Restasis

How old is patient? < 1 1-5 6-15 16-29 30-45 46-60 > 60

Restasis uses

• Warning
• For psoriasis patients (see also boxed warning above)
• Description
• Clinical pharmacology
• Clinical trials
• Indications and usage
• Contraindications
• Warnings
• Precautions
• Laboratory tests
• Drug interactions
• Carcinogenesis, mutagenesis, and impairment of fertility
• Pregnancy
• Nursing mothers
• Pediatric use
• Geriatric use
• Adverse reactions
• Overdosage
• Dosage and administration
• How supplied
• Restasis reviews

WARNING

Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Restasis. At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Restasis. 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.

Restasis, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Restasis 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.

Restasis Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED have increased bioavailability in comparison to Sandimmune Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune Oral Solution (cyclosporine oral solution, USP). Restasis and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, Restasis exposure will be greater with Restasis than with Sandimmune. If a patient who is receiving exceptionally high doses of Sandimmune is converted to Restasis, particular caution should be exercised. Restasis blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Restasis 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

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 Restasis.

Restasis, the active ingredient in Restasis, in recommended dosages, can cause systemic hypertension and nephrotoxicity. The risk increases with increasing dose and duration of Restasis therapy. Renal dysfunction, including structural kidney damage, is a potential consequence of Restasis, and therefore, renal function must be monitored during therapy.

DESCRIPTION

Restasis is an oral formulation of Restasis that immediately forms a microemulsion in an aqueous environment.

Restasis, the active principle in Restasis, is a cyclic polypeptide immunosuppressant agent consisting of 11 amino acids. It is produced as a metabolite by the fungus species Beauveria nivea.

Chemically, Restasis is designated as [R-[R*,R *-]]-cyclic-(L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α -amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).

chemical structure of Restasis

Restasis Soft Gelatin Capsules

(cyclosporine capsules, USP) MODIFIED are available in 25 mg and 100 mg strengths.

Each 25 mg capsule contains:

cyclosporine………………………………………………………………………………25 mg

alcohol, USP dehydrated...11.9% v/v (9.5% wt/vol.)

Each 100 mg capsule contains:

cyclosporine……………………………………………………………………………...100 mg

alcohol, USP dehydrated...11.9% v/v (9.5% wt/vol.)

Inactive Ingredients: Corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-α-tocopherol USP, gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium dioxide USP, carmine, and other ingredients.

Restasis Oral Solution

(cyclosporine oral solution, USP) MODIFIED is available in 50 mL bottles.

Each mL contains:

cyclosporine……………………...100 mg/mL

alcohol, USP dehydrated...11.9% v/v (9.5% wt/vol.)

Inactive Ingredients: Corn oil-mono-di-triglycerides, polyoxyl 40 hydrogenated castor oil NF, DL-α -tocopherol USP, propylene glycol USP.

The chemical structure of Restasis (also known as cyclosporin A) is:

CLINICAL PHARMACOLOGY

Restasis 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. Restasis 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 Restasis results from specific and reversible inhibition of immunocompetent lymphocytes in the G₀- and G₁-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. Restasis also inhibits lymphokine production and release including interleukin-2.

No effects on phagocytic function have been detected in animals. Restasis does not cause bone marrow suppression in animal models or man.

Pharmacokinetics

The immunosuppressive activity of Restasis is primarily due to parent drug. Following oral administration, absorption of Restasis is incomplete. The extent of absorption of Restasis is dependent on the individual patient, the patient population, and the formulation. Elimination of Restasis is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in urine. The disposition of Restasis 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 Restasis (assay: HPLC) is approximately 5 to 7 mL/min/kg in adult recipients of renal or liver allografts. Blood Restasis clearance appears to be slightly slower in cardiac transplant patients.

The Restasis Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED are bioequivalent. Restasis Oral Solution diluted with orange juice or apple juice is bioequivalent to Restasis Oral Solution diluted with water. The effect of milk on the bioavailability of Restasis when administered as Restasis Oral Solution has not been evaluated.

The relationship between 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 Restasis exposure (AUC) when Restasis 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 . Intrasubject variability of AUC in renal transplant recipients (%CV) was 9% to 21% for Restasis and 19% to 26% for Sandimmune. In the same studies, intrasubject variability of trough concentrations (%CV) was 17% to 30% for Restasis and 16% to 38% for Sandimmune.

Absorption

Restasis has increased bioavailability compared to Sandimmune. The absolute bioavailability of Restasis administered as Sandimmune 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 Restasis administered as Restasis has not been determined in adults. In studies of renal transplant, rheumatoid arthritis and psoriasis patients, the mean Restasis AUC was approximately 20% to 50% greater and the peak blood Restasis concentration was approximately 40% to 106% greater following administration of Restasis compared to following administration of Sandimmune. The dose normalized AUC in de novo liver transplant patients administered Restasis 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune. AUC and Cmax are also increased (Neoral relative to Sandimmune) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on Restasis relative to Sandimmune, the predose trough concentrations (dose-normalized) are similar for the two formulations.

Following oral administration of Restasis, the time to peak blood Restasis concentrations (T_max) ranged from 1.5 to 2.0 hours. The administration of food with Restasis decreases the Restasis AUC and C_max. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Restasis administration decreased the AUC by 13% and C_max by 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 Restasis from Restasis was investigated in eleven de novo liver transplant patients. When the patients were administered Restasis with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal Restasis blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range -55% to 68%).

Pharmacokinetic Parameters (mean±SD)
	Dose/day 1	Dose/weight	AUC 2	C max	Trough 3	CL/F	CL/F
Patient Population	(mg/d)	(mg/kg/d)	(ng·hr/mL)	(ng/mL)	(ng/mL)	(mL/min)	(mL/min/kg)
De novo renal transplant4	597±174	7.95±2.81	8772±2089	1802±428	361±129	593±204	7.8±2.9
Week 4 (N=37)
Stable renal transplant4	344±122	4.10±1.58	6035±2194	1333±469	251±116	492±140	5.9±2.1
(N=55)
De novo liver transplant5	458±190	6.89±3.68	7187±2816	1555±740	268±101	577±309	8.6±5.7
Week 4 (N=18)
De novo rheumatoid arthritis6	182±55.6	2.37±0.36	2641±877	728±263	96.4±37.7	613±196	8.3±2.8
(N=23)
De novo psoriasis6	189±69.8	2.48±0.65	2324±1048	655±186	74.9±46.7	723±186	10.2±3.9
Week 4 (N=18)
1Total daily dose was divided into two doses administered every 12 hours 2AUC was measured over one dosing interval 3Trough concentration was measured just prior to the morning Restasis dose, approximately 12 hours after the previous dose 4Assay: TDx specific monoclonal fluorescence polarization immunoassay 5Assay: Cyclo-trac specific monoclonal radioimmunoassay 6Assay: INCSTAR specific monoclonal radioimmunoassay

Distribution

Restasis is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3 to 5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33% to 47% is in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes, and 41% to 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. Restasis is excreted in human milk.

Metabolism

Restasis is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of Restasis can be altered by the coadministration of a variety of agents. 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 Restasis concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered Restasis and Sandimmune in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered Restasis, 3 administered Sandimmune), the percentage of dose present as M1, M9, and M4N metabolites is similar when either Restasis or Sandimmune is administered.

Excretion

Only 0.1% of a Restasis 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 alters Restasis clearance significantly.

Drug Interactions

When diclofenac or methotrexate was coadministered with Restasis in rheumatoid arthritis patients, the AUC of diclofenac and methotrexate, each was significantly increased. No clinically significant pharmacokinetic interactions occurred between Restasis and aspirin, ketoprofen, piroxicam, or indomethacin.

Specific Populations

Renal Impairment

In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5 mL/min), an intravenous infusion of 3.5 mg/kg of Restasis over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of Restasis in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of Restasis on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of Restasis was recovered in the dialysate.

Hepatic Impairment

Restasis is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased Restasis exposures, the dosage of Restasis may need to be reduced in these patients.

Pediatric Population

Pharmacokinetic data from pediatric patients administered Restasis or Sandimmune are very limited. In 15 renal transplant patients aged 3-16 years, Restasis whole blood clearance after IV administration of Sandimmune was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal transplant patients aged 2-16, the Restasis clearance ranged from 9.8-15.5 mL/min/kg. In 9 liver transplant patients aged 0.6-5.6 years, clearance was 9.3±5.4 mL/min/kg (assay: HPLC).

In the pediatric population, Restasis also demonstrates an increased bioavailability as compared to Sandimmune. In 7 liver de novo transplant patients aged 1.4-10 years, the absolute bioavailability of Restasis was 43% (range 30%-68%) and for Sandimmune in the same individuals absolute bioavailability was 28% (range 17%-42%).

Pediatric Pharmacokinetic Parameters (mean±SD)
	Dose/day	Dose/weight	AUC 1	C max	CL/F	CL/F
Patient Population	(mg/d)	(mg/kg/d)	(ng·hr/mL)	(ng/mL)	(mL/min)	(mL/min/kg)
Stable liver transplant2
Age 2-8, Dosed TID (N=9)	101±25	5.95±1.32	2163±801	629±219	285±94	16.6±4.3
Age 8-15, Dosed BID (N=8)	188±55	4.96±2.09	4272±1462	975±281	378±80	10.2±4.0
Stable liver transplant3
Age 3, Dosed BID (N=1)	120	8.33	5832	1050	171	11.9
Age 8-15, Dosed BID (N=5)	158±55	5.51±1.91	4452±2475	1013±635	328±121	11.0±1.9
Stable renal transplant3
Age 7-15, Dosed BID (N=5)	328±83	7.37±4.11	6922±1988	1827±487	418±143	8.7±2.9
1AUC was measured over one dosing interval 2Assay: Cyclo-trac specific monoclonal radioimmunoassay 3Assay: TDx specific monoclonal fluorescence polarization immunoassay

Geriatric Population

Comparison of single dose data from both normal elderly volunteers (N=18, mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age 68 years) to single dose data in young adult volunteers (N=16, mean age 26 years) showed no significant difference in the pharmacokinetic parameters.

CLINICAL TRIALS

Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to 1 of 2 treatment groups Neoral® and (2) Restasis, both of which were started at 2.5 mg/kg/day and increased after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of 5 mg/kg/day and decreased at any time for toxicity. Treatment duration was 24 weeks. The mean Restasis dose at the last visit was 2.91 mg/kg/day (range: 0.72-5.17) for Neoral® and 3.27 mg/kg/day (range: 0.73 5.68) for Restasis.

Rheumatoid Arthritis

The effectiveness of Sandimmune and Restasis in the treatment of severe rheumatoid arthritis was evaluated in 5 clinical studies involving a total of 728 Restasis treated patients and 273 placebo treated patients.

A summary of the results is presented for the “responder” rates per treatment group, with a responder being defined as a patient having completed the trial with a 20% improvement in the tender and the swollen joint count and a 20% improvement in 2 of 4 of investigator global, patient global, disability, and erythrocyte sedimentation rates (ESR) for the Studies 651 and 652 and 3 of 5 of investigator global, patient global, disability, visual analog pain, and ESR for Studies 2008, 654 and 302.

Study 651 enrolled 264 patients with active rheumatoid arthritis with at least 20 involved joints, who had failed at least one major RA drug, using a 3:3:2 randomization to one of the following three groups: (1) Restasis dosed at 2.5 to 5 mg/kg/day, (2) methotrexate at 7.5 to 15 mg/week, or (3) placebo. Treatment duration was 24 weeks. The mean Restasis dose at the last visit was 3.1 mg/kg/day. See Graph below.

Study 652 enrolled 250 patients with active RA with >6 active painful or tender joints who had failed at least one major RA drug. Patients were randomized using a 3:3:2 randomization to 1 of 3 treatment arms: (1) 1.5 to 5 mg/kg/day of Restasis, (2) 2.5 to 5 mg/kg/day of Restasis, and (3) placebo. Treatment duration was 16 weeks. The mean Restasis dose for group 2 at the last visit was 2.92 mg/kg/day. See Graph below.

Study 2008 enrolled 144 patients with active RA and >6 active joints who had unsuccessful treatment courses of aspirin and gold or Penicillamine. Patients were randomized to 1 of 2 treatment groups (1) Restasis 2.5 to 5 mg/kg/day with adjustments after the first month to achieve a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean Restasis dose at the last visit was 3.63 mg/kg/day. See Graph below.

Study 654 enrolled 148 patients who remained with active joint counts of 6 or more despite treatment with maximally tolerated methotrexate doses for at least three months. Patients continued to take their current dose of methotrexate and were randomized to receive, in addition, one of the following medications: (1) Restasis 2.5 mg/kg/day with dose increases of 0.5 mg/kg/day at weeks 2 and 4 if there was no evidence of toxicity and further increases of 0.5 mg/kg/day at weeks 8 and 16 if a <30% decrease in active joint count occurred without any significant toxicity; dose decreases could be made at any time for toxicity or (2) placebo. Treatment duration was 24 weeks. The mean Restasis dose at the last visit was 2.8 mg/kg/day (range: 1.3-4.1). See Graph below.

Study 302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive or intolerant to at least one prior major RA drug. Patients were randomized to 1 of 2 treatment groups (1) Restasis and (2) Restasis, both of which were started at 2.5 mg/kg/day and increased after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of 5 mg/kg/day and decreased at any time for toxicity. Treatment duration was 24 weeks. The mean Restasis dose at the last visit was 2.91 mg/kg/day (range: 0.72 to 5.17) for Restasis and 3.27 mg/kg/day (range: 0.73 to 5.68) for Restasis. See Graph below.

INDICATIONS AND USAGE

Kidney, Liver, and Heart Transplantation

Restasis is indicated for the prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants. Restasis has been used in combination with azathioprine and corticosteroids.

Rheumatoid Arthritis

Restasis is indicated for the treatment of patients with severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate. Restasis can be used in combination with methotrexate in rheumatoid arthritis patients who do not respond adequately to methotrexate alone.

Psoriasis

Restasis 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 Restasis as with other therapies upon cessation of treatment.

CONTRAINDICATIONS

General

Restasis is contraindicated in patients with a hypersensitivity to Restasis or to any of the ingredients of the formulation.

Rheumatoid Arthritis

Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Restasis.

Psoriasis

Psoriasis patients who are treated with Restasis 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 Restasis.

WARNINGS

All Patients

Restasis, the active ingredient of Restasis, can cause nephrotoxicity and hepatotoxicity. The risk increases with increasing doses of Restasis. Renal dysfunction including structural kidney damage is a potential consequence of Restasis and therefore renal function must be monitored during therapy. Care should be taken in using Restasis with nephrotoxic drugs.

Patients receiving Restasis require frequent monitoring of serum creatinine. 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, Restasis 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 Restasis 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 Restasis therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.

Because Restasis is not bioequivalent to Sandimmune, conversion from Restasis to Sandimmune using a 1:1 ratio (mg/kg/day) may result in lower Restasis blood concentrations. Conversion from Restasis to Sandimmune should be made with increased monitoring to avoid the potential of underdosing.

Kidney, Liver, and Heart Transplant

Nephrotoxicity

Restasis, the active ingredient of Restasis, can cause nephrotoxicity and hepatotoxicity when used in high doses. It is not unusual for serum creatinine and BUN levels to be elevated during Restasis 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 Restasis 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 Restasis 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 Restasis 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.

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 postopb Prolonged initial nonfunction	Often < 4 weeks postopb 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)a Cr plateau < 25% above baseline BUN/Cr ≥ 20	CyA serum trough level < 150 ng/mL Rapid rise in Cr (> 0.3 mg/dL/day)a Cr > 25% above baseline BUN/Cr < 20
Biopsy	Arteriolopathy (medial hypertrophy a, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) Tubular atrophy, isometric vacuolization, isolated calcifications Minimal edema Mild focal infiltratesc Diffuse interstitial fibrosis, often striped form	Endovasculitisc (proliferationa, intimal arteritisb, necrosis, sclerosis) Tubulitis with RBCb and WBCb casts, some irregular vacuolization Interstitial edemac and hemorrhageb Diffuse moderate to severe mononuclear infiltratesd Glomerulitis (mononuclear cells)c
Aspiration Cytology	CyA deposits in tubular and endothelial cells Fine isometric vacuolization of tubular cells	Inflammatory infiltrate with mononuclear phagocytes, macrophages, lymphoblastoid cells, and activated T-cells These strongly express HLA-DR antigens
Urine Cytology	Tubular cells with vacuolization and granularization	Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment
Manometry Ultrasonography	Intracapsular pressure < 40 mm Hgb Unchanged graft cross sectional area	Intracapsular pressure > 40 mm Hgb Increase in graft cross sectional area AP 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 perfusion Decrease in tubular function (131 I-hippuran) > decrease in perfusion (99m Tc DTPA)	Patchy arterial flow Decrease in perfusion > decrease in tubular function Increased uptake of Indium 111 labeled platelets or Tc-99m in colloid
Therapy	Responds to decreased Restasis	Responds to increased steroids or antilymphocyte globulin
ap < 0.05, bp < 0.01, cp < 0.001, dp < 0.0001

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 Restasis will fail to show a reduction in rising serum creatinine despite a decrease or discontinuation of Restasis 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 Restasis. 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 Restasis. 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 Restasis 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 Restasis dose to excessive blood concentrations.

Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering Restasis with other drugs that may impair renal function. (See PRECAUTIONS, Drug Interactions)

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 Restasis and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans.

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 Restasis. 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 ADVERSE REACTIONS, Postmarketing Experience, Kidney, Liver and Heart Transplantation)

Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with Restasis 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 Restasis were used. The chemistry elevations usually decreased with a reduction in dosage.

Malignancies

As in patients receiving other immunosuppressants, those patients receiving Restasis are at increased risk for development of lymphomas and other malignancies, particularly those of the skin. Patients taking Restasis 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 Restasis are at increased risk for serious infection with fatal outcome.

Serious Infections

Patients receiving immunosuppressants, including Restasis, 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 BOXED WARNING, and ADVERSE REACTIONS)

Polyoma Virus Infections

Patients receiving immunosuppressants, including Restasis, 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 Restasis. PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss, (See ADVERSE REACTIONS, Postmarketing Experience, Kidney, Liver and Heart Transplantation). Patient monitoring may help detect patients at risk for PVAN.

Cases of PML have been reported in patients treated with Restasis. 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 Restasis, 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 Restasis 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 Restasis, 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 Restasis with nephrotoxic drugs.

Rheumatoid Arthritis

Restasis 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 Restasis. The “maximal creatinine increase” appears to be a factor in predicting Restasis nephropathy.

There is a potential, as with other immunosuppressive agents, for an increase in the occurrence of malignant lymphomas with Restasis. It is not clear whether the risk with Restasis 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 Restasis 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 Restasis other than for malignant lymphomas.

Patients should be thoroughly evaluated before and during Restasis treatment for the development of malignancies. Moreover, use of Restasis therapy with other immunosuppressive agents may induce an excessive immunosuppression which is known to increase the risk of malignancy.

Psoriasis

Since Restasis is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Restasis should be considered before treatment of patients with psoriasis. Restasis, the active ingredient in Restasis, can cause nephrotoxicity and hypertension 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 Restasis.

Renal dysfunction is a potential consequence of Restasis therefore renal function must be monitored during therapy.

Patients receiving Restasis require frequent monitoring of serum creatinine. 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, Restasis therapy can cause structural kidney damage and persistent renal dysfunction.

An increase in serum creatinine and BUN may occur during Restasis 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 Restasis showed evidence of Restasis 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 Restasis for a mean of 2 additional years, the number with Restasis 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 Restasis 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 Restasis 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 Restasis worldwide from clinical trials. Additional tumors have been reported in 7 patients in Restasis 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 Restasis 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 Restasis. There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon discontinuation of Restasis, 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 Restasis and PUVA or UVB, other radiation therapy, or other immunosuppressive agents, because of the possibility of excessive immunosuppression and the subsequent risk of malignancies. 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 Restasis only after complete resolution of suspicious lesions, and only if there are no other treatment options.

Special Excipients

Alcohol (ethanol)

The alcohol content (See DESCRIPTION) of Restasis 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.

PRECAUTIONS

General

Hypertension

Restasis is the active ingredient of Restasis. Hypertension is a common side effect of Restasis therapy which may persist. 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 Restasis, antihypertensive therapy may be required. However, since Restasis 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 Restasis metabolism.

Vaccination

During treatment with Restasis, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.

Special Monitoring of Rheumatoid Arthritis Patients

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 Restasis treatment. If coadministered with methotrexate, CBC and liver function tests are recommended to be monitored monthly.

In patients who are receiving Restasis, the dose of Restasis should be decreased by 25% to 50% if hypertension occurs. If hypertension persists, the dose of Restasis should be further reduced or blood pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to baseline when Restasis 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 Restasis, respectively. The corresponding placebo rates were 22% and 8%.

Special Monitoring for Psoriasis Patients

Before initiating treatment, a careful dermatological and physical examination, including blood pressure measurements (on at least two occasions) should be performed. Since Restasis 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 Restasis. Skin lesions not typical for psoriasis should be biopsied before starting Restasis. Patients with malignant or premalignant changes of the skin should be treated with Restasis 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 Restasis 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 Restasis is administered, and the dose of Restasis 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 Restasis 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, Restasis should be reduced by 25% to 50%. If at any time the serum creatinine increases by greater than or equal to 50% above pretreatment level, Restasis should be reduced by 25% to 50%. Restasis 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 Restasis 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 Restasis, should have the drug reduced by 25%-50% if found to have sustained hypertension. If the patient continues to be hypertensive despite multiple reductions of Restasis, then Restasis should be discontinued. For patients with treated hypertension, before the initiation of Restasis therapy, their medication should be adjusted to control hypertension while on Restasis. Restasis 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. Restasis dosage should be reduced by 25%–50% for any abnormality of clinical concern.

In controlled trials of Restasis in psoriasis patients, Restasis 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 Restasis 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 Restasis. 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 Restasis, vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Patients should be given careful dosage instructions. Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED should be diluted, preferably with orange or apple juice that is at room temperature. The combination of Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED with milk can be unpalatable.

Patients should be advised to take Restasis on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of Restasis, thus should be avoided.

Laboratory Tests

In all patients treated with Restasis, 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. Restasis blood concentrations should be routinely monitored in transplant patients , and periodically monitored in rheumatoid arthritis patients.

Drug Interactions

A. Effect of Drugs and Other Agents on Restasis Pharmacokinetics and/or Safety

All of the individual drugs cited below are well substantiated to interact with Restasis. In addition, concomitant use of NSAIDs with Restasis, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function. (See WARNINGS, Nephrotoxicity)

Drugs That May Potentiate Renal Dysfunction

Antibiotics	Antineoplastics	Antifungals	Anti-inflammatory Drugs	Gastrointestinal Agents	Immunosuppressives	Other Drugs
ciprofloxacin	melphalan	amphotericin B	azapropazon	cimetidine	tacrolimus	fibric acid derivatives
gentamicin		ketoconazole	colchicine	ranitidine		(e.g., bezafibrate, fenofibrate)
tobramycin			diclofenac			methotrexate
vancomycin			naproxen
trimethoprim with sulfamethoxazole			sulindac

During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with Restasis, 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.

Restasis 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 Restasis usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease Restasis absorption such as orlistat should be avoided. Appropriate Restasis dosage adjustment to achieve the desired Restasis concentrations is essential when drugs that significantly alter Restasis concentrations are used concomitantly.

1. Drugs That Increase Restasis Concentrations

Calcium Channel Blockers	Antifungals	Antibiotics	Glucocorticoids	Other Drugs
diltiazem	fluconazole	azithromycin	methylprednisolone	Allopurinol
nicardipine	itraconazole	clarithromycin		Amiodarone
verapamil	ketoconazole	erythromycin		Bromocriptine
	voriconazole	quinupristin/ dalfopristin		colchicine
				danazol
				imatinib
				metoclopramide
				nefazodone
				oral contraceptives

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 Restasis, 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 Restasis, thus should be avoided.

2. Drugs/Dietary Supplements That Decrease Restasis Concentrations

Antibiotics	Anticonvulsants	Other Drugs/Dietary Supplements
nafcillin	carbamazepine	bosentan	St. John’s Wort
rifampin	oxcarbazepine	octreotide
	phenobarbital	orlistat
	phenytoin	sulfinpyrazone
		terbinafine
		ticlopidine

Bosentan

Coadministration of bosentan (250 to 1000 mg every 12 hours based on tolerability) and Restasis (300 mg every 12 hours for 2 days then dosing to achieve a C_min of 200 to 250 ng/mL) for 7 days in healthy subjects resulted in decreases in the Restasis mean dose-normalized AUC, C_max, and trough concentration of approximately 50%, 30%, and 60%, respectively, compared to when Restasis was given alone . Coadministration of Restasis with bosentan should be avoided.

Boceprevir

Coadministration of boceprevir (800 mg three times daily for 7 days) and Restasis (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and C_max of Restasis approximately 2.7-fold and 2-fold, respectively, compared to when Restasis was given alone.

Telaprevir

Coadministration of telaprevir (750 mg every 8 hours for 11 days) with Restasis (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and C_max of Restasis approximately 4.5-fold and 1.3-fold, respectively, compared to when Restasis (100 mg single dose) was given alone.

St. John’s Wort

There have been reports of a serious drug interaction between Restasis and the herbal dietary supplement St. John’s Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of Restasis, 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 Restasis has not been studied. Care should be exercised when these two drugs are administered concomitantly.

B. Effect of Restasis on the Pharmacokinetics and/or Safety of Other Drugs or Agents

Restasis 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.

Restasis 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 Restasis 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 Restasis in several patients taking digoxin. If digoxin is used concurrently with Restasis, serum digoxin concentrations should be monitored.

Colchicine

There are reports on the potential of Restasis to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. Concomitant administration of Restasis and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with Restasis, 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 Restasis with lovastatin, simvastatin, atorvastatin, pravastatin, and, rarely fluvastatin. When concurrently administered with Restasis, 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

Restasis 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 Restasis 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 Restasis initial dose, the repaglinide mean C_max 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 Restasis and repaglinide concomitantly.

Ambrisentan

Coadministration of ambrisentan (5 mg daily) and Restasis (100 to 150 mg twice daily initially, then dosing to achieve C_min 150 to 200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and C_max of approximately 2-fold and 1.5–fold, respectively, compared to ambrisentan alone. When coadministering ambrisentan with Restasis, the ambrisentan dose should not be titrated to the recommended maximum daily dose

Anthracycline antibiotics

High doses of Restasis (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

Restasis alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of Restasis (200 mg) and reduced dose aliskiren (75 mg), the mean C_max 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 Restasis prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the T_max (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and C_max of Restasis were comparable to reported literature values. Coadministration of Restasis 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 Restasis with aliskiren is not recommended.

Bosentan

In healthy subjects, coadministration of bosentan and Restasis 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. Coadministration of Restasis with bosentan should be avoided.

Dabigatran

The effect of Restasis on dabigatran concentrations had not been formally studied. Concomitant administration of dabigatran and Restasis may result in increased plasma dabigatran concentrations due to the P-gp inhibitory activity of Restasis. Coadministration of Restasis with dabigatran should be avoided.

Potassium-Sparing Diuretics

Restasis should not be used with potassium-sparing diuretics because hyperkalemia can occur. Caution is also required when Restasis is coadministered with potassiumsparing 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 Restasis is used with NSAIDs in rheumatoid arthritis patients.

Pharmacodynamic interactions have been reported to occur between Restasis and both naproxen and sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by ^99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood concentrations of Restasis, 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 Restasis 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. Restasis 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 Restasis. This effect is often reversible with Restasis dose reduction. Simultaneous coadministration of Restasis significantly increases blood levels of sirolimus. To minimize increases in sirolimus concentrations, it is recommended that sirolimus be given 4 hours after Restasis administration.

Nifedipine

Frequent gingival hyperplasia when nifedipine is given concurrently with Restasis has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of Restasis.

Methylprednisolone

Convulsions when high dose methylprednisolone is given concurrently with Restasis 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 Restasis because of the possibility of excessive immunosuppression.

C. Effect of Restasis on the Efficacy of Live Vaccines

During treatment with Restasis, vaccination may be less effective. The use of live vaccines should be avoided.

For additional information on Restasis Drug Interactions please contact Novartis Medical Affairs Department at 1-888-NOW-NOVA [1-888-669-6682].

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 Restasis or other immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.

Restasis was not mutagenic in appropriate test systems. Restasis 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 Restasis using human lymphocytes in vitro 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 Restasis in utero (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 Restasis 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 Restasis 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 Restasis.

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 Restasis 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 Restasis, development of malignancies, especially those of the skin has been reported. Skin lesions not typical for psoriasis should be biopsied before starting Restasis treatment. Patients with malignant or premalignant changes of the skin should be treated with Restasis only after appropriate treatment of such lesions and if no other treatment option exists.

Pregnancy

Pregnancy Category C

Animal studies have shown reproductive toxicity in rats and rabbits. Restasis 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. Restasis 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. Restasis 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 therefore, Restasis 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 Restasis during pregnancy, 90% of whom were transplant patients, and most of whom received Restasis 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 Restasis during pregnancy should be carefully weighed.

A limited number of observations in children exposed to Restasis in utero 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 Restasis in psoriasis patients during pregnancy should carefully be weighed with serious consideration for discontinuation of Restasis.

The alcohol content of the Restasis formulations should also be taken into account in pregnant women. (See WARNINGS, Special Excipients)

Nursing Mothers

Restasis is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Restasis, 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. Restasis 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 .

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 Restasis with no unusual adverse effects. The safety and efficacy of Restasis 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 Restasis, 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 Restasis 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.

ADVERSE REACTIONS

Kidney, Liver, and Heart Transplantation

The principal adverse reactions of Restasis 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 Restasis 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 Restasis 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 Restasis appear to be related to the neurological manifestations of Restasis toxicity.

Clinical Studies

In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493 transplanted patients treated with Restasis 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 Restasis 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.

		Randomized Kidney Patients		Restasis Patients
		Sandimmune	Azathioprine	Kidney	Heart	Liver
Body System	Adverse Reactions	(N=227)%	(N=228)%	(N=705)%	(N=112)%	(N=75)%
Genitourinary	Renal Dysfunction	32	6	25	38	37
Cardiovascular	Hypertension	26	18	13	53	27
	Cramps	4	<1	2	<1	0
Skin	Hirsutism	21	<1	21	28	45
	Acne	6	8	2	2	1
Central Nervous System	Tremor	12	0	21	31	55
	Convulsions	3	1	1	4	5
	Headache	2	<1	2	15	4
Gastrointestinal	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
Autonomic Nervous System	Paresthesia	3	0	1	2	1
	Flushing	<1	0	4	0	4
Hematopoietic	Leukopenia	2	19	<1	6	0
	Lymphoma	<1	0	1	6	1
Respiratory	Sinusitis	<1	0	4	3	7
Miscellaneous	Gynecomastia	<1	0	<1	4	3

Among 705 kidney transplant patients treated with Restasis 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 (Neoral), 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 Restasis and Restasis -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.

Infectious Complications in Historical Randomized Studies in Renal Transplant Patients Using Sandimmune
	Restasis Treatment	Azathioprine with Steroids*
	(N=227)	(N=228)
Complication	% of Complications	% of Complications
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
*Some patients also received ALG.

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.

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.

Headache, including Migraine

Cases of migraine have been reported. In some cases, patients have been unable to continue Restasis, 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 Restasis. 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 Restasis in rheumatoid arthritis are renal dysfunction , hypertension , headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.

In rheumatoid arthritis patients treated in clinical trials within the recommended dose range, Restasis 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 Restasis therapy. These elevations are likely to become more pronounced without dose reduction or discontinuation.

The following adverse events occurred in controlled clinical trials:

Restasis /Sandimmune Rheumatoid Arthritis
Percentage of Patients with Adverse Events ≥ 3% in any Restasis Treated Group
		Studies	Study	Study		Study		Study		Studies
		651+652+2008	302	654		654		302		651+652+2008
Body	Preferred	Sandimmune†	Sandimmune	Methotrexate & Sandimmune		Methotrexate & Placebo		Restasis		Placebo
System	Term	(N=269)	(N=155)	(N=74)		(N=73)		(N=143)		(N=201)
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%
† Includes patients in 2.5 mg/kg/day dose group only. *NOS=Not Otherwise Specified.

In addition, the following adverse events have been reported in 1% to <3% of the rheumatoid arthritis patients in the Restasis treatment group in controlled clinical trials.

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 Restasis 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, Restasis 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 Restasis.

There has been one reported death associated with the use of Restasis in psoriasis. A 27-year-old male developed renal deterioration and was continued on Restasis. He had progressive renal failure leading to death.

Frequency and severity of serum creatinine increases with dose and duration of Restasis therapy. These elevations are likely to become more pronounced and may result in irreversible renal damage without dose reduction or discontinuation.

Adverse Events Occurring in 3% or More of Psoriasis Patients in Controlled Clinical Trials
Body System*	Preferred Term	Restasis (N=182)	Sandimmune (N=185)
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%
*Total percentage of events within the system **Newly occurring hypertension = SBP ≥160 mm Hg and/or DBP ≥90 mm Hg

The following events occurred in 1% to less than 3% of psoriasis patients treated with Restasis:

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

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. Restasis 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 Restasis.

Postmarketing Experience, Psoriasis

Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of Restasis in patients with chronic plaque psoriasis have been reported.

OVERDOSAGE

There is a minimal experience with Restasis overdosage. Forced emesis and gastric lavage can be of value up to 2 hours after administration of Restasis. Transient hepatotoxicity and nephrotoxicity may occur which should resolve following drug withdrawal. Oral doses of Restasis 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 Restasis in premature neonates. General supportive measures and symptomatic treatment should be followed in all cases of overdosage. Restasis 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.

DOSAGE AND ADMINISTRATION

Restasis Soft Gelatin Capsules MODIFIED and Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED

Restasis has increased bioavailability in comparison to Sandimmune. Restasis and Sandimmune are not bioequivalent and cannot be used interchangeably without physician supervision.

The daily dose of Restasis should always be given in two divided doses (BID). It is recommended that Restasis 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 Restasis, thus should be avoided.

Specific Populations

Renal Impairment in Kidney, Liver, and Heart Transplantation

Restasis undergoes minimal renal elimination and its pharmacokinetics do not appear to be significantly altered in patients with end-stage renal disease who receive routine hemodialysis treatments (See CLINICAL PHARMACOLOGY). However, due to its nephrotoxic potential (See WARNINGS), careful monitoring of renal function is recommended; Restasis dosage should be reduced if indicated. (See WARNINGS and PRECAUTIONS)

Renal Impairment in Rheumatoid Arthritis and Psoriasis

Patients with impaired renal function should not receive Restasis. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS)

Hepatic Impairment

The clearance of Restasis may be significantly reduced in severe liver disease patients (See CLINICAL PHARMACOLOGY). Dose reduction may be necessary in patients with severe liver impairment to maintain blood concentrations within the recommended target range (See WARNINGS and PRECAUTIONS).

Newly Transplanted Patients

The initial oral dose of Restasis can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Restasis 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 Restasis 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 US 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 Restasis dose is subsequently adjusted to achieve a pre-defined Restasis blood concentration. If Restasis trough blood concentrations are used, the target range is the same for Restasis as for Sandimmune. Using the same trough concentration target range for Restasis as for Sandimmune results in greater Restasis exposure when Restasis is administered. Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Restasis 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 2.0 mg/kg/day for the first 4 days tapered to 1.0 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.

Conversion from Sandimmune to Restasis in Transplant Patients

In transplanted patients who are considered for conversion to Restasis from Sandimmune, Restasis should be started with the same daily dose as was previously used with Sandimmune. The Restasis dose should subsequently be adjusted to attain the pre-conversion Restasis blood trough concentration. Using the same trough concentration target range for Restasis as for Sandimmune results in greater Restasis exposure when Restasis is administered. Patients with suspected poor absorption of Sandimmune require different dosing strategies. 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 Restasis blood trough concentration be monitored every 4 to 7 days after conversion to Restasis. 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 Restasis must be adjusted accordingly.

Transplant Patients with Poor Absorption of Sandimmune

Patients with lower than expected Restasis blood trough concentrations in relation to the oral dose of Sandimmune may have poor or inconsistent absorption of Restasis from Sandimmune. After conversion to Restasis, patients tend to have higher Restasis concentrations. Due to the increase in bioavailability of Restasis following conversion to Restasis, the Restasis blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Restasis at doses greater than 10 mg/kg/day. The dose of Restasis should be titrated individually based on Restasis trough concentrations, tolerability, and clinical response. In this population the Restasis 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.

Rheumatoid Arthritis

The initial dose of Restasis is 2.5 mg/kg/day, taken twice daily as a divided oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued. 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 0.5–0.75 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, Restasis 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.

If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, Restasis should be discontinued. The same initial dose and dosage range should be used if Restasis is combined with the recommended dose of methotrexate. Most patients can be treated with Restasis 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 4 weeks after stopping Restasis.

Psoriasis

The initial dose of Restasis should be 2.5 mg/kg/day. Restasis 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/day should be made to a maximum of 4.0 mg/kg/day.

Dose decreases by 25% to 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, Restasis should be discontinued.

Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Restasis 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 Restasis 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, Restasis 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 Restasis, relapse will occur in approximately 6 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 Restasis. 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 Restasis 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.

Restasis Oral Solution MODIFIED–Recommendations for Administration

To make Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED 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 Restasis and should be avoided. The combination of Restasis solution with milk can be unpalatable. The effect of milk on the bioavailability of Restasis when administered as Restasis Oral Solution has not been evaluated.

Take the prescribed amount of Restasis Oral Solution (cyclosporine oral solution, USP) MODIFIED from the container using the dosing syringe supplied, after removal of the protective cover, 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 with more diluent to ensure that the total dose is consumed. After use, dry the outside of the dosing syringe with a clean towel and replace the protective cover. 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.

Blood Concentration Monitoring in Transplant Patients

Transplant centers have found blood concentration monitoring of Restasis 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 Restasis. Older studies using a nonspecific 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 Restasis concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of Restasis pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

HOW SUPPLIED

Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED

25 mg

Oval, blue-gray imprinted in red, “Neoral” over “25 mg.”

Packages of 30 unit-dose blisters (NDC 0078-0246-15).

100 mg

Oblong, blue-gray imprinted in red, “NEORAL” over “100 mg.”

Packages of 30 unit-dose blisters (NDC 0078-0248-15).

Store and Dispense

In the original unit-dose container at controlled room temperature 68°F to 77°F (20°C to 25°C).

Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED

A clear, yellow liquid supplied in 50 mL bottles containing 100 mg/mL (NDC 0078-0274-22).

Store and Dispense

In the original container at controlled room temperature 68°F to 77°F (20° to 25°C). 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.

Restasis^® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED

Restasis^® Oral Solution (cyclosporine oral solution, USP) MODIFIED

Distributed by:

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936

© Novartis

T2015-47

March 2015

Restasis pharmaceutical active ingredients containing related brand and generic drugs:

• Cyclosporine

Restasis available forms, composition, doses:

• Emulsion; Ophthalmic; Cyclosporine 0.05%

Restasis destination | category:

• Human:
• Disease-modifying anti-rheumatic drugs (DMARDs)
• Immunosuppressive agents

Restasis Anatomical Therapeutic Chemical codes:

• S01XA18 - Ciclosporin

Restasis pharmaceutical companies:

• Allergan
• DKSH
• The Glory Medicina
• Zuellig Pharma

References

1. Dailymed."NEORAL (CYCLOSPORINE) CAPSULE, LIQUID FILLED NEORAL (CYCLOSPORINE) SOLUTION [NOVARTIS PHARMACEUTICALS CORPORATION]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Restasis?

Depending on the reaction of the Restasis after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Restasis not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Restasis addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

Review

sdrugs.com conducted a study on Restasis, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Restasis consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

Visitor reports

Visitor reviews

There are no reviews yet. Be the first to write one!

Your name:  Email:  Spam protection:  < Type 22 here

The information was verified by Dr. Rachana Salvi, MD Pharmacology