Brand Name
Mavenclad
Generic Name
Cladribine
View Brand Information FDA approval date: February 28, 2000
Classification: Purine Antimetabolite
Form: Injection, Tablet
What is Mavenclad (Cladribine)?
MAVENCLAD is indicated for the treatment of relapsing forms of multiple sclerosis , 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. Limitations of Use MAVENCLAD is not recommended for use in patients with clinically isolated syndrome because of its safety profile. MAVENCLAD is a purine antimetabolite indicated for the treatment of relapsing forms of multiple sclerosis , 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. Limitations of Use MAVENCLAD is not recommended for use in patients with clinically isolated syndrome because of its safety profile.
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Brand Information
Mavenclad (Cladribine)
WARNING: MALIGNANCIES AND RISK OF TERATOGENICITY
- Malignancies
- Risk of Teratogenicity .
1INDICATIONS AND USAGE
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
Limitations of Use
MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile
2DOSAGE 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.
3CONTRAINDICATIONS
MAVENCLAD is contraindicated:
- in patients with current malignancy
- in pregnant women and in females and males 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 for females, and 14 weeks for males. May cause fetal harm
- in patients infected with the human immunodeficiency virus (HIV
- in patients with active chronic infections (e.g., hepatitis or tuberculosis)
- in patients with a history of hypersensitivity to cladribine
- in females intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose
4ADVERSE REACTIONS
The following serious adverse reactions and potential risks are discussed, or discussed in greater detail, in other sections of the labeling:
- Malignancies
- Risk of Teratogenicity
- Lymphopenia
- Infections
- Hematologic Toxicity
- Graft-Versus-Host Disease With Blood Transfusion
- Liver Injury
- Hypersensitivity
- Cardiac Failure
4.1Clinical 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
Hypersensitivity
In clinical studies, 11% of MAVENCLAD patients had hypersensitivity adverse reactions, compared to 7% of placebo patients
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.
4.2Postmarketing Experience
The following adverse reactions have been identified during postapproval use of MAVENCLAD. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Infections and Infestations: nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis
Hepatobiliary Disorders: liver injury
5OVERDOSAGE
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
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.
6DESCRIPTION
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.
7CLINICAL 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
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
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.
8REFERENCES
- "OSHA Hazardous Drugs". OSHA.
9PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Malignancies
Inform patients that MAVENCLAD may increase their risk of malignancies. Instruct patients to follow standard cancer screening guidelines
Risk of Teratogenicity
Inform patients that MAVENCLAD may cause fetal harm. Discuss with females of reproductive potential whether they are pregnant, might be pregnant, or are trying to become pregnant. Before initiating each treatment course, inform patients about the potential risk to the fetus if female patients or partners of male patients get pregnant during MAVENCLAD dosing or within 6 months after the last dose for female patients, and within 14 weeks after the last dose for male patients, in each treatment course
Instruct females of reproductive potential to use effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose in each treatment course to avoid pregnancy.
Instruct males of reproductive potential to take precautions to prevent pregnancy of their partner during MAVENCLAD dosing and for at least 14 weeks after the last dose in each treatment course.
Advise patients that female patients or partners of male patients who get pregnant to immediately inform their healthcare provider.
Advise patients that there is a pregnancy safety study that monitors the pregnancy outcomes in female patients exposed to cladribine during pregnancy or within 6 months before conception, as well as pregnancies fathered by male patients exposed to cladribine within 14 weeks before conception, and they can report the pregnancy by calling EMD Serono's Adverse Event reporting line at 1-800-283-8088 ext. 5563 or by faxing 1-781-681-2961
Lactation
Inform women that they cannot breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose
Lymphopenia and Other Hematologic Toxicity
Inform patients that MAVENCLAD decreases lymphocyte counts and may also decrease counts of other blood cells. A blood test should be obtained before starting a treatment course, 2 and 6 months after start of treatment in each treatment course, periodically thereafter, and when clinically needed. Advise patients to keep all appointments for lymphocyte monitoring during and after MAVENCLAD treatment
Infections
Inform patients that infections, some of which were serious, have been reported in patients receiving MAVENCLAD. Instruct patients to notify their healthcare provider promptly if fever or other signs of infection such as aching, painful muscles, headache, generally feeling unwell or loss of appetite occur while on therapy or after a course of treatment
Advise patients that PML has happened with parenteral cladribine used in oncologic indications. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes
Advise patients that some vaccines containing live virus (live attenuated vaccines) should be avoided during and after treatment with MAVENCLAD. Advise patients to complete any live or live-attenuated vaccinations at least 4 to 6 weeks prior to initiation of MAVENCLAD. Instruct patients to contact their healthcare provider prior to receiving any vaccinations.
Liver Injury
Inform patients that liver injury has been reported in patients receiving MAVENCLAD. Instruct patients treated with MAVENCLAD to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. A blood test should be obtained prior to each treatment cycle and course with MAVENCLAD and as clinically indicated thereafter
Hypersensitivity
Advise patients to seek immediate medical attention if they experience any symptoms of serious or severe hypersensitivity reactions, including skin reactions
Cardiac Failure
Advise patients that MAVENCLAD may cause cardiac failure. Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling)
Treatment Handling and Administration
Instruct patients that MAVENCLAD is a cytotoxic drug and to use care when handling MAVENCLAD tablets, limit direct skin contact with the tablets, and wash exposed areas thoroughly. Advise patients to keep the tablets in the original package until just prior to each scheduled dose and consult their pharmacist on the proper disposal of unused tablets
10PRINCIPAL DISPLAY PANEL - 4 Tablet Blister Pack Carton
NDC 44087-4000-4
MAVENCLAD
Contents:
Dosage and Administration:
Separate ingestion of other oral medicines by at
Cytotoxic Agent:
Dispense with enclosed Medication Guide.
Rx Only
4 Tablets
EMD
