Dosage & Administration
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Mavenclad Prescribing Information
- Malignancies
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)].
- Patients with current malignancy.
- Pregnant women, and 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.
- HIV infection.
- Active chronic infections (e.g., hepatitis or tuberculosis).
- History of hypersensitivity to cladribine.
- Women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose.
Treatment with MAVENCLAD may increase the risk of malignancy. In controlled and extension clinical studies worldwide, malignancies occurred more frequently in MAVENCLAD-treated patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)]. Malignancy cases in MAVENCLAD patients included metastatic pancreatic carcinoma, malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo patients, all of which were curable by surgical resection [basal cell carcinoma, cervical carcinoma in situ (2 cases)]. The incidence of malignancies in United States MAVENCLAD clinical study patients was higher than the rest of the world [4 events in 189 patient-years (2.21 events per 100 patient-years) compared to 0 events in United States placebo patients]; however, the United States results were based on a limited amount of patient data.
After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years
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.
- Risk of Teratogenicity
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)].
- Patients with current malignancy.
- Pregnant women, and 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.
- HIV infection.
- Active chronic infections (e.g., hepatitis or tuberculosis).
- History of hypersensitivity to cladribine.
- Women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose.
MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals
In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of MAVENCLAD and prevented by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment
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
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.
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.
In females of reproductive potential, pregnancy should be excluded before the initiation of each treatment course of MAVENCLAD
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
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
Dosage and Administration (Cancer Screening Follow standard cancer screening guidelines because of the risk of malignancies [see Boxed Warningand 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:
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)]
Liver Injury Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course [see Warnings and Precautions (5.7)]. | 5/2024 |
Warnings and Precautions (Serious, including life-threatening or fatal, bacterial, viral, parasitic, and fungal infections have been reported in patients receiving MAVENCLAD. MAVENCLAD reduces the body's immune defense, and an increased risk of infections has been observed in patients receiving MAVENCLAD. Infections occurred in 49% of MAVENCLAD-treated patients compared to 44% of placebo patients in clinical studies; serious or severe infections occurred in 2.4% of MAVENCLAD-treated patients and 2.0% of placebo-treated patients. The most frequent serious infections in MAVENCLAD-treated patients included herpes zoster and pyelonephritis (see Herpes Virus Infections). Fungal infections were observed, including cases of coccidioidomycosis.In the postmarketing setting, serious infections have been reported, including nocardiosis, varicella zoster, histoplasmosis, cryptococcosis, and toxoplasmosis. The majority of patients with these infections who had an available absolute lymphocyte count at the time of the event had concurrent lymphopenia, consistent with the mechanism of action of MAVENCLAD [see Warnings and Precautions (5.3)] .HIV infection, active tuberculosis, and active hepatitis must be excluded before initiation of each treatment course of MAVENCLAD [see Contraindications (4)]. Delay initiation of MAVENCLAD in patients with an acute infection until the infection is fully resolved or controlled. Initiation of MAVENCLAD in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended [see Drug Interactions (7.1)]. Concomitant use of MAVENCLAD with these therapies could increase the risk of immunosuppression.Tuberculosis Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment. Perform tuberculosis screening prior to initiation of the first and second treatment course of MAVENCLAD. Latent tuberculosis infections may be activated with use of MAVENCLAD. In patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has been adequately treated. Hepatitis One clinical study patient died from fulminant hepatitis B infection. Perform screening for hepatitis B and C prior to initiation of the first and second treatment course of MAVENCLAD. Latent hepatitis infections may be activated with use of MAVENCLAD. Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of MAVENCLAD until the infection has been adequately treated. Herpes Virus Infections In controlled clinical studies, 6% of MAVENCLAD-treated patients developed a herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of MAVENCLAD-treated patients. Vaccination of patients who are seronegative for varicella zoster virus is recommended prior to initiation of MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Vaccination with zoster vaccine recombinant, adjuvanted is recommended for patients who are seropositive to VZV, either prior to or during MAVENCLAD treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter. The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter . Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of MAVENCLAD until resolution of the infection. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. 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. No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting. Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first treatment course of MAVENCLAD. At the first sign or symptom suggestive of PML, withhold MAVENCLAD and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms. Vaccinations 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, because of a risk of active vaccine infection (see Herpes Virus Infections). Avoid vaccination with live-attenuated or live vaccines during and after MAVENCLAD treatment while the patient's white blood cell counts are not within normal limits. Mavenclad can cause liver injury. In clinical studies, 0.3% of MAVENCLAD-treated patients had liver injury (serious or causing treatment discontinuation) considered related to treatment, compared to 0 placebo patients. Onset ranged from a few weeks to several months after initiation of treatment with MAVENCLAD. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 20-fold the upper limit of normal, were observed. These abnormalities resolved upon treatment discontinuation. Clinically significant and life-threatening liver injury has been reported in patients treated with MAVENCLAD in the postmarketing setting. Patients with pre-existing liver disease and patients taking other hepatotoxic drugs may be at increased risk for developing liver injury when taking MAVENCLAD. Most reported cases of liver injury associated with MAVENCLAD occurred approximately 30 days after initiation (i.e., course 1, cycle 1) of treatment. MAVENCLAD is not recommended in patients with moderate to severe hepatic impairment (Child-Pugh score greater than 6) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)] .Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course [see Dosage and Administration (2.1)] . If a patient develops clinical signs, including unexplained liver enzyme elevations, or symptoms suggestive of hepatic dysfunction (e.g., unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine), promptly measure serum transaminases and total bilirubin and interrupt or discontinue treatment with MAVENCLAD, as appropriate. | 5/2024 |
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
- Lymphopenia: Monitor lymphocyte counts before, during and after treatment.
- Infections: Serious, including life-threatening and fatal infections, have occurred. Screen patients for active and latent infections; delay treatment until infection is fully resolved or controlled. Vaccination of patients seronegative to varicella zoster virus (VZV) is recommended prior to treatment. Vaccination of patients seropositive to VZV with zoster vaccine recombinant, adjuvanted, is recommended prior to or during treatment. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter. Monitor for infections.
- Hematologic toxicity: Monitor complete blood count before, during and after treatment.
- Graft-versus-host-disease with blood transfusion: Irradiation of cellular blood components is recommended.
- Liver injury: Clinically significant liver injury has occurred. Obtain tests prior to treatment. Discontinue if clinicallysignificant injury is suspected.
Treatment with MAVENCLAD may increase the risk of malignancy. In controlled and extension clinical studies worldwide, malignancies occurred more frequently in MAVENCLAD-treated patients [10 events in 3,754 patient-years (0.27 events per 100 patient-years)], compared to placebo patients [3 events in 2,275 patient-years (0.13 events per 100 patient-years)]. Malignancy cases in MAVENCLAD patients included metastatic pancreatic carcinoma, malignant melanoma (2 cases), ovarian cancer, compared to malignancy cases in placebo patients, all of which were curable by surgical resection [basal cell carcinoma, cervical carcinoma in situ (2 cases)]. The incidence of malignancies in United States MAVENCLAD clinical study patients was higher than the rest of the world [4 events in 189 patient-years (2.21 events per 100 patient-years) compared to 0 events in United States placebo patients]; however, the United States results were based on a limited amount of patient data.
After the completion of 2 treatment courses, do not administer additional MAVENCLAD treatment during the next 2 years
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.
MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals
In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of MAVENCLAD and prevented by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment
MAVENCLAD causes a dose-dependent reduction in lymphocyte count. In clinical studies, 87% of MAVENCLAD-treated patients experienced lymphopenia. The lowest absolute lymphocyte counts occurred approximately 2 to 3 months after the start of each treatment course and were lower with each additional treatment course. In patients treated with a cumulative dose of MAVENCLAD 3.5 mg per kg over 2 courses as monotherapy, 26% and 1% had nadir absolute lymphocyte counts less than 500 and less than 200 cells per microliter, respectively. At the end of the second treatment course, 2% of clinical study patients had lymphocyte counts less than 500 cells per microliter; median time to recovery to at least 800 cells per microliter was approximately 28 weeks.
Additive hematological adverse reactions may be expected if MAVENCLAD is administered prior to or concomitantly with other drugs that affect the hematological profile
Obtain complete blood count (CBC) with differential including lymphocyte count prior to, during, and after treatment with MAVENCLAD.
Initiation of MAVENCLAD in patients currently receiving immunosuppressive or myelosuppressive therapy is not recommended
Three of 1,976 (0.2%) cladribine-treated patients in the clinical program developed tuberculosis. All three cases occurred in regions where tuberculosis is endemic. One case of tuberculosis was fatal, and two cases resolved with treatment.
Perform tuberculosis screening prior to initiation of the first and second treatment course of MAVENCLAD. Latent tuberculosis infections may be activated with use of MAVENCLAD. In patients with tuberculosis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.
One clinical study patient died from fulminant hepatitis B infection. Perform screening for hepatitis B and C prior to initiation of the first and second treatment course of MAVENCLAD. Latent hepatitis infections may be activated with use of MAVENCLAD. Patients who are carriers of hepatitis B or C virus may be at risk of irreversible liver damage caused by virus reactivation. In patients with hepatitis infection, delay initiation of MAVENCLAD until the infection has been adequately treated.
In controlled clinical studies, 6% of MAVENCLAD-treated patients developed a herpes viral infection compared to 2% of placebo patients. The most frequent types of herpes viral infections were herpes zoster infections (2.0% vs. 0.2%) and oral herpes (2.6% vs. 1.2%). Serious herpes zoster infections occurred in 0.2% of MAVENCLAD-treated patients.
Vaccination of patients who are seronegative for varicella zoster virus is recommended prior to initiation of MAVENCLAD. Administer live-attenuated or live vaccines at least 4 to 6 weeks prior to starting MAVENCLAD. Vaccination with zoster vaccine recombinant, adjuvanted is recommended for patients who are seropositive to VZV, either prior to or during MAVENCLAD treatment, including when their lymphocyte counts are less than or equal to 500 cells per microliter.
The incidence of herpes zoster was higher during the period of absolute lymphocyte count less than 500 cells per microliter, compared to the time when the patients were not experiencing this degree of lymphopenia. Administer anti-herpes prophylaxis in patients with lymphocyte counts less than 200 cells per microliter
Patients with lymphocyte counts below 500 cells per microliter should be monitored for signs and symptoms suggestive of infections, including herpes infections. If such signs and symptoms occur, initiate treatment as clinically indicated. Consider interruption or delay of MAVENCLAD until resolution of the infection.
Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. 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.
No case of PML has been reported in clinical studies of cladribine in patients with multiple sclerosis. In patients treated with parenteral cladribine for oncologic indications, cases of PML have been reported in the postmarketing setting.
Obtain a baseline (within 3 months) magnetic resonance imaging (MRI) before initiating the first treatment course of MAVENCLAD. At the first sign or symptom suggestive of PML, withhold MAVENCLAD and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.
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, because of a risk of active vaccine infection
In addition to lymphopenia
In clinical studies at dosages similar to or higher than the approved MAVENCLAD dosage, serious cases of thrombocytopenia, neutropenia, and pancytopenia (some with documented bone marrow hypoplasia) requiring transfusion and granulocyte-colony stimulating factor treatment have been reported
Obtain complete blood count (CBC) with differential prior to, during, and after treatment with MAVENCLAD
Transfusion-associated graft-versus-host disease has been observed rarely after transfusion of nonirradiated blood in patients treated with cladribine for non-MS treatment indications.
In patients who require blood transfusion, irradiation of cellular blood components is recommended prior to administration to decrease the risk of transfusion-related graft-versus-host disease. Consultation with a hematologist is advised.
In clinical studies, 11% of MAVENCLAD-treated patients had hypersensitivity reactions, compared to 7% of placebo patients. Hypersensitivity reactions that were serious and/or led to discontinuation of MAVENCLAD (e.g., dermatitis, pruritus) occurred in 0.5% of 13 MAVENCLAD-treated patients, compared to 0.1% of placebo patients. One patient had a serious hypersensitivity reaction with rash, mucous membrane ulceration, throat swelling, vertigo, diplopia, and headache after the first dose of MAVENCLAD.
If a hypersensitivity reaction is suspected, discontinue MAVENCLAD therapy. Do not use MAVENCLAD in patients with a history of hypersensitivity to cladribine
In clinical studies, one MAVENCLAD-treated patient experienced life-threatening acute cardiac failure with myocarditis, which improved after approximately one week. Cases of cardiac failure have also been reported with parenteral cladribine used for treatment indications other than multiple sclerosis.
Instruct patients to seek medical advice if they experience symptoms of cardiac failure (e.g., shortness of breath, rapid or irregular heartbeat, swelling).
- Assessments are required prior to starting each MAVENCLAD treatment course. ()
2.1 Assessments Prior to Starting Each MAVENCLAD Treatment CourseCancer ScreeningFollow standard cancer screening guidelines because of the risk of malignancies
[see Boxed Warningand Warnings and Precautions (5.1)].PregnancyExclude 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 InjuryObtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to each treatment cycle and course[see Warnings and Precautions (5.7)]. - Cumulative dosage of 3.5 mg/kg administered orally and divided into 2 treatment courses (1.75 mg/kg per treatment course). Each treatment course is divided into 2 treatment cycles. ()
2.2 Recommended DosageThe 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 40The use of MAVENCLAD in patients weighing less than 40 kg has not been investigated.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. - MAVENCLAD is a cytotoxic drug. ()
2.4 AdministrationMAVENCLAD 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.
- Separate administration from any other oral drug by at least 3 hours. ()
2.4 AdministrationMAVENCLAD 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.
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 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
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.
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)].
- Patients with current malignancy.
- Pregnant women, and 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.
- HIV infection.
- Active chronic infections (e.g., hepatitis or tuberculosis).
- History of hypersensitivity to cladribine.
- Women intending to breastfeed on a MAVENCLAD treatment day and for 10 days after the last dose.
MAVENCLAD may cause fetal harm when administered to pregnant women. Malformations and embryolethality occurred in animals
In females of reproductive potential, pregnancy should be excluded before initiation of each treatment course of MAVENCLAD and prevented by the use of effective contraception during MAVENCLAD dosing and for at least 6 months after the last dose of each treatment course. Women who become pregnant during treatment with MAVENCLAD should discontinue treatment
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.