The Food and Drug Administration has approved two new oral drugs, cladribine (Mavenclad) and siponimod (Mayzent), to treat multiple sclerosis (MS).
Cladribine. Cladribine is approved for adults with relapsing forms of MS, including relapsing-remitting MS (in which periods of worsening function are followed by periods of recovery) and active secondary progressive MS (in which disability progresses independently of relapses). Cladribine is recommended for patients who have been unable to tolerate or who haven't been successfully managed with other MS therapy.
For the treatment of MS, cladribine is given orally once daily for four or five consecutive days twice a year. An intravenous form of the drug is approved for treating hairy cell leukemia; the two preparations are not interchangeable. Cladribine's therapeutic effect on MS is believed to involve cytotoxic effects on B and T lymphocytes.
A 96-week, randomized, double-blind, placebo-controlled clinical study of cladribine included 1,326 patients with MS who had experienced, at minimum, one relapse in the last year. Cladribine significantly reduced the number of relapses and the progression of disability compared with placebo.
Cladribine carries a black box warning that it can increase the risk of malignancy and fetal harm. It also carries warnings that it can decrease lymphocyte count and cause hematologic toxicity and bone marrow suppression, increase the risk of infections (the most common serious infections in clinical trials were herpes zoster and pyelonephritis; fatal cases of tuberculosis and hepatitis B or C also occurred), increase the risk of graft-versus-host disease following blood transfusions with nonirradiated blood, and cause liver injury. More rarely, cladribine also produced hypersensitivity reactions (in 11% of patients) and heart failure (in one patient).
The most common adverse effects of cladribine (seen in more than 20% of patients) include respiratory tract infections, headache, and decreased lymphocyte count. The lowest absolute lymphocyte count occurs approximately two to three months after each treatment cycle begins.
Cladribine is contraindicated in patients with current malignancy, HIV infection, active chronic infections (tuberculosis, hepatitis), and history of hypersensitivity to cladribine. It is also contraindicated in pregnant women, patients who don't plan to use effective birth control during treatment, and women intending to breastfeed on a treatment day or for 10 days after the last dose of a treatment cycle.
Prior to starting treatment with cladribine, patient assessment should include standard cancer screening, a pregnancy test, a complete blood count (CBC) including lymphocyte count, screening for latent infections (HIV, tuberculosis, hepatitis B or C), and liver enzyme levels. Lymphocyte counts need to be monitored during therapy and a CBC may be indicated yearly after the treatment course. Prior to starting treatment, patients should receive all needed vaccinations.
Cladribine must be taken immediately once the blister pack is opened. Patients should place the pill in their mouth with clean, dry hands and swallow it whole with water. Patients should not receive any other oral drug for at least three hours. After administration, patients should wash their hands and avoid touching their nose, eyes, and skin until they have done so.
For complete prescribing information, see http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022561s000lbl.pdf.
Siponimod. Siponimod is approved to treat adults with relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting MS, and active secondary progressive MS. The drug is taken orally daily. Siponimod blocks the ability of lymphocytes to leave the lymph nodes, thus decreasing the number of lymphocytes in the peripheral blood. Its effect on MS is believed to be related to this action.
A randomized, double-blind, placebo-controlled, parallel-group study of siponimod included 1,651 patients with secondary progressive MS and disability progression who hadn't experienced a relapse within three months of starting the trial. Results showed that those receiving siponimod were less likely to progress in their disability or experience a relapse than those receiving placebo.
Siponimod carries the risk of serious adverse effects but has no black box warnings. The drug may increase the risk of infections; produce a decline in pulmonary function; elevate blood pressure; and cause fetal harm, liver injury, macular edema, and transient decreases in heart rate (bradyarrhythmias and atrioventricular [AV] conduction delays, most common when first starting therapy). It may also increase the risk of posterior reversible encephalopathy syndrome. The most common adverse effects of siponimod (seen in more than 10% of patients) include headache, high blood pressure, and elevations in liver enzymes.
Siponimod is contraindicated in people with the cytochrome P-450 2C9*3/*3 genotype, because its presence decreases siponimod metabolism, significantly raising circulating levels of the drug. Siponimod is also contraindicated in patients who have experienced myocardial infarction; unstable angina; stroke; transient ischemic attack; severe heart failure; or some types of AV block, or sick sinus syndrome (unless there is a functioning pacemaker).
Prior to patients starting siponimod, assessment should include genotype testing, CBC to rule out infection, spirometry tests, an electrocardiogram (ECG) for preexisiting conduction problems, a cardiology consult (if the patient receives other drugs that decrease heart rate), liver enzymes, and blood pressure. Women of childbearing age should use effective contraception. Vaccinations should be up to date.
The first dose of siponimod should be given in a health care setting. The patient should be monitored for six hours afterward for signs and symptoms of bradycardia. An ECG should be completed after six hours. If heart rate is less than 45 beats per minute or the patient hasn't recovered from its lowest postdose value, or there is new-onset second-degree or higher AV block, the patient requires treatment and further monitoring.
Patients should be instructed to call their health care provider if they have symptoms of bradycardia or infection and to see a physician for any vision changes (patients with diabetes or a history of uveitis may be at increased risk for macular edema).
For complete prescribing information, see: http://www.accessdata.fda.gov/drugsatfda_docs/label/2019/209884s000lbl.pdf.