CinnoTec®


(Dimethyl Fumarate)


Description

CINNOTEC contains dimethyl fumarate which is also known by its chemical name, dimethyl (E) butenedioate, (C6H8O4). It has the following structure:

Dimethyl fumarate is a white to off-white powder that is highly soluble in water with a molecular mass of 144.13.

CINNOTEC is provided as hard gelatin delayed-release capsules for oral administration, containing 120 mg or 240 mg of dimethyl fumarate consisting of the following inactive ingredients: microcrystalline cellulose, silicified microcrystalline cellulose, croscarmellose sodium, talc, silica colloidal silicon dioxide, magnesium stearate, triethyl citrate, methacrylic acid copolymer - Type A, methacrylic acid copolymer dispersion, simethicone (30% emulsion), sodium lauryl sulphate, and polysorbate 80. The capsule shell, printed with black ink, contains the following inactive ingredients: gelatin, titanium dioxide, FD&C blue 1; brilliant blue FCF, yellow iron oxide and black iron oxide.

Dosage Forms and Strengths

CINNOTEC is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate.

Indication and Usage

CINNOTEC is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

Dosage and Administration

Dosing Information

The starting dose for CINNOTEC is 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. CINNOTEC should be swallowed whole and intact. CINNOTEC should not be crushed or chewed and the capsule contents should not be sprinkled on food. CINNOTEC can be taken with or without food.

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 CINNOTEC should be considered for patients unable to tolerate return to the maintenance dose. The incidence of flushing may be reduced by administration of CINNOTEC with food. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to CINNOTEC dosing may reduce the incidence or severity of flushing.

Blood Test Prior to Initiation of Therapy

Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of therapy.

Contraindications

CINNOTEC is contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of CINNOTEC. Reactions have included anaphylaxis and angioedema.

Warning and Precautions

Anaphylaxis and Angioedema

CINNOTEC 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 CINNOTEC and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.

Progressive Multifocal Leukoencephalopathy

A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received CINNOTEC for 4 years while enrolled in a clinical trial. 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. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years) while taking CINNOTEC. The role of lymphopenia in this case is unknown. 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. At the first sign or symptom suggestive of PML, withhold CINNOTEC 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.

Lymphopenia

CINNOTEC may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with CINNOTEC and then remained stable. Four weeks after stopping CINNOTEC, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of CINNOTEC patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with CINNOTEC or placebo, respectively. There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or 0.5x109/L in controlled trials, although one patient in an

with lymphocyte counts <0.8x10 /L or 0.5x10 /L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years). In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5 x 109/L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x109/L with continued therapy. CINNOTEC has not been studied in patients with pre-existing low lymphocyte counts.

Before initiating treatment with CINNOTEC, a CBC including lymphocyte count should be obtained. A CBC including lymphocyte count should also be obtained after 6 months of treatment, every 6 to 12

months thereafter, and as clinically indicated. Consider interruption of CINNOTEC in patients with lymphocyte counts <0.5 x 109/L persisting for more than six months. Given the potential for delay in lymphocyte recovery after discontinuation of CINNOTEC, consider following lymphocyte counts until lymphopenia is resolved. Withholding treatment should be considered in patients with serious infections until the infection(s) is resolved. Decisions about whether or not to restart CINNOTEC should be individualized based on clinical circumstances.

Flushing

CINNOTEC may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of CINNOTEC treated patients experienced flushing. Flushing symptoms generally began soon after initiating CINNOTEC and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued CINNOTEC for flushing and <1% had serious flushing symptoms that were not lifethreatening but led to hospitalization. Administration of CINNOTEC with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to CINNOTEC dosing may reduce the incidence or severity of flushing.

Adverse Reactions / Side Effects

>10%:

Cardiovascular: Flushing (40%)

Gastrointestinal: Abdominal pain (18%), diarrhea (14%), nausea (12%)

Infection: Infection (60%; placebo: 58%)

1% to 10%:

Dermatologic: Pruritus (8%), skin rash (8%), erythema (5%)

Gastrointestinal: Vomiting (9%), dyspepsia (5%)

Genitourinary: Proteinuria (6%)

Hematologic: Lymphocytopenia (2% to 6%)

Hepatic: Increased serum AST (4%)

<1% (Limited to important or life-threatening: Anaphylaxis, angioedema, eosinophilia (transient), progressive multifocal leukoencephalopathy

Use in Specific Populations

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of CINNOTEC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Pregnancy and Lactation

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. CINNOTEC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD.

Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD.

Pregnancy Registry

There is a pregnancy registry that monitors pregnancy outcomes in women exposed to CINNOTEC during pregnancy. Encourage patients to enroll by calling 1-866-810-1462 or visiting www.CinnoTecpregnancyregistry.com.

Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when CINNOTEC is administered to a nursing woman.

Clinical Pharmacology

Mechanism of Action

The mechanism by which dimethyl fumarate (DMF) exerts its therapeutic effect in multiple sclerosis is unknown. DMF and the metabolite, monomethyl fumarate (MMF), have been shown to activate the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in vitro and in vivo in animals and humans. The Nrf2 pathway is involved in the cellular response to oxidative stress. MMF has been identified as a nicotinic acid receptor agonist in vitro.

Pharmacodynamics

Potential to prolong the QT interval

In a placebo controlled thorough QT study performed in healthy subjects, there was no evidence that dimethyl fumarate caused QT interval prolongation of clinical significance (i.e., the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 ms).

Pharmacokinetics

After oral administration of CINNOTEC, dimethyl fumarate undergoes rapid presystemic hydrolysis by esterases and is converted to its active metabolite, monomethyl fumarate (MMF). Dimethyl fumarate is not quantifiable in plasma following oral administration of CINNOTEC. Therefore all pharmacokinetic analyses related to CINNOTEC were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.

 

Non-Clinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of dimethyl fumarate (DMF) were conducted in mice and rats. In mice, oral administration of DMF (25, 75, 200, and 400 mg/kg/day) for up to two years resulted in an increase in nonglandular stomach (forestomach) and kidney tumors: squamous cell carcinomas and papillomas of the forestomach in males and females at 200 and 400 mg/kg/day; leiomyosarcomas of the forestomach at 400 mg/kg/day in males and females; renal tubular adenomas and carcinomas at 200 and 400 mg/kg/day in males; and renal tubule adenomas at 400 mg/kg/day in females. Plasma MMF exposure (AUC) at the highest dose not associated with tumors in mice (75 mg/kg/day) was similar to that in humans at the recommended human dose (RHD) of 480 mg/day.

In rats, oral administration of DMF (25, 50, 100, and 150 mg/kg/day) for up to two years resulted in increases in squamous cell carcinomas and papillomas of the forestomach at all doses tested in males and females, and in testicular interstitial (Leydig) cell adenomas at 100 and 150 mg/kg/day. Plasma MMF AUC at the lowest dose tested was lower than that in humans at the RHD.

Mutagenesis

Dimethyl fumarate (DMF) and monomethyl fumarate (MMF) were not mutagenic in the in vitro bacterial reverse mutation (Ames) assay. DMF and MMF were clastogenic in the in vitro chromosomal aberration assay in human peripheral blood lymphocytes in the absence of metabolic activation. DMF was not clastogenic in the in vivo micronucleus assay in the rat.

Impairment of Fertility

In male rats, oral administration of DMF (75, 250, and 375 mg/kg/day) prior to and throughout the mating period had no effect on fertility; however, increases in non-motile sperm were observed at the mid and high doses. The no-effect dose for adverse effects on sperm is similar to the recommended human dose (RHD) of 480 mg/day on a body surface area (mg/m2) basis.

In female rats, oral administration of DMF (20, 100, and 250 mg/kg/day) prior to and during mating and continuing to gestation day 7 caused disruption of the estrous cycle and increases in embryolethality at the highest dose tested. The highest dose not associated with adverse effects (100 mg/kg/day) is twice the RHD on a mg/m2 basis.

Testicular toxicity (germinal epithelial degeneration, atrophy, hypospermia, and/or hyperplasia) was observed at clinically relevant doses in mice, rats, and dogs in subchronic and chronic oral toxicity studies of DMF, and in a chronic oral toxicity study evaluating a combination of four fumaric acid esters (including DMF) in rats.

Animal Toxicology and/or Pharmacology

Kidney toxicity was observed after repeated oral administration of dimethyl fumarate (DMF) in mice, rats, dogs, and monkeys. Renal tubule epithelia regeneration, suggestive of tubule epithelial injury, was observed in all species. Renal tubular hyperplasia was observed in rats with dosing for up to two years. Cortical atrophy and interstitial fibrosis were observed in dogs and monkeys at doses above 5 mg/kg/day. In monkeys, the highest dose tested (75 mg/kg/day) was associated with single cell necrosis and multifocal and diffuse interstitial fibrosis, indicating irreversible loss of renal tissue and function. In dogs and monkeys, the 5 mg/kg/day dose was associated with plasma MMF exposures less than or similar to that in humans at the recommended human dose (RHD).

A dose-related increase in incidence and severity of retinal degeneration was observed in mice following oral administration of DMF for up to two years at doses above 75 mg/kg/day, a dose associated with plasma MMF exposure (AUC) similar to that in humans at the RHD.

How Supplied / Storage and Handling

CINNOTEC is available as hard gelatin delayed-release capsules in two strengths containing either 120 mg or 240 mg of dimethyl fumarate. The green and white 120 mg capsules are printed with “BG-12 120 mg” in black ink. The green 240 mg capsules are printed with “BG-12 240 mg” in black ink. CINNOTEC is available as follows:

30-day Starter Pack:

  7-day bottle 120 mg capsules, quantity 14

  23-day bottle 240 mg capsules, quantity 46

120 mg capsules:

 7-day bottle of 14 capsules

  240 mg capsules:

  30-day bottle of 60 capsules

Store at 15°C to 30°C (59 to 86°F). Protect the capsules from light. Store in original container.

 

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