drugs that affect gastrointestinal motility or emptying (eg, prokinetic agents) may adversely affect
absorption of calcineurin inhibitors. Laxatives, for example, can reduce oral cyclosporine and tacrolimus
absorption by accelerating their passage through the intestine. By contrast, narcotics may prolong transit
time in the intestine, increasing the time for absorption.

• Concomitant administration of cyclosporine or tacrolimus with other potentially nephrotoxic drugs (eg,
nonsteroidal anti-inflammatory drugs) should be avoided because increased toxicity may result. Since
calcineurin inhibitors may produce or worsen hyperkalemia, serum potassium le vels should be monitored
closely in patients concomitantly taking drugs that ma
y increase potassium (eg,amiloride, triamterene,
and spironolactone). (See "Cyclosporine and tacrolimus nephrotoxicity".)
 • Divalent cations may influence the absorption oftacrolimus. In a single-dose, crossover study in healthy
volunteers, coadministration of tacrolimus and magnesium/aluminumhydroxide resulted in a 21 percent
increase in the mean tacrolimus area under the curve (AUC) and a 10 percent decrease in the mean
tacrolimus Cmax relative to tacrolimus administration alone [19]. However, in another study, patients did
not require tacrolimus dose adjustment when magnesium/aluminumwas prescribed with tacrolimus
therapy [50]. To minimize these potential interactions, magnesium- and aluminum-containing pr oducts
should not be administered within two hours of tacrolimus products, and tacrolimus drug concentrations
should be closely monitored.

• Cyclosporine is substrate and inhibitor of P-glycoprotein [51,52]. In vitro data suggest thattacrolimus is
neither a substrate nor an inhibitor of P-glycoprotein [53]. Cyclosporine can enhance the efficacy of some
chemotherapy agents by inhibiting P-glycoprotein and reducing the efflux of drug out of the tumor cell.
Additionally, carvedilol inhibits P-glycoprotein and may increase the blood concentrations of cyclosporine
[54].

SIDE EFFECTS — The side effects of cyclosporine and tacrolimus are generally similar. When used for the treatment
of autoimmune disorders, the frequency and severity of side effects are lower compared with those seen in
transplant recipients. This observation is explained by the lower doses used and the option ot decrease the dose or
discontinue the medication when oxicity
t appears in patients with autoimmune disorders; these options may not be
available in transplant recipients.

Nephrotoxicity — Nephrotoxicity is a significant adverse effect of both drugs.Cyclosporine and tacrolimus

nephrotoxicity is manifested as an acute increase in plasma creatinine, which is largely reversible after reducing the
dose, or as chronic occasionally progressive renal disease, which is usually irreversible. Other renal effects of
cyclosporine include tubular dysfunction and,arely,
r a thrombotic microangiopathy (TMA). (See "Cyclosporine and
tacrolimus nephrotoxicity".)

Hypertension — Hypertension, caused by renal vasoconstriction and sodium er tention, generally develops within the
first few weeks of therapy. Stimulation of the renal sodium chloride cotransporter is a potential mechanism by
which calcineurin inhibitors may mediate this effect [55]. The blood pressure elevation usually responds to dose
reduction, but antihypertensive medications may be required. (See "Cyclosporine and tacrolimus nephrotoxicity" and
"Hypertension after renal transplantation", section on 'Patient is taking a calcineurin inhibitor'.)

Calcium channel blockers are usually considered the drugs of choice if antihypertensive therapy is needed in the
setting of cyclosporine therapy. As noted above, diltiazem also impairs cyclosporine metabolism, thereby allowing a
lower dose to be given. Initiation of diltiazem should prompt immediate reduction in the dose of cyclosporine or
tacrolimus and careful monitoring of blood concentrations. Diltiazem also reverses the acute vasoconstriction
induced by cyclosporine; there is, however, no convincing evidence that this prevents chronic cyclosporine
nephrotoxicity. (See "Cyclosporine and tacrolimus nephrotoxicity", section on 'Prevention of chronic calcineurin
inhibitor nephrotoxicity'.)

Neurotoxicity — Neurotoxicity associated withcyclosporine and tacrolimus may manifest as follows [56-61]:

● Mild tremor is common with bothcyclosporine and tacrolimus use, occurring in 35 to 55 percent of patients
[58,59]. It may improve despite continued therapy.

● Rarely, patients develop severe headache, visual abnormalities, and seizures. This syndrome is associated with
acute hypertension and resembles hypertensive encephalopathy [56]. Posterior leukoencephalopathy is usually
seen on brain imaging [61]. (See "Reversible posterior leukoencephalopathy syndr ome".)

● Akinetic mutism, encephalopathy,seizures, focal neurologic abnormalities, and even coma have been reported
with intravenous tacrolimus [57].
 ● A calcineurin-inhibitor pain syndrome has been reported with both cyclosporine and tacrolimus [62]. This
syndrome is characterized by symmetrical pain in the lower limbs, usually inv
olving the bones of the feet,
ankles, and knees. Magnetic er sonance imaging (MRI) may show marrow edema. Symptoms usually improve
with cessation of the drugand/or use of calcium channel blockers.

The neurologic side effects are usually reversible following a change from intravenous to an oral preparation,
lowering of the drug dose, or drug discontinuation56,57,60].
[ They are generally more common with tacrolimus than
with cyclosporine [58,59].

Metabolic abnormalities — Cyclosporine and tacrolimus have been associated with the following metabolic
abnormalities:

● Glucose intolerance and diabetes mellitus (see"New-onset diabetes after transplant (NODAT) in renal
transplant recipients")

● Hyperlipidemia (see"Lipid abnormalities after cardiac transplantation" and "Lipid abnormalities after renal
transplantation")

● Hyperuricemia and gout (see"Hyperuricemia and gout in e

r nal transplant recipients")

● Hyperkalemia (see"Cyclosporine and tacrolimus nephrotoxicity", section on 'Hyperkalemia')

● Hypomagnesemia (see"Cyclosporine and tacrolimus nephrotoxicity", section on 'Hypomagnesemia')

Cyclosporine may also contribute to bone loss after organ transplantation [63]; this effect may be due to the
induction of high bone turnover. (See "Drugs that affect bone metabolism" and "Bone disease after renal
transplantation", section on 'Pathogenesis and risk factors'.)

Infections — Bacterial, viral (most often, cytomegalovirus [CMV]), and fungal infections often develop in transplant
recipients receiving combined immunosuppressive therapy. In a large trial of liver transplant recipients comparing
the efficacy and safety of cyclosporine- and tacrolimus-based immunosuppressive regimens, infection, sepsis, and
CMV disease occurred in approximately 40, 20, and 15 to 25 percent of patients, respectively [58].

Infection in the solid organ transplant recipient is discussed in more detail elsewhere. (See "Infection in the solid
organ transplant recipient".)

Risk of malignancy — Both cyclosporine and tacrolimus are associated with an increased risk of squamous cell skin
cancer and benign or malignant lymphopr oliferative disorders. Spontaneous regression of lymphoma may occur if
the drug is discontinued early. (See "Development of malignancy following solid or gan transplantation".)

The overall level of immunosuppression appears to be the principal factor that increases the risk of posttransplant
malignancy. However, evidence from animal models suggests thatcyclosporine itself may promote cancer
progression, principally via the production of transforming growth factor (TGF)-beta. In vitro, cyclosporine treatment
of a normally noninvasive adenocarcinoma cell line induced an invasive phenotype; in addition, cyclosporine
promoted tumor growth in immunodeficient animals 64]. [ Both the in vitro and in vivo changes were prevented by
the administration of anti-TGF-beta antibodies.

Pregnancy and lactation — The effects of cyclosporine on pregnancy and lactation are discussed in more detail
elsewhere. (See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy
and lactation", section on 'Cyclosporine' and "Safety of antiinflammatory and immunosuppressive drugs in
rheumatic diseases during pregnancy and lactation", section on 'Tacrolimus' and "Pregnancy in women with
underlying renal disease", section on 'Pregnancy in the renal transplant recipient'.)
Other side effects — Other side effects associated with the useof cyclosporine and tacrolimus include the
following:

● Gastrointestinal – Gastrointestinal side effects include anorexia, nausea, vomiting, diarrhea, and abdominal
discomfort. These symptoms are more frequent with tacrolimus (72 versus 47 percent for cyclosporine in one
report) [59]. Elevated serum aminotransferase levels with mild hyperbilirubinemia may also occur; if present,
this abnormality is reversible with dose reduction or discontinuation of the drug65].
[

● Cosmetic – Gingival hyperplasia and hirsutism occur withcyclosporine therapy [66,67] but not with tacrolimus.
Poor dental hygiene, higher doses of cyclosporine, and concomitant use ofnifedipine appear to be the principal
risks [68]. Case reports suggest that the gingival hyperplasia can be effectively treated with a two-week course
of metronidazole (750 mg three times daily) while cyclosporine is continued [69,70]. It is not clear whether
metronidazole acts in this setting via its antibacterial activity or via another mechanism.reatment
T with
azithromycin (500 mg/day for three consecutive days) may also be effective, particularly among those with
mild or early disease 7[ 1]. In the transplant setting, the substitutionof cyclosporine with tacrolimus was found
to significantly ameliorate gingival hyperplasia without increasing the risk of renal allograft dysfunction or
rejection [72].

An uncommon but increasingly recognized complication of immunosuppressive therapy in transplant recipients

is alopecia, a finding attributed, in one study
, to the use of tacrolimus [73]. At one transplant center, alopecia
was noted in 3 to 6 percent of recipients receiving this agent [74]. Higher doses were associated with an
increased risk. Another study reported an incidence of 30 percent among kidney-pancreas recipients who
received tacrolimus [75].

CONTRAINDICATIONS — Hypersensitivity to cyclosporine, tacrolimus, or polyoxyl castor oil products (used as

solvents for injection preparation of both drugs) is a contraindication to their use. The following conditions are
generally accepted contraindications to the use of cyclosporine or tacrolimus:

● Concurrent malignancy (except for nonmelanoma skin carcinoma)

● Uncontrolled hypertension

● Uncontrolled infections

● Hypersensitivity

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four orfive key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the
Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the
10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with
some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these
topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on
"patient info" and the keyword(s) of interest.)

● Beyond the Basics topics (see "Patient education: Disease-modifying antirheumatic drugs (DMARDs) (Beyond
the Basics)" and "Patient education: Heart transplantation (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Cyclosporine and tacrolimus are immunosuppressive agents occasionally used in the treatment of various
immune-mediated diseases and more commonly used to prevent rejection in solid organ transplantation; the
drugs are available in oral, intravenous, ophthalmic, and topical formulations (table 1).

● Cyclosporine and tacrolimus reduce T cell activation through the inhibition of calcineurin after forming
complexes in the cytoplasm with cyclophilins and FK-binding proteins, respectively. Calcineurin inhibition
results in reduced transcription of early cytokine genes, including those for interleukin (IL)-2, tumor necr
osis
factor (TNF), and several others. (See 'Mechanism of action' above.)

● Oral cyclosporine and tacrolimus are only partially absorbed, with large inter- and intra-individual variability that
also varies with ethnicity. The oral bioavailability is limited for both drugs due ot poor absorption, partial
metabolism by enzymes in the bowel mucosa, and first-pass hepatic metabolism. The drugs ar e lipophilic and
undergo extensive body distribution. Cyclosporine does not cross the blood-brain barrier. (See
'Pharmacokinetics'above and 'Absorption' above and 'Distribution' above.)

● Cyclosporine and tacrolimus are metabolized by hepatic cytochrome P-450 3A enzymes in the liver and are
excreted into the bile. Liver dysfunction prolongs the half-life of both agents. A variety of important drug
interactions with drugs that either affect or are metabolized by these enzymes can occur t(able 4 and table 5
and table 6). Details about specific interactions are available by using the Lexi-Interact program included with
UpToDate. (See 'Metabolism' above and 'Elimination' above and 'Food and drug interactions' above.)

● The side effects of cyclosporine and tacrolimus are similar. Nephrotoxicity is the most common and clinically
significant adverse effect of both drugs, and hypertension, caused by renal vasoconstriction and sodium
retention, generally develops within the first few weeks of therapy. Other potential adverse effects include
neurotoxicity, metabolic abnormalities, infections, and an increased risk of malignancy. Contraindications to
use depend upon the presence of various comorbidities or hypersensitivity ot the agents. (See'Side effects'
above and "Cyclosporine and tacrolimus nephrotoxicity" and 'Contraindications' above.)

● The dose, route, formulation, and drug concentrations of calcineurin inhibitors depend upon several factors
(see 'Dose' above and 'Administration' above). Routine blood monitoring is recommended (see'Drug monitoring'
above). Many factors should be considered when making dose adjustments ot calcineurin inhibitors. (See
'Dose adjustments'above.)

Use of UpToDate is subject to the Subscription and License Agreement.

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40. Mancinelli LM, Frassetto L, Floren LC, et al. The pharmacokinetics and metabolic disposition of tacr
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42. García-Roca P, Medeiros M, Reyes H, et al. CYP3A5 polymorphism in Mexican enal
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43. Jacobson PA, Oetting WS, Brearley AM, et al. Novel polymorphisms associated withtacrolimus trough
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46. Olson KA, West K, McCarthy PL. Toxic tacrolimus levels after application of topical tacrolimus and use of
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49. Jusko WJ, Piekoszewski W, Klintmalm GB, et al. Pharmacokinetics of tacr
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Topic 7995 Version 20.0

GRAPHICS

Cyclosporine and tacrolimus preparations

Cyclosporine non-modified
Oral

Capsules: Liquid filled  – 25 mg, 50 mg, 100 mg (Sandimmune and generics)

Solution: 100 mg/mL in 50 mL bottles

Topical

Ophthalmic emulsion: 0.05% in 0.4 mL vials (Restasis)

Parenteral

Concentrate for injection: F or IV infusion 50 mg/mL i n 5 mL ampules

Cyclosporine modified (microemulsion)

Oral

Capsules: 25 mg, 100 mg (Neor al and generics)

Solution: 100 mg/mL in 50 mL bottles

Tacrolimus
Oral

Immediate-release capsules: 0.5 mg, 1 mg, 5 mg (Pr ograf)

Extended-release capsules: 0.5 mg, 1 mg, 5 mg (Astagr af XL)

Extended-release tablet: 0.75 mg, 1 mg, 4 mg (Env arsus XR)

Topical

Ointment: 0.03 and 0.1% in 30 g, 60 g, 100 g tubes (Pr otopic)

Parenteral

Concentrate for injection: F or IV infusion 5 mg/mL in 1 mL ampules

Formulation descriptions ar e for pr oducts a vailable in the United States, Canada, and some other countries. Consult local pr oduct
information befor e use.

Lexicomp Online. Cop yright © 1978-2018 Lexicomp, Inc. All Rights Reser ved.

Graphic 57518 V ersion 6.0

Factors influencing pharmacokinetics of calcineurin inhibit
ors

Absorption
Interacting medications (eg, cholestyr amine)

Motility agents

Diarrhea or constipation

Presence or absence of food

Brand versus generic, formulation

Distribution
Hematocrit

Metabolism
Interacting prescription medications

Interacting over-the-counter medications

Interacting herbal supplements

Interacting beverages (eg, grapefruit juice)

Genetic polymorphism in CYP3A5

Hepatic impairment

Other
Timing of concentr ation

Type of laboratory immunoassa y

Schedule and fr equency

Adherence

Courtesy of Karen Hardinger, PharmD, BCPS.

Graphic 106494 V ersion 1.0

Pharmacokinetics of orally administered immunosuppressive drugs in adults

Half-life in
Drug (US brand Oral Effect of food on Metabolism and Enzyme/transporter
hours
name) bioavailability absorption clearance* inhibition*
(range)

Antimetabolites

Mycophenolate 80.7% (renal High-fat meal: Rapidly hydrolyzed to None known 17.9 (11.4 to
mofetil (MMF, transplant ↓ Cmax by 40%; its active metabolite 24.4) ¶ (MPA)
CellCept) patients) AUC is unchanged mycophenolic acid MPAG can
94% (healthy Should be tak en on (MPA), which is accumulate in
volunteers) an empty stomach further metaboliz ed renal failure
or at a consistent by UGT to the
time each da y in inactive metabolite
relation to meals mycophenolic acid
to improve GI glucuronide (MPAG),
tolerability which is excreted
Giving total daily primarily via urine;
dose in three or MPA undergoes
four equally enterohepatic
divided doses ma y recirculation, and
improve GI secondary increases
tolerability in MPA levels are
seen 6 to 12 hours
after a dose of MMF

Mycophenolate 72% (renal High-fat meal: Rapidly hydrolyzed to None known 12 (8 to 16)
sodium, enteric transplant ↓ Cmax by 33%; the active metabolite (MPA)
coated patients) AUC is unchanged mycophenolic acid MPAG can
(Myfortic) Δ Should be tak en on (MPA), which is accumulate in
an empty stomach further metaboliz ed renal failure
by UGT to the
inactive metabolite
mycophenolic acid
glucuronide (MPAG),
which is excreted
primarily via urine;
MPA undergoes
enterohepatic
recirculation, and
secondary increases
in MPA levels are
seen 6 to 8 hours
after a dose of
mycophenolate
sodium

Calcineurin inhibit ors

Cyclosporine Generally poor High-fat meal: Metabolized by Inhibitor of P-gp 19 (10 to 27)
non-modified and ↑ (highly variable) CYP3A4 to reduced
Prolonged in
(Sandimmune) unpredictable: Should be tak en at activity and inactiv e
hepatic
10 to 89% a consistent time metabolites (eg, M1,
impairment
(renal each day in M9, M4N) clear ed
transplant relation to meals fecally via bile
patients) Substrate of P-gp
<10% (liver
transplant
patients)

Cyclosporine 23 to 50% better 8.4 (5 to 18)

 Cyclosporine 23 to 50% better 8.4 (5 to 18)
modified absorbed than High-fat meal: Prolonged in
(microemulsion) non-modified ↓ Cmax by 33% hepatic
(Neoral) formulation in ↓
and AUC by 13% impairment
renal and liver Should be tak en at
transplant a consistent time
patients, each day in
respectively relation to meals

Tacrolimus 7 to 32% High-fat meal: Metabolized by May be an inhibit or of P- 12 (2 to 36)

immediate- ↓ Cmax by 77% CYP3A4/5 to active gp; suppor tive data are Prolonged in
release capsule ↓
and AUC by 37% (eg, 13-O-demethyl) limited to in-vitro effects severe hepatic
(Prograf) High-carbohy drate and inactive (ie, clinical eff ect is impairment
↓
meal: Cmax by metabolites clear ed unknown)
↓
65% and AUC by fecally via bile
28% Substrate of P-gp
Should be tak en on
an empty stomach

Tacrolimus 12 to 19% High-fat meal: 38 (35 to 41)

extended- ↓ Cmax by 77% Prolonged in
release capsule ↓
and AUC by 25% severe hepatic
(Astagraf XL) Should be tak en impairment
preferably on an
empty stomach at
least 1 hour befor e
a meal or at least 2
hours after a meal

Tacrolimus 50% better High-fat meal: 31 (23 to 39)

extended- absorbed than ↓ Cmax by 22% Prolonged in
release tablet immediate- ↓
and AUC by 55% severe hepatic
(Envarsus XR) release capsule Evening impairment
administration:
↓ AUC by 15%
Should be tak en on
an empty stomach

mTOR inhibitors

Everolimus 30% High-fat meal: Metabolized by None known 30 (19 to 41)

(Zortress) ↓ Cmax by 60%; CYP3A4 to six Prolonged in
↓ AUC by 16% weakly active hepatic
Should be tak en at metabolites that ar e impairment
a consistent time excreted primarily via
each day in feces
relation to meals Substrate of P-gp

Sirolimus 18% (tablet) High-fat meal: Metabolized by None known 62 (46 to 78)
(Rapamune) 14% (oral ↑ AUC by 23 to CYP3A4 to seven Prolonged in
solution) 35% metabolites (some hepatic
Should be tak en at have weak activity) impairment
a consistent time that are excreted
each day in primarily via f eces
relation to meals Substrate of P-gp

Careful ther apeutic drug monit oring (TDM) of sys temic calcineurin inhibit ors and mT OR inhibit ors is essential due t o the narr ow
margin between adequate immunosuppr ession and t oxicity. Blood concentr ation monit oring is necessar y for any change in
formulation (including switch between generics or br ands) and between methods of administr ation (eg, or al, sublingual,
intravenous) t o determine the need for dose alter ation. Ref er to accompanying text.
MMF: mycophenolate mof etil; Cmax: maximum concentr ation; AUC: area under the 24-hour serum concen tration x time plot; GI:
gastrointestinal; MPA: mycophenolic acid (activ e form of mycophenolate); UGT: uridine diphosphate (UDP) glucur onosyltransferase; MPAG:
mycophenolic acid glucur onide (inactiv e metabolite of my cophenolic acid); CYP3A4: cyt ochrome P450 3A4; P-gp: P-gly coprotein efflux
membrane transporters (multi-drug efflux pump); mT OR inhibitors: mammalian (mechanistic) tar get of rapamycin inhibitors.
* Data provided on drug metabolism ar e included to assess the potential for drug inter actions. Only str ong or moder ate effects are listed.
Specific drug inter actions may be determined b y use of Lexi-Interact, the drug inter actions tool included with UpToDate.
¶ Standard deviation 6.5 hours per US manufactur er.
Δ To convert from mycophenolate mof etil (MMF, CellCept) 1000 mg e very 12 hours, switch t o mycophenolate sodium enteric coated
(Myfortic) 720 mg e very 12 hours.

Prepared with data fr om Lexicomp Online. Cop yright © 1978-2018 Lexicomp, Inc. All Rights Reser ved with additional data fr om US prescribing
information a vailable at https://www.accessdata.f da.gov/scripts/cder/drugsatf da/index.cfm .

Graphic 109680 V ersion 4.0

Examples of common drug interactions of immunosuppressants used in solid-organ transplant:
Cyclosporine, tacrolimus, sirolimus, and everolimus

Common types of Approach to management in the absence

Examples of interacting drugs
drug interactions of appropriate noninteracting alternatives

Coadministration of Amiodarone Closely monit or immunosuppr essant

drugs that inhibit CYP3A ART-boosting agents (eg, rit onavir, cobicistat) concentrations and signs of t oxicity (eg, tremors
metabolism and/or P-gp Azole antifungals (eg, fluconaz ole, and headaches).
efflux can increase posaconazole, voriconazole) Substantial, including pr eemptive, dose
immunosuppr essant reduction of immunosuppr essant drug ma y be
HIV protease inhibit ors (eg, atazana vir, nelfinavir,
serum concentr ations, needed (eg, on a verage, only 25% of the standar d
saquinavir)
leading to significant dose of cyclosporine is r equired if administer ed
Macrolide antibiotics (ex cept azithromycin)
toxicities. concomitantly with HIV pr otease inhibit ors).
Non-dihydropyridine calcium channel block ers
Some combinations ar e considered
Ombitasvir-paritapr evir-ritonavir with or without
contraindicated accor ding to product labeling;
dasabuvir (an HCV, direct-acting antivir al
refer to appropriate topic reviews for detail.
regimen)
Lists of CYP3A and P-gp inhibitors are provided
Grapefruit juice
as separate tables within UpToDate.

Coadministration of Antiseizure drugs, enzyme inducing (eg, Closely monit or immunosuppr essant serum
drugs that induce CYP3A carbamazepine, fosphenyt oin, oxcarbazepine, concentrations and signs of or gan rejection.
metabolism and/or P-gp phenobarbital, phenyt oin, primidone) Significant immunosuppr essant dose incr eases
efflux pumping can Enzalutamide may be needed.
decrease Nafcillin Avoid concomitant tr eatment with e verolimus if
immunosuppr essant possible.
Rifamycins (eg, rifabutin, rifampin, rifapentine)
serum concentr ations,
St. John's wort Enzyme induction can r equire up to two weeks t o
increasing the risk of
achieve maximum eff ect and persists for up t o
organ rejection.
two weeks after discontinuation of the
interacting medication. Clinically significant
effects can occur within hours t o days of
starting a CYP inducer.
Lists of CYP3A and P-gp inducers are provided
as separate tables within UpToDate.

Coadministration of Aminoglycosides Concomitant administr ation of cyclosporine and

nephrotoxic drugs with Amphotericin B tacrolimus with other potentially nephr otoxic
cyclosporine or Colchicine drugs should be a voided.
tacrolimus can cause Suggested dose adjustments for use with
Nonsteroidal antiinflammat ory drugs (NSAIDs)
additive or synergistic colchicine ar e available in the Lexicomp
kidney injury. monograph included within UpT oDate.

Coadministration of ACE inhibitors/ARBs Closely monit or serum potassium le vels.

drugs that incr ease Amiloride
serum potassium with Spironolactone
cyclosporine or
Triamterene
tacrolimus may cause
Trimethoprim, trimethoprim-sulfametho xazole
severe hyperkalemia .
(cotrimoxazole)

Coadministration of Cyclosporine Separate administration of sirolimus from

cyclosporine cyclosporine b y four hours; giv e sirolimus at a
with sirolimus can consistent time with r espect to cyclosporine.
increase sirolimus Closely monit or immunosuppr essant serum
concentrations. concentrations.

Coadministration of Atorvastatin Pravastatin and fluv astatin are preferred due to

statin drugs with Lovastatin decreased interactions.
cyclosporine can Tacrolimus may be preferred over cyclosporine
Pitavastatin
in patients receiving statin ther apy.
 increase statin le vels Rosuvastatin Cyclosporine and simv astatin should not be
and risk of my otoxicity. Simvastatin used together.
Some combinations ar e considered
contraindicated or statin daily dose limits
are recommended in the pr oduct labeling; r efer
to the Lexicomp monogr aphs included within
UpToDate for detailed information.

Impor tant no te: The inter actions listed in this table illustr ate some of the common types of inter actions with
immunosuppr essive drugs; this is not a complete list, and many other significant drug inter actions can occur .
Cyclosporine, tacr olimus, sir olimus, and e verolimus ar e highly dependent upon CYP3A metabolism for clear ance and ar e also
substr ates of P-gp drug efflux pump. Some inter actions can lead t o subther apeutic or danger ously toxic levels of
immunosuppr essant concentr ations.
When appr opriate noninter acting alternativ es are readily a vailable, consider modifying tr eatment to avoid combined use with
potent metabolic inhibit ors/inducers or agents k nown t o have additiv e toxicities with immunosuppr essants.
Drug ther apy should be managed b y transplant specialists with exper tise in ther apeutic drug mon itoring, and doses should be
adjusted based upon measur ement of immunosuppr essant concentr ations, par ticularly whene ver drug ther apy is alter ed. If
there are any concerns about the saf ety of a giv en medication or supplement, the y should be discussed with the patient' s
transplant center prior t o initiation.

CYP: cytochrome P450 metabolism; P-gp: P-gly coprotein drug efflux pump; AR T: HIV antiretroviral therapy; HIV: human immunodeficiency
virus; HCV: hepatitis C virus; A CE: angiotensin-conv erting enzyme; ARB: angiotensin II r eceptor blocker.

Prepared with data fr om Lexicomp Online. Cop yright © 1978-2018 Lexicomp, Inc. All Rights Reser ved.

Graphic 110436 V ersion 7.0

Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers*

Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Atazanavir Amiodarone ¶ Carbamazepine Bexarotene

Boceprevir Aprepitant Enzalutamide Bosentan

Ceritinib Cimetidine ¶ Fosphenytoin Dabrafenib

Clarithromycin Conivaptan Lumacaftor  Dexamethasone ¶

Cobicistat and cobicistat Crizotinib Mitotane Efavirenz

containing coformulations
Cyclosporine ¶ Phenobarbital Eslicarbazepine
Darunavir
Diltiazem Phenytoin Etravirine
Idelalisib
Dronedarone Primidone Modafinil
Indinavir
Erythromycin Rifampin (rifampicin) Nafcillin
Itraconazole
Fluconazole Rifabutin ¶
Ketoconazole
Fosamprenavir Rifapentine
Lopinavir
Fosaprepitant ¶ St. John's wort
Mifepristone
Grapefruit juice
Nefazodone
Imatinib
Nelfinavir
Isavuconazole
Ombitasvir-paritapr evir- (isavuconazonium sulfate)
ritonavir
Netupitant
Ombitasvir-paritapr evir-
Nilotinib
ritonavir plus dasabuvir
Ribociclib
Posaconazole
Schisandra
Ritonavir and ritonavir
containing coformulations Verapamil

Saquinavir

Telaprevir

Telithromycin

Voriconazole

Data ar e for systemic drug forms. Degr ee of inhibition or induction ma y be alter ed by dose, method, and timing of administr ation.
Specific drug inter actions and management suggestions ma y be determined b y using Lexi-Inter act, the drug inter actions pr ogram
included with UpT oDate. Ref er to UpToDate t opics on specific agents and indications for fur ther details.

* The CYP3A4 inhibit ors and inducers listed in this ta ble are relevant for determining potential inter actions of drugs that ar e CYP3A subfamily
substrates.
¶ Weak effect on CYP3A4.

Data from: Lexicomp Online (Lexi-Inter act). Copyright © 1978-2018 Lexicomp, Inc. All Rights Reser ved

Graphic 76992 V ersion 44.0

Inhibitors and inducers of P-glycoprotein (P-gp) drug efflux pump

Inhibitors of P-gp Inducers of P-gp

Amiodarone Lopinavir-ritonavir Fosphenytoin

Azithromycin (systemic) Neratinib Phenobarbital*

Carvedilol Ombitasvir-paritapr evir- Phenytoin

ritonavir (Technivie) ¶
Rifampin (rifampicin)
Clarithromycin Propafenone
St. John's wort
Cobicistat and cobicistat- Quinidine
containing coformulations*

Cyclosporine (systemic) Quinine

Daclatasvir Ranolazine

Dronedarone Ritonavir and ritonavir -

containing coformulations ¶

Eliglustat Rolapitant

Erythromycin (systemic) Simeprevir

Flibanserin Tacrolimus (systemic)*

Glecaprevir-pibrentasvir Tamoxifen*

Itraconazole Telaprevir

Ivacaftor Ticagrelor*

Ketoconazole (systemic) Velpatasvir

Lapatinib Vemurafenib

Ledipasvir Verapamil

Inhibit ors of the P-gp drug efflux pump listed abo ve may increase serum concentr ations of drugs that ar e substr ates of P-gp,
whereas inducers of P-gp drug efflux ma y decrease serum concentr ations of substr ates of P-gp. Examples of drugs that ar e
substr ates of P-gp efflux pump include: A pixaban, cy closporine, dabigatr an, digo xin, riv aroxaban, and tacr olimus.
The degr ee of eff ect on P-gp substr ate serum co ncentr ation ma y be alter ed by dose and timing of or ally administer ed P-gp
inhibitor or inducer .
Specific drug inter action eff ects ma y be determin ed by using Lexi-Inter act, the drug inter actions pr ogram included with
UpToDate. Ref er to UpToDate clinical t opics on s pecific agents and conditions for fur ther details.

* Minor clinical eff ect or suppor tive data are limited to in-vitro effects (ie, clinical eff ect is unknown).
¶ The combination of ombitasvir-paritapr evir-ritonavir plus dasabuvir ( Viekira Pak) is not a significant inhibit or of P-gp efflux pump [1].

Reference:
1. Menon RM, Badri PS, W ang T, et al. Drug-drug inter action profile of the all-or al anti-hepatitis C virus r egimen of paritapr evir/ritonavir,
ombitasvir, and dasabuvir. J Hepatol 2015; 63:20.
Lexicomp Online (Lexi-Inter act). Copyright © 1978-2018 Lexicomp, Inc. All Rights Reser ved.

Graphic 73326 V ersion 33.0