Interferons (immunomodulators).

Interferon beta-1a

Each BIOSET vial contains 30 micrograms (6 million IU) of interferon beta1a. Following reconstitution with the solvent (water for injections) the vial contains 1.0 ml of solution. The concentration is 30 micrograms per ml. Using the World Health Organisation (WHO) International Standard for Interferon, 30 micrograms of AVONEX contains 6 million IU of antiviral activity. The activity against other standards is not known

Powder and solvent for solution for injection. The vial contains a white to off-white cake.

AVONEX is indicated for the treatment of

• Patients diagnosed with relapsing multiple sclerosis (MS). In clinical trials, this was characterised by two or more acute exacerbations (relapses) in the previous three years without evidence of continuous 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 it is severe enough to warrant treatment with intravenous corticosteroids, 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 MS.

Treatment should be initiated under supervision of a physician experienced in the treatment of the disease.

Adults: The recommended dosage for the treatment of relapsing MS is 30 micrograms (1 ml solution), administered by intramuscular (IM) injection once a week. No additional benefit has been shown by administering a higher dose (60 micrograms) once a week.

The intramuscular injection site should be varied each week.

Doctors may prescribe a 25 mm, 25 gauge needle to patients for whom such a needle is appropriate to administer an intramuscular injection.

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advised to decrease flulike symptoms associated with AVONEX administration. These symptoms are usually present during the first few months of treatment.

At the present time, it is not known for how long patients should be treated. Patients should be clinically evaluated after two 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 MS.

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents. However, limited published data suggest that the safety profile in adolescents from 12 to 16 years of age receiving AVONEX 30 micrograms IM once per week is similar to that seen in adults. There is no information on the use of AVONEX in children under 12 years of age and therefore AVONEX should not be used in this population.

Clinical studies did not include a sufficient number of patients aged 65 and over to determine whether they respond differently than younger patients. However, based on the mode of clearance of the active substance there are no theoretical reasons for any requirement for dose adjustments in the elderly.

 Initiation of treatment in pregnancy.

Patients with a history of hypersensitivity to natural or recombinant interferon -ß, human albumin or to any excipients.

Patients with current severe depression and/or suicidal ideation.

AVONEX should be administered with caution to patients with previous or current depressive disorders, in particular to those with antecedents of suicidal ideation. Depression and suicidal ideation are known to occur in increased frequency in the multiple sclerosis population and in association with interferon use. Patients 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 and treated appropriately. Cessation of therapy with AVONEX should be considered.

AVONEX should be administered with caution to patients with a history of seizures, to those receiving treatment with anti-epileptics, particularly if their epilepsy is not adequately controlled with anti-epileptics.

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 postmarketing. In some cases, these reactions have occurred in the presence of other medicinal products that have been associated with hepatic injury. The potential of additive effects from multiple medicinal products or other hepatotoxic agents (e.g. alcohol) has not been determined. Patients should be monitored for signs of hepatic injury and caution exercised when interferons are used concomitantly with other medicinal products 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. Flu-like symptoms associated with AVONEX therapy may prove stressful to patients with underlying cardiac conditions.

Laboratory abnormalities are associated with the use of interferons. Therefore, in addition to those laboratory tests normally required for monitoring patients with MS, complete and differential white blood cell counts, platelet counts, and blood chemistry, 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 beta1a in vitro (neutralising antibodies). Neutralising antibodies are associated with a reduction in 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 the incidence of neutralising antibody formation is reached after 12 months of treatment. Data from patients treated up to two years with AVONEX suggests that approximately 8% develop neutralising antibodies.

The use of various assays to detect serum antibodies to interferons limits the ability to compare antigenicity among different products.

No formal interaction studies have been performed in humans.

The interaction of AVONEX with corticosteroids or adrenocorticotropic hormone (ACTH) has not been studied systematically. The 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 P450dependent enzymes in humans and animals. The effect of high-dose AVONEX administration on P450dependent 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 medicinal products that have a narrow therapeutic index and are largely dependent on the hepatic cytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants.

The highest incidence of adverse reactions associated with AVONEX therapy is related to flulike symptoms. The most commonly reported flulike symptoms are myalgia, fever, chills, sweating, asthenia, headache and nausea. Flulike symptoms 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 flulike symptoms.

The frequencies of adverse reactions are expressed in patientyears, according to the following categories:

Very common (1/10 patientyears);

Common (1/100 to <1/10 patientyears);

Uncommon (1/1, 000 to <1/100 patientyears);

Rare (1/10, 000 to <1/1,000 patientyears);

Very rare (<1/10,000 patientyears);

Not known (cannot be estimated from the available data).

Patienttime 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 personyears 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.

Adverse reactions identified from studies (clinical trials and observational studies, with a period of follow-up ranging from two years to six years) and other adverse reactions identified through spontaneous reporting from the market, with unknown frequency, are provided in the table below.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Investigations
common	lymphocyte count decreased, white blood cell count decreased, neutrophil count decreased, hematocrit decreased, blood potassium increased, blood urea nitrogen increased
Uncommon	platelet count decreased
Not known	weight decreased, weight increased, liver function tests abnormal
Cardiac disorders
not known	cardiomyopathy, congestive heart failure, palpitations, arrhythmia, tachycardia
Blood and lymphatic system disorders
not known	pancytopenia, thrombocytopenia
Nervous system disorders
very common	headache2
common	muscle spasticity, hypoesthesia
not known	neurological symptoms, syncope3 , hypertonia, dizziness, paraesthesia, seizures, migraine
Respiratory, thoracic and mediastinal disorders
Common	rhinorrhoea
Rare	dyspnoea
Gastrointestinal disorders
common	vomiting, diarrhoea, nausea2
Skin and subcutaneous tissue disorders
Common	rash, sweating increased, contusion
Uncommon	alopecia
Not known	angioneurotic oedema, pruritus, rash vesicular, urticaria, aggravation of psoriasis
Musculoskeletal and connective tissue disorders
Common	muscle cramp, neck pain, myalgia2 , arthralgia, pain in extremity, back pain, muscle stiffness, musculoskeletal stiffness
Uncommon	systemic lupus erythematosus, muscle weakness, arthritis
Endocrine disorders
not known	hypothyroidism, hyperthyroidism
Metabolism and nutrition disorders
common	anorexia
Infections and infestations
Not known	injection site abscess1
Vascular disorders
Common	flushing
not known	vasodilatation
General disorders and administration site conditions
very common	flulike symptoms, pyrexia2 , chills2 , sweating2
common	injection site pain, injection site erythema, injection site bruising, asthenia2 , pain, fatigue2 , malaise, night sweats
Uncommon	Injection site burning
Not known	injection site reaction, injection site inflammation, injection site cellulitis1 , injection site necrosis, injection site bleeding, chest pain
Immune system disorders
Not known
Hepatobiliary disorders
Not known	hepatic failure, hepatitis, autoimmune hepatitis
Reproductive system and breast disorders
Uncommon	metrorrhagia, menorrhagia
Psychiatric disorders
Common	depression, insomnia
Not known	suicide, psychosis, anxiety, confusion, emotional lability

¹Injection site reactions including pain, inflammation and very rare cases of abscess or cellulitis that may require surgical intervention have been reported.

²The frequency of occurrence is higher at the beginning of treatment.

³A 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.

Biogen

(POM)

26 June 2009