Active ingredients: Interferon beta-1a
AVONEX 30 micrograms / 0.5ml solution for injection
Avonex package inserts are available for pack sizes:- AVONEX 30 micrograms / 0.5ml solution for injection
- AVONEX 30 micrograms / 0.5 ml solution for injection, in pre-filled pen
Why is Avonex used? What is it for?
What is AVONEX
The active substance in Avonex is a protein called interferon beta-1a. Interferons are natural substances that the body produces to protect itself from infection and disease. The protein contained in Avonex has exactly the same composition as the interferon beta produced by the human body.
What is AVONEX
Avonex is used to treat multiple sclerosis (MS). Treatment with Avonex can help you avoid getting worse, even though it cannot cure MS.
Each has an individual variety of MS symptoms. Possible symptoms include:
- Feeling dizzy or unbalanced, walking problems, muscle stiffness and spasms, tiredness, numbness in the face, arms or legs
- Acute or chronic pain, bladder or bowel disorders, sexual problems and vision disturbances
- Difficulty thinking and concentrating, depression.
MS also tends to flare up from time to time: this phenomenon is called relapse (relapse).
(Additional information)
Avonex works best when taken regularly, once a week, at the same time. Do not stop taking Avonex without first talking to your neurologist.
Avonex can help reduce the number of relapses (relapses) you may have and slow the disabling progression of MS. Your doctor will tell you how long to take Avonex or when it will be time to stop.
How AVONEX works
Multiple sclerosis is associated with damage to the nerves (brain or spinal cord). In MS, the immune system reacts by attacking myelin - the "insulating" coating that surrounds nerve fibers. Damage to myelin impairs the exchange of messages between the brain and other parts of the body. This is what causes MS symptoms. The action of Avonex appears to be to stop the body's immune system from attacking myelin.
Contraindications When Avonex should not be used
Do not use AVONEX:
- If you are allergic to interferon beta or any of the other ingredients of this medicine (listed in section 6)
- If you are pregnant, do not start using Avonex
- If you have severe depression or are thinking about suicide.
Tell your doctor immediately if you have any of these circumstances.
(Additional information)
Avonex and allergic reactions. Since Avonex contains a protein, there is a low chance of an allergic reaction.
More on depression. If you have severe depression or have thoughts of suicide, you should not use Avonex. If you have depression, your doctor may still prescribe Avonex, but it is important that you tell your doctor if you have suffered from depression or other similar mood disorders.
Precautions for use What you need to know before taking Avonex
Warnings and Precautions
Talk to your doctor before using Avonex if you are suffering or have suffered in the past from the following problems:
- Depression or mood problems
- Thoughts of suicide.
You should report any mood swings, thoughts of suicide, unusual feelings of sadness, anxiety or weakness to your doctor immediately.
- Epilepsy or other similar disorders not controlled by drugs
- Severe kidney or liver problems
- Low amount of white blood cells or platelets, which can increase the risk of infection, bleeding or anemia
- Heart problems, which can cause symptoms such as chest pain (angina) especially after physical activity, swollen ankles, breathlessness (congestive heart failure) or irregular heartbeat (arrhythmias).
Talk to your doctor if you have any of these conditions, or if they get worse while using Avonex.
Thrombi (blood clots) may form inside small blood vessels during treatment. These thrombi may have an effect on the kidneys. Thrombi formation may occur several weeks to several years after starting treatment with Avonex.
Your doctor may decide to have your blood pressure, blood (platelet count) and kidney function checked. Tell your doctor that you are taking Avonex:
- If you have to do a blood test, because Avonex can alter the results.
(Additional information)
In some cases, you will need to tell your healthcare professional that you are using Avonex. For example, if you are prescribed other medicines or need to have a blood test, Avonex can alter the effect of the medicines or the test results.
Interactions Which drugs or foods may change the effect of Avonex
Tell your doctor if you are taking any other medicines, especially medicines to treat epilepsy and depression. Avonex can affect or be affected by other medicines. This applies to any medicine, including non-prescription ones.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant, do not start using Avonex.
- if you are of childbearing age and sexually active, you must use adequate contraception while taking Avonex.
- if you plan to become pregnant or become pregnant while using Avonex, talk to your doctor to discuss whether or not to continue the treatment.
- if you are already pregnant or think you are, contact your doctor as soon as possible.
- if you intend to breastfeed, talk to your doctor first.
Driving and using machines
If you feel dizzy, don't drive. In some people, Avonex causes a dizziness effect. If this happens to you, or if you have other side effects which may affect your abilities, you should not drive or operate machinery.
Important information about some of the ingredients of AVONEX
This medicine is essentially "sodium free". It contains less than 23 mg (1 mmol) of sodium per weekly dose.
Dose, Method and Time of Administration How to use Avonex: Posology
The recommended dose for adults and adolescents 12 years of age and older.
One injection of Avonex per week.
Try to take Avonex every week, always on the same day and at the same time.
Not for children
Avonex should not be used in children under 12 years of age.
If you have decided to start treatment with Avonex, your doctor may provide you with an Avostartclip titration kit. The Avostartclip clips onto the syringe and allows you to gradually increase the dose of Avonex at the start of treatment. This limits the flu-like symptoms that some people experience when they start using Avonex. Your doctor or nurse will teach you to use the Avostartclip titration kit.
(Additional information)
Start of Avonex therapy
If you have never taken Avonex before, your doctor may advise you to gradually increase the dose to get used to the effects of Avonex before taking the full dose. You will likely be provided with an Avostartclip titration kit, which is mounted on the syringe allowing the administration of a reduced dose of Avonex at the start of therapy. Each Avostartclip is for single use only and must then be disposed of with the remaining Avonex. For more information on the use of this device, ask your doctor.
Perform the injection yourself
You can inject Avonex without your doctor's help if you have been told how to do it. Instructions for injection are provided at the end of this leaflet (see section 7, How to inject AVONEX).
If you have problems handling the syringe, ask your doctor, who can help you.
(Additional information)
At the bottom of the leaflet you will find more details on how to inject Avonex.
Alternative needle:
An injection needle is already included in the Avonex package. Your doctor may prescribe a shorter, thinner needle depending on your physical characteristics. If you think this is the case, talk to your doctor.
If you have trouble handling the syringe, talk to your doctor about using a suitable tool. This tool consists of a holder specially designed to facilitate the injection of Avonex. How long to use AVONEX Your doctor will decide how long you need to use Avonex. It is important to continue using Avonex regularly. Do not change anything to your therapy except on the advice of your doctor. .
How to inject AVONEX
You must have already been instructed on how to inject Avonex. These directions are just a reminder. If you have any further questions, ask your doctor or pharmacist.
Choice of injection site
- Avonex is injected into a muscle, such as one of the upper thigh muscles. It is not recommended to inject Avonex into the buttocks.
- Choose a different injection site each week. This reduces the risk of skin or muscle irritation.
- Do not choose skin areas with bruises, lesions or infections and do not inject into an open wound.
Preparation
- Remove a sealed tray from the refrigerator - Check the expiration date on the lid of the tray. Do not use the product if it has expired. - Remove the paper cover completely. Check that the tray contains a pre-filled syringe and an injection needle (see figure "Contents of the plastic tray").
- Allow the syringe to warm up - Leave the syringe at room temperature for half an hour. This will make it more comfortable to inject than to inject immediately after removal from the refrigerator. Caution: Do not use external heat sources, such as hot water, to warm the syringe.
- Wash your hands thoroughly with soap and water and dry them.
- Prepare alcohol wipes and patches (not provided) if you need them. Look for a clean, hard surface to lay the material needed for the injection. Place the tray on it.
Preparation of the injection
- Check the liquid in the syringe. It should appear clear and colorless. If the solution is cloudy or colored, or if suspended particles are visible, do not use the pre-filled syringe.
- Remove the syringe cap The syringe has a white tamper evident cap. Make sure the cap is intact and has not been opened. If it looks like the cap has been opened, do not use the syringe. Hold the syringe with the white cap pointing up. Bend the cap at right angles until it pops out. Do not touch the joint. Do not push the plunger.
- Attaching the needle Open the needle to expose the joint. Keep the protective wrapping on the needle. Push the needle onto the syringe. Turn it clockwise until it clicks into place. Caution: Make sure the needle is fully inserted into the syringe, otherwise it may leak. If you have been told to increase your Avonex dose gradually, you may need an Avostartclip titration kit provided by your doctor. For further details, please ask your doctor. Now remove the protective wrapping from the needle. Don't rotate it. Caution: If you rotate the protective wrapper as you remove it, you may inadvertently remove the needle as well.
Carrying out the injection
- Clean and stretch the injection site. If desired, use an alcohol wipe to cleanse the skin at the injection site of your choice. Wait for the skin to dry. With one hand, stretch the skin around the injection site. Relax the muscle.
- Perform the injection. Insert the needle into the muscle with a quick push perpendicular to the skin. The needle should go all the way in. Slowly push the plunger down until the syringe is empty. If you use the syringe with the Avostartclip, you will receive a lower dose of Avonex. The syringe will not empty.
- Pull out the needle. Remove the injection needle by keeping the skin firmly stretched or compressed around the injection site. If you are using cotton swabs with alcohol, place one over the injection site. If you wish, apply a patch to the site. injection.
Properly dispose of used material
After giving the injection, place the needle and syringe in an appropriate container (a sharps container), not in household waste. If you have used Avostartclip, you must throw away the syringe (and Avostartclip) after injection. The unused portion of Avonex should not be reused. Paper and swabs can be placed in a regular waste bin.
Overdose What to do if you have taken too much Avonex
If you inject too much
You only need to have one Avonex injection per week. If you have had more than one "Avonex injection" in three days, ask your doctor or pharmacist for advice immediately.
If you forget an injection
If you miss the usual weekly dose, inject a dose as soon as possible. Then allow one week to pass before your next Avonex injection. Continue the injections on this new day every week. If there is a particular day of the week on which you prefer to inject, ask your doctor for instructions on how to return the injection to your preferred day.
Do not inject a double dose to make up for a forgotten dose.
Side Effects What are the side effects of Avonex
Like all medicines, this medicine can cause side effects, although not everybody gets them.
(Additional information)
While the list of possible side effects seems worrying, you may not experience any of them.
Serious side effects: seek medical attention
Severe allergic reactions
If it occurs:
- Swelling of the face, lips or tongue
- Difficulty in breathing
- Redness
call your doctor immediately. Do not continue using Avonex until you have told your doctor.
Depression
If you experience symptoms of depression:
- Unusual feeling of sadness, anxiety or a sense of worthlessness
call your doctor immediately.
Liver problems
If it occurs:
- Yellowing of the skin or whites of the eyes (jaundice)
- Widespread itching
- Nausea and vomit
- Ease of bruising call your doctor immediately, as these may be symptoms of a liver problem.
Undesirable effects found in clinical trials
(Additional information)
Undesirable effects found in clinical studies. These are side effects reported during the time Avonex was studied. The figures shown are based on the number of people who have reported the effect and are used to give an idea of the likelihood that you may also experience the adverse effect in question.
Very common side effects (affecting at least 1 in 10 people)
- flu-like symptoms - headache, body aches, chills or fever: see Flu-like symptoms below
- headache.
Common side effects (affecting less than 1 in 10 people)
- Loss of appetite
- Feeling of weakness and tiredness
- Difficulty sleeping
- Depression
- Redness
- Runny nose
- Diarrhea
- Nausea or vomiting
- Numbness or tingling of the skin
- Rashes or bruises
- Increased sweating, night sweats
- Muscle or joint pain, pain in the arms, legs or neck
- Muscle cramps, muscle or joint stiffness
- Pain, bruising and redness at the injection site
- Changes in blood test results. Symptoms you may notice are fatigue, repeated infections, bruising or unexplained bleeding.
Uncommon side effects (affecting less than 1 in 100 people)
- Hair loss
- Alterations in the menstrual cycle
- Burning sensation at the injection site.
Rare side effects (affecting less than 1 in 1000 people)
- Difficulty in breathing.
- Kidney problems, including scarring, which may reduce kidney function If you get any or all of these symptoms: Foamy urine Fatigue Swelling, particularly in the ankles and eyelids, and weight gain. Tell your doctor as these could be signs of a possible kidney problem.
- Thrombus (blood clots) within small blood vessels which may affect the kidneys (thrombotic thrombocytopenic purpura or haemolytic uremic syndrome). Symptoms may include increased bruising, bleeding, fever, extreme weakness, headache, dizziness or light-headedness Your doctor is likely to find changes in your blood and kidney function If any of these side effects bother you, talk to your doctor.
Other side effects
(Additional information)
These effects have been seen in people using Avonex, but it is not known what the likelihood of them occurring is.
- Hypo- or hyperthyroidism
- Nervousness or anxiety, emotional instability, irrational thoughts or hallucinations (imaginary visions or sounds), confusion, suicidal ideation
- Numbness, dizziness, seizures and migraines
- Awareness of heartbeat (palpitations), rapid or irregular heart rate, heart problems with the following symptoms: decreased ability to exercise, inability to lie in bed, shortness of breath or swollen ankles
- Liver problems, described above
- Hives or vesicular rash, itching or flare-up of psoriasis, if you have them
- Swelling or bleeding at the injection site or chest pain after injection
- Weight gain or loss
- Changes in laboratory test results, including liver function tests.
If any of these side effects bother you, talk to your doctor.
Undesirable effects of the injection
- Feeling faint: Your first injection of Avonex may be given by your doctor, as it may make you feel faint or may actually make you pass out. This is unlikely to happen more than once.
- Immediately after the injection you may experience muscle hypertonia or weakness - a relapse-like effect of MS. This is rare, only occurs at the time of injection and passes shortly after. However, this side effect can occur at any time after starting Avonex therapy.
- If you notice any irritation or skin problems after the injection, please talk to your doctor.
Flu-like symptoms
(Additional information)
Three simple ways to reduce the intensity of flu-like symptoms:
- Inject Avonex just before bedtime. So when side effects occur, you will be asleep.
- Take acetaminophen or ibuprofen half an hour before the Avonex injection and continue taking them for one more day. Get advice on a suitable dose from your doctor or pharmacist.
- If you get a fever, drink plenty of water to keep your body hydrated.
After injecting the dose of Avonex, some people feel like they have the flu. The symptoms are:
- Headache
- Muscle aches
- Chills or fever.
These symptoms do not stem from a real flu.
For this reason, he should not be afraid of infecting other people. Symptoms of this type are more common at the start of Avonex therapy. Your doctor may provide you with an Avostartclip titration kit which allows you to gradually increase your dose at the start of therapy, helping you to limit flu-like symptoms. As you continue with the injections, the flu-like symptoms will gradually subside.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last day of that month. C.
Store in the original package (sealed plastic tray) to protect the medicine from light. Store in the refrigerator (between 2 ° C and 8 ° C). Do not freeze.
Avonex can also be stored at room temperature (between 15 ° C and 30 ° C) for no more than a week.
DO NOT use Avonex if you notice that:
- the pre-filled syringe is broken.
- the sealed plastic tray is damaged or open.
- the solution does not appear colorless or if suspended particles are visible.
- the tamper-proof cap has been broken.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Composition and pharmaceutical form
What AVONEX
The active substance is: interferon beta-1a, 30 micrograms / 0.5ml
The other ingredients are: sodium acetate, trihydrate, glacial acetic acid, arginine hydrochloride, polysorbate 20 and water for injections.
What AVONEX looks like and contents of the pack
Avonex Solution for Injection consists of ready-to-use injections.
A pack of Avonex includes four or twelve ready-to-use (pre-filled) syringes, each containing 0.5 ml of clear, colorless liquid. Not all pack sizes may be marketed. Each syringe is packed in a tray of sealed plastic. An injection needle is also included in each package.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
AVONEX 30 MCG / 0.5 ML SOLUTION FOR INJECTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 0.5 ml pre-filled syringe contains 30 mcg (6 million IU) of interferon beta-1a.
The concentration is equal to 30 mcg per 0.5 ml.
Using the World Health Organization (WHO) International Standard for Interferon, 30 mcg of AVONEX contains 6 million IU of antiviral activity. The activity related to other standards is not known.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Injectable solution.
Clear and colorless solution.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
AVONEX is indicated for the treatment of:
• Patients diagnosed with relapsing multiple sclerosis (MS). In clinical trials this was characterized by two or more acute exacerbations (relapses) in the previous three years with no evidence of continued progression between relapses; AVONEX slows the progression of disability and decreases the frequency of relapses.
• Patients with a single demyelinating event with an active inflammatory process, if this event is severe enough to require treatment with intravenous corticosteroids, other diagnoses have been ruled out, and if it has been established that patients are high risk of developing clinically defined multiple sclerosis (see section 5.1).
AVONEX should be discontinued in patients who develop progressive MS.
04.2 Posology and method of administration
Treatment should be initiated under the supervision of a physician experienced in the treatment of the disease.
Dosage
Adults: the recommended dose for the treatment of relapsing forms of MS is 30 micrograms (0.5 ml solution), administered by intramuscular (IM) injection once weekly (see section 6.6). No additional benefit was demonstrated by administering a higher dose (60 mcg) once a week.
Titration: To help patients reduce the incidence and severity of flu-like symptoms (see section 4.8), titration can be performed at the start of therapy.
Titration can be achieved with either BIOSET or pre-filled syringe by starting therapy in ¼ weekly dose increments until full dose (30 mcg / week) is reached by the fourth week.
An alternative titration schedule can be obtained by initiating therapy with approximately ½ dose of AVONEX once weekly before reaching the full dose. To achieve adequate therapy efficacy, a dose of 30 micrograms per week should be reached and maintained after the initial titration period.
The AVOSTARTCLIP Titration Kit has been designed to be used only with the pre-filled syringe. It can be used to achieve ¼ or ½ dose increments. Each AVOSTARTCLIP should be used once and then discarded with the AVONEX content remaining in the syringe.
Before the injection and for a further 24 hours after each injection, an antipyretic analgesic is recommended to decrease the flu-like symptoms associated with the administration of AVONEX. These symptoms are usually present during the first months of treatment.
Pediatric population: The safety and efficacy of AVONEX in adolescents aged 12 to 16 years have not yet been established. Currently available data are described in sections 4.8 and 5.1 but no recommendation on a posology can be made.
The safety and efficacy of AVONEX in children aged less than 12 years have not yet been established. There are no data available.
Senior citizens: clinical trials did not include enough patients aged 65 and over to determine whether they respond differently than younger subjects. However, based on the mode of clearance of the active substance, there is no theoretical reason why dosage adjustment is necessary in elderly patients.
Method of administration
The site of the intramuscular injection should be changed every week (see section 5.3).
Your physician may prescribe a 25 by 25 mm diameter needle for patients in whom it is appropriate to use this needle for administering an intramuscular injection.
It is currently unknown how long the patient should be treated. Patients should be clinically evaluated after two years of treatment and the decision for longer term treatment should be made on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive MS.
04.3 Contraindications
- Initiation of therapy in pregnancy (see section 4.6).
- Patients with a history of hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed in section 6.1.
- Patients with severe depression and / or ongoing suicidal ideation (see sections 4.4 and 4.8).
04.4 Special warnings and appropriate precautions for use
AVONEX should be administered with caution to patients with current or previous depressive syndrome or other mood disorders, particularly patients with a history of suicidal ideation (see section 4.3). Depression and suicidal ideation are known to be conditions they occur more frequently in patients with multiple sclerosis and in association with the use of interferon. Patients should be advised to report any symptoms of depression and / or suicidal thoughts immediately to their treating physician.
Patients with signs of depression should be closely monitored during therapy and treated appropriately. Discontinuation of AVONEX therapy should be considered (see also sections 4.3 and 4.8).
AVONEX should be administered with caution to patients with a history of seizures and to those treated with antiepileptic drugs, especially if their epilepsy is not adequately controlled by antiepileptics (see sections 4.5 and 4.8).
Caution should be exercised and close monitoring considered when administering AVONEX to patients with severe renal and hepatic impairment and to patients with severe myelosuppression.
Thrombotic microangiopathy (TMA): There have been reports of TMA manifesting as thrombotic thrombocytopenic purpura (TTP) or haemolytic uremic syndrome (HUS), including fatal cases with interferon-beta products. The events have been reported at different times during the course of treatment and can occur from several weeks to several years after the start of treatment with interferon-beta. Initial clinical features include thrombocytopenia, new onset hypertension, fever, symptoms related to the central nervous system (eg, confusion, paresis) and impaired renal function. Laboratory findings suggesting the presence of TMA include decreased platelet counts, increased serum lactate dehydrogenase (LDH) due to hemolysis, and presence of schistocytes (erythrocyte fragmentation) on a blood smear. Consequently, if clinical features of TMA are observed, further testing of blood platelet levels, serum LDH, blood smears, and renal function is recommended. prompt treatment (considering plasma exchange) and immediate discontinuation of Avonex is recommended.
Nephrotic syndrome - Cases of nephrotic syndrome with several underlying nephropathies have been reported during treatment with interferon beta products, including collapsing focal segmental glomerulosclerosis (FSGS), minimal change disease , MCD), membrano-proliferative glomerulonephritis (membranoproliferative glomerulonephritis MPGN) and membranous glomerulopathy (MGN). The events have been reported at different times during the course of treatment and can occur after several years of treatment with interferon beta. Periodic monitoring for early signs or symptoms, such as edema, proteinuria and impaired renal function, is recommended, particularly in patients at increased risk of renal disease. Nephrotic syndrome should be treated promptly and discontinuation of AVONEX should be considered.
Post-marketing cases of hepatic injury, including elevated serum liver enzymes, hepatitis, autoimmune hepatitis and hepatic failure associated with the use of interferon beta have been reported (see section 4.8). In some cases, such reactions have occurred. in the presence of other medicinal products that have been associated with hepatic injury. The potential for additional effects from administration of multiple medicinal products or other hepatotoxic agents (e.g. alcohol) has not been established. Patients should be monitored for signs of liver injury and caution should be exercised when using interferons concomitantly with other medicinal products associated with hepatic injury.
Patients with heart disease such as angina, congestive heart failure or arrhythmia should be monitored closely for worsening of their medical condition during treatment with AVONEX. Flu-like symptoms associated with AVONEX therapy can be stressful for patients. patients with associated cardiac dysfunctions.
Abnormalities in laboratory data can occur with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring MS patients, it is recommended to perform complete and differential leukocyte counts, platelet counts during AVONEX therapy. and blood tests including liver function tests Patients with myelosuppression may require more intensive monitoring of blood counts, with differential and platelet counts.
Patients can develop antibodies to AVONEX. Antibodies from some of these patients reduce the activity of interferon beta-1a in vitro (neutralizing antibodies). Neutralizing antibodies are associated with a reduction in vivo of the biological effects of AVONEX and potentially may be associated with a reduction in clinical efficacy. It is estimated that the plateau of incidence of neutralizing antibody formation is reached after 12 months of treatment. Recent clinical studies performed on patients treated for up to three years with AVONEX suggest that approximately 5% to 8% of them develop neutralizing antibodies.
The use of various methods to determine serum antibodies to interferon limits the ability to compare antigenicity between different products.
04.5 Interactions with other medicinal products and other forms of interaction
No formal interaction studies have been performed in humans.
The interaction of AVONEX with corticosteroids or with adrenocorticotropic hormone (ACTH) has not been systematically studied. Clinical studies indicate that MS patients can receive AVONEX and corticosteroids or ACTH during relapses.
Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymes in humans and animals. The effect of high dose administration of AVONEX on P450-dependent metabolism in monkeys has been evaluated and no changes in liver metabolising capacity were observed. Caution should be exercised when AVONEX is administered in combination with medicinal products that have a narrow therapeutic index. and whose "clearance" is largely dependent on the hepatic cytochrome P450 system, for example some classes of antiepileptics and antidepressants.
04.6 Pregnancy and lactation
Pregnancy
There are limited data on the use of AVONEX in pregnancy. Available data indicate a possible increased risk of spontaneous abortion. Initiation of treatment is contraindicated in pregnancy (see section 4.3).
Women of childbearing age must use adequate contraceptive methods. Patients who become pregnant and those planning to become pregnant during AVONEX therapy should be informed of the potential risks and discontinuation of AVONEX therapy should be considered (see section 5.3). In patients with a high incidence of relapse prior to initiation of therapy, the risk of serious relapse following discontinuation of AVONEX due to pregnancy should be weighed against a possible increased risk of spontaneous abortion.
Feeding time
It is not known whether AVONEX is excreted in human milk. Because of the possibility of serious adverse reactions in breastfed infants, a decision must be made whether to discontinue breastfeeding or AVONEX therapy.
Fertility
Fertility and developmental studies have been conducted in rhesus monkeys with a related form of interferon beta-1a. Anovulatory and abortive effects were observed in study animals at very high doses (see section 5.3).
No information is available on the effects of interferon beta-1a on male fertility.
04.7 Effects on ability to drive and use machines
No studies on the effects of AVONEX on the ability to drive and use machines have been performed. Reported adverse reactions affecting the central nervous system may have a minor effect on the ability to drive and operate machines in sensitive patients (see section 4.8).
04.8 Undesirable effects
The highest incidence of adverse reactions associated with AVONEX therapy is related to flu-like symptoms. The most commonly reported flu-like symptoms are: muscle aches, fever, chills, sweating, asthenia, headache and nausea. Titration of AVONEX at initiation of therapy demonstrated a reduction in the severity and incidence of flu-like symptoms. Flu-like symptoms tend to be more pronounced at initiation of therapy and become less frequent with continued treatment.
After injection of the product, transient neurological symptoms may occur, which may appear similar to an exacerbation of MS. Transient episodes of hypertonia and / or severe muscle weakness that prevent voluntary movement may occur at any time during treatment. These episodes are of limited duration, temporally related to the injections and may recur after subsequent injections. In some cases these symptoms are associated with flu-like symptoms.
The frequencies of observed adverse reactions are expressed in patient-years, according to the following categories:
Very common (≥1 / 10 patient-years);
Common (≥1 / 100,
Uncommon (≥1 / 1,000 to
Rare (≥1 / 10,000,
Very rare (
Not known (frequency cannot be estimated from the available data).
The patient-time index represents the sum of the individual units of time that the patient in the study was exposed to AVONEX before experiencing the adverse reaction. For example, 100 person-years can indicate 100 patients treated for one year or 200 patients treated for half a year.
The following table lists adverse reactions from studies (clinical and observational studies, with a follow-up period ranging from two to six years) and other adverse reactions identified through spontaneous user reports, with an unknown frequency.
Within each frequency class, undesirable effects are reported in descending order of severity.
* Class effect for interferon-beta products (see section 4.4)
+ Class effect for interferon-containing medicines, see below Pulmonary arterial hypertension.
1 Injection site reactions have been reported, including pain, inflammation and very rare cases of abscess or cellulitis that may require surgery.
2 The frequency of the manifestation is higher at the beginning of the therapy.
3 A syncope episode may occur after an AVONEX injection, but this is usually an isolated episode that usually occurs at the start of therapy and does not recur with subsequent injections.
Pulmonary arterial hypertension
Cases of pulmonary arterial hypertension (PAH) have been reported with medicinal products containing interferon beta. The events were reported at various times, including several years after starting treatment with beta interferon.
Pediatric population
The few published data suggest that the safety profile in adolescents aged 12-16 years receiving AVONEX 30 micrograms intramuscularly (IM) once weekly is similar to that seen in adults.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. . Website: www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
No cases of overdose have been reported. However, in the event of an overdose, the patient should be hospitalized for observation and given appropriate supportive treatment.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: interferons.
ATC code: L03 AB07.
Interferons are a family of natural proteins produced by eukaryotic cells in response to viral infection and other biological inducers. Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities. Three main forms of interferon have been distinguished: alpha, beta and gamma Interferons alpha and beta are classified as Type I interferons and interferon gamma as a Type II interferon. These interferons possess overlapping but clearly distinguishable biological activities. They may also differ with respect to the cellular site of synthesis.
Interferon beta is produced by various cell types including fibroblasts and macrophages. Natural interferon beta and AVONEX (interferon beta-1a) are glycosylated and have a single complex carbohydrate molecule bound to nitrogen. For other proteins it is known. that glycosylation affects blood stability, activity, biological distribution and half-life. However, the effects of interferon beta which are dependent on glycosylation are not fully defined.
Mechanism of action
AVONEX exerts its biological effects by binding to specific receptors on the surface of human cells. This link initiates a complex cascade of intracellular events leading to the expression of numerous interferon-induced gene products and markers. These include Class I MHC, Mx protein, 2 "/ 5" - oligoadenylate synthase, β2 microglobulin and neopterin. Some of these products have been measured in serum and cell fractions of blood collected from patients treated with AVONEX. After a single intramuscular dose of AVONEX, the serum levels of these products remain elevated for at least four days and up to one week.
It is not known whether the mechanism of action of AVONEX in multiple sclerosis follows the same sequence of biological events as described above, because the pathophysiology of multiple sclerosis is not well established.
Clinical efficacy and safety
The effects of MS treatment with lyophilized AVONEX were demonstrated in a single placebo-controlled study in 301 patients (AVONEX n = 158, placebo n = 143) with relapsed MS characterized by at least 2 exacerbations in the previous 3 years or at least one exacerbation at "year prior to entry into the study, when the disease duration was less than 3 years. Patients with an EDSS at entry 1 to 3.5 were entered into the study. Due to the design of the study, patients were followed for varying periods of time. 150 AVONEX-treated patients completed 1 year of study and 85 completed two years of study. In the study, the cumulative percentage of patients who developed disability progression (survival analysis according to the Kaplan-Meier method) at the end of the two years was 35% for patients treated with placebo and 22% for patients treated with AVONEX . Disability progression was measured as a 1.0 point increase in the Expanded Scale for Disability Status (EDSS), lasting at least six months. A one-third reduction in the annual relapse rate has also been demonstrated. This last clinical effect was observed after more than one year of treatment.
A double-blind, randomized, dose comparison study of 802 patients with relapsed MS (AVONEX 30 mcg n = 402, AVONEX 60 mcg n = 400) demonstrated no statistically significant difference or trend between the 30 mcg and 60 mcg of AVONEX for clinical and general parameters of Nuclear Magnetic Resonance (MRI).
The effects of AVONEX in the treatment of MS were also demonstrated in a randomized, double-blind study involving 383 patients (AVONEX n = 193, placebo n = 190) with a single demyelinating event associated with at least two compatible brain lesions detected at RMN. A reduction in the risk of experiencing a second event was observed in the AVONEX treatment group. An effect on MRI parameters was also found. The estimated risk of a second event was 50% over three years and 39% over two years in the placebo group, and 35% (three years) and 21% (two years) in that treated with AVONEX. In a post-hoc analysis, in patients who had at least one gadolinium-enhancing lesion and nine T2 lesions at baseline MRI, the risk of a second event within two years was 56% in the placebo group and 21% in the treatment group. with AVONEX. However, the impact of early AVONEX treatment is not known even in this high-risk subgroup, as the study was designed primarily to evaluate the time interval between first and second events, rather than evolution. long-term disease. Furthermore, there is currently no well-established definition of high-risk patients, although a more conservative approach is to "accept at least nine hyperintense T2 lesions on the initial scan and at least one new T2 lesion or one new gadolinium-enhancing lesion on a subsequent scan. performed at least three months after the first In any case, treatment should only be considered for patients classified as high risk.
Pediatric population
The few data on the efficacy / safety of AVONEX obtained by administering 15 micrograms intramuscularly (IM) once weekly (n = 8) compared to an untreated group (n = 8), with 4-year follow-up, have results were consistent with those seen in adults, however the Expanded Disability Status Scale (EDSS) scores increased in the treated group over the 4-year follow-up, thus indicating disease progression. There is no direct comparison with the currently recommended dose in adults.
05.2 "Pharmacokinetic properties
The pharmacokinetic profile of AVONEX was indirectly assessed by a method that measures the antiviral activity of interferon. This method of analysis is limited in that it is sensitive for interferon but lacks specificity for interferon beta. Alternative analysis techniques are not sensitive enough.
Following intramuscular administration of AVONEX, serum levels of antiviral activity peak between 5 and 15 hours after treatment and decrease with a half-life of approximately 10 hours. With an appropriate correction for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such corrections. Intramuscular administration cannot be substituted for subcutaneous administration.
05.3 Preclinical safety data
Carcinogenicity: No carcinogenic data are available for interferon beta-1a in animals and humans.
Chronic toxicity: In a 26-week repeat toxicity study in rhesus monkeys, intramuscularly administered once a week, in combination with another immunomodulatory agent, a monoclonal antibody to CD40 ligand, no immune response or any sign of toxicity towards interferon beta-1a.
Local Tolerability: Intramuscular irritation has not been evaluated in animals after repeated administration at the same injection site.
Mutagenicity: Limited but relevant mutagenicity studies have been conducted. The results were negative.
Impaired Fertility: Fertility and developmental studies have been conducted in rhesus monkeys with a related form of interferon beta-1a. At very high doses, anovulatory and abortive effects were observed in the study animals. Similar dose-related effects on reproductive activity have also been observed with other forms of alpha and beta interferons.No teratogenic or fetal developmental effects have been observed, but available information on the effects of interferon beta-1a in the peri- and postnatal periods is limited.
No information is available on the effects of interferon beta-1a on male fertility.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium acetate trihydrate
Glacial acetic acid
Arginine hydrochloride
Polysorbate 20
Water for injections
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C)
DO NOT FREEZE.
AVONEX can be stored at room temperature (between 15 ° C and 30 ° C) for up to one week.
Store in the original package (sealed plastic tray) to protect from light (see section 6.5).
06.5 Nature of the immediate packaging and contents of the package
1 ml pre-filled glass syringe (Type I) with tamper evident cap and plunger stopper (bromobutyl rubber) containing 0.5 ml of solution.
Pack size: carton containing four or twelve 0.5 ml pre-filled syringes. Each syringe is packaged in a sealed plastic tray which also contains an injection needle for intramuscular use.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
AVONEX is supplied as a ready-to-use solution for injection in a pre-filled syringe.
Once removed from the refrigerator, AVONEX in pre-filled syringe should be warmed to room temperature (15 ° C - 30 ° 7C) for approximately 30 minutes.
Do not use external heat sources such as hot water to warm AVONEX 30 mcg solution for injection.
If the solution for injection contains particles or is not clear and colorless, the pre-filled syringe should not be used. The injection needle is provided for intramuscular injection. The formulation does not contain preservatives. Each AVONEX pre-filled syringe contains only a single dose. Discard the unused portion of each pre-filled syringe.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
BIOGEN IDEC LIMITED Innovation House 70 Norden Road Maidenhead Berkshire SL6 4AY
UK
08.0 MARKETING AUTHORIZATION NUMBER
A.I.C. 033283033
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 13 March 1997
Date of last renewal: March 13, 2007
10.0 DATE OF REVISION OF THE TEXT
10/2015
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