Peginterferon alpha-2a interacts in the following cases:
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 alfa interferon. If treatment with alfa 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.
There are no data on the effects of peginterferon alfa-2a on fertility in women. A prolongation of the menstrual cycle has been seen with peginterferon alfa-2a in female monkeys.
Ribavirin, 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 peginterferon alfa-2a and ribavirin concomitantly with azathioprin should be avoided. In individual cases where the benefit of administering ribavirin concomitantly with azathioprine warrants the potential risk, it is recommended that close haematologic monitoring be done during concomitant azathioprine use to identify signs of myelotoxicity, at which time treatment with these medicinal products should be stopped.
In a pharmacokinetic study of 24 HCV patients concomitantly receiving methadone maintenance therapy (median dose 95 mg; range 30 mg to 150 mg), treatment with peginterferon alpha-2a 180 micrograms sc once weekly for 4 weeks was associated with mean methadone levels that were 10% to 15% higher than at baseline. The clinical significance of this finding is unknown; nonetheless, patients should be monitored for the signs and symptoms of methadone toxicity. Especially in patients on a high dose of methadone, the risk for QTc prolongation should be considered.
A 25% increase in the AUC of theophylline (marker of cytochrome P450 1A2 activity) was observed, demonstrating that peginterferon alpha-2a is an inhibitor of cytochrome P450 1A2 activity. Serum concentrations of theophylline should be monitored and appropriate dose adjustments of theophylline made for patients taking theophylline and peginterferon alpha-2a concomitantly. The interaction between theophylline and peginterferon alpha-2a is likely to be maximal after more than 4 weeks of peginterferon alpha-2a therapy.
In patients who develop evidence of hepatic decompensation during treatment, peginterferon alpha-2a should be discontinued. Increases in ALT levels above baseline have been observed in patients treated with peginterferon alpha-2a, including patients with a viral response. When the increase in ALT levels is progressive and clinically significant, despite dose reduction, or is accompanied by increased direct bilirubin, therapy should be discontinued.
In CHB, unlike CHC, disease exacerbations during therapy are not uncommon and are characterised by transient and potentially significant increases in serum ALT. In clinical trials with peginterferon alpha-2a in HBV, marked transaminase flares have been accompanied by mild changes in other measures of hepatic function and without evidence of hepatic decompensation. In approximately half the cases of flares exceeding 10x ULN, peginterferon alpha-2a dosing was reduced or withheld until the transaminase elevations subsided, while in the rest therapy was continued unchanged. More frequent monitoring of hepatic function was recommended in all instances.
Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during peginterferon alpha-2a therapy, and even after treatment discontinuation mainly during the 6-month follow-up period. Other CNS effects including aggressive behaviour (sometimes directed against others such as homicidal ideation), bipolar disorders, mania, confusion and alterations of mental status have been observed with alfa interferons. All patients should be closely monitored for any signs or symptoms of psychiatric disorders. If symptoms of psychiatric disorders 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 ideation is identified, it is recommended that treatment with peginterferon alpha-2a be discontinued, and the patient followed, with psychiatric intervention as appropriate.
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving peginterferon alpha-2a 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 peginterferon alpha-2a 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.
Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with the use of alfa interferons, including peginterferon alpha-2a. Prior to initiation of peginterferon alpha-2a therapy, TSH and T4 levels should be evaluated. Peginterferon alpha-2a treatment may be initiated or continued if TSH levels can be maintained in the normal range by pharmaceutical means. TSH levels should be determined during the course of therapy if a patient develops clinical symptoms consistent with possible thyroid dysfunction. Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with peginterferon alpha-2a. Patients with these conditions who cannot be effectively controlled by medication should not begin peginterferon alpha-2a monotherapy or peginterferon alpha-2a/ribavirin combination therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue peginterferon alpha-2a or peginterferon alpha-2a/ribavirin therapy.
Retinopathy including retinal haemorrhages, cotton wool spots, papilloedema, optic neuropathy and retinal artery or vein obstruction which may result in loss of vision have been reported in rare instances with peginterferon alpha-2a. All patients should have a baseline eye examination. Any patient complaining of decrease or loss of vision must have a prompt and complete eye examination. Adult and paediatric patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during peginterferon alpha-2a therapy. Peginterferon alpha-2a treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.
While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of persistent fever, particularly serious infections (bacterial, viral, fungal) must be ruled out, especially in patients with neutropenia. Serious infections (bacterial, viral, fungal) and sepsis have been reported during treatment with alfa interferons including peginterferon alpha-2a. Appropriate antiinfective therapy should be started immediately and discontinuation of therapy should be considered.
Pulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia, and pneumonitis have been reported during therapy with peginterferon alpha-2a. In case of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.
Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with alfa interferon therapies, including peginterferon alpha-2a. It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation of peginterferon alpha-2a therapy. If there is any deterioration of cardiovascular status, therapy should be suspended or discontinued. In patients with cardiovascular disease, anaemia may necessitate dose reduction or discontinuation of ribavirin.
The development of auto-antibodies and autoimmune disorders has been reported during treatment with alfa 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 re-assessed.
Cases of Vogt-Koyanagi-Harada (VKH) syndrome have been reported in patients with CHC 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.
Serious, acute hypersensitivity reactions (e.g., urticaria, angioedema, bronchoconstriction, anaphylaxis) have been rarely observed during alfa interferon therapy. If this occurs, therapy must be discontinued and appropriate medical therapy instituted immediately. Transient rashes do not necessitate interruption of treatment.
During therapy with peginterferon alpha-2a +/- ribavirin lasting up to 48 weeks in patients aged 3 to 17 years, weight loss and growth inhibition were common.
The expected benefit of treatment should be carefully weighed against the safety findings observed for children and adolescents in the clinical trials on a case by case basis. It is important to consider the treatment with peginterferon alpha-2a +/- ribavirin induced a growth inhibition during treatment, the reversibility of which is uncertain.
The risk of growth inhibition 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 (for HBVinfection mainly HBV genotype and ALT levels; for HCV-infection mainly HCV genotype and HCV-RNA levels).
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.
In order to improve the traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded (or stated) in the patient file.
Use of alfa interferons has been associated with exacerbation or provocation of psoriasis and sarcoidosis. Peginterferon alpha-2a must be used with caution in patients with psoriasis, and in cases of onset or worsening of psoriatic lesions, discontinuation of therapy should be considered.
There are no or limited amount of data from the use of peginterferon alfa-2a in pregnant women. Studies in animals with interferon alfa-2a have shown reproductive toxicity and the potential risk for humans is unknown. Peginterferon alpha-2a is to be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is unknown whether peginterferon alfa-2a/metabolites are excreted in human milk. Because of the potential for adverse reactions in breast-fed infants, breast-feeding should be discontinued prior to initiation of treatment.
There are no data on the effects of peginterferon alfa-2a on fertility in women. A prolongation of the menstrual cycle has been seen with peginterferon alfa-2a in female monkeys.
Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Ribavirin therapy is contraindicated in women who are pregnant. Extreme care must be taken to avoid pregnancy in female patients or in partners of male patients taking peginterferon alpha-2a in combination with ribavirin. Female patients 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. Please refer to the ribavirin SmPC.
Peginterferon alpha-2a has minor or moderate influence on the ability to drive and use machines. Patients who develop dizziness, confusion, somnolence or fatigue should be cautioned to avoid driving or operating machinery.
In clinical trials of 48 weeks treatment and 24 weeks follow-up, the safety profile for peginterferon alpha-2a in CHB was similar to that seen in CHC. With the exception of pyrexia the frequency of the majority of the reported adverse reactions was notably less in CHB patients treated with peginterferon alpha-2a monotherapy compared with CHC patients treated with peginterferon alpha-2a monotherapy (see List 1). Adverse events were experienced by 88% of peginterferon alpha-2a-treated patients as compared with 53% of patients in the lamivudine comparator group, while 6% of the peginterferon alpha-2a-treated and 4% of the lamivudine-treated patients experienced serious adverse events during the studies. Adverse events or laboratory abnormalities led to 5% of patients withdrawing from peginterferon alpha-2a treatment, while less than 1% of patients withdrew from lamivudine treatment for these reasons. The percentage of patients with cirrhosis who withdrew from treatment was similar to that of the overall population in each treatment group.
The frequency and severity of the most commonly reported adverse reactions with peginterferon alpha-2a are similar to those reported with interferon alfa-2a (see List 1). The most frequently reported adverse reactions with peginterferon alpha-2a 180 micrograms were mostly mild to moderate in severity and were manageable without the need for modification of doses or discontinuation of therapy.
Overall, the safety profile for peginterferon alpha-2a in combination with ribavirin in prior non-responder patients was similar to that in naïve patients. In a clinical trial of non-responder patients to prior pegylated interferon alfa-2b/ribavirin, which exposed patients to either 48 or 72 weeks of treatment, the frequency of withdrawal for adverse events or laboratory abnormalities from peginterferon alpha-2a treatment and ribavirin treatment was 6% and 7%, respectively, in the 48 week arms and 12% and 13%, respectively, in the 72 week arms. Similarly for patients with cirrhosis or transition to cirrhosis, the frequencies of withdrawal from peginterferon alpha-2a treatment and ribavirin treatment were higher in the 72-week treatment arms (13% and 15%) than in the 48-week arms (6% and 6%). Patients who withdrew from previous therapy with pegylated interferon alfa-2b/ribavirin because of haematological toxicity were excluded from enrolling in this trial.
In another clinical trial, non-responder patients with advanced fibrosis or cirrhosis (Ishak score of 3 to 6) and baseline platelet counts as low as 50,000 cells/mm³ were treated for 48 weeks. Haematologic laboratory abnormalities observed during the first 20 weeks of the trial included anaemia (26% of patients experienced a haemoglobin level of <10 g/dl), neutropenia (30% experienced an ANC <750 cells/mm³), and thrombocytopenia (13% experienced a platelet count <50,000 cells/mm³).
In HIV-HCV co-infected patients, the clinical adverse reaction profiles reported for peginterferon alpha-2a, alone or in combination with ribavirin, were similar to those observed in HCV mono-infected patients. For HIV-HCV patients receiving peginterferon alpha-2a and ribavirin combination therapy other undesirable effects have been reported in ≥1% to ≤2% of patients: hyperlactacidaemia/lactic acidosis, influenza, pneumonia, affect lability, apathy, tinnitus, pharyngolaryngeal pain, cheilitis, acquired lipodystrophy and chromaturia. peginterferon alpha-2a treatment 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 peginterferon alpha-2a had no observable negative impact on the control of HIV viraemia during therapy or follow-up. Limited safety data are available in co-infected patients with CD4+ cell counts <200/µl.
List 1 summarises the undesirable effects reported with peginterferon alpha-2a monotherapy in CHB or CHC adult patients and with peginterferon alpha-2a in combination with ribavirin in CHC patients. Undesirable effects reported in clinical studies are grouped according to frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000). For spontaneous reports of undesirable effects from post-marketing experience, the frequency is not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of seriousness.
List 1. Undesirable effects reported with peginterferon alpha-2a monotherapy for CHB or CHC or in combination with ribavirin for CHC patients in clinical trials and post marketing:
Common: Bronchitis, upper respiratory infection, oral candidiasis, herpes simplex, fungal, viral and bacterial infections
Uncommon: Pneumonia, skin infection
Rare: Endocarditis, otitis externa
Frequency not known: Sepsis
Uncommon: Hepatic neoplasm
Common: Thrombocytopenia, anaemia, lymphadenop athy
Rare: Pancytopenia
Very rare: Aplastic anaemia
Frequency not known: Pure red cell aplasia
Uncommon: Sarcoidosis, thyroiditis
Rare: Anaphylaxis, systemic lupus erythematosus rheumatoid arthritis
Very rare: Idiopathic or thrombotic thrombocytop enic purpura
Frequency not known: Liver and renal graft rejection, Vogt-Koyanagi-Harada disease
Common: Hypothyroidism, hyperthyroidism
Uncommon: Diabetes
Rare: Diabetic ketoacidosis
Very common: Anorexia
Uncommon: Dehydration
Very common: Depression*, anxiety, insomnia*
Common: Aggression, mood alteration, emotional disorders, nervousness, libido decreased
Uncommon: Suicidal ideation, hallucinations
Rare: Suicide, psychotic disorder
Frequency not known: Mania, bipolar disorders, homicidal ideation
Very common: Headache, dizziness*, concentration impaired
Common: Syncope, migraine, memory impairment, weakness, hypoaesthesia, hyperaesthesia, paraesthesia, tremor, taste disturbance, nightmares, somnolence
Uncommon: Peripheral neuropathy
Rare: Coma, convulsions, facial palsy
Frequency not known: Cerebral ischaemia
Common: Vision blurred, eye pain, eye inflammation, xerophthalmia
Uncommon: Retinal haemorrhage
Rare: Optic neuropathy, papilloedema, retinal vascular disorder, retinopathy, corneal ulcer
Very rare: Vision loss
Frequency not known: Serous retinal detachment
Common: Vertigo, earache
Uncommon: Hearing loss
Common: Tachycardia, oedema peripheral, palpitations
Rare: Myocardial infarction, congestive heart failure, cardiomyopathy, angina, arrhythmia, atrial fibrillation, pericarditis, supraventricular tachycardia
Common: Flushing
Uncommon: Hypertension
Rare: Cerebral haemorrhage, vasculitis
Frequency not known: Peripheral ischaemia
Very common: Dyspnoea, cough
Common: Dyspnoea exertional, epistaxis, nasopharyngitis, sinus congestion, nasal congestion, rhinitis, sore throat
Uncommon: Wheezing
Rare: Interstitial pneumonitis including fatal outcome, pulmonary embolism
Frequency not known: Pulmonary arterial hypertension§
Very common: Diarrhoea*, nausea*, abdominal pain*
Common: Vomiting, dyspepsia, dysphagia, mouth ulceration, gingival bleeding, glossitis, stomatitis, flatulence, dry mouth
Uncommon: Gastrointestinal bleeding
Rare: Peptic ulcer, pancreatitis
Frequency not known: Ischaemic colitis, tongue pigmentation
Uncommon: Hepatic dysfunction
Rare: Hepatic failure, cholangitis, fatty liver
Very common: Alopecia, dermatitis, pruritis, dry skin
Common: Psoriasis, urticaria, eczema, rash, sweating increased, skin disorder, photosensitivi ty reaction, night sweats
Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema, erythema multiforme
Very common: Myalgia, arthralgia
Common: Back pain, arthritis, muscle weakness, bone pain, neck pain, musculoskeletal pain, muscle cramps
Rare: Myositis
Frequency not known: Rhabdomyolysis
Rare: Renal insufficiency
Common: Impotence
Very common: Pyrexia, rigors*, pain*, asthenia, fatigue, injection site reaction*, irritability*
Common: Chest pain, influenza like illness, malaise, lethargy, hot flushes, thirst
Common: Weight decreased
Rare: Substance overdose
* These adverse reactions were common (≥1/100 to <1/10) in CHB patients treated with peginterferon alpha-2a monotherapy
§ Class label for interferon products, see below Pulmonary arterial hypertension
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.
Peginterferon alpha-2a treatment was associated with abnormal laboratory values: ALT increase, bilirubin increase, electrolyte disturbance (hypokalaemia, hypocalcaemia, hypophosphataemia), hyperglycaemia, hypoglycaemia and elevated triglycerides. With both peginterferon alpha-2a monotherapy, and also the combined treatment with ribavirin, up to 2% of patients experienced increased ALT levels that led to dose modification or discontinuation of the treatment.
Treatment with peginterferon alpha-2a was associated with decreases in haematological values (leucopenia, neutropenia, lymphopenia, thrombocytopenia and haemoglobin), which generally improved with dose modification, and returned to pre-treatment levels within 4-8 weeks upon cessation of therapy.
Moderate (ANC: 0.749 – 0.5 × 109/l) and severe (ANC: <0.5 × 109/l) neutropenia was observed respectively in 24% (216/887) and 5% (41/887) of patients receiving peginterferon alpha-2a 180 micrograms and ribavirin 1000/1200 milligrams for 48 weeks.
1-5% of patients treated with peginterferon alpha-2a developed neutralising anti-interferon antibodies. As with other interferons, a higher incidence of neutralising antibodies was seen in CHB. However in neither disease was this correlated with lack of therapeutic response.
Peginterferon alpha-2a treatment was associated with clinically significant abnormalities in thyroid laboratory values requiring clinical intervention. The frequencies observed (4.9%) in patients receiving peginterferon alpha-2a/ribavirin (NV15801) are similar to those observed with other interferons.
Although haematological toxicities of neutropenia, thrombocytopenia and anaemia occurred more frequently in HIV-HCV patients, the majority could be managed by dose modification and the use of growth factors and infrequently required premature discontinuation of treatment. Decrease in ANC levels below 500 cells/mm³ was observed in 13% and 11% of patients receiving peginterferon alpha-2a monotherapy and combination therapy, respectively. Decrease in platelets below 50,000 cells/mm³ was observed in 10% and 8% of patients receiving peginterferon alpha-2a monotherapy and combination therapy, respectively. Anaemia (haemoglobin <10 g/dl) was reported in 7% and 14% of patients treated with peginterferon alpha-2a monotherapy or in combination therapy, respectively.
In a clinical trial (YV25718) with 111 paediatric patients (3 to 17 years of age) treated with peginterferon alpha-2a for 48 weeks, the safety profile was consistent with that seen in adults with CHB and in paediatric patients with CHC.
The mean changes from baseline in height and weight for age Z-scores at Week 48 of treatment in study YV25718 were -0.07 and -0.21(n=108 and n=106 respectively) for peginterferon alpha-2a-treated patients as compared to -0.01 and -0.08 (n=47 each) in untreated patients. At Week 48 of peginterferon alpha-2a treatment, a height or weight percentile decrease of more than 15 percentiles on the normative growth curves was observed in 6% of patients for height and 11% of patient for weight, whereas in the untreated group it was 2% of patients for height and 9% for weight. No data is available on long-term follow-up posttreatment in these patients.
In a clinical trial with 114 paediatric patients (5 to 17 years of age) treated with peginterferon alpha-2a alone or in combination with ribavirin, dose modifications were required in approximately onethird of patients, most commonly for neutropenia and anaemia. In general, the safety profile observed in paediatric patients was similar to that seen in adults. In the paediatric study, the most prevalent adverse reactions in patients treated with combination therapy for up to 48 weeks with peginterferon alpha-2a and ribavirin were influenza-like illness (91%), headache (64%), gastrointestinal disorder (56%), and injection-site reaction (45%). A full listing of adverse reactions reported in this treatment group (n=55) is provided in List 2. Seven patients receiving combination peginterferon alpha-2a and ribavirin treatment for 48 weeks discontinued therapy for safety reasons (depression, psychiatric evaluation abnormal, transient blindness, retinal exudates, hyperglycaemia, type 1 diabetes mellitus, and anaemia). Most of the adverse reactions reported in the study were mild or moderate in severity. Severe adverse reactions were reported in 2 patients in the peginterferon alpha-2a plus ribavirin combination therapy group (hyperglycaemia and cholecystectomy).
Growth inhibition was observed in paediatric patients. Paediatric patients treated with peginterferon alpha-2a plus ribavirin combination therapy showed a delay in weight and height increases after 48 weeks of therapy compared with baseline. Patient ‘weight for age’ and ‘height for age’ percentiles of the normative population decreased during treatment. At the end of 2 years follow-up after treatment, most patients had returned to baseline normative growth curve percentiles for weight and height (mean weight percentile was 64% at baseline and 60% at 2 years post-treatment; mean height percentile was 54% at baseline and 56% at 2 years post-treatment). At the end of treatment, 43% of patients experienced a weight percentile decrease of 15 percentiles or more, and 25% (13 of 53) experienced a height percentile decrease of 15 percentiles or more on the normative growth curves. At 2 years posttreatment, 16% (6 of 38) of patients remained 15 percentiles or more below their baseline weight curve and 11% (4 of 38) remained 15 percentiles or more below their baseline height curve.
55% (21 of 38) of subjects who completed the original study enrolled in the long-term follow up extending up to 6 years post-treatment. The study demonstrated that the post-treatment recovery in growth at 2 years post-treatment was maintained to 6 years post-treatment. For a few subjects who were more than 15 percentiles below their baseline height curve at 2 years post-treatment, they either returned to baseline comparable height percentiles at 6 years post-treatment or a non-treatment related causative factor has been identified. The extent of available data is not sufficient to conclude that growth inhibition due to peginterferon alpha-2a exposure is always reversible.
List 10. Adverse reactions reported among paediatric patients infected with HCV and assigned to peginterferon alpha-2a plus ribavirin in study NV17424:
Common: Infectious mononucleosis, pharyngitis streptococcal, influenza, gastroenteritis viral, candidiasis, gastroenteritis, tooth abscess, hordeolum, urinary tract infection, nasopharyngitis
Common: Anaemia
Very common: Decreased appetite
Common: Hyperglycaemia, type 1 diabetes mellitus
Very common: Insomnia
Common: Depression, anxiety, hallucination, abnormal behaviour, aggression, anger, attention deficit/hyperactivity disorder
Very common: Headache
Common: Dizziness, disturbance in attention, migraine
Common: Blindness transient, retinal exudates, visual impairment eye irritation, eye pain, eye pruritis
Common: Ear pain
Common: Dyspnoea, epistaxis
Very common: Gastrointestinal disorder
Common: Abdominal pain upper, stomatitis, nausea, aphthous stomatitis, oral disorder
Very common: Rash, pruritus, alopecia
Common: Swollen face, drug eruption,
Very common: Musculoskeletal pain
Common: Back pain, pain in extremity
Common: Dysuria, incontinence, urinary tract disorder
Common: Vaginal discharge
Very common: Influenza-like illness, injection site reaction, irritability, fatigue
Common: Pyrexia, vessel puncture site haematoma, pain
Common: Psychiatric evaluation abnormal
Common: Tooth extraction, cholecystectomy
Common: Educational problem
Decreases in haemoglobin, neutrophils, platelets or increased ALT may require dose reduction or permanent discontinuation from treatment. Most laboratory abnormalities noted during the clinical trial returned to baseline levels shortly after discontinuation of treatment.
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