Movectro^® (Tablets) Instructions for Use

Marketing Authorization Holder

Merck Serono Europe, Limited (United Kingdom)

Manufactured By

Nerviano Medical Sciences, S.R.L. (Italy)

ATC Code

L04AA40 (Cladribine)

Active Substance

Cladribine (Rec.INN registered by WHO)

Dosage Form

Movectro®

Tablets 10 mg: 1, 4, 5, 6, 7, 8, 9 or 10 pcs.

Dosage Form, Packaging, and Composition

Tablets are white, round, biconvex, with an engraving “C” on one side and “10” on the other.

Excipients: hydroxypropylbetadex, sorbitol, magnesium stearate.

1 pc. – blister packs (1) – plastic holders (1) – cardboard packs.
4 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.
5 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.
6 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.
7 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.
8 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.
9 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.
10 pcs. – blister packs (1) – plastic holders (1) – cardboard packs.

Clinical-Pharmacological Group

Immunosuppressive drug used in multiple sclerosis

Pharmacotherapeutic Group

Immunosuppressive agent

Pharmacological Action

Immunosuppressive agent. Cladribine, 2-chloro-deoxyadenosine, is a chlorine-containing purine derivative resistant to adenosine deaminase.

The drug 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.

Clinical studies of Movectro^® in patients with cancer and in patients with multiple sclerosis suggest that treatment efficacy, as well as the reduction in lymphocyte count, depend on the total dose of the drug (cumulative effect).

Treatment with Movectro^® resulted in a reduction in the number of relapses, a decrease in disease activity in the brain tissue, and a slowing of the progression of patient disability.

Pharmacokinetics

The pharmacokinetic parameters of cladribine were studied after intravenous administration and oral administration in patients with multiple sclerosis and patients with cancer, as well as in in vitro studies. Linear dependence of pharmacokinetic parameters after intravenous administration was shown at doses from 2.5 to 21.5 mg/m².

Absorption

After oral administration of Movectro^® tablets at a dose of 10 mg, the drug is rapidly absorbed. C_max in plasma is 22-29 ng/ml, AUC is from 80 to 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 AUC does not change. The bioavailability of cladribine tablets when taken orally at a dose of 10 mg is about 40%.

Food intake does not have a clinically significant effect on the absorption of cladribine.

Distribution

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

Cladribine penetrates the blood-brain barrier. The intracellular concentration of phosphorylated cladribine is several hundred times higher than the corresponding concentration in plasma.

Metabolism

The main substance found in plasma and urine, both after intravenous administration and after 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.

Intracellular metabolism: after penetration into the cell, with the participation of deoxycytidine kinase, phosphorylation of cladribine occurs to form Cladribine-5′-monophosphate. Phosphorylation then continues, resulting in the formation of cladribine diphosphate and triphosphate. Cytoplasmic 5′-nucleotidase catalyzes the processes of dephosphorylation and deactivation of cladribine monophosphate. Intracellular phosphorylation is necessary for the activation of cladribine.

Elimination

T_1/2 of cladribine is about 23 h. Renal and extrarenal pathways of cladribine elimination are equivalent. Renal clearance is 23.1 L/h, and metabolic (extrarenal) clearance is 22.7 L/h. Renal clearance exceeds the glomerular filtration rate, indicating active renal excretion of cladribine. Extrarenal pathways of cladribine elimination include both the process of metabolic changes in the liver and extensive intracellular metabolism and excretion.

Renal clearance is about 50%.

Pharmacokinetics in special clinical cases

No accumulation of cladribine in plasma was noted during course treatment lasting from 4 to 5 days.

No effect of age (18-65 years) and gender on the pharmacokinetic parameters of cladribine was noted.

The pharmacokinetics of cladribine has not been studied in elderly patients and children with multiple sclerosis, as well as in patients with impaired renal or liver function.

The total clearance of cladribine depends on CrCl. The total clearance of the drug in patients with mild renal failure (CrCl = 65 ml/min) decreases by 18%. The predicted decrease in cladribine clearance in patients with moderate renal failure (CrCl = 40 ml/min) and severe renal failure (CrCl = 20 ml/min) is 30% and 40%, respectively. Extrarenal elimination pathways account for about 50%. They are largely represented by intracellular mechanisms and only partially by hepatic metabolism. Thus, the role of the liver in the elimination of cladribine is insignificant.

Indications

• Treatment of relapsing-remitting multiple sclerosis.

ICD codes

Dosage Regimen

The drug is taken orally, before or after meals, at the same time. The tablets should be swallowed whole without chewing and washed down with water.

Treatment is course-based. Each course consists of taking 1 or 2 tablets of 10 mg over the first four or five days of a 4-week period.

Initial therapy usually begins with 2 treatment courses. Depending on the severity of the disease, 4 courses of treatment may be recommended immediately. The interval between treatment courses with Movectro^® as part of Initial Therapy is 4 weeks.

Initial therapy, including 4 consecutive courses, is recommended for patients with high disease activity, confirmed before the start of treatment by MRI in T₁ mode using diagnostic contrast agents based on gadolinium.

Re-treatment – these are additional courses that begin 48 and 52 weeks after the completion of Initial Therapy.

The efficacy and safety of the drug at higher doses or additional course treatment after 96 weeks from the start of treatment have not been studied.

Criteria for starting and continuing therapy

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.

The patient is informed when treatment will start or continue in the future.

Starting treatment with Movectro^® is recommended only in the absence of abnormalities in the complete blood count.

Before starting each of the subsequent courses of treatment, it is necessary to ensure that the hematological parameters meet the criteria given in Table 1.

Table 1.

** – the efficacy and safety of Movectro^® in patients with a body weight of less than 40 kg have not been studied, the decision on dose selection is made by the attending physician.

Duration of the treatment course

The required number of tablets should be taken over 4 or 5 days according to the calculated dose. The packaging contains instructions on the number of tablets (1 or 2 tablets) to be taken daily. The usual dosing schedule is shown in Table 5.

Table 5.

Tablets should be taken in accordance with the Instructions for Use of the special Movectro^® packaging.

Missed dose

If a dose is missed during the day (1 or 2 tablets), the tablets should be taken on the same day.

If more than 24 hours have passed after missing a dose, the missed dose should not be taken together with the planned dose. The missed dose should be taken the next day, thus extending the drug intake by one day.

For example, if the patient forgot to take the drug on Day 3 and remembered it only the next day (Day 4), then the missed dose should be taken on Day 4, and the course of treatment will be extended by 1 day. If 2 consecutive doses are missed (for example, Day 3 and Day 4), then the missed tablets should be taken over the next 2 days, and the course of treatment will be extended by 2 days.

If the patient has taken a dose higher than recommended, they should seek medical help to assess their condition and determine the possibility of continuing treatment.

Instructions for use of the special Movectro^® packaging

1. Wash and dry your hands, prepare a glass of drinking water.
2. Turn the drug packaging over to determine which tablet(s) need to be taken.
3. Hold the packaging in your left hand so that the central button is facing you.
4. Press the central button with your right thumb and hold it pressed.
5. Press and hold the buttons on the side surfaces of the packaging with the fingers of your left hand. Release the central button. Pull out the blister with tablets with your right hand and release the buttons on the side surfaces of the packaging.
6. Push out 1 or 2 tablets into your palm with your thumb, according to the prescribed treatment regimen.
7. Place the tablet in your mouth and swallow with water. The tablet should be swallowed immediately, without chewing or sucking. Avoid prolonged contact of the tablet with the skin of your hands, and do not touch your nose, eyes, or other parts of your body with your hands.
8. Return the blister with tablets back into the packaging.
9. Wash your hands thoroughly with soap.

Tablets should be stored in the packaging until the next dose. Do not transfer tablets to another container. The packaging with tablets should be stored in a safe place, out of the reach of children.

Adverse Reactions

From the hematopoietic system 30% – clinically significant lymphopenia, which can be severe and contributes to an increased risk of infection.

Infectious complications typical infections (due to lymphopenia) when using cladribine are acute respiratory infections (e.g., nasopharyngitis), infectious diseases of the genitourinary organs in women, as well as herpes zoster.

From the central nervous system frequently (> 1/100) – headache, dizziness (vertigo).

From the sensory organs frequently (> 1/100) – ringing in the ears.

Dermatological reactions frequently (> 1/100) – skin rash (pustules, papules, macules, itchy or erythematous rash). One case of skin reaction involving mucous membranes and the development of erythema multiforme has been registered.

From the reproductive system frequently (> 1/100) – menstrual cycle disorders (menorrhagia and metrorrhagia).

The patient should be warned and instructed to immediately consult a doctor in case of the development of the adverse reactions listed above or any other adverse reactions, especially if they are sudden, rapidly progressive, or severe.

Contraindications

• Acute infectious disease or exacerbation of a chronic disease (including active or latent tuberculosis, hepatitis);
• Decreased immunity due to disease or as a result of taking 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 period;
• Age under 18 years (insufficient clinical data);
• Hypersensitivity to the components of the drug.

Not recommended for patients with fructose intolerance, because Movectro^® contains sorbitol; for patients with moderate and severe renal failure (CrCl <50 ml/min), because clinical experience with the drug in such patients is limited. Although the role of the liver in the elimination of cladribine is insignificant, the use of Movectro^® in patients with moderate or severe hepatic impairment is not recommended, because clinical experience with the drug in such patients is limited.

With caution the drug should be used 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.

Use in Pregnancy and Lactation

Movectro^® is contraindicated during pregnancy and lactation (breastfeeding).

Adequate and strictly controlled studies of the drug during pregnancy have not been conducted. In a limited number of observations, women took Movectro^® before pregnancy was diagnosed. The period from the end of drug use to confirmation of pregnancy ranged from 1 week to 16 months. Both term births and spontaneous abortions were noted.

Clinical data did not confirm the teratogenic effect of the drug, but it was established that Movectro^® inhibits DNA synthesis. It is known that other drugs that inhibit DNA synthesis (for example, methotrexate) have a teratogenic effect. Experimental study data confirm the embryotoxic and teratogenic effects of cladribine. No effect on the reproductive function of the offspring and their general condition was noted.

If pregnancy occurs during treatment with the drug, it should be discontinued. If therapy continues, the patient should be warned about the risk of adverse effects of Movectro^® on the fetus.

In women of childbearing age, a pregnancy test should be performed before starting treatment and before starting each treatment cycle. It is necessary to ensure that the woman uses effective methods of contraception throughout the entire treatment period.

Men should use effective methods of contraception, both during treatment and for 3 months after taking the last dose of the drug. This precaution is due to the possible negative effect of the drug on spermatogenesis. If the partner of a patient taking Movectro^® becomes pregnant, she 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 of the drug, it is recommended to either discontinue breastfeeding during treatment with the drug, or discontinue the drug, depending on the importance of continuing cladribine therapy.

Use in Hepatic Impairment

Although the role of the liver in the elimination of cladribine is insignificant, the use of Movectro^® in patients with moderate or severe hepatic impairment is not recommended, as clinical experience with the drug in such patients is limited.

Use in Renal Impairment

The drug should be used with caution in patients with moderately severe renal impairment (CrCl = 50-80 ml/min), because the total clearance of cladribine depends on CrCl.

Pediatric Use

Contraindication: age under 18 years (insufficient clinical data).

Geriatric Use

The drug should be used with caution in elderly patients (insufficient clinical data and considering the greater likelihood of impaired renal or hepatic function, concomitant diseases, and co-administered drugs).

Special Precautions

A complete blood count should be performed for all patients

• Before starting treatment with Movectro^®;
• Before each subsequent course of treatment with Movectro^®;
• 1 month after the last course of treatment with Movectro^® as part of the Initial Therapy and 1 month after the last course of treatment with Movectro^® as part of the Retreatment Therapy;
• Every 3 months between the courses of Initial Therapy and Retreatment Therapy.

Due to lymphopenia and potential myelosuppression during treatment with Movectro^®, the body’s immune defense may be weakened and the likelihood of developing or exacerbating infectious diseases may increase. Activation of latent infections is also possible, including tuberculosis, hepatitis, or herpes infection. The reduction in lymphocyte count is dose-dependent and may be more pronounced in elderly patients. During treatment, the patient’s condition should be carefully monitored, and if symptoms of an infectious disease appear, treatment with Movectro^® should be interrupted or postponed until complete recovery.

Patients who require blood transfusion due to cladribine-induced lymphopenia are recommended to have cellular blood components irradiated prior to transfusion to prevent transfusion-associated graft-versus-host disease. Consultation with a hematology specialist is recommended.

Several cases of myelodysplastic syndrome have been reported during parenteral use of cladribine and other purine analogue drugs for multiple sclerosis and other conditions. The risk of developing myelodysplastic syndrome during treatment with Movectro^® is unknown.

There is no experience with the use of Movectro^® 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 Movectro^® is unknown. In patients with malignant neoplasms and multiple sclerosis, the decision to prescribe Movectro^® should be made individually, taking into account the risk-benefit ratio for the patient. There are isolated reports of the development of non-hematological malignancies, including choriocarcinoma, melanoma, ovarian cancer, pancreatic cancer, as well as stage 0 cervical cancer in situ, considered a precancerous condition. A causal relationship with the drug intake has not been established. However, given the prolonged immunosuppressive effect of Movectro^®, the risk of developing neoplasms cannot be excluded.

Movectro^® is supplied in blisters containing the exact number of tablets required for a treatment course.

The patient is advised to double-check the correct calculation of the number of tablets: in the left column of Table 3 or 4, find the line corresponding to body weight in kg, and then verify the number of tablets that should be contained in the blister intended for the specific treatment course for a patient of that body weight. The patient should contact their treating physician if the number of tablets in the blister does not correspond to their body weight and the sequential number of the treatment course; the number of required tablets may differ depending on the sequential number of the treatment course.

Tablets should not be left for a long time on an open surface, for example, on a table after removal from the blister. If a tablet is broken, its fragments must be carefully removed from the surface with water. If a tablet is lost, the patient should contact the treating physician for a replacement. If necessary, special packaging containing 1 tablet can be used.

Effect on Ability to Drive and Use Machines

No studies have been conducted on the effect of Movectro^® on the ability to drive and use machines. Dizziness (vertigo) may occur during treatment. In such cases, refrain from driving a car or engaging in other activities requiring increased attention.

Overdose

No cases of Movectro^® overdose have been reported. It is known that some side effects of Movectro^®, such as lymphopenia, may be dose-dependent.

Treatment an antidote for Movectro^® overdose is unknown. Immediate discontinuation of the drug, administration of symptomatic therapy, and careful observation are recommended. The effectiveness of hemodialysis for cladribine overdose has not been proven. If a patient has taken a dose of the drug higher than recommended, they should immediately inform their doctor. Complete blood count parameters should be carefully monitored in patients after cladribine overdose.

Drug Interactions

Hydroxypropylbetadex, one of the components of Movectro^® tablets, is capable of increasing the solubility and systemic bioavailability of poorly soluble drugs when taken concomitantly. Other medicinal products should be taken either 3 hours before or 3 hours after taking Movectro^®.

Concomitant or subsequent use of immunomodulatory drugs should be carried out under careful clinical control with assessment of hematological parameters. Short-term therapy with glucocorticoids is allowed when Movectro^® is co-administered with drugs that have hematotoxic properties (e.g., interferons, carbamazepine, NSAIDs), under careful monitoring of hematological parameters.

The use of Movectro^® in immunocompromised patients, including patients receiving immunosuppressants (e.g., cyclosporine, methotrexate, mitoxantrone, natalizumab) or long-term glucocorticoid therapy, is contraindicated due to an increased risk of adverse reactions.

Treatment with Movectro^® 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 against which prophylaxis was carried out.

Vaccination with live, including attenuated vaccines, should not be administered either during treatment with Movectro^® or within 3 months after taking the last dose of the drug.

The degree of absorption of cladribine and its bioavailability depend on a 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 effect of cladribine.

Known inhibitors of ABCG2 that in vivo change the pharmacokinetic parameters of substrates by more than 20% are cyclosporine and reverse transcriptase inhibitors: ritonavir, lopinavir, and atazanavir. Caution is required when co-administering such drugs with Movectro^®. The bioavailability of Movectro^® after oral administration is about 40%, suggesting that with complete blockade of intestinal ABCG2 protein function, the drug’s bioavailability may increase by no more than 2.5 times.

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

Cladribine has not demonstrated potential interaction with cytochrome P450 isoenzymes.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F) in the original packaging.

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.