Interferon and ribavirin combination therapy for chronic hepatitis C produces a number of well-described side effects that are dominated by fatigue, influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Combination therapy with pegylated interferons (peginterferon alfa-2a and alfa-2b) yields an adverse event profile similar to standard interferon, although the frequency of certain adverse events may vary by preparation. Premature withdrawal from therapy due to adverse events was required in 10% to 14% of participants in registration trials of these agents. Most adverse events were safely and effectively managed by dose reduction using predetermined criteria. The most common indications for dose reduction were hematologic abnormalities, such as anemia and neutropenia, with the latter more frequent in peginterferon treatment arms. Recent data suggest that maintaining adherence to a prescribed treatment regimen can enhance antiviral response. Strategies to maximize adherence are being developed and, in the future, may include early identification of and therapy for depression and the selective use of hematopoietic growth factors to ameliorate hematologic abnormalities. (HEPATOLOGY 2002;36:S237-S244.)

 

The side effect profile of combination therapy using standard interferon and ribavirin has been well described.^1-4 The major types of side effects include fatigue, influenza-like symptoms, gastrointestinal disturbances, neuropsychiatric symptoms, and hematologic abnormalities.^1,2 These side effects may be treatment limiting and require dose reduction or drug discontinuation.^3,4 Numerous other side effects occur with lower frequencies but may still have an impact on the tolerability of antiviral therapy.² Pegylated interferons (peginterferon alfa-2a and peginterferon alfa-2b) have significantly improved pharmacokinetics,^5-8 resulting in improved antiviral efficacy, which also has the potential to alter the side effect profile. This review will focus on the frequency and management of side effects reported with the use of peginterferon and ribavirin for the treatment of chronic hepatitis C based on data from 2 large registration trials that compared these agents with standard interferon and ribavirin combination therapy.


 

Peginterferon alfa-2a and ribavirin

 

Discontinuations and dose modification

The results of a large phase III clinical trial of peginterferon alfa-2a and ribavirin have been reported recently.⁸ More than 1,100 subjects were randomized to therapy with peginterferon alfa-2a and ribavirin, peginterferon alfa-2a and placebo, or standard interferon alfa-2b and ribavirin. Premature withdrawal from therapy due to laboratory abnormalities or adverse events in the combination arms with either peginterferon (10%) or standard interferon (11%) was comparable⁸ (Table 1).

 

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Table 1. Frequency of discontinuations and dose modifications for peginterferon alfa-2a and ribavirin compared with standard interferon alfa-2b and ribavirin

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		Peginterferon Alfa-2a and Ribavirin (%)			Interferon Alfa-2b and Ribavirin (%)
Discontinuation (total)		10			11
Adverse event		7			10
Laboratory abnormality		3			1
Dose modifications	Peginterferon (%)		Ribavirin (%)	Interferon (%)		Ribavirin (%)
Adverse event	11		22	11		21
Anemia	1		22	3		19
Neutropenia	20		1	5		<1
Thrombocytopenia	4		<1	<1		<1
Adapted from Fried et al.8

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Interestingly, this rate of discontinuation for either combination arm was lower than previously reported in earlier trials using standard interferon and ribavirin (approximately 20%),^4,9 suggesting improved strategies for managing side effects of therapy (see below).

Dose reductions (temporary or permanent) of peginterferon for any adverse event were required in 32% of patients compared with 27% in those treated with standard interferon.⁸ Laboratory abnormalities such as neutropenia, anemia, and thrombocytopenia were the most frequent indications for dose reduction. Thus, approximately 25% of patients required at least one dose reduction for laboratory abnormalities during therapy. The frequency of dose reduction for neutropenia was greater in the peginterferon combination arm compared with standard interferon (20% vs. 5%). Among these participants, approximately 5% experienced grade 4 neutropenia (<500 cells/mm³). Thrombocytopenia was also more common with peginterferon. The frequency of ribavirin dose reduction was similar in the combination arms of the study (40% and 37%). Despite the need for dose reductions, only a minority of patients discontinued therapy due to laboratory abnormalities (3% for peginterferon and ribavirin vs. 1% for standard interferon and ribavirin).

 

Frequency of adverse events

Table 2 shows the frequency of adverse events that were reported in at least 20% of participants in this trial.

 

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Table 2. Frequency of adverse events for peginterferon alfa-2a and ribavirin compared with standard interferon alfa-2b and ribavirin (>20%)

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	Peginterferon Alfa-2a and Ribavirin	Interferon Alfa-2b and Ribavirin
Fatigue	54	55
Headache	47	52
Pyrexia	43	56
Myalgia	42	50
Rigors	24	35
Insomnia	37	39
Nausea	29	33
Alopecia	28	34
Irritability	24	28
Arthralgia	27	25
Anorexia	21	22
Dermatitis	21	18
Depression	22	30
Fatigue	54	55
Adapted from Fried et al.8

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The study design allowed for a comparison of the side effect profiles between combination therapies using peginterferon or standard interferon. In general, the adverse events were all predictable based on previous experience with interferon and ribavirin combination therapy, and no significant new classes of side effects were observed. Most adverse events in subjects treated with peginterferon and ribavirin were of similar frequency or significantly less frequent than for those treated with standard interferon and ribavirin. Thus, influenza-like symptoms (fever, myalgia, and rigors), headaches, and alopecia occurred less frequently (by at least 5%) in the peginterferon alfa-2a combination arm. Depression also occurred less frequently in those treated with peginterferon and ribavirin (22%) compared with standard interferon and ribavirin (30%).⁸
 

Peginterferon alfa-2b and ribavirin

A large phase III trial that compared the antiviral efficacy of 2 different regimens of peginterferon alfa-2b and ribavirin with standard interferon alfa-2b and ribavirin has also been reported and allows a comparison between side effect profiles.⁷ The frequency of treatment discontinuation due to any adverse event or laboratory abnormality was similar between the higher-dose (1.5 µg/kg) peginterferon combination arm and standard interferon (14% and 13%, respectively)⁷ (Table 3).

 

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Table 3. Frequency of discontinuations and dose modifications for peginterferon alfa-2b and ribavirin compared with standard interferon alfa-2b and ribavirin

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	Peginterferon Alfa-2b and Ribavirin (%)	Interferon Alfa-2b and Ribavirin (%)
Discontinuation (total)	14	13
Adverse event	12	12
Laboratory abnormality	2	1
Dose modifications
Adverse event	42	34
Anemia	9	13
Neutropenia	18	8
Adapted from Manns et al.7

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Most dose discontinuations resulted from adverse events (12% for each arm), whereas only a minority required discontinuation due to laboratory abnormalities (2% and 1%) (Janice Albrecht, personal communication, June 2002).

Dose modification for any adverse event was required in 42% of participants treated with peginterferon and 34% treated with standard interferon. Similar to the other peginterferon preparation, dose reduction for neutropenia was more common in those treated with peginterferon than standard interferon (18% vs. 10%). Four percent of patients treated with peginterferon and ribavirin experienced neutrophil counts less than 500 cells/mm³.

 

Frequency of adverse events

The frequency of adverse events reported by more than 20% of participants is shown in Table 4.

 

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Table 4. Frequency of adverse events for peginterferon alfa-2b and ribavirin compared with standard interferon alfa-2b and ribavirin (>20%)

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	Peginterferon Alfa-2b and Ribavirin (%)	Interferon Alfa-2b and Ribavirin (%)
Fatigue	64	60
Headache	62	58
Pyrexia	46	33
Myalgia	56	50
Rigors	48	41
Insomnia	40	41
Nausea	43	33
Alopecia	36	32
Irritability	35	34
Arthralgia	34	28
Anorexia/weight loss	32	27
Weight loss	29	20
Depression	31	34
Injection site reaction	58	36
Injection site inflammation	25	18
Adapted from Manns et al.7

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Compared with the standard combination arm, a number of adverse events were reported more frequently in those treated with the peginterferon combination.⁷ Thus, influenza-like symptoms (fevers, myalgias, and rigors) and several gastrointestinal disturbances (nausea, diarrhea, and weight loss) occurred with increased frequency (>5% difference) in those treated with peginterferon and ribavirin compared with the standard interferon combination. Injection site reactions and injection site inflammation were particularly common, although it was noted that these were generally mild and rarely dose limiting.⁷ Other adverse events, including depression, were reported with similar frequencies in both treatment groups.

 

Uncommon serious adverse events

The previous discussion has focused on the most frequent dose-limiting side effects reported with peginterferon and ribavirin. Numerous case reports from patients treated with standard interferon with or without ribavirin show that more serious adverse events may occur with the potential to cause significant morbidity and end-organ damage. A partial list of severe adverse events is given in Table 5.

 

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Table 5. uncommon serious adverse events of interferon and ribavirin^10-19

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Acute psychosis

Severe depression

Suicidal ideation or attempt

Confusion and coma

Personality change

Memory loss

Alcohol relapse

Drug use relapse

Tinnitus

Hearing loss

Retinal hemorrhage

Visual loss

Neuropathy

Seizures

Photosensitivity

Severe skin rash

Local abscess formation

Acute renal failure

Interstitial pneumonitis

Induction of autoantibodies

Autoimmune disease

Hypothyroidism

Hyperthyroidism

Type 1 diabetes mellitus

Celiac disease

Hemolytic anemia

Thrombocytopenic purpura

Addison's disease

Myasthenia gravis

Lupus-like syndrome

Autoimmune hepatitis

Acute congestive heart failure

Arrhythmias

Myocardial infarction

Angina pectoris

Transient ischemic attack

Stroke

Exacerbation of hepatitis

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Among the infrequently reported (<1%) prominent serious adverse events associated with standard interferon therapy are retinopathy, retinal hemorrhage, visual loss, tinnitus, hearing loss, cardiac arrhythmias, congestive heart failure, interstitial pneumonitis, acute renal failure, bacterial infections (particularly in patients with cirrhosis), and induction or exacerbation of autoimmune diseases, hyperthyroidism, hypothyroidism, acute psychosis, panic attacks, severe depression, and suicide.^2,10-19 Healthcare providers should be aware that some of these isolated events have also been reported rarely in association with peginterferon therapy (see package inserts), so that appropriate aggressive investigations may be undertaken when warranted.


 

Management of side effects

In the registration trials of peginterferon combination therapy, significant side effects often required dose reductions and occasionally discontinuation of therapy. Because most of the side effects associated with treatment are dose related, this strategy has been proven to be a safe and effective way to decrease adverse events and minimize serious, life-threatening sequelae. However, recent interest has focused on the importance of adherence to a prescribed medication regimen in maximizing response to antiviral therapy. Decreased adherence due to dose reductions or premature discontinuations could underestimate the true effect of combination therapy for hepatitis C. Indeed, retrospective analyses from 2 large trials of combination therapy with peginterferons suggested that participants who were able to maintain nearly all their prescribed therapy had significantly higher sustained virological response than those who required substantial dose reductions or early treatment withdrawal.^8,20,21 Thus, developing strategies that maximize adherence will likely further improve the efficacy of currently available antiviral agents.


 

General strategies for management of side effects

Management of side effects can begin even before the first dose of medication is administered. Careful patient selection for entry into the registration trials previously described undoubtedly contributed to the low rates of serious adverse events and premature discontinuations of therapy. Thus, patients were excluded if they had significant psychiatric illnesses, active substance abuse, or comorbid medical conditions that could compromise tolerability of the agents under investigation. In clinical practice, proper selection of patients for therapy based on an understanding of the risks of adverse events remains an important safeguard for the use of these agents. However, it is likely that these agents will be used more frequently in patients who do not meet such rigorous standards, so the frequency and severity of adverse events may differ in the expanded treated population. Nevertheless, the concepts for managing adverse events remain applicable.

Before beginning therapy, patients should be educated about the expectations from treatment, particularly the likelihood of experiencing one or more adverse events that could impact transiently on their quality of life. Instructions in self-management techniques can enable a patient to play an active role. Simple interventions such as maintaining adequate hydration, altering dosing schedules to coincide with lighter workdays or weekend activities, maintaining mild to moderate exercise schedules, and judicious use of analgesics and antipyretics can ameliorate some of these side effects. Equally important is providing the patient with regular follow-up visits within a supportive environment. This will facilitate early detection of emerging adverse events and promote rapid intervention when warranted. Incorporation of physician extenders, such as nurse practitioners and physician assistants, and other support personnel such as nurse clinicians, pharmacists, and psychologists into a unified team will enhance greatly the experiences of patients on antiviral therapy.


 

Management of specific adverse events

Certain adverse events associated with antiviral therapy have been responsible for most dose reductions and discontinuations and also have the greatest potential for altering the quality of life of individuals on antiviral therapy. Specific interventions may be available and deserve further discussion.

Anemia

Hemolytic anemia is a universal event associated with ribavirin combination therapy, although the extent of anemia can vary greatly between individuals. The mechanism of anemia due to ribavirin has recently been described.²² Ribavirin is taken up into erythrocytes and activated to ribavirin triphosphate. Erythrocytes are unable to hydrolyze ribavirin triphosphate, which therefore remains “trapped” within the erythrocyte, where concentrations can increase to levels 60-fold greater than plasma concentrations. The associated depletion of red blood cell adenosine triphosphate impairs antioxidant defense and induces red blood cell membrane oxidative damage, promoting extravascular hemolysis via the reticuloendothelial system.²²

During therapy with standard interferon and ribavirin, hemoglobin levels decreased within the first 2–4 weeks of therapy (Fig. 1) with a mean maximal decrease of approximately 3 g/dL.²

Fig. 1. Change in hemoglobin during a 48-week course of combination therapy with peginterferon alfa-2a and ribavirin (), peginterferon alfa-2a alone (), or standard interferon alfa-2b and ribavirin (×). Data courtesy of Hoffmann-La Roche.

Click on Image to view full size

When peginterferon alfa-2a and standard interferon alfa-2b combination regimens were compared, similar maximal decreases in hemoglobin were noted (3.7 vs. 3.6 g/dL). Nevertheless, 9% of participants treated with peginterferon and ribavirin required dose reductions due to decreased hemoglobin levels less than 10 g/dL.⁷ Fortunately these levels of anemia have not been associated with significant cardiovascular events, likely due to careful pretreatment patient selection and the exclusion from therapy of patients with cardiovascular risk factors. Hemoglobin levels promptly return to normal once therapy is discontinued.

Significant anemia associated with ribavirin therapy can increase fatigue, has a demonstrable effect on quality of life, and is a frequent indication for dose reduction of ribavirin.^7,8,23 A number of studies in patients undergoing cancer chemotherapy and a preliminary report from patients undergoing therapy for hepatitis C have suggested that epoetin alfa can relieve many of the symptoms related to chronic anemia.^24-27 Dieterich et al. randomized patients receiving standard interferon and ribavirin to epoetin alfa 40,000 U/wk or standard of care when hemoglobin levels decreased to 12 g/dL or less. After 16 weeks of study, hemoglobin levels were significantly higher in those treated with epoetin alfa compared with standard of care (14.2 vs. 11.2 g/dL; P < .05) and enabled maintenance of higher doses of ribavirin.²⁸ Although these results are of interest, what remains unclear are specific guidelines for using these medications to bolster hemoglobin levels. Additional studies are required to determine at what levels of hemoglobin should consideration be given to hematopoietic growth factors, which subgroups of patients would benefit most, whether treatment should be limited to symptomatic patients, and, ultimately, whether hematopoietic growth factors will have an impact on sustained virological response rates.

Neutropenia

Peginterferons induce neutropenia to a greater degree than standard interferons. Rapid decreases in neutrophil counts may be seen within the first 2 weeks of initiation of therapy and usually stabilize over the next 4 weeks as steady-state concentrations of peginterferon are achieved. Neutrophil counts rapidly return to baseline after therapy is discontinued (Fig. 2).

 

Fig. 2. Change in neutrophil count during a 48-week course of combination therapy with peginterferon alfa-2a with ribavirin (), peginterferon alfa-2a alone (), or standard interferon alfa-2b and ribavirin (×). Data courtesy of Hoffmann-La Roche.

Click on Image to view full size

Clinical trials of therapy of hepatitis C have relied on dose reduction at predefined levels of neutropenia to minimize the risk of potential infectious consequences. Recommendations for dose reduction of peginterferon alfa-2b at neutrophil counts of less than 750 cells/mm,²⁹ which are similar to criteria used in studies of peginterferon alfa-2a, seem to be based on empiric evidence extrapolated from patients undergoing cancer chemotherapy whose risk of infection is considered increased at neutrophil counts less than 500 cells/mm,^30,31 although the greatest risk of infection seems to be at counts less than 100 cells/mm.³⁰

Although this strategy has been successful in terms of safety, neutropenia is the most common reason for dose reduction of peginterferon and, thus, significantly interferes with adherence.^7,8 Cytokines, such as granulocyte colony–stimulating factor and granulocyte-macrophage colony–stimulating factor, have been shown to significantly increase white blood cells and neutrophils in congenital neutropenia, idiopathic neutropenia, leukemic neutropenia, and aplastic anemia.^32,33 It is conceivable that these agents could be used to support neutrophil counts during antiviral therapy. However, data remain extremely limited. Several small clinical trials using granulocyte colony–stimulating factor as an adjunctive agent have suggested that higher neutrophil counts can be maintained during interferon therapy.^34-38 However, further investigation is required before these agents can be recommended for routine use to treat neutropenia associated with peginterferon therapy.

Although dose reductions for neutropenia will remain the standard of care until additional information is developed, new information suggests that the timing of the interferon injection relative to measuring neutrophil counts should also be considered when making decisions about dose reductions. A detailed analysis of hematopoietic changes induced by standard interferon or peginterferon during therapy for hepatitis C has recently been reported.³⁹ After a single injection of peginterferon, neutrophils decreased by a median of 21% within the first 24 hours but generally stabilized over the ensuing 4 weeks. Thus, measurement of neutrophil counts just before, rather than just after, injection may provide a more complete picture and minimize dose reductions.

Although the low rate of infections associated with neutropenia in clinical trials of peginterferons may reflect preemptive dose reductions, it may also be indicative of a lower risk for neutropenic infections in patients with chronic hepatitis C compared with immunosuppressed patients undergoing cancer chemotherapy. This is supported by a recent retrospective study that evaluated the clinical implications and risk factors for neutropenia in patients treated with standard interferon and ribavirin.⁴⁰ One possible exception to this might be patients with underlying cirrhosis. Nevertheless, even among febrile neutropenic patients with cancer, a recent meta-analysis suggests marginal benefit for the therapeutic use of cytokine growth factors.³³ Thus, a more liberal definition of neutropenia for the patient with hepatitis C on therapy might permit dose reductions at lower neutrophil counts than currently recommended without compromising safety. This may have particular implications for some black patients, whose constitutional neutropenia may exclude them from therapy or may necessitate early dose reductions based on current guidelines.^40,41

Thrombocytopenia

Decreases in platelet counts also occur with therapy but have been infrequently associated with dose reduction or discontinuation. Rare instances of autoimmune thrombocytopenic purpura have been reported with peginterferon therapy, and marked decreases in platelet counts should be investigated for the role of autoimmunity. Typical sequential changes in platelet counts during therapy with peginterferon alfa-2a with and without ribavirin are shown in Fig. 3.

Fig. 3. Change in platelet count during a 48-week course of combination therapy with peginterferon alfa-2a and ribavirin (), peginterferon alfa-2a alone (), or standard interferon alfa-2b and ribavirin (×). Data courtesy of Hoffmann-La Roche.

Click on Image to view full size

Depression

Approximately 20% to 30% of patients treated with peginterferon and ribavirin report depression during therapy, making this a frequent cause of decreased quality of life and an indication for dose reduction and discontinuation. The relationship of depression and interferon therapy has recently been reviewed.^42,43 Mechanisms of interferon-induced depression remain largely speculative. Interferon may induce proinflammatory cytokines (tumor necrosis factor, interleukin 1, interleukin 6) to promote “sickness behavior” and may also have effects on the hypothalamic-pituitary-adrenal axis.⁴² Recent attention has also focused on the relationship of interferon to alterations in serotonin activity. Serum levels of tryptophan, a serotonin precursor, are reduced during interferon therapy.⁴⁴ In addition, there is increased activity of serotonin transporter activity that could decrease synaptic serotonin concentrations and contribute to depression.^42,45,46 The involvement of serotonin pathways favors the rationale for the use of selective serotonin reuptake inhibitors for the treatment of depression in patients with chronic hepatitis C.

The neuropsychiatric side effects of interferon can be quite varied, and their interactions may be complex. In addition to depression, other manifestations such as irritability, anxiety, emotional lability, aggressive behaviors, mood disorders, and panic reactions have been reported.⁴⁷ Evaluation of treatment-emergent side effects may be complicated by recently described subtle cognitive impairment before therapy,^48,49 pretreatment functional status,⁵⁰ and overlap with other side effects of interferon, such as fatigue and insomnia, which could exacerbate neuropsychiatric symptoms.^51,52 Interestingly, depressive events associated with treatment with peginterferon alfa-2a and ribavirin occurred more frequently during the first 24 weeks of therapy than during the latter period of a 48-week course (Hoffman La-Roche, data on file). Overall, depression was reported less frequently with peginterferon alfa-2a than standard interferon alfa-2b.⁸

Early identification of depression by directed questioning of the patient during regular follow-up visits is critical to subsequent management. Numerous self-report scales are available to assess the severity of depression and other neuropsychiatric effects.^46,47,53-56 These scales are useful research tools but require additional validation in the treatment setting before they can be used to dictate specific interventions to treat depression.

At the extreme end of the spectrum of depressive side effects are patients who relate suicidal ideation or suicidal behavior, and suicide has been reported with interferon therapy.^2,29 For patients judged to be at risk, treatment should be terminated and immediate referral to a mental health professional accomplished. Fortunately, most episodes of depression remain mild to moderate in severity and can be managed by the use of specific antidepressants, particularly members of the selective serotonin reuptake inhibitor class.^57,58 Judicious use of serotonin reuptake inhibitors with attention to the potential for additional side effects may help minimize dose reductions and discontinuations of antiviral therapy.^59,60 A recent study evaluated the use of prophylactic paroxetine for patients with melanoma undergoing high-dose interferon therapy. Compared with placebo, those treated with paroxetine had fewer episodes of major depression and were able to maintain better adherence with the intensive interferon regimen.⁶¹ Although preemptive strategies may be attractive, they would be inappropriate for the 70% to 80% of participants who do not report depression during therapy with peginterferon and ribavirin.^7,8 Thus, use of antidepressants in the setting of therapy for hepatitis C should be tailored to the history and symptomatology of the individual patient.
 

Brand Names

Category

Description

Before Using This Medicine

Proper Use of This Medicine

Precautions While Using This Medicine

Side Effects of This Medicine

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

How much to inject

Your doctor will tell you how much PEGASYS to inject according to your individual needs.

When given in combination with COPEGUS tablets, PEGASYS is usually administered as a 180 micrograms/0.5 mL injection once weekly for 24 or 48 weeks (depending on the type of hepatitis C disease you have).

When given alone, the usual recommended dose of PEGASYS is a 180 micrograms/0.5 mL injection once weekly for 48 weeks.

If necessary, your dose may be changed by your doctor during therapy, or PEGASYS treatment may be stopped altogether, according to your response.

Do not exceed or change the dose recommended by your doctor.

How to inject it

PEGASYS is administered by subcutaneous injection. This means that PEGASYS is injected with a short needle into the fatty tissue just under the skin in the stomach or thigh.

Your doctor may discuss whether it would be more convenient for you to receive your injection at home, in which case, you or a family member would be instructed on how to give the injection. This is a simple procedure and many patients prefer it.

If your doctor has directed you to use PEGASYS by subcutaneous injection at home, please follow the instructions below.

Directions for self-administration

You should read these directions from beginning to end before starting so that each step of the procedure becomes familiar. These instructions must be carefully followed. Consult your doctor or nurse if you require further instructions.

Remember that cleanliness is vital.

I. Before subcutaneous injection

• Check the expiry date. Do not use PEGASYS after the expiry date shown on the prefilled syringe label
• Check the dose that you have been prescribed
• Check the liquid has no discolouration, cloudiness or particles. The liquid should look clear and colourless to slightly yellow
• Allow the solution to reach room temperature.
• Wash your hands thoroughly
• Place everything you need within easy reach on a cleaned surface: the prefilled syringe, the injection needle, several alcohol swab packets and container for disposal of needle and syringe.

II. How to prepare the syringe

1. Take the sealed needle in both hands and snap the cap backwards. Remove the cap. Do not remove the plastic needle shield.
   
   
2. Remove the rubber tip from the syringe. Do not touch the tip of the syringe.
   
   
3. Attach the needle with the plastic shield firmly to the syringe.
   
   
4. Remove the plastic cover from the needle while holding the syringe. Avoid pushing the plunger.
   
   

To remove air bubbles from the syringe, hold the syringe with the needle pointing up. Tap the syringe gently to bring the bubbles to the top. Push up the plunger slowly to the correct dose. Replace the needle guard and place the syringe on a clean flat surface.

The syringe is now ready for use.

III. Performing subcutaneous injection

5. Select an injection site in the stomach or thigh area (except your navel or waistline, see diagram).
   Change your injection site each time.
   
   
6. Remove an alcohol swab from one packet and clean and disinfect the site by wiping with the swab.
   
   
7. Remove the alcohol swab from the site. Allow the injection site to dry for 10 seconds.
8. Grasp the skin firmly between the thumb and forefingers (without squeezing) to elevate the subcutaneous tissue.
   
   
9. Insert the needle into the grasped skin at an angle of 45° to 90°.
   
   
10. Inject the solution by gently pushing the plunger all the way down, while keeping the skin grasped.
    
    
11. After injecting, remove the needle and release the skin. Immediately disinfect the site with a new alcohol swab and apply finger pressure for a minute or so.
    
    (i)
    
    (ii)

Remember: Most people can learn to give themselves a subcutaneous injection, but if you experience difficulty, please do not be afraid to ask for help and advice from your doctor, nurse or pharmacist.

IV. How to dispose of used needles and syringes

The needle and syringe are to be used once only. Dispose of the needle and syringe immediately after injection into a sturdy glass or hard plastic container away from children. Do not replace the needle cover.

Never put used needles and syringes into your normal household waste bin.

If you are not sure how to dispose of the needles and syringes, consult your doctor or pharmacist on how to properly dispose of them.

Please note that the needle supplied with the PEGASYS prefilled syringe is for subcutaneous injection only and is not suitable for any other type of injection (e.g. intravenous or intramuscular injection).

When to inject PEGASYS

Your doctor will tell you how often to use this medicine. PEGASYS is usually given as a single injection once a week.

If you are injecting this medicine yourself, use it at bedtime, as PEGASYS may cause increased tiredness or flu-like symptoms.

How long to use PEGASYS

Continue using PEGASYS until your doctor tells you to stop.

Your doctor will determine when your treatment should be stopped.

If you forget to use PEGASYS

If you realise you missed your injection within 2 days after the scheduled dose, you should inject your recommended dose as soon as you remember. Take your next injection on the following regularly scheduled day.

If you have trouble remembering when to use your medicine, ask your pharmacist for some hints.

If you use too much PEGASYS (overdose)

Immediately telephone your doctor or National Poisons Information Centre (telephone 0800 POISON or 0800 764 766) for advice or go to your nearest Accident and Emergency centre if you think that you or anyone else may have used too much PEGASYS, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you are not sure what to do, contact your doctor or pharmacist.

While you are using PEGASYS

Things you must do

Use PEGASYS exactly as your doctor has prescribed.

Tell your doctor if, for any reason, you have not used PEGASYS exactly as prescribed.

Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

Be sure to keep all of your appointments with your doctor so that your progress can be checked.

Your doctor will keep track of your response to PEGASYS by asking questions and performing occasional laboratory tests.

Things you must not do

Do not stop using PEGASYS or change the dose without first checking with your doctor.

Do not take any other medicines whether they require a prescription or not without first telling your doctor or consulting a pharmacist.

Things to be careful of

PEGASYS may cause dizziness, drowsiness or light-headedness in some people. Be careful driving or operating machinery until you know how PEGASYS affects you. If you drink alcohol, dizziness, drowsiness or light-headedness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using PEGASYS.

PEGASYS helps most people with chronic hepatitis C but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

• flu-like symptoms such as fever, tiredness/fatigue, chills, muscle or joint pain and headache (these symptoms can usually be relieved by paracetamol)
• nausea (feeling sick)
• insomnia (difficulty sleeping)
• poor concentration
• temporary hair loss (reversible after finishing treatment)
• loss of appetite
• diarrhoea
• itchiness
• irritability
• dizziness
• depression or feeling anxious
• reaction at injection site

Tell your doctor immediately or go to your nearest Accident and Emergency centre if you notice any of the following:

• severe chest pain
• feeling very depressed or suicidal
• persistent cough
• trouble breathing
• irregular heartbeat
• problems with your eyesight
• severe stomach pain
• confusion
• unusual bleeding or bruising
• fever or chills beginning a few weeks after treatment has started
• tingling finger and toes

These are serious side effects. You may need urgent medical attention. Serious side effects are rare.

This is not a complete list of all possible side effects. Your doctor or pharmacist has a more complete list. Others may occur in some people and there may be some side effects not yet known.

Tell your doctor if you notice anything else that is making you feel unwell, even if it is not on this list.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After using PEGASYS

Storage

Always keep this medicine in the carton until it is time to take it.

If you take the prefilled syringes out of the pack they may not keep well.

Store PEGASYS prefilled syringes in the fridge at 2 to 8°C. Do not freeze.

Do not shake PEGASYS.

Shaking can destroy PEGASYS so that it will not work.

Protect PEGASYS prefilled syringes from light.

Do not leave it in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep PEGASYS where young children cannot reach it.

The top shelf of the refrigerator is a good place to store this medicine.

PEGASYS prefilled syringes are for single use only.

The prefilled syringe should be used once only and any remaining contents should be discarded with the needle.

Disposal

If your doctor tells you to stop using PEGASYS, or the prefilled syringe has passed its expiry date, ask your pharmacist what to do with any prefilled syringes that are left over.

If you use PEGASYS at home, you must put the used syringes and needles in a container that will not let the needles stick through it. The full container should be disposed of following the directions given by your doctor or pharmacist. This will help protect you and other people from being accidentally pricked by a used needle. Being pricked by a used needle can pass diseases onto other people.

Product description

Availability

PEGASYS prefilled syringes are available in packs of one in the following strengths:

• 135 micrograms in 0.5 mL solution
• 180 micrograms in 0.5 mL solution

What PEGASYS prefilled syringes look like

PEGASYS solution for injection is contained in a disposable glass syringe. The solution is clear and colourless to light yellow.

A stainless steel needle is also supplied with the syringe to allow for subcutaneous injection.

Ingredients

Active ingredient

• peginterferon alfa-2a (40 KD)

Inactive ingredients

Each prefilled syringe also contains:

• sodium chloride, benzyl alcohol, sodium acetate, acetic acid, polysorbate 80, water for injections

Distributor

PEGASYS prefilled syringes are distributed by:

Roche Products (New Zealand) Ltd
P O Box 12-492
Penrose
AUCKLAND

Telephone: (09) 633 0700
Toll Free: 0800 656 464

This leaflet was prepared on 4 August 2003.

Reference: Pegasys Data Sheet dated 5 February 2003.