Roche Products Limited

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4.4         Special warning and precautions for use

Roferon-A should be administered under the supervision of a qualified physician experienced in the management of the respective indication. Appropriate management of the therapy and its complications is possible only when adequate diagnostic and treatment facilities are readily available.

Patients should be informed not only of the benefits of therapy but also that they will probably experience adverse reactions.

Hypersensitivity: If a hypersensitivity reaction occurs during treatment with Roferon-A or in the combination therapy with ribavirin, treatment has to be discontinued and appropriate medical therapy has to be instituted immediately. Transient rashes do not necessitate interruption of treatment.

In transplant patients (e.g., kidney or bone marrow transplant) therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action. As with other alpha interferons, graft rejections have been reported in patients taking Roferon-A.

Fever/Infections: While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) have been reported during treatment with alfa interferons including Roferon-A. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

Psychiatric: Severe psychiatric adverse reactions may manifest in patients receiving therapy with interferons, including Roferon-A. Depression, suicidal ideation, suicidal attempt, and suicide may occur in patients with and without previous psychiatric illness. Physicians should monitor all patients treated with Roferon-A for evidence of depression. Physicians should inform patients of the possible development of depression prior to initiation of therapy, and patients should report any sign or symptom of depression immediately. Psychiatric intervention and/or drug discontinuation should be considered in such cases.

Ophthalmologic: As with other interferons, retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, retinal artery or vein thrombosis and optic neuropathy which may result in loss of vision, have been reported after treatment with Roferon-A. Any patient complaining of decrease or loss of vision must have an eye examination. Because these ocular events may occur in conjunction with other disease states, a visual examination prior to initiation of Roferon-A monotherapy or in the combination therapy with ribavirin is recommended in patients with diabetes mellitus or hypertension. Roferon-A monotherapy or the combination therapy with ribavirin should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Endocrine: Hyperglycemia has been observed rarely in patients treated with Roferon-A. All patients who develop symptoms of hyperglycemia should have their blood glucose measured and followed-up accordingly. Patients with diabetes mellitus may require adjustment of their antidiabetic regimen.

When mild to moderate renal, hepatic or myeloid dysfunction is present, close monitoring of these functions is required.

Hepatic function: In rare cases interferon alpha has been suspected of causing an exacerbation of an underlying autoimmune disease in hepatitis patients. Therefore, when treating hepatitis patients with a history of autoimmune disease caution is recommended. If a deterioration in liver function in these patients develops a determination of autoimmune antibodies should be considered. If necessary treatment should be discontinued.

Bone marrow suppression: Extreme caution should be exercised when administering Roferon-A to patients with severe myelosuppression as it has a suppressive effect on the bone marrow, leading to a fall in the white blood count, particularly granulocytes, platelet count and, less commonly, hemoglobin concentration. This can lead to an increased risk of infection or of haemorrhage. It is important to monitor closely these events in patients and periodic complete blood counts should be performed during the course of Roferon-Atreatment, both prior to therapy and at appropriate periods during therapy.

Autoimmune: The development of different auto-antibodies has been reported during treatment with alpha interferons. Clinical manifestations of autoimmune disease during interferon therapy occur more frequently in subjects predisposed to the development of autoimmune disorders. In patients with an underlying or clinical history of auto-immune disorders, monitoring of symptoms suggestive of these disorders, as well as measurement of auto antibodies and TSH level, is recommended.

The use of Roferon-A in children is not recommended as the safety and effectiveness of Roferon-A in children have not been established.

Efficacy in patients with chronic hepatitis B or C who are on hemodialysis or have hemophilia or are coinfected with human immunodeficiency virus has not been demonstrated.

This product contains less than 1 mmol sodium (23 mg) per 0.6 ml, i.e. essentially ‘sodium-free’.

Combination therapy with ribavirin: Also see ribavirin labelling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should be used when adding Roferon-A and ribavirin to HAART therapy (see ribavirin SPC).

Co-infected patients with advanced cirrhosis receiving HAART may be at increased risk of hepatic decompensation and death. Adding treatment with alfa interferons alone or in combination with ribavirin may increase the risk in this patient subset.

4.8         Undesirable effects

Combination therapy with ribavirin:  Also see ribavirin labeling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.

The following data on adverse reactions are based on information derived from the treatment of cancer patients with a wide variety of malignancies and often refractory to previous therapy and suffering from advanced disease, patients with chronic hepatitis B, and patients with chronic hepatitis C.

Approximately two thirds of cancer patients experienced anorexia and one half nausea. Cardiovascular and pulmonary disorders were seen in about one fifth of cancer patients and consisted of transient hypotension, hypertension, edema, cyanosis, arrhythmias, palpitations and chest pain. Most cancer patients received doses that were significantly higher than the dose now recommended and may explain the higher frequency and severity of adverse reactions in this patient group compared with patients with hepatitis B where adverse reactions are usually transient, and patients return to pre-treatment status within 1 to 2 weeks after the end of therapy. Cardiovascular disorders were very rarely seen in patients with hepatitis B.  In hepatitis B patients, changes in transaminases usually signal an improvement in the clinical state of the patient.

The majority of the patients experienced flu‑like symptoms such as fatigue, pyrexia, rigors, decreased appetite, myalgia, headache, arthralgia and diaphoresis. These acute side‑effects can usually be reduced or eliminated by concurrent administration of paracetamol and tend to diminish with continued therapy or dose modification although continuing therapy can lead to lethargy, asthenia and fatigue.

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

¹(including exacerbations of herpes labialis)

²In myelosuppressed patients, thrombocytopenia and decreased hemoglobin occurred more frequently. Recovery of severe hematological deviations to pre-treatment levels usually occurred within seven to ten days after discontinuing Roferon-A treatment.

³(e.g. urticaria, angioedema, bronchospasm and anaphylaxis)

⁴including atrioventricular block

⁵(reversible upon discontinuation; increased hair loss may continue for several weeks after end of treatment)

⁶exacerbation of, or provocation of psoriasis

⁷(mainly in cancer patients with renal disease)

† Identified in postmarketing experience

Rarely, alpha interferons including Roferon-A used alone or in combination with ribavirin, may be associated with pancytopenia, and very rarely, aplastic anemia has been reported.

Neutralizing antibodies to interferons may form in some patients. In certain clinical conditions (cancer, systemic lupus erythematosus, herpes zoster) antibodies to human leukocyte interferon may also occur spontaneously in patients who have never received exogenous interferons. The clinical significance of the development of antibodies has not been fully clarified.

In clinical trials where lyophilised Roferon-Awhich had been stored at 25°C was used, neutralizing antibodies to Roferon-A have been detected in approximately one fifth of patients. In patients with hepatitis C, a trend for responding patients who develop neutralizing antibodies to lose response while still on treatment and to lose it earlier than patients who do not develop such antibodies, has been seen. No other clinical sequelae of the presence of antibodies to Roferon-A have been documented. The clinical significance of the development of antibodies has not been fully clarified.

No data on neutralizing antibodies yet exist from clinical trials in which lyophilized Roferon-A or Roferon-A solution for injection which is stored at 4°C has been used. In a mouse model, the relative immunogenicity of lyophilized Roferon-A increases with time when the material is stored at 25°C - no such increase in immunogenicity is observed when lyophilised Roferon-A/Roceron-A/Roféron-A is stored at 4°C, the recommended storage conditions.

Postmarketing adverse events

Immune system disorders:

Graft rejections: As with other alpha interferons, graft rejections have been reported in patients taking Roferon-A.

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4.2.      Posology and method of administration

COMBINATION WITH BEVACIZUMAB (AVASTIN)

The combination of Roferon-A with Avastin as first line therapy showed substantial benefit to patients with advanced and/or metastatic renal cell carcinoma (mRCC) with a statistically significant, 1.9-fold increase in the median duration of progression-free survival (10.2 months versus 5.4 months, p<0.0001).

Dosage recommendations:

9 MIU by subcutaneous injection three times weekly until disease progression or up to 12 months.

The safety and efficacy of Roferon-A therapy after 12 months have not been evaluated.

Roferon-A therapy may be initiated with a lower dose (3 or 6 MIU), the recommended dose of 9 MIU should however be reached within the first 2 weeks of treatment.

If the Roferon-A dosage of 9MIU three times per week is not tolerated, the dosage may be reduced to a minimum dosage of 3 MIU three times per week. 

Roferon-A injections are given after completion of the Avastin infusion.  For more information on combination use with Avastin, refer to the Avastin SmPC.

4.5       Interaction with other medicinal products and other forms of interaction

Results from a controlled clinical study in renal cancer patients demonstrated no significant effect of bevacizumab (Avastin) on the pharmacokinetics of interferon alfa-2a (Roferon-A).

5.1       Pharmacodynamic properties

2) Combination with bevacizumab (Avastin)

The pivotal phase III study compared bevacizumab in combination with interferon alfa-2a (N=327) to placebo plus interferon alfa-2a (N=322) as first-line therapy of nephrectomised patients with advanced and/or metastatic rena; cell carcinoma. RCC.A controlled clinical study to evaluate the efficacy and safety of Roferon-A in combination with Avastin as first line therapy showed substantial benefit to patients with advanced and/or metastatic renal cell cancer.  A clinically relevant and The controlled clinical study showed a(Complete Responders + Partial Responders) However, the observed increase of 2 months in overall survival was not significant (median 23.3 vs 21.3 months; hazard ratio 0.91; p=0.3360).

Ninety seven (97) patients in the IFN alfa-2a arm and 131 patients in the Avastin arm reduced the dose of IFN alfa-2a from 9 MIU to either 6 or 3 MIU, three times a week as pre-specified in the protocol.

Dose-reduction of IFN alfa-2a did not appear to affect the efficacy of the combination of Avastin and IFN alfa-2a, based on PFS event free rates over time, as shown by the sub-group analysis. The 131 patients in the Avastin + IFN alfa-2a arm who reduced the IFN alfa-2a dose at 6 or 3 MIU during the study, exhibited at 6, 12 and 18 months, PFS event free rates of 73, 52 and 21% respectively, as compared to 61, 43 and 17% in the total population of patients receiving Avastin + IFN alfa-2a.

Table 1: Efficacy results for study BO17705

α - determined with a 95 % CI. For ORR, a difference in rates between study arms is given instead.

β - p-value was obtained using Log-Rank Test

g - populations for reference are those patients with measurable disease at baseline [ITT N = 289 / 306]

d - p-value was obtained using c2 Test

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1.         NAME OF MEDICINAL PRODUCT

Roferon-A 18 MIU/0.6ml /Roceron-A 18 MIU/0.6ml /Roféron-A 18 MIU/0.6ml

million international units (MIU) solution for injection in cCartridges containing solution for injection

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Roferon-A/Roceron-A/Roféron-A is supplied in cartridges as a ready-to-use solution for injectionEach cartridge contains 18 Million International Units interferon alfa-2a* per 0.6 millilitres** (18MIU/0.6ml).

*Recombinant interferon alfa-2a produced by genetic engineering from Escherichia coliproduced in Escherichia coli by recombinant  DNA technology.

**Contains volume overages

For a full list of excipients, see section 6.1.

Excipients recognized to have a known effect:

Benzyl alcohol (10mg/1ml)

3.         PHARMACEUTICAL FORM

Cartridge containing sSolution for injection in cartridge.

Solution is clear and colourless to light yellow.

4.6Pregnancy and lactation

Combination therapy with ribavirin: Also see ribavirin labelling if interferon alfa-2a is to be administered in combination with ribavirin in patients with chronic hepatitis C.

Use with ribavirin in patients with chronic hepatitis C

Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant.  Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking Roferon-A in combination with ribavirin. Female patients of childbearing potential and their partners must each use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients and their female partners must each use an effective contraceptive during treatment and for 7 months after treatment has been concluded. Please refer to the ribavirin SPC.

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.

However dDepending on dose and schedule as well as the sensitivity of the individual patient, Roferon-A/Roceron-A/Roféron-A may have an effect on the speed of reaction which could impair certain operations, e.g., driving, operation of machinery etc.

4.8     Undesirable effects

Infections & Infestations:

Rare: pneumonia, herpes simplex (including exacerbations of herpes labialis)

Blood & Lymphatic System Disorders:

Very Common: leukopenia

Common: thrombocytopenia, anemia

Rare: agranulocytosis, hemolytic anemia

Very Rare: idiopathic thrombocytopenia purpura

In myelosuppressed patients, thrombocytopenia and decreased hemoglobin occurred more frequently. Recovery of severe hematological deviations to pre-treatment levels usually occurred within seven to ten days after discontinuing Roferon-A/Roceron-A/Roféron-A treatment.

Rarely, alpha interferons including Roferon-A/Roceron-A/Roféron-A, used alone or in combination with ribavirin, may be associated with pancytopenia, and very rarely, aplastic anemia has been reported.

Immune System Disorders:

Rare: autoimmune disorder, acute hypersensitivity reactions (e.g. urticaria, angioedema, bronchospasm and anaphylaxis)

Very Rare: sarcoidosis

Endocrine Disorders:

Rare: hyperthyroidism, hypothyroidism, thyroid dysfunction

Metabolism & Nutrition Disorders:

Very Common: anorexia, nausea, inconsequential hypocalcemia

Uncommon: electrolyte imbalance, dehydration

Rare: hyperglycemia

Very Rare: diabetes mellitus, hypertriglyceridaemia

Psychiatric Disorders:

Uncommon: depression, anxiety, mental status changes, confusional state, abnormal behavior, nervousness, memory impairment, sleep disorder

Rare: suicide, suicide attempt, suicidal ideation

Nervous System Disorders:

Very Common: headache

Uncommon: neuropathy, dizziness, somnolence, dysgeusia, paresthesia, hypoesthesia, tremor

Rare: coma, cerebrovascular accident, convulsions, transient erectile dysfunction

Eye Disorders:

Uncommon: conjunctivitis, visual disturbance

Rare: ischemic retinopathy

Very Rare: optic neuropathy, retinal artery thrombosis, retinal vein thrombosis, retinopathy, retinal hemorrhage, papilledema, retinal exudates

Ear & Labyrinth Disorders:

Uncommon: vertigo

Cardiac Disorders:

Uncommon: arrhythmias, including atrioventricular block, palpitations

Rare: cardiorespiratory arrest, myocardial infarction, congestive heart failure, pulmonary edema, cyanosis

Vascular Disorders:

Uncommon: hypertension, hypotension

Rare: vasculitis

Respiratory, Thoracic & Mediastinal Disorders:

Rare: dyspnea, cough

Gastrointestinal Disorders:

Very Common: diarrhea

Common: nausea/vomiting

Uncommon: abdominal pain, dry mouth

Rare: intestinal hypermotility, constipation, dyspepsia, flatulence, pancreatitis

Very Rare: reactivation of peptic ulcer, non-life threatening gastrointestinal bleeding,

Hepatobiliary Disorders:

Rare: hepatic failure, hepatitis, hepatic dysfunction

Skin & Subcutaneous Tissue Disorders:

Very Common: alopecia (reversible upon discontinuation; increased hair loss may continue for several weeks after end of treatment), sweating increased

Uncommon: exacerbation of, or provocation of, psoriasis, pruritus

Rare: rash, dry skin, epistaxis, mucosal dryness, rhinorrhea

Musculoskeletal & Connective Tissue Disorders:

Very Common: myalgia, arthralgia

Rare: systemic lupus erythematosus, arthritis

Renal & Urinary Disorders:

Uncommon: proteinuria and increased cell count in urine

Rare: acute renal failure (mainly in cancer patients with renal disease), renal impairment

General Disorders & Administration Site Conditions:

Very Common: flu-like illness, fatigue, pyrexia, rigors, appetite decreased

Uncommon: chest pain, edema

Very Rare: injection site necrosis, injection site reaction

Investigations:

Uncommon: Increases in ALT, blood alkaline phosphatase and transaminase, weight loss

Rare: Increases in blood LDH, blood bilirubin, blood creatinine, blood uric acid, blood urea

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

¹(including exacerbations of herpes labialis)

²In myelosuppressed patients, thrombocytopenia and decreased haemoglobin occurred more frequently. Recovery of severe haematological deviations to pre-treatment levels usually occurred within seven to ten days after discontinuing Roferon-A treatment.

³(e.g. urticaria, angioedema, bronchospasm and anaphylaxis)

⁴including atrioventricular block

⁵(reversible upon discontinuation; increased hair loss may continue for several weeks after end of treatment)

⁶exacerbation of, or provocation of psoriasis

⁷(mainly in cancer patients with renal disease)

6.1       List of excipients

Ammonium acetate

Sodium Chloride

Benzyl alcohol (10mg/1ml)

Polysorbate 80

Glacial Acetic acid

Sodium Hydroxide Solution

Water for Injections

6.2       Incompatibilities

Not applicable.In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3       Shelf-life

2 years

After the first dose, Roferon^®-A cartridges may be stored at room temperature (below 25°C) for up to 28 days.

Chemical and physical in use stability has been demonstrated for 3028 days at 25°C.

From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days at 25°C. Other in-use storage times and conditions are the responsibility of the user.

However, it is recommended that the Roferon-Pen/cartridge combination be returned to the fridge after each injection.

6.4       Special precautions for storage

Store cartridges atin a refrigerator (2 °C - 8°C). Do not freeze. Keep containercartridge in the outer carton.

The 18 MIU/0.6 ml solution for injection is suitable for multiple-dose use.

For storage conditions of the reconstituted medicinal product, see section 6.3.

6.5       Nature and contents of container

Cartridge barrel (0.6 ml) composed of Type I flint glass Ph. Eur., PTFE laminated plunger stopper, aluminium crimp cap with PTFE laminated butyl rubber inner seal.0.6 ml of solution in cartridge (type I glass), with a plunger stopper (PTFE laminated), aluminium crimp cap with PTFE laminated butyl rubber stopper inner seal.

Pack sizes: Pack of 1, 3 and  6. Not all pack sizes may be marketed.

After each injection the Roferon^®-Pen/cartridge combination should be returned to the fridge. However, cartridges can be stored continually below 25°C for a maximum period of 28 days with no deterioration in quality.

Always discard cartridges containing residual drug after expiry of the in-use shelf life. Needles should be discarded safely after use.

Any unused product or waste material should be disposed of in accordance with local requirements.

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4.4  Special warnings and precautions for use

Infections: While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) have been reported during treatment with alfa interferons including Roferon-A. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

4.8       Undesirable effects

Rarely, alpha interferons including Roferon-A, used alone or in combination with ribavirin, may be associated with pancytopenia, and very rarely, aplastic anaemia has been reported.

10.        DATE OF REVISION OF THE TEXT

November 2005April 2007