Consumer medicine information

Tecfidera

Dimethyl fumarate

BRAND INFORMATION

Brand name

Tecfidera

Active ingredient

Dimethyl fumarate

Schedule

What is in this leaflet

This leaflet answers some common questions about TECFIDERA. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet.

Speak to your pharmacist or doctor to obtain the most up to date information on this medicine.

You can also download the most up to date leaflet from: www.biogen.com.au/products/tecfidera-CMI.pdf

All medicines have risks and benefits. Your doctor has weighed the risks of you taking TECFIDERA against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What TECFIDERA is used for

TECFIDERA is used to treat relapsing multiple sclerosis (MS).

TECFIDERA slows down the progression of physical disability in people with relapsing forms of MS and decreases the number of flare ups (relapses).

Some people feel better when they start to take TECFIDERA. However TECFIDERA cannot repair damage that has already been caused by MS. When you start TECFIDERA you might not notice an improvement, but TECFIDERA may still be working to help prevent your MS from becoming worse.

The cause of MS is not yet known, MS affects the brain and spinal cord. In MS, the body's immune system reacts against its own myelin (the 'insulation' surrounding nerve fibres). In relapsing forms of MS, people have 'exacerbations' from time to time (e.g. blurred vision, weakness in the legs or arms, or loss of control of bowel or bladder function). They are followed by periods of recovery. Recovery may be complete or incomplete. If it is incomplete there is 'progression of disability'.

TECFIDERA contains the active ingredient dimethyl fumarate. Dimethyl fumarate decreases the inflammation in your brain that is caused by MS and thereby reduces nerve damage.

TECFIDERA works by reducing inflammatory responses in cells and helps to protect the central nervous system cells against attack. Inflammation of the brain is an important part of the MS disease process.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

TECFIDERA has not been studied in patients with chronic progressive MS.

Safety and effectiveness in children younger than 18 years have not been established.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

Before you take TECFIDERA

When you must not take it

Do not take TECFIDERA if you have an allergy to:

any medicine containing dimethyl fumarate
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin.

Do not take TECFIDERA if you are being treated with other medicines containing fumaric acid (creams or tablets/capsules).

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

liver problems
kidney problems
infection
recently received a vaccination.

Tell your doctor at your earliest opportunity if you suspect you have any symptoms of shingles.

Tell your doctor if you are pregnant or intend to become pregnant. There is no information on the use of TECFIDERA during pregnancy. Your doctor will discuss the risks and benefits of taking it if you are pregnant.

Tell your doctor if you are breast-feeding or planning to breast-feed. It is not known whether TECFIDERA passes into breast milk. Your doctor will discuss the risks and benefits of taking it if you are breast-feeding.

If you have not told your doctor about any of the above, tell them before you start taking TECFIDERA.

Taking other medicines

Tell your doctor if you have previously taken or are currently taking medicines containing fumaric acid (creams or tablets/capsules).

You should not take TECFIDERA together with these medicines.

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and TECFIDERA may interfere with each other. These include:

medicines which affect immune function including other medicines to treat MS such as fingolimod, natalizumab or mitoxantrone or some other commonly used cancer medicines
medicines which affect the kidneys, including some antibiotics (used to treat infections), "water tablets" (diuretics), certain types of painkillers (such as ibuprofen and other similar anti-inflammatory medicines and medicines purchased without a doctor’s prescription) and medicines that contain lithium
live vaccines.

These medicines may be affected by TECFIDERA or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take TECFIDERA

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

The recommended starting dose of TECFIDERA is 120 mg taken twice daily. After 7 days the recommended dose is 240 mg twice daily.

How to take it

Swallow each capsule whole with a glass of water. Do not crush, divide or dissolve the capsule or its contents.

When to take it

Take one capsule twice a day.

Taking it at the same time each day (e.g. at morning during breakfast and at night during dinner) will help you remember when to take it.

TECFIDERA can be taken with or without food. For those patients who experience gastrointestinal side effects or flushing, taking TECFIDERA with food may help reduce these effects.

Your doctor may tell you to take TECFIDERA with aspirin or may temporarily reduce your dose.

Do not reduce your dose unless your doctor tells you to.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. The positive effects of TECFIDERA may not be seen immediately. It is important to keep taking your medicine even if you feel well.

It is important not to interrupt treatment with TECFIDERA unless your doctor tells you to.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (in Australia telephone 13 11 26, in New Zealand telephone 0800 764 766) for advice, or go to Emergency at the nearest hospital, if you think that you or anyone else may have taken too much TECFIDERA. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking TECFIDERA

Things you must do

If you are about to have any blood or urine tests, tell your doctor that you are taking TECFIDERA.

Blood and urine test results may be affected by treatment with TECFIDERA.

Before you start TECFIDERA, your doctor will do a blood test to check the number of your white blood cells. Your doctor may also test these periodically during treatment.

Before you start TECFIDERA, your doctor will make sure you have results from a recent urine test to check your kidney function and may repeat the test periodically during treatment. TECFIDERA may cause proteins (such as albumin) to be detected in a urine test.

TECFIDERA may also cause increases in the level of liver enzymes that will show up in a blood test.

Take TECFIDERA exactly as your doctor has prescribed.

Tell your doctor if you are going to be vaccinated.

Tell your partner or caregiver about your treatment.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking TECFIDERA.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you become pregnant while taking this medicine, tell your doctor immediately.

Things you must not do

Do not take TECFIDERA to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Tell your doctor straight away if you think you have an infection, have fever, or feel like you have the flu. TECFIDERA may decrease lymphocyte (white blood cell) counts. White blood cells fight infection. You may get infections more easily while you are taking TECFIDERA. Any infection that you already have may get worse. Infections could be serious and sometimes life-threatening. If you have a serious infection, your doctor may recommend that you stop taking TECFIDERA until you recover.

Tell your doctor straight away if you think you are experiencing symptoms similar to an MS relapse, new or worsening weakness on one side of the body; clumsiness; changes in vision, thinking, or memory; or confusion or personality changes lasting for more than several days. These could be signs of a rare and very serious brain infection called progressive multifocal leukoencephalopathy (PML). The symptoms of PML may be similar to an MS relapse.

Having low lymphocyte levels, particularly for a long period of time, can increase your risk of PML.

Keep all of your doctor's appointments so that your progress can be checked. Before you start TECFIDERA, your doctor will do a blood test to check the number of your white blood cells. Your doctor may also test these periodically during treatment.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking TECFIDERA.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

reddening of the face or body feeling warm, hot, burning or itchy (flushing)
loose stools (diarrhoea)
feeling sick (nausea)
stomach pain or stomach cramps
inflammation of the lining of the intestines (gastroenteritis)
being sick (vomiting)
indigestion (dyspepsia)
inflammation of the lining of the stomach (gastritis)
gastrointestinal disorder
burning sensation
hot flush, feeling hot
itchy skin (pruritus)
rash
pink or red blotches on the skin (erythema)
runny nose (rhinorrhoea)
hair thinning.

The above list includes the more common side effects of your medicine. If any of these persist or worsen, talk to your doctor as some of them may also be due to an infection or allergic reaction.

Tell your doctor as soon as possible if you notice the following:

signs of infection (e.g., unexplained fever, severe diarrhoea).

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

If any of the following happen, stop taking TECFIDERA and tell your doctor immediately or go to Emergency at your nearest hospital:

swelling of your face, lips, tongue or other parts of the body
shortness of breath, wheezing, difficulty breathing, chest pain or discomfort
symptoms similar to an MS relapse, new or worsening weakness on one side of the body; clumsiness; changes in vision, thinking, or memory; or confusion or personality changes.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation. These side effects are very rare.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

After taking TECFIDERA

Storage

Keep your capsules in the pack until it is time to take them. If you take the capsules out of the pack they may not keep well.

Keep your capsules in a cool dry place away from light where the temperature stays below 30°C.

Do not store TECFIDERA or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

TECFIDERA capsules are available in two strengths: 120 mg and 240 mg.

The 120 mg capsules are green and white printed with 'BG-12, 120 mg' in black ink on the capsule body. Available in blister wallet cards containing 14 or 112 capsules packed in a box.

The 240 mg capsules are green printed with 'BG-12, 240 mg' in black ink on the capsule body. Available in blister wallet cards containing 14 or 56 capsules packed in a box.

Not all pack sizes may be available.

Ingredients

TECFIDERA contains dimethyl fumarate as the active ingredient.

Other ingredients:

microcrystalline cellulose (E460)
croscarmellose sodium (E468)
purified talc (E553b)
colloidal anhydrous silica (E551)
magnesium stearate (E572)
triethyl citrate (E1505)
methylacrylate-methyl methacrylate copolymer
methacrylic acid-ethyl acrylate copolymer
simethicone
sodium lauryl sulfate (E514)
polysorbate 80 (E433)
gelatin
titanium dioxide (E171)
brilliant blue FCF CI42090 (E133)
iron oxide yellow CI77492 (E172)
iron oxide black CI77499 (E172).

Further information

You can obtain more information from your doctor, pharmacist or the MS Society in your State, or by telephoning the MS Alliance on 1800 852 289 in Australia or 0800 852 289.

Sponsor

TECFIDERA is supplied in Australia by:

Biogen Australia Pty Ltd
Level 4, 2 Banfield Road
Macquarie Park NSW 2113

TECFIDERA is supplied in New Zealand by:

Biogen NZ Biopharma Limited
188 Quay Street
Auckland

® = Registered Trademark or
© Copyright

This leaflet was prepared in September 2021.

TECFIDERA 120 mg - AUST R 197118

TECFIDERA 240 mg - AUST R 197119

TECFIDERA® is a registered trademark of Biogen.

BIOGEN® is a registered trademark of Biogen MA Inc.

Published by MIMS November 2021

BRAND INFORMATION

Brand name

Tecfidera

Active ingredient

Dimethyl fumarate

Schedule

1 Name of Medicine

Dimethyl fumarate (DMF).

2 Qualitative and Quantitative Composition

Tecfidera (dimethyl fumarate [DMF]) is formulated as enteric coated microtablets enclosed within hard gelatin capsules, containing the active ingredient dimethyl fumarate.
Each Tecfidera capsule contains 120 mg or 240 mg DMF. The inactive ingredients of Tecfidera are: microcrystalline cellulose, croscarmellose sodium, purified talc, colloidal anhydrous silica, magnesium stearate, triethyl citrate, methylacrylate-methyl methacrylate copolymer, methacrylic acid - ethyl acrylate copolymer (1:1), simethicone, sodium lauryl sulfate, polysorbate 80, gelatin, titanium dioxide, brilliant blue FCF (CI42090), iron oxide yellow (CI77492), iron oxide black (CI77499).

3 Pharmaceutical Form

Modified release capsules.

120 mg capsules.

Tecfidera is supplied as green and white capsules printed with "BG-12 120 mg" in black ink on the capsule body. Each capsule contains 120 mg DMF.

240 mg capsules.

Tecfidera is supplied as green capsules printed with "BG-12 240 mg" in black ink on the capsule body. Each capsule contains 240 mg DMF.

4 Clinical Particulars

4.1 Therapeutic Indications

Tecfidera is indicated in patients with relapsing multiple sclerosis to reduce the frequency of relapses and to delay the progression of disability.

4.2 Dose and Method of Administration

The starting dose for Tecfidera is 120 mg twice a day orally. After 7 days, increase to the recommended dose of 240 mg twice a day orally.
The capsule or its contents should not be crushed, divided or dissolved as the enteric coating of the microtablets prevents irritant effects on the gut.
Temporary dose reduction to 120 mg twice a day may reduce the occurrence of flushing and gastrointestinal (GI) side effects. Within 1 month, the recommended dose of 240 mg twice a day orally should be resumed.
Tecfidera can be taken with or without food. For those patients who may experience gastrointestinal or flushing side effects, taking Tecfidera with food may improve tolerability.
Administration of 325 mg nonenteric coated aspirin prior to Tecfidera dosing reduced the occurrence and severity of flushing in a healthy volunteer study (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Tecfidera has not been studied in patients with renal or hepatic impairment. Based on clinical pharmacology studies, no dose adjustments are needed.

4.3 Contraindications

Tecfidera is contraindicated in patients with known hypersensitivity to DMF or any excipients in this product.

4.4 Special Warnings and Precautions for Use

Infection.

Decreases in lymphocyte counts observed in patients treated with Tecfidera in clinical trials were not associated with increased frequencies of infections. However, due to the risk of serious, possibly fatal infection, patients who develop lymphopenia as a result of treatment with Tecfidera require close monitoring. Patients should be instructed to report symptoms of infection to their physician. For patients with signs and symptoms of serious infections, interrupting treatment with Tecfidera should be considered until the infection(s) resolves.

Lymphopenia.

Tecfidera may decrease lymphocyte counts (see Section 4.8 Adverse Effects (Undesirable Effects)). In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with Tecfidera and then remained stable. WBC counts < 3.0 x 10⁹/L and lymphocyte counts < 0.5 x 10⁹/L were reported in 6 to 7% of subjects given Tecfidera. Prior to initiating treatment with Tecfidera, a recent complete blood count (CBC) including lymphocytes (i.e. within 6 months) is recommended. A CBC, including lymphocytes, is also recommended after 6 months of treatment and every 6 to 12 months thereafter, and as clinically indicated. In clinical studies, 9% of patients had lymphocyte counts ≥ 0.5 x 10⁹/L and < 0.8 x 10⁹/L for at least six months. 2% 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 x 10⁹/L with continued therapy. In controlled and uncontrolled clinical studies, the mean time for lymphocyte counts to return to normal after discontinuing Tecfidera treatment was 4.7 weeks in patients without prolonged, severe lymphopenia and 29 weeks in patients with prolonged, severe lymphopenia (patients with lymphocyte counts < 0.5 x 10⁹/L for six months or greater).
Consider interruption of Tecfidera in patients with lymphocyte counts < 0.5 x 10⁹/L persisting for more than six months. Lymphocytes counts should be followed until recovery. Assess the benefit/risk in patients who experience moderate lymphopenia for more than 6 months.
Interrupting treatment should be considered in patients with serious infections until the infection(s) resolved. Tecfidera has not been studied in patients with pre-existing low lymphocyte counts and caution should be exercised when treating these patients.

Progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) has occurred in the setting of lymphopenia (< 0.91 x 10⁹/L) in patients with multiple sclerosis (MS) treated with Tecfidera (see Section 4.8 Adverse Effects (Undesirable Effects)). These PML cases have occurred predominantly in the setting of prolonged moderate to severe lymphopenia. PML is an opportunistic viral infection of the brain that may lead to death or severe disability.
The symptoms of PML may be similar to a MS relapse. 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. At the first sign or symptom suggestive of PML, withhold Tecfidera and perform an appropriate diagnostic evaluation.

Anaphylactic reactions.

Cases of anaphylaxis have been reported following Tecfidera administration. These reactions generally occurred after the first dose, but may occur at any time during treatment, and may be serious and life threatening. Patients should be instructed to discontinue Tecfidera and seek immediate medical care if they experience signs or symptoms of anaphylaxis. Treatment should not be restarted. (See Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

Herpes zoster infections.

Serious cases of herpes zoster have occurred with Tecfidera, 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 Tecfidera for signs and symptoms of herpes zoster. If herpes zoster occurs, appropriate treatment for herpes zoster should be administered. Consider withholding Tecfidera treatment in patients with serious infections until the infection has resolved (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).

Vaccination.

Patients taking Tecfidera may receive non-live vaccines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The safety of administration of live attenuated vaccines during treatment with Tecfidera has not been evaluated in clinical trials. Live vaccines have a potential risk of clinical infection and are not recommended during treatment with Tecfidera.

Use in renal impairment.

In clinical trials with patients with multiple sclerosis, adverse events of proteinuria (proteinuria, microalbuminuria and urine albumin present) were reported at slightly higher frequencies in patients treated with Tecfidera compared to patients that received placebo. The significance of these clinical observations is not known at this time.
Prior to initiating treatment with Tecfidera, urinalysis should be available (within 6 months prior to starting therapy). During treatment, urinalysis is recommended annually and as clinically indicated.
The use of Tecfidera in patients who receive chronic treatment with medications that are associated with potential nephrotoxic risk (e.g. aminoglycosides, diuretics, NSAIDs, lithium) has not been evaluated. Therefore, caution should be exercised if Tecfidera is used in patients receiving chronic treatment with such medications.

Use in the elderly.

There are limited data available for the use of Tecfidera in patients aged 65 years and over, therefore it is unknown whether elderly patients respond differently to younger patients.

Paediatric use.

The safety and effectiveness of Tecfidera in paediatric patients with multiple sclerosis below the age of 18 have not been established.

Effects on laboratory tests.

There are no data available on whether Tecfidera interferes with laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

In humans, Tecfidera is extensively metabolised by esterases before it reaches the systemic circulation and further metabolism occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. Potential drug interaction risks were not identified from in vitro CYP inhibition and induction studies, a p-glycoprotein study, or studies of the protein binding of DMF and MMF.
A pharmacokinetic study with a combined oral contraceptive has been performed with dimethyl fumarate (Tecfidera). There were no relevant effects of dimethyl fumarate on the pharmacokinetic profile of norelgestromin and ethinyl estradiol. No interaction studies have been performed with oral contraceptives containing other progestogens; however an effect of Tecfidera on their exposure is not expected.
Commonly used drugs in patients with multiple sclerosis, intramuscular (IM) interferon beta-1a and GA, were clinically tested for potential drug interactions with Tecfidera and did not alter the pharmacokinetic profile of Tecfidera. Aspirin (nonenteric coated), 325 mg, when administered approximately 30 minutes before Tecfidera, did not alter the pharmacokinetic profile of Tecfidera.
Patients treated with Tecfidera were able to mount an effective immune response to inactivated neoantigen (first vaccination), recall antigen (re-exposure), or polysaccharide antigen in a clinical study in patients with relapsing forms of MS. This response was comparable to patients treated with non-pegylated interferons. Patients taking Tecfidera may receive non-live vaccines. No clinical data are available on the efficacy and safety of live attenuated vaccines in patients taking Tecfidera.
During treatment with Tecfidera, simultaneous use of other fumaric acid derivatives (topical or systemic) should be avoided as such clinical scenarios have not been studied.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Data from nonclinical studies do not suggest that Tecfidera would be associated with an increased risk of reduced fertility.
Administration of DMF to male rats at daily oral doses of up to 7-9 times the maximum recommended human dose (MRHD) based on mg/m² prior to and during mating had no effects on fertility. Administration of DMF to female rats at daily oral doses of up to 5-6 times the MRHD based on mg/m² prior to and during mating, and continuing to day 7 of gestation, delayed oestrus cycling at the highest dose but had no effects on fertility.
(Category B1)
Oral treatment of pregnant rats and rabbits during the period of organogenesis with dimethyl fumarate showed no evidence of teratogenicity. In rats, the high dose of 250 mg/kg/day (9 times the MRHD based on AUC) reduced foetal weight and caused minor impairment of ossification in foetuses, concomitant with maternal toxicity; the no effect dose for foetal effects was 100 mg/kg/day (4 times the MRHD based on AUC). In rabbits, the high dose of 150 mg/kg/day (14 times the MRHD based on AUC) elicited toxicity and abortions in does, but did not affect embryofoetal development.
The effects of Tecfidera on labour and delivery are unknown. In rats given oral dimethyl fumarate from early gestation to the end of lactation, there were no effects on delivery at doses up to 250 mg/kg/day (9 times the MRHD based on AUC).
Tecfidera should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the foetus.
It is not known whether this drug is excreted in milk. A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Tecfidera treatment. The benefit of breast-feeding for the child and the benefit of treatment for the woman should be taken into account.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
The most common adverse reactions (incidence ≥ 10% and > 2% than placebo) for Tecfidera were flushing and gastrointestinal (GI) events (i.e. diarrhoea, nausea, abdominal pain, upper abdominal pain).
The most commonly reported adverse events leading to discontinuation (incidence > 1%) in patients treated with Tecfidera were flushing (3%) and gastrointestinal events (4%).
In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received Tecfidera for periods up to 12 years and been followed for periods up to 13 years with an overall exposure equivalent to 11,318 person-years. A total of 1169 patients have received at least 5 years of treatment with Tecfidera, and 426 patients have received at least 10 years of treatment with Tecfidera. The experience in uncontrolled clinical trials is consistent with the experience in the placebo-controlled clinical trials.
In the two phase 3 placebo controlled trials, 1529 patients received Tecfidera with an overall exposure of 2371 person years (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The adverse reactions presented in Table 2 are based on safety information from 769 patients treated with Tecfidera 240 mg twice a day and 771 patients treated with placebo.
The adverse reactions are presented as MedDRA preferred terms under the MedDRA system organ class.
The incidence of the adverse reactions in Tables 1 and 2 is expressed according to the following categories. Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

Other relevant ADRs (< 2% difference) include: gastroenteritis, gastritis, gastrointestinal disorder, burning sensation, feeling hot, alanine aminotransferase increased, proteinuria, white blood cell count decreased and leucopenia.

Description of selected adverse events.

Flushing.

The incidence of patients with flushing events (e.g. warmth, redness, itching, burning sensation) was higher early in the course of treatment (primarily in month 1) and decreased over time, which might indicate that this symptom became less prevalent with continued use. In patients with flushing, the majority had flushing events that were mild or moderate in severity. Overall, 3% of patients treated with Tecfidera discontinued due to flushing. The incidence of serious flushing which may be characterised by generalised erythema, rash and/or pruritus was seen in less than 1% of patients treated with Tecfidera (see Section 4.2 Dose and Method of Administration).

Gastrointestinal.

The incidence of patients with GI events (e.g. nausea, vomiting, diarrhoea, abdominal pain, upper abdominal pain and dyspepsia) was higher early in the course of treatment (primarily in month 1) and decreased over time in patients treated with Tecfidera compared with placebo. Four percent (4%) of patients treated with Tecfidera discontinued due to gastrointestinal events. The incidence of serious GI events, including gastroenteritis and gastritis, was seen in less than 1% of patients treated with Tecfidera.

Hepatic transaminases.

In placebo controlled studies, elevations of hepatic transaminases were observed. The majority of patients with elevations had hepatic transaminases that were < 3 times the upper limit of normal (ULN). The increased incidence of elevations of hepatic transaminases in patients treated with Tecfidera relative to placebo was primarily seen during the first 6 months of treatment. Elevations of alanine aminotransferase and aspartate aminotransferase ≥ 3 times ULN, respectively, were seen in 5% and 2% of patients treated with placebo and 6% and 2% of patients treated with Tecfidera. Discontinuations due to elevated hepatic transaminases were < 1% and similar in patients treated with Tecfidera or placebo. Elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN were not observed during placebo-controlled studies but have been observed in the post-marketing experience (see Post-marketing experience).

Haematological.

In the placebo controlled studies, most patients (> 98%) had normal lymphocyte values prior to initiating treatment. Upon treatment with Tecfidera, lymphocytes counts decreased over the first year with a subsequent plateau. On average, lymphocyte counts decreased by approximately 30% of baseline value. Mean and median lymphocyte counts remained within normal limits. Patients with lymphocyte counts < 0.5 x 10⁹/L were observed in < 1% of patients treated with placebo and 6% of patients treated with Tecfidera. In controlled and uncontrolled clinical studies, 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 < 0.5 x 10⁹/L with continued therapy.
The incidence of infections (58% vs 60%) and serious infections (2% vs 2%) was similar in patients treated with placebo or Tecfidera, respectively. An increased incidence of infections and serious infections was not observed in patients with lymphocyte counts < 0.8 x 10⁹/L or 0.5 x 10⁹/L. A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Post-marketing experience.

In post marketing experience, hypersensitivity reactions including urticaria, angioedema, and difficulty breathing have been reported following Tecfidera administration. Cases of anaphylaxis have also been reported (see Section 4.4 Special Warnings and Precautions for Use, Anaphylactic reactions).
Progressive multifocal leukoencephalopathy has occurred in the setting of lymphopenia (< 0.91 x 10⁹/L) following Tecfidera administration. These PML cases have occurred predominantly in the setting of prolonged moderate to severe lymphopenia (see Section 4.4 Special Warnings and Precautions for Use, Progressive multifocal leukoencephalopathy).
Liver function abnormalities (elevations in transaminases ≥ 3 times ULN with concomitant elevations in total bilirubin > 2 times ULN) have been reported following Tecfidera administration in post marketing experience. These abnormalities resolved upon treatment discontinuation over a varying period of time. Therefore, ongoing monitoring of LFTs is recommended in patients being treated with Tecfidera, as clinically indicated.
Herpes zoster infection has been reported with Tecfidera administration in post marketing experience. The majority of cases were non-serious (see Section 4.4 Special Warnings and Precautions for Use, Herpes zoster infections). Other serious opportunistic infections have occurred with Tecfidera, including cases of serious viral (herpes simplex virus, West Nile virus, cytomegalovirus), fungal (Candida and Aspergillus), and bacterial (Nocardia, Listeria monocytogenes, Mycobacterium tuberculosis) infections.
Rhinorrhoea and alopecia have been reported with Tecfidera administration in post marketing experience.

4.9 Overdose

Cases of overdose with Tecfidera have been reported. There are no known therapeutic interventions to enhance elimination of Tecfidera nor is there a known antidote. In the event of overdose, it is recommended that symptomatic supportive treatment be initiated as clinically indicated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The mechanism by which DMF exerts therapeutic effects in multiple sclerosis is not fully understood. Nonclinical studies indicate that pharmacodynamic responses to DMF appear to be mediated, at least in part, through activation of the nuclear factor (erythroid derived 2)-like 2 (Nrf2) transcriptional pathway, which is a critical cellular defence system for responding to a variety of potentially toxic stimuli through up regulation of antioxidant response genes.
Biological response markers of Nrf2 activation (e.g. NAD(P)H dehydrogenase, quinone 1 [NQO1]) are detected at elevated levels in blood from patients with multiple sclerosis following 12 or 48 weeks of oral dosing with DMF. These clinical data appear to be consistent with nonclinical studies demonstrating DMF dependent up regulation of Nrf2 antioxidant response genes in multiple tissue types, although the magnitude of up regulation observed in tissues of the central nervous system was small. The relationships between blood NQO1 levels and the mechanism(s) by which DMF exerts its effects in multiple sclerosis are unknown.
In nonclinical and clinical studies, DMF demonstrates anti-inflammatory and immunomodulatory properties. DMF and monomethyl fumarate (MMF), the primary metabolite of DMF, significantly reduce immune cell activation and subsequent release of proinflammatory cytokines in response to inflammatory stimuli, and moreover affects lymphocyte phenotypes through a down regulation of proinflammatory cytokine profiles (T_H1, T_H17), and biases towards anti-inflammatory production (T_H2). DMF demonstrates therapeutic activity in models of inflammatory and neuroinflammatory injury, and also appears to promote improvement in blood brain barrier integrity. All of these anti-inflammatory effects appear consistent with the significant clinical activity of DMF in reducing brain lesions and relapses in multiple sclerosis patients.
In nonclinical studies MMF was shown to penetrate into the central nervous system where it promotes cyto- and neuroprotective responses. DMF and/or MMF significantly improve cell viability after oxidative challenge in primary cultures of astrocytes and neurons, suggesting that DMF and MMF prevent neurodegeneration in response to toxic stress. DMF showed therapeutic benefit in acute neurotoxic injury models and models of neurodegenerative disease. These nonclinical data combined with imaging and functional endpoints from clinical studies suggest DMF may promote a neuroprotective benefit in the central nervous system.

Potential to prolong the QTc interval.

Single doses of 240 mg or 360 mg DMF did not have any effect on the QTc interval when compared to placebo in a thorough QTc study.

Clinical trials.

The efficacy and safety of Tecfidera was demonstrated in three studies that evaluated Tecfidera taken either twice or three times a day in patients with relapsing remitting multiple sclerosis (RRMS).
The starting dose for Tecfidera was 120 mg twice or three times a day for the first 7 days, followed by an increase to either 240 mg twice or three times a day. Two of the three studies (Study 1 and Study 2) included patients with Expanded Disability Status Scale (EDSS) scores ranging from 0 to 5, who had experienced at least 1 relapse during the year prior to randomisation, or, within 6 weeks of randomisation had a brain magnetic resonance imaging (MRI) demonstrating at least one gadolinium enhancing (Gd+) lesion.
Study 1 (DEFINE) was a 2 year randomised, double blind, placebo controlled study in 1234 patients with RRMS who had not received interferon-beta or glatiramer acetate (GA) for at least the previous 3 months or natalizumab for at least the previous 6 months. Neurological evaluations were performed at baseline, every 3 months and at time of suspected relapse. MRI evaluations were performed at baseline, month 6, and year 1 and 2. The primary endpoint in study 1 was the reduction in the proportion of patients relapsed at 2 years. Patients were randomised to receive Tecfidera 240 mg twice a day (n = 410), Tecfidera 240 mg three times a day (n = 416), or placebo (n = 408) for up to 2 years. Median age: 39 years, median years since diagnosis: 4.0 years and median EDSS score at baseline: 2.0. Median time on study was 96 weeks for all three treatment groups.
The proportion of patients relapsed was significantly lower in the group treated with Tecfidera than in the group treated with placebo at 2 years. Secondary endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of Gd enhancing lesions, annualised relapse rate (ARR), and time to confirmed disability progression. Confirmed disability progression was defined as at least a 1 point increase from baseline EDSS (1.5 point increase for patients with baseline EDSS of 0) sustained for 12 weeks. Tecfidera had a clinically meaningful and statistically significant effect on all primary and secondary study endpoints. The 240 mg three times daily dose resulted in no additional benefit over the Tecfidera 240 mg twice daily dose. The results for this study are shown in Table 3.

Study 2 (CONFIRM) was a 2 year multicentre, randomised, double blind, placebo controlled study which contained a rater blinded (i.e. study physician/investigator assessing the response to study treatment is blinded) reference comparator of glatiramer acetate (GA) in 1417 patients with RRMS.
Patients had not received interferon-beta for at least the previous 3 months, natalizumab for at least the previous 6 months and had not previously received GA. The efficacy and safety evaluations were similar to study 1 and the endpoints were broadly consistent, but the primary endpoint of study 2 was the annualized relapse rate at 2 years, whereas the primary endpoint of study 1 was the proportion of subjects relapsed at 2 years. Median age: 37 years, median years since diagnosis: 3.0 years and median EDSS score at baseline: 2.5. Patients were randomised to receive Tecfidera 240 mg twice a day (n = 359), Tecfidera 240 mg three times a day (n = 344), placebo (n = 363) or glatiramer acetate (n = 351) for up to 2 years. Median time on study was 96 weeks for all treatment groups.
The annualised relapse rate was significantly lower in patients treated with Tecfidera than in patients treated with placebo at 2 years. Secondary endpoints at 2 years included the number of new or newly enlarging T2 hyperintense lesions, number of T1 hypointense lesions, proportion of patients relapsed and time to confirmed disability progression defined as in study 1.
Tecfidera had a clinically meaningful and statistically significant effect on the primary endpoint and secondary relapse and MRI endpoints. In study 2, the annualised relapse rate for glatiramer acetate versus placebo was 0.286 and 0.401, corresponding to a reduction of 29% (p = 0.013) which is consistent with approved product labelling. The results for this study are shown in Table 4.

Pooled results at 2 years for study 1 and study 2 showed consistent and statistically significant results for Tecfidera versus placebo in all primary and secondary endpoints, including time to confirmed disability progression (32% relative reduction compared to placebo).
Study 3 (ENDORSE) enrolled eligible patients from Study 1 and 2 into an 8-year two phase extension study of 1736 patients with RRMS. The first phase was a multicentre, parallel group, randomised, dose blind, dose comparison study in which patients received Tecfidera at a dose of 240 mg twice a day or 240 mg three times a day. The second phase was an open label study during which all patients received Tecfidera at a dose of 240 mg twice a day. Eligible patients were enrolled at Week 96 (Visit 24) of their previous Study 1 or Study 2 visit, which served as the baseline visit for this extension study.
The primary objective of Study 3 was to evaluate the long-term safety of Tecfidera. The secondary objectives were to evaluate the long-term efficacy of Tecfidera using clinical endpoints (including relapse and ARR) and disability progression (EDSS) and on MS brain lesions on MRI scans.
The median age of patients was 40.0 years. Most patients (945 participants, 54%) were in the study for 7 years or longer and the median time spent in the study (min, max) was 6.759 (0.04, 10.98) years.
In the first year of treatment with Tecfidera in Study 3, the adjusted ARR (95% CI) ranged from 0.125 (0.084, 0.188) to 0.183 (0.108, 0.308), and remained low in the eighth year, ranging from 0.077 (0.039, 0.153) to 0.129 (0.063, 0.265), in all treatment arms. During the overall study period, the adjusted ARR (95% CI) ranged from 0.126 (0.098, 0.162) to 0.185 (0.129, 0.265) and the majority of patients treated with Tecfidera (between 59% and 69%) had no relapses.
The estimated proportion of relapse (95% CI), at 8 years (384 weeks), in Study 3 ranged from 0.414 (0.314, 0.531) to 0.502 (0.426, 0.584).
In an integrated analysis of Study 1 and Study 2 with Study 3, for patients continuously treated with Tecfidera twice a day/twice a day (n = 501; patients treated with Tecfidera 240 mg twice a day in Study 1 or 2 and then Tecfidera 240 mg twice a day in study 3), adjusted ARR was 0.187 (95% CI, 0.156,0.224) in Study 1 and 2, and was 0.141 (95% CI, 0.119, 0.167) in Study 3. The data in Figure 1 demonstrates that the adjusted ARR in patients treated with Tecfidera was steady throughout the treatment time in Study 1 or 2 and Study 3. For placebo/Tecfidera patients (n = 249; patients treated with placebo in Study 1 or Study 2 and then switched to Tecfidera in Study 3), adjusted ARR was 0.330 (95% CI, 0.266, 0.408) and decreased after initiating Tecfidera, in Study 3, to 0.149 (95% CI, 0.116, 0.190), shown in Figure 2.
In Study 3, the mean (median) EDSS score at baseline ranged from 2.37 (2.0) to 2.64 (2.0). The estimated proportion of patients with confirmed progression (95% CI) in the eighth year of Study 3 after treatment with Tecfidera ranged from 0.314 (0.268, 0.365) to 0.387 (0.311, 0.475).
In an integrated analysis of Study 1 and Study 2 with Study 3, at Week 480, the estimated proportion (95%) of patients with confirmed disability progression (Study 1, 2, and 3 data combined) was 0.349 (0.302, 0.401) in the Tecfidera twice a day/twice a day group and 0.362 (0.292, 0.443) in the placebo/Tecfidera group.
In Study 3, 752 patients were included in an MRI cohort, which included patients who had previously been included in the MRI cohort of Study 1 or Study 2. Due to sample size restrictions (by year 8 all groups has < 30 patients), MRI results are presented only through Year 6 of Study 3. Across all treatment arms, the adjusted mean number of new or newly enlarging T2 lesions relative to Study 3 baseline over 6 years ranged from 3.911 to 8.650 (the adjusted mean was based on negative binomial regression, adjusted for region and baseline volume of T2 lesions). The median number of new or newly enlarging T2 lesions over 6 years ranged from 1.0 to 3.0. Across all treatment arms, the mean (median) number of Gd+ lesions at 6 years ranged from 0.0 (0.0) to 0.7 (0.0). The percentage of patients with no Gd+ lesions ranged from 84% to 100%. The mean number of new T1 hypointense lesions over 6 years, adjusted for region and baseline volume of T1 lesions (based on negative binomial regression), ranged from 1.060 to 4.326. The median ranged from 1.0 to 2.5.

5.2 Pharmacokinetic Properties

Orally administered Tecfidera undergoes rapid presystemic hydrolysis by esterases and is converted to its primary metabolite, MMF, which is also active. DMF is not quantifiable in plasma following oral administration of Tecfidera. Therefore all pharmacokinetic analyses related to Tecfidera were performed with plasma MMF concentrations. Pharmacokinetic data were obtained in subjects with multiple sclerosis and healthy volunteers.

Absorption.

The Tmax of Tecfidera is 2-2.5 hours. As Tecfidera microtablets are protected by an enteric coating, absorption does not commence until the microtablets leave the stomach (generally less than 1 hour). Following 240 mg administered twice a day with food, the median peak (Cmax) was 1.72 mg/L and overall (AUC) exposure was 8.02 h.mg/L in subjects with MS. Cmax and AUC increased approximately dose proportionally in the dose range studied (120 mg to 360 mg).
Food does not have a clinically significant effect on exposure of Tecfidera. Therefore, Tecfidera may be taken with or without food.

Distribution.

The apparent volume of distribution following oral administration of 240 mg Tecfidera varies between 60 and 90 L. Human plasma protein binding of MMF generally ranges between 27%-40%.

Metabolism.

In humans, Tecfidera is extensively metabolised by esterases, which are ubiquitous in the gastrointestinal tract, blood and tissues, before it reaches the systemic circulation. Further metabolism occurs through the tricarboxylic acid (TCA) cycle, with no involvement of the cytochrome P450 (CYP) system. A single 240 mg ¹⁴C-DMF dose study identified monomethyl fumarate, fumaric and citric acid, and glucose as the major metabolites in plasma. The downstream metabolism of fumaric and citric acid occurs through the TCA cycle, with exhalation of CO₂ serving as a primary route of elimination.

Excretion.

Exhalation of CO₂ is the primary route of Tecfidera elimination accounting for approximately 60% of the dose. Renal and faecal elimination are secondary routes of elimination, accounting for 15.5% and 0.9% of the dose respectively.
The terminal half-life of MMF is short (approximately 1 hour) and no circulating MMF is present at 24 hours in the majority of individuals. Accumulation of parent drug or MMF does not occur with multiple doses of Tecfidera at the therapeutic regimen.
Tecfidera exposure increases in an approximately dose proportional manner with single and multiple doses in the 120 to 360 mg dose range studied.
Based on the results of ANOVA, bodyweight is the main covariate of exposure (by Cmax and AUC) in RRMS subjects, but did not affect safety and efficacy measures evaluated in the clinical studies. Gender and age did not have a statistically significant impact on Cmax and AUC.
Race and ethnicity have no effect on the pharmacokinetics of Tecfidera.
Since the renal pathway is a secondary route of elimination for Tecfidera, accounting for less than 16% of the dose administered, evaluation of pharmacokinetics in individuals with renal impairment was not conducted.
As DMF and MMF are metabolised by esterases, without the involvement of the CYP450 system, evaluation of pharmacokinetics in individuals with hepatic impairment was not conducted.

5.3 Preclinical Safety Data

Genotoxicity.

DMF and MMF were negative in the following in vitro assays (bacterial reverse mutation test, chromosomal aberration assay in human lymphocytes, and [DMF only] a forward mutation assay in Chinese hamster ovary cells) and in vivo assays (rat micronucleus assay with DMF, bone marrow cytogenetic test with MMF). Results did not suggest a risk of genotoxicity in patients.

Carcinogenicity.

Carcinogenicity studies were conducted in mice and rats with oral dosing with DMF for up to 2 years. Doses in mice were 25, 75, 200 and 400 mg/kg/day and in rats were 25, 50, 100 and 150 mg/kg/day.
Incidences of tumours in the nonglandular stomach were increased in mice and rats (squamous cell papillomas and carcinomas in mice and rats; leiomyosarcomas and fibrosarcomas in mice). As the nonglandular stomach of mice and rats does not have a human counterpart, these tumours are not considered to be a risk in patients.
Incidences of renal tubular adenomas (benign) and carcinomas were increased in both mice and rats. Higher incidences of at least one of these tumours were observed at doses of 75 mg/kg/day in mice (1.3 times the MRHD based on AUC) and 100 mg/kg/day in rats (2 times the MRHD based on AUC), with significantly higher incidences at 200 mg/kg/day in mice and 150 mg/kg/day in rats (4 times the MRHD in both species). The clinical relevance of these findings is unclear but they might pose a human risk.
In male rats, an increase in the incidence of benign interstitial cell (Leydig cell) adenoma of the testes was observed at ≥ 100 mg/kg/day (2 times the MRHD based on AUC). The rat is particularly sensitive to developing this tumour type and the relevance of these findings to human risk is considered low.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C. Store in original packaging in order to protect from light.

6.5 Nature and Contents of Container

120 mg capsules.

Capsules are supplied in PVC/PE/PVDC aluminium blister packs, in pack sizes of 14 and 112*.

240 mg capsules.

Capsules are supplied in PVC/PE/PVDC aluminium blister packs, in pack sizes of 14* and 56.
*Not all presentations are currently marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

The structural formula of DMF is shown below.

DMF is a white to off-white powder that is slightly soluble in water. It has a molecular formula of C₆H₈O₄ and a molecular weight of 144.13. The chemical name for DMF is dimethyl (2E)but-2-enedioate.

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Dimethyl fumarate

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Tecfidera 120 mg Capsules

Tecfidera 240 mg Capsules