Dosage & Administration
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Mavenclad Prescribing Information
- Malignancies
Treatment with MAVENCLAD may increase the risk of malignancy. MAVENCLAD is contraindicated in patients with current malignancy. In patients with prior malignancy or with increased risk of malignancy, evaluate the benefits and risks of the use of MAVENCLAD on an individual patient basis. Follow standard cancer screening guidelines in patients treated with MAVENCLAD [see Contraindications (4) and Warnings and Precautions (5.1)].
- Risk of Teratogenicity
MAVENCLAD is contraindicated for use in pregnant women and in women and men of reproductive potential who do not plan to use effective contraception because of the potential for fetal harm. Malformations and embryolethality occurred in animals. Exclude pregnancy before the start of treatment with MAVENCLAD in females of reproductive potential. Advise females and males of reproductive potential to use effective contraception during MAVENCLAD dosing and for 6 months after the last dose in each treatment course. Stop MAVENCLAD if the patient becomes pregnant [see Contraindications (4), Warnings and Precautions (5.2), and Use in Specific Populations (8.1, 8.3)].
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 (5)].
Limitations of Use
MAVENCLAD is not recommended for use in patients with clinically isolated syndrome (CIS) because of its safety profile [see Warnings and Precautions (5)].
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 (5.1)].
Pregnancy
Exclude pregnancy prior to treatment with MAVENCLAD in females of reproductive potential [see Contraindications (4), Warnings and Precautions (5.2), and Use in Specific Populations (8.1, 8.3)].
Complete Blood Count (CBC)
Obtain a CBC with differential including lymphocyte count [see Dosage and Administration (2.5) and Warnings and Precautions (5.3)]. 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 (5.4)]
- 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 prior to each treatment cycle and course [see Warnings and Precautions (5.7)].
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.
| 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) |
Administer the cycle dosage as 1 or 2 tablets once daily over 4 or 5 consecutive days [see How Supplied/Storage and Handling (16.1)]. 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 (5.1)]. 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 (12.6)].
MAVENCLAD is a cytotoxic drug. Follow applicable special handling and disposal procedures [see References (15)]. 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 (2.1) and Warnings and Precautions (5.1)].
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 (5.3, 5.4) 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 (5.5)]
Recommended Concomitant Medication
Herpes Prophylaxis
Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter [see Warnings and Precautions (5.4)].
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.
Pregnancy
Risk Summary
MAVENCLAD is contraindicated in pregnant women and in females and males of reproductive potential who do not plan to use effective contraception. There are no adequate data on the developmental risk associated with use of MAVENCLAD in pregnant women. Cladribine was embryolethal when administered to pregnant mice and produced malformations in mice and rabbits [see Data]. The observed developmental effects are consistent with the effects of cladribine on DNA [see Contraindications (4) and Warnings and Precautions (5.2)].
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.
There is a pregnancy safety study that monitors the pregnancy and infant outcomes following exposure to cladribine. Physicians and patients are encouraged to report pregnancies of women with multiple sclerosis exposed to oral cladribine during pregnancy or within 6 months before conception as well as pregnancies fathered by men with multiple sclerosis who had taken oral cladribine within 6 months before conception by calling EMD Serono's Adverse Event reporting line at 1-800-283-8088 ext. 5563 or by faxing 1-781-681-2961.
Data
Animal Data
When cladribine was administered intravenously (0, 0.5, 1.5, or 3 mg/kg/day) to pregnant mice during the period of organogenesis, fetal growth retardation and malformations (including exencephaly and cleft palate) and embryofetal death were observed at the highest dose tested. An increase in skeletal variations was observed at all but the lowest dose tested. There was no evidence of maternal toxicity.
When cladribine was administered intravenously (0, 0.3, 1, and 3 mg/kg/day) to pregnant rabbits during the period of organogenesis, fetal growth retardation and a high incidence of craniofacial and limb malformations were observed at the highest dose tested, in the absence of maternal toxicity.
When cladribine was administered intravenously (0, 0.5, 1.5, or 3.0 mg/kg/day) to mice throughout pregnancy and lactation, skeletal anomalies and embryolethality were observed at all but the lowest dose tested.
Lactation
Risk Summary
MAVENCLAD is contraindicated in breastfeeding women because of the potential for serious adverse reactions in breastfed infants [see Contraindications (4) and Warnings and Precautions (5)]. Advise women not to breastfeed during dosing with MAVENCLAD and for 10 days after the last dose.
There are no data on the presence of cladribine in human milk, the effects on the breastfed infant, or the effects of the drug on milk production.
Females and Males of Reproductive Potential
Pregnancy Testing
In females of reproductive potential, pregnancy should be excluded before the initiation of each treatment course of MAVENCLAD [see Use in Specific Populations (8.1)].
Contraception
Females
Females of reproductive potential should prevent pregnancy by use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose in each treatment course. Women who become pregnant during MAVENCLAD therapy should discontinue treatment [see Warnings and Precautions (5.2)].
Males
As cladribine interferes with DNA synthesis, adverse effects on human gametogenesis could be expected. Therefore, male patients of reproductive potential should take precautions to prevent pregnancy of their partner during MAVENCLAD dosing and for at least 6 months after the last dose in each treatment course [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1)].
Pediatric Use
The safety and effectiveness in pediatric patients (below 18 years of age) have not been established. Use of MAVENCLAD is not recommended in pediatric patients because of the risk of malignancies [see Warnings and Precautions (5.1)].
Geriatric Use
Clinical studies with MAVENCLAD did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Caution is recommended when MAVENCLAD is used in elderly patients, taking into account the potential greater frequency of decreased hepatic, renal, or cardiac function, concomitant diseases, and other drug therapy.
Patients with Renal Impairment
The concentration of cladribine is predicted to increase in patients with renal impairment [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild renal impairment (creatinine clearance 60 to 89 mL per minute). MAVENCLAD is not recommended in patients with moderate to severe renal impairment (creatinine clearance below 60 mL per minute) [see Clinical Pharmacology (12.3)].
Patients with Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of cladribine is unknown [see Clinical Pharmacology (12.3)]. No dosage adjustment is recommended in patients with mild hepatic impairment. MAVENCLAD is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].
MAVENCLAD is contraindicated:
- in patients with current malignancy [see Warnings and Precautions (5.1)].
- 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 (5.2) and Use in Specific Populations (8.1, 8.3)].
- in patients infected with the human immunodeficiency virus (HIV) [see Warnings and Precautions (5.4)].
- in patients with active chronic infections (e.g., hepatitis or tuberculosis) [see Warnings and Precautions (5.4)].
- in patients with a history of hypersensitivity to cladribine [see Warnings and Precautions (5.8)].
- in women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose [see Use in Specific Populations (8.2)].