Panimun Bioral (Capsules) Instructions for Use

Marketing Authorization Holder

Panacea Biotec, Ltd. (India)

ATC Code

L04AD01 (Ciclosporin)

Active Substance

Ciclosporin (Rec.INN registered by WHO)

Dosage Forms

	Panimun Bioral	Capsules 25 mg: 50 pcs.
		Capsules 50 mg: 50 pcs.
		Capsules 100 mg: 50 pcs.

Dosage Form, Packaging, and Composition

Capsules soft gelatin, oval in shape, reddish-brown in color; capsule contents are a clear liquid.

5 pcs. – blisters (10) – cardboard packs.

Capsules soft gelatin, oblong in shape, dark brown in color; capsule contents are a clear liquid.

5 pcs. – blisters (10) – cardboard packs.

Capsules soft gelatin, oblong in shape, reddish-brown in color; capsule contents are a clear liquid.

5 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Immunosuppressant, is a cyclic polypeptide consisting of 11 amino acids. It has a selective effect on T-lymphocytes. It inhibits the activation of lymphocyte calcineurin in the G₀ or G₁ phase of the cell cycle. Thus, it prevents the activation of T-lymphocytes and, at the cellular level, antigen-dependent release of lymphokines, including interleukin-2 (T-lymphocyte growth factor). Ciclosporin acts on lymphocytes specifically and reversibly. Unlike cytostatics, it does not suppress hematopoiesis and does not affect the function of phagocytes.

Ciclosporin increases the survival time of allogeneic skin, heart, kidney, pancreas, bone marrow, small intestine, and lung transplants. Ciclosporin also suppresses the development of cellular reactions against the allograft, delayed-type hypersensitivity skin reactions, experimental allergic encephalomyelitis, adjuvant-induced arthritis, graft-versus-host disease (GVHD) and T-lymphocyte-dependent antibody formation. The efficacy of ciclosporin has been demonstrated in bone marrow and solid organ transplantation in humans for the prevention and treatment of rejection and GVHD, as well as in the treatment of various conditions that are autoimmune in nature or can be considered as such.

Indications

• The need for immunosuppression after kidney, bone marrow, solid organ transplantation;
• Rheumatoid arthritis with high activity in case of resistance to basic therapy agents;
• Severe forms of psoriasis and atopic dermatitis in case of standard therapy inefficacy;
• Nephrotic syndrome due to glomerular vascular pathology (minimal change nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis).

ICD codes

Dosage Regimen

Transplantation

For adults, Ciclosporin is usually prescribed together with other immunosuppressive agents. The initial dose is 10-14 mg/kg/day in 2 divided doses at 12-hour intervals for 1-2 weeks after surgery. Then, the concentration of ciclosporin in the blood plasma is monitored and the dose is gradually reduced to 2-6 mg/kg/day, also in 2 divided doses. The therapeutic range of ciclosporin concentrations in blood plasma during subsequent use is from 100 to 400 ng/ml.

In kidney transplantation, when using ciclosporin in doses less than 3-4 mg/kg and with a ciclosporin plasma concentration of about 100 ng/ml, there is a risk of developing rejection reactions.

For some patients one month after transplantation, with simultaneous administration of corticosteroids, a dose of less than 5 mg/kg is recommended.

For bone marrow transplantation, short-term use of ciclosporin in combination with methotrexate is usually recommended. The dose of ciclosporin is selected individually (1-2 days before surgery, intravenous administration of ciclosporin at a dose of 2.5-5 mg/kg/day is recommended). After surgery, as soon as oral administration of the drug becomes possible, switch to oral administration at a dose of 12.5 mg/kg/day (in 2 divided doses) for 3-6 months. Then the dose is gradually reduced until the course of treatment is completely finished.

When conducting therapy for acute graft-versus-host reaction, the initial dose of ciclosporin is 12.5-15 mg/kg/day in 2 divided doses. After 50 days, the dose begins to be reduced by 5% each time per week and therapy is discontinued after approximately 20 weeks. If acute reaction recurs after discontinuation of ciclosporin, therapy should be restarted.

If transient gastrointestinal complaints are observed when taking ciclosporin during organ transplantation, bone marrow transplantation and acute graft-versus-host reaction, one third of the recommended daily dose can be administered once intravenously (in the appropriate dosage form).

The duration of ciclosporin use in organ transplantation (except for therapy of acute graft-versus-host reaction) is determined individually.

Other diseases

For severe endogenous uveitis, the initial dose of ciclosporin is 5-10 mg/kg/day in 2 divided doses until inflammation decreases and visual acuity improves. In acute cases, prednisolone at a dose of 200-600 mcg/kg/day or another similar corticosteroid can be additionally prescribed.

During maintenance therapy, the dose should be gradually reduced to achieve the minimum effective dose.

The therapeutic level of ciclosporin concentration in the blood is from 100 to 150 ng/ml.

The duration of use is from 3 to 16 months.

For severe forms of psoriasis, the drug is recommended to be prescribed at a dose of 2.5 mg/kg/day in 2 divided doses. If no improvement in skin condition is observed after 1 month of therapy, the dose can be gradually increased by 1 mg/kg, up to a maximum of 5 mg/kg/day in 2 divided doses. When repeating treatment, Ciclosporin should be used at the minimum effective dose.

If significant improvement does not occur after 6 weeks of using ciclosporin at a dose of 5 mg/kg/day, the drug should be discontinued.

The duration of use is generally 12 weeks.

For nephrotic syndrome provided normal renal function, it is recommended to prescribe the drug to adults at a daily dose not exceeding 5 mg/kg, to children – not exceeding 6 mg/kg, in 2 divided doses.

For patients with impaired renal function, the initial dose of ciclosporin should not exceed 2.5 mg/kg. With serum creatinine levels in adults above 200 µmol/L and in children – above 140 µmol/L, the use of ciclosporin is contraindicated.

In case of severe liver dysfunction, the initial dose of ciclosporin should be reduced by 25-50%.

For patients with corticosteroid-resistant nephrotic syndrome, in case of insufficient efficacy of ciclosporin alone, its combination with low doses of corticosteroids is recommended.

If symptoms of nephrotic syndrome persist after 3 months of treatment with ciclosporin, the drug should be discontinued.

For severe rheumatoid arthritis in the first 6 weeks of therapy, the recommended daily dose of ciclosporin is 2.5 mg/kg in 2 divided doses. If the drug is poorly tolerated, the dose can be reduced. Then the dose is set individually, depending on the clinical manifestations of the disease and tolerance; the drug should be used at the minimum effective dose. The daily dose of 4 mg/kg should not be exceeded. In emergency cases, it is possible to increase the dose of ciclosporin to 5 mg/kg/day.

Ciclosporin can be prescribed in combination with low doses of corticosteroids and/or NSAIDs.

If there is no therapeutic effect after 3 months of treatment, the drug should be discontinued.

For severe forms of atopic dermatitis, to relieve acute symptoms of the disease, the drug is used at a daily dose of 2.5 mg/kg in 2 divided doses. If no significant improvement is observed after 2 weeks of treatment, it is necessary to increase the dose of ciclosporin to a maximum of 5 mg/kg/day.

In isolated, most severe cases, the use of ciclosporin at an initial dose of 5 mg/kg is required. Upon improvement, the daily dose should be gradually reduced.

If no significant improvement is observed after 6 weeks of treatment or effective doses do not correspond to those recommended above, the drug must be discontinued.

As a rule, therapy for 6-8 weeks is sufficient for the disappearance of clinical symptoms of the disease.

Adverse Reactions

From the digestive system, a feeling of heaviness in the epigastric region, loss of appetite, nausea (especially at the beginning of treatment), vomiting, diarrhea, pancreatitis, gum swelling, liver function disorders are possible.

From the nervous system: headache, tremor, paresthesia, hyperesthesia, epileptic syndrome, lethargy, disorientation, agitation, sleep disturbance, consciousness impairment, visual disturbances; rarely – optic disc edema.

From the cardiovascular system: increased blood pressure.

From the urinary system: renal function disorders, nephropathy, interstitial fibrosis, hematuria.

From the metabolism: hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia; rarely – hyperglycemia.

From the endocrine system: hypertrichosis, reversible dysmenorrhea and amenorrhea.

From the musculoskeletal system: rarely – muscle spasms, muscle weakness, myopathy.

From the hematopoietic system: slight anemia; rarely – thrombocytopenia.

Allergic reactions: skin rash, respiratory distress syndrome; flushing of the skin of the face and upper body, bronchospasm, decreased blood pressure, tachycardia; in severe cases – shock. The occurrence of allergic reactions may be associated with the presence of polyoxyl castor oil in the composition of some dosage forms.

Other: fatigue, edematous syndrome, weight gain, burning sensation in the hands and feet.

Lymphoproliferative diseases after transplantation: lymphoma, malignant skin diseases.

Contraindications

• Uncontrolled arterial hypertension;
• Malignant neoplasms and precancerous skin diseases;
• Lactation period (breastfeeding);
• Children under 1 year of age;
• Childhood (for the treatment of psoriasis and rheumatoid arthritis);
• Hypersensitivity to the components of the drug (including polyoxyl castor oil).

With caution

• Hyperkalemia;
• Hyperuricemia;
• Liver diseases;
• Behçet’s disease with neurological manifestations;
• Traumatic brain injury or brain diseases, epilepsy;
• Viral diseases, including chickenpox (currently existing or recently suffered, including recent contact with a patient), herpes zoster (due to the risk of generalization of the process);
• Arterial hypertension;
• Alcoholism;
• Elderly patients;
• Pediatric patients.

Use in Pregnancy and Lactation

Experience with the use of ciclosporin during pregnancy is limited. Data obtained from patients after transplantation show that, compared with traditional treatment methods, Ciclosporin does not increase the risk of negative effects on the course and outcome of pregnancy.

Ciclosporin is excreted in breast milk. If it is necessary to use it during lactation, breastfeeding should be discontinued.

In experimental studies, it has been shown that Ciclosporin does not have a teratogenic effect.

Use in Hepatic Impairment

Local use of ciclosporin in ophthalmology has not been studied in patients with impaired liver function.

Use in Renal Impairment

Contraindicated in renal impairment (except for patients with nephrotic syndrome). Local use of ciclosporin in ophthalmology has not been studied in patients with impaired renal function.

Pediatric Use

Contraindicated for use in children under 1 year of age.

Drug Interactions

Potassium preparations or potassium-sparing diuretics – increased risk of hyperkalemia.

ACE inhibitors, antiviral drugs, antibiotics of the aminoglycoside group, cephalosporins, amphotericin B, trimethoprim, co-trimoxazole, colchicine, ciprofloxacin, melphalan – increased nephrotoxicity of ciclosporin.

NSAIDs – risk of side effects from the kidneys. In patients receiving Ciclosporin, a significant increase in the bioavailability of diclofenac is observed, with the possible development of reversible renal dysfunction. The increase in diclofenac bioavailability is apparently associated with inhibition of its first-pass metabolism in the liver.

Possible decrease in clearance of digoxin, colchicine, lovastatin, pravastatin, simvastatin, prednisolone, which may lead to increased toxic effects: glycoside intoxication when using digoxin and manifestations of toxicity of colchicine, lovastatin, pravastatin and simvastatin on muscles, in particular the appearance of muscle pain, weakness, myositis and, in rare cases – rhabdomyolysis.

Drugs that increase the concentration of ciclosporin in plasma – erythromycin, clarithromycin, josamycin, doxycycline, chloramphenicol, roxithromycin, midecamycin, ketoconazole, fluconazole (apparently in high doses), itraconazole, diltiazem, nicardipine, verapamil, propafenone, amiodarone, carvedilol, metoclopramide; oral contraceptives; danazol; methylprednisolone (high doses); allopurinol; amiodarone; cholic acid and its derivatives.

Drugs that cause a decrease in the concentration of ciclosporin in plasma – barbiturates, carbamazepine, phenytoin; metamizole, nafcillin, sulfadimidine when administered intravenously; rifampicin, griseofulvin, terbinafine, octreotide, probucol, orlistat, troglitazone, preparations containing St. John’s wort (Hypericum perforatum).

Prednisolone, methylprednisolone – it was noted that Ciclosporin reduces the clearance of prednisolone, and treatment with high doses of prednisolone can increase the concentration of ciclosporin in the blood. Methylprednisolone increases the concentration of ciclosporin in the blood.

Glibenclamide – possible increase in the steady-state plasma concentration of ciclosporin.

Diuretics – the risk of developing renal function disorders increases.

Doxorubicin – increase in doxorubicin plasma concentration and increase in its toxicity.

Methotrexate – increase in ciclosporin plasma concentration, increase in the frequency of nephrotoxic effects and arterial hypertension.

Melphalan (when administered intravenously in high doses) – possible development of severe renal failure.

Teniposide – decrease in teniposide clearance, increase in its T_1/2, increase in toxicity.

Warfarin – decrease in the effectiveness of ciclosporin and warfarin.

Enalapril – possible development of acute renal failure.

Nifedipine – increased gum hyperplasia.

Cisapride – increase in its C_max of ciclosporin in plasma and absorption rate.

Quinidine and its derivatives, theophylline and its derivatives – possible enhancement of the effects of quinidine and its derivatives, theophylline and its derivatives.

Imipenem in combination with cilastatin – possible increase in ciclosporin concentration, which may lead to symptoms of neurotoxicity (tremor, increased excitability).

Other immunosuppressants – increased risk of developing infections and lymphoproliferative diseases.

Storage Conditions

Store at 8°C (46°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.