Mavenclad

Patient Information

MAVENCLAD®Â 
(MAY-ven-klad)
(cladribine) tablets, for oral use

What is the most important information I should know about MAVENCLAD?

MAVENCLAD can cause serious side effects, including:

• Risk of cancer (malignancies). Treatment with MAVENCLAD may increase your risk of developing cancer. Talk to your healthcare provider about your risk of developing cancer if you receive MAVENCLAD. You should follow your healthcare provider instructions about screening for cancer.
• MAVENCLAD may cause birth defects if used during pregnancy. Females must not be pregnant when they start treatment with MAVENCLAD or become pregnant during MAVENCLAD dosing and within 6 months after the last dose of each yearly treatment course. Stop your treatment with MAVENCLAD and call your healthcare provider right away if you become pregnant during treatment with MAVENCLAD.
  • For females who are able to become pregnant:
    • Your healthcare provider should order a pregnancy test for you before you begin your first and second yearly treatment course of MAVENCLAD to make sure that you are not pregnant. Your healthcare provider will decide when to do the test.
    • Use effective birth control (contraception) on the days on which you take MAVENCLAD and for at least 6 months after the last dose of each yearly treatment course.
      • Talk to your healthcare provider if you use oral contraceptives (the “pill”).
      • You should use a second method of birth control on the days on which you take MAVENCLAD and for at least 4 weeks after your last dose of each yearly treatment course.
  • For males with female partners who are able to become pregnant:
    • Use effective birth control (contraception) during the days on which you take MAVENCLAD and for at least 6 months after the last dose of each yearly treatment course.

What is MAVENCLAD?

MAVENCLAD is a prescription medicine used to treat relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, MAVENCLAD is generally used in people who have tried another MS medicine that they could not tolerate or that has not worked well enough.

MAVENCLAD is not recommended for use in people with clinically isolated syndrome (CIS).

It is not known if MAVENCLAD is safe and effective in children under 18 years of age.

Do not take MAVENCLAD if you:

• have cancer (malignancy).
• are pregnant, plan to become pregnant, or are a woman of childbearing age or a man able to father a child and you are not using birth control. See “What is the most important information I should know about MAVENCLAD?”
• are human immunodeficiency virus (HIV) positive.
• have active infections, including tuberculosis (TB), hepatitis B or C.
• are allergic to cladribine.
• are breastfeeding. See “Before you take MAVENCLAD, tell your healthcare provider about all of your medical conditions, including if you:”

Before you take MAVENCLAD, tell your healthcare provider about all of your medical conditions, including if you:

• think you have an infection.
• have heart failure.
• have liver or kidney problems.
• have taken, take, or plan to take medicines that affect your immune system or your blood cells, or other treatments for MS. Certain medicines can increase your risk of getting an infection.
• have had a recent vaccination or are scheduled to receive any vaccinations. You should not receive live or live-attenuated vaccines within the 4 to 6 weeks preceding your treatment with MAVENCLAD. You should not receive these types of vaccines during your treatment with MAVENCLAD and until your healthcare provider tells you that your immune system is no longer weakened.
• have or have had cancer.
• are breastfeeding or plan to breastfeed. It is not known if MAVENCLAD passes into your breast milk. Do not breastfeed on the days, on which you take MAVENCLAD, and for 10 days after the last dose. See “Do not take MAVENCLAD if you:”

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

How should I take MAVENCLAD?

• MAVENCLAD is given as two yearly treatment courses.
• Each yearly treatment course consists of 2 treatment weeks (also called cycles) that will be about a month apart. Your healthcare provider will tell you when you have to start your treatment weeks and how many tablets per week you need, depending on your weight. Each treatment week is 4 or 5 days.
• Your pharmacist will dispense a carton of MAVENCLAD for each treatment week. The prescribed number of tablets per day are provided in child resistant day packs.
• Take MAVENCLAD exactly as your healthcare provider tells you. Do not change your dose or stop taking MAVENCLAD unless your healthcare provider tells you to.
• Take MAVENCLAD with water and swallow whole without chewing. MAVENCLAD can be taken with or without food.
• Swallow MAVENCLAD right away after opening the blister pack.
• Your hands must be dry when handling MAVENCLAD and washed well with water afterwards.
• Limit contact with your skin. Avoid touching your nose, eyes and other parts of the body. If you get MAVENCLAD on your skin or on any surface, wash it right away with water.
• Take MAVENCLAD at least 3 hours apart from other medicines taken by mouth during the 4-to 5-day MAVENCLAD treatment week.
• If you miss a dose, take it as soon as you remember on the same day. If the whole day passes before you remember, take your missed dose the next day. Do not take 2 doses at the same time. Instead, you will extend the number of days in that treatment week.

Your healthcare provider will continue to monitor your health during the 2 yearly treatment courses, and for at least another 2 years during which you do not need to take MAVENCLAD. It is not known if MAVENCLAD is safe and effective in people who restart MAVENCLAD treatment more than 2 years after completing 2 yearly treatment courses.

What are the possible side effects of MAVENCLAD?

MAVENCLAD can cause serious side effects, including:

• • See “What is the most important information I should know about MAVENCLAD?”
  • low blood cell counts. Low blood cell counts have happened and can increase your risk of infections during your treatment with MAVENCLAD. Your healthcare provider will do blood tests before you start treatment with MAVENCLAD, during your treatment with MAVENCLAD, and afterward, as needed.
  • serious infections such as:
    • TB, hepatitis B or C, and shingles (herpes zoster). Fatal cases of TB and hepatitis have happened with cladribine during clinical studies. Tell your healthcare provider right away if you get any symptoms of the following infection related problems or if any of the symptoms get worse, including:
      • fever
      • loss of appetite
      • aching painful muscles
      • burning, tingling, numbness or itchiness of the skin in the affected area
      • headache
      • skin blotches, blistered rash and severe pain
      • feeling of being generally unwell
    • progressive multifocal leukoencephalopathy (PML). PML is a rare brain infection that usually leads to death or severe disability. Although PML has not been seen in MS patients taking MAVENCLAD, it may happen in people with weakened immune systems. Symptoms of PML get worse over days to weeks. Call your healthcare provider right away if you have any new or worsening neurologic signs or symptoms of PML, that have lasted several days, including:
      • weakness on 1 side of your body
      • changes in your vision
      • loss or coordination in your arms and legs
      • changes in your thinking or memory
      • decreased strength
      • confusion
      • problems with balance
      • changes in your personality

• liver problems. MAVENCLAD may cause liver problems. Your healthcare provider should do blood tests to check your liver before you start taking MAVENCLAD. Call your healthcare provider right away if you have any of the following symptoms of liver problems:
  • nausea
  • loss of appetite
  • vomiting
  • your skin or the whites or your eyes turn yellow
  • stomach pain o dark urine o tiredness
• allergic reactions (hypersensitivities). MAVENCLAD can cause serious allergic reactions. Stop your treatment with MAVENCLAD and go to the closest emergency room for medical help right away if you have any signs or symptoms of allergic reactions. Symptoms of an allergic reaction may include: skin rash, swelling or itching of the face, lips, tongue or throat, or trouble breathing.
• heart failure. MAVENCLAD may cause heart failure, which means your heart may not pump as well as it should. Call your healthcare provider or go to the closest emergency room for medical help right away if you have any signs or symptoms such as shortness of breath, a fast or irregular heart beat, or unusual swelling in your body.

Your healthcare provider may delay or completely stop treatment with MAVENCLAD if you have severe side effects.

The most common side effects of MAVENCLAD include:

• upper respiratory infection
• headache
• low white blood cell counts

These are not all the possible side effects of MAVENCLAD. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store MAVENCLAD?

• MAVENCLAD comes in a child resistant package.
• Store MAVENCLAD at room temperature between 68°F and 77°F (20°C and 25°C).
• Store MAVENCLAD in the original package to protect from moisture.
• Ask your healthcare provider or pharmacist about how to safely throw away any unused or expired MAVENCLAD tablets and packaging.

Keep MAVENCLAD and all medicines out of the reach of children.

General information about the safe and effective use of MAVENCLAD

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use MAVENCLAD for a condition for which it was not prescribed. Do not give MAVENCLAD to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider for information about MAVENCLAD that is written for health professionals.

What are the ingredients in MAVENCLAD?

Active ingredient: cladribine

Inactive ingredients: hydroxypropyl betadex, magnesium stearate, and sorbitol.

This Medication Guide has been approved by the U.S.Food and Drug Administration.

Description

MAVENCLAD contains the nucleoside metabolic inhibitor cladribine, which is a white or almost white, non-hydroscopic, crystalline powder with the molecular formula C₁₀H₁₂ClN₅O₃ and molecular weight 285.69. It differs in structure from the naturally occurring nucleoside, deoxyadenosine, by the substitution of chlorine for hydrogen in the 2-position of the purine ring.

The chemical name of cladribine is 2-chloro-2′-deoxy-adenosine. The structural formula is shown below:

 

 

Cladribine is stable at slightly basic and at neutral pH. The main degradation pathway is hydrolysis and at acidic pH significant decomposition occurs with time. The ionization behavior of the molecule over the pH range 0 to 12 is characterized by a single pKa of approximately 1.21.

MAVENCLAD is provided as 10 mg tablets for oral use. Each MAVENCLAD 10 mg tablet contains cladribine as an active ingredient and hydroxypropyl betadex, magnesium stearate, and sorbitol as inactive ingredients.

MAVENCLAD is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include relapsing-remitting disease and active secondary progressive disease, in adults. Because of its safety profile, use of MAVENCLAD is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of MS [see WARNINGS AND PRECAUTIONS].

Limitations Of U4se

MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see WARNINGS AND PRECAUTIONS].

Dosage And Administration

Assessments Prior To Starting Each MAVENCLAD Treatment Course

Cancer Screening

Follow standard cancer screening guidelines because of the risk of malignancies [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Pregnancy

Exclude pregnancy prior to treatment with MAVENCLAD in females of reproductive potential [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and Use In Specific Populations].

Complete Blood Count (CBC)

Obtain a CBC with differential including lymphocyte count [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS]. Lymphocytes must be:

• within normal limits before initiating the first treatment course
• at least 800 cells per microliter before initiating the second treatment course

If necessary, delay the second treatment course for up to 6 months to allow for recovery of lymphocytes to at least 800 cells per microliter. If this recovery takes more than 6 months, the patient should not receive further treatment with MAVENCLAD.

Infections [see WARNINGS AND PRECAUTIONS]

• Exclude HIV infection.
• Perform tuberculosis screening.
• Screen for hepatitis B and C.
• Evaluate for acute infection. Consider a delay in MAVENCLAD treatment until any acute infection is fully controlled.
• Vaccination of patients who are seronegative for VZV is recommended prior to initiation of MAVENCLAD.
• Vaccination of patients who are seropositive to VZV is recommended with zoster vaccine recombinant, adjuvanted. Patients may be administered zoster vaccine recombinant, adjuvanted at any time prior to or during the year 1 or year 2 course of MAVENCLAD treatment. These patients may also be administered the vaccine if their lymphocyte counts are ≤ 500 cells per microliter.
• Administer all immunizations (except as noted for VZV) according to immunization guidelines prior to starting MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD.
• Obtain a baseline (within 3 months) magnetic resonance imaging prior to the first treatment course because of the risk of progressive multifocal leukoencephalopathy (PML).

Liver Injury

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels [see WARNINGS AND PRECAUTIONS].

Recommended Dosage

The recommended cumulative dosage of MAVENCLAD is 3.5 mg per kg body weight administered orally and divided into 2 yearly treatment courses (1.75 mg per kg per treatment course) (see Table 1). Each treatment course is divided into 2 treatment cycles:

Administration Of First Treatment Course

• First Course/First Cycle: start any time.
• First Course/Second Cycle: administer 23 to 27 days after the last dose of First Course/First Cycle.

Administration Of Second Treatment Course

• Second Course/First Cycle: administer at least 43 weeks after the last dose of First Course/Second Cycle.
• Second Course/Second Cycle: administer 23 to 27 days after the last dose of Second Course/First Cycle.

Table 1 : Dose of MAVENCLAD per Cycle by Patient Weight in Each Treatment Course

Weight Range	Dose in mg (Number of 10 mg Tablets) per Cycle
kg	First Cycle	Second Cycle
40* to less than 50	40 mg (4 tablets)	40 mg (4 tablets)
50 to less than 60	50 mg (5 tablets)	50 mg (5 tablets)
60 to less than 70	60 mg (6 tablets)	60 mg (6 tablets)
70 to less than 80	70 mg (7 tablets)	70 mg (7 tablets)
80 to less than 90	80 mg (8 tablets)	70 mg (7 tablets)
90 to less than 100	90 mg (9 tablets)	80 mg (8 tablets)
100 to less than 110	100 mg (10 tablets)	90 mg (9 tablets)
110 and above	100 mg (10 tablets)	100 mg (10 tablets)
*The use of MAVENCLAD in patients weighing less than 40 kg has not been investigated.

 

Administer the cycle dosage as 1 or 2 tablets once daily over 4 or 5 consecutive days [see HOW SUPPLIED/Storage And Handling]. Do not administer more than 2 tablets daily.

Following the administration of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years. Treatment during these 2 years may further increase the risk of malignancy [see WARNINGS AND PRECAUTIONS]. The safety and efficacy of reinitiating MAVENCLAD more than 2 years after completing 2 treatment courses has not been studied.

Missed Dose

If a dose is missed, patients should not take double or extra doses.

If a dose is not taken on the scheduled day, then the patient must take the missed dose on the following day and extend the number of days in that treatment cycle. If two consecutive doses are missed, the treatment cycle is extended by 2 days.

Administration

MAVENCLAD tablets are taken orally, with water, and swallowed whole without chewing. MAVENCLAD can be taken with or without food.

Separate administration of MAVENCLAD and any other oral drugs by at least 3 hours during the 4 to 5 day MAVENCLAD treatment cycles [see CLINICAL PHARMACOLOGY].

MAVENCLAD is a cytotoxic drug. Follow applicable special handling and disposal procedures [see REFERENCES]. MAVENCLAD is an uncoated tablet and must be swallowed immediately once removed from the blister. 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 with water.

The patient’s hands must be dry when handling the tablets and washed thoroughly afterwards. Avoid prolonged contact with skin.

Laboratory Testing And Monitoring To Assess Safety

Cancer Screening

Follow standard cancer screening guidelines in patients treated with MAVENCLAD [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Complete Blood Count

Obtain complete blood count (CBC) with differential including lymphocyte count:

• • before initiating the first treatment course of MAVENCLAD
  • before initiating the second treatment course of MAVENCLAD
  • 2 and 6 months after start of treatment in each treatment course; if the lymphocyte count at month 2 is below 200 cells per microliter, monitor monthly until month 6. See WARNINGS AND PRECAUTIONS for instructions based on the patient’s lymphocyte counts and clinical status (e.g., infections). Hold MAVENCLAD therapy if the lymphocyte count is below 200 cells per microliter

• periodically thereafter and when clinically indicated [see WARNINGS AND PRECAUTIONS]

Recommended Concomitant Medication

Herpes Prophylaxis

Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter [see WARNINGS AND PRECAUTIONS].

How Supplied

Dosage Forms And Strengths

MAVENCLAD is available as 10 mg tablets. The tablets are uncoated, white, round, biconvex, and engraved with a “C” on one side and “10” on the other side.

MAVENCLAD tablets, 10 mg, are uncoated, white, round, biconvex, and engraved with a “C” on one side and “10” on the other side. Each tablet is packaged in a child-resistant day pack containing one or two tablets in a blister card.

Dispense one box for each treatment cycle with a Medication Guide [see DOSAGE AND ADMINISTRATION].

Presentations

NDC 44087-4000-4 Box of 4 tablets: Four day packs each containing one tablet.
NDC 44087-4000-5 Box of 5 tablets: Five day packs each containing one tablet.
NDC 44087-4000-6 Box of 6 tablets: One day pack containing two tablets. Four day packs each containing one tablet.
NDC 44087-4000-7 Box of 7 tablets: Two day packs each containing two tablets. Three day packs each containing one tablet.
NDC 44087-4000-8 Box of 8 tablets: Three day packs each containing two tablets. Two day packs each containing one tablet.
NDC 44087-4000-9 Box of 9 tablets: Four day packs each containing two tablets. One day pack containing one tablet.
NDC 44087-4000-0 Box of 10 tablets: Five day packs each containing two tablets.

Storage And Handling

Store at controlled room temperature, 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Store in original package in order to protect from moisture.

MAVENCLAD is a cytotoxic drug. Follow applicable special handling and disposal procedures [see REFERENCES].¹

REFERENCES

1 “OSHA Hazardous Drugs”. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

Distributed by: EMD Serono, Inc. Rockland, MA 02370.  Revised: Sep 2022

The following serious adverse reactions and potential risks are discussed, or discussed in greater detail, in other sections of the labeling:

• Malignancies [see WARNINGS AND PRECAUTIONS]
• Risk of Teratogenicity [see WARNINGS AND PRECAUTIONS]
• Lymphopenia [see WARNINGS AND PRECAUTIONS]
• Infections [see WARNINGS AND PRECAUTIONS]
• Hematologic Toxicity [see WARNINGS AND PRECAUTIONS]
• Graft-Versus-Host Disease With Blood Transfusion [see WARNINGS AND PRECAUTIONS]
• Liver Injury [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity [see WARNINGS AND PRECAUTIONS]
• Cardiac Failure [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

In the clinical trial program of cladribine in MS, 1,976 patients received cladribine for a total of 9,509 patient years. The mean time on study including follow-up was approximately 4.8 years, and approximately 24% of cladribine-treated patients had approximately 8 years of time on study including follow-up. Of these, 923 patients aged 18 to 66 years received MAVENCLAD as monotherapy at a cumulative dose of 3.5 mg per kg.

Table 2 shows adverse reactions in Study 1 [see Clinical Studies] with an incidence of at least 5% for MAVENCLAD and higher than placebo. The most common (> 20%) adverse reactions reported in Study 1 are upper respiratory tract infection, headache, and lymphopenia.

Table 2 : Adverse Reactions in Study 1 with an Incidence of at Least 5% for MAVENCLAD and Higher than Placebo

	MAVENCLAD (N=440) %	Placebo (N=435) %
Upper respiratory tract infection	38	32
Headache	25	19
Lymphopenia	24	2
Nausea	10	9
Back pain	8	6
Arthralgia and arthritis	7	5
Insomnia	6	4
Bronchitis	5	3
Hypertension	5	3
Fever	5	3
Depression	5	3

 

Hypersensitivity

In clinical studies, 11% of MAVENCLAD patients had hypersensitivity adverse reactions, compared to 7% of placebo patients [see WARNINGS AND PRECAUTIONS].

Alopecia

Alopecia occurred in 3% of MAVENCLAD-treated patients compared to 1% of placebo patients.

Myelodysplastic Syndrome

Cases of myelodysplastic syndrome have been reported in patients that had received parenteral cladribine at a higher dosage than that approved for MAVENCLAD. These cases occurred several years after treatment.

Herpes Meningoencephalitis

Fatal herpes meningoencephalitis occurred in one MAVENCLAD-treated patient, at a higher dosage and longer duration of therapy than the approved MAVENCLAD dosage and in combination with interferon beta-1a treatment.

Stevens-Johnson Syndrome (SJS) And Toxic Epidermal Necrolysis (TEN)

SJS and TEN are identified risks of parenteral cladribine for the treatment of oncologic indications.

Seizures

In clinical studies, serious events of seizure occurred in 0.3% of MAVENCLAD-treated patients compared to 0 placebo patients. Serious events included generalized tonic-clonic seizures and status epilepticus. It is unknown whether these events were related to the effects of multiple sclerosis alone, to MAVENCLAD, or to a combination of both.

Table 3 : Drug Interactions with MAVENCLAD

Potent ENT, CNT And BCRP Transporter Inhibitors

 

Clinical Impact	Concomitant use of MAVENCLAD with immunomodulatory, immunosuppressive, or myelosuppressive drugs may increase the risk of adverse reactions because of the additive effects on the immune system [see WARNINGS AND PRECAUTIONS].
Prevention or Management	Concomitant use with myelosuppressive or other immunosuppressive drugs is not recommended. Acute shortterm therapy with corticosteroids can be administered. In patients who have previously been treated with immunomodulatory or immunosuppressive drugs, consider potential additive effect, the mode of action, and duration of effect of the other drugs prior to initiation of MAVENCLAD.

 

Interferon-Beta

 

Clinical Impact	Concomitant use of MAVENCLAD with interferon-beta did not change the exposure of cladribine to a clinically significant effect; however, lymphopenia risk may be increased [see WARNINGS AND PRECAUTIONS].
Prevention or Management	Concomitant use is not recommended.

 

Hematotoxic Drugs

 

Clinical Impact	Concomitant use of MAVENCLAD with hematotoxic drugs may increase the risk of adverse reactions because of the additive hematological effects [see WARNINGS AND PRECAUTIONS].
Prevention or Management	Monitor hematological parameters.

 

Antiviral And Antiretroviral Drugs

 

Clinical Impact	Compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine) could interfere with the intracellular phosphorylation and activity of cladribine.
Prevention or Management	Avoid concomitant use.

 

Potent ENT, CNT And BCRP Transporter Inhibitors

 

Clinical Impact

Cladribine is a substrate of breast cancer resistance protein (BCRP), equilibrative nucleoside (ENT1), and concentrative nucleoside (CNT3) transport proteins. The bioavailability, intracellular distribution, and renal elimination of cladribine may be altered by potent ENT1, CNT3, and BCRP transporter inhibitors.

Prevention or Management

Avoid co-administration of potent ENT1, CNT3, or BCRP transporter inhibitors (e.g., ritonavir, eltrombopag, curcumin, cyclosporine, dilazep, nifedipine, nimodipine, cilostazol, sulindac, dipyridamole, or reserpine) during the 4 to 5 day MAVENCLAD treatment cycles. If this is not possible, consider selection of alternative concomitant drugs with no or minimal ENT1, CNT3, or BCRP transporter inhibiting properties. If this is not possible, dose reduction to the minimum mandatory dose of drugs containing these compounds, separation in the timing of administration, and careful patient monitoring is recommended.

 

Potent BCRP And P-gp Transporter Inducers

 

Clinical Impact	Possible decrease in cladribine exposure if potent BCRP or P-gp transporter inducers are co-administered.
Prevention or Management	Consider a possible decrease in cladribine efficacy if potent BCRP (e.g., corticosteroids) or P-gp (e.g., rifampicin, St. John’s Wort) transporter inducers are co-administered.

 

Hormonal Contraceptives

 

Clinical Impact	It is currently unknown whether MAVENCLAD may reduce the effectiveness of systemically acting hormonal contraceptives.
Prevention or Management	Women using systemically acting hormonal contraceptives should add a barrier method during MAVENCLAD dosing and for at least 4 weeks after the last dose in each treatment course.

 

Included as part of the “PRECAUTIONS” Section

Precautions

Hypertension

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypertension was reported in 145/359 patients (40%) receiving INLYTA and 103/355 patients (29%) receiving sorafenib. Grade 3/4 hypertension was observed in 56/359 patients (16%) receiving INLYTA and 39/355 patients (11%) receiving sorafenib. Hypertensive crisis was reported in 2/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. The median onset time for hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >100 mmHg) was within the first month of the start of INLYTA treatment and blood pressure increases have been observed as early as 4 days after starting INLYTA. Hypertension was managed with standard anti-hypertensive therapy. Discontinuation of INLYTA treatment due to hypertension occurred in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see ADVERSE REACTIONS].

Ensure that blood pressure is well-controlled prior to initiating INLYTA. Monitor patients for hypertension and treat as needed with standard anti-hypertensive therapy. Withhold and then dose reduce INLYTA or permanently discontinue based on severity of hypertension [see DOSAGE AND ADMINISTRATION].

Arterial Thromboembolic Events

In clinical trials, arterial thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, Grade 3/4 arterial thromboembolic events were reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. Fatal cerebrovascular accident was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see ADVERSE REACTIONS].

INLYTA has not been studied in patients who had an arterial thromboembolic event within the previous 12 months. In clinical trials with INLYTA, arterial thromboembolic events (including transient ischemic attack, cerebrovascular accident, myocardial infarction, and retinal artery occlusion) were reported in 17/715 patients (2%), with two deaths secondary to cerebrovascular accident.

Permanently discontinue INLYTA if an arterial thromboembolic event occurs during treatment.

Venous Thromboembolic Events

In clinical trials, venous thromboembolic events have been reported, including deaths. In a controlled clinical study with INLYTA for the treatment of patients with RCC, venous thromboembolic events were reported in 11/359 patients (3%) receiving INLYTA and 2/355 patients (1%) receiving sorafenib. Grade 3/4 venous thromboembolic events were reported in 9/359 patients (3%) receiving INLYTA (including pulmonary embolism, deep vein thrombosis, retinal vein occlusion and retinal vein thrombosis) and 2/355 patients (1%) receiving sorafenib. Fatal pulmonary embolism was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib.

INLYTA has not been studied in patients who had a venous thromboembolic event within the previous 6 months. In clinical trials with INLYTA, venous thromboembolic events were reported in 22/715 patients (3%), with two deaths secondary to pulmonary embolism.

Monitor for signs and symptoms of VTE and PE. Withhold INLYTA and then resume at same dose or permanently discontinue based on severity of VTE.

Hemorrhage

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hemorrhagic events were reported in 58/359 patients (16%) receiving INLYTA and 64/355 patients (18%) receiving sorafenib. Grade 3/4 hemorrhagic events were reported in 5/359 (1%) patients receiving INLYTA (including cerebral hemorrhage, hematuria, hemoptysis, lower gastrointestinal hemorrhage, and melena) and 11/355 (3%) patients receiving sorafenib. Fatal hemorrhage was reported in 1/359 patients (<1%) receiving INLYTA (gastric hemorrhage) and 3/355 patients (1%) receiving sorafenib.

INLYTA has not been studied in patients who have evidence of untreated brain metastasis or recent active gastrointestinal bleeding and should not be used in those patients. Withhold and then dose reduce INLYTA or discontinue based on severity and persistence of hemorrhage.

Cardiac Failure

In a controlled clinical study with INLYTA for the treatment of patients with RCC, cardiac failure was reported in 6/359 patients (2%) receiving INLYTA and 3/355 patients (1%) receiving sorafenib. Grade 3/4 cardiac failure was observed in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Fatal cardiac failure was reported in 2/359 patients (1%) receiving INLYTA and 1/355 patients (<1%) receiving sorafenib. Monitor for signs or symptoms of cardiac failure throughout treatment with INLYTA. Management of cardiac failure may require dose reduction, dose interruption or permanent discontinuation of INLYTA [see DOSAGE AND ADMINISTRATION].

Gastrointestinal Perforation And Fistula Formation

In a controlled clinical study with INLYTA for the treatment of patients with RCC, gastrointestinal perforation was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib. In clinical trials with INLYTA, gastrointestinal perforation was reported in 5/715 patients (1%), including one death. In addition to cases of gastrointestinal perforation, fistulas were reported in 4/715 patients (1%).

Monitor for symptoms of gastrointestinal perforation or fistula periodically throughout treatment with INLYTA.

Thyroid Dysfunction

In a controlled clinical study with INLYTA for the treatment of patients with RCC, hypothyroidism was reported in 69/359 patients (19%) receiving INLYTA and 29/355 patients (8%) receiving sorafenib. Hyperthyroidism was reported in 4/359 patients (1%) receiving INLYTA and 4/355 patients (1%) receiving sorafenib. In patients who had thyroid stimulating hormone (TSH) <5 μU/mL before treatment, elevations of TSH to ≥10 μU/mL occurred in 79/245 patients (32%) receiving INLYTA and 25/232 patients (11%) receiving sorafenib [see ADVERSE REACTIONS].

Monitor thyroid function before initiation of, and periodically throughout, treatment with INLYTA. Treat hypothyroidism and hyperthyroidism according to standard medical practice to maintain euthyroid state.

Impaired Wound Healing

Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, INLYTA has the potential to adversely affect wound healing.

Withhold INLYTA for at least 2 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. Resume INLYTA at a reduced dose or discontinue based on severity and persistence of the impaired wound healing. The safety of resumption of INLYTA after resolution of wound healing complications has not been established [see DOSAGE AND ADMINISTRATION].

Reversible Posterior Leukoencephalopathy Syndrome

In a controlled clinical study with INLYTA for the treatment of patients with RCC, reversible posterior leukoencephalopathy syndrome (RPLS) was reported in 1/359 patients (<1%) receiving INLYTA and none of the patients receiving sorafenib [see ADVERSE REACTIONS]. There were two additional reports of RPLS in other clinical trials with INLYTA.

RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of RPLS. Permanently discontinue INLYTA in patients developing RPLS. The safety of reinitiating INLYTA therapy in patients previously experiencing RPLS is not known [see DOSAGE AND ADMINISTRATION].

Proteinuria

In a controlled clinical study with INLYTA for the treatment of patients with RCC, proteinuria was reported in 39/359 patients (11%) receiving INLYTA and 26/355 patients (7%) receiving sorafenib.

Grade 3 proteinuria was reported in 11/359 patients (3%) receiving INLYTA and 6/355 patients (2%) receiving sorafenib [see ADVERSE REACTIONS].

Monitoring for proteinuria before initiation of, and periodically throughout, treatment with INLYTA is recommended. For patients who develop moderate to severe proteinuria, withhold and then dose reduce INLYTA [see DOSAGE AND ADMINISTRATION].

Hepatotoxicity

INLYTA AS A Single Agent

In a controlled clinical study with INLYTA for the treatment of patients with RCC, alanine aminotransferase (ALT) elevations of all grades occurred in 22% of patients on both arms, with Grade 3/4 events in <1% of patients on the INLYTA arm. When used as a single agent, monitor ALT, aspartate aminotransferase (AST) and bilirubin before initiation of and periodically throughout treatment with INLYTA.

INLYTA In Combination With Avelumab Or With Pembrolizumab

INLYTA in combination with avelumab or with pembrolizumab can cause hepatotoxicity with higher than expected frequencies of Grade 3 and 4 ALT and AST elevations. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt or permanently discontinue INLYTA and avelumab or pembrolizumab, and administer corticosteroids as needed [see DOSAGE AND ADMINISTRATION].

With the combination of INLYTA and avelumab, Grades 3 and 4 increased ALT and increased AST were reported in 9% and 7% of patients, respectively. In patients with ALT ≥3 times ULN (Grades 2-4, n=82), ALT resolved to Grades 0-1 in 92%. Among the 73 patients who were rechallenged with either avelumab (n=3) or axitinib (n=25) administered as a single agent or with both (n=45), recurrence of ALT ≥3 times ULN was observed in no patient receiving avelumab, 6 patients receiving INLYTA, and 15 patients receiving both avelumab and INLYTA. Twenty-two (88%) patients with a recurrence of ALT ≥3 ULN subsequently recovered to Grade 0-1 from the event. Immune-mediated hepatitis was reported in 7% of patients including 4.9% with Grade 3 or 4 immune-mediated hepatitis. Hepatotoxicity led to permanent discontinuation in 7% and immune-mediated hepatitis led to permanent discontinuation of either avelumab or INLYTA in 5% of patients. Thirty-four patients were treated with corticosteroids and one patient was treated with a non-steroidal immunosuppressant. Resolution of hepatitis occurred in 31 of the 35 patients at the time of data cut-off.

With the combination of INLYTA and pembrolizumab, Grades 3 and 4 increased ALT (20%) and increased AST (13%) were seen. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times ULN (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either pembrolizumab (n=3) or INLYTA (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving pembrolizumab, 16 patients receiving INLYTA, and 24 patients receiving both pembrolizumab and INLYTA. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.

Use In Patients With Hepatic Impairment

The systemic exposure to axitinib was higher in subjects with moderate hepatic impairment (Child-Pugh class B) compared to subjects with normal hepatic function. A dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B). INLYTA has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see DOSAGE AND ADMINISTRATION, Use In Specific Populations, and CLINICAL PHARMACOLOGY].

Major Adverse Cardiovascular Events (MACE)

INLYTA in combination with avelumab can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Permanently discontinue INLYTA and avelumab for Grade 3-4 cardiovascular events.

MACE occurred in 7% of patients with advanced RCC treated with INLYTA in combination with avelumab compared to 3.4% treated with sunitinib in a randomized trial, JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal studies, INLYTA can cause fetal harm when administered to a pregnant woman. There are no available human data to inform the drug-associated risk. In developmental toxicity studies in mice, axitinib was teratogenic, embryotoxic and fetotoxic at maternal exposures that were lower than human exposures at the recommended clinical dose. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with INLYTA and for 1 week after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose [see Use In Specific Populations, CLINICAL PHARMACOLOGY].

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy and contraception information.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Hypertension

Advise patients that hypertension may develop during INLYTA treatment and that blood pressure should be monitored regularly during treatment [see WARNINGS AND PRECAUTIONS].

Arterial/Venous Thromboembolic Events

Advise patients that arterial and venous thromboembolic events have been observed during INLYTA treatment and to inform their doctor if they experience symptoms suggestive of thromboembolic events [see WARNINGS AND PRECAUTIONS].

Hemorrhage

Advise patients that INLYTA may increase the risk of bleeding and to promptly inform their doctor of any bleeding episodes [see WARNINGS AND PRECAUTIONS].

Cardiac Failure

Advise patients that cardiac failure may develop during INLYTA treatment and that signs or symptoms of cardiac failure should be regularly monitored for during treatment [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Disorders

Advise patients that gastrointestinal disorders such as diarrhea, nausea, vomiting, and constipation may develop during INLYTA treatment and to seek immediate medical attention if they experience persistent or severe abdominal pain because cases of gastrointestinal perforation and fistula have been reported in patients taking INLYTA [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Abnormal Thyroid Function

Advise patients that abnormal thyroid function may develop during INLYTA treatment and to inform their doctor if symptoms of abnormal thyroid function occur [see WARNINGS AND PRECAUTIONS].

Impaired Wound Healing

Advise patients that INLYTA may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see WARNINGS AND PRECAUTIONS].

Reversible Posterior Leukoencephalopathy Syndrome

Advise patients to inform their doctor if they have worsening of neurological function consistent with RPLS (headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances) [see WARNINGS AND PRECAUTIONS].

Hepatotoxicity

Inform patients of the signs and symptoms of hepatotoxicity. Advise patients to contact their healthcare provider immediately for signs or symptoms of hepatotoxicity [see WARNINGS AND PRECAUTIONS].

Major Adverse Cardiovascular Events

Advise patients receiving INLYTA in combination with avelumab to contact their healthcare provider immediately for signs or symptoms of cardiovascular events including but not limited to new or worsening chest discomfort, dyspnea, or peripheral edema [see WARNINGS AND PRECAUTIONS].

Embryo-Fetal Toxicity

Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to a fetus and potential loss of the pregnancy [see Use In Specific Populations].

Advise females of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment and for 1 week following the last dose [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy and contraception information.

Lactation

Advise patients not to breastfeed while taking INLYTA and for 2 weeks after receiving the last dose [see Use In Specific Populations].

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for lactation information.

Infertility

Advise males and females of reproductive potential that INLYTA may impair fertility [see Use In Specific Populations].

Concomitant Medications

Advise patients to inform their doctor of all concomitant medications, vitamins, or dietary and herbal supplements.

This product’s labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been conducted with axitinib.

Axitinib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay. Axitinib was genotoxic in the in vivo mouse bone marrow micronucleus assay.

INLYTA has the potential to impair reproductive function and fertility in humans. In repeat-dose toxicology studies, findings in the male reproductive tract were observed in the testes/epididymis (decreased organ weight, atrophy or degeneration, decreased numbers of germinal cells, hypospermia or abnormal sperm forms, reduced sperm density and count) at ≥15 mg/kg/dose administered orally twice daily in mice (approximately 7 times the systemic exposure (AUC) in patients at the recommended starting dose) and ≥1.5 mg/kg/dose administered orally twice daily in dogs (approximately 0.1 times the AUC in patients at the recommended starting dose). Findings in the female reproductive tract in mice and dogs included signs of delayed sexual maturity, reduced or absent corpora lutea, decreased uterine weights and uterine atrophy at ≥5 mg/kg/dose (approximately 1.5 or 0.3 times the AUC in patients at the recommended starting dose compared to mice and dogs, respectively).

In a fertility study in mice, axitinib did not affect mating or fertility rate when administered orally twice daily to males at any dose tested up to 50 mg/kg/dose following at least 70 days of administration (approximately 57 times the AUC in patients at the recommended starting dose). In female mice, reduced fertility and embryonic viability were observed at all doses tested (≥15 mg/kg/dose administered orally twice daily) following at least 15 days of treatment with axitinib (approximately 10 times the AUC in patients at the recommended starting dose).

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings in animal studies and its mechanism of action, INLYTA can cause fetal harm when administered to a pregnant woman. There are no available human data to inform the drug-associated risk. In developmental toxicity studies, axitinib was teratogenic, embryotoxic and fetotoxic in mice at exposures lower than human exposures at the recommended starting dose (see Data). Advise females of reproductive potential of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the United States (U.S.) general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for pregnancy information.

Data

Animal Data

Oral axitinib administered twice daily to female mice prior to mating and through the first week of pregnancy caused an increase in post-implantation loss at all doses tested (≥15 mg/kg/dose, approximately 10 times the systemic exposure (AUC) in patients at the recommended starting dose). In an embryo-fetal developmental toxicity study, pregnant mice received oral doses of 0.15, 0.5 and 1.5 mg/kg/dose axitinib twice daily during the period of organogenesis. Embryo-fetal toxicities observed in the absence of maternal toxicity included malformation (cleft palate) at 1.5 mg/kg/dose (approximately 0.5 times the AUC in patients at the recommended starting dose) and variation in skeletal ossification at ≥0.5 mg/kg/dose (approximately 0.15 times the AUC in patients at the recommended starting dose).

Lactation

Risk Summary

There are no data on the presence of axitinib in human milk, or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in a breastfed child from INLYTA, advise lactating women not to breastfeed during treatment and for 2 weeks after the last dose.

When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for lactation information.

Females And Males Of Reproductive Potential

Based on findings in animal studies, INLYTA can cause fetal harm when administered to a pregnant woman [see Pregnancy]. When INLYTA is used in combination with avelumab or pembrolizumab, refer to the full prescribing information of avelumab or pembrolizumab for contraception information.

Pregnancy Testing

Verify pregnancy status in females of reproductive potential prior to initiating treatment with INLYTA.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with INLYTA and for 1 week after the last dose.

Males

Based on findings in animal studies, advise males with female partners of reproductive potential to use effective contraception during treatment and for 1 week after the last dose.

Infertility

Females and Males

Based on findings in animals, INLYTA may impair fertility in females and males of reproductive potential [see Nonclinical Toxicology].

Pediatric Use

The safety and efficacy of INLYTA in pediatric patients have not been studied.

Juvenile Animal Toxicity Data

Toxicities in bone and teeth were observed in immature mice and dogs administered oral axitinib twice daily for 1 month or longer. Effects in bone consisted of thickened growth plates in mice and dogs at ≥15 mg/kg/dose (approximately 6 and 15 times, respectively, the systemic exposure (AUC) in patients at the recommended starting dose). Abnormalities in growing incisor teeth (including dental caries, malocclusions and broken and/or missing teeth) were observed in mice administered oral axitinib twice daily at ≥5 mg/kg/dose (approximately 1.5 times the AUC in patients at the recommended starting dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Geriatric Use

In a controlled clinical study with INLYTA for the treatment of patients with RCC, 123/359 patients (34%) treated with INLYTA were ≥65 years of age. Although greater sensitivity in some older individuals cannot be ruled out, no overall differences were observed in the safety and effectiveness of INLYTA between patients who were ≥65 years of age and younger.

Of the 434 patients randomized to INLYTA 5 mg twice daily administered in combination with avelumab 10 mg/kg in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger.

Of the 432 patients randomized to INLYTA 5 mg twice daily administered in combination with pembrolizumab 200 mg in the KEYNOTE-426 trial, 40% were 65 years or older. No overall difference in safety or efficacy was reported between patients who were ≥65 years of age and younger.

No dosage adjustment is required in elderly patients [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Hepatic Impairment

In a dedicated hepatic impairment trial, compared to subjects with normal hepatic function, systemic exposure following a single dose of INLYTA was similar in subjects with baseline mild hepatic impairment (Child-Pugh class A) and higher in subjects with baseline moderate hepatic impairment (Child-Pugh class B).

No starting dose adjustment is required when administering INLYTA to patients with mild hepatic impairment (Child-Pugh class A). A starting dose decrease is recommended when administering INLYTA to patients with moderate hepatic impairment (Child-Pugh class B) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY].

INLYTA has not been studied in subjects with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

No dedicated renal impairment trial for axitinib has been conducted. Based on the population pharmacokinetic analyses, no significant difference in axitinib clearance was observed in patients with pre-existing mild to severe renal impairment (15 mL/min ≤creatinine clearance [CLcr] <89 mL/min) [see CLINICAL PHARMACOLOGY]. No starting dose adjustment is needed for patients with pre-existing mild to severe renal impairment. Caution should be used in patients with end-stage renal disease (CLcr <15 mL/min).

There is no experience with overdose of MAVENCLAD. Lymphopenia is known to be dose-dependent. Particularly close monitoring of hematological parameters is recommended in patients who have been exposed to an overdose of MAVENCLAD [see WARNINGS AND PRECAUTIONS].

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 rapid and extensive intracellular and tissue distribution, hemodialysis is unlikely to eliminate cladribine to a significant extent.

MAVENCLAD is contraindicated:

• in patients with current malignancy [see WARNINGS AND PRECAUTIONS].
• in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. May cause fetal harm [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
• in patients infected with the human immunodeficiency virus (HIV) [see WARNINGS AND PRECAUTIONS].
• in patients with active chronic infections (e.g., hepatitis or tuberculosis) [see WARNINGS AND PRECAUTIONS].
• in patients with a history of hypersensitivity to cladribine [see WARNINGS AND PRECAUTIONS].
• in women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose [see Use In Specific Populations].

Mechanism Of Action

The mechanism by which cladribine exerts its therapeutic effects in patients with multiple sclerosis has not been fully elucidated but is thought to involve cytotoxic effects on B and T lymphocytes through impairment of DNA synthesis, resulting in depletion of lymphocytes.

Pharmacodynamics

MAVENCLAD causes a dose-dependent reduction in lymphocyte count. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment cycle and were lower with each additional treatment cycle. At the end of Year 2, 2% of patients continued to have absolute lymphocyte counts less than 500 cells per microliter. The median time to recovery from lymphocyte counts less than 500 cells per microliter to at least 800 cells per microliter was approximately 28 weeks [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Cladribine is a prodrug that becomes active upon phosphorylation to its 2-chlorodeoxyadenosine triphosphate (Cd-ATP) metabolite.

The pharmacokinetic parameters presented below were assessed following oral administration of cladribine 10 mg, unless otherwise specified. The cladribine mean maximum concentration (Cmax) was in the range of 22 to 29 ng/ mL and corresponding mean AUC was in the range of 80 to 101 ng•h/mL.

The Cmax and AUC of cladribine increased proportionally across a dose range from 3 to 20 mg.

No accumulation of cladribine concentration in plasma was observed after repeated dosing.

Absorption

The bioavailability of cladribine was approximately 40%. Following fasted administration of cladribine, the median time to maximum concentration (Tmax) was 0.5 h (range 0.5 to 1.5 hours).

Effect Of Food

Following administration of cladribine with a high fat meal, the geometric mean Cmax decreased by 29% and AUC was unchanged. The Tmax was prolonged to 1.5 hours (range 1 to 3 hours). This difference is not expected to be clinically significant.

Distribution

Cladribine mean apparent volume of distribution ranges from 480 to 490 liters. The plasma protein binding of cladribine is 20% and is independent of concentration, in vitro.

Intracellular concentrations of cladribine and/or its metabolites in human lymphocytes were approximately 30 to 40 times extracellular, in vitro.

Cladribine has the potential to penetrate the blood brain barrier. A cerebrospinal fluid/plasma concentration ratio of approximately 0.25 was observed in cancer patients.

Elimination

Cladribine estimated terminal half-life is approximately 1 day. The intracellular half-life of the cladribine phosphorylated metabolites cladribine monophosphate (Cd-AMP) is 15 hours and Cd-ATP is 10 hours. Cladribine estimated median apparent renal clearance is 22.2 liter per hour and non-renal clearance is 23.4 liter per hour.

Metabolism

Cladribine is a prodrug that is phosphorylated to Cd-AMP by deoxycytidine kinase (and also by deoxyguanosine kinase in the mitochondria) in lymphocytes. Cd-AMP is further phosphorylated to cladribine diphosphate (Cd-ADP) and the active moiety Cd-ATP. The dephosphorylation and deactivation of Cd-AMP is catalyzed by cytoplasmic 5’-nucleotidase (5’-NTase).

The metabolism of cladribine in whole blood has not been fully characterized. However, extensive whole blood and negligible hepatic enzyme metabolism was observed, in vitro.

Excretion

After administration of 10 mg oral cladribine in MS patients, 28.5 [20] (mean [SD]) percent of the dose was excreted unchanged via the renal route. Renal clearance exceeded the glomerular filtration rate, indicating active renal secretion of cladribine.

Specific Populations

No studies have been conducted to evaluate the pharmacokinetics of cladribine in elderly or in patients with renal or hepatic impairment.

There were no clinically significant differences in the pharmacokinetics of cladribine based on age (range 18 to 65 years) or gender. The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown.

Patients With Renal Impairment

Renal clearance of cladribine was shown to be dependent on creatinine clearance (CLCR). No dedicated studies have been conducted in patients with renal impairment, however patients with mild renal impairment (CLCR of 60 mL to below 90 mL per minute) were included in Study 1. A pooled pharmacokinetic analysis estimated a decrease of 18% in total clearance in a typical subject with a CLCR of 65 mL per minute leading to an increase in cladribine exposure of 25%. Clinical experience in patients with moderate to severe renal impairment (i.e., CLCR below 60 mL per minute) is limited [see Use In Specific Populations].

Drug Interaction Studies

Clinical Studies

No clinically significant differences in cladribine pharmacokinetics were observed when used concomitantly with pantoprazole or interferon beta-1a.

In Vitro Studies

It has been reported that lamivudine can inhibit the phosphorylation of cladribine intracellularly. Potential competition for intracellular phosphorylation exists between cladribine and compounds that require intracellular phosphorylation to become active (e.g., lamivudine, zalcitabine, ribavirin, stavudine, and zidovudine).

Cytochrome P450 (CYP) Enzymes: Cladribine is not a substrate of cytochrome P450 enzymes and does not show significant potential to act as inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Cladribine has no clinically meaningful inductive effect on CYP1A2, CYP2B6 and CYP3A4 enzymes.

Transporter Systems: Cladribine is a substrate of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), equilibrative nucleoside transporter 1 (ENT1) and concentrative nucleoside transporter 3 (CNT3). Inhibition of BCRP in the gastrointestinal tract may increase the oral bioavailability and systemic exposure of cladribine. Intracellular distribution and renal elimination of cladribine may be altered by potent ENT1, CNT3 transporter inhibitors.

Hydroxypropyl Betadex-Related Complex Formation

MAVENCLAD contains hydroxypropyl betadex that may be available for complex formation with the active ingredients of other drugs. Complex formation between free hydroxypropyl betadex, released from the cladribine tablet formulation, and concomitant ibuprofen, furosemide, and gabapentin was observed. Concomitant use with MAVENCLAD may increase the bioavailability of other drugs (especially agents with low solubility), which may increase the risk or severity of adverse reactions [see DOSAGE AND ADMINISTRATION].

Clinical Studies

The efficacy of MAVENCLAD was demonstrated in a 96-week randomized, double-blind, placebo-controlled clinical study in patients with relapsing forms of MS (Study 1; NCT00213135).

Patients were required to have at least 1 relapse in the previous 12 months. The median age was 39 years (range 18 to 65) and the female-to-male ratio was approximately 2:1. The mean duration of MS prior to study enrollment was 8.7 years, and the median baseline neurological disability based on Kurtzke Expanded Disability Status Scale (EDSS) score across all treatment groups was 3.0. Over two thirds of the study patients were treatment-naive for drugs used to treat relapsing forms of MS.

1,326 patients were randomized to receive either placebo (n = 437), or a cumulative oral dosage of MAVENCLAD 3.5 mg per kg (n = 433) or 5.25 mg per kg body weight (n = 456) over the 96-week study period in 2 treatment courses. Patients randomized to the 3.5 mg per 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 [see DOSAGE AND ADMINISTRATION]. Patients randomized to the 5.25 mg per kg cumulative dose received additional treatment at Weeks 9 and 13 of the first year. Higher cumulative doses did not add any clinically meaningful benefit, but were associated with a higher incidence in grade 3 lymphopenia or higher (44.9% in the 5.25 mg per kg group vs. 25.6% in the 3.5 mg per kg group). Ninety-two percent of patients treated with MAVENCLAD 3.5 mg per kg and 87% of patients receiving placebo completed the full 96 weeks of the study.

The primary outcome of Study 1 was the annualized relapse rate (ARR). Additional outcome measures included the proportion of patients with confirmed disability progression, the time to first qualifying relapse, the mean number of MRI T1 Gadolinium-enhancing (Gd+) lesions, and new or enlarging MRI T2 hyperintense lesions. Disability progression was measured in terms of a 3-month sustained change in EDSS score of at least one point, if baseline EDSS score was between 0.5 and 4.5 inclusively, or at least 1.5 points if the baseline EDSS score was 0, or at least 0.5 point if the baseline EDSS score was at least 5, over a period of at least 3 months.

MAVENCLAD 3.5 mg per kg significantly lowered the annualized relapse rate. The results from Study 1 are presented in Table 4.

Table 4 : Clinical Outcomes in Study 1 (96 Weeks) -Primary and Secondary Endpoints

Endpoints	MAVENCLAD Cumulative Dose 3.5 mg per kg (n = 433)	Placebo (n = 437)
Clinical Endpoints
Annualized relapse rate (ARR)	0.14*	0.33
Relative reduction in ARR	58%
Proportion of patients without relapse	81%**	63%
Time to 3-month confirmed EDSS progression, HR	0.67**
Proportion of patients with 3-month EDSS progression	13%	19%
MRI Endpoints
Median Number of Active T1 Gd+ Lesions	0*	0.33
Median Number of Active T2 Lesions	0*	0.67
* p < 0.001 compared to placebo ** nominal p < 0.05 compared to placebo HR: Hazard Ratio