AVONEX® SOLUTION FOR INJECTION
(and dosage form)
AVONEX® SOLUTION FOR INJECTION
Each pre-filled syringe of 0,5 mL contains 30 micrograms (6 million IU) of interferon beta-1a.
Interferons are cytokines that mediate antiviral, antiproliferative and immunomodulatory activities.
Interferon beta-1a exerts its biological effects by binding to specific receptors on the surface of human cells. This binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers.
These include MHC Class 1, Mx protein, 2/5-oligoadeylate synthetase, beta2-microglobulin, and neopterin. After a single IM dose of interferon beta-1a, serum levels of these products remain elevated for at least 4 days and up to 1 week.
The effects of interferon beta-1a in the treatment of multiple sclerosis (MS) were demonstrated in a single placebo-controlled study of 301 patients (interferon beta-1a n=158; placebo n=143) with relapsing multiple sclerosis. Due to the design of the study, patients were followed for variable lengths of time. 150 interferon beta-1a -treated patients completed 1 year on the study and 85 completed 2 years on study. In the study, the cumulative percentage of patients who developed disability progression (by Kaplan-Meier Life Table Analysis) by the end of 2 years was 35% for placebo-treated patients and 22% for interferon beta-1a-treated patients.
Disability progression was measured as an increase in the Expanded Disability Status Scale (EDSS) of 1,0 point, sustained for at least 6 months. It was also known that there was one-third reduction in annual relapse rate. This latter clinical effect was observed after more than one year of treatment.
A double-blind randomised dose comparison study of 802 relapsing MS patients (interferon beta-1a 30 micrograms n=402; interferon beta-1a 60 micrograms n=400) has shown no statistically significant differences or trends between the 30 microgram and 60 microgram doses of interferon beta-1a in clinical and general MRI efficacy parameters.
The effects of interferon beta-1a in the treatment of multiple sclerosis were also demonstrated in a randomised, double blind study performed with 383 patients (interferon beta-1a n=193; placebo n=190) with a single demyelinating event associated with at least two compatible brain MRI lesions. A reduction of the risk of experiencing a second event was noted in the interferon beta-1a treatment group. An effect on MRI parameters was also seen. The estimated risk of a second event was 50% in 3 years and 39% in 2 years in the placebo group and 35% (3 years), 21% (2 years) in the interferon beta-1a group.
In a post-hoc analysis, those patients with a baseline MRI with at least 1 Gd-enhancing lesion and 9 T2 lesions had a 2-year risk of suffering a second event of 56% in the placebo group and 21% in the interferon beta-1a treatment group. However, the impact of early treatment with interferon beta-1a is unknown even in this high-risk subgroup as the study was mainly designed to assess the time to the second event rather than the long term evolution of the disease. Furthermore, for the time-being there is no well established definition of a high risk patient although a more conservative approach is to accept at least 9 T2 hyperintense lesions on the initial scan and at least 1 new T2 or 1 new Gd-enhancing lesion on a follow-up scan taken at least 3 months after the initial scan. In any case treatment should only be considered for patients classified at high risk.
Following IM administration of interferon beta-1a, serum antiviral activity levels peak between 5 and 15 hours post-dose and decline with a half-life of approximately 10 hours. With appropriate adjustment for the rate of absorption from the injection site, the calculated bioavailability is approximately 40%. The calculated bioavailability is greater without such adjustments. Intramuscular bioavailability is three-fold higher than subcutaneous bioavailability. Subcutaneous administration cannot be substituted for IM administration.
AVONEX® is indicated for the treatment of ambulatory patients with relapsing multiple sclerosis (MS) characterized by at least 2 recurrent attacks of neurologic dysfunction (relapses) over the preceding 3-year period without evidence of continuous progression between relapses.
AVONEX® slows the progression of disability and decreases the frequency of relapses.
AVONEX® is also indicated for the treatment of patients who have experienced a single demyelinating event with an active inflammatory process confirmed by at least 9 T2 hyperintense lesions on the initial scan and at least 1 new T2 or one new Gd-enhancing lesion on the follow-up scan taken at least 3 months after the initial scan. If alternative diagnoses have been excluded, and if they are determined to be at high risk of developing clinically definite multiple sclerosis.
AVONEX® should be discontinued in patients who develop progressive multiple sclerosis.
AVONEX® is contra-indicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, or any other component of the formulation.
AVONEX® is contra-indicated in pregnant and breastfeeding patients, patients with severe depressive disorders and/or suicidal ideation, and in epileptic patients with a history of seizures not adequately controlled by treatment.
Depression and suicide: AVONEX® should be used with caution in patients with depression or other mood disorders, conditions that are common with multiple sclerosis. Depression has been reported in association with AVONEX® use and it may occur at any time during treatment. Patients treated with AVONEX® should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibiting depression should be monitored closely during therapy with AVONEX® and treated appropriately. Cessation of therapy with AVONEX® should be considered.
Anaphylaxis has been reported.
No formal drug interaction studies have been conducted with AVONEX® in humans.
The interaction of AVONEX® with corticosteroids or ACTH has not been studied systematically. The clinical studies indicate that multiple sclerosis 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 AVONEX® administration on P450-dependent metabolism in monkeys was evaluated and no changes in liver metabolising capabilities were observed.
Caution should be exercised when AVONEX® is administered in combination with medical products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. anti-epileptics and some classes of antidepressants.
PREGNANCY AND LACTATION
Because of the potential hazards to the foetus, AVONEX® is contra-indicated in pregnancy. There are no studies of interferon beta-1a in pregnant women. Fertile women receiving AVONEX® should take appropriate contraceptive measures. Patients planning for pregnancy and those becoming pregnant should be informed of the potential hazards and AVONEX® should be discontinued.
It is not known whether AVONEX® is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made either to discontinue nursing or to discontinue AVONEX® therapy.
DOSAGE AND DIRECTIONS FOR USE
The recommended dosage of AVONEX® (interferon beta-1a) is 30 micrograms injected intramuscularly once a week.
AVONEX® is intended for use under the guidance and supervision of a physician. Patients may self-inject only if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in intramuscular injection technique. Sites for injection include the thigh or upper arm.
The IM injection site should be varied each week.
Once removed from the refrigerator, AVONEX® Solution for Injection should be allowed to warm to room temperature (15 to 30 °C) for about 30 minutes and used within 12 hours. Do not use external heat sources such as hot water to warm the pre-filled syringes.
If the solution for injection contains particulate matter or if it is any colour other than clear colourless, the pre-filled syringes should not be used. The injection needle for the IM injection is provided.
The formulation does not contain a preservative.
Each pre-filled syringe contains a single dose and any unused portion of the pre-filled syringe should be discarded.
Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flu-like symptoms associated with AVONEX® administration. These symptoms are usually present during the first few months of treatment.
There is no experience with AVONEX® in patients aged 18 years or less. Therefore AVONEX® should not be used in children.
At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after 2 years of treatment and longer-term treatment should be decided on an individual basis by the treating physician. Treatment should be discontinued if the patient develops chronic progressive multiple sclerosis.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS
The highest incidence of adverse events associated with AVONEX® therapy is related to flu syndrome. The most commonly reported symptoms of the flu syndrome are myalgia, fever, chills, sweating, asthenia, headache and nausea. Symptoms of the flu syndrome tend to be most prominent at the initiation of therapy and decrease in frequency with continued treatment.
Transient neurological symptoms that may mimic MS exacerbations may occur following injections. Transient episodes of hypertonia and/or severe muscular weakness that prevent voluntary movements 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 adverse reactions are expressed in patient-years, according to the following categories.
Very common (>1/10 patient-years);
Common (>1/100, <1/10 patient-years);
Uncommon (>1/1000, <1/100 patient-years);
Rare (>1/10 000, <1/1000 patient-years);
Very rare (<1/10 000 patient-years)
Patient-time is the sum of individual units of time that the patient in the study has been exposed to AVONEX® before experiencing the adverse reaction. For example, 100 person-years could be observed in 100 patients who were on treatment for one year or in 200 patients who were on treatment for half a year.
EXPERIENCE FROM STUDIES (clinical trials and observational studies, with a period of follow-up ranging from 2 years to 6 years).
Metabolism and nutritional disorders
Common: Insomnia, depression (see WARNINGS).
Nervous system disorders
Very common: Headache*.
Common: Hypoaesthesia, muscle spasticity.
Common: Vomiting, diarrhoea, nausea*.
Skin and subcutaneous tissue disorders
Common: Rash, sweating increased, contusion.
Musculoskeletal, connective tissue and bone disorders
Common: Muscle cramp, neck pain, myalgia*, arthralgia, pain in extremity, back pain, muscle stiffness, musculoskeletal stiffness.
Reproductive system disorders
Uncommon: Metrorrhagia, menorrhagia.
General disorders and administration site conditions
Very common: Influenza-like illness, pyrexia*, chills*, sweating*.
Common: Injection site pain, injection site erythema, injection site bruising, asthenia*, pain, fatigue*, malaise, night sweats.
Uncommon: Injection site burning.
Common: Lymphocyte count decreased, white blood cells count decreased, neutrophil count decreased, haematocrit decreased, blood potassium increased, blood urea and creatinine increased.
Uncommon: Platelet count decreased.
*The frequency of occurrence is higher at the beginning of treatment.
Other adverse reactions identified through spontaneous reporting, with unknown frequency are:
Blood and lymphatic system disorders
Anxiety, suicide, psychosis, confusion, emotional lability.
Nervous system disorders
Neurological symptoms, syncope(1), hypertonia, dizziness, paraesthesia, seizures, migraine.
Palpitations, tachycardia, arrhythmia, cardiomyopathy, congestive heart failure (see Special Precautions).
Hepatitis, autoimmune hepatitis, hepatic failure (see Special Precautions).
Skin and subcutaneous tissue disorders
Pruritus, rash vesicular, urticaria, aggravation of psoriasis.
Muscle weakness, arthritis, systemic lupus erythematosus.
General disorders and administration site conditions
Injection site reaction, injection site inflammation, injection site cellulitis(2), injection site necrosis, chest pain.
Immune system disorders
Hypersensitivity, allergic reactions, anaphylactic reaction, anaphylactic shock.
Weight decreased, weight increased, liver function tests abnormal.
Infections and infestations
Injection site abscess(2).
(1) A syncope episode may occur after AVONEX® injection, it is normally a single episode that usually appears at the beginning of the treatment and does not recur with subsequent injections.
(2) Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported.
Patients should be informed of the most common adverse events associated with interferon beta administration, including symptoms of the flu-like syndrome. These symptoms tend to be most prominent at the initiation of therapy and decrease in frequency and severity with continued treatment.
Caution should be exercised when administering AVONEX® to patients with pre-existing seizure disorders. For patients without a pre-existing seizure disorder who develop seizures during therapy with AVONEX®, an aetiologic basis should be established and appropriate anti-convulsant therapy instituted prior to resuming AVONEX® treatment.
Caution should be used and close monitoring considered when administering AVONEX® to patients with severe renal and hepatic failure and to patients with severe myelosuppression.
Hepatic injury including elevated serum hepatic enzyme levels, hepatitis, autoimmune hepatitis and hepatic failure has been reported with interferon beta in post-marketing. In some patients a recurrence of elevated serum levels of hepatic enzymes has occurred upon AVONEX® re-challenge. In some cases, these events have occurred in the presence of other drugs that have been associated with hepatic injury. The potential of additive effects from multiple drugs or other hepatotoxic agents (e.g. alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when AVONEX® is used concomitantly with other drugs associated with hepatic injury.
Patients with cardiac disease such as angina, congestive heart failure or arrhythmia should be closely monitored for worsening of their clinical condition during treatment with AVONEX®. Symptoms of the flu-like syndrome associated with AVONEX® therapy may prove stressful to patients with underlying cardiac conditions.
Patients should be advised about the abortifacient potential of AVONEX®.
Laboratory abnormalities are associated with the use of AVONEX®. Therefore in addition to those laboratory tests normally required for monitoring patients with multiple sclerosis, complete and differential white blood cell counts, platelet counts and blood chemistries, including liver function tests, are recommended during AVONEX® therapy. Patients with myelosuppression may require more intensive monitoring of complete blood cell counts, with differential and platelet counts.
Patients may develop antibodies to AVONEX®. The antibodies of some of those patients reduce the activity of interferon beta-1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction of the in vivo biological effects of AVONEX® and may potentially be associated with a reduction of clinical efficacy.
It is estimated that the plateau for incidence of neutralising antibody formation is reached after 12 months of treatment in the majority of patients. Approximately 8% of patients develop neutralising antibodies to AVONEX® treatment.
The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products.
Effects on the ability to drive and use machines
Certain less commonly reported undesirable effects on the central nervous system may influence the ability to drive and operate a machine in susceptible patients.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
There are no reports of overdosage. However in case of overdosage, patients should be hospitalised for observation and appropriate supportive treatment given.
Clear, colourless solution.
1 mL pre-filled glass syringe with tamper evident cap and plunger stopper (bromobutyl) containing 0,5 mL of solution. Each syringe is packed in a sealed plastic tray, which also contains one injection needle for intramuscular use. Four trays are packed into an outer carton box.
Store at 2 to 8°C in a refrigerator.
Do not freeze.
Store in original package in order to protect from light.
KEEP OUT OF REACH OF CHILDREN.
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
DATE OF PUBLICATION OF THE PACKAGE INSERT
22 February 2008
New addition to this site: May 2014
Source: Pharmaceutical Industry
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