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Articles On Side Effects
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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.
Discontinuations and dose modification
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).
Frequency of adverse events
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
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).
Frequency of adverse events
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.
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.
Anemia 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
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. Neutropenia
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.
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.
Future studies should emphasize the importance of developing additional management strategies that will maximize adherence to antiviral therapy. Prospective studies of adherence could evaluate the impact of early versus late dose reductions and the effects on response in different genotypes. Additional information is required about the mechanisms of interferon-induced depression, which will facilitate the development of new therapeutic approaches. Prospective studies of hematopoietic growth factors to determine their effects on sustained virological response and quality of life and refining guidelines for dose reduction for neutropenia may also improve the management of adverse events during therapy with peginterferon and ribavirin for chronic hepatitis C.
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Peginterferon Alfa–2a (Systemic)
Brand Names
In the U.S.—
Peginterferon alfa-2a (peg in-ter-FEER-on alf-a 2a) is a synthetic
(man-made) version of substances normally produced in the body to fight
infection. Peginterferon alfa-2a is used to treat chronic hepatitis C. It
is used for patients who have never been treated by alpha interferons.
This medicine is available only with your doctor's prescription, in the following dosage forms:
Before Using This Medicine
In deciding to use a medicine, the risks of using peginterferon alfa-2a
must be weighed against the good it will do. This is a decision you and
your doctor will make. For peginterferon alfa–2a, the following should be
considered:
Allergies—Tell your doctor if you have ever had any unusual or allergic reaction to peginterferon alfa–2a. Also tell your doctor and pharmacist if you are allergic to any other substances, such as foods, preservatives, or dyes. Pregnancy—Peginterferon alfa-2a has not been studied in pregnant women. However, studies in animals have shown that peginterferon alfa-2a causes pregnancy losses. This medicine should only be given to fertile women if they are using a proven form of birth control. Patients using peginterferon alfa-2a should assume that it is dangerous to pregnant women and their babies Breast-feeding—It is not known if peginterferon alfa-2a passes into breast milk. It is sometimes dangerous to use medicines while breast feeding. Mothers who are taking this medicine and who wish to breast-feed should discuss this with their doctor. A decision must be made whether to stop breast-feeding or to stop using peginterferon alfa-2a. Children—Studies of this medicine have been done only in adult patients and there is no specific information comparing use of peginterferon alfa–2a in children with use in other age groups. However, this medicine should not be used in newborns and infants because it has a substance that is harmful to newborns and infants. Older adults—Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults or if they cause different side effects or problems in older people. There is no specific information comparing use of peginterferon alfa–2a in the elderly with use in other age groups. Other medicines—Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking peginterferon alfa 2a, it is especially important that your doctor and pharmacist know if you are taking any of the following:
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your health care professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.
Other medical problems—The presence of other medical
problems may affect the use of peginterferon alfa–2a. Make sure you tell
your doctor if you have any other medical problems, especially:
Proper Use of This Medicine
Dosing—
The dose of peginterferon alfa-2a will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of peginterferon alfa-2aIf your dose is different, do not change it unless your doctor tells you to do so. The length of time you take the medicine depends on the medical problem for which you are taking peginterferon alfa-2a
Missed dose— If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses. Storage— To store this medicine:
Precautions While Using This Medicine
This medicine may cause some people to become drowsy, dizzy, or less alert
than they are normally.Make sure you know how you react to this
medicine before you drive, use machines, or do anything else that could be
dangerous if you are dizzy and not alert.
It is very important that your doctor check your progress at regular visits. This will allow your doctor to see if the medicine is working properly and to check for any problems that this medicine may cause.
Side Effects of This Medicine
Side Effects of This Medicine
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention. Check with your doctor immediately if any of the following side effects occur:
Other side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. However, check with your doctor if any of the following side effects continue or are bothersome.
Other side effects not listed above may also occur in some patients. If you notice any other effects, check with your doctor. Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet. How much to injectYour 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 itPEGASYS 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-administrationYou 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
II. How to prepare the syringe
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
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 syringesThe 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 PEGASYSYour 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 PEGASYSContinue using PEGASYS until your doctor tells you to stop. Your doctor will determine when your treatment should be stopped. If you forget to use PEGASYSIf 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 realise you missed your injection 3 to 5 days after your scheduled dose, you should inject your recommended dose as soon as you remember. Take your next doses at 5 day intervals until you return to your regularly scheduled day of the week. If you realise you missed your injection 6 days after the scheduled dose, you should wait and inject your dose on the next day. Do not take a double dose to make up for the injection that you missed. If you are not sure what to do, ask your doctor or pharmacist. 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. Keep telephone numbers for these places handy. If you are not sure what to do, contact your doctor or pharmacist. While you are using PEGASYSThings you must doUse PEGASYS exactly as your doctor has prescribed. Tell all doctors, dentists and pharmacists who are treating you that you are using PEGASYS. Tell your doctor if you become pregnant while using PEGASYS. 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 doDo not stop using PEGASYS or change the dose without first checking with your doctor. Do not let yourself run out of medicine over the weekend or on holidays. Do not give PEGASYS to anyone else even if they have the same condition as you. Do not use PEGASYS to treat other complaints unless your doctor says to. Do not switch to any other brand of interferon without consulting your doctor because a change in dose may be required. 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 ofPEGASYS 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 effectsTell 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:
Tell your doctor immediately or go to your nearest Accident and Emergency centre if you notice any of the following:
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. Ask your doctor or pharmacist if you don't understand anything in this list. Do not be alarmed by this list of possible side effects. You may not experience any of them. After using PEGASYSStorageAlways 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. DisposalIf 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 descriptionAvailabilityPEGASYS prefilled syringes are available in packs of one in the following strengths:
What PEGASYS prefilled syringes look likePEGASYS 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. IngredientsActive ingredient
Inactive ingredients Each prefilled syringe also contains:
DistributorPEGASYS prefilled syringes are distributed by: Roche Products (New Zealand) Ltd Telephone: (09) 633 0700 This leaflet was prepared on 4 August 2003. Reference: Pegasys Data Sheet dated 5 February 2003.
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