tion and renalelimination of cladribine may be altered by potent ENT1, CNT3 transporter inhibitors.
12.6 Hydroxypropyl Betadex-Related Complex Formation
MAVENCLAD contains hydroxypropyl betadex that may be available for complex formationwith the active ingredients of other drugs. Complex formation between free hydroxypropylbetadex, released from the cladribine tablet formulation, and concomitant ibuprofen, furosemide,and gabapentin was observed. Concomitant use with MAVENCLAD may increase thebioavailability of other drugs (especially agents with low solubility), which may increase the riskor severity of adverse reactions [see Dosage and Administration (2.4)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In mice administered cladribine (0, 0.1, 1, or 10 mg/kg) by subcutaneous injection intermittently(7 daily doses followed by 21 days of non-dosing per cycle) for 22 months, an increase inHarderian gland tumors (adenoma) was observed at the highest dose tested.
Mutagenesis
Cladribine was negative for mutagenicity in in vitro (reverse mutation in bacteria, CHO/HGPRTmammalian cell) assays.
Cladribine was positive for clastogenicity in an in vitro mammalian cell assay, in the absence andpresence of metabolic activation, and in an in vivo mousemicronucleus assay.
Impairment of Fertility
When cladribine (0, 1, 5, 10, or 30 mg/kg/day) was administered by subcutaneous injection tomale mice prior to and during mating to untreated females, no effects on fertility were observed.
However, an increase in non-motile sperm was observed at the highest dose tested. In femalemice, administration of cladribine (0, 1, 2, 4, or 8 mg/kg/day) by subcutaneous injection prior toand during mating to untreated males and continuing to gestation day 6 caused an increase inembryolethality at the highest dose tested.
In monkeys administered cladribine (0, 0.15, 0.3, or 1.0 mg/kg) by subcutaneous injectionintermittently (7 consecutive daily doses followed by 21 days of non-dosing per cycle) for oneyear, testicular degeneration was observed at the highest dose tested.
14 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 was39 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 neurologicaldisability based on Kurtzke Expanded Disability Status Scale (EDSS) score across all treatmentgroups was 3.0. Over two thirds of the study patients were treatment-naive for drugs used to treatrelapsing forms of MS.
1,326 patients were randomized to receive either placebo (n = 437), or a cumulative oral dosageof MAVENCLAD 3.5 mg per kg (n = 433) or 5.25 mg per kg body weight (n = 456) over the96-week study period in 2 treatment courses. Patients randomized to the 3.5 mg per kgcumulative dose received a first treatment course at Weeks 1 and 5 of the first year and a secondtreatment course at Weeks 1 and 5 of the second year [see Dosage and Administration (2.2)].
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 meaningfulbenefit, but were assoc |
