DIMETHYL FUMARATE- dimethyl fumarate capsule, delayed release
Amneal Pharmaceuticals NY LLC
Dimethyl fumarate delayed-release capsules are indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
The starting dose for dimethyl fumarate delayed-release capsules are 120 mg twice a day orally. After 7 days, the dose should be increased to the maintenance dose of 240 mg twice a day orally. Temporary dose reductions to 120 mg twice a day may be considered for individuals who do not tolerate the maintenance dose. Within 4 weeks, the recommended dose of 240 mg twice a day should be resumed. Discontinuation of dimethyl fumarate delayed-release capsules should be considered for patients unable to tolerate return to the maintenance dose. The incidence of flushing may be reduced by administration of dimethyl fumarate delayed-release capsules with food. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to dimethyl fumarate delayed-release capsules dosing may reduce the incidence or severity of flushing [see Clinical Pharmacology (12.3)].
Dimethyl fumarate delayed-release capsules should be swallowed whole and intact. Dimethyl fumarate delayed-release capsules should not be crushed or chewed and the capsule contents should not be sprinkled on food. Dimethyl fumarate delayed-release capsules can be taken with or without food.
Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of therapy [see Warnings and Precautions (5.4)].
Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with dimethyl fumarate delayed-release capsules [see Warnings and Precautions (5.5)].
Dimethyl fumarate delayed-release capsules are available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate.
Dimethyl Fumarate Delayed-Release Capsules, 120 mg have an opaque green cap printed “AN” on cap with black ink and opaque white body printed “1318” on body with black ink.
Dimethyl Fumarate Delayed-Release Capsules, 240 mg have an opaque green cap printed “AN” on cap with black ink and opaque green body printed “1319” on body with black ink.
Dimethyl fumarate delayed-release capsule are contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of dimethyl fumarate delayed-release capsule. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.1)].
Dimethyl fumarate can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue. Patients should be instructed to discontinue dimethyl fumarate and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.
Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with dimethyl fumarate. 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. A fatal case of PML occurred in a patient who received dimethyl fumarate for 4 years while enrolled in a clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly < 0.5×109 /L for 3.5 years) while taking dimethyl fumarate [see Warnings and Precautions (5.4)]. The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.
PML has also occurred in the postmarketing setting in the presence of lymphopenia (< 0.9×109 /L). While the role of lymphopenia in these cases is uncertain, the PML cases have occurred predominantly in patients with lymphocyte counts < 0.8x 109 /L persisting for more than 6 months.
At the first sign or symptom suggestive of PML, withhold dimethyl fumarate and perform an appropriate diagnostic evaluation. 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.
MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.
Serious cases of herpes zoster have occurred with dimethyl fumarate, including disseminated herpes zoster, herpes zoster ophthalmicus, herpes zoster meningoencephalitis, and herpes zoster meningomyelitis. These events may occur at any time during treatment. Monitor patients on dimethyl fumarate for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered.
Other serious opportunistic infections have occurred with dimethyl fumarate, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections. These infections have been reported in patients with reduced absolute lymphocyte counts (ALC) as well as in patients with normal ALC. These infections have affected the brain, meninges, spinal cord, gastrointestinal tract, lungs, skin, eye, and ear. Patients with symptoms and signs consistent with any of these infections should undergo prompt diagnostic evaluation and receive appropriate treatment.
Consider withholding dimethyl fumarate treatment in patients with herpes zoster or other serious infections until the infection has resolved [see Adverse Reactions (6.2)].
Dimethyl fumarate may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with dimethyl fumarate and then remained stable. Four weeks after stopping dimethyl fumarate, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of dimethyl fumarate patients and < 1% of placebo patients experienced lymphocyte counts < 0.5×109 /L (lower limit of normal 0.91×109 /L). The incidence of infections (60% vs. 58%) and serious infections (2% vs. 2%) was similar in patients treated with dimethyl fumarate or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts < 0.8×109 /L or ≤ 0.5×109 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly < 0.5×109 /L for 3.5 years) [see Warnings and Precautions (5.2)].
In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts < 0.5 x 109 /L for at least six months, and in this group the majority of lymphocyte counts remained < 0.5×109 /L with continued therapy. Dimethyl fumarate has not been studied in patients with pre-existing low lymphocyte counts.
Obtain a CBC, including lymphocyte count, before initiating treatment with dimethyl fumarate, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of dimethyl fumarate in patients with lymphocyte counts less than 0.5 x 109 /L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if dimethyl fumarate is discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution. Decisions about whether or not to restart dimethyl fumarate should be individualized based on clinical circumstances.
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