Psychiatric and Central Nervous System (CNS)

Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during PegIntron therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alpha interferons. Patients should be closely monitored for any signs or symptoms of psychiatric disorders. If such symptoms appear, the potential seriousness of these undesirable effects must be borne in mind by the prescribing physician and the need for adequate therapeutic management should be considered. If psychiatric symptoms persist or worsen, or suicidal or homicidal ideation is identified, it is recommended that treatment with PegIntron be discontinued, and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions

If treatment with peginterferon alfa-2b is judged necessary in adult patients with existence or history of severe psychiatric conditions, this should only be initiated after having ensured appropriate individualised diagnostic and therapeutic management of the psychiatric condition.

• The use of PegIntron in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.3). Among children and adolescents treated with interferon alfa-2b in combination with ribavirin, suicidal ideation or attempts were reported more frequently compared to adult patients (2.4% vs 1%) during treatment and during the 6-month follow-up after treatment. As in adult patients, children and adolescents experienced other psychiatric adverse events (e.g. depression, emotional lability, and somnolence).

Patients with substance use/abuse

HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with alpha interferon. If treatment with alpha interferon is judged necessary in these patients, the presence of psychiatric co-morbidities and the potential for other substance use should be carefully assessed and adequately managed before initiating therapy. If necessary, an inter-disciplinary approach including a mental health care provider or addiction specialist should be considered to evaluate, treat and follow the patient. Patients should be closely monitored during therapy and even after treatment discontinuation. Early intervention for re-emergence or development of psychiatric disorders and substance use is recommended.

Growth and development (children and adolescents)

During the course of therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common. Long-term data available in children treated with the combination therapy of pegylated interferon/ribavirin are indicative of substantial growth retardation. Thirty two percent (30/94) of subjects demonstrated >15 percentile decrease in height-for-age percentile 5 years after completion of therapy (see sections 4.8 and 5.1).

Case by case benefit/risk assessment in children

The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials (see sections 4.8 and 5.1).

• It is important to consider that the combination therapy induced a growth inhibition, that resulted in reduced height in some patients.
• This risk should be weighed against the disease characteristics of the child, such as evidence of disease progression (notably fibrosis), co-morbidities that may negatively influence the disease progression (such as HIV co-infection), as well as prognostic factors of response (HCV genotype and viral load).

Whenever possible the child should be treated after the pubertal growth spurt, in order to reduce the risk of growth inhibition. Although data are limited, no evidence of long-term effects on sexual maturation was noted in the 5-year observational follow-up study.

More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses for oncology indications. While these effects are generally reversible, in a few patients full resolution took up to three weeks. Very rarely, seizures have occurred with high doses of interferon alpha.

All patients in the selected chronic hepatitis C studies had a liver biopsy before inclusion, but in certain cases (i.e. patients with genotype 2 and 3), treatment may be possible without histological confirmation. Current treatment guidelines should be consulted as to whether a liver biopsy is needed prior to commencing treatment.

Acute hypersensitivity

Acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely during interferon alfa-2b therapy. If such a reaction develops during treatment with PegIntron, discontinue treatment and institute appropriate medical therapy immediately. Transient rashes do not necessitate interruption of treatment.

Cardiovascular system

As with interferon alfa-2b, adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, receiving PegIntron therapy require close monitoring. It is recommended that patients who have pre-existing cardiac abnormalities have electrocardiograms taken prior to and during the course of treatment. Cardiac arrhythmias (primarily supraventricular) usually respond to conventional therapy but may require discontinuation of PegIntron therapy. There are no data in children or adolescents with a history of cardiac disease.

Hepatic Failure

PegIntron increases the risk of hepatic decompensation and death in patients with cirrhosis. As with all interferons, discontinue treatment with PegIntron in patients who develop prolongation of coagulation markers which might indicate liver decompensation. Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.

Pyrexia

While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.

Hydration

Adequate hydration must be maintained in patients undergoing PegIntron therapy since hypotension related to fluid depletion has been seen in some patients treated with alpha interferons. Fluid replacement may be necessary.

Pulmonary changes

Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients. Any patient developing pyrexia, cough, dyspnea or other respiratory symptoms must have a chest X-ray taken. If the chest X-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient is to be monitored closely, and, if appropriate, discontinue interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.

Autoimmune disease

The development of auto-antibodies and autoimmune disorders has been reported during treatment with alpha interferons. Patients predisposed to the development of autoimmune disorders may be at increased risk. Patients with signs or symptoms compatible with autoimmune disorders should be evaluated carefully, and the benefit-risk of continued interferon therapy should be reassessed (see also section 4.4 Thyroid changes and section 4.8).

Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with chronic hepatitis C treated with interferon. This syndrome is a granulomatous inflammatory disorder affecting the eyes, auditory system, meninges, and skin. If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed (see section 4.8).

Ocular changes

Ophthalmologic disorders, including retinal haemorrhages, retinal exudates, serous retinal detachment, and retinal artery or vein occlusion have been reported in rare instances after treatment with alpha interferons (see section 4.8). All patients should have a baseline eye examination. Any patient complaining of ocular symptoms, including loss of visual acuity or visual field must have a prompt and complete eye examination. Periodic visual examinations are recommended during PegIntron therapy, particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of PegIntron should be considered in patients who develop new or worsening ophthalmological disorders.

Thyroid changes

Infrequently, adult patients treated for chronic hepatitis C with interferon alpha have developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. Approximately 21 % of children treated with PegIntron/ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another approximately 2 % had a transient decrease below the lower limit of normal. Prior to initiation of PegIntron therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. Determine TSH levels if, during the course of therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, PegIntron treatment may be continued if TSH levels can be maintained in the normal range by medicine. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).

Metabolic disturbances

Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.

HCV/HIV Co-infection

Mitochondrial toxicity and lactic acidosis

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 PegIntron and ribavirin to HAART therapy (see ribavirin SmPC).

Hepatic decompensation in HCV/HIV co-infected patients with advanced cirrhosis

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. Other baseline factors in co-infected patients that may be associated with a higher risk of hepatic decompensation include treatment with didanosine and elevated bilirubin serum concentration.

Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.

Haematological abnormalities in HCV/HIV co-infected patients

HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and HAART may be at increased risk to develop haematological abnormalities (as neutropenia, thrombocytopenia and anaemia) compared to HCV mono-infected patients. Although, the majority of them could be managed by dose reduction, close monitoring of haematological parameters should be undertaken in this population of patients (see section 4.2 and below “Laboratory tests” and section 4.8).

Patients treated with PegIntron and ribavirin combination therapy and zidovudine are at increased risk of developing anaemia and therefore the concomitant use of this combination with zidovudine is not recommended (see section 4.5).

Patients with low CD4 counts

In patients co-infected with HCV/HIV, limited efficacy and safety data (N=25) are available in subjects with CD4 counts less than 200 cells/µl. Caution is therefore warranted in the treatment of patients with low CD4 counts.

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with PegIntron and ribavirin.

HCV/HBV Coinfection

Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients coinfected with hepatitis B and C viruses treated with interferon. The frequency of such re-activation appears to be low.

All patients should be screened for hepatitis B before starting treatment with interferon for hepatitis C; patients co-infected with hepatitis B and C must then be monitored and managed according to current clinical guidelines.

Dental and periodontal disorders

Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving PegIntron and ribavirin combination therapy. In addition, dry mouth could have a damaging effect on teeth and mucous membranes of the mouth during long-term treatment with the combination of PegIntron and ribavirin. Patients should brush their teeth thoroughly twice daily and have regular dental examinations. In addition some patients may experience vomiting. If this reaction occurs, they should be advised to rinse out their mouth thoroughly afterwards.

Organ transplant recipients

The safety and efficacy of PegIntron alone or in combination with ribavirin for the treatment of hepatitis C in liver or other organ transplant recipients have not been studied. Preliminary data indicate that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.

Other

Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of PegIntron in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.

Laboratory tests

Standard haematologic tests, blood chemistry and a test of thyroid function must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of PegIntron therapy are:

• Platelets ≥100,000/mm³
• Neutrophil count ≥1,500/mm³
• TSH level must be within normal limits

Laboratory evaluations are to be conducted at weeks 2 and 4 of therapy, and periodically thereafter as clinically appropriate. HCV-RNA should be measured periodically during treatment (see section 4.2).

Long term maintenance monotherapy

It has been demonstrated in a clinical study that peginterferon alfa-2b at low-dose (0.5 μg/kg/week) is not effective in long term maintenance monotherapy (for a mean duration of 2.5 years) for the prevention of disease progression in non responders with compensated cirrhosis. No statistically significant effect on the time to development of the first clinical event (liver decompensation, hepatocellular carcinoma, death and/or liver transplantation) was observed as compared to the absence of treatment. PegIntron should therefore not be used as long term maintenance monotherapy.

Important information about some of the ingredients of PegIntron

Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucraseisomaltase insufficiency should not take this medicine.

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.7 ml, i.e., essentially “sodium-free”.

Interaction studies have only been performed in adults.

Telbivudine

A clinical trial investigating the combination of telbivudine, 600 mg daily, with pegylated interferon alfa-2a, 180 micrograms once weekly by subcutaneous administration, indicates that this combination is associated with an increased risk of developing peripheral neuropathy. The mechanism behind these events is not known (see sections 4.3, 4.4 and 4.5 of the telbivudine SmPC). Moreover, the safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B has not been demonstrated. Therefore, the combination of PegIntron with telbivudine is contraindicated (see section 4.3).

Methadone

In patients with chronic hepatitis C that were on stable methadone maintenance therapy and naïve to peginterferon alfa-2b, addition of 1.5 microgram/kg/week of PegIntron subcutaneously for 4 weeks increased R-methadone AUC by approximately 15% (95% Cl for AUC ratio estimate 103–128%). The clinical significance of this finding is unknown; however, patients should be monitored for signs and symptoms of increased sedative effect, as well as respiratory depression. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.

Effect of Peginterferon alfa-2b on Co-administered Medicines

The potential interaction of peginterferon alfa-2b (PegIntron) on substrates of metabolic enzymes was evaluated in 3 multiple-dose clinical pharmacology studies. In these studies, the effects of multiple-dose regimens of peginterferon alfa-2b (PegIntron) were investigated in Hepatitis C subjects (1.5 mcg/week) or healthy subjects (1 mcg/week or 3 mcg/week) (Table 4). A clinically significant pharmacokinetic interaction was not observed between peginterferon alfa-2b (PegIntron) and tolbutamide, midazolam or dapsone; therefore, no dosing adjustment is necessary when peginterferon alfa-2b (PegIntron) is administered with medicines metabolized by CYP2C9, CYP3A4 and N-acetyltransferase. Concomitant administration of peginterferon alfa-2b (PegIntron) with caffeine or desipramine modestly increased the exposure of caffeine and desipramine. When patients are administered PegIntron with medications metabolized by CYP1A2 or CYP2D6, the extent of the decrease in cytochrome P 450 activity is unlikely to have a clinical impact, except with medicines which have a narrow therapeutic margin (Table 5).

Table 4. Effect of Peginterferon alfa-2b on Co-administered Medicines:

^# Calculated from urine data collected over an interval of 48-hours
^## Calculated from urine data collected over an interval of 24-hours

Table 5. Precautions for co-administration (PegIntron should be administered with care when co-administered with the following medicines):

No pharmacokinetic interactions were noted between PegIntron and ribavirin in a multiple-dose pharmacokinetic study.

HCV/HIV Co-infection

Nucleoside analogues

Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, ribavirin increases phosphorylated metabolites of purine nucleosides in vitro. This activity could potentiate the risk of lactic acidosis induced by purine nucleoside analogs (e.g. didanosine or abacavir). Co-administration of ribavirin and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see ribavirin SmPC).

Exacerbation of anaemia due to ribavirin has been reported when zidovudine is part of the regimen used to treat HIV, although the exact mechanism remains to be elucidated. The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.4). Consideration should be given to replacing zidovudine in a combination anti-retroviral treatment (ART) regimen if this is already established. This would be particularly important in patients with a known history of zidovudine-induced anaemia.

Women of childbearing potential/contraception in males and females

PegIntron is recommended for use in fertile women only when they are using effective contraception during the treatment.

Combination therapy with ribavirin

Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking PegIntron in combination with ribavirin. Females of childbearing potential must use an effective contraceptive during treatment and for 4 months after treatment has been concluded. Male patients or their female partners must use an effective contraceptive during treatment and for 7 months after treatment has been concluded (see ribavirin SmPC).

Pregnancy

There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Interferon alfa-2b has been shown to be abortifacient in primates. PegIntron is likely to also cause this effect.

The potential risk in humans is unknown. PegIntron is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.

Combination therapy with ribavirin

Ribavirin causes serious birth defects when administered during pregnancy, therefore ribavirin therapy is contraindicated in women who are pregnant.

Breast-feeding

It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment.

Fertility

There are no data available regarding potential effects of PegIntron treatment on male or female fertility.

Patients who develop fatigue, somnolence or confusion during treatment with PegIntron are cautioned to avoid driving or operating machines.

Adults

Tritherapy

Refer to the SmPC for boceprevir.

Bitherapy and monotherapy

Summary of the safety profile

The most common treatment-related adverse reactions reported during clinical trials with PegIntron in combination with ribavirin in adults, seen in more than half of the study subjects, were fatigue, headache, and injection site reaction. Additional adverse reactions reported in more than 25% of subjects included nausea, chills, insomnia, anaemia, pyrexia, myalgia, asthenia, pain, alopecia, anorexia, weight decreased, depression, rash and irritability. The most frequently reported adverse reactions were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy. Fatigue, alopecia, pruritus, nausea, anorexia, weight decreased, irritability and insomnia occur at a notably lower rate in patients treated with PegIntron monotherapy compared to those treated with combination therapy (see Table 6).

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron/ribavirin. These reactions are listed in table 6 by system organ class and frequency (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) or not known (cannot be estimated from the available data).

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

Table 6. Adverse reactions reported in adults in clinical trials or through post-marketing surveillance in patients treated with peginterferon alfa-2b, including PegIntron monotherapy or PegIntron + ribavirin:

Infections and infestations

Very common: Viral infection*, pharyngitis*

Common: Bacterial infection (including sepsis), fungal infection, influenza, upper respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis

Uncommon: Injection site infection, lower respiratory tract infection

Not known: Hepatitis B reactivation in HCV/HBV co-infected patients

Blood and lymphatic system disorders

Very common: Anaemia, neutropenia

Common: Haemolytic anaemia, leukopenia, thrombocytopenia, lymphadenopathy

Very rare: Aplastic anaemia

Not known: Aplasia pure red cell

Immune system disorders

Uncommon: Drug hypersensitivity

Rare: Sarcoidosis

Not known: Acute hypersensitivity reactions including angioedema, anaphylaxis and anaphylactic reactions including anaphylactic shock, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, systemic lupus erythematosus

Endocrine disorders

Common: Hypothyroidism, hyperthyroidism

Metabolism and nutrition disorders

Very common: Anorexia

Common: Hypocalcemia, hyperuricemia, dehydration, increased appetite

Uncommon: Diabetes mellitus, hypertriglyceridaemia

Rare: Diabetic ketoacidosis

Psychiatric disorders

Very common: Depression, anxiety*, emotional lability*, concentration impaired, insomnia

Common: Aggression, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, libido decreased, apathy, abnormal dreams, crying

Uncommon: Suicide, suicide attempt, suicidal ideation, psychosis, hallucination, panic attack

Rare: Bipolar disorders

Not known: Homicidal ideation, mania

Nervous system disorders

Very common: Headache, dizziness

Common: Amnesia, memory impairment, syncope, migraine, ataxia, confusion, neuralgia, paraesthesia, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia

Uncommon: Neuropathy, neuropathy peripheral

Rare: Convulsion

Very rare: Cerebrovascular haemorrhage, cerebrovascular ischaemia, encephalopathy

Not known: Facial palsy, mononeuropathies

Eye disorders

Common: Visual disturbance, vision blurred, photophobia, conjunctivitis, eye irritation, lacrimal disorder, eye pain, dry eye

Uncommon: Retinal exudates

Rare: Loss of visual acuity or visual fields, retinal haemorrhage, retinopathy, retinal artery occlusion, retinal vein occlusion, optic neuritis, papilloedema, macular oedema

Not known: Serous retinal detachment

Ear and labyrinth disorders

Common: Hearing impaired/loss, tinnitus, vertigo

Uncommon: Ear pain

Cardiac disorders

Common: Palpitations, tachycardia

Uncommon: Myocardial infarction

Rare: Congestive heart failure, cardiomyopathy, arrhythmia, pericarditis

Very rare: Cardiac ischaemia

Not known: Pericardial effusion

Vascular disorders

Common: Hypotension, hypertension, flushing

Rare: Vasculitis

Respiratory, thoracic and mediastinal disorders

Very common: Dyspnoea*, cough*

Common: Dysphonia, epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain

Very rare: Interstitial lung disease

Not known: Pulmonary fibrosis, pulmonary arterial hypertension#

Gastrointestinal disorders

Very common: Vomiting*, nausea, abdominal pain, diarrhoea, dry mouth*

Common: Dyspepsia, gastroesophageal reflux disease, stomatitis, mouth ulceration, glossodynia, gingival bleeding, constipation, flatulence, haemorrhoids, cheilitis, abdominal distension, gingivitis, glossitis, tooth disorder

Uncommon: Pancreatitis, oral pain

Rare: Colitis ischaemic

Very rare: Colitis ulcerative

Not known: Tongue pigmentation

Hepatobiliary disorders

Common: Hyperbilirubinemia, hepatomegaly

Skin and subcutaneous tissue disorders

Very common: Alopecia, pruritus*, dry skin*, rash*

Common: Psoriasis, photosensitivity reaction, rash maculo-papular, dermatitis, erythematous rash, eczema, night sweats, hyperhidrosis, acne, furuncle, erythema, urticaria, abnormal hair texture, nail disorder

Rare: Cutaneous sarcoidosis

Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme

Musculoskeletal and connective tissue disorders

Very common: Myalgia, arthralgia, musculoskeletal pain

Common: Arthritis, back pain, muscle spasms, pain in extremity

Uncommon: Bone pain, muscle weakness

Rare: Rhabdomyolysis, myositis, rheumatoid arthritis

Renal and urinary disorders

Common: Micturition frequency, polyuria, urine abnormality

Rare: Renal failure, renal insufficiency

Reproductive system and breast disorders

Common: Amenorrhoea, breast pain, menorrhagia, menstrual disorder, ovarian disorder, vaginal disorder, sexual dysfunction, prostatitis, erectile dysfunction

General disorders and administration site conditions

Very common: Injection site reaction*, injection site inflammation, fatigue, asthenia, irritability, chills, pyrexia, influenza like illness, pain

Common: Chest pain, chest discomfort, injection site pain, malaise, face oedema, oedema peripheral, feeling abnormal, thirst

Rare: Injection site necrosis

Investigations

Very common: Weight decreased

* These adverse reactions were common (≥1/100 to <1/10) in clinical trials in patients treated with PegIntron monotherapy.
^# Class label for interferon products, see below Pulmonary arterial hypertension.

Description of selected adverse reactions in adults

Most cases of neutropenia and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with the recommended doses of PegIntron in combination with ribavirin (WHO grade 3: 39 of 186 [21%]; and WHO grade 4: 13 of 186 [7%]).

In a clinical trial, approximately 1.2% of patients treated with PegIntron or interferon alfa-2b in combination with ribavirin reported life-threatening psychiatric events during treatment. These events included suicidal ideation and attempted suicide (see section 4.4).

Cardiovascular (CVS) adverse events, particularly arrhythmia, appeared to be correlated mostly with pre-existing CVS disease and prior therapy with cardiotoxic agents (see section 4.4). Cardiomyopathy, that may be reversible upon discontinuation of interferon alpha, has been reported rarely in patients without prior evidence of cardiac disease.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon alfa products, notably in patients with risk factors for PAH (such as portal hypertension, HIV-infection, cirrhosis). Events were reported at various time points typically several months after starting treatment with interferon alfa.

Ophthalmological disorders that have been reported rarely with alpha interferons include retinopathies (including macular oedema), retinal haemorrhages, retinal artery or vein occlusion, retinal exudates, loss of visual acuity or visual field, optic neuritis, and papilloedema (see section 4.4).

A wide variety of autoimmune and immune-mediated disorders have been reported with alpha interferons including thyroid disorders, systemic lupus erythematosus, rheumatoid arthritis (new or aggravated), idiopathic and thrombotic thrombocytopenic purpura, vasculitis, neuropathies including mononeuropathies and Vogt-Koyanagi-Harada syndrome (see also section 4.4).

HCV/HIV co-infected patients

Summary of the safety profile

For HCV/HIV co-infected patients receiving PegIntron in combination with ribavirin, other undesirable effects (that were not reported in mono-infected patients) which have been reported in the larger studies with a frequency >5% were: oral candidiasis (14%), lipodystrophy acquired (13%), CD4 lymphocytes decreased (8%), appetite decreased (8%), gamma-glutamyltransferase increased (9%), back pain (5%), blood amylase increased (6%), blood lactic acid increased (5%), cytolytic hepatitis (6%), lipase increased (6%) and pain in limb (6%).

Description of selected adverse reactions

Mitochondrial toxicity

Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated ribavirin for co-HCV infection (see section 4.4).

Laboratory values for HCV/HIV co-infected patients

Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HCV/HIV co-infected patients, the majority could be managed by dose modification and rarely required premature discontinuation of treatment (see section 4.4). Haematological abnormalities were more frequently reported in patients receiving PegIntron in combination with ribavirin when compared to patients receiving interferon alfa-2b in combination with ribavirin. In Study 1 (see section 5.1), decrease in absolute neutrophil count levels below 500 cells/mm³ was observed in 4% (8/194) of patients and decrease in platelets below 50,000/mm³ was observed in 4% (8/194) of patients receiving PegIntron in combination with ribavirin. Anaemia (hemoglobin <9.4 g/dl) was reported in 12% (23/194) of patients treated with PegIntron in combination with ribavirin.

CD4 lymphocytes decrease

Treatment with PegIntron in combination with ribavirin was associated with decreases in absolute CD4+ cell counts within the first 4 weeks without a reduction in CD4+ cell percentage. The decrease in CD4+ cell counts was reversible upon dose reduction or cessation of therapy. The use of PegIntron in combination with ribavirin had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data (N=25) are available in co-infected patients with CD4+ cell counts <200/µl (see section 4.4).

Please refer to the respective SmPCs of the antiretroviral medicinal products that are to be taken concurrently with HCV therapy for awareness and management of toxicities specific for each product and the potential for overlapping toxicities with PegIntron in combination with ribavirin.

Paediatric population

Summary of the safety profile

In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of PegIntron and ribavirin, dose modifications were required in 25% of patients, most commonly for anaemia, neutropenia and weight loss. In general, the adverse reactions profile in children and adolescents was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition. During combination therapy for up to 48 weeks with PegIntron and ribavirin, growth inhibition was observed that resulted in reduced height in some patients (see section 4.4). Weight loss and growth inhibition were very common during the treatment (at the end of treatment, mean decrease from baseline in weight and height percentile were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (<3^rd percentile in 70% of the patients).

At the end of 24 weeks post-treatment follow-up, mean decrease from baseline in weight and height percentiles were still of 3 percentiles and 7 percentiles respectively, and 20% of the children continued to have inhibited growth (growth velocity <3^rd percentile). Ninety-four of 107 subjects enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those subjects treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term followup among subjects treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of subjects (11/46) treated for 24 weeks and 40 % of subjects (19/48) treated for 48 weeks had a >15 percentile height-for-age decrease from pre-treatment to the end of the 5 year long-term follow-up compared to pre-treatment baseline percentile. Eleven percent of subjects (5/46) treated for 24 weeks and 13 % of subjects (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline of >30 height-for-age percentiles to the end of the 5 year long-term follow-up. For weight, pre-treatment to end of long-term follow-up, weightfor-age percentiles decreased 1.3 and 5.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. For BMI, pre-treatment to end of long-term follow-up, BMI-for-age percentiles decreased 1.8 and 7.5 percentiles among subjects treated for 24 weeks or 48 weeks, respectively. Decrease in mean height percentile at year 1 of long-term follow-up was most prominent in prepubertal age children. The decline of height, weight and BMI Z scores observed during the treatment phase in comparison to a normative population did not fully recover at the end of long-term follow-up period for children treated with 48 weeks of therapy (see section 4.4).

In the treatment phase of this study, the most prevalent adverse reactions in all subjects were pyrexia (80%), headache (62%), neutropenia (33%), fatigue (30%), anorexia (29%) and injection-site erythema (29%). Only 1 subject discontinued therapy as the result of an adverse reaction (thrombocytopenia). The majority of adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 7% (8/107) of all subjects and included injection site pain (1%), pain in extremity (1%), headache (1%), neutropenia (1%), and pyrexia (4%). Important treatment-emergent adverse reactions that occurred in this patient population were nervousness (8%), aggression (3%), anger (2%), depression/depressed mood (4%) and hypothyroidism (3%) and 5 subjects received levothyroxine treatment for hypothyroidism/elevated TSH.

Tabulated summary of adverse reactions

The following treatment-related adverse reactions were reported in the study in children and adolescent patients treated with PegIntron in combination with ribavirin. These reactions are listed in Table 7 by system organ class and frequency (very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) or not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 7. Adverse reactions very commonly, commonly and uncommonly reported in the clinical trial in children and adolescent patients treated with PegIntron in combination with ribavirin:

Infections and infestations

Common: Fungal infection, influenza, oral herpes, otitis media, pharyngitis streptococcal, nasopharyngitis, sinusitis Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis, urinary tract infection, gastroenteritis

Blood and lymphatic system disorders

Very common: Anaemia, leucopenia, neutropenia

Common: Thrombocytopenia, lymphadenopathy

Endocrine disorders

Common: Hypothyroidism

Metabolism and nutrition disorders

Very common: Anorexia, decreased appetite

Psychiatric disorders

Common: Suicidal ideation§, suicide attempt§, depression, aggression, affect lability, anger, agitation, anxiety, mood altered, restlessness, nervousness, insomnia

Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare

Nervous system disorders

Very common: Headache, dizziness

Common: Dysgeusia, syncope, disturbance in attention, somnolence, poor quality sleep

Uncommon: Neuralgia, lethargy, paraesthesia, hypoaesthesia, psychomotor hyperactivity, tremor

Eye disorders

Common: Eye pain

Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia

Ear and labyrinth disorders

Common: Vertigo

Cardiac disorders

Common: Palpitations, tachycardia

Vascular disorders

Common: Flushing

Uncommon: Hypotension, pallor

Respiratory, thoracic and mediastinal disorders

Common: Cough, epistaxis, pharyngolaryngeal pain

Uncommon: Wheezing, nasal discomfort, rhinorrhoea

Gastrointestinal disorders

Very common: Abdominal pain, abdominal pain upper, vomiting, nausea

Common: Diarrhoea, aphthous stomatitis, cheilosis, mouth ulceration, stomach discomfort, oral pain

Uncommon: Dyspepsia, gingivitis

Hepatobiliary disorders

Uncommon: Hepatomegaly

Skin and subcutaneous tissue disorders

Very common: Alopecia, dry skin

Common: Pruritus, rash, rash erythematous, eczema, acne, erythema

Uncommon: Photosensitivity reaction, rash maculo-papular, skin exfoliation, pigmentation disorder, dermatitis atopic, skin discolouration

Musculoskeletal and connective tissue disorders

Very common: Myalgia, arthralgia

Common: Musculoskeletal pain, pain in extremity, back pain

Uncommon: Muscle contracture, muscle twitching

Renal and urinary disorders

Uncommon: Proteinuria

Reproductive system and breast disorders

Uncommon: Female: Dysmenorrhoea

General disorders and administration site conditions

Very common: Injection site erythema, fatigue, pyrexia, rigors, influenza-like illness, asthenia, pain, malaise, irritability

Common: Injection site reaction, injection site pruritus, injection site rash injection site dryness, injection site pain, feeling cold

Uncommon: Chest pain, chest discomfort, facial pain

Investigations

Very common: Growth rate decrease (height and/or weight decrease for age)

Common: Blood thyroid stimulating hormone increased, thyroglobulin increased

Uncommon: Anti-thyroid antibody positive

Injury and poisoning

Uncommon: Contusion

^§ class effect of interferon-alfa containing products – reported with standard interferon therapy in adult and paediatric patients; with PegIntron reported in adult patients.

Description of selected adverse reactions in children and adolescents

Most of the changes in laboratory values in the PegIntron/ribavirin clinical trial were mild or moderate. Decreases in haemoglobin, white blood cells, platelets, neutrophils and increase in bilirubin may require dose reduction or permanent discontinuation from therapy (see section 4.2). While changes in laboratory values were observed in some patients treated with PegIntron used in combination with ribavirin in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product should only be reconstituted with the solvent provided (see section 6.6). In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.