Cladribine

Registered South African indications:

• Highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features

South African recommendations

Caution in the following patient groups

• Hepatic impairment
• Elderly

Prescriber precautions

• Cladribine should be prescribed by a medical practitioner experienced in the management of multiple sclerosis

Haematological monitoring

• Cladribine’s mode of action is closely linked to a reduction in lymphocyte count. The effect on lymphocyte count is dose dependent
• Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count have also been observed, although these parameters usually remain within normal limits
• Lymphocyte counts must be determined: before initiating cladribine in year 1, before initiating cladribine in year 2, 2 and 6 months after start of treatment in each treatment year
• If the lymphocyte count is below 500 cells/mm³, it should be actively monitored until values increase again

Infections

• Cladribine can reduce the body’s immune defence and may increase the likelihood of infections
• HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine
• Latent infections, including tuberculosis or hepatitis, may be activated
• Screening for latent infections, in particular tuberculosis and hepatitis B and C, must be performed prior to initiation of therapy in year 1 and year 2
• Initiation of cladribine should be delayed until the infection has been adequately treated
• Particular attention is recommended for patients with no history of exposure to varicella zoster virus
• Vaccination of antibody-negative patients is recommended prior to initiation of cladribine therapy
• If lymphocyte counts drop below 200 cells/mm³, anti-herpes prophylaxis should be considered during the time of grade 4 lymphopenia
• Patients with lymphocyte counts below 500 cells/mm³ should be actively monitored for signs and symptoms suggestive of infections, particularly herpes zoster
• If signs and symptoms of infection occur, anti-infective treatment should be initiated as clinically indicated
• Interruption or delay of cladribine may be considered until proper resolution of the infection

Progressive multifocal leukoencephalopathy (PML)

• Cases of PML have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen
• No case of PML has been reported in the clinical study data base of cladribine in MS
• A baseline MRI should be performed before initiating cladribine

Malignancies

• Events of malignancies were observed more frequently in cladribine-treated patients compared to placebo
• Cladribine is contraindicated in MS patients with active malignancies
• An individual benefit-risk evaluation should be performed before initiating cladribine in patients with prior malignancy
• Patients treated with cladribine should be advised to follow standard cancer screening guidelines

Liver function

• Liver injury, including serious cases, has been reported uncommonly in patients treated with cladribine
• Before initiating cladribine, a comprehensive patient history regarding previous episodes of liver injury with other medicines or underlying disorders should be taken
• Patients should have their serum aminotransferase, alkaline phosphatase and total bilirubin levels assessed prior to initiation of therapy in year 1 and year 2
• During treatment, liver enzyme and bilirubin monitoring should be obtained based on clinical signs and symptoms
• If clinical signs of hepatic dysfunction occur, serum transaminases and total bilirubin should be measured promptly
• Treatment with cladribine should be interrupted or discontinued, as appropriate, based on the results

Contraception

• Women with childbearing potential and males who could potentially father a child should be counselled regarding the potential for serious risk to the foetus and the need for effective contraception
• Women must prevent pregnancy by use of effective contraception during cladribine treatment and for at least 6 months after the last dose
• Male patients must take precautions to prevent pregnancy of their female partner during cladribine treatment and for at least 6 months after the last dose

Blood transfusions

• In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to prevent transfusion-related graft-versus-host disease
• Consultation with a haematologist is advised

Switching to and from cladribine treatment

• When switching from another MS medicine, a baseline MRI should be performed

Excipients

• Cladribine contains Sorbitol. Patients with hereditary fructose intolerance (HFI) should not take cladribine

Ability to drive and use machinery

• Cladribine has no influence on the ability to drive and use machines

Recommendations in other jurisdictions

Caution in the following patient groups

• Moderate to severe hepatic impairment
• Elderly

Haematological monitoring

• Cladribine's mode of action is closely linked to a reduction in lymphocyte count. The effect on lymphocyte count is dose dependent
• Decreases in neutrophil count, red blood cell count, haematocrit, haemoglobin or platelet count compared to baseline values have also been observed, although these parameters usually remain within normal limits
• Lymphocyte counts must be determined: before initiating treatment in year 1, before initiating treatment in year 2, 2 and 6 months after start of treatment in each treatment year
• If the lymphocyte count is below 500 cells/mm³, it should be actively monitored until values increase again

Infections

• Cladribine can reduce the body's immune defence and may increase the likelihood of infections. Serious, severe, and opportunistic infections - including events with fatal outcome- have been observed with cladribine treatment
• HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of cladribine
• Latent infections may be activated, including tuberculosis or hepatitis. Screening for latent infections, particularly tuberculosis and hepatitis B and C, must be performed prior to initiation of therapy in year 1 and year 2
• Initiation of cladribine should be delayed until the infection has been adequately treated
• A delay in initiation of cladribine should also be considered in patients with an acute infection until the infection is fully controlled
• Particular attention is recommended for patients who have no history of exposure to varicella zoster virus. Vaccination of antibody-negative patients is recommended prior to initiation of cladribine therapy
• Initiation of treatment with cladribine should be postponed for 4 to 6 weeks to allow for the full effect of vaccination to occur
• If lymphocyte counts drop below 200 cells/mm³, anti-herpes prophylaxis should be considered during the time of grade 4 lymphopenia
• Patients with lymphocyte counts below 500 cells/mm³ should be actively monitored for signs and symptoms suggestive of infections, particularly herpes zoster
• If such signs and symptoms occur, anti-infective treatment should be initiated as clinically indicated. Interruption or delay of cladribine may be considered until proper resolution of the infection

Progressive multifocal leukoencephalopathy (PML)

• Cases of PML have been reported for parenteral cladribine in patients treated for hairy cell leukaemia with a different treatment regimen
• No case of PML has been reported with cladribine tablets, but a baseline MRI should be performed before initiating cladribine tablets treatment (usually within 3 months)

Malignancies

• In clinical studies, events of malignancies were observed more frequently in cladribine-treated patients compared to patients who received placebo
• Cladribine is contraindicated in MS patients with active malignancies
• An individual benefit-risk evaluation should be performed before initiating treatment in patients with prior malignancy
• Patients treated with cladribine should be advised to follow standard cancer screening guidelines

Liver function

• Liver injury, including serious cases, has been reported uncommonly in patients treated with cladribine
• Before initiating cladribine, a comprehensive patient history regarding previous episodes of liver injury with other drugs or underlying liver disorders should be taken
• Patients should have their serum aminotransferase, alkaline phosphatase, and total bilirubin levels assessed prior to initiation of therapy in year 1 and year 2
• During treatment, liver enzyme and bilirubin monitoring should be obtained based on clinical signs and symptoms
• If a patient develops clinical signs, unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction, serum transaminases and total bilirubin should be measured promptly. Treatment with cladribine should be interrupted or discontinued, as appropriate

Contraception

• Before initiation of treatment both in year 1 and year 2, women of childbearing potential and males who could potentially father a child should be counselled regarding the potential for serious risk to the foetus and the need for effective contraception
• Women of childbearing potential must prevent pregnancy by use of effective contraception during cladribine treatment and for at least 6 months after the last dose
• Male patients must take precautions to prevent pregnancy of their female partner during cladribine treatment and for at least 6 months after the last dose

Blood transfusions

• In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to prevent transfusion-related graft-versus-host disease
• Consultation with a haematologist is advised

Switching to and from cladribine treatment

• When switching from another MS medicinal product, a baseline MRI should be performed

Sorbitol

• The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account
• The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal products for oral use administered concomitantly

Effects on ability to drive and use machines

• Cladribine has no or negligible influence on the ability to drive and use machines

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredients or any of its excipients
• Infection with human immunodeficiency virus (HIV)
• Active chronic infection (tuberculosis or hepatitis)
• Initiation of cladribine treatment in immunocompromised patients, including patients currently receiving immunosuppressive or myelosuppressive therapy
• Active malignancy
• Moderate or severe renal impairment (CrCl<60ml/min)
• Pregnancy
• Breastfeeding

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Treatment must be initiated and supervised by a medical practitioner experienced in the treatment of multiple sclerosis

Highly active relapsing multiple sclerosis (MS) as defined by clinical or imaging features

• Oral (tab): 10-20mg, as a single dly dose, depending on body weight, for 4-5 days per treatment week (Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year). Recommended cumulative dose: 3.5mg/kg body weight over 2 years, admin. as 1 treatment course of 1.75mg/kg per year (see table below)

Table 1: Dose of cladribine per treatment week by patient weight in each treatment year
Weight range (kg)	Dose in mg (number of 10mg tablets) per treatment week
	Treatment week 1	Treatment week 2
40 to <50	40mg (4 tabs)	40mg (4 tabs)
50 to <60	50mg (5 tabs)	50mg (5 tabs)
60 to <70	60mg (6 tabs)	60mg (6 tabs)
70 to <80	70mg (7 tabs)	70mg (7 tabs)
80 to <90	80mg (8 tabs)	70mg (7 tabs)
90 to <100	90mg (9 tabs)	80mg (8 tabs)
100 to <110	100mg (10 tabs)	90mg (9 tabs)
110 and above	100mg (10 tabs)	100mg (10 tabs)

The distribution of the total dose over the 2 years of treatment is provided in Table 1. For some weight ranges the number of tablets may vary from one treatment week to the next

Table 2: Cladribine 10mg tabs per week day
Total number of tablets per week	Day 1	Day 2	Day 3	Day 4	Day 5
4	1	1	1	1	0
5	1	1	1	1	1
6	2	1	1	1	1
7	2	2	1	1	1
8	2	2	2	1	1
9	2	2	2	2	1
10	2	2	2	2	2

Table 2 shows how the total number of tablets per treatment week is distributed over the individual days

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It is recommended that the daily cladribine doses in each treatment week be taken at intervals of 24 hours at approximately the same time each day. If a daily dose consists of two tablets, both tablets are taken together as a single dose

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Following completion of the 2 treatment courses, no further cladribine treatment is required in years
3 and 4. Re-initiation of therapy after year 4 has not been studied

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Criteria for initiating and continuing therapy
Lymphocyte counts must be:
- Normal before initiating cladribine in year 1,
- At least 800 cells/mm³ before initiating cladribine in year 2
If necessary, the treatment course in year 2 can be delayed for up to 6 months to allow for recovery of lymphocytes. If this recovery takes more than 6 months the patient should not receive cladribine anymore

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Missed dose
A missed dose must be taken as soon as remembered on the same day according to the treatment schedule. A missed dose must not be taken together with the next scheduled dose on the following day. In the case of a missed dose, the patient must take the missed dose on the following day and extend the number of days in that treatment week. If two consecutive doses are missed, the same rule applies, and the number of days in the treatment week is extended by two days

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Concomitant use of other oral medicinal products It is recommended that administration of any other oral medicinal product be separated from that of cladribine by at least 3 hours during the limited number of days of cladribine administration

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Use of oral cladribine in patients weighing less than 40kg has not been investigated

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Method of Administration
Cladribine is for oral use. The tablets are taken with water and swallowed without chewing. Cladribine can be taken independent of food intake. As the tablets are uncoated, they must be swallowed immediately once removed from the blister and not be left exposed on surfaces or handled for any period of time greater than that required for dosing. If a tablet is left on a surface, or if a broken or fragmented tablet is released from the blister, the area must be thoroughly washed. The patient’s hands must be dry when handling the tablets and washed thoroughly afterwards

Not established for use in children below 18 years

Pregnancy

Recommendations below are applicable to South Africa and other jurisdictions

• Contraindicated
• Based on human experience with other substances inhibiting DNA synthesis, cladribine could cause congenital malformations when administered during pregnancy. Studies in animals have shown reproductive toxicity. Cladribine is contraindicated in pregnant women
• Contraception in males and females
  • Before initiation of treatment both in year 1 and year 2, women of childbearing potential and males who could potentially father a child should be counselled regarding the potential for serious risk to the foetus and the need for effective contraception
  • In women of childbearing potential, pregnancy must be excluded before the initiation of cladribine in year 1 and year 2 and prevented by use of effective contraception during cladribine treatment and for at least 6 months after the last dose. Women who become pregnant under therapy with cladribine should discontinue treatment
  • Women using systemically hormonal contraceptives should add a barrier method during cladribine treatment and for at least 4 weeks after the last dose in each treatment year (South African recommendations)
  • As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6 months after the last dose

Breastfeeding

Recommendations below are applicable to South Africa and other jurisdictions

• Contraindicated
• It is not known whether cladribine is excreted in human milk
• Because of the potential for serious adverse reactions in breastfed infants, breastfeeding is contraindicated during treatment with cladribine and for 1 week after the last dose

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• In mice, there were no effects on fertility or the reproductive function of offspring. However, testicular effects were observed in mice and monkeys. As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6 months after the last dose

Recommendations below are applicable to South Africa and other jurisdictions

• Mild (CrCl 60-89ml/min): No dose adjustment recommended
• Moderate or severe (CrCl<60ml/min): Contraindicated
  No dedicated studies have been conducted in patients with renal impairment
  Safety and efficacy in patients with moderate or severe renal impairment have not been established

South African recommendations

• Mild: Caution; no information available
  No studies have been conducted in patients with hepatic impairment
• Moderate or severe (Child-Pugh score >6): Caution; not recommended
  Although the importance of hepatic function for the elimination of cladribine is considered negligible, in the absence of data, use of cladribine is not recommended

Recommendations in other jurisdictions

• Mild: No dose adjustment recommended
  No studies have been conducted in patients with hepatic impairment. No dose adjustment is required because the importance of hepatic function for the elimination of cladribine is considered negligible
• Moderate or severe (Child-Pugh score >6): Caution; not recommended
  In absence of data, the use of cladribine is not recommended

South African recommendations

• Caution; no dose adjustment recommended
  Clinical studies with oral cladribine did not include patients over 65 years of age; therefore, it is not known whether they respond differently from younger patients
  Caution is recommended when cladribine is used in elderly patients, taking into account the potential greater frequency of decreased hepatic or renal function, concomitant diseases, and other medicinal therapies

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Caution is recommended when cladribine is used in elderly patients, taking into account the potential greater frequency of decreased hepatic or renal function, concomitant diseases and other medicinal therapies

Infections and Infestations

Common

• Oral herpes
• Dermatomal herpes zoster (incidence higher during periods of grade 3 or 4 lymphopenia (<500 to 200 cells/mm³ or <200 cells/mm³) compared to when patients were not experiencing grade 3 or 4 lymphopenia) 

Very rare

• Tuberculosis

Blood and Lymphatic System Disorders

Very common

• Lymphopenia

Common

• Decrease in neutrophil count

Immune System Disorders

Common

• Hypersensitivity including pruritus, urticaria, rash and rare cases of angio-oedema (identified during post-marketing surveillance)

Hepatobiliary Disorders

Uncommon

• Liver injury (identified during post-marketing surveillance)

Skin and Subcutaneous Tissue Disorders

Common

• Rash
• Alopecia

Others

• Malignancies 

• Medicinal products with low solubility (separate administration by at least 3 hours)
• Immunosuppressive agents
• Methotrexate
• Cyclophosphamide
• Cyclosporine
• Azathioprine
• Corticosteroids (chronic use)
• Other disease-modifying medicinal products
• Interferon beta
• Haematotoxic agents
• Carbamazepine
• Live vaccines
• Live attenuated vaccines
• Potent ENT1, CNT3 and BCRP transporter inhibitors
• Eltrombopag
• Dilazep
• Nifedipine
• Nimodipine
• Cilostazol
• Sulindac
• Reserpine
• Potent BCRP and P-gp transporter inducers
• Rifampicin

Other interactions

• St. John's Wort (Hypericum perforatum)

• Complete blood count (including lymphocyte count)
  • Before each treatment course, 2 and 6 months after the start of each yearly course
  • If 2-month lymphocyte count <200 cells/mm³, monitor monthly until month 6
  • Periodically during and after treatment
• Hepatic function (prior to each treatment cycle and course, and as clinically appropriate)
  • Serum aminotransferase
  • Alkaline phosphatase
  • Total bilirubin
• HIV (prior to each treatment course)
• Tuberculosis (prior to each treatment course)
• Hepatitis B (HBV) (prior to each treatment course)
• Hepatitis C (HCV) status (prior to each treatment course)
• Varicella zoster virus (VZV) antibody status (prior to each treatment course)

Specific cases may require

• Pregnancy status
  • Prior to each treatment course in patients who could become pregnant

Additional Observations

• Magnetic resonance imaging (MRI)
  • Baseline (within 3 months) (prior to first treatment course)
  • If progressive multifocal leukoencephalopathy is suspected, perform diagnostic evaluation and obtain brain MRI
• Cancer screening (follow standard guidelines)
• Monitor for signs or symptoms of acute infection

Cladribine is a nucleoside analogue of deoxyadenosine. A chlorine substitution in the purine ring protects cladribine from degradation by adenosine deaminase, increasing the intracellular residence time of the cladribine prodrug. Subsequent phosphorylation of cladribine to its active triphosphate form, 2-chlorodeoxyadenosine triphosphate (Cd-ATP), is particularly efficiently achieved in lymphocytes, due to their constitutively high deoxycytidine kinase (DCK) and relatively low 5'-nucleotidase (5'-NTase) levels. A high DCK to 5'-NTase ratio favours the accumulation of Cd-ATP, making lymphocytes particularly susceptible to cell death. As a result of a lower DCK/5'-NTase ratio other bone marrow derived cells are less affected than lymphocytes. DCK is the rate limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to selective depletion of dividing and non-dividing T and B cells.

The primary apoptosis-inducing mechanism of action of Cd-ATP has direct and indirect actions on DNA synthesis and mitochondrial function. In dividing cells, Cd-ATP interferes with DNA synthesis via inhibition of ribonucleotide reductase and competes with deoxyadenosine triphosphate for incorporation into DNA by DNA polymerases. In resting cells cladribine causes DNA single-strand breaks, rapid nicotinamide adenine dinucleotide consumption, ATP depletion and cell death. There is evidence that cladribine can also cause direct caspase-dependent and -independent apoptosis via the release of cytochrome c and apoptosis-inducing factor into the cytosol of non-dividing cells.

MS pathology involves a complex chain of events in which different immune cell types, including autoreactive T and B cells play a key role. The mechanism by which cladribine exerts its therapeutic effects in MS is not fully elucidated but its predominant effect on B and T lymphocytes is thought to interrupt the cascade of immune events central to MS.

Variations in the expression levels of DCK and 5'-NTases between immune cell subtypes may explain differences in immune cell sensitivity to cladribine. Because of these expression levels, cells of the innate immune system are less affected than cells of the adaptive immune system.