Special Warning : אזהרת שימוש

4.4             Special warnings and precautions for use

Psychiatric and Central Nervous System (CNS): Severe CNS effects, particularly depression, suicidal ideation and attempted suicide have been observed in some patients during Pegasys 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 Pegasys be discontinued, and the patient followed, with psychiatric intervention as appropriate.

Patients with existence of, or history of severe psychiatric conditions: If treatment with Pegasys is judged necessary in 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 Pegasys in children and adolescents with existence of or history of severe psychiatric conditions is contraindicated (see section 4.


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PEGASYS                                                      MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                 December 2015 Patients with substance use/abuse: HCV infected patients having a co-occurring substance use disorder (alcohol, cannabis, etc) are at an increased risk of developing psychiatric disorders or exacerbation of already existing psychiatric disorders when treated with 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.

Growth and development (children and adolescents): During the course of Pegasys plus ribavirin therapy lasting up to 48 weeks in patients aged 5 to 17 years, weight loss and growth inhibition were common (see sections 4.8 and 5.1).

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 (see sections 4.8 and 5.1).
-     It is important to consider that the combination therapy induced a growth inhibition, during treatment, the reversibility of which is uncertain.
-     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.

Please refer also to the ribavirin prescribing information when Pegasys is to be used in combination with ribavirin.

In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file.

Laboratory tests prior to and during therapy
Prior to beginning Pegasys therapy, standard haematological and biochemical laboratory tests are recommended for all patients.

The following may be considered as baseline values for initiation of treatment: -     Platelet count  90,000/mm3
-     Absolute neutrophil counts  1500/mm3
-     Adequately controlled thyroid function (TSH and T4)

Haematological tests should be repeated after 2 and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy (including glucose monitoring).

In clinical trials, Pegasys treatment was associated with decreases in both total white blood cell (WBC) count and absolute neutrophil count (ANC), usually starting within the first 2 weeks of treatment (see section 4.8). Progressive decreases after 8 weeks of therapy were infrequent. The decrease in ANC was reversible upon dose reduction or cessation of therapy (see section 4.2), reached normal values by 8 weeks in the majority of patients and returned to baseline in all patients after about 16 weeks.


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PEGASYS                                                      MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                 December 2015 Pegasys treatment has been associated with decreases in platelet count, which returned to pre-treatment levels during the post-treatment observation period (see section 4.8). In some cases, dose modification may be necessary (see section 4.2).

The occurrence of anaemia (haemoglobin <10 g/dl) has been observed in up to 15% of chronic hepatitis C patients in clinical trials on the combined treatment of Pegasys with ribavirin. The frequency depends on the treatment duration and the dose of ribavirin (see section 4.8). The risk of developing anaemia is higher in the female population.

Caution should be exercised when administering Pegasys in combination with other potentially myelosuppressive agents.

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 ribavirin 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 re-introduction of either treatment alone (see section 4.5).

The use of Pegasys and ribavirin combination therapy in chronic hepatitis C patients who failed prior treatment has not been adequately studied in patients who discontinued prior therapy for haematological adverse reactions. Physicians considering treatment in these patients should carefully weigh the risks versus the benefits of re-treatment.

Endocrine system
Thyroid function abnormalities or worsening of pre-existing thyroid disorders have been reported with the use of alfa interferons, including Pegasys. Prior to initiation of Pegasys therapy, TSH and T4 levels should be evaluated. Pegasys 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 (see section 4.8). Hypoglycaemia, hyperglycaemia and diabetes mellitus have been observed with Pegasys (see section 4.8).
Patients with these conditions who cannot be effectively controlled by medication should not begin Pegasys monotherapy or Pegasys/ribavirin combination therapy. Patients who develop these conditions during treatment and cannot be controlled with medication should discontinue Pegasys or Pegasys/ribavirin therapy.

Cardiovascular system
Hypertension, supraventricular arrhythmias, congestive heart failure, chest pain and myocardial infarction have been associated with alfa interferon therapies, including Pegasys.
It is recommended that patients who have pre-existing cardiac abnormalities have an electrocardiogram prior to initiation of Pegasys 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 (see section 4.2).

Liver function
In patients who develop evidence of hepatic decompensation during treatment, Pegasys should be discontinued. Increases in ALT levels above baseline have been observed in patients treated with Pegasys, 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 (see sections 4.2 and 4.8).

In chronic hepatitis B, unlike chronic hepatitis C, disease exacerbations during therapy are not uncommon and are characterised by transient and potentially significant increases in serum ALT. In clinical trials with Pegasys in HBV, marked transaminase flares have been 
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PEGASYS                                                       MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                  December 2015 accompanied by mild changes in other measures of hepatic function and without evidence of hepatic decompensation. In approximately half the cases of flares exceeding 10 times the upper limit of normal, Pegasys 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.

Hypersensitivity
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.

Autoimmune disease
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 (see also Endocrine system in sections 4.4 and 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).

Fever/infections
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 Pegasys. Appropriate anti-infective therapy should be started immediately and discontinuation of therapy should be considered.

Ocular changes
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 Pegasys. 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. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during Pegasys therapy. Pegasys treatment should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Pulmonary changes
Pulmonary symptoms, including dyspnoea, pulmonary infiltrates, pneumonia, and pneumonitis have been reported during therapy with Pegasys. In case of persistent or unexplained pulmonary infiltrates or pulmonary function impairment, treatment should be discontinued.

Skin disorder
Use of alfa interferons has been associated with exacerbation or provocation of psoriasis and sarcoidosis. Pegasys 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.


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PEGASYS                                                        MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                   December 2015 Transplantation
The safety and efficacy of Pegasys and ribavirin treatment have not been established in patients with liver and other transplantations. Liver and renal graft rejections have been reported with Pegasys, alone or in combination with ribavirin.

HIV-HCV coinfection
Please refer to the respective prescribing information 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 Pegasys with or without ribavirin. In study NR15961, patients concurrently treated with stavudine and interferon therapy with or without ribavirin, the incidence of pancreatitis and/or lactic acidosis was 3% (12/398).

Patients co-infected with HIV and receiving Highly Active Anti-Retroviral Therapy (HAART) may be at increased risk of developing lactic acidosis. Caution should therefore be exercised when adding Pegasys and ribavirin to HAART therapy (see ribavirin PI).

Co-infected patients with advanced cirrhosis receiving HAART may also be at increased risk of hepatic decompensation and possibly death if treated with ribavirin in combination with interferons, including Pegasys. Baseline variables in co-infected cirrhotic patients that may be associated with hepatic decompensation include: increased serum bilirubin, decreased haemoglobin, increased alkaline phosphatase or decreased platelet count, and treatment with didanosine (ddI).

The concomitant use of ribavirin with zidovudine is not recommended due to an increased risk of anaemia (see section 4.5).

During treatment, co-infected patients should be closely monitored for signs and symptoms of hepatic decompensation (including ascites, encephalopathy, variceal bleeding, impaired hepatic synthetic function; e.g., Child-Pugh score of 7 or greater). The Child-Pugh scoring may be affected by factors related to treatment (i.e. indirect hyperbilirubinemia, decreased albumin) and not necessarily attributable to hepatic decompensation. Treatment with Pegasys should be discontinued immediately in patients with hepatic decompensation.

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

Dental and periodontal disorders
Dental and periodontal disorders, which may lead to loss of teeth, have been reported in patients receiving Pegasys 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 Pegasys 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.

Use of peginterferon as long term maintenance monotherapy (unapproved use) In a randomised, controlled US study (HALT-C) of HCV non-responder patients with varied degrees of fibrosis where 3.5 years of treatment with 90 micrograms/week of Pegasys monotherapy was studied, no significant reductions were observed in the rate of fibrosis progression or related clinical events.



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PEGASYS                                                     MoH Approved Prescribing Information Pre-Filled Syringe, Pre-Filled Pen 135 & 180 mcg                                December 2015 Excipient
Pegasys contains benzyl alcohol. Must not be given to premature babies or neonates. May cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old.

Effects on Driving