Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for contraindications specific to these products.
Rebetol must be used in combination with other medicinal products (see section 5.1).
Please refer to the SmPC of (peg)interferon alfa for details on the recommendations of monitoring and management regarding the adverse reactions listed below before initiating therapy and other precautions associated with (peg)interferon alfa.
There are several serious adverse reactions associated with the combination therapy of Rebetol with (peg)interferon alfa. These include:
When deciding not to defer combination treatment with peginterferon alfa-2b or interferon alfa-2b until adulthood, it is important to consider that this combination therapy induced a growth inhibition that may be irreversible in some patients. The decision to treat should be made on a case by case.
A decrease in haemoglobin levels to < 10 g/dL was observed in up to 14 % of adult patients and 7 % of children and adolescents treated with Rebetol in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials. Although Rebetol has no direct cardiovascular effects, anaemia associated with Rebetol may result in deterioration of cardiac function, or exacerbation of the symptoms of coronary disease, or both. Thus, Rebetol must be administered with caution to patients with pre-existing cardiac disease (see section 4.3). Cardiac status must be assessed before start of therapy and monitored clinically during therapy; if any deterioration occurs, therapy must be stopped (see section 4.2).
Adult patients with a history of congestive heart failure, myocardial infarction and/or previous or current arrhythmic disorders must be closely monitored. It is recommended that those 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 therapy. There are no data in children or adolescents with a history of cardiac disease.
Prior to initiation of treatment with Rebetol the physician must comprehensively inform both male and female patients of the teratogenic risk of Rebetol, the necessity of effective and continuous contraception, the possibility that contraceptive methods may fail and the possible consequences of pregnancy should it occur during or following treatment with Rebetol (see section 4.6). For laboratory monitoring of pregnancy, please refer to Laboratory tests.
If an acute hypersensitivity reaction (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) develops, Rebetol must be discontinued immediately and appropriate medical therapy instituted. Transient rashes do not necessitate interruption of treatment.
Any patient developing significant liver function abnormalities during treatment must be monitored closely. Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for discontinuation or dose modification recommendations.
The pharmacokinetics of Rebetol is altered in patients with renal dysfunction due to reduction of apparent clearance in these patients. Therefore, it is recommended that renal function be evaluated in all patients prior to initiation of Rebetol. Due to substantial increases in ribavirin plasma concentrations in patients with moderate and severe renal impairment, Rebetol dose adjustments are recommended in adult patients with creatinine clearance < 50 mL/minute. No data are available regarding dose modification for paediatric patients with renal impairment (see sections 4.2 and 5.2). Haemoglobin concentrations should be monitored closely during treatment and corrective action taken as necessary (see section 4.2).
Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the administration of a peginterferon and Rebetol concomitantly with azathioprine. This myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of HCV antiviral therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone (see section 4.5).
Caution should be taken in HIV-positive subjects co-infected with HCV who receive nucleoside reverse transcriptase inhibitor (NRTI) treatment (especially ddI and d4T) and associated interferon alfa/ribavirin treatment. In the HIV-positive population receiving an NRTI regimen, physicians should carefully monitor markers of mitochondrial toxicity and lactic acidosis when Rebetol is administered. For additional details see section 4.5.
Co-infected patients with advanced cirrhosis receiving combined anti-retroviral therapy (cART) may be at increased risk of hepatic decompensation and death. 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 concentrations.
Co-infected patients receiving both antiretroviral (ARV) and anti-hepatitis treatment should be closely monitored, assessing their Child-Pugh score during treatment. Please refer to the corresponding SmPC of medicinal products used in combination with Rebetol for discontinuation or dose modification recommendations. Patients progressing to hepatic decompensation should have their anti-hepatitis treatment immediately discontinued and the ARV treatment reassessed.
HCV/HIV co-infected patients receiving peginterferon alfa-2b/ribavirin treatment and cART 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 Rebetol and zidovudine are at increased risk of developing anaemia; therefore, the concomitant use of Rebetol with zidovudine is not recommended (see section 4.5).
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 corresponding SmPC 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 Rebetol.
Standard haematologic tests, blood chemistries (complete blood count [CBC] and differential, platelet count, electrolytes, serum creatinine, liver function tests, uric acid) and pregnancy tests must be conducted in all patients prior to initiating therapy. Acceptable baseline values that may be considered as a guideline prior to initiation of Rebetol therapy:
Haemoglobin:
Adult: ≥12 g/dL (females); ≥13 g/dL (males)
Children and adolescents: ≥11 g/dL (females); ≥12 g/dL (males)
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).
Uric acid may increase with Rebetol due to haemolysis; therefore, the potential for development of gout must be carefully monitored in pre-disposed patients.
Each Rebetol capsule contains 40 mg of lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Interaction studies have only been performed in adults.
Results of in vitro studies using both human and rat liver microsome preparations indicated no cytochrome P450 enzyme mediated metabolism of Rebetol. Rebetol does not inhibit cytochrome P450 enzymes. There is no evidence from toxicity studies that Rebetol induces liver enzymes. Therefore, there is a minimal potential for P450 enzyme-based interactions.
Rebetol, by having an inhibitory effect on inosine monophosphate dehydrogenase, may interfere with azathioprine metabolism possibly leading to an accumulation of 6-methylthioinosine monophosphate (6-MTIMP), which has been associated with myelotoxicity in patients treated with azathioprine. The use of pegylated alpha interferons and Rebetol concomitantly with azathioprine should be avoided. In individual cases where the benefit of administering Rebetol concomitantly with azathioprine warrants the potential risk, it is recommended that close hematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicines should be stopped (see section 4.4).
No interaction studies have been conducted with Rebetol and other medicinal products, except for peginterferon alfa-2b, interferon alfa-2b and antacids.
No pharmacokinetic interactions were noted between Rebetol and peginterferon alfa-2b or interferon alfa-2b in a multiple-dose pharmacokinetic study.
The bioavailability of Rebetol 600 mg was decreased by co-administration with an antacid containing magnesium aluminium and simethicone; AUCtf decreased 14 %. It is possible that the decreased bioavailability in this study was due to delayed transit of Rebetol or modified pH. This interaction is not considered to be clinically relevant.
Use of nucleoside analogs, alone or in combination with other nucleosides, has resulted in lactic acidosis. Pharmacologically, Rebetol 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 Rebetol and didanosine is not recommended. Reports of mitochondrial toxicity, in particular lactic acidosis and pancreatitis, of which some fatal, have been reported (see section 4.4).
The exacerbation of anaemia due to Rebetol 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 Rebetol 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.
Any potential for interactions may persist for up to two months (five half-lives for Rebetol) after cessation of Rebetol therapy due to the long half-life (see section 5.2).
There is no evidence that Rebetol interacts with non-nucleoside reverse transcriptase inhibitors or protease inhibitors.
Conflicting findings are reported in literature on co-administration between abacavir and Rebetol. Some data suggest that HIV/HCV co-infected patients receiving abacavir-containing ART may be at risk of a lower response rate to pegylated interferon/Rebetol therapy. Caution should be exercised when both medicines are co-administered.
Rebetol must not be used by females who are pregnant (see sections 4.3 and 5.3). Extreme care must be taken to avoid pregnancy in female patients (see section 5.3). Rebetol therapy must not be initiated until a report of a negative pregnancy test has been obtained immediately prior to initiation of therapy. Females of childbearing potential must use an effective contraceptive during treatment and for four months after treatment has been concluded; routine monthly pregnancy tests must be performed during this time. If pregnancy does occur during treatment or within four months from stopping treatment, the patient must be advised of the significant teratogenic risk of Rebetol to the foetus (see section 4.4).
Extreme care must be taken to avoid pregnancy in partners of male patients taking Rebetol (see sections 4.3, 4.4 and 5.3). Rebetol accumulates intracellularly and is cleared from the body very slowly. It is unknown whether the Rebetol that is contained in sperm will exert its potential teratogenic or genotoxic effects on the human embryo/foetus. Although data on approximately 300 prospectively followed pregnancies with paternal exposure to Rebetol have not shown an increased risk of malformation compared to the general population, nor any specific pattern of malformation, either male patients or their female partners of childbearing age must be advised to use an effective contraceptive during treatment with Rebetol and for seven months after treatment. Routine monthly pregnancy tests must be performed during this time. Men whose partners are pregnant must be instructed to use a condom to minimise delivery of Rebetol to the partner.
The use of Rebetol is contraindicated during pregnancy. Rebetol has been shown in preclinical studies to be teratogenic and genotoxic (see section 4.4 and 5.3).
It is not known whether Rebetol is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding must be discontinued prior to initiation of treatment.
Fertility: In animal studies, Rebetol produced reversible effects on spermatogenesis (see section 5.3).
Teratogenicity: Significant teratogenic and/or embryocidal potential have been demonstrated for Rebetol in all animal species in which adequate studies have been conducted, occurring at doses as low as one twentieth of the recommended human dose (see section 5.3).
Genotoxicity: Rebetol induces genotoxicity (see section 5.3).
Rebetol has no or negligible influence on the ability to drive and use machines; however, other medicinal products used in combination may have an effect. Thus, patients who develop fatigue, somnolence, or confusion during treatment must be cautioned to avoid driving or operating machinery.
The salient safety issue of Rebetol is haemolytic anaemia occurring within the first weeks of therapy. The haemolytic anaemia associated with Rebetol therapy may result in deterioration of cardiac function and/or worsening of pre-existing cardiac disease. An increase in uric acid and indirect bilirubin values associated with haemolysis were also observed in some patients.
The adverse reactions listed in this section are primarily derived from clinical trials and/or as adverse drug reactions from spontaneous reports when Rebetol was used in combination with interferon alfa-2b or peginterferon alfa-2b.
Please refer to the corresponding SmPC of medicinal products that are used in combination with Rebetol for additional undesirable effects reported with these products.
The safety of Rebetol capsules is evaluated from data from four clinical trials in patients with no previous exposure to interferon (interferon-naïve patients): two trials studied Rebetol in combination with interferon alfa-2b, two trials studied Rebetol in combination with peginterferon alfa-2b.
Patients who are treated with interferon alfa-2b and Rebetol after previous relapse from interferon therapy or who are treated for a shorter period are likely to have an improved safety profile than that described below.
The adverse reactions listed in Table 5 are based on experience from clinical trials in adult naïve patients treated for 1 year and post-marketing use. A certain number of adverse reactions, generally attributed to interferon therapy but that have been reported in the context of hepatitis C therapy (in combination with Rebetol) are also listed for reference in Table 5. Also, refer to peginterferon alfa-2b and interferon alfa-2b SmPCs for adverse reactions that may be attributable to interferons monotherapy. 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); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 5. Adverse reactions reported during clinical trials or following the marketing use of Rebetol with pegylated interferon alfa-2b or interferon alfa-2b:
Very common: Viral infection, pharyngitis
Common: Bacterial infection (including sepsis), fungal infection, influenza, respiratory tract infection, bronchitis, herpes simplex, sinusitis, otitis media, rhinitis, urinary tract infection
Uncommon: Lower respiratory tract infection
Rare: Pneumonia*
Common: Neoplasm unspecified
Very common: Anaemia, neutropenia
Common: Haemolitic anaemia, leukopenia, thrombocytopenia, lymphadenopathy, lymphopenia
Very rare: Aplastic anaemia*
Not known: Pure red cell aplasia, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura
Uncommon: Drug hypersensitivity
Rare: Sarcoidosis*, rheumatoid arthritis (new or aggravated)
Not known: Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, vasculitis, acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction, anaphylaxis
Common: Hypothyroidism, hyperthyroidism
Very common: Anorexia
Common: Hyperglycaemia, hyperuricaemia, hypocalcaemia, dehydration, increased appetite
Uncommon: Diabetes mellitus, hypertriglyceridemia*
Very common: Depression, anxiety, emotional lability, insomnia
Common: Suicidal ideation, psychosis, aggressive behaviour, confusion, agitation, anger, mood altered, abnormal behaviour, nervousness, sleep disorder, decreased libido apathy, abnormal dreams, crying
Uncommon: Suicide attempts, panic attack, hallucination
Rare: Bipolar disorder*
Very rare: Suicide*
Not known: Homicidal ideation*, mania*, mental status change
Very common: Headache, dizziness, dry mouth, concentration impaired
Common: Amnesia, memory impairment, syncope, migraine, ataxia, paraesthaesia, dysphonia, taste loss, hypoaesthesia, hyperaesthesia, hypertonia, somnolence, disturbance in attention, tremor, dysgeusia
Uncommon: Neuropathy, peripheral neuropathy
Rare: Seizure (convulsion)*
Very rare: Cerebrovascular haemorrhage*, cerebrovascular ischaemia*, encephalopathy*, polyneuropathy*
Not known: Facial palsy, mononeuropathies
Common: Visual disturbance, blurred vision, conjunctivitis, eye irritation, eye pain, abnormal vision, lacrimal gland disorder, dry eye
Rare: Retinal haemorrhages*, retinopathies (including macular oedema), retinal artery occlusion, retinal vein occlusion*, optic neuritis*, papilloedema*, loss of visual acuity or visual field*, retinal exudates
Common: Vertigo, hearing impaired/loss, tinnitus, ear pain
Common: Palpitation, tachycardia
Uncommon: Myocardial infarction
Rare: Cardiomyopathy, arrhythmia*
Very rare: Cardiac ischaemia*
Not known: Pericardial effusion*, pericarditis*
Common: Hypotension, hypertension, flushing
Rare: Vasculitis
Very rare: Peripheral ischaemia*
Very common: Dyspnoea, coughing
Common: Epistaxis, respiratory disorder, respiratory tract congestion, sinus congestion, nasal congestion, rhinorrhea, increased upper airway secretion, pharyngolaryngeal pain, nonproductive cough
Very rare: Pulmonary infiltrates*, pneumonitis*, interstitial pneumonitis*
Very common: Diarrhoea, vomiting, nausea, abdominal pain
Common: Ulcerative stomatitis, stomatitis, mouth ulceration, colitis, upper right quadrant pain, dyspepsia, gastroesophoageal reflux*, glossitis, cheilitis, abdominal distension, gingival bleeding, gingivitis, loose stools, tooth disorder, constipation, flatulence
Uncommon: Pancreatitis, oral pain
Rare: Ischaemic colitis
Very rare: Ulcerative colitis*
Not known: Periodontal disorder, dental disorder, tongue pigmentation
Common: Hepatomegaly, jaundice, hyperbilirubinemia*
Very rare: Hepatotoxicity (including fatalities)*
Very common: Alopecia, pruritus, skin dry, rash
Common: Psoriasis, aggravated psoriasis, eczema, photosensitivity reaction, maculopapular rash, erythematous rash, night sweats, hyperhidrosis, dermatitis, acne, furuncule, erythema, urticaria, skin disorder, bruise, sweating increased, abnormal hair texture, nail disorder*
Rare: Cutaneous sarcoidosis
Very rare: Stevens Johnson syndrome*, toxic epidermal necrolysis*, erythema multiforme*
Very common: Arthralgia, myalgia, musculoskeletal pain
Common: Arthritis, back pain, muscle spasms, pain in extremity
Uncommon: Bone pain, muscle weakness
Rare: Rhabdomyolysis*, myositis*
Common: Micturition frequency, polyuria, urine abnormality
Rare: Renal failure, renal insufficiency*
Very rare: Nephrotic syndrome*
Common: Female: amenorrhea, menorrhagia, menstrual disorder, dysmenorrhea, breast pain, ovarian disorder, vaginal disorder. Male: impotence, prostatitis, erectile dysfunction. Sexual dysfunction (not specified)*
Very common: Fatigue, rigors, pyrexia, influenza like illness, asthenia, irritability
Common: Chest pain, chest discomfort, peripheral oedema, malaise, feeling abnormal, thirst
Uncommon: Face oedema
Very common: Weight decrease
Common: Cardiac murmur
* Since Rebetol has always been prescribed with an alpha interferon product, and the listed adverse drug reactions included reflecting post-marketing experience do not allow precise quantification of frequency, the frequency reported above is from clinical trials using Rebetol in combination with interferon alfa-2b (pegylated or non-pegylated).
A reduction in haemoglobin concentrations by >4 g/dL was observed in 30% of patients treated with Rebetol and peginterferon alfa-2b and 37% of patients treated with Rebetol and interferon alfa-2b. Haemoglobin levels dropped below 10 g/dL in up to 14% of adult patients and 7% of children and adolescents treated with Rebetol in combination with either peginterferon alfa-2b or interferon alfa-2b.
Most cases of anaemia, neutropenia, and thrombocytopenia were mild (WHO grades 1 or 2). There were some cases of more severe neutropenia in patients treated with Rebetol in combination with peginterferon alfa-2b (WHO grade 3: 39 of 186 [21%]; and WHO grade 4: 13 of 186 [7%]); WHO grade 3 leukopenia was also reported in 7% of this treatment group.
An increase in uric acid and indirect bilirubin values associated with haemolysis was observed in some patients treated with Rebetol used in combination with peginterferon alfa-2b or interferon alfa-2b in clinical trials, but values returned to baseline levels by four weeks after the end of therapy. Among those patients with elevated uric acid levels, very few patients treated with the combination developed clinical gout, none of which required treatment modification or discontinuation from the clinical trials.
For HCV/HIV co-infected patients receiving Rebetol in combination with peginterferon alfa-2b, other adverse reactions (that were not reported in mono-infected patients) which have been reported in the 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%).
Mitochondrial toxicity and lactic acidosis have been reported in HIV-positive patients receiving NRTI regimen and associated-Rebetol for co-HCV infection (see section 4.4).
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 Rebetol in combination with peginterferon alfa-2b when compared to patients receiving Rebetol in combination with interferon alfa-2b. 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 Rebetol in combination with peginterferon alfa-2b. Anaemia (haemoglobin <9.4 g/dL) was reported in 12% (23/194) of patients treated with Rebetol in combination with peginterferon alfa-2b.
Treatment with Rebetol in combination with peginterferon alfa-2b 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 Rebetol in combination with peginterferon alfa-2b 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 corresponding SmPC 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 Rebetol in combination with other medicinal products.
In a clinical trial with 107 children and adolescent patients (3 to 17 years of age) treated with combination therapy of peginterferon alfa-2b and Rebetol, 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 pegylated interferon alfa-2b and Rebetol, 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 in height percentiles were of 15 percentiles and 8 percentiles, respectively) and growth velocity was inhibited (<3rd 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 3 percentiles and 7 percentiles, respectively, and 20% of the children continued to have inhibited growth (growth velocity <3rd percentile). Ninety-four of 107 children enrolled in the 5 year long-term follow-up trial. The effects on growth were less in those children treated for 24 weeks than those treated for 48 weeks. From pre-treatment to end of long-term follow-up among children treated for 24 or 48 weeks, height-for-age percentiles decreased 1.3 and 9.0 percentiles, respectively. Twenty-four percent of children (11/46) treated for 24 weeks and 40% of children (19/48) treated for 48 weeks had a >15 percentile height-for-age decrease from pre-treatment to the end of 5 year long-term follow-up compared to pre-treatment baseline percentiles. Eleven percent of children (5/46) treated for 24 weeks and 13% of children (6/48) treated for 48 weeks were observed to have a decrease from pre-treatment baseline >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, weight-for-age percentiles decreased 1.3 and 5.5 percentiles among children 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 children 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.
In clinical trials of 118 children and adolescents 3 to 16 years of age treated with combination therapy of interferon alfa-2b and Rebetol, 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 44th percentile, which was below the median of the normative population and less than their mean baseline height (48th 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 alfa-2b and Rebetol, 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 reactions (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 neutropenia.
Reported adverse reactions listed in Table 6 are based on experience from the two multicentre children and adolescents clinical trials using Rebetol with interferon alfa-2b or peginterferon alfa-2b. 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), and uncommon (≥1/1,000 to <1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 6. Adverse reactions very commonly, commonly and uncommonly reported during clinical trials in children and adolescents with Rebetol in combination with interferon alfa-2b or peginterferon alfa-2b:
Very common: Viral infection, pharyngitis
Common: Fungal infection, bacterial infection, pulmonary infection, nasopharyngitis, pharyngitis streptococcal, otitis media, sinusitis, tooth abscess, influenza, oral herpes, herpes simplex, urinary tract infection, vaginitis, gastroenteritis
Uncommon: Pneumonia, ascariasis, enterobiasis, herpes zoster, cellulitis Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common: Neoplasm unspecified
Very common: Anaemia, neutropenia
Common:__ Thrombocytopenia, lymphadenopathy
Very common: Hypothyroidism
Common: Hyperthyroidism, virilism
Very common: Anorexia, increased appetite, decreased appetite
Common: Hypertriglyceridemia, hyperuricemia
Very common: Depression, insomnia, emotional lability
Common: Suicidal ideation, aggression, confusion, affect liability, behaviour disorder, agitation, somnambulism, anxiety, mood altered, restlessness, nervousness, sleep disorder, abnormal dreaming, apathy
Uncommon: Abnormal behaviour, depressed mood, emotional disorder, fear, nightmare
Very common: Headache, dizziness
Common: Hyperkinesia, tremor, dysphonia, paresthaesia, hypoaesthesia, hyperaesthesia, concentration impaired, somnolence, disturbance in attention, poor quality of sleep
Uncommon: Neuralgia, lethargy, psychomotor hyperactivity
Common: Conjunctivitis, eye pain, abnormal vision, lacrimal gland disorder
Uncommon: Conjunctival haemorrhage, eye pruritus, keratitis, vision blurred, photophobia
Common: Vertigo
Common: Tachycardia, palpitations
Common: Pallor, flushing
Uncommon: Hypotension
Common: Dyspnoea, tachypnea, epistaxis, coughing, nasal congestion, nasal irritation, rhinorrhoea, sneezing, pharyngolaryngeal pain
Uncommon: Wheezing, nasal discomfort
Very common: Abdominal pain, abdominal pain upper, vomiting , diarrhoea, nausea
Common: Mouth ulceration, stomatitis ulcerative, stomatitis, aphthous stomatitis, dyspepsia, cheilosis, glossitis, gastroesophoageal reflux, rectal disorder, gastrointestinal disorder, constipation, loose stools, toothache, tooth disorder, stomach discomfort, oral pain
Uncommon: Gingivitis
Common: Hepatic function abnormal
Uncommon: Hepatomegaly
Very common: Alopecia, rash
Common: Pruritus, photosensitivity reaction, maculopapular rash, eczema, hyperhidrosis, acne, skin disorder, nail disorder, skin discolouration, dry skin, erythema, bruise
Uncommon: Pigmentation disorder, dermatitis atopic, skin exfoliation
Very common: Arthralgia, myalgia, musculoskeletal pain
Common: Pain in extremity, back pain, muscle contracture
Common: Enuresis, micturition disorder, urinary incontinence, proteinuria
Common: Female: amenorrhea, menorrhagia, menstrual disorder, vaginal disorder, Male: testicular pain
Uncommon: Female: dysmenorrhoea
Very common: Fatigue, rigors, pyrexia, influenza-like illness, asthenia, malaise, irritability
Common: Chest pain, oedema, pain, feeling cold
Uncommon: Chest discomfort, facial pain
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
Common: Skin laceration
Uncommon: Contusion
Most of the changes in laboratory values in the Rebetol/peginterferon alfa-2b 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 Rebetol used in combination with peginterferon alfa-2b in the clinical trial, values returned to baseline levels within a few weeks after the end of therapy.
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.
Not applicable.
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