Equoral
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EQUORAL® (EQUORAL®)
Composition:
active ingredient: cyclosporine;
1 capsule contains cyclosporine 25 mg, 50 mg, or 100 mg;
excipients: anhydrous ethanol, macrogol glycerol hydroxystearate, polyglycerol (3) monooleate, polyglycerol (10) monooleate, alpha-tocopherol, gelatin, glycerol (85%), glycine, non-crystallizing sorbitol solution (E 420), titanium dioxide (E 171), iron oxide yellow (E 172) – for 25 mg and 50 mg capsules, iron oxide brown (E 172) – for 100 mg capsules.
Pharmaceutical form. Soft capsules.
Main physicochemical properties:
25 mg capsules: yellow soft gelatin capsules (Oval 5) containing an oily liquid ranging from yellowish to yellowish-brown. Each capsule is identified by an imprint with a sandglass logo and the text "25 mg";
50 mg capsules: ochre-colored soft gelatin capsules (Oblong 11) containing an oily liquid ranging from yellowish to yellowish-brown. Each capsule is identified by an imprint with a sandglass logo and the text "50 mg";
100 mg capsules: brown soft gelatin capsules (Oblong 20) containing an oily liquid ranging from yellowish to yellowish-brown. Each capsule is identified by an imprint with a sandglass logo and the text "100 mg".
Pharmacotherapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. ATC code L04A D01.
Pharmacological Properties
Pharmacodynamics
Cyclosporine (known as cyclosporine A) is a cyclic polypeptide composed of 11 amino acids. Cyclosporine is a potent immunosuppressive agent that prolongs the survival of allogeneic skin, heart, kidney, pancreas, bone marrow, small intestine, lung, and other organ transplants in animals. Cyclosporine suppresses cell-mediated immune reactions, including immune responses against allografts, delayed-type hypersensitivity of the skin, experimental allergic encephalomyelitis, adjuvant-induced arthritis, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody production. At the cellular level, cyclosporine inhibits the synthesis and release of lymphokines, including interleukin-2 (T-cell growth factor). Cyclosporine arrests resting lymphocytes in the G0 or G1 phase of the cell cycle and suppresses antigen-dependent lymphokine release by activated T-lymphocytes. All available evidence indicates that cyclosporine acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not suppress hematopoiesis and does not affect phagocyte function. Patients receiving cyclosporine are less susceptible to infections than those receiving other immunosuppressive agents.
Successful bone marrow and solid organ transplantations in humans have been performed using cyclosporine for the prevention and treatment of rejection and GVHD. Cyclosporine has been used in both hepatitis C virus (HCV)-positive and HCV-negative liver transplant recipients. Beneficial effects of cyclosporine have also been demonstrated in the treatment of various conditions that are autoimmune in nature or may be considered as such.
Cyclosporine has demonstrated efficacy in steroid-dependent nephrotic syndrome in children.
Pharmacokinetics
Absorption
After oral administration, maximum blood concentration (Cmax) of cyclosporine is observed within 1–2 hours. Absolute oral bioavailability of cyclosporine ranges from 20% to 50%. When cyclosporine is administered with a high-fat meal, a reduction in the area under the concentration-time curve (AUC) and Cmax by 13% and 33%, respectively, has been observed. The relationship between administered dose and cyclosporine exposure is linear within the therapeutic dose range. Intra- and inter-individual variability in AUC and Cmax values is approximately 10–20%. Cyclosporine solution and soft capsules are bioequivalent.
Administration of Neoral® results in a 59% increase in Cmax and approximately a 29% increase in bioavailability compared to the original cyclosporine formulation. Available data indicate that when switching from the original cyclosporine soft gelatin capsules to Neoral® soft gelatin capsules, blood concentrations of cyclosporine are comparable and fall within the desired therapeutic range. Neoral® administration enhances dose linearity of cyclosporine exposure (AUC). This provides a more stable absorption profile with reduced dependence on concomitant food intake or circadian rhythms compared to the original cyclosporine formulation.
Distribution
Cyclosporine is distributed predominantly outside the vascular compartment, with a mean volume of distribution of 3.5 L/kg. In blood, approximately 33–47% of the drug is found in plasma, 4–9% in lymphocytes, 5–12% in granulocytes, and 41–58% in erythrocytes. In plasma, about 90% of cyclosporine is bound to plasma proteins, primarily lipoproteins.
Biotransformation
Cyclosporine is metabolized to form approximately 15 metabolites. Metabolism of cyclosporine occurs primarily in the liver via the cytochrome P450 3A4 (CYP3A4) system. The main metabolic pathways include mono- and dihydroxylation, as well as N-demethylation. All known metabolites retain the intact peptide structure of the parent compound, and some metabolites exhibit weak immunosuppressive activity, up to 1/10 that of the parent substance.
Elimination
Cyclosporine is eliminated primarily via bile. A small amount of orally administered cyclosporine is excreted in urine (6% of the dose), with only 0.1% excreted unchanged in urine.
There are significant discrepancies in reported data on the terminal half-life of cyclosporine, depending on the analytical method used and the target population. The terminal half-life ranges from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe hepatic impairment.
The terminal half-life in patients with transplanted kidneys is approximately 11 hours, with a range of 4–25 hours.
Special Patient Populations
Patients with Renal Impairment
In patients with end-stage renal disease, systemic clearance of the drug has been reported to be approximately two-thirds of the average systemic clearance observed in patients with normal renal function. Less than 1% of the administered dose is removed by dialysis.
Patients with Hepatic Impairment
In patients with impaired liver function, two- to three-fold increases in cyclosporine exposure have been observed. In patients with severe liver disease and biopsy-confirmed cirrhosis, the terminal half-life has been reported to be 20.4 hours (ranging from 10.8 to 48 hours), compared to 7.4–11 hours in healthy volunteers.
Children
Pharmacokinetic data on cyclosporine use in children are very limited.
Clinical characteristics.
Indications.
Indications in transplantation
Solid organ transplantation:
- prevention of rejection of solid organ transplants;
- treatment of transplant rejection in patients previously treated with other immunosuppressive agents.
Bone marrow transplantation:
- prevention of rejection of allogeneic bone marrow and stem cell transplants;
- prevention and treatment of graft-versus-host disease.
Non-transplant indications
Endogenous uveitis:
- active intermediate or posterior uveitis threatening vision loss, non-infectious etiology, in cases where alternative treatment has proven ineffective or unacceptable due to adverse reactions;
- uveitis in Behçet’s disease with recurrent inflammatory episodes involving the retina without neurological symptoms.
Nephrotic syndrome:
- steroid-dependent or steroid-resistant nephrotic syndrome due to minimal change disease in primary glomerulonephritis, focal segmental glomerulosclerosis, or membranous glomerulonephritis;
- induction or maintenance of remission;
- maintenance of remission induced by corticosteroids, enabling their discontinuation.
Rheumatoid arthritis:
- treatment of severe active rheumatoid arthritis.
Psoriasis:
- severe forms of psoriasis when standard therapy has proven ineffective or unacceptable.
Atopic dermatitis:
- treatment of severe forms of atopic dermatitis when systemic therapy is required.
Contraindications.
Hypersensitivity to cyclosporine or to any of the excipients of the medicinal product.
Concomitant use with medicinal products containing St. John’s wort (Hypericum perforatum).
Concomitant use with medicinal products that are substrates of the multidrug efflux transporter P-glycoprotein (P-gp) or organic anion transporting polypeptides (OATPs), for which increased plasma concentrations are associated with serious or life-threatening adverse reactions, such as bosentan, dabigatran etexilate, and aliskiren.
Renal impairment, except in patients with nephrotic syndrome and moderately elevated baseline creatinine levels up to 200 µmol/L in adults and 140 µmol/L in children. In nephrotic syndrome, cautious use at doses not exceeding 2.5 mg/kg/day is permitted only if cyclosporine treatment contributes to normalization of creatinine levels elevated due to the disease.
Interaction with other medicinal products and other forms of interaction.
Food interactions
An increase in cyclosporine bioavailability has been observed when grapefruit or grapefruit juice is consumed concomitantly.
Drug interactions
The following medicinal products have well-documented interactions considered clinically significant.
It is known that several drugs increase or decrease cyclosporine plasma or whole blood concentrations by inhibiting or inducing enzymes, particularly CYP3A4, involved in cyclosporine metabolism. Cyclosporine is also an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein (P-gp), and organic anion transporting polypeptides (OATPs). This may increase plasma concentrations of concomitantly administered medicinal products that are substrates of CYP3A4 and/or these transporters.
Medicinal products that decrease or increase cyclosporine bioavailability
Frequent monitoring of cyclosporine concentrations is necessary in transplant patients, especially when initiating or discontinuing concomitant medications. For patients treated for non-transplant indications, the relationship between blood concentration and clinical effects is less well established. In patients receiving concomitant medications that increase cyclosporine concentrations, frequent assessment of renal function and careful monitoring of cyclosporine-related adverse effects may be more appropriate than measuring blood levels.
Medicinal products that decrease cyclosporine concentration
All inducers of CYP3A4 and/or P-glycoprotein are expected to reduce cyclosporine concentrations.
Examples of medicinal products that decrease cyclosporine concentration: barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, sulfadimidine (intravenous), orlistat, probucol, products containing Hypericum perforatum (St. John’s wort), ticlopidine, sulfinpyrazone, terbinafine, bosentan, rifampicin, octreotide, trimethoprim (intravenous).
Concomitant use of medicinal products containing Hypericum perforatum (St. John’s wort) with the product Ekvoral® should be avoided due to the risk of reduced cyclosporine blood concentrations and thus diminished therapeutic effect.
Rifampicin is an inducer of cyclosporine metabolism in the intestine and liver. Therefore, when used concomitantly, a 3–5-fold increase in cyclosporine dose may be necessary.
Octreotide reduces oral absorption of cyclosporine, potentially requiring a 50% increase in cyclosporine dose or switching to an intravenous formulation.
Medicinal products that increase cyclosporine concentration
All inhibitors of CYP3A4 and/or P-glycoprotein may increase cyclosporine concentrations. Examples include: chloroquine, nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high doses), allopurinol, cholic acid and its derivatives, protease inhibitors, imatinib, colchicine, nefazodone.
Macrolide antibiotics: erythromycin may increase cyclosporine exposure by 4–7 times, sometimes leading to nephrotoxicity. Clarithromycin has been reported to double cyclosporine exposure. Azithromycin increases cyclosporine concentration by approximately 20%.
Azole antifungals: ketoconazole, fluconazole, itraconazole, and voriconazole can increase cyclosporine exposure by more than two-fold.
Cannabidiol (P-gp inhibitor): there have been reports of increased blood levels of another calcineurin inhibitor when used concomitantly with cannabidiol. This interaction may occur due to inhibition of intestinal P-glycoprotein efflux, leading to increased calcineurin inhibitor bioavailability. Therefore, cyclosporine and cannabidiol should be used cautiously with close monitoring for adverse reactions. In transplant recipients, cyclosporine trough concentrations in whole blood should be monitored and the dose adjusted as needed. Monitoring of cyclosporine blood levels with appropriate dose adjustment should also be considered for non-transplant patients (see sections "Special precautions for use" and "Dosage and administration").
Verapamil increases cyclosporine blood concentration by 2–3 times.
Concomitant use with telaprevir resulted in an approximately 4.64-fold increase in normalized cyclosporine exposure (AUC).
Amiodarone significantly increases cyclosporine plasma concentration along with elevated serum creatinine. This interaction may occur after a long interval following amiodarone discontinuation due to its very long elimination half-life (approximately 50 days).
Danazol has been shown to increase cyclosporine blood concentration by approximately 50%.
Diltiazem (at a dose of 90 mg daily) may increase plasma cyclosporine concentration by 50%.
Imatinib may enhance cyclosporine exposure and increase its Cmax by approximately 20%.
Combinations with increased risk of nephrotoxicity
Caution is required when cyclosporine is used concomitantly with other agents exhibiting synergistic nephrotoxic effects, such as aminoglycosides (including gentamicin and tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+sulfamethoxazole), fibric acid derivatives (e.g., bezafibrate, fenofibrate), nonsteroidal anti-inflammatory drugs (NSAIDs) (including diclofenac, indomethacin, naproxen, and sulindac), melphalan, histamine H2-receptor antagonists (e.g., cimetidine, ranitidine), methotrexate, and tacrolimus.
When used concomitantly with medicinal products that may exert synergistic nephrotoxic effects, careful monitoring of renal function is required. In case of pronounced renal dysfunction, the dose of the concomitantly administered medicinal product should be reduced or alternative therapy considered.
Concomitant use of tacrolimus should be avoided, as it increases the risk of nephrotoxicity and due to pharmacokinetic interactions involving CYP3A4 and/or P-gp.
Effect of direct-acting antiviral agents
Changes in liver function during treatment with direct-acting antiviral agents, related to clearance of hepatitis C virus, may affect cyclosporine pharmacokinetics. Careful monitoring and dose adjustment of cyclosporine, if necessary, are required to ensure consistent efficacy.
Effect of cyclosporine on other medicinal products
Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), and etoposide. Careful clinical monitoring is required when any of these medicinal products are used concomitantly with cyclosporine to allow early detection of toxic effects, followed by dose reduction or discontinuation. Cases of myotoxicity, including myalgia and weakness, myositis, and rhabdomyolysis, have been reported in medical literature and post-marketing studies in patients receiving cyclosporine concomitantly with lovastatin, simvastatin, atorvastatin, pravastatin, and also fluvastatin (rarely). When used concomitantly with cyclosporine, statin doses should be reduced; concomitant use with certain statins should be avoided according to recommendations in the prescribing information. Changes in exposure values of commonly used statins when co-administered with cyclosporine are summarized in the table below.
Table
Summary of changes in exposure values of commonly used statins when co-administered with cyclosporine
| Statin |
Available doses |
Fold changes in exposure with cyclosporine |
| Atorvastatin |
10–80 mg |
8–10 |
| Simvastatin |
10–80 mg |
6–8 |
| Fluvastatin |
20–80 mg |
2–4 |
| Lovastatin |
20–40 mg |
5–8 |
| Pravastatin |
20–80 mg |
5–10 |
| Rosuvastatin |
5–40 mg |
5–10 |
| Pitavastatin |
1–4 mg |
4–6 |
Caution should be exercised when cyclosporine is used concomitantly with lercanidipine.
Following concomitant administration of cyclosporine and aliskiren, an approximately 2.5-fold increase in aliskiren Cmax and an approximately 5-fold increase in AUC, both substrates of P-gp, were observed. However, the pharmacokinetic profile of cyclosporine was not significantly altered. Concomitant use of cyclosporine and aliskiren is not recommended.
Concomitant use of dabigatran etexilate is also not recommended due to the P-gp inhibitory activity of cyclosporine.
It has been established that concomitant use of diclofenac and cyclosporine leads to a significant increase in diclofenac bioavailability, with a potential for reversible renal impairment. This increase is most likely due to reduced first-pass effect of diclofenac. Concomitant use of cyclosporine with NSAIDs that have low first-pass effect (such as acetylsalicylic acid) is generally not associated with increased bioavailability.
Elevated serum creatinine levels have been observed in studies with concomitant use of everolimus or sirolimus and full doses of cyclosporine in microemulsion form. This effect is often reversible upon reduction of cyclosporine doses. Everolimus and sirolimus have only a minor effect on the pharmacokinetics of cyclosporine. Concomitant use of cyclosporine significantly increases blood concentrations of everolimus and sirolimus.
Cyclosporine should be administered with caution together with potassium-sparing agents (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing preparations, as this may lead to a significant increase in serum potassium levels.
Cyclosporine may also increase plasma levels of repaglinide, thereby increasing the risk of hypoglycemia.
Concomitant administration of bosentan with cyclosporine in healthy volunteers markedly increases bosentan exposure several-fold and reduces cyclosporine exposure by 35%; therefore, concomitant use of cyclosporine with bosentan is not recommended.
Repeated dosing of ambrisentan together with cyclosporine in healthy volunteers resulted in approximately a 2-fold increase in ambrisentan exposure, while cyclosporine exposure was slightly increased (approximately 10%).
In oncology patients, concomitant use of intravenous forms of anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) and very high doses of cyclosporine was associated with a marked increase in anthracycline antibiotic exposure.
During cyclosporine therapy, vaccine efficacy may be reduced. Use of live attenuated vaccines should be avoided.
Children
Drug interaction studies have been conducted exclusively in adult patients.
Special precautions for use.
EQUORAL® should be prescribed only by physicians experienced in immunosuppressive therapy who can provide the necessary additional monitoring (regular comprehensive physical examinations, blood pressure monitoring, laboratory tests). Patients who have undergone transplantation and are receiving EQUORAL® must be treated only in medical centers equipped with appropriate laboratory and medical facilities. The physician responsible for maintenance therapy should be provided with all necessary information to ensure proper patient care.
Absorption of calcineurin inhibitors may be impaired in patients with cystic fibrosis.
Lymphomas and other malignancies
Like other immunosuppressants, cyclosporine increases the risk of developing lymphomas and other malignancies, including skin tumors. Regular monitoring of patients receiving long-term cyclosporine therapy is necessary to ensure early diagnosis. Treatment should be discontinued if a premalignant condition or tumor is diagnosed. There is evidence that the increased risk is related to the degree and duration of immunosuppression, rather than to the use of specific agents.
Therefore, treatment regimens involving multiple immunosuppressive agents (including cyclosporine) should be used with caution, as they may lead to lymphoproliferative disorders and solid organ tumors, sometimes with fatal outcomes.
Due to the potential risk of skin malignancies, patients receiving EQUORAL®, particularly those treated for psoriasis or atopic dermatitis, should be advised to avoid excessive exposure to sunlight and should not receive concurrent UVB irradiation or PUVA photochemotherapy.
Infections
As with other immunosuppressive agents, the use of cyclosporine may lead to the development of various bacterial, fungal, parasitic, and viral infections, often involving opportunistic pathogens. In patients receiving cyclosporine, reactivation of latent polyomavirus infection has been reported, potentially leading to polyomavirus-associated nephropathy (PVAN), including BK virus nephropathy (BKVN) or progressive multifocal leukoencephalopathy associated with JC virus (PML). These complications are often secondary to high levels of immunosuppression and should be considered in the differential diagnosis of immunosuppressed patients with worsening renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. Effective prophylactic and therapeutic strategies should be employed, especially in patients requiring repeated long-term immunosuppressive therapy.
Nephrotoxicity
During treatment with EQUORAL®, an increase in serum creatinine and urea levels is a common and potentially serious adverse effect. These functional changes are dose-dependent and usually reversible, with values returning to normal upon dose reduction. In some patients, prolonged use of the drug may lead to structural changes in the kidneys (e.g., interstitial fibrosis), which should be differentiated from signs of chronic rejection in kidney transplant recipients. Therefore, frequent monitoring of renal function according to local guidelines, considering the specific indication for use, is essential.
Hepatotoxicity
Cyclosporine may also cause dose-dependent, reversible increases in serum bilirubin levels and, occasionally, elevated liver enzymes. There have been case reports and spontaneous reports of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and hepatic failure, in patients receiving cyclosporine. Most reports involved patients with significant comorbidities, underlying pathological conditions, and other concurrent factors, including infectious complications and concomitant medications with hepatotoxic potential. In some cases, primarily in transplant patients, fatal outcomes have been reported.
Regular monitoring of appropriate liver function parameters is required, and the dose should be reduced if abnormalities are detected.
Elderly patients (aged 65 years and older)
Renal function should be monitored particularly carefully in elderly patients.
Monitoring of cyclosporine levels
When administering EQUORAL® to post-transplant patients, systematic monitoring of cyclosporine blood concentration is an important safety measure. Cyclosporine blood levels are best determined using specific monoclonal antibodies (measurement of unchanged drug). However, high-performance liquid chromatography (HPLC) may also be used (also for measurement of unchanged drug). Standardized sample processing (time and temperature) is required when quantifying cyclosporine in blood plasma or serum.
In liver transplant recipients, monitoring of blood levels at the beginning of treatment should be performed either using only specific monoclonal antibodies or by parallel measurements using both specific and non-specific monoclonal antibodies to ensure adequate immunosuppression.
It should also be noted that cyclosporine levels in blood, plasma, or serum are only one of many factors influencing the patient's clinical status. Therefore, results should be interpreted only as guidance in treatment, within the context of other clinical and biochemical parameters.
Arterial hypertension
Blood pressure should be monitored regularly during treatment with EQUORAL®. If arterial hypertension is detected, appropriate antihypertensive treatment should be initiated. Antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine (e.g., isradipine) are preferred.
Increased blood lipid levels
Isolated reports associated with EQUORAL® treatment have indicated mild, reversible increases in blood lipids. Lipid levels should be measured before starting treatment and one month after initiation. If elevated lipid levels are detected, dietary fat intake should be reduced and, if necessary, the dose of the drug should be reduced.
Hyperkalemia
The risk of hyperkalemia increases during cyclosporine therapy, especially in patients with renal dysfunction. Cyclosporine should be used with caution in combination with potassium-sparing agents (e.g., potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium-containing preparations, or in patients on a potassium-rich diet. In such cases, potassium levels should be monitored.
Hypomagnesemia
Cyclosporine increases magnesium excretion, which may lead to symptomatic hypomagnesemia, particularly in the peri-transplant period. Monitoring of serum magnesium levels is recommended during the peri-transplant period, especially in the presence of neurological symptoms. Magnesium supplementation may be required if necessary.
Hyperuricemia
Caution is required when treating patients with hyperuricemia.
Live attenuated vaccines
Vaccination during cyclosporine therapy may be less effective. The use of live attenuated vaccines should also be avoided.
Interactions
Cyclosporine should be administered with caution together with medicinal products that significantly increase or decrease cyclosporine plasma concentrations due to inhibition or induction of CYP3A4 and/or P-glycoprotein (see section "Interaction with other medicinal products and other forms of interaction").
Monitoring for nephrotoxicity is required when cyclosporine is used concomitantly with active substances that increase cyclosporine concentration or exhibit synergism in the development of nephrotoxic effects (see section "Interaction with other medicinal products and other forms of interaction"). The patient's clinical status should be closely monitored. Monitoring of cyclosporine blood levels and dose adjustment may be required.
Concomitant use of cyclosporine and tacrolimus should be avoided (see section "Interaction with other medicinal products and other forms of interaction").
Cyclosporine is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein, and organic anion transporting polypeptides (OATPs), and may increase plasma concentrations of concomitantly administered drugs that are substrates of these enzymes and/or transporters. Caution should be exercised or such concomitant use should be avoided when cyclosporine is used with these medicinal products (see section "Interaction with other medicinal products and other forms of interaction"). Cyclosporine enhances exposure to HMG-CoA reductase inhibitors (statins). When used concomitantly with cyclosporine, the dose of statins should be reduced; concomitant use with certain statins should be avoided according to recommendations specified in the instructions for medical use of these medicinal products. Statin therapy should be temporarily or permanently discontinued in patients with signs and symptoms of myopathy or risk factors for severe renal injury, including renal failure due to rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").
After concomitant use of cyclosporine and lercanidipine, the AUC of the latter increased threefold, and the AUC of cyclosporine increased by 21%. Therefore, concomitant use of cyclosporine with lercanidipine should be avoided. Administration of cyclosporine 3 hours after lercanidipine did not alter the AUC of the latter, but the AUC of cyclosporine increased by 27%. Therefore, this combination should be used with caution, with at least a 3-hour interval between drug administrations.
Patients with psoriasis should avoid concomitant use of beta-blockers or diuretics.
Additional precautions for non-transplant indications
Cyclosporine should not be administered to patients with renal dysfunction (except patients with nephrotic syndrome with acceptable degree of renal impairment), uncontrolled arterial hypertension, uncontrolled infections, or any type of malignancy.
Prior to initiating treatment, a reliable assessment of baseline renal function should be performed by at least two measurements of estimated glomerular filtration rate (eGFR). Frequent assessment of renal function during therapy is necessary for appropriate dose adjustment.
Additional precautions for endogenous uveitis
EQUORAL® should be used with caution in patients with Behçet's syndrome who have neurological manifestations. Close monitoring of the neurological status of these patients is required. Experience with the use of the drug in children with endogenous uveitis is limited.
Additional precautions for nephrotic syndrome
Patients with baseline renal dysfunction should initially receive a dose of 2.5 mg/kg/day, with very careful monitoring.
In some patients, it may be difficult to distinguish cyclosporine-induced renal dysfunction from changes in renal function caused by nephrotic syndrome itself. This explains why, in rare cases, structural changes in the kidneys associated with EQUORAL® may occur without an increase in serum creatinine levels. Renal biopsy should be considered in patients with steroid-dependent minimal-change nephropathy who have been treated with EQUORAL® for more than one year.
Occasional reports have described the development of malignancies (including Hodgkin's lymphoma) in patients with nephrotic syndrome who received immunosuppressive therapy (including cyclosporine).
Additional precautions for rheumatoid arthritis
After 6 months of therapy, renal function should be assessed every 4–8 weeks, depending on disease stability, concomitant medication, and comorbidities. More frequent assessments are required when the dose of EQUORAL® is increased or when concomitant nonsteroidal anti-inflammatory drugs are initiated or their doses increased.
Discontinuation of the drug may also be necessary if arterial hypertension arising during EQUORAL® therapy cannot be controlled with appropriate antihypertensive therapy.
As with long-term use of other immunosuppressive agents, an increased risk of lymphoproliferative disorders should be considered. Particular caution is required when using EQUORAL® in combination with methotrexate due to synergistic nephrotoxic effects.
Additional precautions for psoriasis
Discontinuation of EQUORAL® therapy is recommended if arterial hypertension arising during treatment cannot be controlled with appropriate therapy.
Treatment of elderly patients should be initiated only in cases of disabling forms of psoriasis and with particularly careful monitoring of renal function.
Experience with the use of EQUORAL® in children with psoriasis is limited.
Malignant tumors (including skin) have been reported in patients with psoriasis who received cyclosporine as standard immunosuppressive therapy. Atypical skin lesions suspicious for malignant or premalignant changes should undergo biopsy before initiating EQUORAL® therapy. Patients with malignant or premalignant skin changes should receive the drug only after appropriate treatment of skin lesions and if no other successful treatment options are available.
Lymphoproliferative disorders have occurred in some patients with psoriasis receiving EQUORAL®. These disorders resolved after rapid discontinuation of the drug.
Patients receiving EQUORAL® should not receive concurrent UVB irradiation or PUVA photochemotherapy.
Additional precautions for atopic dermatitis
Discontinuation of EQUORAL® therapy is recommended if arterial hypertension arising during treatment cannot be controlled with appropriate therapy.
Experience with the use of EQUORAL® in children with atopic dermatitis is limited.
Treatment of elderly patients should be initiated only in cases of disabling forms of atopic dermatitis and with particularly careful monitoring of renal function.
Benign lymphadenopathy is often associated with exacerbations of atopic dermatitis and usually resolves spontaneously or with general improvement of the disease.
Lymphadenopathy observed during cyclosporine therapy requires regular monitoring.
If lymphadenopathy persists despite reduced disease activity, a biopsy should be performed as a precautionary measure to rule out lymphoma.
Before initiating EQUORAL® therapy, patients should recover from active herpes simplex virus infection. However, such an infection does not necessarily require discontinuation of the drug if it occurs during treatment (except in cases of severe infection).
Skin infections caused by Staphylococcus aureus are not an absolute contraindication for EQUORAL® therapy but require treatment with appropriate antibacterial agents. Oral erythromycin, known to increase cyclosporine blood concentration, should be avoided; if no alternative is available, careful monitoring of cyclosporine blood levels, renal function, and cyclosporine side effects is recommended.
Patients receiving EQUORAL® should not receive concurrent UVB irradiation or PUVA photochemotherapy.
Use in pediatric patients for non-transplant indications
Except for the treatment of nephrotic syndrome, adequate experience with EQUORAL® is lacking; its use in children under 16 years of age for non-transplant indications other than nephrotic syndrome cannot be recommended.
Do not use after the expiry date stated on the packaging.
Excipients
EQUORAL® capsules contain 18.8% v/v ethanol. A 500 mg dose of EQUORAL® capsules contains 798 mg of ethanol, approximately equivalent to 20 ml of beer (5%) or 8.3 ml of wine (12%). This should be considered when administering the drug to patients with alcohol dependence, liver disease or epilepsy, pregnant women, breastfeeding women, and children.
The medicinal product contains macrogolglycerol hydroxystearate, which may cause gastrointestinal disturbances and diarrhea.
Patients with rare hereditary fructose intolerance should avoid using this product due to its sorbitol content.
Use during pregnancy or breastfeeding
Animal studies have demonstrated reproductive toxicity in rats and rabbits.
Experience with cyclosporine use in pregnant women is limited. Pregnant women receiving immunosuppressants after transplantation, including cyclosporine, or treatment regimens containing cyclosporine, have an increased risk of preterm delivery (< 37 weeks).
Very limited data are available on the in utero effects of cyclosporine on children, with follow-up monitoring conducted in children up to 7 years of age. Renal function and blood pressure in these children were within normal limits.
However, adequate and well-controlled studies in pregnant women have not been conducted; therefore, EQUORAL® should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus. The presence of ethanol in EQUORAL® formulations should also be considered during pregnancy.
Cyclosporine passes into breast milk. The presence of ethanol in EQUORAL® formulations should be considered for women during breastfeeding. Women receiving cyclosporine therapy should avoid breastfeeding due to the potential for cyclosporine to cause serious adverse reactions in breastfed newborns/infants. A decision should be made whether to discontinue breastfeeding or discontinue/abstain from cyclosporine therapy, taking into account the importance of the drug to the mother.
Data on the effect of cyclosporine on human fertility are limited.
Ability to affect reaction speed when driving or operating machinery
There are no data on the effect of cyclosporine on the ability to drive or operate machinery.
Dosage and Administration
EQUORAL® must be prescribed only by a physician experienced in immunosuppressive therapy and/or organ transplantation, or under such physician's supervision.
Administration
The recommended dosage ranges for oral administration should be considered only as guidelines. The daily dose of EQUORAL® should always be divided into two doses administered at equal intervals. EQUORAL® should be taken according to a strict schedule with regard to time of day and dietary regimen. Capsules should be taken with a small amount of water and swallowed whole, without chewing. If administration of cyclosporine at a dose less than 10 mg is required, the appropriate dosage strength or pharmaceutical form should be used.
Indications in Transplantation
Regular monitoring of blood cyclosporine levels using a radioimmunoassay with monoclonal antibodies is necessary. The results obtained should guide dose adjustments to achieve target concentrations.
Organ Transplantation
The initial dose is 10–15 mg/kg body weight, divided into two doses and administered up to 12 hours before transplantation. For 1–2 weeks after surgery, the same daily dose should be continued, after which the dose should be gradually reduced under monitoring of cyclosporine blood levels and renal function to a maintenance dose of 2–6 mg/kg/day (in two divided doses).
EQUORAL® may be used in combination with other immunosuppressants—corticosteroids—and as part of combined triple or quadruple therapy. At the beginning of treatment, lower doses may be used (e.g., 3–6 mg/kg/day orally, divided into two doses).
Bone Marrow Transplantation/Prophylaxis and Treatment of Graft-versus-Host Disease (GvHD)
The recommended dose should be initiated one day before transplantation.
Intravenous cyclosporine solution is generally preferred at the beginning of therapy, although EQUORAL® soft capsules may also be used.
The recommended intravenous dose is 3–5 mg/kg/day. Intravenous administration at this dose should continue during the early post-transplant period for up to 2 weeks, after which transition to oral maintenance therapy with EQUORAL® at a daily dose of approximately 12.5 mg/kg, divided into two doses, should be made.
Maintenance therapy should be continued for 3–6 months (preferably 6 months). The dose should be gradually reduced to zero over one year after transplantation. If EQUORAL® is used from the beginning of therapy, the recommended dose is 12.5–15 mg/kg/day in two divided doses, starting the day before transplantation.
In patients with gastrointestinal disorders that reduce absorption, higher doses of capsules or intravenous concentrate may be required.
In some patients, graft-versus-host disease (GvHD) may occur after discontinuation of EQUORAL®, which usually resolves upon resumption of therapy. In such cases, an initial oral loading dose of 10–12.5 mg/kg should be prescribed, followed by oral maintenance therapy at the dose effective during prior treatment. For treatment of chronic, mild forms of this condition, EQUORAL® should be used at low doses.
Indications Not Related to Transplantation
When EQUORAL® is used for any approved indications not related to transplantation, the following general principles should be observed.
Before initiating treatment, an objective baseline assessment of renal function should be established based on at least two measurements. Estimated glomerular filtration rate (eGFR), calculated using the MDRD formula, may be used to assess renal function in adults. For children, the appropriate formula should be used to estimate eGFR. Since EQUORAL® may impair renal function, frequent monitoring is necessary. If eGFR decreases by more than 25% compared to baseline in more than one measurement, the dose of EQUORAL® should be reduced by 25–50%. If the reduction in eGFR exceeds 35% compared to baseline, further dose reduction of EQUORAL® should be considered. These recommendations apply even if the patient's values remain within the normal laboratory reference range. If dose reduction does not restore eGFR within one month, treatment with EQUORAL® should be discontinued.
Continuous monitoring of blood pressure is essential.
Before starting therapy, bilirubin concentration and other liver function parameters should be determined. These parameters should be carefully monitored during treatment.
Serum lipid levels, potassium, magnesium, and uric acid concentrations should be measured before starting therapy and periodically during treatment.
Periodic monitoring of cyclosporine blood concentration may be appropriate when used for indications not related to transplantation, for example, when EQUORAL® is co-administered with drugs that may affect cyclosporine pharmacokinetics, or in cases of unusual clinical response (e.g., inadequate efficacy or increased sensitivity to the drug, manifested as impaired renal function).
The usual route of administration is oral. When using the concentrate for infusion solution, careful calculations should be performed to determine the appropriate intravenous dose equivalent to the oral dose. Consultation with a physician experienced in cyclosporine use is recommended.
The total daily dose should not exceed 5 mg/kg, except in patients with sight-threatening endogenous uveitis and children with nephrotic syndrome.
For maintenance therapy, the lowest effective and well-tolerated dose should be individually determined.
Treatment with EQUORAL® should be discontinued in patients who do not achieve an adequate response within a defined time period (for detailed information, see below), or when the effective dose does not comply with established safety recommendations.
Endogenous Uveitis
The recommended initial dose to promote remission is 5 mg/kg/day orally in two divided doses until remission of active uveitic inflammation and improvement in visual acuity. In refractory cases, the dose may be temporarily increased up to 7 mg/kg/day.
To achieve initial remission or prevent exacerbation of ocular inflammation, if adequate control cannot be achieved with EQUORAL® monotherapy, concomitant use with systemic corticosteroids (e.g., prednisone at 0.2–0.6 mg/kg or equivalent) may be considered. After 3 months of treatment, the corticosteroid dose may be reduced to the lowest effective dose.
EQUORAL® should be discontinued if no improvement is observed after 3 months of treatment.
During maintenance therapy, the dose should be gradually reduced to the lowest effective dose, which should not exceed 5 mg/kg/day during remission.
Before initiating immunosuppressive therapy, infectious causes of uveitis should be ruled out.
The daily dose should be reduced by 25–50% if plasma creatinine concentration exceeds the baseline level by more than 30% in more than one measurement, even if this concentration is within the normal range.
Nephrotic Syndrome
The recommended daily dose to promote remission is 5 mg/kg for adults and 6 mg/kg for children, divided into two doses, provided that renal function is normal except for proteinuria. For patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day orally.
In cases of inadequate monotherapy with EQUORAL®, particularly in steroid-resistant patients, combination therapy with EQUORAL® and low-dose oral corticosteroids may be beneficial.
Time to improvement ranges from 3 to 6 months, depending on the type of glomerulopathy. If no improvement is observed within this period, treatment with EQUORAL® should be discontinued.
Doses should be individually adjusted based on efficacy (proteinuria) and safety, and should not exceed 5 mg/kg/day for adults and 6 mg/kg/day for children.
For maintenance therapy, doses should be gradually and individually reduced to the lowest effective level.
Rheumatoid Arthritis
During the first 6 weeks of treatment, the recommended dose is 3 mg/kg/day orally, divided into two doses. If the response is inadequate, the daily dose may be gradually increased, as tolerated, but should not exceed 5 mg/kg/day. To achieve maximum efficacy, treatment with EQUORAL® may continue for up to 12 weeks.
For maintenance therapy, the dose should be individually titrated to the lowest effective dose, depending on tolerability.
EQUORAL® may be prescribed in combination with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs). EQUORAL® may also be used in combination with weekly low-dose methotrexate in cases of inadequate response to methotrexine monotherapy. In such cases, EQUORAL® should be initiated at a dose of 2.5 mg/kg, divided into two daily doses, with the possibility of dose escalation within the limits of tolerability.
Psoriasis
Treatment with EQUORAL® should be initiated by a physician experienced in the diagnosis and treatment of psoriasis. Due to the variability of this disease, treatment should be individualized. The recommended initial dose for induction of remission is 2.5 mg/kg/day, divided into two doses. If no improvement is observed after 1 month, the dose may be gradually increased up to a maximum of 5 mg/kg/day. Treatment should be discontinued if an adequate response is not achieved within 6 weeks of daily administration at 5 mg/kg/day or if the effective dose is not consistent with established safety recommendations.
For patients requiring particularly rapid improvement, an initial dose of 5 mg/kg/day may be justified. Discontinuation of EQUORAL® after achieving a satisfactory response is possible, with reinitiation using the previously effective dose of EQUORAL® in case of relapse. Some patients may require continuous maintenance therapy.
For maintenance therapy, the dose should be individually adjusted to the lowest effective level and should not exceed 5 mg/kg/day.
Treatment with EQUORAL® should be gradually discontinued if remission persists for more than 6 months. However, the risk of relapse after discontinuation is very high.
Atopic Dermatitis
Treatment with EQUORAL® should be initiated by a physician experienced in the diagnosis and treatment of atopic dermatitis. Due to the variability of this disease, treatment should be individually tailored. For adults and adolescents aged 16 years and older, the recommended dose is 2.5–5 mg/kg/day, divided into two doses.
If the response to treatment at the initial dose of 2.5 mg/kg/day is unsatisfactory after 2 weeks, the daily dose may be rapidly increased to the maximum dose of 5 mg/kg/day. In very severe cases, rapid and adequate disease control may be achieved by using an initial dose of 5 mg/kg/day. After achieving a satisfactory effect, the dose should be gradually reduced and, if possible, EQUORAL® should be discontinued. Subsequent relapses may be treated by reinitiating EQUORAL®.
Treatment should be discontinued if patients with atopic dermatitis do not show sufficient improvement after one month of treatment at a dose of 5 mg/kg/day.
Current data on long-term treatment of atopic dermatitis with this drug are limited; therefore, the recommended duration of individual treatment cycles is no more than 8 weeks.
Switching from Original Cyclosporine Formulation to EQUORAL®
Available data confirm that switching from the original cyclosporine formulation to EQUORAL® at a 1:1 ratio results in comparable minimum cyclosporine concentrations in whole blood. In many patients, higher maximum (peak) concentrations (Cmax) and increased drug exposure (AUC) may be observed. In a small percentage of patients, these changes may be more pronounced and clinically significant. Additionally, absorption of cyclosporine from EQUORAL® shows less variability, and the correlation between trough cyclosporine concentrations and drug exposure (expressed as AUC) is stronger than with the original cyclosporine formulation.
Since switching from the original cyclosporine formulation to EQUORAL® may lead to increased cyclosporine exposure, the following guidelines should be followed.
In post-transplant patients, treatment with EQUORAL® should be initiated at the same daily dose as previously used with the original cyclosporine formulation. Initial monitoring of trough cyclosporine blood levels should be performed 4–7 days after switching to EQUORAL®. Additionally, clinical safety parameters such as renal function and blood pressure should be monitored during the first 2 months after the switch. If trough cyclosporine blood concentrations fall outside the therapeutic range and/or clinical safety parameters worsen, appropriate dose adjustments should be made.
For indications not related to transplantation, EQUORAL® should be prescribed at the same daily dose as the original cyclosporine formulation.
Renal function and blood pressure should be monitored 2, 4, and 8 weeks after switching. If blood pressure measurements significantly exceed pre-switch levels in more than one measurement, or if eGFR decreases by more than 25% compared to the value measured before starting therapy with the original cyclosporine formulation, the dose should be reduced. Monitoring of trough cyclosporine blood concentrations should also be performed in cases of unexpected toxic effects or lack of efficacy.
Switching from One Oral Cyclosporine Formulation to Another
Switching from one oral cyclosporine formulation to another should be done cautiously and under specialist supervision. Initiation of a new formulation should be accompanied by monitoring of cyclosporine blood levels in post-transplant patients.
Special Populations
Patients with Impaired Renal Function
All Indications
Cyclosporine is minimally excreted by the kidneys, and its pharmacokinetics are not significantly affected by impaired renal function. However, due to its nephrotoxic potential, careful monitoring of renal function is recommended.
Indications Not Related to Transplantation
Cyclosporine should not be prescribed to patients with impaired renal function. Exceptions include patients being treated for nephrotic syndrome. For patients with nephrotic syndrome and impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.
Patients with Impaired Hepatic Function
Cyclosporine is extensively metabolized in the liver. In patients with impaired hepatic function, approximately two- to threefold increases in cyclosporine exposure may occur. In cases of severe hepatic impairment, dose reduction may be necessary to maintain drug concentrations within the recommended target range. In such cases, monitoring of cyclosporine blood concentrations is recommended until stable levels are achieved.
Use in Pediatric Patients
Clinical studies have included children from 1 year of age. In several studies, pediatric patients required and tolerated higher doses of cyclosporine per unit of body weight than adults.
Use of EQUORAL® in children for indications not related to transplantation is not recommended, except for nephrotic syndrome (see sections "Special Warnings and Precautions for Use" and "Pediatric Use").
Use in Elderly Patients
Experience with EQUORAL® in elderly patients is limited.
In clinical trials of cyclosporine for rheumatoid arthritis, patients aged 65 years and older, after 3–4 months of therapy, were more prone to develop systolic hypertension and showed an increase in serum creatinine levels exceeding the baseline value by 50% or more.
Overall, dose selection in elderly patients should be cautious, considering the higher prevalence of decreased hepatic, renal, or cardiac function, concomitant diseases, or concomitant medications that may increase susceptibility to infections. Treatment should generally be initiated with a dose at the lower end of the dosing range.
Children.
Clinical studies have included children from 1 year of age. In several studies, pediatric patients required and tolerated higher doses of cyclosporine per unit of body weight than adults.
Except for the treatment of nephrotic syndrome, adequate experience with cyclosporine is lacking; its use in children under 16 years of age for indications not related to transplantation, other than nephrotic syndrome, cannot be recommended.
Overdose.
Symptoms
Data on acute cyclosporine overdose are limited. Oral intake of doses up to 10 g (approximately 150 mg/kg) has resulted in relatively minor clinical consequences such as vomiting, drowsiness, headache, tachycardia, and in some patients, relatively significant reversible renal function impairment. However, accidental parenteral overdose in premature infants has led to severe intoxication.
Treatment
In all cases of overdose, symptomatic treatment and general supportive measures should be implemented. Inducing vomiting and gastric lavage may be beneficial within the first few hours after overdose. The drug is practically not removed by hemodialysis and is inadequately removed by hemoperfusion using activated charcoal.
Side effects
The main adverse reactions associated with the use of cyclosporine include renal dysfunction, tremor, hirsutism, arterial hypertension, diarrhea, anorexia, nausea, and vomiting.
Numerous adverse reactions associated with cyclosporine are dose-dependent and are reversible upon dose reduction.
In post-transplant patients, adverse reactions occur more frequently and are more pronounced due to the need for higher initial doses and longer duration of maintenance therapy, compared to patients with other indications for cyclosporine use.
Anaphylactoid reactions have been observed following intravenous administration of the drug.
Infections and infestations. Patients receiving immunosuppressive therapy including cyclosporine or cyclosporine-containing products are at increased risk of developing various infections (viral, bacterial, fungal, parasitic). Both localized and systemic infections may occur. Pre-existing infections may be exacerbated, and reactivation of infections caused by polyomaviruses may lead to polyomavirus-associated nephropathy (PVAN) or JC virus-associated progressive multifocal leukoencephalopathy (PML). Serious and/or fatal outcomes have been reported.
Other reported adverse reactions include upper and lower respiratory tract infections (including bronchioles), urinary tract infections, cytomegalovirus infection, sepsis, and herpes infections.
Benign, malignant and unspecified neoplasms (including cysts and polyps). Patients receiving immunosuppressive therapy including cyclosporine or cyclosporine-containing products are at increased risk of developing lymphomas and lymphoproliferative disorders, as well as other malignancies, particularly of the skin. The incidence of malignancies increases with more intensive and prolonged immunosuppression. Some malignancies may result in fatal outcomes.
Blood and lymphatic system disorders: anemia, thrombocytopenia, leukopenia, microangiopathic hemolytic anemia, hemolytic-uremic syndrome, thrombotic microangiopathy, thrombotic thrombocytopenic purpura.
Metabolism and nutrition disorders: hyperlipidemia, hyperuricemia, hyperkalemia, hypomagnesemia, anorexia, hyperglycemia.
Nervous system disorders: tremor, headache, migraine, paresthesia, seizures, signs of encephalopathy (including posterior reversible encephalopathy syndrome (PRES)), such as seizures, confusion, disorientation, slowed reaction, excitement, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia, motor polyneuropathy, optic disc swelling including papilledema, potentially leading to visual disturbances due to benign intracranial hypertension.
Ear and labyrinth disorders: hearing impairment.
Cardiac disorders: arterial hypertension, flushing.
Gastrointestinal disorders: nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia, peptic ulcer of the stomach and duodenum, pancreatitis.
Hepatobiliary disorders: liver function abnormalities, hepatotoxicity and liver damage, including cholestasis, jaundice, hepatitis, and hepatic failure with fatal outcome.
Skin and subcutaneous tissue disorders: hirsutism, rash, acne, allergic skin reactions, hypertrichosis.
Musculoskeletal and connective tissue disorders: muscle spasms, myalgia, muscle weakness, myopathy, limb pain.
Renal and urinary disorders: renal function impairment.
Reproductive system and breast disorders: menstrual cycle disturbances, gynecomastia.
General disorders and administration site conditions: pyrexia, increased fatigue, edema, weight gain.
Description of selected adverse reactions
Hearing impairment. Hearing impairment has been reported during the post-marketing period in patients with high cyclosporine levels.
Other adverse reactions reported during post-marketing use. Hepatotoxicity and liver damage, including cholestasis, jaundiced forms of hepatitis, and hepatic failure, have been reported in patients receiving cyclosporine therapy. In most cases, these reports involved patients with significant comorbidities, underlying diseases, and other complicating factors, including infectious complications and concomitant use of other hepatotoxic drugs. Fatal cases, mostly in post-transplant patients, have been reported.
Acute and chronic nephrotoxicity. Patients receiving treatment with calcineurin inhibitors (CNI), including cyclosporine and cyclosporine-containing products, are at increased risk of developing acute or chronic nephrotoxicity. In acute nephrotoxicity, disturbances in ion homeostasis such as hyperkalemia, hypomagnesemia, and hyperuricemia have been reported. Cases of chronic morphological changes included arteriolar hyalinosis, tubular atrophy, and interstitial fibrosis.
The safety profile in children aged 1 year and older treated with standard doses of cyclosporine has been reported to be similar to that in adults.
Reporting suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.
**Shelf life. **3 years.
Storage conditions.
Store at temperatures not exceeding 30 °C in the original packaging, in a place inaccessible to children. Do not freeze.
Packaging.
10 capsules in a blister, 5 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Teva Czech Industries s.r.o.
Manufacturer's address and location of operations.
Ostravska 305/29, Komarov, 747 70 Opava, Czech Republic.