Vero-cladribine (Concentrate) Instructions for Use

Marketing Authorization Holder

Veropharm, LLC (Russia)

ATC Code

L01BB04 (Cladribine)

Active Substance

Cladribine

Dosage Form

Vero-Cladribine

Concentrate for solution for infusion 10 mg/10 ml: fl. 1, 6, 7 or 10 pcs.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion as a clear, colorless or slightly yellowish liquid.

Excipients: sodium chloride – 9 mg, potassium dihydrogen phosphate solution and sodium hydrogen phosphate solution – to pH 6.3, water for injections – to 1 ml.

10 ml – glass bottles (1) – cardboard packs.
10 ml – glass bottles (6) – cardboard packs with partitions.
10 ml – glass bottles (7) – cardboard packs with partitions.
10 ml – glass bottles (10) – cardboard packs with partitions.

Clinical-Pharmacological Group

Antitumor drug. Antimetabolite

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Immunosuppressive agent. Cladribine, 2-chloro-deoxyadenosine, is a chlorine-containing purine derivative that is resistant to the action of adenosine deaminase. It suppresses autoimmune inflammatory processes underlying the development of multiple sclerosis by selectively inhibiting lymphocyte activity. Cladribine is effective against both dividing and non-dividing lymphocytes. Due to the prolonged anti-inflammatory effect of cladribine, the severity of inflammatory changes in the nervous system tissues in multiple sclerosis is reduced.

The relationship between the plasma concentration of cladribine and efficacy in multiple sclerosis has not been established.

Treatment with cladribine has been noted to reduce the number of relapses, decrease disease activity in brain tissue, and slow the progression of patient disability.

Cladribine exhibits cytotoxic effects (due to the active metabolite 5′-triphosphate-2-chloro-2′-deoxyadenosine) against dividing and non-dividing cells, inhibiting DNA synthesis and repair (inhibits ribonucleotide reductase, which catalyzes the formation of deoxynucleoside triphosphates, DNA polymerase, and activates a specific endonuclease, leading to single-strand DNA breaks), which ultimately leads to cell death. Lymphoid cells are more sensitive to the drug (due to higher deoxycytidine kinase activity and lower 5′-nucleotidase activity in them) than non-lymphoid cells.

Pharmacokinetics

Linear dependence of pharmacokinetic parameters after intravenous administration has been shown at doses from 2.5 to 21.5 mg/m².

When taken orally at a dose of 10 mg, Cladribine is rapidly absorbed. C_max in plasma is 22-29 ng/ml, AUC is 80-101 ng × h/ml. The mean T_max of cladribine in plasma is 0.5 h. When taken simultaneously with high-calorie food, the absorption of cladribine is slowed: the mean T_max is 1.5 h, and C_max decreases by 29%, while the AUC does not change. Food intake does not have a clinically significant effect on the absorption of cladribine.

The binding of cladribine to plasma proteins is 20% and does not depend on its concentration. V_d is large, on average – 482 l (standard deviation ±185).

After intravenous administration, 25% of the dose penetrates into the cerebrospinal fluid.

The intracellular concentration of phosphorylated cladribine is several hundred times higher than the corresponding concentration in plasma.

It undergoes intracellular metabolism. At the initial stage, phosphorylation to 5′-monophosphate is carried out by deoxycytidine kinase. Since the activity of deoxycytidine kinase is higher than that of 5′-nucleotidase, and also due to the drug’s resistance to the action of adenosine deaminase, all three phosphorylated forms of 2-chloro-2′-deoxyadenosine rapidly accumulate in the cell.

The main substance found in plasma and urine, both after intravenous administration and oral administration, is unchanged Cladribine. The main metabolite formed in the liver, 2-chloroadenosine, is detected in minimal amounts in blood and urine. Other metabolites are also detected in trace amounts.

Renal clearance is 23.1 l/h, and metabolic (non-renal) clearance is 22.7 l/h. Renal clearance exceeds the glomerular filtration rate, indicating active excretion of cladribine by the kidneys. Non-renal routes of cladribine elimination include both the process of metabolic changes in the liver and extensive intracellular metabolism and excretion. It is excreted in small amounts through the intestine.

The total clearance of cladribine depends on CrCl. The total clearance of cladribine in patients with mild renal impairment (CrCl = 65 ml/min) decreases by 18%. The predicted decrease in cladribine clearance in patients with moderate (CrCl = 40 ml/min) and severe (CrCl = 20 ml/min) renal impairment is 30% and 40%, respectively.

Indications

Treatment of relapsing-remitting multiple sclerosis.

Hairy cell leukemia.

ICD codes

Dosage Regimen

Multiple sclerosis: orally, 10-20 mg/day. The regimen and duration of treatment are established individually. Before starting treatment and then at certain intervals, a complete blood count is performed to confirm the possibility of starting or continuing treatment. If necessary, the course can be postponed until the patient’s general condition improves (for example, in case of an acute infectious disease), as well as for the restoration of blood counts. It is recommended to start treatment only in the absence of abnormalities in the complete blood count.

Hairy cell leukemia: administered intravenously by drip at a dose of 0.09-0.1 mg/kg/day for 7 days. The dose and duration of treatment are established depending on the characteristics of the disease and the severity of the condition.

Adverse Reactions

From the hematopoietic system clinically significant lymphopenia, leukopenia, neutropenia, thrombocytopenia, anemia, pancytopenia, aplastic and hemolytic anemia; very rarely – myelodysplastic syndrome.

From the digestive system nausea, vomiting, anorexia, diarrhea, constipation, gastralgia, increased bilirubin and/or transaminases.

From the nervous system headache, dizziness, insomnia, peripheral sensory neuropathy.

From the sensory organs often – ringing in the ears.

From the cardiovascular system: tachycardia, edema.

From the respiratory system cough, rapid breathing, interstitial pneumonitis, change in percussion sound and auscultatory characteristics of breathing.

From the reproductive system often – menstrual cycle disorders (menorrhagia and metrorrhagia).

Dermatological reactions often – skin rash (pustules, papules, macules, itchy or erythematous rash); in isolated cases – skin reaction involving mucous membranes and the development of erythema multiforme.

Local reactions at the infusion site – erythema, pain, swelling, thrombosis, phlebitis.

Other: hyperthermia, weakness, asthenia, increased fatigue, pain of various localization, purpura, petechiae, nosebleeds, decreased immunity; predisposition to opportunistic infections, infections caused by Herpes simplex, Herpes zoster, cytomegalovirus.

Contraindications

Moderate or severe chronic renal failure (CrCl less than 50 ml/min); moderate or severe hepatic failure (4 or more on the Child-Pugh scale); simultaneous use of myelosuppressive drugs; acute infectious disease or exacerbation of a chronic disease (including active or latent tuberculosis, hepatitis); decreased immunity due to disease or due to the use of immunosuppressants, including cyclosporine, methotrexate, mitoxantrone, natalizumab, or long-term use of corticosteroids (a short course of corticosteroid treatment is allowed); vaccination within 3 months prior to treatment with an attenuated vaccine (live or attenuated vaccines); pregnancy, lactation (breastfeeding); children and adolescents under 18 years of age; hypersensitivity to cladribine.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Men should use effective methods of contraception, both during treatment and for 3 months after taking the last dose. This precaution is due to the possible negative effect of cladribine on spermatogenesis. If a female partner of a patient taking Cladribine becomes pregnant, the physician should be informed about the possible adverse effects on the fetus.

It has not been established whether Cladribine is excreted in breast milk, but given the potential adverse effects, it is recommended to either discontinue breastfeeding during treatment or discontinue treatment with cladribine, depending on the importance of continuing therapy.

Data from experimental studies confirm the embryotoxic and teratogenic effects of cladribine. No effect on the reproductive function of the offspring and their general condition was noted.

Special Precautions

Cladribine should be used with caution in elderly patients (insufficient clinical data and considering the greater likelihood of impaired renal or liver function, concomitant diseases and co-administered drugs), in patients with moderately impaired renal function (CrCl = 50-80 ml/min), because the total clearance of cladribine depends on CrCl.

Treatment of patients with renal and/or hepatic insufficiency should be carried out under direct monitoring of renal and hepatic function. Treatment should be discontinued in case of development of nephro- or hepatotoxicity.

Careful monitoring of elderly patients is necessary (due to lack of pharmacokinetic data).

It should be used with particular caution in patients with initial bone marrow suppression of any origin due to the risk of prolonged hypoplasia. In some cases, treatment may lead to severe forms of immunosuppression with a decrease in the number of CD4+ leukocytes.

Myelosuppression caused by cladribine is dose-dependent and usually reversible, manifesting within a month from the start of treatment. During treatment and for at least 4-8 weeks after, careful monitoring of hematological blood parameters is necessary.

If hyperthermia occurs against the background of neutropenia, monitoring of the patient’s general condition is necessary during the first month of treatment and, if necessary, the appointment of antibacterial therapy.

In case of neurotoxicity development, treatment should be suspended until the resolution of neurological symptoms.

Due to lymphopenia and possible myelosuppression during treatment with cladribine, a weakening of the body’s immune defense and an increased likelihood of developing or exacerbating infectious diseases are possible. Activation of latent infections, including tuberculosis, hepatitis, or herpes infection, is also possible. The decrease in lymphocyte count is dose-dependent and may be more pronounced in elderly patients. During treatment, it is necessary to carefully monitor the patient’s condition, and if symptoms of an infectious disease appear, interrupt or postpone the intake of cladribine until complete recovery.

For patients who require blood transfusion due to cladribine-induced lymphopenia, it is recommended to irradiate the cellular components before blood transfusion to prevent transfusion-associated graft-versus-host disease.

There is no experience with the use of oral cladribine in patients with multiple sclerosis and malignant neoplasms during treatment or in the period preceding treatment (except for basal cell or squamous cell skin cancer in situ, removed surgically, with a remission period of more than 5 years). Thus, the risk of recurrence of malignant neoplasms after treatment with cladribine is unknown. In patients with malignant neoplasms and multiple sclerosis, the issue of using cladribine should be decided individually, taking into account the ratio of possible risk and benefit for the patient. There are isolated reports of the development of non-hematological malignant neoplasms, including choriocarcinoma, melanoma, ovarian cancer, pancreatic cancer, as well as stage 0 cervical cancer in situ, considered a precancerous condition. At the same time, a causal relationship with the intake of cladribine has not been established. However, given the prolonged immunosuppressive effect when using cladribine, the risk of developing neoplasms cannot be excluded.

Treatment with cladribine should not be started or continued for 3 months after vaccination with live, including attenuated vaccines, due to an increased risk of activation of the infection for which prophylaxis was carried out. Vaccination with live, including attenuated vaccines, should not be prescribed either during treatment with cladribine or for 3 months after the application of the last dose.

Influence on the ability to drive vehicles and mechanisms

During treatment, dizziness (vertigo) may occur. In such a case, the patient should refrain from driving a car or other activities requiring increased attention and speed of psychomotor reactions.

Drug Interactions

Concomitant or subsequent use of immunomodulatory drugs should be carried out under careful clinical control with assessment of hematological parameters. Short-term corticosteroid therapy is allowed when co-administering cladribine with drugs that have hematotoxic properties (for example, interferons, carbamazepine, NSAIDs), under careful monitoring of hematological parameters.

The use of cladribine in immunocompromised patients, including patients receiving immunosuppressants (for example, cyclosporine, methotrexate, mitoxantrone, natalizumab) or long-term corticosteroid treatment, is contraindicated due to an increased risk of adverse reactions.

The degree of absorption of cladribine and its bioavailability depend on the transport mechanism associated with proteins of the ABCG2 family, which also affect the bioavailability of other drugs, such as irinotecan, topotecan, rosuvastatin and sulfasalazine. Inhibitors of ABCG2 proteins in the gastrointestinal tract may increase the bioavailability and systemic action of cladribine.

Known inhibitors of ABCG2 that change the pharmacokinetic parameters of substrates by more than 20% in vivo are cyclosporine and reverse transcriptase inhibitors: ritonavir, lopinavir and atazanavir. Caution is required when using such drugs concomitantly with cladribine. The bioavailability of cladribine when taken orally is about 40%, which suggests that with complete blocking of the function of intestinal ABCG2 proteins, bioavailability may increase by no more than 2.5 times.

Cladribine is sensitive to an acidic environment, so any drugs that affect the acidity of gastric juice may disrupt the stability of the drug and change its bioavailability. However, it has been established that the bioavailability of cladribine does not change when co-administered with pantoprazole or omeprazole.

Storage Conditions

Store at 2°C (36°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.