Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/615
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GENGRAF (Solution)
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Gengraf (cyclosporine
oral solution, USP [MODIFIED]) has increased bioavailability in comparison
to Sandimmune. Gengraf and Sandimmune are
not bioequivalent and cannot be used interchangeably without physician supervision. The daily dose of Gengraf
(cyclosporine oral solution, USP [MODIFIED])
should always be given in two divided doses (BID). It is recommended that
Gengraf be administered on a consistent schedule with regard to time of day
and relation to meals. Grapefruit and grapefruit juice affect metabolism,
increasing blood concentration of cyclosporine, thus should be avoided.<br/>Newly Transplanted Patients: The initial oral dose of Gengraf (cyclosporine oral
solution, USP [MODIFIED]) can be given
4-12 hours prior to transplantation or be given postoperatively. The initial
dose of Gengraf varies depending on the transplanted organ and the other immunosuppressive
agents included in the immunosuppressive protocol. In newly transplanted
patients, the initial oral dose of Gengraf is the same as the initial oral
dose of Sandimmune. Suggested initial doses are available
from the results of a 1994 survey of the use of Sandimmune in
U.S. transplant centers. The mean��SD initial doses were 9��3 mg/kg/day for renal transplant patients (75 centers), 8��4
mg/kg/day for liver transplant patients (30 centers), and 7��3 mg/kg/day
for heart transplant patients (24 centers). Total daily doses were divided
into two equal daily doses. The Gengraf dose is subsequently adjusted to
achieve a pre-defined cyclosporine blood concentration (see DOSAGE
AND ADMINISTRATION -Blood Concentration
Monitoring in Transplant Patients, below). If cyclosporine trough
blood concentrations are used, the target range is the same for Gengraf
as for Sandimmune. Using the same trough concentration target
range for Gengraf as for Sandimmune results in greater cyclosporine
exposure when Gengraf is administered (see CLINICAL
PHARMACOLOGY -Pharmacokinetics, Absorption).
Dosing should be titrated based on clinical assessments of rejection and
tolerability. Lower Gengraf doses may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended
initially. Different tapering dosage schedules of prednisone appear to achieve
similar results. A representative dosage schedule based on the patient's
weight started with 2 mg/kg/day for the first 4 days tapered to 1 mg/kg/day
by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15
mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses
may be further tapered on an individualized basis depending on status of patient
and function of graft. Adjustments in dosage of prednisone must be made according
to the clinical situation.<br/>Conversion From Sandimmune* (Cyclosporine Oral Solution)
To Gengraf (Cyclosporine Oral Solution, USP [MODIFIED]) in Transplant Patients: In transplanted patients who are considered for
conversion to Gengraf from Sandimmune (cyclosporine), Gengraf should be started
with the same daily dose as was previously used with Sandimmune* (cyclosporine)
(1:1 dose conversion). The Gengraf dose should subsequently be adjusted to
attain the pre conversion cyclosporine blood trough concentration. Using
the same trough concentration target range for Gengraf as for Sandimmune*
(cyclosporine) results in greater cyclosporine exposure when Gengraf is administered
(see CLINICAL PHARMACOLOGY -Pharmacokinetics, Absorption). Patients with
suspected poor absorption of Sandimmune* (cyclosporine) require different
dosing strategies (see DOSAGE AND ADMINISTRATION- Transplant
Patients with Poor Absorption of Sandimmune* (cyclosporine), below).
In some patients, the increase in blood trough concentration is more pronounced
and may be of clinical significance. Until the blood trough concentration attains the pre-conversion
value, it is strongly recommended that the cyclosporine blood trough concentration
be monitored every 4 to 7 days after conversion to Gengraf. In
addition, clinical safety parameters such as serum creatinine and blood pressure
should be monitored every two weeks during the first two months after conversion.
If the blood trough concentrations are outside the desired range and/or if
the clinical safety parameters worsen, the dosage of Gengraf must be adjusted
accordingly.<br/>Transplant Patients with Poor Absorption of Sandimmune*
(Cyclosporine): Patients with lower than expected cyclosporine blood
trough concentrations in relation to the oral dose of Sandimmune* (cyclosporine)
may have poor or inconsistent absorption of cyclosporine from Sandimmune*
(cyclosporine). After conversion to Gengraf (cyclosporine oral solution,
USP [MODIFIED]), patients tend to have
higher cyclosporine concentrations. Due to the
increase in bioavailability of cyclosporine following conversion to Gengraf,
the cyclosporine blood trough concentration may exceed the target range.
Particular caution should be exercised when converting patients to Gengraf
at doses greater than 10 mg/kg/day. The dose of Gengraf should
be titrated individually based on cyclosporinetrough concentrations, tolerability,
and clinical response. In this population the cyclosporine blood trough concentration
should be measured more frequently, at least twice a week (daily, if initial
dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired
range.<br/>Rheumatoid Arthritis: The initial dose of Gengraf (cyclosporine oral solution,
USP [MODIFIED]) is 2.5 mg/kg/day,
taken twice daily as a divided (BID) oral dose. Salicylates, nonsteroidal
anti-inflammatory agents, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS
- Drug Interactions). Onset of action generally occurs between
4 and 8 weeks. If insufficient clinical benefit is seen and tolerability
is good (including serum creatinine less than 30% above baseline), the dose
may be increased by 0.5 to 0.75 mg/kg/day after 8 weeks and again after
12 weeks to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks
of therapy, Gengraf therapy should be discontinued. Dose
decreases by 25%-50% should be made at any time to control adverse events,
e.g., hypertension elevations in serum creatinine (30% above patient's
pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS). If dose reduction is not effective in controlling abnormalities
or if the adverse event or abnormality is severe, Gengraf should be discontinued.
The same initial dose and dosage range should be used if Gengraf is combined
with the recommended dose of methotrexate. Most patients can be treated with
Gengraf doses of 3 mg/kg/day or below when combined with methotrexate doses
of up to 15 mg/week (see CLINICAL PHARMACOLOGY -
Clinical Trials). There is limited
long-term treatment data. Recurrence of rheumatoid arthritis disease activity
is generally apparent within four weeks after stopping cyclosporine.<br/>Psoriasis: The initial dose of Gengraf (cyclosporine oral solution,
USP [MODIFIED]) should be 2.5 mg/kg/day.
Gengraf should be taken twice daily, as a divided (1.25 mg/kg BID) oral dose.
Patients should be kept at that dose for at least 4 weeks, barring adverse
events. If significant clinical improvement has not occurred in patients
by that time, the patient's dosage should be increased at 2 week intervals.
Based on patient response, dose increases of approximately 0.5 mg/kg/dayshould be made to a maximum of 4 mg/kg/day. Dose
decreases by 25%-50% should be made at any time to control adverse events,
e.g., hypertension, elevations in serum creatinine (���25% above
the patient's pretreatment level), or clinically significant laboratory
abnormalities. If dose reduction is not effective
in controlling abnormalities, or if the adverse event or abnormality is severe,
Gengraf should be discontinued (see PRECAUTIONS
- Special Monitoring of Psoriasis Patients). Patients generally show some improvement in the clinical manifestations
of psoriasis in 2 weeks. Satisfactory control and stabilization of the
disease may take 12-16 weeks to achieve. Results of a dose-titration clinical
trial with Gengraf indicate that an improvement of psoriasis by 75% or more
(based on PASI) was achieved in 51% of the patients after 8 weeks and in 79%
of the patients after 16 weeks. Treatment should be discontinued if satisfactory
response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient's
maximum tolerated dose. Once a patient is adequately controlled and appears
stable the dose of Gengraf should be lowered, and the patient treated with
the lowest dose that maintains an adequate response (this should not necessarily
be total clearing of the patient).In clinical trials, cyclosporine doses
at the lower end of the recommended dosage range were effective in maintaining
a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day
may also be equally effective. Upon stopping
treatment with cyclosporine, relapse will occur in approximately six weeks
(50% of the patients) to 16 weeks (75% of the patients). In the majority
of patients rebound does not occur after cessation of treatment with cyclosporine.
Thirteen cases of transformation of chronic plaque psoriasis to more severe
forms of psoriasis have been reported. There were 9 cases of pustular and
4 cases of erythrodermic psoriasis. Long term experience with Gengraf in
psoriasis patients is limited and continuous treatment for extended periods
greater than one year is not recommended. Alternation with other forms of
treatment should be considered in the long term management of patients with
this life long disease.<br/>Gengraf Oral Solution (Cyclosporine Oral Solution, USP [MODIFIED])
- Recommendations for Administration: To make Gengraf more palatable, it should be diluted
with orange or apple juice that is at room temperature. Patients should avoid
switching diluents frequently. Grapefruit juice affects metabolism of cyclosporine
and should be avoided. The combination of Gengraf with milk can be unpalatable.
The effect of milk on the bioavailability of cyclosporine when administered
as Gengraf Oral Solution (cyclosporine oral solution, [MODIFIED]) has not been evaluated. Take
the prescribed amount of Gengraf from the container using the dosing syringe
supplied, and transfer the solution to a glass of orange or apple juice.
Stir well and drink at once. Do not allow diluted oral solution to stand
before drinking. Use a glass container (not plastic). Rinse the glass withmore diluent to ensure that the total dose is consumed. After use, dry the
outside of the dosing syringe with a clean towel and store in a clean, dry
place. Do not rinse the dosing syringe with water or other cleaning agents.
If the syringe requires cleaning, it must be completely dry before resuming
use.<br/>Blood Concentration Monitoring in Transplant Patients: Transplant centers have found blood concentration
monitoring of cyclosporine to be an essential component of patient management.
Of importance to blood concentration analysis are the type of assay used,
the transplanted organ, and other immunosuppressant agents being administered.
While no fixed relationship has been established, blood concentration monitoring
may assist in the clinical evaluation of rejection and toxicity, dose adjustments,
and the assessment of compliance. Various assays
have been used to measure blood concentrations of cyclosporine. Older studies
using a non-specific assay often cited concentrations that were roughly twice
those of the specific assays. Therefore, comparison between concentrations
in the published literature and an individual patient concentration using
current assays must be made with detailed knowledge of the assay methods employed.
Current assay results are also not interchangeable and their use should be
guided by their approved labeling. A discussion of the different assay methods
is contained in Annals of Clinical Biochemistry 1994;31:420-446. While several assays and assay matrices are
available, there is a consensus that parent-compound-specific assays correlate
best with clinical events. Of these, HPLC is the standard reference, but
the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity,
reproducibility, and convenience. Most clinicians base their monitoring on
trough cyclosporineconcentrations. Applied
Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992)
contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring
techniques. Blood concentration monitoring is not a replacement for renal
function monitoring or tissue biopsies.
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Cyclosporine is a potent immunosuppressive agent that
in animals prolongs survival of allogeneic transplants involving skin, kidney,
liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine
has been demonstrated to suppress some humoral immunity and to a greater extent,
cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity,
experimental allergic encephalomyelitis, Freund's adjuvant arthritis,
and graft vs. host disease in many animal speciesfor a variety of organs. The effectiveness of cyclosporine results from specific and
reversible inhibition of immunocompetent lymphocytes in the G-and
G-phase of the cell cycle. T-lymphocytes are preferentially
inhibited. The T-helper cell is the main target, although the T-suppressor
cell may also be suppressed. Cyclosporine also inhibits lymphokine production
and release including interleukin-2. No effects
on phagocytic function (changes in enzyme secretions, chemotactic migration
of granulocytes, macrophage migration, carbon clearance in
vivo) have been detected in animals. Cyclosporine does not cause
bone marrow suppression in animal models or man.<br/>Pharmacokinetics: The immunosuppressive activity of cyclosporine is
primarily due to parent drug. Following oral administration, absorption of
cyclosporine is incomplete. The extent of absorption of cyclosporine is dependent
on the individual patient, the patient population, and the formulation. Elimination
of cyclosporine is primarily biliary with only 6% of the dose (parent drug
and metabolites) excreted in urine. The disposition of cyclosporine from
blood is generally biphasic, with a terminal half-life of approximately 8.4
hours (range 5 to 18 hours). Following intravenous administration, the blood
clearance of cyclosporine (assay: HPLC) is approximately 5 to 7 mL/min/kg
in adult recipients of renal or liver allografts. Blood cyclosporine clearance
appears to be slightly slower in cardiac transplant patients. The Gengraf Capsules (cyclosporine capsules, USP [MODIFIED]) and Gengraf Oral Solution (cyclosporine
oral solution, USP [MODIFIED]) are bioequivalent.
Gengraf Oral Solution diluted with orange juice or with apple juice
is bioequivalent to Gengraf Oral Solution diluted with water. The effect
of milk onthe bioavailability of cyclosporine when administered as Gengraf
Oral Solution has not been evaluated. The relationshipbetween administered dose and exposure (area under the concentration versus
time curve, AUC) is linear within the therapeutic dose range. The intersubject
variability (total, % CV) of cyclosporine exposure (AUC) when cyclosporine
(MODIFIED) or Sandimmune is
administered ranges from approximately 20% to 50% in renal transplant patients.
This intersubject variability contributes to the need for individualization
of the dosing regimen for optimal therapy (see DOSAGE
AND ADMINISTRATION). Intrasubject variability of AUC in renal transplant
recipients (% CV) was 9%-21% for cyclosporine (MODIFIED) and 19%-26% for Sandimmune. In the same studies,
intrasubject variability of trough concentrations (% CV) was 17%-30% for cyclosporine
(MODIFIED ) and 16%-38% for Sandimmune.<br/>Absorption: Cyclosporine (MODIFIED) has increased bioavailability compared to Sandimmune.
The absolute bioavailability of cyclosporine administered as Sandimmune (cyclosporine)
is dependent on the patient population, estimated to be less than 10% in liver
transplant patients and as great as 89% in some renal transplant patients.
The absolute bioavailability of cyclosporine administered as cyclosporine
(MODIFIED) has not been determined in
adults. In studies of renal transplant, rheumatoid arthritis and psoriasis
patients, the mean cyclosporine AUC was approximately 20% to 50% greater and
the peak blood cyclosporine concentration (C) was approximately
40% to 106% greater following administration of cyclosporine (MODIFIED) compared to following administration of Sandimmune.
The dose normalized AUC in de novo liver
transplant patients administered cyclosporine (MODIFIED) 28 days after transplantation was 50% greater and Cwas
90% greater than in those patients administered Sandimmune.
AUC and Care also increased (cyclosporine [MODIFIED] relative to Sandimmune) in heart transplant
patients, but data are very limited. Although the AUC and Cvalues
are higher on cyclosporine (MODIFIED)
relative to Sandimmune, the pre-dose trough concentrations
(dose-normalized) are similar for the two formulations. Following oral administration of cyclosporine (MODIFIED), the time to peak blood cyclosporine concentrations (T)
ranged from 1.5 to 2.0 hours. The administration of food with cyclosporine
(MODIFIED) decreases the cyclosporine
AUC and C. A high fat meal (669 kcal, 45 grams fat) consumed
within one-half hour before cyclosporine (MODIFIED) administration decreased the AUC by 13% and Cby
33%. The effects of a low fat meal (667 kcal, 15 grams fat) were similar. The effect of T-tube diversion of bile on the absorption
of cyclosporine from cyclosporine (MODIFIED)
was investigated in eleven de novo liver
transplant patients. When the patients were administered cyclosporine (MODIFIED ) with and without T-tube diversion of
bile, very little difference in absorption was observed, as measured by the
change in maximal cyclosporine blood concentrations from pre-dose values with
the T-tube closed relative to when it was open: 6.9��41%
(range -55% to 68%).<br/>Distribution: Cyclosporine is distributed largely outside the
blood volume. The steady state volume of distribution during intravenous
dosing has been reported as 3-5 L/kg in solid organ transplant recipients.
In blood, the distribution is concentration dependent. Approximately 33%-47%
is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in
erythrocytes. At high concentrations, the binding capacity of leukocytes
and erythrocytes becomes saturated. In plasma, approximately 90% is bound
to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk
(see PRECAUTIONS - Nursing Mothers).<br/>Metabolism: Cyclosporine is extensively metabolized by the
cytochrome P-450 III-A enzyme system in the liver, and to a lesser degree
in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine
can be altered by the coadministration of a variety of agents (see PRECAUTIONS - Drug Interactions). At
least 25 metabolites have been identified from human bile, feces, blood, and
urine. The biological activity of the metabolites and their contributions
to toxicity are considerably less than those of the parent compound. The
major metabolites(M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma,and 4-N-demethylated positions, respectively. At steady state following the
oral administration of Sandimmune, the mean AUCs for blood
concentrations of M1, M9 and M4N are about 70%, 21%, and 7.5% of the AUC for
blood cyclosporine concentrations, respectively. Based on blood concentration
data from stable renal transplant patients (13 patients administered cyclosporine
[MODIFIED ] and Sandimmune in
a crossover study), and bile concentration data from de
novo liver transplant patients (4 administered cyclosporine (MODIFIED), 3 administered Sandimmune),
the percentage of dose present as M1, M9, and M4N metabolites is similar when
either cyclosporine (MODIFIED) or Sandimmune is
administered.<br/>Excretion: Only 0.1% of a cyclosporine dose is excreted unchanged
in the urine. Elimination is primarily biliary with only 6% of the dose (parent
drug and metabolites) excreted in the urine. Neither dialysis nor renal failure
alter cyclosporine clearance significantly.<br/>Drug Interactions: (see PRECAUTIONS -Drug Interactions). When diclofenac or methotrexate
was coadministered with cyclosporine in rheumatoid arthritis patients, the
AUC of diclofenac and methotrexate, each was significantly increased (see PRECAUTIONS - Drug Interactions). No clinically
significant pharmacokinetic interactions occurred between cyclosporine andaspirin, ketoprofen, piroxicam, or indomethacin.<br/>Special Population:
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General: Gengraf (cyclosporine oral solution, USP [MODIFIED]) is contraindicated in patients with
a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.<br/>Rheumatoid Arthritis: Rheumatoid arthritis patients with abnormal renal
function, uncontrolled hypertension or malignancies should not receive Gengraf
(cyclosporine oral solution, USP [MODIFIED]).<br/>Psoriasis: Psoriasis patients who are treated with Gengraf
(cyclosporine oral solution, USP [MODIFIED])
should not receive concomitant PUVA or UVB therapy, methotrexate or other
immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients
with abnormal renal function, uncontrolled hypertension, or malignancies should
not receive Gengraf.
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Gengraf Oral Solution (Cyclosporine Oral Solution,
USP [MODIFIED]): A clear, colorless to yellow liquid supplied in
50 mL bottles containing 100 mg/mL with dispensing syringe (NDC 0074-7269-50).<br/>Store and Dispense: In the original container at controlled room temperature
68��-77��F (20��-25��C) (See USP Controlled Room Temperature).
Do not store in the refrigerator. Once opened, the contents must be used
within two months. At temperatures below 68��F (20��C) the solution
may gel; light flocculation or the formation of a light sediment may also
occur. There is no impact on product performance or dosing using the syringe
provided. Allow to warm to room temperature 77��F (25��C) to reverse
these changes. * Sandimmune is a registered trademark
of Novartis Pharmaceuticals Corporation. ��AbbottAbbott Laboratories, North Chicago, IL 60064, U.S.A .
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WARNING Only physicians experienced in the management of systemic
immunosuppressive therapy for the indicated disease should prescribe Gengraf
(cyclosporine oral solution, USP [MODIFIED]).
At doses used in solid organ transplantation, only physicians experienced
in immunosuppressive therapy and management of organ transplant recipients
should prescribe Gengraf. Patients receiving the drug should be managed in
facilities equipped and staffed with adequate laboratory and supportive medical
resources. The physician responsible for maintenance therapy should have
complete information requisite for the follow-up of the patient. Gengraf, a systemic immunosuppressant, may increase the susceptibility
to infection and the development of neoplasia. In kidney, liver, and heart
transplant patients Gengraf may be administered with other immunosuppressive
agents. Increased susceptibility to infection and the possible development
of lymphoma and other neoplasms may result from the increase in the degree
of immunosuppression in transplant patients. Gengraf
(cyclosporine oral solution, USP [MODIFIED])
has increased bioavailability in comparison to Sandimmune*
(cyclosporine oral solution, USP [Non-Modified]). Gengraf and Sandimmune*
are not bioequivalent and cannot be used interchangeably without physician
supervision. For a given trough concentration, cyclosporine exposure will
be greater with Gengraf than with Sandimmune*. If a patient who is receiving
exceptionally high doses of Sandimmune* is converted to Gengraf, particular
caution should be exercised. Cyclosporine blood concentrations should be
monitored in transplant and rheumatoid arthritis patients taking Gengraf to
avoid toxicity due to high concentrations. Dose adjustments should be made
in transplant patients to minimize possible organ rejection due to low concentrations.
Comparison of blood concentrations in the published literature with blood
concentrations obtained using current assays must be done with detailed knowledge
of the assay methods employed. For
Psoriasis Patients (see also Boxed WARNINGS above)Psoriasis patients previously treated with PUVA and to a lesser
extent, methotrexate or other immunosuppressive agents, UVB, coal tar, or
radiation therapy, are at an increased risk of developing skin malignancies
when taking Gengraf (cyclosporine oral solution, USP [MODIFIED]). Cyclosporine, the active ingredient
in Gengraf, in recommended dosages, can cause systemic hypertension and nephrotoxicity.
The risk increases with increasing dose and duration of cyclosporine therapy.
Renal dysfunction, including structural kidney damage, is a potential consequence
of cyclosporine, and therefore, renal function must be monitored during therapy.
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There is a minimal experience with cyclosporine overdosage.
Forced emesis can be of value up to 2 hours after administration of Gengraf
(cyclosporine oral solution, USP [MODIFIED]).
Transient hepatotoxicity and nephrotoxicity may occur which should resolve
following drug withdrawal. General supportive measures and symptomatic treatment
should be followed in all cases of overdosage. Cyclosporine is not dialyzable
to any great extent, nor is it cleared well by charcoal hemoperfusion. The
oral dosage at which half of experimental animals are estimated to die is
31 times, 39 times and>54 times the human maintenance dose for
transplant patients (6 mg/kg; corrections based on body surface area) in mice,
rats, and rabbits.
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cyclosporine
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GENGRAF (Solution)
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Kidney, Liver, and Heart Transplantation: The principal adverse reactions of cyclosporine
therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia. Hypertension, which is usually mild to moderate, may occur
in approximately 50% of patients following renal transplantation and in most
cardiac transplant patients. Glomerular capillary
thrombosis has been found in patients treated with cyclosporine and may progress
to graft failure. The pathologic changes resembled those seen in the hemolytic-uremic
syndrome and include thrombosis of the renal microvasculature, with platelet-fibrin
thrombi occluding glomerular capillaries and afferent arterioles, microangiopathic
hemolytic anemia, thrombocytopenia, and decreased renal function. Similar
findings have been observed when other immunosuppressives have been employed
post-transplantation. Hypomagnesemia has been
reported in some, but not all, patients exhibiting convulsions while on cyclosporine
therapy. Although magnesium-depletion studies in normal subjects suggest
that hypomagnesemia is associated with neurologic disorders, multiple factors,
including hypertension, high dose methylprednisolone, hypocholesterolemia,
and nephrotoxicity associated with high plasma concentrations of cyclosporine
appear to be related to the neurological manifestations of cyclosporine toxicity. In controlled studies, the nature, severity and incidence
of the adverse events that were observed in 493 transplanted patients treated
with cyclosporine (MODIFIED) were comparable
with those observed in 208 transplanted patients who received Sandimmune
in these same studies when the dosage of the two drugs was adjusted to achieve
the same cyclosporine blood trough concentrations. Based
on the historical experience with Sandimmune, the following
reactions occurred in 3% or greater of 892 patients involved in clinical trials
of kidney, heart, and liver transplants. Among 705 kidney transplant patients treated with
cyclosporine oral solution in clinical trials, the reason for treatment discontinuation
was renal toxicity in 5.4%, infection in 0.9%, lack of efficacy in 1.4%, acute
tubular necrosis in 1.0%, lymphoproliferative disorders in 0.3%, hypertension
in 0.3%, and other reasons in 0.7% of the patients. The
following reactions occurred in 2% or less of Sandimmune-treated
patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis,
edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia,
muscle pain, peptic ulcer, thrombocytopenia, tinnitus. The following reactions occurred rarely: anxiety, chest pain,
constipation, depression, hair breaking, hematuria, joint pain, lethargy,
mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus,
swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness,
weight loss.<br/>Rheumatoid Arthritis: The principal adverse reactions associated with
the use of cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS), hypertension (see PRECAUTIONS), headache, gastrointestinal disturbances and hirsutism/hypertrichosis. In rheumatoid arthritis patients treated in clinical trials
within the recommended dose range, cyclosporine therapy was discontinued in
5.3% of the patients because of hypertension and in 7% of the patients because
of increased creatinine. These changes are usually reversible with timely
dose decrease or drug discontinuation. The frequency and severity of serum
creatinine elevations increase with dose and duration of cyclosporine therapy.
These elevations are likely to become more pronounced without dose reduction
or discontinuation.<br/>The Following Adverse Events Occurred in Controlled Clinical Trials: In addition, the following adverse events have
been reported in 1% to<3% of the rheumatoid arthritis patients in the
cyclosporine treatment group in controlled clinical trials.<br/>Autonomic Nervous System: dry mouth, increased sweating<br/>Body as a Whole: allergy, asthenia, hot flushes, malaise, overdose,
procedure NOS*, tumor NOS*, weight decrease, weight increase<br/>Cardiovascular: abnormal heart sounds, cardiac failure, myocardial
infarction, peripheral ischemia<br/>Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo<br/>Endocrine: goiter<br/>Gastrointestinal: constipation, dysphagia, enanthema, eructation,
esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding,
glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth
disorder<br/>Infection: abscess, bacterial infection, cellulitis, folliculitis,
fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis,
tonsillitis, viral infection<br/>Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy<br/>Liver and Biliary System: bilirubinemia<br/>Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia,
hypoglycemia<br/>Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation,
myalgia, stiffness, synovial cyst, tendon disorder<br/>Neoplasms: breast fibroadenosis, carcinoma<br/>Psychiatric: anxiety, confusion, decreased libido, emotional
lability, impaired concentration, increased libido, nervousness, paroniria,
somnolence<br/>Reproductive (Female): breast pain, uterine hemorrhage<br/>Respiratory System: abnormal chest sounds, bronchospasm<br/>Skin and Appendages: abnormal pigmentation, angioedema, dermatitis,
dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria<br/>Special Senses: abnormal vision, cataract, conjunctivitis, deafness,
eye pain, taste perversion, tinnitus, vestibular disorder<br/>Urinary System: abnormal urine, hematuria, increased BUN, micturition
urgency, nocturia, polyuria, pyelonephritis, urinary incontinence * NOS = Not Otherwise Specified.<br/>Psoriasis: The principal adverse reactions associated with
the use of cyclosporine in patients with psoriasis are renal dysfunction,
headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia
or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal
discomfort, lethargy, and musculoskeletal or joint pain. In psoriasis patients treated in U.S. controlled clinical studies
within the recommended dose range, cyclosporine therapy was discontinued in
1.0% of the patients because of hypertension and in 5.4% of the patients because
of increased creatinine. In the majority of cases, these changes were reversible
after dose reduction or discontinuation of cyclosporine. There has been one reported death associated with the use of
cyclosporine in psoriasis. A 27 year old male
developed renal deterioration and was continued on cyclosporine. He had progressive
renal failure leading to death. Frequency and
severity of serum creatinine increases with dose and duration of cyclosporine
therapy. These elevations are likely to become more pronounced and may result
in irreversible renal damage without dose reduction or discontinuation. The following events occurred in 1% to less than
3% of psoriasis patients treated with cyclosporine:<br/>Body as a Whole: fever, flushes, hot flushes<br/>Cardiovascular: chest pain<br/>Central and Peripheral Nervous System: appetite increased, insomnia, dizziness, nervousness,
vertigo<br/>Gastrointestinal: abdominal distention, constipation, gingival bleeding;
Liver and Biliary System: hyperbilirubinemia<br/>Neoplasms: skin malignancies [squamous cell (0.9%) and basal
cell (0.4%) carcinomas]<br/>Reticuloendothelial: platelet, bleeding, and clotting disorders, red
blood cell disorder<br/>Respiratory: infection, viral and other infection<br/>Skin and Appendages: acne, folliculitis, keratosis, pruritus, rash,
dry skin<br/>Urinary System: micturition frequency<br/>Vision: abnormal vision. Mild
hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases
in uric acid may occur and attacks of gout have been rarely reported. A minor
and dose related hyperbilirubinemia has been observed in the absence of hepatocellular
damage. Cyclosporine therapy may be associated with a modest increase of
serum triglycerides or cholesterol. Elevations of triglycerides (>750 mg/dL)
occur in about 15% of psoriasis patients; elevations of cholesterol (>300
mg/dL) are observed in less than 3% of psoriasis patients. Generally these
laboratory abnormalities are reversible upon dose reduction or discontinuation
of cyclosporine.
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(see also Boxed WARNINGS).<br/>All Patients: Cyclosporine, the active ingredient of Gengraf (cyclosporine
oral solution, USP [MODIFIED]), can cause
nephrotoxicity and hepatotoxicity. The risk increases with increasing doses
of cyclosporine. Renal dysfunction including structural kidney damage is
a potential consequence of Gengraf and therefore renal function must be monitored
during therapy. Care should be taken in using cyclosporine
with nephrotoxic drugs (see PRECAUTIONS). Patients receiving Gengraf require
frequent monitoring of serum creatinine (see Special Monitoring under DOSAGE AND ADMINISTRATION). Elderly patients should
be monitored with particular care, since decreases in renal function also
occur with age. If patients are not properly monitored and doses are
not properly adjusted, cyclosporine therapy can be associated with the occurrence
of structural kidney damage and persistent renal dysfunction. An increase in serum creatinine and BUN may occur during
Gengraf therapy and reflect a reduction in the glomerular filtration rate.
Impaired renal function at any time requires close monitoring, and frequent
dosage adjustment may be indicated. The frequency and severity of serum creatinine
elevations increase with dose and duration of cyclosporine therapy. These
elevations are likely to become more pronounced without dose reduction or
discontinuation. Because
Gengraf (cyclosporine oral solution, USP [MODIFIED]) is not bioequivalent
to Sandimmune(Cyclosporine Oral Solution), conversion from
Gengraf to Sandimmune using a 1:1 ratio (mg/kg/day) may result
in lower cyclosporine blood concentrations. Conversion from Gengraf to Sandimmune should be made with increased monitoring to avoid the potential
of underdosing.<br/>Kidney, Liver, and Heart Transplant: Cyclosporine, the active ingredient of Gengraf (cyclosporine
oral solution, USP [MODIFIED]), can cause
nephrotoxicity and hepatotoxicity when used in high doses. It is not
unusual for serum creatinine and BUN levels to be elevated during cyclosporine
therapy. These elevations in renal transplant patients do not necessarilyindicate rejection, and each patient must be fully evaluated before dosage
adjustment is initiated. Based on the historical
Sandimmune experience with oral solution, nephrotoxicity
associated with cyclosporine had been noted in 25% of cases of renal transplantation,
38% of cases of cardiac transplantation, and 37% of cases of liver transplantation.
Mild nephrotoxicity was generally noted 2-3 months after renal transplant
and consisted of an arrest in the fall of the pre-operative elevations of
BUN and creatinine at a range of 35-45 mg/dL and 2-2.5 mg/dL respectively.
These elevations were often responsive to cyclosporine dosage reduction. More overt nephrotoxicity was seen early after transplantation
and was characterized by a rapidly rising BUN and creatinine. Since these
events are similar to renal rejection episodes, care must be taken to differentiate
between them. This form of nephrotoxicity is usually responsive to cyclosporine
dosage reduction. Although specific diagnostic
criteria which reliably differentiate renal graft rejection from drug toxicity
have not been found, a number of parameters have been significantly associated
with one or the other. It should be noted however, that up to 20% of patients
may have simultaneous nephrotoxicity and rejection. A form of a cyclosporine-associated nephropathy
is characterized by serial deterioration in renal function and morphologic
changes in the kidneys. From 5% to 15% of transplant recipients who have
received cyclosporine will fail to show a reduction in rising serum creatinine
despite a decrease or discontinuation of cyclosporine therapy. Renal biopsies
from these patients will demonstrate one orseveral of the following alterations:
tubular vacuolization, tubular microcalcifications, peritubular capillary
congestion, arteriolopathy, and a striped form of interstitial fibrosis with
tubular atrophy. Though none of these morphologic changes is entirely specific,
a diagnosis of cyclosporine-associated structural nephrotoxicity requires
evidence of these findings. When considering
the development of cyclosporine-associated nephropathy, it is noteworthy that
several authors have reported an association between the appearance of interstitial
fibrosis and higher cumulative doses or persistently high circulating trough
levels of cyclosporine. This is particularly true during the first 6 post-transplant
months when the dosage tends to be highest and when, in kidney recipients,
the organ appears to be most vulnerable to the toxic effects of cyclosporine.
Among other contributing factors to the development of interstitial fibrosis
in these patients are prolonged perfusion time, warm ischemia time, as well
as episodes of acute toxicity, and acute and chronic rejection. The reversibility
of interstitial fibrosis and its correlation to renal function have not yet
been determined. Reversibility of arteriolopathy has been reported after
stopping cyclosporine or lowering the dosage. Impaired
renal function at any time requires close monitoring, and frequent dosage
adjustment may be indicated. In the event of
severe and unremitting rejection, when rescue therapy with pulse steroids
and monoclonal antibodies fail to reverse the rejection episode, it may be
preferable to switch to alternative immunosuppressive therapy rather than
increase the Gengraf dose to excessive levels. Occasionally
patients have developed a syndrome of thrombocytopenia and microangiopathic
hemolytic anemia which may result in graft failure. The vasculopathy can
occur in the absence of rejection and is accompanied by avid platelet consumption
within the graft as demonstrated by Indium 111 labeled platelet studies.
Neither the pathogenesis nor the management of this syndrome is clear. Though
resolution has occurred after reduction or discontinuation of cyclosporine
and 1) administration of streptokinase and heparin or 2) plasmapheresis, this
appears to depend upon early detection with Indium 111 labeled platelet scans
(see ADVERSE REACTIONS). Significant hyperkalemia (sometimes associated with hyperchloremic
metabolic acidosis) and hyperuricemia have been seen occasionally in individual
patients. Hepatotoxicity associated with cyclosporine
use had been noted in 4% of cases of renal transplantation, 7% of cases of
cardiac transplantation, and 4% of cases of liver transplantation. This was
usually noted during the first month of therapy when high doses of cyclosporine
were used and consisted of elevations of hepatic enzymes and bilirubin. The
chemistry elevations usually decreased with a reduction in dosage. As in patients receiving other immunosuppressants, those
patients receiving cyclosporine are at increased risk for development of lymphomas
and other malignancies, particularly those of the skin. The increased risk
appears related to the intensity and duration of immunosuppression rather
than to the use of specific agents. Because of the danger of oversuppression
of the immune system resulting in increased risk of infection or malignancy,
a treatment regimen containing multiple immunosuppressantsshould be used
with caution. There have been reports of convulsions
in adult and pediatric patients receiving cyclosporine, particularly in combination
with high dose methylprednisolone. Encephalopathy
has been described both in postmarketing reports and in the literature. Manifestations
include impaired consciousness, convulsions, visual disturbances (including
blindness), loss of motor function, movement disorders and psychiatric disturbances.
In many cases, changes in the white matter have been detected using imaging
techniques and pathologic specimens. Predisposing factors such as hypertension,
hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine
blood concentrations, and graft-versus-host disease have been noted in many
but not all of the reported cases. The changes in most cases have been reversible
upon discontinuation of cyclosporine, and in some cases improvement was noted
after reduction of dose. It appears that patients receiving liver transplant
are more susceptible to encephalopathy than those patients receiving kidney
transplant. Another rare manifestation of cyclosporine-induced neurotoxicity,
occurring in transplant patients more frequently than in other indications,
is optic disc edema including papilloedema, with possible visual impairment,
secondary to benign intracranial hypertension. Care
should be taken in using cyclosporine with nephrotoxic drugs (see PRECAUTIONS).<br/>Rheumatoid Arthritis: Cyclosporine nephropathy was detected in renal biopsies
of six out of 60 (10%) rheumatoid arthritis patients after the average treatment
duration of 19 months. Only one patient, out of these 6 patients, was treated
with a dose���4 mg/kg/day. Serum creatinine improved in all but one
patient after discontinuation of cyclosporine. The "maximal creatinine increase"
appears to be a factor in predicting cyclosporine nephropathy. There is a potential, as with other immunosuppressive agents,
for an increase in the occurrence of malignant lymphomas with cyclosporine.
It is not clear whether the risk with cyclosporine is greater than that in
Rheumatoid Arthritis patients or in Rheumatoid Arthritis patients on cytotoxic
treatment for this indication. Five cases of lymphoma were detected: four
in a survey of approximately 2,300 patients treated with cyclosporine for
rheumatoid arthritis, and another case of lymphoma was reported in a clinical
trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse
types, and 1 multiple myeloma) were also reported in this survey, epidemiologic
analyses did not support a relationship to cyclosporine other than for malignant
lymphomas. Patients should be thoroughly evaluated
before and during Gengraf (cyclosporine oral solution, USP [MODIFIED]) treatment for the development of malignancies. Moreover, use
of Gengraf therapy with other immunosuppressive agents may induce an excessive
immunosuppression which is known to increase the risk of malignancy.<br/>Psoriasis: (see also Boxed WARNINGS for Psoriasis). Since cyclosporine
is a potent immunosuppressive agent with a number of potentially serious side
effects, the risks and benefits of using Gengraf (cyclosporine oral solution,
USP [MODIFIED]) should be considered before
treatment of patients with psoriasis. Cyclosporine, the active ingredient
in Gengraf, can cause nephrotoxicity and hypertension (see PRECAUTIONS) and the risk increases with increasing dose and duration of therapy.
Patients who may be at increased risk such as those with abnormal renal function,
uncontrolled hypertension or malignancies, should not receive Gengraf. Renal dysfunction is a potential consequence of Gengraf,
therefore renal function must be monitored during therapy. Patients receiving Gengraf require frequent monitoring of
serum creatinine (see Special Monitoring underDOSAGE AND ADMINISTRATION).
Elderly patients should be monitored with particular care, since decreases
in renal function also occur with age. If patients are not properly monitored
and doses are not properly adjusted, cyclosporine therapy can cause structural
kidney damage and persistent renal dysfunction. An
increase in serum creatinine and BUN may occur during Gengraf therapy and
reflects a reduction in the glomerular filtration rate. Kidney biopsies from 86 psoriasis patients treated for a mean
duration of 23 months with 1.2 to 7.6 mg/kg/day of cyclosporine showed evidence
of cyclosporine nephropathy in 18/86 (21%) of the patients. The pathology
consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy
of 13 of these patients maintained on various dosages of cyclosporine for
a mean of 2 additional years, the number with cyclosporine induced nephropathy
rose to 26/86 (30%). The majority of patients (19/26) were on a dose of���5
mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were
also on cyclosporine for greater than 15 months (18/26) and/or had a clinically
significant increase in serum creatinine for greater than 1 month (21/26).
Creatinine levels returned to normal range in 7 of 11 patients in whom cyclosporine
therapy was discontinued. There is an increased
risk for the development of skin and lymphoproliferative malignancies in cyclosporine-treated
psoriasis patients. The relative risk of malignancies is comparable to that
observed in psoriasis patients treated with other immunosuppressive agents. Tumors were reported in 32 (2.2%) of 1439 psoriasis patients
treated with cyclosporine worldwide from clinical trials. Additional tumors
have been reported in 7 patients in cyclosporine postmarketing experience.
Skin malignancies were reported in 16 (1.1%) of these patients; all but 2
of them had previously received PUVA therapy. Methotrexate was received by
7 patients. UVB and coal tar had been used by 2 and 3 patients, respectively.
Seven patients had either a history of previous skin cancer or a potentially
predisposing lesion was present prior to cyclosporine exposure. Of the16
patients with skin cancer, 11 patients had 18 squamous cell carcinomas and
7 patients had 10 basal cell carcinomas. There
were two lymphoproliferative malignancies; one case of non-Hodgkin's
lymphoma which required chemotherapy, and one case of mycosis fungoides which
regressed spontaneously upon discontinuation of cyclosporine. There were
four cases of benign lymphocytic infiltration: 3 regressed spontaneously
upon discontinuation of cyclosporine, while the fourth regressed despite continuation
of the drug. The remainder of the malignancies, 13 cases (0.9%), involved
various organs. Patients
should not be treated concurrently with cyclosporine and PUVA or UVB, other
radiation therapy, or other immunosuppressive agents, because of the possibility
of excessive immunosuppression and the subsequent risk of malignancies (see CONTRAINDICATIONS). Patients should also be warned
to protect themselves appropriately when in the sun, and to avoid excessive
sun exposure.Patients should be thoroughly evaluated before and during treatment
for the presence of malignancies remembering that malignant lesions may be
hidden by psoriatic plaques. Skin lesions not typical of psoriasis should
be biopsied before starting treatment. Patients should be treated with Gengraf
(cyclosporine oral solution, USP [MODIFIED])
only after complete resolution of suspicious lesions, and only if there are
no other treatment options (see Special Monitoring
for Psoriasis Patients).
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Kidney, Liver and Heart Transplantation: Gengraf (cyclosporine oral solution, USP [MODIFIED]) is indicated for the prophylaxis of
organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine
(MODIFIED) has been used in combination
with azathioprine and corticosteroids.<br/>Rheumatoid Arthritis: Gengraf (cyclosporine oral solution, USP [MODIFIED]) is indicated for the treatment of patients
with severe active, rheumatoid arthritis where the disease has not adequately
responded to methotrexate. Gengraf can be used in combination with methotrexate
in rheumatoid arthritis patients who do not respond adequately to methotrexate
alone.<br/>Psoriasis: Gengraf (cyclosporine oral solution, USP [MODIFIED]) is indicated for the treatment of adult, nonimmunocompromised patients with severe
(i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who have
failed to respond to at least one systemic therapy (e.g., PUVA, retinoids,
or methotrexate) or in patients for whom other systemic therapies are contraindicated,
or cannot be tolerated. While rebound rarely
occurs, most patients will experience relapse with Gengraf as with other therapies
upon cessation of treatment.
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GENGRAF
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