Consumer medicine information

Mavenclad

Cladribine

BRAND INFORMATION

Brand name

Mavenclad

Active ingredient

Cladribine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mavenclad.

SUMMARY CMI

MAVENCLAD®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using MAVENCLAD?

MAVENCLAD contains the active ingredient, cladribine. MAVENCLAD is used to treat a type of multiple sclerosis (MS) known as relapsing remitting MS. In this type of MS, MAVENCLAD has been shown to result in fewer relapses, less disease activity in the brain and less progression of disability.
For more information, see Section 1. Why am I using MAVENCLAD? in the full CMI.

2. What should I know before I use MAVENCLAD?

Do not use if you have ever had an allergic reaction to cladribine or any of the ingredients listed at the end of the CMI, you are HIV positive and/or have a weakened immune system, you have active tuberculosis or hepatitis, you are taking other medicines that weaken your immune system or affect your bone marrow, you have moderate or severe kidney disease, or you are pregnant or breastfeeding. If you are a man, do not take MAVENCLAD if you and your partner are trying to have a baby.
Talk to your doctor if you have any other medical conditions or take any other medicines.
For more information, see Section 2. What should I know before I use MAVENCLAD? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with MAVENCLAD and affect how it works.
A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use MAVENCLAD?

  • MAVENCLAD is administered in two treatment courses over two years.
  • Each treatment course consists of two treatment weeks at the start of a 1 year period. For a treatment week, you will be prescribed to take one or two tablets, once a day for 4-5 days.

More instructions can be found in Section 4. How do I use MAVENCLAD? in the full CMI.

5. What should I know while using MAVENCLAD?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using MAVENCLAD.
  • Keep all your doctor and blood test appointments so that your progress can be checked.
  • Tell your doctor if you get symptoms of shingles, if you believe your MS is getting worse or notice any new symptoms, if you or your partner becomes pregnant during or after your treatment with MAVENCLAD, or if you think you have an infection.
  • Stay out of the sun as much as possible. If you need to be in the sun, use a sunscreen and wear a hat and shirt to protect your skin from the sun.
Things you should not do
  • Do not stop taking MAVENCLAD or change the dose, without first checking with your doctor.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how MAVENCLAD affects you.
Looking after your medicine
  • Store below 30°C. Keep your tablets in the pack until it is time to take them. This is important for safety reasons, to protect the tablets and because the labelling includes important information.

For more information, see Section 5. What should I know while using MAVENCLAD? in the full CMI.

6. Are there any side effects?

Common side effects include cold sores, skin rash, hair loss, allergic reactions. Serious side effects include infections and liver problems.
For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

MAVENCLAD®

Active ingredient(s): cladribine

Consumer Medicine Information (CMI)

This leaflet provides important information about using MAVENCLAD. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using MAVENCLAD.

Where to find information in this leaflet:

1. Why am I using MAVENCLAD?
2. What should I know before I use MAVENCLAD?
3. What if I am taking other medicines?
4. How do I use MAVENCLAD?
5. What should I know while using MAVENCLAD?
6. Are there any side effects?
7. Product details

1. Why am I using MAVENCLAD?

MAVENCLAD contains the active ingredient, cladribine. MAVENCLAD acts on cells in your immune system, known as lymphocytes, to reduce inflammation in the nervous system caused by multiple sclerosis (MS).

MAVENCLAD is used to treat a type of MS known as relapsing remitting MS. In this type of MS, MAVENCLAD has been shown to result in fewer relapses, less disease activity in the brain and less progression of disability.

MAVENCLAD has been studied for safety and effectiveness when given as 2 treatment courses over 2 years, each treatment course consists of 2 treatment weeks.

Following completion of the 2 treatment courses, no further cladribine treatment is required in years 3 and 4.

Your doctor is the best person to discuss the long term effects of MAVENCLAD treatment beyond above.

2. What should I know before I use MAVENCLAD?

Warnings

Do not use MAVENCLAD if:

  • You are allergic to cladribine, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • You are HIV positive and/or have a weakened immune system, e.g. due to a medical condition.
  • You have active tuberculosis or hepatitis
  • You are taking other medicines that weaken your immune system or affect your bone marrow (e.g. cyclosporin, methotrexate, mitoxantrone, azathioprine, natalizumab, or on-going use of corticosteroids).
  • You have moderate or severe kidney disease. If necessary, your doctor can do tests to check your kidney function.
  • You are pregnant or breastfeeding

Check with your doctor if you:

  • If you might have or have had an infection. Signs of infection may include fever, chills, sore throat, cough, pain when urinating, or urinating more frequently. If you have any of these or any other signs that make you think you might have an infection or could get an infection, call your doctor as soon as possible. Also, tell your doctor if you have had any herpes infections (e.g. a cold sore, chickenpox or shingles) in the past. You may need vaccination prior to starting the treatment. After receiving a treatment course you may be at risk of developing or experiencing infections, which may be serious and severe. It is important you understand these risks and how to monitor for them. Patients treated with MAVENCLAD may be at a higher risk for getting an infection. If you are suffering from an infection before the initiation of your MAVENCLAD treatment, your doctor will consider delaying the treatment until the infection is under control or resolved.
  • If you have or have had cancer. It is not recommended to use MAVENCLAD if you currently have cancer. If you had cancer in the past, you should discuss this with your doctor and they can help you decide if MAVENCLAD is right for you.
  • If you have been vaccinated recently or if you are planning to be vaccinated (e.g. vaccines for shingles/chickenpox, tuberculosis, hepatitis, influenza, typhoid, yellow fever, etc). Your doctor may need to adjust schedule of your MAVENCLAD treatment (see also Section 3. What if I am taking other medicines?).
  • If you have an intolerance to fructose (a type of sugar). MAVENCLAD contains sorbitol powder. It is not recommended for anyone with fructose intolerance.
  • If you have liver problems. If necessary, your doctor can do tests to check your liver function. Your doctor will decide whether you can take MAVENCLAD under these conditions.
  • Take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take MAVENCLAD if you are pregnant or trying to become pregnant. If you are a man, do not take MAVENCLAD if you and your partner are trying to have a baby.

MAVENCLAD may harm your baby. You must use reliable methods of contraception to prevent becoming pregnant yourself or making anyone else pregnant.

Your doctor will advise you for how long this is necessary.

Do not take MAVENCLAD if you are breastfeeding.

If your doctor believes that MAVENCLAD is essential for you, he/she will advise you to stop breastfeeding.

Use in children

Do not give MAVENCLAD to a child or adolescent.

There is no experience with its use in children or adolescents under 18 years old.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with MAVENCLAD and affect how it works.

Do not take MAVENCLAD at the same time as any other medicine taken by mouth.

This is because MAVENCLAD may interact with other medicines in the stomach. Allow at least 3 hours before and after MAVENCLAD when taking other oral medicines.

Tell your doctor if you are or have been treated with:

  • Any medicine that weakens your immune system or affects your bone marrow, e.g. cyclosporin, methotrexate, mitoxantrone, azathioprine, natalizumab, or on-going use of corticosteroids. These medicines must not be used together with MAVENCLAD (see also Section 2. What should I know before I use MAVENCLAD?). If considered necessary by your doctor, short-term treatment with corticosteroids is possible with MAVENCLAD.
  • Any other MS medicines, e.g. fingolimod, dimethyl fumarate
  • Any medicine which may affect the blood, e.g. carbamazepine. Your doctor may need to supervise your condition more closely if you are using any of these medicines.
  • Certain medicines used to treat the heart, blood, circulation or inflammation, e.g. dipyridamole, nifedipine, nimodipine, cilostazol, dilazep, reserpine, eltrombopag, sulindac, corticosteroids, rifampicin or St. John's wort
  • Planning any vaccinations or have been vaccinated with the last 4-6 weeks. MAVENCLAD must not be taken within 4-6 weeks of vaccination with a 'live' vaccine ('live' vaccines contain weakened forms of infectious agents). You may need to delay your treatment with MAVENCLAD after vaccination and avoid certain vaccinations when taking MAVENCLAD. Your doctor can advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect MAVENCLAD.

4. How do I use MAVENCLAD?

How much to take

  • MAVENCLAD is administered in two treatment courses over two years. Each treatment course consists of two treatment weeks at the start of a 1 year period. For a treatment week, you will be prescribed to take one or two tablets, once a day for 4-5 days. Sometimes the number of tablets will vary from one week to the next.
  • The second treatment week will usually start 4 weeks after the start date of the first.
  • There is no MAVENCLAD treatment between the two courses.
  • Your doctor will decide the number of tablets per day (1 or 2) and number of treatment days (4 or 5) depending on your body weight.
  • You may need to take the same number of tablets each day or some days you might take 2 tablets and then only 1 tablet on the following days.
  • Ask your doctor or pharmacist if you are unclear about how many tablets to take each day.
  • If your doctor determines it to be appropriate, you will receive another course of MAVENCLAD treatment (typically, 1 year after the first treatment course).
  • Follow the instructions provided when MAVENCLAD was prescribed.

When to take MAVENCLAD

  • Take MAVENCLAD at about the same time each day. You may take MAVENCLAD before or after a meal.

How to take MAVENCLAD

  • Follow the instruction illustrated on the carton on how to open the child-resistant pack. Your hands should be dry when handling the tablets.
  • Swallow the tablet(s) whole with water. Never cut or crush the tablets and do not chew them or allow them to dissolve in your mouth.
  • Take the tablet(s) immediately after removal from the blister. Do not leave them exposed on surfaces, e.g. on a table, or handle them longer than necessary.
  • If a tablet is left on a surface or if a broken or fragmented tablet is released from the blister, wash the area thoroughly afterwards.
  • Wash your hands with soap and water after taking MAVENCLAD.
  • If you lose a tablet, contact your doctor or pharmacist for advice.

If you forget to use MAVENCLAD

MAVENCLAD should be used regularly at the same time each day. If you miss your dose at the usual time and you remember on the same day you were supposed to take it, take it on that day.

If you miss a dose and do not remember it until the following day, do not take the missed dose along with the scheduled dose.

Do not take a double dose on the same day to make up for the dose you missed.

  • If you miss a dose, take the missed dose on the next day and extend the number of days in that treatment course.
  • For example: If you forget to take the Day 3 dose and do not remember it until Day 4, take the Day 3 dose on Day 4, and take the Day 4 dose on Day 5. Extend the total number of days in the treatment course by 1 day until the pack is empty.
  • If you miss 2 consecutive doses (e.g. both Day 3 and Day 4 doses), extend the treatment course by 2 days. In this case, you will take your Day 3 dose on Day 5 and your Day 4 dose on Day 6.

If you use too much MAVENCLAD

If you think that you have used too much MAVENCLAD, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

If you take too much MAVENCLAD your white blood cells will be affected and you may need additional blood tests. It may also be necessary to stop treatment with MAVENCLAD. Your doctor will advise you.

5. What should I know while using MAVENCLAD?

Things you should do

Your doctor will check your blood before you start MAVENCLAD and at intervals during and after treatment, to make sure that your treatment can be started or continued. Make sure that you keep all appointments scheduled for these blood tests.

Keep all your doctor and blood test appointments so that your progress can be checked.

If you are about to be started on any new medicine or plan to have any vaccinations, tell your doctor or pharmacist that you are taking or have taken MAVENCLAD. You should not be vaccinated with 'live' or attenuated live vaccines during or after a MAVENCLAD treatment, until your white blood cell counts return to normal.

If you are going to have a blood transfusion, tell the medical staff that you are taking this medicine.

Also tell the medical staff if you are undergoing any procedures where a transfusion may be required, e.g. surgery.

Special precautions may be required to prevent an unwanted reaction to the transfusion.

Stay out of the sun as much as possible. If you need to be in the sun, use a sunscreen and wear a hat and shirt to protect your skin from the sun.

Although not known if related to MAVENCLAD, single events of cancer including melanomas, have been seen in people after treatment. As a precautionary measure, you should follow standard cancer screening recommendations, as advised by your doctor. Check your skin regularly and have a doctor check your skin annually for new skin spots or changes to existing spots, moles or freckles.

Call your doctor straight away if you:

  • If you think you have an infection. Symptoms of infections may include fever; aching, painful muscles; headache; generally feeling unwell; loss of appetite. Your doctor may delay treatment, or interrupt it, until the infection clears up.
  • If you get symptoms of shingles. Symptoms of shingles may include a 'band' of severe pain and blistering rash, typically on one side of the upper body or the face; burning, tingling, numbness or itchiness of the skin in the affected area; signs of infection such as fever, headache or generally feeling unwell.
  • if you believe your MS is getting worse or if you notice any new symptoms (e.g. changes in mood or behaviour, memory lapses, speech and communication difficulties). These may be the symptoms of a rare brain disorder caused by infection and called progressive multifocal leukoencephalopathy (PML). PML is a serious condition that may lead to severe disability or death. PML has not yet been observed with MAVENCLAD.
  • If you or your partner becomes pregnant during or after your treatment with MAVENCLAD. MAVENCLAD may affect the baby if either you or your partner is taking it. Both men and women must use a proven method of birth control while taking and, for as long as your doctor tells you to, after stopping MAVENCLAD. Both men and women should use birth control for at least 6 months (6 menstrual cycles) after their last dose of MAVENCLAD.

Remind any doctor, dentist or pharmacist you visit that you are using MAVENCLAD.

Things you should not do

  • Do not stop taking MAVENCLAD or change the dose, without first checking with your doctor.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.
  • Do not use MAVENCLAD to treat any other complaints.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how MAVENCLAD affects you.

Looking after your medicine

  • MAVENCLAD tablets are provided to you in a blister that is fixed to a child-resistant carton.
  • Keep your tablets in the pack until it is time to take them. This is important for safety reasons, to protect the tablets and because the labelling includes important information.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 30°C; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Viral infections:
  • Cold sore
Skin-related:
  • Skin rash
  • Hair loss
Immune-related:
  • Allergic reaction. Symptoms include rash, itching, hives on the skin, or swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
Speak to your doctor if you have any of these less serious side effects.

Some of the side effects (e.g. decreased neutrophil count) can only be found when your doctor does tests from time to time to check your progress.

Serious side effects

Serious side effectsWhat to do
Infections:
  • Fever, chills, muscle weakness, decreased or difficult urination.
    The most important side effect of MAVENCLAD is reduction in number of a type of white blood cell known as lymphocytes. This is very common in patients on MAVENCLAD treatment and may be severe. Reduced lymphocytes may increase your risk of getting an infection, particularly viral infections.
  • Shingles. Symptoms such as localised 'band' of severe pain and blistering rash, typically on one side of the upper body or the face. Other symptoms may be headache, burning, tingling, numbness or itchiness of the skin in the affected area, feeling generally unwell or fever in the early stages of infection. The infection may require treatment, and treatment with MAVENCLAD may need to be interrupted until the infection is resolved.
Liver problems:
  • nausea, vomiting, abdominal pain, tiredness, loss of appetite, yellowing of the skin or whites of the eyes, dark urine
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What MAVENCLAD contains

Active ingredient
(main ingredient)		cladribine
Other ingredients
(inactive ingredients)		Hydroxypropylbetadex, sorbitol, magnesium stearate
Potential allergensSorbitol

Do not take this medicine if you are allergic to any of these ingredients.

MAVENCLAD does NOT contain gluten, tartrazine or other azo dyes.

What MAVENCLAD looks like

MAVENCLAD tablets are uncoated, white, round, biconvex tablets engraved with 'C' on one side and '10' on the other side.

Each pack contains 1, 4 or 6 tablets in an aluminium-aluminium blister sealed in a cardboard wallet and fixed to a child-resistant carton (Aust R 166483).

Who distributes MAVENCLAD

Merck Healthcare Pty Ltd
Suite 1, Level 1
Building B
11 Talavera Road
Macquarie Park NSW 2113
Medical Information: 1800 633 463

Supplied in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland
Medical Information: 0800 426 252

This leaflet was prepared in July 2024.

Published by MIMS October 2024

BRAND INFORMATION

Brand name

Mavenclad

Active ingredient

Cladribine

Schedule

S4

 

1 Name of Medicine

Cladribine.

2 Qualitative and Quantitative Composition

Each tablet of Mavenclad contains 10 mg cladribine. The tablets also contain hydroxypropylbetadex, sorbitol and magnesium stearate.

3 Pharmaceutical Form

Mavenclad tablets are uncoated, white, round and biconvex, and engraved with 'C' on one side and '10' on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Mavenclad is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS) to reduce the frequency of clinical relapses and to delay the progression of physical disability.
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.

4.2 Dose and Method of Administration

Dosage.

General treatment schedule. The recommended cumulative dose of Mavenclad is 3.5 mg/kg body weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. 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 year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight.
Patients should receive no more than 2 treatment courses over two consecutive years. The recommended dose should not be exceeded. Following completion of the 2 treatment courses, no further cladribine treatment is required in year 3 and year 4. Re-initiation of therapy after year 4 has not been studied (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Criteria for starting and continuing therapy.

Screening for infections.

HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of Mavenclad (see Section 4.3 Contraindications).
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 Mavenclad should be delayed until the infection has been adequately treated (see Section 4.4 Special Warnings and Precautions for Use, Infections).
A delay in initiation of Mavenclad should also be considered in patients with an acute infection until the infection is fully controlled (see Section 4.4 Special Warnings and Precautions for Use, Infections).

Lymphocyte monitoring.

Lymphocyte counts must be normal before initiating Mavenclad therapy, at least 800 cells/mm3 before the second treatment course 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 Mavenclad anymore.

Liver function.

Serum aminotransferase, alkaline phosphatase, and total bilirubin levels should be obtained prior to initiation of each treatment course (see Section 4.4 Special Warnings and Precautions for Use, Liver function).
Distribution of dose. The distribution of the total dose over the 2 years of treatment is provided in Table 1. Note that for some weight ranges the number of tablets may vary from one treatment week to the next.
Table 2 shows how the total number of tablets per treatment week is distributed over the individual days. It is recommended that the daily Mavenclad 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.
Dosing errors. A missed dose can be taken as soon as remembered, if remembered on the same day.
A missed dose must not be taken if it is not remembered until the following day. In this case, the patient must take the next dose as scheduled, and extend the number of days in that treatment week. For example, if a patient forgets to take the day 3 dose and does not remember until day 4, the day 3 dose is taken on day 4, and the total number of days in the treatment week is extended by one day. If two consecutive doses are missed, the same rule applies, and the treatment week is extended by two days.
In case of an accidental dose higher than prescribed, the clinical status of the patient must be reviewed and a decision made as to whether and how to continue treatment.

Method of administration.

Mavenclad tablets must be taken orally, with water, and swallowed without chewing. It is unlikely that food intake will have a clinically significant effect on absorption of cladribine. Therefore, Mavenclad can be taken before or after a meal.
As tablets are uncoated, they must be swallowed immediately once removed from the blister and not 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 afterwards.
The patient's hands must be dry when handling the tablets and washed thoroughly afterwards.

4.3 Contraindications

Mavenclad therapy must not be initiated in:
patients with hypersensitivity to cladribine or to any of the tablet excipients (see Section 2 Qualitative and Quantitative Composition);
patients who are infected with the human immunodeficiency virus (HIV);
patients with active chronic infections (tuberculosis, hepatitis) (see Section 4.4 Special Warnings and Precautions for Use);
immunocompromised patients, including patients receiving immunosuppressive or myelosuppressive therapy with agents such as cyclosporin, methotrexate, mitoxantrone, azathioprine, natalizumab, or chronic use of corticosteroids. Acute short term therapy with corticosteroids can be administered;
patients with moderate or severe renal impairment (creatinine clearance < 60 mL/min) (see Section 5.2 Pharmacokinetic Properties);
pregnancy and breastfeeding (see Section 4.4 Special Warnings and Precautions for Use; Section 4.6 Fertility, Pregnancy and Lactation).

4.4 Special Warnings and Precautions for Use

Therapy is to be initiated and supervised by neurologists. Neurologists must discuss the risks and benefits of therapy with the patient and explain the importance of following the recommendations in the Consumer Medicine Information, in particular with respect to infections and haematological monitoring. The long term safety of Mavenclad has not been assessed. There is no conclusive evidence of an increase in the incidence of malignancies.

Haematological monitoring.

The mode of action of Mavenclad 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 in clinical studies, although these parameters usually remain within the limits of normal.
Lymphocyte counts must be determined: before initiating Mavenclad in year 1; before initiating Mavenclad 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.
Monitoring of other haematological parameters can be considered at the discretion of the physician.
For treatment decisions based on the patient's lymphocyte count, see Section 4.2 Dose and Method of Administration, Infections.

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 Mavenclad treatment. HIV infection, active tuberculosis and active hepatitis must be excluded before initiation of cladribine (see Section 4.3 Contraindications).
Latent infections may be activated, including tuberculosis, viral hepatitis or herpes zoster infections. Therefore, 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 Mavenclad 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.
In clinical trials, a fatal case of hepatitis B was observed, but was not considered related to cladribine. Three cases of reactivation of latent tuberculosis, including one fatal case, were observed before implementation of the pre-screening for infections as recommended above. For most common infections, incidence rates were similar between patients receiving cladribine and those receiving placebo, except for herpes zoster.

Herpes zoster.

Particular attention is recommended for patients who have no history of exposure to varicella zoster virus (VZV). Vaccination of antibody-negative patients is recommended prior to initiation of Mavenclad. Initiation of treatment with Mavenclad must be postponed for 4 to 6 weeks to allow for the full effect of vaccination to occur (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Live or live attenuated vaccines).
The incidence of herpes zoster was increased in patients on cladribine. If lymphocyte counts drop below 200 cells/mm3, anti-herpes prophylaxis according to local standard practice should be considered during the time of grade 4 lymphopenia (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients with lymphocyte counts below 500 cells/mm3 should be actively monitored carefully for signs and symptoms suggestive of infections, in particular herpes zoster. If such signs and symptoms occur, treatment for the infection should be initiated as clinically indicated. Interruption or delay of Mavenclad may be considered until full resolution of the infection.

Progressive multifocal leukoencephalopathy.

In the clinical trial data base of cladribine in MS (1,976 patients, 8,650 patient years) no case of progressive multifocal leukoencephalopathy (PML) has been reported. However, a baseline magnetic resonance imaging (MRI) should be considered before initiating Mavenclad (usually within 3 months). This is particularly recommended if patients are switched from other MS agents that have a risk of PML.

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.

Malignancies.

In clinical studies and long-term follow-up (mean [±SD] duration: 194 ± 111 weeks) of patients treated with a cumulative dose of 3.5 mg/kg oral cladribine, events of malignancies were observed more frequently in cladribine-treated patients (10 events in 3414 patient-years [0.29 events per 100 patient-years]) compared to patients who received placebo (3 events in 2022 patient-years [0.15 events per 100 patient-years]).
Mavenclad has not been studied in MS patients with prior or current malignancies (with the exception of in situ basal or squamous cell skin cancer surgically removed without recurrence for at least five years). Therefore, Mavenclad is not recommended in MS patients with active malignancy.
As with other immunomodulating therapies, caution should be exercised when initiating Mavenclad in patients with prior malignancy. It is currently not known whether oral cladribine confers a higher risk for developing malignancies. Observation over longer treatment periods is required before any effect on the development of malignancies can be determined.
An individual benefit-risk evaluation should be performed before initiating Mavenclad in patients with prior malignancy. Patients treated with Mavenclad should be advised to follow standard cancer screening guidelines.
Malignant events reported during the follow-up or in the extension studies included melanoma and non-melanoma skin cancer. Although a causal relationship has not been established, precautionary measures to monitor and prevent a potential risk of skin cancer are recommended, including regular self-examinations, annual dermatological check-ups, avoiding direct exposure to the sun and using sun protection.

Liver function.

Liver injury, including serious cases, has been reported uncommonly in patients treated with Mavenclad, especially in patients with a medical history of abnormal liver tests. Patients should have their serum aminotransferase, alkaline phosphatase, and total bilirubin levels assessed prior to initiation of each treatment course (see Section 4.2 Dose and Method of Administration, Criteria for starting and continuing therapy).
If a patient develops clinical signs, including unexplained liver enzyme elevations or symptoms suggestive of hepatic dysfunction (e.g. unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with Mavenclad, as appropriate.

Switching to and from Mavenclad treatment.

In patients who have previously been treated with immunomodulating or immunosuppressive agents, the mode of action and duration of effect of the other product should be considered prior to initiation of Mavenclad (see Section 4.2 Dose and Method of Administration). A potential additive effect on the immune system should also be considered when such agents are used after treatment with Mavenclad (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Haematotoxic, immunosuppressive and immunomodulating agents).
When switching from an MS agent with a risk of PML, a baseline MRI is recommended (see subsection 'Infections' above).

Use in renal impairment.

No dedicated studies have been conducted in patients with renal impairment (see Section 4.3 Contraindications).
The safety profile in patients with mild renal impairment (creatinine clearance 60-89 mL/min) was shown to be similar to that in patients with normal renal function; no dosage adjustment is considered necessary.
In patients with moderate or severe renal impairment (creatinine clearance < 60 mL/min), a decrease in cladribine clearance can be predicted (see Section 5.2 Pharmacokinetic Properties). Safety and efficacy in patients with moderate or severe renal impairment have not been established. Therefore, Mavenclad is contraindicated in these patients (see Section 4.3 Contraindications).

Use in hepatic impairment.

No dedicated studies have been conducted in patients with hepatic impairment.
Although the importance of hepatic function for the elimination of cladribine is considered negligible (see Section 5.2 Pharmacokinetic Properties), in the absence of data, use of Mavenclad is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh score > 6).

Fructose intolerance.

Mavenclad contains 64.04 mg sorbitol per tablet. Its use is not recommended in patients with fructose intolerance.

Use in the elderly.

Clinical studies with Mavenclad did not include patients over 65 years of age to determine whether they respond differently from younger patients.
Caution is recommended when Mavenclad is used in elderly patients, taking into account the potential greater frequency of decreased hepatic or renal function, concomitant diseases, and other medicinal therapy.

Paediatric use.

Safety and effectiveness of Mavenclad in paediatric MS patients are not known. Mavenclad is not recommended in patients below the age of 18 years.

Effects on laboratory tests.

For information related to lymphopenia, see Section 4.4 Special Warnings and Precautions for Use, Haematological monitoring.

4.5 Interactions with Other Medicines and Other Forms of Interactions

If any other oral medicines are taken concomitantly, administration must be separated from that of Mavenclad by at least 3 hours during the limited number of days of cladribine administration. This is because hydroxypropylbetadex released from Mavenclad may lead to complex formation with other agents (especially medicines with low solubility), which could cause an increase in bioavailability of such a product.

Haematotoxic, immunosuppressive and immunomodulating agents.

Initiation of Mavenclad is contraindicated in immunocompromised patients, including patients receiving immunosuppressive or myelosuppressive therapy with, e.g. cyclosporin, methotrexate, mitoxantrone, azathioprine, natalizumab, or chronic use of corticosteroids, because of a risk of additive effects on immune system (see Section 4.3 Contraindications). Acute short-term therapy with corticosteroids can be administered if clearly necessary.
The use of Mavenclad with interferon-beta results in an increased risk of lymphopenia. This needs to be considered when interferon-beta is used after cladribine. Safety and efficacy of Mavenclad in combination with other disease-modifying treatments for MS has not been assessed. Concomitant treatment is not recommended.
Because of the cladribine-induced reduction in lymphocyte count, additive haematological adverse effects may be expected if Mavenclad is administered prior to or concomitantly with other agents that affect the haematological profile (e.g. carbamazepine, non-steroidal anti-inflammatory drugs). Careful monitoring of haematological parameters is recommended in such cases.

Live or live attenuated vaccines.

Treatment with Mavenclad must not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccines because of a risk of active vaccine infection. Vaccination with live or attenuated live vaccines must be avoided during and after Mavenclad treatment as long as the patient's white blood cell counts are not within normal limits.

Potent ENT1, CNT3 and ABCG2 transporter inhibitors.

Based on in vitro data suggesting inhibition of ENT1, CNT3 or ABCG2 transport proteins, the bioavailability, intracellular distribution and renal elimination of cladribine may theoretically be altered by medicinal products containing potent ENT1, CNT3 and ABCG2 transporter inhibitors, such as dipyridamole, dilazep, nifedipine, nimodipine, cilostazol, sulindac, reserpine or eltrombopag. The net effects in terms of potential cladribine exposure alterations are difficult to predict and hence, the clinical relevance of these findings is unknown.
It is recommended that co-administration of these products be avoided during the 4 to 5 day Mavenclad treatment. If this is not possible, selection of alternative concomitant medicinal products with no, or minimal ENT1, CNT3 or ABCG2 transporter inhibiting properties should be considered. If this is not possible, dose reduction to the minimum mandatory dose of medicinal products containing these compounds, separation in the timing of administration by several hours, and careful patient monitoring is recommended.

Potent ABCG2 and P-gp transporter inducers.

The effects of potent inducers of the efflux transporters ABCG2 and P-glycoprotein (P-gp) on the bioavailability and disposition of cladribine have not been formally studied. A possible decrease in cladribine exposure should be considered if potent ABCG2 (e.g. corticosteroids) or P-gp (e.g. rifampicin, St. John's wort) transporter inducers are co-administered.

Hormonal contraceptives.

Co-administration of cladribine with oral contraceptives (ethinylestradiol and levonorgestrel) did not result in any change in their pharmacokinetic exposure. Therefore, concomitant use of cladribine is not expected to decrease the efficacy of hormonal contraceptives (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).

Other.

In vitro studies suggest that cladribine efflux is not or only minimally P-gp related. Clinically relevant interactions with inhibitors of P-gp are not expected.
In vitro data indicated that cladribine could be degraded at acidic pH. However, drug interaction studies in vivo showed that the bioavailability of Mavenclad 10 mg tablet was not changed when co-administered with pantoprazole and the bioavailability of cladribine oral solution was not enhanced when co-administered with omeprazole.
Cladribine showed no significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Inhibition of one of these enzymes, or genetic polymorphism (e.g. in CYP2D6, CYP2C9 or CYP2C19) is not expected to result in clinically significant effects on Mavenclad pharmacokinetics.
Cladribine has no inductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of cladribine on human fertility is unknown. Studies in animals have shown reproductive toxicity.
In male mice, cladribine did not affect fertility at subcutaneous doses up to 30 mg/kg per day, but reduced testes weights and increased numbers of non-motile sperm were seen, indicating the presence of testicular effects. For these effects, 5 mg/kg per day was the no observed-adverse-effect level (NOAEL).
A 1-year subcutaneous study in monkeys reported testicular degeneration, prostatic inflammation, prostatic and seminal vesicle secretion depletion, epididymal hypospermia and increased incidence of degenerated cells, while a 3-month oral and subcutaneous study noted only reduced sperm motility. The estimated exposure (plasma AUC) at the no-effect oral dose (3 mg/kg/day) was 3-fold clinical MS exposure.
In female mice, cladribine did not affect fertility up to a subcutaneous dose of 8 mg/kg per day (higher doses were not tested). The extrapolated daily exposure data (based on plasma AUC) associated with these dose levels in mice exceeded the daily exposure with the oral human dose in MS by at least an order of magnitude.
While there were no effects on female fertility, reproductive function or general performance of offspring, cladribine was shown to be embryolethal in pregnant mice, and the compound was teratogenic in mice and rabbits. A significant increase in foetal variations was observed in mice receiving 1.5 mg/kg/day or greater intravenously during the period of organogenesis, or from early gestation to weaning, and increased resorptions, reduced litter size and increased foetal malformations were observed in mice receiving 3 mg/kg/day. Foetal malformations were observed in rabbits that received 3 mg/kg/day intravenously during the period of organogenesis. The observed embryolethal and teratogenic effects are consistent with the pharmacological mechanisms of cladribine.
(Category D)
There are no adequate or well-controlled studies in human pregnancies. A limited amount of data is available from pregnant women exposed to Mavenclad prior to conception. No imbalance of adverse pregnancy outcomes between cladribine and placebo has been observed.
Although clinical data from Mavenclad did not reveal evidence of teratogenicity in humans, Mavenclad has been shown to inhibit DNA synthesis. Other agents that inhibit DNA synthesis (e.g. methotrexate) have been reported to be teratogenic in humans. Based on human experience with other substances inhibiting DNA synthesis, cladribine could cause congenital malformations when administered during pregnancy.
Mavenclad is contraindicated in pregnant women (see Section 4.3 Contraindications).
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.

Male.

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 Mavenclad treatment and for at least 6 months after the last dose. This will allow time for completion of new male reproductive cycles to clear intracellular phosphorylated cladribine from the body.
If the partner of a male patient becomes pregnant during a course of his Mavenclad therapy, it is recommended that the partner be informed about the potential hazard to the foetus.

Female.

In women of childbearing potential, pregnancy must be excluded before the initiation of Mavenclad therapy in year 1 and year 2, and prevented by use of reliable contraception during Mavenclad treatment and for at least 6 months (6 menstrual cycles) after the last dose. This will allow for the removal of any follicle that may have been exposed to cladribine during or immediately after a course of treatment. Women who become pregnant during therapy with Mavenclad tablets should discontinue treatment.
In case of exposure to Mavenclad during pregnancy, it is recommended that the patient be informed about the potential hazard to the foetus.
 It is not known whether cladribine is excreted in human milk. Because many medicines are excreted in human milk and the potential for serious adverse reactions in nursing infants, breastfeeding is contraindicated during treatment with Mavenclad and for 1 week after the last dose. A decision should be made either to discontinue breastfeeding or to discontinue Mavenclad, taking into account the importance of Mavenclad to the mother (see Section 4.3 Contraindications).

4.7 Effects on Ability to Drive and Use Machines

No studies on the effect of Mavenclad on the ability to drive or handle machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

Summary of the safety profile.

The most clinically relevant adverse reactions reported in MS patients who received cladribine at the recommended cumulative dose of 3.5 mg/kg over 2 years in clinical studies were lymphopenia and herpes zoster (see Section 4.4 Special Warnings and Precautions for Use, Haematological monitoring, Infections). Lymphopenia led to treatment discontinuation in a phase 3 trial (CLARITY trial) in approximately 2.2% of patients. The incidence of herpes zoster was higher during the period of grade 3 or 4 lymphopenia (< 500 to 200 cells/mm3 or < 200 cells/mm3) compared to the time when the patients were not experiencing grade 3 or 4 lymphopenia.

Clinical trials.

The safety data described in Table 3 reflect exposure of 884 patients with MS to Mavenclad in a placebo-controlled study (CLARITY trial). The population was 18 to 65 years of age, and gender distribution was approximately 2:1 female to male. 91.2% in the Mavenclad 3.5 mg/kg group and 86.2% in the 5.25 mg/kg group completed all treatment courses (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Table 3 shows all treatment emergent adverse events occurring at any time during the CLARITY trial with an incidence ≥ 5% in any treatment group.

List of adverse reactions.

Listed below are adverse reactions (i.e. causal association with the treatment is considered at least possible) derived from clinical studies with Mavenclad in MS, including those with lower incidence than 5%.
The following definitions apply to the frequency terminology: Very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1,000 to < 1/100; rare: ≥ 1/10,000 to < 1/1,000; very rare: < 1/10,000; frequency not known: cannot be estimated from the available data.

Infections and infestations.

Common: Oral herpes, dermatomal herpes zoster.
Very rare: Tuberculosis.

Blood and lymphatic system disorders.

Very common: Lymphopenia, which may be severe (grade 3 or 4).
Common: Decrease in neutrophil count.

Skin and subcutaneous tissue disorders.

Common: Rash (e.g. pustular, papular, macular, pruritic, erythematous rash), alopecia.

Post-marketing data.

Immune system disorders.

Common: hypersensitivity including pruritus, urticaria, rash and rare cases of angiooedema.

Hepatobiliary disorders.

Uncommon: Liver injury.
Description of selected adverse reactions.

Lymphopenia.

In clinical studies, 20% to 25% of the patients treated with a cumulative dose of cladribine 3.5 mg/kg over 2 years as monotherapy developed transient grade 3 or 4 lymphopenia. Grade 4 lymphopenia was seen in less than 1% of the patients. The largest proportion of patients with grade 3 or 4 lymphopenia was seen 2 months after the first cladribine dose in each year (4.0% and 11.3% of patients with grade 3 lymphopenia in year 1 and year 2, 0% and 0.4% of patients with grade 4 lymphopenia in year 1 and year 2). It is expected that most patients with grade 3 lymphopenia recover to either normal lymphocyte counts or grade 1 lymphopenia within 9 months.
To decrease the risk for severe lymphopenia, lymphocyte counts must be determined before, during and after cladribine treatment and strict criteria for initiating and continuing cladribine treatment must be followed (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

Liver injury.

During post-marketing experience, uncommon events of liver injury, including serious cases and cases leading to discontinuation of treatment, were reported in temporal association with Mavenclad.
Transient elevations of serum transaminases were usually greater than 5-fold the upper limit of normal (ULN). Isolated cases of transient serum transaminase elevations up to 40-fold the ULN and/or symptomatic hepatitis with transient elevation of bilirubin and jaundice have been observed.

4.9 Overdose

There is limited experience with overdose of Mavenclad. Lymphopenia is known to be dose-dependent (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
There is no known specific antidote to an overdose of Mavenclad. Treatment consists of careful observation and initiation of appropriate supportive measures. Discontinuation of Mavenclad may need to be considered. Because of the extensive intracellular and tissue distribution, haemodialysis is unlikely to eliminate cladribine to a significant extent.
Particularly close monitoring of haematological parameters is recommended in patients who have been exposed to an overdose of Mavenclad.
For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AA40.

Mechanism of action.

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.

Pharmacodynamic effects.

Cladribine has been shown to exert long-lasting effects by preferentially targeting lymphocytes and the autoimmune processes involved in the pathophysiology of MS.
Across studies, the largest proportion of patients with grade 3 or 4 lymphopenia (< 500 to 200 cells/mm3 or < 200 cells/mm3) was seen 2 months after the first cladribine dose in each year, indicating a time gap between cladribine plasma concentrations and the maximum haematological effect.
Across clinical studies, data with the proposed cumulative dose of 3.5 mg/kg body weight show a gradual improvement in the median lymphocyte counts back to the normal range at week 84 from the first dose of cladribine (approximately 30 weeks after the last dose of cladribine). The lymphocyte counts of more than 75% of patients returned to the normal range by week 144 from the first dose of cladribine (approximately 90 weeks after the last dose of cladribine).
Treatment with oral cladribine leads to rapid reductions in circulating CD4+ and CD8+ T cells. CD8+ T cells have a less pronounced decrease and a faster recovery than CD4+ T cells, resulting in a temporarily decreased CD4:CD8 ratio. Cladribine reduces CD19+ B cells and CD19+/CD56+ natural killer cells, which also recover faster than CD4+ T cells.

Clinical trials.

Efficacy and safety of Mavenclad tablets for oral use were evaluated in relapsing-remitting MS in the Cladribine Tablets Treating MS Orally (CLARITY) trial, a randomised, multicentre, double-blind, placebo-controlled clinical study in which 1326 patients were enrolled and randomly assigned to receive either placebo (n = 437), or a cumulative dose of Mavenclad of either 3.5 mg/kg (n = 433) or 5.25 mg/kg (n = 456) in 2 treatment courses over the 96 week (2 year) trial period.
Mavenclad was administered orally as 10 mg tablets, with the number of tablets taken daily based on the patient's body weight using 10 kg weight ranges. Patients randomised to the 3.5 mg/kg cumulative dose received a first treatment course at weeks 1 and 5 of the first year and a second treatment course at weeks 1 and 5 of the second year. Patients randomised to the 5.25 mg/kg cumulative dose received additional treatment at weeks 9 and 13 of the first year.
The majority of patients in the placebo (86.3%) and the Mavenclad 3.5 mg/kg (91.2%) and 5.25 mg/kg (86.2%) treatment groups completed both treatment courses through 52 weeks. A correspondingly high proportion of patients in the placebo and the Mavenclad 3.5 mg/kg and 5.25 mg/kg treatment groups (87.0%, 91.9%, and 89.0%, respectively) completed the full 96 weeks of the trial.
In the overall trial population, the median age was 39 years (range 18 to 65), and the female to male ratio was approximately 2:1. The median duration of MS prior to trial enrolment was 6.7 years, and the median baseline neurological disability based on Expanded Disability Status Scale (EDSS) score across all treatment groups was 3.0 (range 0 to 6.0). The mean number of T1 gadolinium-enhancing (Gd+) lesions, T1 hypointense lesions, and mean T2 lesion volumes were 0.93, 7.7, and 15,467 mm3, respectively. Over two thirds of the trial patients were treatment-naive for MS disease-modifying medications.
Both Mavenclad treatment groups, 5.25 mg/kg and 3.5 mg/kg, were significantly superior to placebo in the treatment of relapsing-remitting MS. Clinical outcomes are shown in Table 4.
Time to sustained disability progression was defined as the time to worsening in EDSS score of ≥ 1 unit if baseline EDSS was 0.5 to 4.5, or ≥ 1.5 units if baseline EDSS was 0, or ≥ 0.5 unit if EDSS was ≥ 5, and persistent for at least 12 weeks. Treatment with Mavenclad 3.5 mg/kg and 5.25 mg/kg resulted in a prolongation in time to sustained disability progression of 12 weeks (10th percentile, both treatment groups) compared with placebo (Figure 1).
The 3.5 mg/kg and 5.25 mg/kg treatment groups had a 33% and a 31% relative reduction in risk of developing disability progression over the 96 week trial period, respectively, compared with the placebo group (hazard ratio = 0.67, 95% CI [0.48, 0.93], p = 0.018; hazard ratio 0.69, 95% CI [0.49, 0.96], p = 0.026, respectively). The proportion of patients progressing to sustained disability was 20.6% in the placebo group, 14.3% in the 3.5 mg/kg treatment group and 15.1% in the 5.25 mg/kg treatment group.
In addition, both Mavenclad treatment groups were statistically significantly superior to placebo with regard to number and relative reduction of T1 Gd+ enhancing lesions, active T2 lesions and combined unique lesions as demonstrated on brain magnetic resonance imaging (MRI) over the entire 96 weeks of the trial. Patients in the Mavenclad 3.5 mg/kg and the 5.25 mg/kg treatment groups compared to the placebo treatment group had 86% and 88% relative reductions in the mean number of T1 GD+ lesions, 73% and 77% relative reductions in the mean number of active T2 lesions, and 74% and 78% relative reductions, in the mean number of combined unique lesions per patient per scan (p < 0.001 for both groups across all 3 MRI outcomes).
As shown in Table 4, a higher cumulative dose did not add any clinically meaningful benefit, but was associated with a higher incidence in ≥ grade 3 lymphopenia (44.9% in the 5.25 mg/kg group vs. 25.6% in the 3.5 mg/kg group).
Post hoc analysis showed a greater relative reduction in risk of relapse over 2 years for patients with highly active disease prior to receiving cladribine than in the overall patient population (68% reduction compared with 58% overall). The relative risk of 3-month disability progression over 2 years was reduced to a greater extent in patients with more active disease at baseline (72% reduction compared with 33% overall).
Subgroup analyses of region, gender, age and relapse history all showed positive treatment effects from both doses of Mavenclad with no large differences between subgroups.
Patients who had completed the CLARITY study could be enrolled in CLARITY Extension (EXT) study. In this extension study, 806 patients received either placebo or a cumulative dose of cladribine 3.5 mg/kg (in a regimen similar to that used in CLARITY) over the 96-week study period.
Of these, 98 patients treated for 2 years in CLARITY with Mavenclad 3.5 mg/kg were switched to placebo for 2 years in CLARITY EXT. The magnitude of the effect in reducing the frequency of relapses and slowing disability progression in patients receiving the 3.5 mg/kg dose in years 1 and 2 was maintained during CLARITY EXT (in years 3 and 4). The annualised relapse rate was 0.15 and 72.4% of these patients did not experience 3-month confirmed disability progression during CLARITY EXT. Also, the group continued to exhibit low T1-Gd+ lesion activity.
In CLARITY EXT study, no additional efficacy was demonstrated when patients were given additional treatment courses of Mavenclad (n = 186) in years 3 and 4.

5.2 Pharmacokinetic Properties

Cladribine is a prodrug that has to be phosphorylated intracellularly to be efficacious. The pharmacokinetics of cladribine were studied following oral and intravenous administration in MS patients, in patients with malignancies and in in vitro systems.

Absorption.

Following oral administration of Mavenclad tablets, cladribine is absorbed rapidly. Administration of 10 mg tablets resulted in a mean Cmax in the range of 22 to 29 nanogram/mL and corresponding mean AUC in the range of 80 to 101 nanogram.h/mL (arithmetic means from various studies). When oral cladribine was given in fasted state, median Tmax was 0.5 h (range 0.5 to 1.5 h). When administered with a high-fat meal, absorption of cladribine was delayed (median Tmax 1.5 h, range 1 to 3 h) and Cmax was reduced by 29% (based on geometric mean), while AUC was unchanged.
The oral bioavailability of cladribine 10 mg was approximately 40%.

Distribution.

The volume of distribution is large, indicating extensive tissue distribution and intracellular uptake. The mean volume of distribution of cladribine was estimated as 487 L (SD ± 180). The plasma protein binding is 20%, and independent of plasma concentration. Intracellular concentrations of phosphorylated cladribine were found to be several hundred-folds higher than corresponding plasma concentrations.
Cladribine is able to penetrate the blood brain barrier as shown by a cerebrospinal fluid/plasma concentration ratio of approximately 0.25.

Metabolism.

The metabolism of cladribine was studied in MS patients following the administration of a single 10 mg oral tablet and a single 3 mg intravenous dose. Following both oral and intravenous administration, the parent compound cladribine was the main component present in plasma and urine, e.g. accounting only for ≤ 3% of plasma parent drug exposure after oral administration. The primary metabolite 2-chloroadenine proved to be a minor metabolite both in plasma and in urine. Only traces of other metabolites could be found in plasma and urine.
In hepatic in vitro systems, minor metabolism of cladribine was observed (92% to 99% was unchanged cladribine). In vitro studies also showed negligible transporter-mediated uptake of cladribine into human hepatocytes.
After entering the cell, cladribine is phosphorylated to cladribine monophosphate (Cd-AMP) by deoxycytidine kinase (and also by deoxyguanosine kinase in the mitochondria). Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP) and cladribine triphosphate (Cd-ATP). The dephosphorylation and deactivation of Cd-AMP is catalysed by cytoplasmic 5'-nucleotidase.
In a study of the intracellular pharmacokinetics of Cd-AMP and Cd-ATP in patients with chronic myelogenous leukaemia, the levels of Cd-ATP were approximately half of the Cd-AMP levels. Intracellular t1/2 of Cd-AMP was 15 h. Intracellular t1/2 of Cd-ATP was 10 h.

Excretion.

The renal and the non-renal routes of cladribine elimination are approximately equally important. Based on pooled population pharmacokinetic data from various studies, the median values for the two elimination routes were 22.2 L/h for renal clearance and 23.4 L/h for non-renal clearance. Renal clearance exceeded the glomerular filtration rate, indicating active renal secretion of cladribine.
The non-renal part of the elimination of Mavenclad (approximately 50%) consists of fractional hepatic metabolism and presumably of extensive intracellular distribution and trapping of the active cladribine principle (Cd-ATP) within the targeted intracellular compartment (i.e. the lymphocytes) and subsequent elimination of intracellular Cd-ATP according to the life-cycle and elimination pathways of these cells.
The pharmacokinetics of cladribine are best described by a three-compartment model where the estimated terminal half-life for a typical patient from the population pharmacokinetic analysis is approximately 1 day. This however does not result in any drug accumulation after once daily dosing as this half-life only accounts for a small portion of the AUC.

Dose and time dependence.

After oral administration of cladribine tablets across a dose range from 3 mg to 20 mg, Cmax and AUC increase in a linear dose-proportional fashion, suggesting that absorption is not affected by rate- or capacity-limited processes up to a 20 mg oral dose.
No accumulation of cladribine plasma concentrations have been observed after repeated dosing.
There is no indication that cladribine pharmacokinetic parameters might change in a time-dependent fashion after repeated administration.

Special populations.

No studies have been conducted to evaluate the pharmacokinetics of Mavenclad in elderly or paediatric MS patients, or in subjects with renal or hepatic impairment.
A population pharmacokinetic analysis did not show any effect of age (range 18 to 65 years) or gender on cladribine pharmacokinetics. The effect of age < 18 years and > 65 years on cladribine pharmacokinetics has not been studied.
The results of the clinical trials did not show any evidence of cardiotoxicity, however patients with significant cardiac pathology, such as angina, congestive heart failure or arrhythmias, were not eligible to be enrolled in the clinical trials.

Renal impairment.

Renal and non-renal routes are equally important for the elimination of Mavenclad. Total clearance was shown to be dependent on creatinine clearance. Based on a population pharmacokinetic analysis including patients with normal renal function and with mild renal impairment, total clearance in patients with mild renal impairment (CLCR = 60 mL/min) is expected to decrease moderately, leading to an increase in exposure of 25%.

Hepatic impairment.

The importance of hepatic function for the elimination of cladribine is considered low.

5.3 Preclinical Safety Data

Genotoxicity.

Cladribine was shown to be genotoxic, causing chromosomal damage in the bone marrow of mice in vivo and in CHO-WBL cells in vitro. These findings are expected since cladribine is known to cause inhibition of DNA synthesis by an imbalance of deoxynucleotide triphosphate pools, DNA strand breaks, inhibition of DNA repair, and depletion of intracellular nicotinamide adenine dinucleotide (NAD). Cladribine was not mutagenic in vitro (bacterial and mammalian cell mutation assays) and did not induce unscheduled DNA synthesis in primary rat hepatocyte cultures.

Carcinogenicity.

While no treatment-related tumours were seen in a 26-week carcinogenicity study in transgenic mice by oral administration, an increased incidence of Harderian gland adenomas was seen in a 22-month carcinogenicity study in mice by subcutaneous administration. The clinical relevance of this is unclear as humans do not have this anatomical structure. However, based on its mode of action and positive findings in mammalian genotoxicity tests (in vitro and in vivo), a carcinogenic potential of cladribine cannot be excluded.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging. Do not use after the expiry date.

6.4 Special Precautions for Storage

Protect from moisture. Store below 30°C in the original container.

6.5 Nature and Contents of Container

Tablets (10 mg) in an aluminium-aluminium blister, sealed in a cardboard wallet and fixed in a child-resistant carton: packs of 1, 4, 5, 6, 7, 8, 9 or 10 tablets*.
*Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

For disposal of any expired, damaged or unused, return to pharmacist.
Medicines should not be disposed of via wastewater or household waste.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

4291-63-8. MW: 285.69.
Cladribine differs in structure from the naturally occurring nucleoside, deoxyadenosine, only by the substitution of a chlorine for hydrogen in the 2-position of the purine ring. Decomposition increases over time at acidic pH. The ionisation behaviour of the molecule over the pH range 0 to 12 is characterised by a single pKa of approximately 1.21.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes