Chemical formula: C₁₆H₁₇Cl₃I₂N₃NaO₅S Molecular mass: 744.794 g/mol
Interferon, alfa-2b interacts in the following cases:
Interactions between interferon alpha-2b and other medicinal products have not been fully evaluated. Caution must be exercised when administering interferon alpha-2b in combination with other potentially myelosuppressive agents.
Administration of interferon alpha-2b 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 interferon alpha-2b and for the concomitant chemotherapeutic agents. When interferon alpha-2b is used with hydroxyurea, the frequency and severity of cutaneous vasculitis may be increased.
Narcotics, hypnotics or sedatives must be administered with caution when used concomitantly with interferon alfa-2b.
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.
Interferon may impair fertility.
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. 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 If VKH syndrome is suspected, antiviral treatment should be withdrawn and corticosteroid therapy discussed.
Interferon alpha-2b 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.
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during interferon alpha-2b therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Among children and adolescents treated with interferon alpha-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).
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 interferon alpha-2b be discontinued, and the patient followed, with psychiatric intervention as appropriate.
Hypotension may occur during interferon alpha-2b therapy or up to two days post-therapy and may require supportive treatment.
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving interferon alpha-2b 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 interferon alpha-2b 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.
Hypertriglyceridemia and aggravation of hypertriglyceridemia, sometimes severe, have been observed. Monitoring of lipid levels is, therefore, recommended.
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 interferon alpha-2b.
Ocular adverse events 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 interferon alpha-2b, must have a prompt and complete eye examination. Periodic visual examinations during interferon alpha-2b therapy are recommended particularly in patients with disorders that may be associated with retinopathy, such as diabetes mellitus or hypertension. Discontinuation of interferon alpha-2b should be considered in patients who develop new or worsening ophthalmological disorders.
While pyrexia may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent pyrexia must be ruled out.
Pulmonary infiltrates, pneumonitis, and pneumonia, occasionally resulting in fatality, have been observed rarely in interferon alpha treated patients, including those treated with interferon alpha-2b. 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. 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.
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.
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.
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.
The use of interferon alfa-2b in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated.
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 interferon alpha-2b and ribavirin to HAART therapy. Patients treated with interferon alpha-2b 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.
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.
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.
There are no adequate data from the use of interferon alfa-2b in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Interferon alfa-2b 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.
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.
Interferon alfa-2b 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 interferon alfa-2b 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.
Patients are to be advised that they may develop fatigue, somnolence, or confusion during treatment with interferon, alfa-2b, and therefore it is recommended that they avoid driving or operating machinery.
See ribavirin SPC for ribavirin-related undesirable effects if interferon alpha-2b 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 interferon alpha-2b alone or in combination with ribavirin for one year. All patients in these trials received 3 MIU of interferon alpha-2b three times a week. In the list below 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 below 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.
Adverse reactions reported during clinical trials or following the marketing use of interferon alpha-2b 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 interferon alpha-2b alone.
# Class label for interferon products, see below Pulmonary arterial hypertension.
These undesirable effects have also been reported with interferon alpha-2b alone.
The undesirable effects seen with hepatitis C are representative of those reported when interferon alpha-2b is administered in other indications, with some anticipated dose-related increases in incidence. For example, in a trial of high-dose adjuvant interferon alpha-2b 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. 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.
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.
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 interferon alpha-2b 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.
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). 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 the following list 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.
Adverse reactions very commonly and commonly reported during clinical trials in children and adolescent patients treated with interferon alpha-2b 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
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