Neoral

Patients should be advised that any change of cyclosporine formulation should be made cautiously and only under physician supervision because it may result in the need for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal dysfunction.

Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and the use of live attenuated vaccines should be avoided.

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

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

Neoral is a prescription medication used to prevent transplant rejection in those who have received kidney, liver, and heart transplants. Neoral may also be used to treat psoriasis and symptoms of rheumatoid arthritis. Neoral belongs to a group of drugs called immunosuppressants. They work by decreasing the activity of the immune system.

Neoral comes as a capsule and an oral liquid solution. It is usually taken twice a day. This medication is available as a modified form of cyclosporine that has been slightly changed to be more easily absorbed by the body.

Common side effects of Neoral include high blood pressure, gum overgrowth, and tremors. 

• Neoral is available as a modified (changed) form of cyclosporine so that the medication can be better absorbed in the body. Original cyclosporine and cyclosporine (modified) are absorbed by the body in different amounts, so they cannot be substituted for one another. Take only the type of cyclosporine that was prescribed by your doctor. When your doctor gives you a written prescription, check to be sure that he or she has specified the type of cyclosporine you should receive. Each time you have your prescription filled, look at the brand name printed on your prescription label to be sure that you have received the same type of cyclosporine. Talk to your pharmacist if the brand name is unfamiliar or you are not sure you have received the right type of cyclosporine.
• Taking Neoral may increase the risk that you will develop an infection or cancer, especially lymphoma (cancer of a part of the immune system) or skin cancer. This risk may be higher if you take Neoral with other medications that decrease the functioning of the immune system such as azathioprine (Imuran), cancer chemotherapy, methotrexate (Rheumatrex), sirolimus (Rapamune), and tacrolimus (Prograf). Tell your doctor if you are taking any of these medications, and if you have or have ever had any type of cancer. To reduce your risk of skin cancer, plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen during your treatment. If you experience any of the following symptoms, call your doctor immediately:
  • sore throat
  • fever
  • chills and other signs of infection
  • flu-like symptoms
  • coughing
  • difficulty urinating
  • pain when urinating
  • a red, raised, or swollen area on the skin
  • new sores or discoloration on the skin
  • lumps or masses anywhere in your body
  • night sweats
  • swollen glands in the neck, armpits, or groin
  • trouble breathing
  • chest pain
  • weakness or tiredness that does not go away
  • pain, swelling, or fullness in the stomach
• Neoral may cause high blood pressure and kidney damage. Tell your doctor if you have or have ever had high blood pressure or kidney disease. If you experience any of the following symptoms, call your doctor immediately:
  • dizziness
  • swelling of the arms, hands, feet, ankles, or lower legs
  • fast, shallow breathing
  • nausea
  • irregular heartbeat
• If you have psoriasis, tell your doctor about all the psoriasis treatments and medications you are using or have used in the past. The risk that you will develop skin cancer is greater if you have ever been treated with PUVA (psoralen and UVA; treatment for psoriasis that combines an oral or topical medication with exposure to ultraviolet A light); methotrexate (Rheumatrex) or other medications that suppress the immune system; UVB (exposure to ultraviolet B light to treat psoriasis); coal tar; or radiation therapy. You should not be treated with PUVA, UVB, or medications that suppress the immune system while you are taking Neoral to treat psoriasis.
• Neoral may cause growth of extra tissue in your gums. Be sure to brush your teeth carefully and see a dentist regularly during your treatment to decrease the risk that you will develop this side effect.
• Tell your doctor if you are being treated with phototherapy (a treatment for psoriasis that involves exposing the skin to ultraviolet light) and if you have or have ever had low levels of cholesterol or magnesium.
• Keep all appointments with your doctor and the laboratory. Your doctor will order certain lab tests to check your body's response to Neoral.

Before using Neoral, tell your doctor about all of your medical conditions including:

• if you are allergic to Neoral, any other medications, or any of the inactive ingredients in Neoral. Ask your pharmacist for a list of the inactive ingredients
• tell your doctor if you have or have ever had any of the conditions mentioned in the "Neoral Precautions" section
• tell your doctor if you have low cholesterol, low levels of magnesium in your blood, any condition that makes it difficult for your body to absorb nutrients, or liver disease
• tell your doctor if you have an eye infection, if you have a punctal plug (stopper inserted by a doctor in a tear duct to keep tears in the eye), and if you have or have ever had a herpes infection of the eye
• if you are pregnant or breastfeeding

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements.

Do not have vaccinations without talking to your doctor.

• Keep this medication in the container it came in, tightly closed and out of reach of children.
• Store this medication at room temperature and away from excess heat and moisture (not in the bathroom).
• Do not store this medicine in the refrigerator and do not freeze it.
• Oral Neoral: throw away any medication that is outdated or no longer needed.
• Throw away any remaining oral solution 2 months after you first open the bottle. Talk to your pharmacist about the proper disposal of your medication.

Cyclosporine may increase your risk of developing serious infections, cancer, or transplant failure. Talk with your doctor about the risks and benefits of using this medication.

You may not be able to use this medicine if you have kidney disease, untreated or uncontrolled hypertension (high blood pressure), any type of cancer, or psoriasis that has been treated with PUVA, UVB, radiation, methotrexate (Trexall), or coal tar. MAKE SURE ALL DOCTORS INVOLVED IN YOUR CARE KNOW YOU ARE TAKING CYCLOSPORINE.

Cyclosporine can cause serious side effects, including kidney failure or life-threatening infection. While using cyclosporine, you will need frequent blood tests to be sure cyclosporine is not causing harmful effects.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Grapefruit and grapefruit juice may interact with cyclosporine and lead to unwanted side effects. Avoid the use of grapefruit products while taking cyclosporine.

Avoid being near people who are sick or have infections. Tell your doctor at once if you develop signs of infection.

Do not receive a "live" vaccine while using cyclosporine. The vaccine may not work as well during this time, and may not fully protect you from disease. Live vaccines include measles, mumps, rubella (MMR), polio, rotavirus, typhoid, yellow fever, varicella (chickenpox), zoster (shingles), and nasal flu (influenza) vaccine.

Avoid exposure to sunlight or tanning beds. Cyclosporine can make you sunburn more easily. Wear protective clothing and use sunscreen (SPF 30 or higher) when you are outdoors.

Cyclosporine can harm your kidneys. This effect is increased when you also use certain other medicines, including: antivirals, cholesterol-lowering drugs, chemotherapy, injected antibiotics, medicine for bowel disorders, medicines to treat autoimmune disorders, medicine to prevent organ transplant rejection, stomach acid reducers (Tagamet, Zantac), and some pain or arthritis medicines (including aspirin, Tylenol, Advil, and Aleve).

Many drugs can interact with cyclosporine. Not all possible interactions are listed here. Tell your doctor about all your current medicines and any you start or stop using, especially:

• ambrisentan or bosentan;

• dabigatran;

• rifabutin;

• St. John's wort;

• antibiotic or antifungal medicine;

• antiviral medicine to treat hepatitis C or HIV/AIDS;

• birth control pills;

• cholesterol-lowering medication:

• heart or blood pressure medication, including a diuretic or "water pill";

• seizure medication; or

• steroid medication (oral, nasal, inhaled, or injectable).

This list is not complete and many other drugs can interact with cyclosporine. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Give a list of all your medicines to any healthcare provider who treats you.

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

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

Chemically, cyclosporine is designated as [R-[R*,R*-(E)]]-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).

Neoral 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.

Neoral 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 cyclosporine (also known as cyclosporin A) is:

Rheumatoid Arthritis

The effectiveness of Sandimmune and Neoral in the treatment of severe rheumatoid arthritis was evaluated in 5 clinical studies involving a total of 728 cyclosporine 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) cyclosporine 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 cyclosporine 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 cyclosporine, (2) 2.5 to 5 mg/kg/day of cyclosporine, and (3) placebo. Treatment duration was 16 weeks. The mean cyclosporine 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) cyclosporine 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 cyclosporine 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) cyclosporine 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 cyclosporine 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) Neoral and (2) cyclosporine, 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 cyclosporine dose at the last visit was 2.91 mg/kg/day (range: 0.72 to 5.17) for Neoral and 3.27 mg/kg/day (range: 0.73 to 5.68) for cyclosporine. See Graph below.

General

Neoral is contraindicated in patients with a hypersensitivity to cyclosporine 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 Neoral.

Psoriasis

Psoriasis patients who are treated with Neoral 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 Neoral.

Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Neoral, 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. Neoral contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant (See WARNINGS).

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

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

The daily dose of Neoral should always be given in two divided doses (BID). It is recommended that Neoral be administered on a consistent schedule with regard to time of day and relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus should be avoided.

Specific Populations

Renal Impairment in Kidney, Liver, and Heart Transplantation

Cyclosporine 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; cyclosporine 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 cyclosporine. (See CONTRAINDICATIONS, WARNINGS and PRECAUTIONS)

Hepatic Impairment

The clearance of cyclosporine 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 Neoral can be given 4 to 12 hours prior to transplantation or be given postoperatively. The initial dose of Neoral 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 Neoral 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 Neoral dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration. (See Blood Concentration Monitoring in Transplant Patients, below) If cyclosporine trough blood concentrations are used, the target range is the same for Neoral as for Sandimmune. Using the same trough concentration target range for Neoral as for Sandimmune results in greater cyclosporine exposure when Neoral is administered. (See Pharmacokinetics, Absorption) Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower Neoral 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 Neoral in Transplant Patients

In transplanted patients who are considered for conversion to Neoral from Sandimmune, Neoral should be started with the same daily dose as was previously used with Sandimmune (1:1 dose conversion). The Neoral dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for Neoral as for Sandimmune results in greater cyclosporine exposure when Neoral is administered. (See Pharmacokinetics, Absorption) Patients with suspected poor absorption of Sandimmune require different dosing strategies. (See Transplant Patients with Poor Absorption of Sandimmune, below) In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to Neoral. 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 Neoral must be adjusted accordingly.

Transplant Patients with Poor Absorption of Sandimmune

Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune may have poor or inconsistent absorption of cyclosporine from Sandimmune. After conversion to Neoral, patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to Neoral, the cyclosporine blood trough concentration may exceed the target range. Particular caution should be exercised when converting patients to Neoral at doses greater than 10 mg/kg/day. The dose of Neoral should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range.

Rheumatoid Arthritis

The initial dose of Neoral is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates, NSAIDs, and oral corticosteroids may be continued. (See WARNINGS and PRECAUTIONS, Drug Interactions) Onset of action generally occurs between 4 and 8 weeks. If insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30% above baseline), the dose may be increased by 0.5–0.75 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, Neoral therapy should be discontinued.

Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory abnormalities. (See WARNINGS and PRECAUTIONS)

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

Psoriasis

The initial dose of Neoral should be 2.5 mg/kg/day. Neoral 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, Neoral should be discontinued. (See Special Monitoring of Psoriasis Patients)

Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks. Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with Neoral 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 Neoral should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient). In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

Upon stopping treatment with cyclosporine, relapse will occur in approximately 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 cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis. Long term experience with Neoral 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.

Neoral Oral Solution (cyclosporine oral solution, USP) MODIFIED–Recommendations for Administration

To make Neoral 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 cyclosporine and should be avoided. The combination of Neoral solution with milk can be unpalatable. The effect of milk on the bioavailability of cyclosporine when administered as Neoral Oral Solution has not been evaluated.

Take the prescribed amount of Neoral 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 cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance.

Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a 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 cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.