Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Children and adolescents:
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during IntronA therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Among children and adolescents treated with IntronA 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). 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 IntronA be discontinued, and the patient followed, with psychiatric intervention as appropriate.
If treatment with interferon 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.
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.
During the course of interferon (standard and pegylated)/ribavirin combination therapy lasting up to 48 weeks in patients ages 3 through 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1). The longer term data available in children treated with the combination therapy with standard interferon/ribavirin are also indicative of substantial growth retardation (>15 percentile decrease in height percentile as compared to baseline) in 21% of children (n=20) despite being off treatment for more than 5 years. Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits >15 percentiles, 10 to 12 years after the end of treatment.
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 final adult 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. There are no data on long term effects on sexual maturation.
Hypersensitivity reactions Acute hypersensitivity reactions (e.g. urticaria, angioedema, bronchoconstriction, anaphylaxis) to interferon alfa-2b have been observed rarely during IntronA therapy. If such a reaction develops, discontinue the medicine and institute appropriate medical therapy. Transient rashes do not necessitate interruption of treatment.
Moderate to severe adverse experiences may require modification of the patient’s dose regimen, or in some cases, termination of IntronA therapy. IntronA increases the risk of liver decompensation and death in patients with cirrhosis.
Discontinue treatment with IntronA in patients with chronic hepatitis who develop prolongation of coagulation markers which might indicate liver decomposition.
Any patient developing liver function abnormalities during treatment with IntronA must be monitored closely and treatment discontinued if signs and symptoms progress.
Liver enzymes and hepatic function should be closely monitored in cirrhotic patients.
Hypotension may occur during IntronA therapy or up to two days post-therapy and may require supportive treatment.
Adequate hydration must be maintained in patients undergoing IntronA therapy since hypotension related to fluid depletion has been seen in some patients. Fluid replacement may be necessary.
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.
IntronA must be used cautiously in patients with debilitating medical conditions, such as those with a history of pulmonary disease (e.g. chronic obstructive pulmonary disease) or diabetes mellitus prone to ketoacidosis. Caution must be observed also in patients with coagulation disorders (e.g. thrombophlebitis, pulmonary embolism) or severe myelosuppression.
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.5). 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. While this has been reported more often in patients with chronic hepatitis C treated with interferon alpha, it has also been reported in patients with oncologic diseases treated with interferon alpha. Prompt discontinuation of interferon alpha administration and treatment with corticosteroids appear to be associated with resolution of pulmonary adverse events.
Ocular adverse events (see section 4.8) including retinal haemorrhages, cotton wool spots, serous retinal detachment, and retinal artery or vein obstruction have been reported in rare instances after treatment with alpha interferons. All patients should have a baseline eye examination. Any patient complaining of changes in visual acuity or visual fields, or reporting other ophthalmologic symptoms during treatment with IntronA, must have a prompt and complete eye examination. Periodic visual examinations during IntronA therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of IntronA should be considered in patients who develop new or worsening ophthalmological disorders.
More significant obtundation and coma, including cases of encephalopathy, have been observed in some patients, usually elderly, treated at higher doses. 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 IntronA.
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders, who require IntronA therapy, must be closely monitored. It is recommended that those patients who have pre-existing cardiac abnormalities and/or are in advanced stages of cancer 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 IntronA therapy. There are no data in children or adolescents with a history of cardiac disease.
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.
Due to reports of interferon alpha exacerbating pre-existing psoriatic disease and sarcoidosis, use of IntronA in patients with psoriasis or sarcoidosis is recommended only if the potential benefit justifies the potential risk.
Preliminary data indicates that interferon alpha therapy may be associated with an increased rate of kidney graft rejection. Liver graft rejection has also been reported.
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 Chronic hepatitis C, Monotherapy (thyroid abnormalities) 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).
Administration of IntronA in combination with other chemotherapeutic agents (e.g. Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration), which may be life-threatening or fatal as a result of the concomitantly administered medicinal product. The most commonly reported potentially life-threatening or fatal adverse events include mucositis, diarrhoea, neutropaenia, renal impairment, and electrolyte disturbance. Because of the risk of increased toxicity, careful adjustments of doses are required for IntronA and for the concomitant chemotherapeutic agents (see section 4.5). When IntronA is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may be increased.
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.
All patients in the 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.
Infrequently, adult patients treated for chronic hepatitis C with IntronA developed thyroid abnormalities, either hypothyroidism or hyperthyroidism. In clinical trials using IntronA therapy, 2.8% patients overall developed thyroid abnormalities. The abnormalities were controlled by conventional therapy for thyroid dysfunction. The mechanism by which IntronA may alter thyroid status is unknown. Prior to initiation of IntronA therapy for the treatment of chronic hepatitis C, evaluate serum thyroid-stimulating hormone (TSH) levels. Any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA treatment may be initiated if TSH levels can be maintained in the normal range by medication. Determine TSH levels if, during the course of IntronA therapy, a patient develops symptoms consistent with possible thyroid dysfunction. In the presence of thyroid dysfunction, IntronA treatment may be continued if TSH levels can be maintained in the normal range by medication. Discontinuation of IntronA therapy has not reversed thyroid dysfunction occurring during treatment (also see Thyroid supplemental monitoring specific for children and adolescents).
Approximately 12% of children treated with interferon alfa-2b and ribavirin combination therapy developed increase in thyroid stimulating hormone (TSH). Another 4% had a transient decrease below the lower limit of normal. Prior to initiation of IntronA therapy, TSH levels must be evaluated and any thyroid abnormality detected at that time must be treated with conventional therapy. IntronA therapy may be initiated if TSH levels can be maintained in the normal range by medication. Thyroid dysfunction during treatment with interferon alfa-2b and ribavirin has been observed. If thyroid abnormalities are detected, the patient’s thyroid status should be evaluated and treated as clinically appropriate. Children and adolescents should be monitored every 3 months for evidence of thyroid dysfunction (e.g. TSH).
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 IntronA and ribavirin to HAART therapy (see ribavirin SPC). Patients treated with IntronA and ribavirin combination therapy and zidovudine could be at increased risk of developing anaemia. 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.
Cases of hepatitis B re-activation (some with severe consequences) have been reported in patients co-infected 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, which may lead to loss of teeth, have been reported in patients receiving IntronA 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 IntronA 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.
Standard haematological tests and blood chemistries (complete blood count and differential, platelet count, electrolytes, liver enzymes, serum protein, serum bilirubin and serum creatinine) are to be conducted in all patients prior to and periodically during systemic treatment with IntronA.
During treatment for hepatitis B or C the recommended testing schedule is at weeks 1, 2, 4, 8, 12, 16, and every other month, thereafter, throughout treatment. If ALT flares during IntronA therapy to greater than or equal to 2 times baseline, IntronA therapy may be continued unless signs and symptoms of liver failure are observed. During ALT flare, the following liver function tests must be monitored at two-week intervals: ALT, prothrombin time, alkaline phosphatase, albumin and bilirubin.
In patients treated for malignant melanoma, liver function and white blood cell (WBC) count and differential must be monitored weekly during the induction phase of therapy and monthly during the maintenance phase of therapy.
Interferon may impair fertility (see section 4.6 and section 5.3).
This medicinal product contains less than 1 mmol sodium (23 mg) per 1 mL, i.e. essentially “sodium-free”.
Interaction studies have only been performed in adults.
Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with IntronA.
Interactions between IntronA and other medicinal products have not been fully evaluated. Caution must be exercised when administering IntronA in combination with other potentially myelosuppressive agents.
Interferons may affect the oxidative metabolic process. This must be considered during concomitant therapy with medicinal products metabolised by this route, such as the xanthine derivatives theophylline or aminophylline. During concomitant therapy with xanthine agents, serum theophylline levels must be monitored and dose adjusted if necessary.
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with IntronA. The aetiology has not been defined. These symptoms have been reported more frequently when shosaikoto, a Chinese herbal medicine, is administered concomitantly with interferon alpha (see section 4.4).
Administration of IntronA in combination with other chemotherapeutic agents (e.g. Ara-C, cyclophosphamide, doxorubicin, teniposide) may lead to increased risk of toxicity (severity and duration) (see section 4.4).
Also see ribavirin SPC if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.
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 SPC). 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 IntronA with telbivudine is contraindicated (see section 4.3).
Women of childbearing potential have to use effective contraception during treatment. Decreased serum estradiol and progesterone concentrations have been reported in women treated with human leukocyte interferon.
IntronA must be used with caution in fertile men.
Ribavirin causes serious birth defects when administered during pregnancy. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking IntronA 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 SPC).
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). The potential risk for humans is unknown. IntronA is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Ribavirin therapy is contraindicated in women who are pregnant.
It is not known whether the components of this medicinal product are excreted in human milk. Because of the potential for adverse reactions in nursing infants, nursing should be discontinued prior to initiation of treatment.
Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment with IntronA, and therefore it is recommended that they avoid driving or operating machinery.
See ribavirin SPC for ribavirin-related undesirable effects if IntronA is to be administered in combination with ribavirin in patients with chronic hepatitis C.
In clinical trials conducted in a broad range of indications and at a wide range of doses (from 6 MIU/m²/week in hairy cell leukaemia up to 100 MIU/m²/week in melanoma), the most commonly reported undesirable effects were pyrexia, fatigue, headache and myalgia. Pyrexia and fatigue were often reversible within 72 hours of interruption or cessation of treatment.
In clinical trials conducted in the hepatitis C population, patients were treated with IntronA alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of IntronA three times a week. In Table 1 the frequency of patients reporting (treatment related) undesirable effects is presented from clinical trials in naïve patients treated for one year. Severity was generally mild to moderate. The adverse reactions listed in Table 1 are based on experience from clinical trials and post-marketing.
Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rarely (≥1/10,000 to <1/1,000); very rarely (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Adverse reactions reported during clinical trials or following the marketing use of IntronA alone or in combination with ribavirin:
Very common: Pharyngitis*, infection viral*
Common: Bronchitis, sinusitis, herpes simplex (resistance), rhinitis
Uncommon: Bacterial infection
Rarely: Pneumonia§, sepsis
Not known: Hepatitis B reactivation in HCV/HBV co-infected patients
Very common: Leukopaenia
Common: Thrombocytopaenia, lymphadenopathy, lymphopenia
Very rarely: Aplastic anaemia
Not known: Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Very rarely: Sarcoidosis, exacerbation of sarcoidosis
Not known: Systemic lupus erythematosus, vasculitis, rheumatoid arthritis (new or aggravated), Vogt-Koyanagi-Harada syndrome, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis§
Common: Hypothyroidism§, hyperthyroidism§
Very rarely: Diabetes, aggravated diabetes
Very common: Anorexia
Common: Hypocalcaemia, dehydration, hyperuricemia, thirst
Very rarely: Hyperglycaemia, hypertriglyceridaemia§, increased appetite
Very common: Depression, insomnia, anxiety, emotional lability*, agitation, nervousness
Common: Confusion, sleep disorder, libido decreased
Rarely: Suicide ideation
Very rarely: Suicide, suicide attempts, aggressive behaviour (sometimes directed against others), psychosis including hallucinations
Not known: Homicidal ideation, mental status change§, mania, bipolar disorders
Very common: Dizziness, headache, concentration impaired, mouth dry
Common: Tremor, paresthesia, hypoesthesia, migraine, flushing, somnolence, taste perversion
Uncommon: Peripheral neuropathy
Very rarely: Cerebrovascular haemorrhage, cerebrovascular ischaemia, seizure, impaired consciousness, encephalopathy
Not known: Mononeuropathies, coma§
Very common: Vision blurred
Common: Conjunctivitis, vision abnormal, lacrimal gland disorder, eye pain
Rarely: Retinal haemorrhages§, retinopathies (including macular oedema), retinal artery or vein obstruction§, optic neuritis, papilloedema, loss of visual acuity or visual field, cottonwool spots§
Not known: Serous retinal detachment
Common: Vertigo, tinnitus
Very rarely: Hearing loss, hearing disorder
Common: Palpitation, tachycardia
Uncommon: Pericarditis
Rarely: Cardiomyopathy
Very rarely: Myocardial infarction, cardiac ischaemia
Not known: Congestive heart failure, pericardial effusion, arrhythmia
Common: Hypertension
Very rarely: Peripheral ischaemia, hypotension§
Very common: Dyspnoea*, coughing*
Common: Epistaxis, respiratory disorder, nasal congestion, rhinorrhea, cough nonproductive
Very rarely: Pulmonary infiltrates§, pneumonitis§
Not known: Pulmonary fibrosis, pulmonary arterial hypertension#
Very common: Nausea/vomiting, abdominal pain, diarrhoea, stomatitis, dyspepsia
Common: Stomatitis ulcerative, right upper quadrant pain, glossitis, gingivitis, constipation, loose stools
Very rarely: Pancreatitis, ischaemic colitis, ulcerative colitis, gingival bleeding
Not known: Periodontal disorder NOS, dental disorder NOS, tongue pigmentation§
Common: Hepatomegaly
Very rarely: Hepatotoxicity, (including fatality)
Very common: Alopecia, pruritus*, skin dry*, rash*, sweating increased
Common: Psoriasis (new or aggravated)§ , rash maculopapular, rash erythematous, eczema, erythema, skin disorder
Very rarely: Stevens Johnson syndrome, toxic epidermal necrolysis, erythema multiforme
Very common: Myalgia, arthralgia, musculoskeletal pain
Common: Arthritis
Very rarely: Rhabdomyolysis, myositis, leg cramps, back pain
Common: Micturition frequency
Very rarely: Renal failure, renal insufficiency, nephrotic syndrome
Common: Amenorrhea, breast pain, dysmenorrhea, menorrhagia, menstrual disorder, vaginal disorder
Very common: Injection site inflammation, injection site reaction*, fatigue, rigors, pyrexia§, flu-like symptoms§, asthenia, irritability, chest pain, malaise
Common: Injection site pain
Very rarely: Injection site necrosis, face oedema
Very common: Weight decrease
* These events were only common with IntronA alone.
§ See section 4.4
# Class label for interferon products, see below Pulmonary arterial hypertension.
These undesirable effects have also been reported with IntronA alone.
The undesirable effects seen with hepatitis C are representative of those reported when IntronA is administered in other indications, with some anticipated dose-related increases in incidence. For example, in a trial of high-dose adjuvant IntronA treatment in patients with melanoma, incidences of fatigue, pyrexia, myalgia, neutropaenia/anaemia, anorexia, nausea and vomiting, diarrhoea, chills, flu- like symptoms, depression, alopecia, altered taste, and dizziness were greater than in the hepatitis C trials. Severity also increased with high dose therapy (WHO Grade 3 and 4, in 66% and 14% of patients, respectively), in comparison with the mild to moderate severity usually associated with lower doses. Undesirable effects were usually managed by dose adjustment. 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 (see section 4.4).
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.
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 (see also section 4.4).
Clinically significant laboratory abnormalities, most frequently occurring at doses greater than 10 million IU daily, include reduction in granulocyte and white blood cell counts; decreases in haemoglobin level and platelet count; increases in alkaline phosphatase, LDH, serum creatinine and serum urea nitrogen levels. Moderate and usually reversible pancytopenia has been reported. Increase in serum ALT/AST (SGPT/SGOT) levels have been noted as an abnormality in some non-hepatitis subjects and also in some patients with chronic hepatitis B coincident with clearance of viral DNAp.
In clinical trials of 118 children and adolescents (3 to 16 years of age), 6% discontinued therapy due to adverse reactions. In general, the adverse reaction profile in the limited children and adolescent population studied was similar to that observed in adults, although there is a paediatric-specific concern regarding growth inhibition as decrease in height percentile (mean percentile decrease of 9 percentile) and weight percentile (mean percentile decrease of 13 percentile) were observed during treatment. Within the 5 years follow-up post-treatment period, the children had a mean height of 44 th percentile, which was below the median of the normative population and less than their mean baseline height (48 th percentile). Twenty (21%) of 97 children had a >15 percentile decrease in height percentile, of whom 10 of the 20 children had a >30 percentile decrease in their height percentile from the start of treatment to the end of long-term follow-up (up to 5 years). Final adult height was available for 14 of those children and demonstrated that 12 continued to show height deficits >15 percentiles, 10 to 12 years after the end of treatment. During combination therapy for up to 48 weeks with IntronA and ribavirin, growth inhibition was observed that resulted in reduced final adult height in some patients. In particular, decrease in mean height percentile from baseline to the end of the long- term follow-up was most prominent in prepubertal age children (see section 4.4).
Furthermore, 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 also experienced other psychiatric adverse events (e.g., depression, emotional lability, and somnolence) (see section 4.4). In addition, injection site disorders, pyrexia, anorexia, vomiting, and emotional lability occurred more frequently in children and adolescents compared to adult patients. Dose modifications were required in 30% of patients, most commonly for anaemia and neutropaenia.
The adverse reactions listed in Table 2 are based on experience from the two multicentre children and adolescent clinical trials. Within the organ system classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥1/10); common (≥1/100, <1/10). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 2. Adverse reactions very commonly and commonly reported during clinical trials in children and adolescent patients treated with IntronA in combination with ribavirin:
Very common: Viral infection, pharyngitis
Common: Fungal infection, bacterial infection, pulmonary infection, otitis media, tooth abscess, herpes simplex, urinary tract infection, vaginitis, gastroenteritis
Common: Neoplasm (unspecified)
Very common: Anaemia, neutropaenia
Common: Thrombocytopaenia, lymphadenopathy
Very common: Hypothyroidism§
Common: Hyperthyroidism§, virilism
Very common: Anorexia
Common: Hypertriglyceridemia§, hyperuricemia, increased appetite
Very common: Depression, emotional lability, insomnia
Common: Suicidal ideation, aggressive reaction, confusion, behaviour disorder, agitation, somnambulism, anxiety, nervousness, sleep disorder, abnormal dreaming, apathy
Very common: Headache, dizziness
Common: Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Common: Flushing, pallor
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhea, sneezing
Very common: Diarrhoea, vomiting, nausea, abdominal pain
_Common:__ Mouth ulceration, stomatitis ulcerative, stomatitis, right upper quadrant pain, dyspepsia, glossitis, gastroesophageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder
Common: Hepatic function abnormal
Skin and subcutaneous tissue disorders
Very common: Alopecia, rash
Common: Photosensitivity reaction, maculopapular rash, eczema, acne, skin disorder, nail disorder, skin discolouration, pruritus, dry skin, erythema, bruise, sweating increased
Very common: Arthralgia, myalgia, musculoskeletal pain
Common: Enuresis, micturition disorder, urinary incontinence
Common:
Female: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder
Male: testicular pain
Very common: Injection site inflammation, injection site reaction, fatigue, rigors, pyrexia§, influenza-like symptoms§, malaise, irritability
Common: Chest pain, asthenia, oedema, injection site pain
Very common: Growth rate decrease (height and/or weight decrease for age)§
Common: Skin laceration
§ See section 4.4
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 must not be mixed with other medicinal products except those mentioned in section 6.6.
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