Panimun Bioral - instructions for use, dose, side effects, contraindications

Each capsule contains: Active substance:
Cyclosporin	25.0 mg	50.0 mg	100.0 mg.
Excipients:
Glycol A (Mm 76.09) (propylene glycol)	44.25 mg	88.50 mg	177.00 mg
Glycol B (Mm 258.4) (propylene glycol monolaurate)	150.00 mg	300.00 mg	600.00 mg
Glycol C (MM 1513) (alpha-tocopherol-macrogol succinate)	0.495 mg	0.99 mg	2.00 mg
Macrogol glycerylricinoleate	30.3 mg	60.6 mg	121.1 mg
Capsule shell composition
Low molecular weight gelatin	500 mg	850 mg	1000 mg
FRD 046	100 mg	170.0 mg	200.0 mg
Glycerol (glycerol)	74.0 mg	125.80 mg	148.0 mg
Sorbitol solution, 70% (not crystallized)	86.4 mg	146.20 mg	172.0 mg
Methylparahydroxybenzoate (methylparaben)	2.4 mg	4.08 mg	4.8 mg
Propyl parahydroxybenzoate (propylparaben)	1.4 mg	2.38 mg	2.8 mg
Purified water	425 mg	722.50 mg	850.0 mg
Iron Oxide Dye Oxide (Red)	4.0 mg	4.25 mg	8.0 mg
Iron Oxide Dye Oxide (Black)		1.7 mg

Description:

Capsules 25 mg: soft gelatin capsules, oval and reddish-brown in color, containing a clear liquid.

Capsules 50 mg: soft gelatin capsules, oblong and coffee-brown, containing a clear liquid.

Capsules 100 mg: soft gelatin capsules, elongated and reddish-brown in color, containing a clear liquid.

Pharmacotherapeutic group:Immunosuppressive remedy.

ATX: & nbsp

Pharmacodynamics:

Cyclosporine (also known as Cyclosporin A) is a cyclic polypeptide consisting of 11 amino acids and is a potent immunosuppressive agent. Cyclosporin is a potent immunosuppressive drug that increases the lifetime of allogeneic grafts of the skin, heart, kidneys, pancreas, bone marrow, small intestine, lungs in animals. Animal studies have shown that ciclosporin inhibits the development of cell-mediated immunity,including allografts, delayed-type hypersensitivity skin reactions, experimental allergic encephalomyelitis, Freund's adjuvant-related arthritis, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody production.

At the cellular level ciclosporin suppresses the formation and release of lymphokines, including interleukin-2 (growth factor of T-lymphocytes). Cyclosporin blocks lymphocytes at rest in phase G₀ or G₁ cell cycle and suppresses the antigen-dependent release of lymphokines by activated T lymphocytes. All the data obtained indicate that ciclosporin acts on lymphocytes specifically and reversibly.

Cyclosporine does not inhibit hemopoiesis and does not affect the function of phagocytic cells. Patients receiving ciclosporinare less susceptible to infection than patients receiving other immunosuppressive drugs.

Successful bone marrow transplantation and solid organs in humans using cyclosporine have been performed to prevent and treat rejection and BTGH.The positive effects of cyclosporine have also been demonstrated in the treatment of various conditions that are inherently autoimmune or can be considered as such.

Pharmacokinetics:

After oral administration, the maximum concentration in the blood plasma is reached between the first and third hours. Panimune Bioral absorption occurs rapidly, the average value of the maximum concentration of C_max in plasma is more by 59% and bioavailability is higher by 29% in comparison with Panimun. After oral administration of 175 mg of cyclosporine (capsule), the maximum concentration of C_max, the time to reach the maximum concentration T_max and the area under the pharmacokinetic curve AUFROM_{0-12 hours} correspond to the values: 792.94 ± 54.07 ng / ml; 2.09 ± 0.08 hours and 3266.71 ± 197.12 ng * h / ml. The value of the final half-life of T1 / 2 cyclosporine is 4.80 ± 1.58 h. Cyclosporin is distributed mainly outside the bloodstream. In the blood, about 33-47% of the drug is detected in the plasma; in lymphocytes 4-9%, in granulocytes 5-12%, in erythrocytes 41-58%. In plasma, about 90% of the cyclosporin binds to proteins, mainly lipoproteins. Excretion is carried out mainly with bile, only 6% of the dose is excreted by the kidneys. Cyclosporin metabolized in the liver, to a lesser extent in the wall of the gastrointestinal tract (GIT) and kidneys. There is no basic way of metabolism. Only about 0.1% of the drug is excreted by the kidneys unchanged. Absorption decreases after liver transplant, with liver diseases or gastrointestinal pathology (diarrhea, vomiting, paralytic intestinal obstruction). In the metabolism of the drug, isozymes CYP3A4, CYP3A5 and CYP3A7 are involved.

Indications:

a) Transplantation of solid organs

Panimun Bioral is indicated as an immunosuppressive agent for the prevention of rejection of allogeneic graft of the kidney, liver, heart, combined heart-lung preparation, lung or pancreas. It is used alone or in combination with low doses of glucocorticosteroids. Treatment of transplant rejection in patients who had previously received other immunosuppressants.

b) Bone marrow transplantation

Panimun Bioral is used alone or in combination with other drugs as an immunosuppressant to prevent bone marrow transplant rejection and to prevent or treat GVHD.

Indications, not related to transplantation

Endogenous uveitis

Panimun Bioral is indicated for the treatment of acute middle or posterior uveitis of non-infectious etiology when there is a serious risk of vision loss if standard therapy does not produce a result or leads to severe adverse reactions. Panimun Bioral is indicated in the treatment of Behavior's uveitis with recurrent attacks of inflammation affecting the retina.

Rheumatoid arthritis

Panimun Bioral is indicated for the treatment of severe rheumatoid arthritis in the exacerbation phase in patients whose treatment with classic basal antirheumatoid drugs is impossible or ineffective.

Psoriasis

Panimun Bioral is indicated for patients with severe forms of psoriasis, in whom standard therapy is impossible or ineffective.

Nephrotic syndrome

Panimun Bioral is used for induction of remission and for maintenance therapy in patients with nephrotic syndrome - steroid-dependent and steroid-resistant, due to glomerular disorders such as minor changes in nephropathy, focal and segmental glomerulosclerosis or membrane glomerulonephritis.

Atopic dermatitis

In severe form, in cases when systemic therapy is indicated.

Contraindications:

Hypersensitivity to cyclosporine.

Children under 3 years (for this dosage form).

For indications not related to transplantation: renal dysfunction (with the exception of patients with a nephrotic syndrome with an acceptable degree of these disorders), uncontrolled arterial hypertension, infectious diseases that are not amenable to standard therapy, malignant neoplasms, children under 18 years (for treatment of psoriasis and rheumatoid arthritis).

Carefully:

Chicken pox (currently or recently transferred, including recent contact with the patient), Varicella zoster (risk of generalization of the process) and other viral diseases, renal and / or hepatic insufficiency, hyperkalemia, hyperuricemia, hypertension, infections, malabsorption syndrome, sugar deficiency / isomaltase, fructose intolerance, glucose-galactose malabsorption (the preparation contains sorbitol).

Pregnancy and lactation:

Observations in animals showed no teratogenic effects of cyclosporine. There is still not a wide enough experience in the use of cyclosporine in pregnant women.Data on organ transplantation among women show that, compared with conventional immunosuppressive therapy, the use of cyclosporine is not an additional risk for the course and outcome of pregnancy. But since there is no high-quality, well-inspected observations on the use of cyclosporine during pregnancy, it should be used only in the apparent predominance of the potential benefits to the mother of the potential risk to the fetus.

Sick women taking ciclosporin, should not breast-feed, as the drug passes through breast milk.

Dosing and Administration:

The drug is administered orally, regardless of food intake. The daily dose of Panimun Bioral should always be divided into 2 divided doses.

Regular blood monitoring is recommended, preferably using methods for determining the starting material based on monoclonal antibodies.

a) Transplantation of solid organs

When transplanting solid organs, treatment with cyclosporine should be started 12 hours prior to surgery at a dose of 10-15 mg / kg divided into 2 divided doses. Within 1-2 weeks after the operation the drug is prescribed daily in the same dose,after which the dose is gradually reduced by 5% per week with the control of the concentration of cyclosporine in the blood, until a maintenance dose of 2-6 mg / kg / day, divided into 2 doses. If intolerance to cyclosporine for oral administration (taking into account side effects from the gastrointestinal tract (GIT)) is recommended intravenous administration of the drug. As far as possible, it is recommended to switch to oral medications as soon as possible. In those cases where ciclosporin prescribe in combination with other immunosuppressive drugs (for example, with corticosteroids or as an element of a three-component or four-component therapy), smaller doses of the drug (3-6 mg / kg / day, divided into 2 doses, at the initial stage of therapy) are required.

b) Bone marrow transplantation

The initial dose of cyclosporine should be given on the day preceding the transplant. In most cases, intravenous administration at a dose of 2.5-5 mg / kg / day, divided into 2 divided doses, is preferred as the initial dose and for no more than 2 weeks after transplantation. Then they switch to oral maintenance therapy with a daily dose of 12.5 mg / kg, divided into 2 doses.

With complications from the gastrointestinal tract, which reduce the absorption of the drug, higher oral doses are required. Therapy can be started with cyclosporine, in which case a dose of 12.5-15 mg / kg / day, divided into 2 doses, is recommended from the first day after transplantation. Supportive therapy is carried out at least 3-6 months (preferably 6 months), after which the dose of cyclosporine is gradually reduced to zero within 1 year. In some patients, discontinuation of cyclosporine therapy may lead to GVHD. In such cases, continued cyclosporine therapy leads to positive results. In the treatment of mild degree of GVHD, a low dose of cyclosporine is used. It is recommended intravenous administration of cyclosporine at a dose of 3.5 mg / kg / day, divided into 2 doses, until it is not possible to use it inside. And if possible, apply first inwards ciclosporin in a dose of 12.5-15 mg / kg / day, divided into 2 doses. This introductory regimen is continued for 2 months, then gradually reduce the dose (5% per week), reaching a dose of 2 mg / kg / day, divided into 2 doses. With this dose, you can stop treatment.

c) Endogenous uveitis

When endogenous uveite drug prescribed in the initial daily dose of 5 mg / kg, divided into 2 doses, orally until the remission of active inflammation and improve visual acuity. In severe cases, the dose may be increased to 7 mg / kg / day for a short period. Cyclosporin is prescribed under conditions of its tolerability and no changes in biochemical parameters (creatinineemia) or blood pressure.

To achieve primary remission or to stop an attack of inflammation, you can add systemic steroid medications at a daily dose of 0.2-0.6 mg / kg / day of prednisolone (or equivalent doses of other corticosteroids).

During maintenance therapy, the dose should be slowly reduced to the lowest effective dose, which during the remission period of the disease should not exceed 5 mg / kg per day.

A warning: as ciclosporin has a negative effect on kidney function, it can be prescribed only to patients with normal renal function. When the concentration of creatinine in the serum is increased by 30%, the dose of the drug should be reduced by 25-50%. If dose reduction does not lead to a decrease in creatinine concentration within 1 month, then treatment should be discontinued.In the absence of improvement in intraocular inflammation 3 months after treatment with cyclosporine in appropriate doses and in conjunction with steroids, alternative treatments should be considered.

The experience of using the drug in children is limited.

d) Psoriasis

To induce remission, the recommended initial dose is 2.5 mg / kg / day, divided into 2 doses. If there is no improvement within 1 month of therapy, the daily dose may be gradually increased, but should not exceed 5 mg / kg / day. Patients who do not improve in the condition 6 weeks after therapy at a dose of 5 mg / kg / day, it is better to interrupt therapy; It is also better to discontinue treatment for patients who have a minimal effective dose that does not match the standards given below (see warning) to provide treatment. The use of an initial dose of 5 mg / kg / day is justified in patients whose condition requires a speedy improvement. For maintenance therapy, the doses should be individually selected at the lowest effective concentration and should not exceed 5 mg / kg / day.

A warning: ciclosporin is not assigned to patients with impaired renal function, hypertension,not responding to therapy, with clinically significant infections or any kind of malignant formation (with the exception of dermal formations, see below). Patients with hyperuricemia or hyperkalemia prescribe the drug with caution. As ciclosporin can increase the disturbance of kidney function, it is advised to measure creatinine concentrations every two weeks during the first 3 months of therapy. Further, patients who received 2.5 mg / kg / day of the drug, with persistent creatinine concentrations in the blood, should be tested every 2 months, and those who receive higher doses - once a month. It is necessary to reduce the dose of the drug by 25-50% with an increase in the concentration of creatinine in the serum by 30% of the initial concentration. If this is not accompanied by a decrease in the concentration of creatinine per month, it is necessary to stop cyclosporine therapy. In the treatment, if uncontrollable arterial hypertension develops against the background of appropriate antihypertensive therapy, it is preferable to complete the treatment with cyclosporin. There are reports of the occurrence of malignant neoplasms, especially the skin, in patients with psoriasis, treated with cyclosporine or other drugs.Untypical skin lesions for psoriasis suggest the presence of preneoplastic or neoplastic foci, therefore, they need to be examined by biopsy, before starting treatment with cyclosporine. Patients who have cutaneous foci with preneoplastic or neoplastic changes can begin therapy with cyclosporine only after treatment of these foci, and only in the absence of other alternative therapies. In patients with psoriasis, treated with cyclosporine, there is rarely a development of lymphoproliferative disorders, which disappear upon discontinuation of therapy.

e) Rheumatoid arthritis

It is recommended that the initial dose of cyclosporine is 2.5-3.5 mg / kg / day, divided into 2 doses, which can be gradually increased in 1-2 months by 0.5 mg / kg / day, but should not exceed 5 mg / kg with insufficient clinical response. When obtaining a clinical effect, you can gradually reduce the dose of 0.5 mg / kg / day every 1-2 months to the minimum effective dose. For maintenance therapy, the dose should be selected individually, depending on the tolerability of the drug. Cyclosporin can be administered in combination with low doses of glucocorticosteroids and / or non-steroidal anti-inflammatory drugs (NSAIDs).

A warning: ciclosporin is not prescribed for patients with impaired renal function, arterial hypertension, not responding to therapy, with clinically significant infections or any kind of malignant formations. Cyclosporin can worsen kidney function, so it is necessary to determine serum creatinine concentration at least twice before starting treatment. During the first 3 months of therapy, a blood test is recommended for serum creatinine at 2-week intervals, then at intervals of 4 weeks, but more frequent monitoring is required in cases of increased cyclosporine dose or simultaneous treatment with non-steroidal agents. If the serum creatinine is increased by more than 30%, the dose of the drug should be reduced. If this is not accompanied by a decrease in the concentration of creatinine per month, it is necessary to stop cyclosporine therapy. In the treatment, if uncontrollable arterial hypertension develops against the background of appropriate antihypertensive therapy, it is preferable to stop cyclosporine treatment. As with other immunosuppressive drugs, one should be aware of the possibility of increasing the risk of developing lymphoproliferative disorders.

e) Nephrotic syndrome

To induce remission, the recommended daily dose administered orally is 5 mg / kg / day for adults and 6 mg / kg / day for children divided into 2 divided doses. In patients with impaired renal function, the initial dose does not exceed 2.5 mg / kg / day, divided into 2 doses. Recommend to combine ciclosporin with low doses of corticosteroids with an unsatisfactory effect of cyclosporine alone, especially in patients with resistance to steroids. In the absence of any improvement 3 months after treatment, cyclosporine therapy is interrupted. Doses are selected individually for effectiveness (proteinuria) and safety (mainly serum creatinine), but they should not exceed 5 mg / kg / day for adults and 6 mg / kg / day for children. With maintenance therapy, the dose is gradually reduced to the minimum effective concentration.

A warning: ciclosporin is capable of causing impaired renal function, so it is often necessary to monitor kidney function. If serum creatinine increases by 30% or more, compared to its concentration before cyclosporine therapy, in analyzes taken 2 times separately, a reduction of the dose of cyclosporin by 25-50% is required.Patients with pathology of kidney function are initially prescribed a dose of 2.5 mg / kg / day of the drug, divided into 2 doses, under which they are carefully monitored by the doctor. In some patients, it is difficult to distinguish renal dysfunction caused by cyclosporine from renal dysfunction due to nephrotic syndrome. This explains why, in rare cases, there are changes in the kidney structure caused by cyclosporine without an increase in serum creatinine. It is necessary to make a kidney biopsy in patients with steroid-dependent nephropathy with minimal changes, in which the therapy with cyclosporine has been going on for more than a year. There are several reports that patients with nephrotic syndrome who take immunosuppressants (including ciclosporin) develop malignant tumors (including Hodgkins lymphoma).

g) Atopic dermatitis

The dosage regimen should be selected individually. The recommended initial dose is 2.5-5 mg / kg / day, divided into 2 divided doses. If the initial dose of 2.5 mg / kg per day does not allow a satisfactory response within two weeks, the daily dose can be rapidly increased to a maximum of 5 mg / kg.In very severe cases of rapid and adequate control of the disease can be achieved by applying initially a dose of 5 mg / kg per day, divided into 2 doses. When a satisfactory response is achieved, the dose should be gradually reduced and, if possible, Panimum Bioral should be discontinued. In case of relapse, a second course of treatment with cyclosporin can be performed.

Although a course of treatment of 8 weeks may be sufficient to cleanse the skin, it has been shown that therapy of up to 1 year is effective and well tolerated, provided that all necessary indications are mandatory.

The experience of using the drug in children is limited.

Use in elderly patients

In clinical studies on the use of cyclosporine for the treatment of rheumatoid arthritis, the proportion of patients aged 65 years and older was 17.5%. It was shown that in these patients the development of systolic hypertension is more likely, as well as an increase in serum creatinine concentration more than 50% higher than the baseline after 3-4 months of cyclosporine therapy.

Based on the available information on the use of cyclosporine in clinical practice, it can be concluded that,that the response to treatment in elderly and younger patients is not different.

Dose selection for elderly patients should be conducted with caution; usually treatment starts with the lowest dose, taking into account the greater frequency of violations of the liver, kidney or heart, as well as taking into account co-morbidities or other concomitant therapy.

Application features

Do not remove the Panimun Bioral capsules from the blister until it is required. When you open the blister, you can smell a characteristic smell, it is characteristic of the drug and does not affect its use. Swallow the capsules whole and store them at a temperature not exceeding 30 ° C, and take them in two divided doses.

Side effects:

Adverse reactions of cyclosporine are moderately expressed and are usually eliminated with a decrease in the dose of the drug.

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including ciclosporin, the risk of developing local and generalized infections (viral, bacterial, fungal etiology) and parasitic infestations increases. It is also possible to exacerbate existing infectious diseases.Cases of development of infectious lesions with a lethal outcome were reported.

In patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including ciclosporin, the risk of developing lymphoproliferative diseases increases after transplantation: lymphomas, malignant skin tumors. The frequency of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy.

The incidence of adverse events is estimated as follows: very often (> 1/10), often (> 1/100; <1/10), infrequently (> 1/1000; <1/100), rarely (> 1/10000; <1/1000), very rarely (<1/10000), including individual messages.

Violations of the blood and lymphatic system. Infrequent: anemia, thrombocytopenia; rarely: against a background of microangiopathic hemolytic anemia and renal insufficiency: hemolytic syndrome: arrhythmias, bronchospasm, weakness.

Disorders from the metabolism and nutrition. Very often: hyperlipidemia; often: hyperuricemia, hyperkalemia, hypomagnesemia; rarely: hyperglycemia.

Violations from the nervous system. Very often: tremor,headache; often: paresthesia, a feeling of tingling on the hands and feet (usually the first week of therapy); infrequently: signs of encephalopathy, such as convulsions, inhibition, disorientation, slowness of psychomotor reactions, agitation, sleep disturbance, visual disorders, cortical blindness, coma, paresis, cerebellar ataxia; rarely: motor polyneuropathy, epileptic syndrome, impaired consciousness; very rarely: edema of the optic disc, including edema of the optic nerve papilla secondary to benign intracranial hypertension.

Violations from the vessels. Very often: increased blood pressure (BP). Disorders from the digestive system. Often: anorexia, nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia; rarely: pancreatitis.

Disorders from the side of baking and biliary tract. Often: a violation of the liver.

Disturbances from the skin and subcutaneous tissues. Often: hypertrichosis; infrequently: an allergic rash.

Disturbances from the musculoskeletal and connective tissue. Often: muscle spasms, myalgia; rarely: muscle weakness, myopathy.

Disorders from the kidneys and urinary tract. Very often: renal dysfunction.

General disorders and disorders at the site of administration. Often: increased fatigue; infrequently: swelling, weight gain.

Disorders from the endocrine system. Rarely: dysmenorrhea, amenorrhea, gynecomastia.

Overdose:

There are no data on acute overdose of cyclosporine. Symptoms: when administered with cyclosporine in a dose of up to 10 g (about 150 mg / kg) in most cases, marked clinical signs, such as vomiting, dizziness, headache, tachycardia. There are transitory hepatotoxicity and nephrotoxicity, which subside when therapy is discontinued. However, in case of accidental overdose of cyclosporine with parenteral administration, the development of severe toxic complications was reported in the neonatal period in preterm infants.

Treatment: symptomatic therapy, there is no specific antidote. During the first 2 hours after ingestion, the drug can be removed from the body by inducing vomiting or by rinsing the stomach. Cyclosporin is practically not excreted in hemodialysis and hemoperfusion with the use of activated charcoal.

Interaction:

It is known that various agents are capable of increasing or decreasing the concentration of cyclosporin, affecting the inhibition or involvement of hepatic enzymes involved in metabolism and in the release of cyclosporin (in particular cytochrome P 450). Drugs that reduce the concentration of cyclosporine in the serum: barbiturates, carbamazepine, oxcarbazepine, phenytoin; nafcillin, sulfadimidine with its iv introduction; rifampicin; octreotide; probucol; orlistat; preparations containing St. John's wort (Hypericum perforatum); ticlopidine, sulfinpyrazone, terbinafine, bosentan. Therefore, the use of these drugs with cyclosporine is not recommended.

Drugs that increase the concentration of cyclosporine in the serum: some antibiotics from the macrolide group (for example, erythromycin, josamycin, azithromycin and clarithromycin); ketoconazole, fluconazole, itraconazole, voriconazole; diltiazem, nicardipine, verapamil; oral contraceptives; danazol; methylprednisolone (high doses), allopurinol; amiodarone; cholic acid and its derivatives; protease inhibitors; imatinib, colchicine; metoclopramide, ranitidine, metronidazole, norfloxacin, nefazadon.

If simultaneous administration of one of these drugs is required together with cyclosporine, it is necessary to measure the concentration of cyclosporine in the blood and to make appropriate changes in the dosage of cyclosporine.

It is necessary to pay special attention to the appointment of Panimun Bioral together with drugs that have nephrotic effects, for example, aminoglycosides (incl. gentamicin, tobramycin), amphotericin B, digoxin, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole), NSAIDs (incl. diclofenac, naproxen, sulindac), melphalan, colchicine, antagonists of H2-histamine receptors (incl. cimetidine, ranitidine), methotrexate. Since NSAIDs have an effect on renal function, their use with cyclosporine or an increase in their dosage is performed only with close monitoring of kidney function, especially at the beginning of therapy.

It should avoid the simultaneous use of cyclosporine with tacrolimus - an increased risk of nephrotoxicity.

The combination of cyclosporine with nifedipine may lead to more pronounced gingival hyperplasia than with cyclosporin alone.

With the simultaneous administration of cyclosporine and lercanidipine, the increase in AUC of lercanidipine is 3-fold and AUC of cyclosporine is 21%. Caution should be exercised when combined use of cyclosporine and lercanidipine.

The combined use of diclofenac and cyclosporine can significantly increase the bioavailability of diclofenac, with the possible development of reversible renal dysfunction. The increase in the bioavailability of diclofenac is most likely due to a decrease in its metabolism in the "first pass" through the liver. When combined with cyclosporine with NSAIDs with a less pronounced "first pass" effect (for example, acetylsalicylic acid) increase in their bioavailability is not expected.

Cyclosporine can reduce the clearance of digoxin, colchicine, prednisolone, inhibitors of HMG-CoA reductase (statins) and etoposide.

Several cases of severe glycoside intoxication were reported within a few days after starting treatment with cyclosporine in patients receiving digoxin. There are also reports that ciclosporin can enhance the toxic effects of colchicine, for example, the development of myopathy or neuropathy, especially in patients with impaired renal function.With the simultaneous use of cyclosporine with digoxin or colchicine, careful clinical observation is necessary to detect toxicity in time and to decide whether to reduce the dose or to cancel treatment.

The use of cyclosporine in clinical practice, as well as in literature, reported cases of muscle toxicity, including muscle pain, weakness, myositis and rhabdomyolysis, when simultaneous cyclosporine was used with lovastatin, simvastatin, atorvastatin, pravastatin and fluvastatin. If it is necessary to use the above medicines simultaneously with cyclosporine, a reduction in their dose is necessary. Statin therapy should be temporarily discontinued or abolished in patients with symptoms of myopathy, as well as in the presence of risk factors for the development of severe renal dysfunction, including renal failure secondary to rhabdomyolysis.

An increase in creatinine concentration was observed in studies in which the combined use of everolimus or sirolimus with high doses of cyclosporin in the form of a microemulsion was studied.This effect is often reversible after lowering the dose of cyclosporine. Everolimus and sirolimus have an insignificant effect on the pharmacokinetic parameters of cyclosporine. Joint use of cyclosporine with everolimus or sirolimus leads to a significant increase in the concentration of the latter in the blood plasma.

Care must be taken when assigning cyclosporin together with potassium-sparing drugs (potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium preparations, as with the simultaneous use of cyclosporine with the above drugs may develop severe hyperkalemia.

With the simultaneous use of cyclosporine and repaglinide, it is possible to increase the concentration in the plasma of the latter and increase the risk of developing hypoglycemia. There are anecdotal reports on the development of a significant, but reversible renal dysfunction (with a corresponding increase in creatinine concentrations) in patients who underwent transplantation, while the use of cyclosporine to fibric acid derivatives (e.g., bezafibrate, fenofibrate). Therefore, in this category of patients, renal function should be monitored. In case of development of severe renal dysfunction, joint application of the above drugs should be discontinued.

There are reports that grapefruit juice increases the bioavailability of cyclosporine.

Special instructions:

Panimun Bioral can be prescribed only by physicians with experience with immunosuppressive therapy, which can also provide adequate dynamic monitoring of patients. Patients after organ or bone marrow transplant receiving the drug should be treated in institutions that have adequate laboratory facilities and trained medical personnel.

Possible difficulties in achieving therapeutic concentrations in patients with malabsorption syndrome.

With cyclosporine, hypertension is the most common side effect. Mild or moderate hypertension is more common than severe. But with prolonged treatment, its frequency decreases with time. Antihypertensives are recommended.

There is hyperkalemia in the treatment of cyclosporine, therefore, potassium-sparing diuretics are not recommended for the treatment of this effect. In these cases, calcium antagonists are effective for the treatment of arterial hypertension. It is necessary to take into account changes in the metabolism of cyclosporine due to calcium antagonists, leading to changes in the doses of cyclosporins.

During treatment with cyclosporine, immunization with vaccines is less effective. The use of live attenuated vaccines should be avoided. It is necessary to conduct repeated laboratory tests to monitor kidney and liver function.

Use with caution in patients with hyperuricemia. Use absolutely accurate doses and perform tests periodically. In cases of infections, even the slightest (colds, flu, etc.), immediately inform the doctor.

To monitor the concentration of Panimun Bioral in whole blood, it is preferable to use a method based on specific monoclonal antibodies (determination of the parent drug). A high performance liquid chromatography (HPLC) method can also be used. It is necessary to adhere to the standard separation protocol (time and temperature).It should be remembered that the concentration of cyclosporine in the blood is only one of the few factors affecting the clinical condition of the patient. Therefore, the results of determining the concentration of cyclosporine in the blood should serve only as a guideline for the selection of a dose, in comparison with other clinical and laboratory indicators.

In the application of cyclosporin, as well as the use of other immunosuppressants, increased risk of lymphomas and other malignancies (including skin). The increased risk of developing this complication is associated mostly with the degree and duration of immunosuppression than with the use of a particular drug. Thus, caution should be exercised when using combined modes of immunosuppressive therapy in terms of the likelihood of developing lymphoproliferative disorders and solid organ tumors, sometimes leading to fatal outcomes.

Given the potential risk of skin cancer, patients receiving cyclosporin therapy, to avoid over-exposure to direct sunlight, ultraviolet UV-B radiation, PUVA therapy (photochemotherapy).

The use of cyclosporine, like other immunosuppressants, predisposes to the development of various bacterial, fungal, parasitic and viral infections, often caused by opportunistic pathogens. Given the potential danger of these infections for the life of the patient, an effective system of preventive and curative measures should be applied, especially in cases of prolonged use of combined immunosuppressive treatment.

During the first few weeks of therapy with the drug, a frequent and potentially dangerous complication may occur-an increase in serum creatinine and urea, which is reversible and dose-dependent, and normalizes with a reduced dose of the drug. With prolonged treatment in some patients, it is possible to develop structural changes in the kidneys (including interstitial fibrosis), which in patients with renal transplants should be differentiated with changes in chronic rejection.

Panimun Bioral can also cause a dose-dependent reversible increase in serum bilirubin and, rarely, activity of "liver" transaminases.In these cases, careful monitoring of kidney and liver function is required. In case of deviations of these parameters from the norm, a dose reduction may be required.

In elderly patients, monitoring of kidney function should be particularly careful.

Since there are rare reports of insignificant reversible hyperlipidemia in the treatment with cyclosporine, it is recommended that before the start of treatment and 1 month after the beginning of the treatment, a determination of the lipid concentration in the blood be made. In case of an increased concentration of lipids, a diet with a restriction of fat should be recommended and, if necessary, a dose of the drug should be reduced.

Cyclosporine increases the excretion of magnesium from the body, which can lead to symptomatic hypomagnesemia, especially in the peri-transplant period. In this regard, it is recommended to monitor the concentration of magnesium in the blood, especially when neurologic symptoms appear. If necessary, prescribe magnesium preparations.

Additional indications for use in nephrotic syndrome

Due to changes in renal function due to nephrotic syndrome, it may be difficult for some patients to detect renal dysfunction caused by the use of cyclosporine.This explains the fact that in a number of cases the structural changes in the kidneys associated with cyclosporine have been observed without an increase in the serum creatinine concentration. A kidney biopsy was shown in patients with steroid-dependent nephropathy who received maintenance therapy with Panimun Bioral for more than 1 year.

In rare cases, patients with nephrotic syndrome treated with immunosuppressants (including cyclosporine), noted the appearance of malignant neoplasms (including Hodgkin's lymphoma).

Additional indications for use in rheumatoid arthritis

With prolonged immunosuppressive treatment (including cyclosporine therapy), one should remember about the increased risk of lymphoproliferative disorders. Particular care should be taken when using Panimuna Bioral in combination with methotrexate.

Additional indications for use in psoriasis

Use in elderly patients is possible only in cases of disabling psoriasis, and careful monitoring of renal function is necessary. In patients with psoriasis, treated with cyclosporine, as with other conventional immunosuppressive treatment, the occurrence of malignant tumors, especially the skin, has been reported.In the presence of skin lesions that are not typical for psoriasis, and if there is a suspicion of their malignancy or precancerous condition, a biopsy should be performed before starting treatment with cyclosporine. Panimun Bioral treatment of patients with malignant or precancerous skin lesions is possible only after their appropriate treatment and in the absence of alternative effective therapy.

Additional indications for use in atopic dermatitis

The use of Panimun Bioral in elderly patients is possible only in cases of a disabling course of the disease, with careful monitoring of kidney function. Benign lymphadenopathy is usually associated with sudden exacerbations of atopic dermatitis. It passes either alone or against a background of general improvement in the course of the disease. Lymphadenopathy, which appeared on the background of treatment with cyclosporine, should be monitored regularly. Lymphadenopathy, which persists despite a decrease in the activity of the disease, should be biopsy to exclude the presence of lymphoma.

Cases of simple herpes simplex active course should be cured before the beginning of therapy by Panimun Bioral,but the appearance of herpes simplex is not a reason to discontinue the drug, if the treatment has already begun, except in severe cases.

The experience of using Panimun Bioral in children with atopic dermatitis is limited.

Cyclosporin in children:

Data on the experience of using the drug in children are rather limited. However, in children aged 1 year or more who took the drug at the recommended dose, there are no abnormalities in the condition. In most cases, patients of the child's age transferred the drug ciclosporin in large doses (in mg / kg) compared with adults.

Effect on the ability to drive transp. cf. and fur:

There is no evidence of the influence of Panimoun Bioral on the ability to drive vehicles and mechanisms.

Form release / dosage:

Capsules 25 mg, 50 mg, 100 mg.

Packaging:

5 capsules per blister of aluminum foil and PVC or Al / Al.

For 10 blisters in a cardboard box with instructions for use.

Storage conditions:

Capsules should be stored in a dry, protected from light place at a temperature of no higher than 30 ° C. Keep out of the reach of children. Do not store in the refrigerator.

Shelf life:

2 years.

Do not use the drug after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N011061 / 01

Date of registration:25.11.2011

The owner of the registration certificate:Panacea Biotech Co., Ltd.Panacea Biotech Co., Ltd. India

Manufacturer: & nbsp

PANACEA BIOTEC, Ltd. India

Representation: & nbspKORAL-MED, CJSCKORAL-MED, CJSC

Information update date: & nbsp25.10.2015

Illustrated instructions

Instructions

Panimoun Boral (Panimun Bioral)