Effect Of Drugs And Other Agents On Cyclosporine
Pharmacokinetics And/Or Safety
All of the individual drugs cited below are well
substantiated to interact with cyclosporine. In addition, concomitant use of
nonsteroidal anti-inflammatory drugs (NSAIDs) with cyclosporine, particularly
in the setting of dehydration, may potentiate renal dysfunction. Caution should
be exercised when using other drugs which are known to impair renal function.
(See WARNINGS, Nephrotoxicity)
Drugs That May Potentiate Renal Dysfunction
||Anti- Inflammatory Drugs
||fibric acid derivatives (e.g., bezafibrate, fenofibrate)
|trimethoprim with sulfamethoxazole
During the concomitant use of a
drug that may exhibit additive or synergistic renal impairment potential with
cyclosporine, close monitoring of renal function (in particular serum
creatinine) should be performed. If a significant impairment of renal function
occurs, reduction in the dosage of cyclosporine and/or coadministered drug or
an alternative treatment should be considered.
Cyclosporine is extensively
metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a substrate of
the multidrug efflux transporter P-glycoprotein. Various agents are known to
either increase or decrease plasma or whole blood concentrations of
cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein
transporter or both. Compounds that decrease cyclosporine absorption such as
orlistat should be avoided. Appropriate Sandimmune (cyclosporine) dosage
adjustment to achieve the desired cyclosporine concentrations is essential when
drugs that significantly alter cyclosporine concentrations are used
concomitantly. (See Blood Concentration Monitoring)
Drugs That Increase Cyclosporine Concentrations
|Calcium Channel Blockers
HIV Protease inhibitors
The HIV protease inhibitors
(e.g., indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit
cytochrome P-450 3A and thus could potentially increase the concentrations of
cyclosporine, however no formal studies of the interaction are available. Care
should be exercised when these drugs are administered concomitantly.
Grapefruit and grapefruit juice
affect metabolism, increasing blood concentrations of cyclosporine, thus should
Drugs/Dietary Supplements That
Decrease Cyclosporine Concentrations
||Other Drugs /Dietary Supplements
|St. John's Wort
Co-administration of bosentan (250 to 1000 mg every 12
hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days
then dosing to achieve a Cmin of 200 to 250 ng/mL) for 7 days in healthy
subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, Cmax,
and trough concentration of approximately 50%, 30% and 60%, respectively,
compared to when cyclosporine was given alone. (See also Effect of
Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents)
Coadministration of cyclosporine with bosentan should be avoided.
Coadministration of boceprevir (800 mg three times daily
for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted
in increases in the mean AUC and Cmax of cyclosporine approximately 2.7-fold
and 2-fold, respectively, compared to when cyclosporine was given alone.
Coadministration of telaprevir (750 mg every 8 hours for
11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in
increases in the mean dose-normalized AUC and Cmax of cyclosporine
approximately 4.5-fold and 1.3-fold, respectively, compared to when
cyclosporine (100 mg single dose) was given alone.
St. John's Wort
There have been reports of a serious drug interaction
between cyclosporine and the herbal dietary supplement, St. John's Wort. This
interaction has been reported to produce a marked reduction in the blood
concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of
transplanted organs, and graft loss.
Rifabutin is known to increase the metabolism of other
drugs metabolized by the cytochrome P-450 system. The interaction between
rifabutin and cyclosporine has not been studied. Care should be exercised when
these two drugs are administered concomitantly.
Effect Of Cyclosporine On The Pharmacokinetics And/Or
Safety Of Other Drugs Or Agents
Cyclosporine is an inhibitor of CYP3A4 and of multiple
drug efflux transporters (e.g., P-glycoprotein) and may increase plasma
concentrations of comedications that are substrates of CYP3A4, PÂglycoprotein,
or organic anion transporter proteins.
Cyclosporine may reduce the clearance of digoxin,
colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and aliskiren,
bosentan, dabigatran, repaglinide, NSAIDs, sirolimus, etoposide, and other
See the full prescribing information of the other drug
for further information and specific recommendations. The decision on
coadministration of cyclosporine with other drugs or agents should be made by
the healthcare provider following the careful assessment of benefits and risks.
Severe digitalis toxicity has been seen within days of
starting cyclosporine in several patients taking digoxin. If digoxin is used
concurrently with cyclosporine, serum digoxin concentrations should be
There are reports on the potential of cyclosporine to
enhance the toxic effects of colchicine such as myopathy and neuropathy,
especially in patients with renal dysfunction. Concomitant administration of
cyclosporine and colchicine results in significant increases in colchicine
plasma concentrations. If colchicine is used concurrently with cyclosporine, a
reduction in the dosage of colchicine is recommended.
HMG Co-A Reductase Inhibitors (statins)
Literature and postmarketing cases of myotoxicity,
including muscle pain and weakness, myositis, and rhabdomyolysis, have been
reported with concomitant administration of cyclosporine with lovastatin, simvastatin,
atorvastatin, pravastatin, and rarely, fluvastatin. When concurrently
administered with cyclosporine, the dosage of these statins should be reduced
according to label recommendations. Statin therapy needs to be temporarily
withheld or discontinued in patients with signs and symptoms of myopathy or
those with risk factors predisposing to severe renal injury, including renal
failure, secondary to rhabdomyolysis.
Cyclosporine may increase the plasma concentrations of
repaglinide and thereby increase the risk of hypoglycemia. In 12 healthy male
subjects who received two doses of 100 mg cyclosporine capsule orally 12 hours
apart with a single dose of 0.25 mg repaglinide tablet (one half of a 0.5 mg
tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide
mean Cmax and AUC were increased 1.8 fold (range: 0.6 to 3.7 fold) and 2.4 fold
(range 1.2 to 5.3 fold), respectively. Close monitoring of blood glucose level
is advisable for a patient taking cyclosporine and repaglinide concomitantly.
Coadministration of ambrisentan (5 mg daily) and
cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve Cmin 150
to 200 ng/mL) for 8 days in healthy subjects resulted mean increases in
ambrisentan AUC and Cmax of approximately 2-fold and 1.5-fold, respectively,
compared to ambrisentan alone. When coadministering ambrisentan with
cyclosporine, the ambrisentan dose should not be titrated to the recommended
maximum daily dose.
High doses of cyclosporine (e.g., at starting intravenous
dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics
(e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients.
Cyclosporine alters the pharmacokinetics of aliskiren, a
substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received
concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren
(75 mg), the mean Cmax of aliskiren was increased by approximately 2.5-fold
(90% CI: 1.96 to 3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52
to 5.21), compared to when these subjects received aliskiren alone. The
concomitant administration of aliskiren with cyclosporine prolonged the median
aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the Tmax (0.5
hours versus 1.5 to 2.0 hours). The mean AUC and Cmax of cyclosporine were
comparable to reported literature values. Coadministration of cyclosporine and
aliskiren in these subjects also resulted in an increase in the number and/or
intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and
somnolence. The coadministration of cyclosporine with aliskiren is not
In healthy subjects, coadministration of bosentan and
cyclosporine resulted in time-dependent mean increases in dose-normalized
bosentan trough concentrations (i.e., approximately 21-fold on day 1 and 2-fold
on day 8 (steady state)) compared to when bosentan was given alone as a single
dose on day 1. (See also Effect of Drugs and Other Agents on Cyclosporine
Pharmacokinetics and/or Safety) Coadministration of cyclosporine with
bosentan should be avoided.
The effect of cyclosporine on dabigatran concentrations
had not been formally studied. Concomitant administration of dabigatran and
cyclosporine may result in increased plasma dabigatran concentrations due to
the P-gp inhibitory activity of cyclosporine. Coadministration of cyclosporine
with dabigatran should be avoided.
Potassium Sparing Diuretics
Cyclosporine should not be used with potassium-sparing
diuretics because hyperkalemia can occur. Caution is also required when
cyclosporine is coadministered with potassium-sparing drugs (e.g.,
angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists),
potassium-containing drugs as well as in patients on a potassium-rich diet.
Control of potassium levels in these situations is advisable.
Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions
Clinical status and serum creatinine should be closely
monitored when cyclosporine is used with NSAIDs in rheumatoid arthritis
patients. (See WARNINGS)
Pharmacodynamic interactions have been reported to occur
between cyclosporine and both naproxen and sulindac, in that concomitant use is
associated with additive decreases in renal function, as determined by 99mTc-diethylenetriaminepentaacetic
acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant
administration of diclofenac does not affect blood concentrations of
cyclosporine, it has been associated with approximate doubling of diclofenac
blood levels and occasional reports of reversible decreases in renal function.
Consequently, the dose of diclofenac should be in the lower end of the
Preliminary data indicate that when methotrexate and
cyclosporine were coadministered to rheumatoid arthritis patients (N=20),
methotrexate concentrations (AUCs) were increased approximately 30% and the
concentrations (AUCs) of its metabolite, 7-hydroxy methotrexate, were decreased
by approximately 80%. The clinical significance of this interaction is not
known. Cyclosporine concentrations do not appear to have been altered (N=6).
Elevations in serum creatinine were observed in studies
using sirolimus in combination with full-dose cyclosporine. This effect is
often reversible with cyclosporine dose reduction. Simultaneous
coadministration of cyclosporine significantly increases blood levels of
sirolimus. To minimize increases in sirolimus blood concentrations, it is
recommended that sirolimus be given 4 hours after cyclosporine administration.
Frequent gingival hyperplasia when nifedipine is given
concurrently with cyclosporine has been reported. The concomitant use of
nifedipine should be avoided in patients in whom gingival hyperplasia develops
as a side effect of cyclosporine.
Convulsions when high dose methylprednisolone is given
concomitantly with cyclosporine have been reported.
Other Immunosuppressive Drugs and Agents
Psoriasis patients receiving other immunosuppressive
agents or radiation therapy (including PUVA and UVB) should not receive
concurrent cyclosporine because of the possibility of excessive
Effect Of Cyclosporine On The Efficacy Of Live Vaccines
During treatment with cyclosporine, vaccination may be
less effective. The use of live vaccines should be avoided.
For additional information on Cyclosporine Drug
Interactions please contact Novartis Medical Affairs Department at