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Gengraf
Overview
What is Gengraf?
Gengraf Capsules (cyclosporine capsules, USP []) is a modified oral formulation of cyclosporine that forms an aqueous dispersion in an aqueous environment.
Cyclosporine, the active principle in Gengraf, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species .
Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl--methyl-L-leucyl--methyl-L-leucyl--methyl-L-valyl-3-hydroxy-,4-dimethyl- L-2-amino-6-octenoyl-L-α-amino-butyryl--methylglycyl- -methyl-L-leucyl-L-valyl--methyl-L-leucyl).
Gengraf Capsules (cyclosporine capsules, USP []) are available in 25 mg, 50 mg, and 100 mg strengths.
What does Gengraf look like?
What are the available doses of Gengraf?
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What should I talk to my health care provider before I take Gengraf?
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How should I use Gengraf?
Gengraf Capsules (cyclosporine capsules, USP []) is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Cyclosporine () has been used in combination with azathioprine and corticosteroids.
Gengraf Capsules (cyclosporine capsules, USP [MODIFIED]) has increased bioavailability in comparison to Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP). Gengraf and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision.
The daily dose of Gengraf Capsules (cyclosporine capsules, USP []) 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.
What interacts with Gengraf?
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What are the warnings of Gengraf?
For screening tests in patients with hypertension, the generally available urinary assay of catecholamines or other biochemical assays have largely replaced the Phentolamine Mesylate for Injection, USP and other pharmacological tests for reasons of accuracy and safety. None of the chemical or pharmacological tests is infallible in the diagnosis of pheochromocytoma. The Phentolamine Mesylate for Injection, USP blocking test is not the procedure of choice and should be reserved for cases in which additional confirmatory evidence is necessary and the relative risks involved in conducting the test have been considered.
All Patients
Cyclosporine, the active ingredient of Gengraf Capsules (cyclosporine capsules, USP []), 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.
Patients receiving Gengraf require frequent monitoring of serum creatinine. (See Special Monitoring under ) 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 Capsules (cyclosporine capsules, USP [MODIFIED]) is not bioequivalent to Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP), 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.
Kidney, Liver, and Heart Transplant
Nephrotoxicity
Cyclosporine, the active ingredient of Gengraf Capsules (cyclosporine capsules, USP []), 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 necessarily indicate 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 to 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 to 45 mg/dL and 2.0 to 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 or several 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 concentrations 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 blood concentrations.
Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering Gengraf with other drugs that may impair renal function. (See )
Thrombotic Microangiopathy
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 )
Hyperkalemia
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.
Hepatotoxicity
Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported. (See )
Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used. The chemistry elevations usually decreased with a reduction in dosage.
Malignancies
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. Patients taking cyclosporine should be warned to avoid excess ultraviolet light exposure. 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 immunosuppressants should be used with caution. Some malignancies may be fatal. Transplant patients receiving cyclosporine are at increased risk for serious infection with fatal outcome.
Serious Infections
Patients receiving immunosuppressants, including Gengraf, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. (See and )
Polyoma Virus Infections
Patients receiving immunosuppressants, including Gengraf, are at increased risk for opportunistic infections, including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine. PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss, (See ). Patient monitoring may help detect patients at risk for PVAN.
Cases of PML have been reported in patients treated with Gengraf. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.
Neurotoxicity
There have been reports of convulsions in adult and pediatric patients receiving cyclosporine, particularly in combination with high dose methylprednisolone.
Encephalopathy, including Posterior Reversible Encephalopathy Syndrome (PRES), has been described both in post-marketing 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 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 )
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| Nephrotoxicity vs. Rejection | |||||
| Parameter | Nephrotoxicity | Rejection | |||
| History | Donor >50 years old or hypotensive Prolonged kidney preservation Prolonged anastomosis time Concomitant nephrotoxic drugs | Anti-donor immune response Retransplant patient | |||
| Clinical | Often >6 weeks postop Prolonged initial nonfunction (acute tubular necrosis) | Often <4 weeks postop Fever >37.5°C Weight gain >0.5 kg Graft swelling and tenderness Decrease in daily urine volume >500 mL (or 50%) | |||
| Laboratory | CyA serum trough level >200 ng/mL Gradual rise in Cr (<0.15 mg/dL/day) Cr plateau <25% above baseline BUN/Cr ≥20 | CyA serum trough level <150 ng/mL Rapid rise in Cr (>0.3 mg/dL/day) Cr >25% above baselineBUN/Cr <20 | |||
| Biopsy | Arteriolopathy (medial hypertrophy, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, isolated calcifications Minimal edema Mild focal infiltrates Diffuse interstitial fibrosis, often striped form | Endovasculitis (proliferation, intimal arteritis, necrosis, sclerosis) Tubulitis with RBC and WBC casts, some irregular vacuolizationInterstitial edema and hemorrhage Diffuse moderate to severe mononuclear infiltrates Glomerulitis (mononuclear cells) | |||
| Aspiration Cytology | CyA deposits in tubular and endothelial cellsFine isometric vacuolization of tubular cells | Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cellsThese strongly express HLA-DR antigens | |||
| Urine Cytology | Tubular cells with vacuolization and granularization | Degenerative tubular cells, plasma cells, and lymphocyturia >20% of sediment | |||
| ManometryUltrasonography | Intracapsular pressure <40 mm Hg Unchanged graft cross sectional area | Intracapsular pressure >40 mm Hg Increase in graft cross sectional areaAP diameter ≥ Transverse diameter | |||
| Magnetic Resonance Imagery | Normal appearance | Loss of distinct corticomedullary junction, swelling image intensity of parachyma approaching that of psoas, loss of hilar fat | |||
| Radionuclide Scan | Normal or generally decreased perfusionDecrease in tubular function( I-hippuran) > decrease in perfusion( Tc DTPA) | Patchy arterial flowDecrease in perfusion > decrease in tubular functionIncreased uptake of Indium 111 labeled platelets or Tc-99m in colloid | |||
| Therapy | Responds to decreased cyclosporine | Responds to increased steroids or antilymphocyte globulin |
Rheumatoid Arthritis
Cyclosporine nephropathy was detected in renal biopsies of 6 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 Capsules (cyclosporine capsules, USP []) 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.
Psoriasis
(See also for Psoriasis)
Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Gengraf Capsules (cyclosporine capsules, USP []) should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in Gengraf, can cause nephrotoxicity and hypertension (See ) 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 under ) 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 ≥5.0 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 the 16 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.
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Special Excipients
Alcohol (ethanol)
The alcohol content (See ) of Gengraf should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g., pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol which is approximately 6% of the amount of alcohol contained in a standard drink.
What are the precautions of Gengraf?
General
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Cyclosporine is the active ingredient of Gengraf Capsules (cyclosporine capsules, USP []). Hypertension is a common side effect of cyclosporine therapy which may persist. (See and for monitoring recommendations) Mild or moderate hypertension is encountered more frequently than severe hypertension and the incidence decreases over time. In recipients of kidney, liver, and heart allografts treated with cyclosporine, antihypertensive therapy may be required. (See ) However, since cyclosporine may cause hyperkalemia, potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in treating cyclosporine-associated hypertension, they can interfere with cyclosporine metabolism. (See )
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During treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.
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Before initiating treatment, a careful physical examination, including blood pressure measurements (on at least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure and serum creatinine should be evaluated every 2 weeks during the initial 3 months and then monthly if the patient is stable. It is advisable to monitor serum creatinine and blood pressure always after an increase of the dose of nonsteroidal anti-inflammatory drugs (NSAIDs) and after initiation of new NSAID therapy during Gengraf Capsules (cyclosporine capsules, USP []) treatment. If coadministered with methotrexate, CBC and liver function tests are recommended to be monitored monthly. (See also )
In patients who are receiving cyclosporine, the dose of Gengraf should be decreased by 25% to 50% if hypertension occurs. If hypertension persists, the dose of Gengraf should be further reduced or blood pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to baseline when cyclosporine was discontinued.
In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an occurrence of two systolic blood pressure readings >140 mmHg) and diastolic hypertension (defined as two diastolic blood pressure readings >90 mmHg) occurred in 33% and 19% of patients treated with cyclosporine, respectively. The corresponding placebo rates were 22% and 8%.
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Before initiating treatment, a careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Gengraf (cyclosporine capsules, USP []) is an immunosuppressive agent, patients should be evaluated for the presence of occult infection on their first physical examination and for the presence of tumors initially, and throughout treatment with Gengraf. Skin lesions not typical for psoriasis should be biopsied before starting Gengraf. Patients with malignant or premalignant changes of the skin should be treated with Gengraf only after appropriate treatment of such lesions and if no other treatment option exists.
Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium, potassium, uric acid, and lipids.
The risk of cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the maximum dose does not exceed 4.0 mg/kg/day, serum creatinine is monitored regularly while cyclosporine is administered, and the dose of Gengraf is decreased when the rise in creatinine is greater than or equal to 25% above the patient’s pretreatment level. The increase in creatinine is generally reversible upon timely decrease of the dose of Gengraf or its discontinuation.
Serum creatinine and BUN should be evaluated every 2 weeks during the initial 3 months of therapy and then monthly if the patient is stable. If the serum creatinine is greater than or equal to 25% above the patient's pretreatment level, serum creatinine should be repeated within two weeks. If the change in serum creatinine remains greater than or equal to 25% above baseline, Gengraf should be reduced by 25% to 50%. If at the serum creatinine increases by greater than or equal to 50% above pretreatment level, Gengraf should be reduced by 25% to 50%. Gengraf should be discontinued if reversibility (within 25% of baseline) of serum creatinine is not achievable after two dosage modifications. It is advisable to monitor serum creatinine after an increase of the dose of nonsteroidal anti-inflammatory drug and after initiation of new nonsteroidal anti-inflammatory therapy during Gengraf treatment.
Blood pressure should be evaluated every 2 weeks during the initial 3 months of therapy and then monthly if the patient is stable, or more frequently when dosage adjustments are made. Patients without a history of previous hypertension before initiation of treatment with Gengraf, should have the drug reduced by 25% to 50% if found to have sustained hypertension. If the patient continues to be hypertensive despite multiple reductions of Gengraf, then Gengraf should be discontinued. For patients with treated hypertension, before the initiation of Gengraf therapy, their medication should be adjusted to control hypertension while on Gengraf. Gengraf should be discontinued if a change in hypertension management is not effective or tolerable.
CBC, uric acid, potassium, lipids, and magnesium should also be monitored every 2 weeks for the first 3 months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments are made. Gengraf dosage should be reduced by 25% to 50% for any abnormality of clinical concern.
In controlled trials of cyclosporine in psoriasis patients, cyclosporine blood concentrations did not correlate well with either improvement or with side effects such as renal dysfunction.
Information for Patients: Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.
Patients should be informed of the necessity of repeated laboratory tests while they are receiving cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.
Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.
Patients should be advised to take Gengraf 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.
Laboratory Tests
In all patients treated with cyclosporine, renal and liver functions should be assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium, and potassium should also be monitored. Cyclosporine blood concentrations should be routinely monitored in transplant patients (See ), and periodically monitored in rheumatoid arthritis patients.
Drug Interactions
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All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of 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 )
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During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment 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 Gengraf dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly. (See )
| ciprofloxacin | melphalan | azapropazon | cimetidine | |
| gentamicin | colchicine | ranitidine | ||
| tobramycin | Antifungals | diclofenac | ||
| vancomycin | amphotericin B | naproxen | Immunosuppressives | |
| trimethoprim with sulfamethoxazole | ketoconazole | sulindac | tacrolimus | |
| Other Drugs | ||||
| fibric acid derivatives (e.g.,bezafibrate, fenofibrate) | ||||
| methotrexate |
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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 juice
Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.
| diltiazem | fluconazole | azithromycin | methylprednisolone | Allopurinol |
| nicardipine | itraconazole | clarithromycin | Amiodarone | |
| verapamil | ketoconazole | erythromycin | Bromocriptine | |
| voriconazole | quinupristin/ dalfopristin | colchicine | ||
| danazol | ||||
| imatinib | ||||
| metoclopramide | ||||
| nefazodone | ||||
| oral contraceptives |
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Bosentan
Coadministration 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 C of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, C, and trough concentration of approximately 50%, 30%, and 60%, respectively, compared to when cyclosporine was given alone (See also ). Coadministration of cyclosporine with bosentan should be avoided.
Boceprevir
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 C of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.
Telaprevir
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 C 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
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.
| nafcillin | carbamazepine | bosentan |
| rifampin | oxcarbazepine | octreotide |
| phenobarbital | orlistat | |
| phenytoin | sulfinpyrazone | |
| St. John's Wort | ||
| terbinafine | ||
| ticlopidine |
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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, P-glycoprotein 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 drugs.
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.
Digoxin
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 monitored.
Colchicine
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-CoA 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.
Repaglinide
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 0.5mg tablet) orally 13 hours after the cyclosporine initial dose, the repaglinide mean C 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.
Ambrisentan
Coadministration of ambrisentan (5 mg daily) and cyclosporine (100 to 150 mg twice daily initially, then dosing to achieve C 150 to 200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and C 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.
Anthracycline antibiotics
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.
Aliskiren
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 C 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 T (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and C 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 recommended.
Bosentan
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 ) Coadministration of cyclosporine with bosentan should be avoided.
Dabigatran
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 )
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 Tc-diethylenetriaminepentaacetic acid (DTPA) and (-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 concentrations and occasional reports of reversible decreases in renal function. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.
Methotrexate Interaction
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).
Sirolimus
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 concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine administration.
Nifedipine
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.
Methylprednisolone
Convulsions when high dose methylprednisolone is given concurrently 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 immunosuppression.
Array
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 AbbVie Inc. Medical Information Department at 1-800-633-9110.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month rat study, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose level. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6 mg/kg). The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. Published reports indicate that co-treatment of hairless mice with UV irradiation and cyclosporine or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.
Cyclosporine was not mutagenic in appropriate test systems. Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes gave indication of a positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research studies, rabbits exposed to cyclosporine (10 mg/kg/day subcutaneously) demonstrated reduced numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to 35 weeks of age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal defect. These findings have not been demonstrated in other species and their relevance for humans is unknown.
No impairment in fertility was demonstrated in studies in male and female rats.
Widely distributed papillomatosis of the skin was observed after chronic treatment of dogs with cyclosporine at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg, where doses are expressed on a body surface area basis. This papillomatosis showed a spontaneous regression upon discontinuation of cyclosporine.
An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants and patients with rheumatoid arthritis and psoriasis. The most common forms of neoplasms are non-Hodgkin's lymphoma and carcinomas of the skin. The risk of malignancies in cyclosporine recipients is higher than in the normal, healthy population but similar to that in patients receiving other immunosuppressive therapies. Reduction or discontinuance of immunosuppression may cause the lesions to regress.
In psoriasis patients on cyclosporine, development of malignancies, especially those of the skin has been reported. (See ) Skin lesions not typical for psoriasis should be biopsied before starting cyclosporine treatment. Patients with malignant or premalignant changes of the skin should be treated with cyclosporine only after appropriate treatment of such lesions and if no other treatment option exists.
Pregnancy
Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats. Cyclosporine has been shown to be embryo- and fetotoxic in rats and rabbits following oral administration at maternally toxic doses. Fetal toxicity was noted in rats at 0.8 and rabbits at 5.4 times the transplant doses in humans of 6.0 mg/kg, where dose corrections are based on body surface area. Cyclosporine was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardation.
There are no adequate and well-controlled studies in pregnant women and, therefore, Gengraf Capsules (cyclosporine capsules, USP []) should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.
In pregnant transplant recipients who are being treated with immunosuppressants the risk of premature birth is increased. The following data represent the reported outcomes of 116 pregnancies in women receiving cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom received cyclosporine throughout the entire gestational period. The only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by disorders; including, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and fetoplacental dysfunction. Pre-term delivery occurred in 47%. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were small for gestational age. Neonatal complications occurred in 27%. Therefore, the risks and benefits of using Gengraf during pregnancy should be carefully weighed.
A limited number of observations in children exposed to cyclosporine are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.
Because of the possible disruption of maternal-fetal interaction, the risk/benefit ratio of using Gengraf in psoriasis patients during pregnancy should carefully be weighed with serious consideration for discontinuation of Gengraf.
The alcohol content of the Gengraf formulations should also be taken into account in pregnant women. (See )
Nursing Mothers
Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Gengraf, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Gengraf contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant (See ).
Pediatric Use
Although no adequate and well-controlled studies have been completed in children, transplant recipients as young as one year of age have received cyclosporine () with no unusual adverse effects. The safety and efficacy of cyclosporine () treatment in children with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established.
Geriatric Use
In rheumatoid arthritis clinical trials with cyclosporine, 17.5% of patients were age 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥50% above the baseline after 3 to 4 months of therapy.
Clinical studies of cyclosporine oral solution (modified) in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
What are the side effects of Gengraf?
Kidney, Liver, and Heart Transplantation
The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism, hypertension, and gum hyperplasia.
Hypertension
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
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 included 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
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.
Clinical Studies
In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with cyclosporine () 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 (Sandimmune) 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 cyclosporine-treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, migraine (Gengraf), 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.
Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported. (See )
| Randomized Kidney Patients | Cyclosporine Patients (Sandimmune | |||||
| Renal Dysfunction | 32 | 6 | 25 | 38 | 37 | |
| Hypertension | 26 | 18 | 13 | 53 | 27 | |
| Cramps | 4 | <1 | 2 | <1 | 0 | |
| Hirsutism | 21 | <1 | 21 | 28 | 45 | |
| Acne | 6 | 8 | 2 | 2 | 1 | |
| Tremor | 12 | 0 | 21 | 31 | 55 | |
| Convulsions | 3 | 1 | 1 | 4 | 5 | |
| Headache | 2 | <1 | 2 | 15 | 4 | |
| Gum Hyperplasia | 4 | 0 | 9 | 5 | 16 | |
| Diarrhea | 3 | <1 | 3 | 4 | 8 | |
| Nausea/Vomiting | 2 | <1 | 4 | 10 | 4 | |
| Hepatotoxicity | <1 | <1 | 4 | 7 | 4 | |
| Abdominal Discomfort | <1 | 0 | <1 | 7 | 0 | |
| Paresthesia | 3 | 0 | 1 | 2 | 1 | |
| Flushing | <1 | 0 | 4 | 0 | 4 | |
| Leukopenia | 2 | 19 | <1 | 6 | 0 | |
| Lymphoma | <1 | 0 | 1 | 6 | 1 | |
| Sinusitis | <1 | 0 | 4 | 3 | 7 | |
| Gynecomastia | <1 | 0 | <1 | 4 | 3 | |
| Complication | ||||||
| Septicemia | 5.3 | 4.8 | ||||
| Abscesses | 4.4 | 5.3 | ||||
| Systemic Fungal Infection | 2.2 | 3.9 | ||||
| Local Fungal Infection | 7.5 | 9.6 | ||||
| Cytomegalovirus | 4.8 | 12.3 | ||||
| Other Viral Infections | 15.9 | 18.4 | ||||
| Urinary Tract Infections | 21.1 | 20.2 | ||||
| Wound and Skin Infections | 7.0 | 10.1 | ||||
| Pneumonia | 6.2 | 9.2 | ||||
Postmarketing Experience, Kidney, Liver and Heart Transplantation
Hepatotoxicity
Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported. (See )
Increased Risk of Infections
Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported. (See )
Headache, including Migraine
Cases of migraine have been reported. In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks.
Pain of lower extremities
Isolated cases of pain of lower extremities have been reported in association with cyclosporine. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature.
Rheumatoid Arthritis
The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction (See ), hypertension (See ), 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.
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.
| Autonomic Nervous System Disorders | |||||||
| Flushing | 2% | 2% | 3% | 0% | 5% | 2% | |
| Body As A Whole–General Disorders | |||||||
| Accidental Trauma | 0% | 1% | 10% | 4% | 4% | 0% | |
| Edema NOS* | 5% | 14% | 12% | 4% | 10% | <1% | |
| Fatigue | 6% | 3% | 8% | 12% | 3% | 7% | |
| Fever | 2% | 3% | 0% | 0% | 2% | 4% | |
| Influenza-like symptoms | <1% | 6% | 1% | 0% | 3% | 2% | |
| Pain | 6% | 9% | 10% | 15% | 13% | 4% | |
| Rigors | 1% | 1% | 4% | 0% | 3% | 1% | |
| Cardiovascular Disorders | |||||||
| Arrhythmia | 2% | 5% | 5% | 6% | 2% | 1% | |
| Chest Pain | 4% | 5% | 1% | 1% | 6% | 1% | |
| Hypertension | 8% | 26% | 16% | 12% | 25% | 2% | |
| Central and Peripheral Nervous System Disorders | |||||||
| Dizziness | 8% | 6% | 7% | 3% | 8% | 3% | |
| Headache | 17% | 23% | 22% | 11% | 25% | 9% | |
| Migraine | 2% | 3% | 0% | 0% | 3% | 1% | |
| Paresthesia | 8% | 7% | 8% | 4% | 11% | 1% | |
| Tremor | 8% | 7% | 7% | 3% | 13% | 4% | |
| Gastrointestinal System Disorders | |||||||
| Abdominal Pain | 15% | 15% | 15% | 7% | 15% | 10% | |
| Anorexia | 3% | 3% | 1% | 0% | 3% | 3% | |
| Diarrhea | 12% | 12% | 18% | 15% | 13% | 8% | |
| Dyspepsia | 12% | 12% | 10% | 8% | 8% | 4% | |
| Flatulence | 5% | 5% | 5% | 4% | 4% | 1% | |
| Gastrointestinal Disorder NOS* | 0% | 2% | 1% | 4% | 4% | 0% | |
| Gingivitis | 4% | 3% | 0% | 0% | 0% | 1% | |
| Gum Hyperplasia | 2% | 4% | 1% | 3% | 4% | 1% | |
| Nausea | 23% | 14% | 24% | 15% | 18% | 14% | |
| Rectal Hemorrhage | 0% | 3% | 0% | 0% | 1% | 1% | |
| Stomatitis | 7% | 5% | 16% | 12% | 6% | 8% | |
| Vomiting | 9% | 8% | 14% | 7% | 6% | 5% | |
| Hearing and Vestibular Disorders | |||||||
| Ear Disorder NOS* | 0% | 5% | 0% | 0% | 1% | 0% | |
| Metabolic and Nutritional Disorders | |||||||
| Hypomagnesemia | 0% | 4% | 0% | 0% | 6% | 0% | |
| Musculoskeletal System Disorders | |||||||
| Arthropathy | 0% | 5% | 0% | 1% | 4% | 0% | |
| Leg Cramps /Involuntary Muscle Contractions | 2% | 11% | 11% | 3% | 12% | 1% | |
| Psychiatric Disorders | |||||||
| Depression | 3% | 6% | 3% | 1% | 1% | 2% | |
| Insomnia | 4% | 1% | 1% | 0% | 3% | 2% | |
| Renal | |||||||
| Creatinine elevations ≥30% | 43% | 39% | 55% | 19% | 48% | 13% | |
| Creatinine elevations ≥50% | 24% | 18% | 26% | 8% | 18% | 3% | |
| Reproductive Disorders, Female | |||||||
| Leukorrhea | 1% | 0% | 4% | 0% | 1% | 0% | |
| Menstrual Disorder | 3% | 2% | 1% | 0% | 1% | 1% | |
| Respiratory System Disorders | |||||||
| Bronchitis | 1% | 3% | 1% | 0% | 1% | 3% | |
| Coughing | 5% | 3% | 5% | 7% | 4% | 4% | |
| Dyspnea | 5% | 1% | 3% | 3% | 1% | 2% | |
| Infection NOS* | 9% | 5% | 0% | 7% | 3% | 10% | |
| Pharyngitis | 3% | 5% | 5% | 6% | 4% | 4% | |
| Pneumonia | 1% | 0% | 4% | 0% | 1% | 1% | |
| Rhinitis | 0% | 3% | 11% | 10% | 1% | 0% | |
| Sinusitis | 4% | 4% | 8% | 4% | 3% | 3% | |
| Upper Respiratory Tract | 0% | 14% | 23% | 15% | 13% | 0% | |
| Skin and Appendages Disorders | |||||||
| Alopecia | 3% | 0% | 1% | 1% | 4% | 4% | |
| Bullous Eruption | 1% | 0% | 4% | 1% | 1% | 1% | |
| Hypertrichosis | 19% | 17% | 12% | 0% | 15% | 3% | |
| Rash | 7% | 12% | 10% | 7% | 8% | 10% | |
| Skin Ulceration | 1% | 1% | 3% | 4% | 0% | 2% | |
| Urinary System Disorders | |||||||
| Dysuria | 0% | 0% | 11% | 3% | 1% | 2% | |
| Micturition Frequency | 2% | 4% | 3% | 1% | 2% | 2% | |
| NPN, Increased | 0% | 19% | 12% | 0% | 18% | 0% | |
| Urinary Tract Infection | 0% | 3% | 5% | 4% | 3% | 0% | |
| Vascular (Extracardiac) Disorders | |||||||
| Purpura | 3% | 4% | 1% | 1% | 2% | 0% | |
Autonomic Nervous System: dry mouth, increased sweating
Body as a Whole: allergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase
Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia
Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo
Endocrine: goiter
Gastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder
Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection
Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy
Liver and Biliary System: bilirubinemia
Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia
Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder
Neoplasms: breast fibroadenosis, carcinoma
Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence
Reproductive (Female): breast pain, uterine hemorrhage
Respiratory System: abnormal chest sounds, bronchospasm
Skin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria
Special Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder
Urinary System: abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence
*NOS=Not Otherwise Specified
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 US 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:
| Body System* | Preferred Term | ||
| Infection or Potential Infection | 24.7% | 24.3% | |
| Influenza-Like Symptoms | 9.9% | 8.1% | |
| Upper Respiratory Tract Infections | 7.7% | 11.3% | |
| Cardiovascular System | 28.0% | 25.4% | |
| Hypertension** | 27.5% | 25.4% | |
| Urinary System | 24.2% | 16.2% | |
| Increased Creatinine | 19.8% | 15.7% | |
| Central and Peripheral Nervous System | 26.4% | 20.5% | |
| Headache | 15.9% | 14.0% | |
| Paresthesia | 7.1% | 4.8% | |
| Musculoskeletal System | 13.2% | 8.7% | |
| Arthralgia | 6.0% | 1.1% | |
| Body As a Whole–General | 29.1% | 22.2% | |
| Pain | 4.4% | 3.2% | |
| Metabolic and Nutritional | 9.3% | 9.7% | |
| Reproductive, Female | 8.5% (4 of 47 females) | 11.5% (6 of 52 females) | |
| Resistance Mechanism | 18.7% | 21.1% | |
| Skin and Appendages | 17.6% | 15.1% | |
| Hypertrichosis | 6.6% | 5.4% | |
| Respiratory System | 5.0% | 6.5% | |
| Bronchospasm, Coughing, Dyspnea, Rhinitis | 5.0% | 4.9% | |
| Psychiatric | 5.0% | 3.8% | |
| Gastrointestinal System | 19.8% | 28.7% | |
| Abdominal Pain | 2.7% | 6.0% | |
| Diarrhea | 5.0% | 5.9% | |
| Dyspepsia | 2.2% | 3.2% | |
| Gum Hyperplasia | 3.8% | 6.0% | |
| Nausea | 5.5% | 5.9% | |
| White cell and RES | 4.4% | 2.7% | |
Body as a Whole: fever, flushes, hot flushes
Cardiovascular: chest pain
Central and Peripheral Nervous System: appetite increased, insomnia, dizziness, nervousness, vertigo
Gastrointestinal: abdominal distention, constipation, gingival bleeding
Liver and Biliary System: hyperbilirubinemia
Neoplasms: skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas]
Reticuloendothelial: platelet, bleeding, and clotting disorders, red blood cell disorder
Respiratory: infection, viral and other infection
Skin and Appendages: acne, folliculitis, keratosis, pruritus, rash, dry skin
Urinary System: micturition frequency
Array
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.
Array
Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of cyclosporine in patients with chronic plaque psoriasis have been reported.
What should I look out for while using Gengraf?
(See also )
What might happen if I take too much Gengraf?
There is a minimal experience with cyclosporine overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of Gengraf Capsules (cyclosporine capsules, USP []). Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150 mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness, headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function. However, serious symptoms of intoxication have been reported following accidental parenteral overdosage with cyclosporine in premature neonates. 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 (6mg/kg; corrections based on body surface area) in mice, rats, and rabbits.
How should I store and handle Gengraf?
Store at 20º to 25ºC (68º to 77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].The tablets are available in the following strengths: 3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side, 6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side, 12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side, 25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.The tablets are available in the following strengths: 3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side, 6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side, 12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side, 25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.The tablets are available in the following strengths: 3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side, 6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side, 12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side, 25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.The tablets are available in the following strengths: 3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side, 6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side, 12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side, 25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.The tablets are available in the following strengths: 3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side, 6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side, 12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side, 25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.The tablets are available in the following strengths: 3.125 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and plain on the other side, 6.25 mg – White, film coated circular shaped tablets with ‘G’ engraved on one side and ‘41’ engraved on the other side, 12.5 mg – White, film coated capsule shaped tablets with ‘G’ engraved on one side and ‘164’ engraved on the other side, 25 mg – White, film coated circular shaped tablets with ‘G41’ engraved on one side and ‘25’ engraved on the other side.Store below 30°C (86°F). Protect from moisture. Dispense in a tight, light-resistant container.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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 versus host disease in many animal species for 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 ) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.
Non-Clinical Toxicology
(See also )Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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