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SIDE EFFECTS
Shortness of Breath (Pulmonary)
Thyroid
http://pegintron.com/pegintron/faqs.html#Q10
Thyroid Disorders in Chronic Hepatitis C All patients were free of cirrhosis and hepatocellular carcinoma, and were not on interferon alfa treatment. Also included were a control group of 389 subjects from an iodine-deficient area, another control group of 268 persons living in an area of iodine sufficiency, and 86 patients >40 years of age with chronic hepatitis B. Levels of thyroid-stimulating hormone (TSH), free thyroxine (T(4)), and triiodothyronine (T(3)), as well as anti-thyroglobulin and anti-thyroid peroxidase antibodies, were measured. ResultsMean TSH levels were higher (P = 0.001), and free T(3) and free T(4) levels were lower (P <0.0001), in patients with chronic hepatitis C than in all other groups. Patients with chronic hepatitis C were more likely to have hypothyroidism (13% [n = 82]), anti-thyroglobulin antibodies (17% [n = 108]), and anti-thyroid peroxidase antibodies (21% [n = 132]) than were any of the other groups. ConclusionsBoth hypothyroidism and thyroid autoimmunity are more common in patients with chronic hepatitis C, even in the absence of cirrhosis, hepatocellular carcinoma, or interferon treatment, than in normal controls or those with chronic hepatitis B infection. Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa School of Medicine, Pisa, Italy. a.antonelli@med.unipi.it 06/30/04
Reference
THYROID DYSFUNCTION WARNING: Patients with pre-existing thyroid abnormalities whose thyroid function cannot be maintained in the normal range by medication should not be treated with interferon or peginterferon. Therapy should be discontinued for patients developing thyroid abnormalities during treatment whose thyroid function cannot be normalized by medication. Discontinuation of interferon-based therapy has not always reversed thyroid dysfunction occurring during treatment. PATHOPHYSIOLOGY The thyroid is a bilobed gland located on either side of the trachea directly above the larynx.1 It secretes the hormones thyroxine (T4) and triiodothyronine (T3). T4 represents 90% of secreted hormone and T3 represents 10%.2 Of T4, 99.97% is protein bound, with T3 less strongly protein bound. T3 and T4 affect most body tissues by regulating protein, fat, and carbohydrate catabolism as well as metabolism. T3 and T4 also regulate CNS development, cardiac rate, and gastrointestinal tract functioning. Thyroid function is regulated by the hypothalamic-pituitary axis. Thyrotropin-releasing hormone (TRH) is released by the hypothalamus, which stimulates the pituitary to secrete TSH. TSH stimulates the thyroid gland to produce T3 and T4. T3 and T4 circulating levels inhibit release of TSH when sufficient synthesis has occurred. When T3 and T4 levels decrease, the pituitary releases TSH.1 Hypothyroidism results from decreased thyroid gland hormone production and secretion. Primary hypothyroidism results from lower levels of T4 than T3. Increased TSH secretion increases T3 secretion. Secondary hypothyroidism results in decreased synthesis of both hormones.2 Hyperthyroidism occurs when tissues are exposed to excessive thyroid hormone concentrations. It has multiple causes, some of which are transient and others of which are permanent, ie, Graves’ disease, thyroiditis.2 Interferon alfa stimulates production of various cytokines (eg, interferon-gamma [IFN-g], interleukin-2 [IL-2]) that have direct effects on endocrine cells.3 As a result, cytokines have been identified as important factors in the pathogenesis of autoimmune endocrinopathies, particularly IFN-g and IL-2. It is postulated that interferon alfa stimulates production of IFN-g and IL-2 from thyroid-infiltrating lymphocytes, hence potentiating antithyroid autoimmunity. Specific antithyroid autoantibodies, antithyroid peroxidase, and antithyroglobulin have also been observed in patients on interferon alfa, resulting in an AI thyroiditis. This is generally reversible, but can take up to 18 months to resolve. In some patients, hypothyroidism developed while on treatment may be permanent.3 Hypothyroidism is more commonly manifested in patients undergoing interferon therapy, with a ratio of hypothyroidism to hyperthyroidism of 2:1 or 3:1.4 Transient hyperthyroidism followed by persistent hypothyroidism has been reported.4 All patients should be counseled prior to initiation of interferon-based therapy that irreversible thyroid disease can occur. Side Effects Management Handbook • VI. Endocrine • p. 5 HIGH-RISK PATIENTS · Women · Age >40 years · IL-2 and interferon concomitant therapy · Pre-existing thyroid disease · Family history DIAGNOSTIC TESTS AND INTERPRETATION 1. TSH recommended initially (all patients) 2. If TSH is abnormal, complete thyroid panel including T4 and free T3. a. High TSH, normal T4: compensated hypothyroidism b. High TSH, low T4: clinical hypothyroidism c. Low TSH, high T3: hyperthyroidism 3. Consider measuring antithyroid antibodies to rule out AI thyroid disease, such as Hashimoto’s thyroiditis. Antithyroid antibodies: antithyroid peroxides, antithyroglobulin, and antimicrosomal antibodies. Antithyroid autoantibodies are very common in the general population, occurring in about 16% of women. Normal aging increases the number of circulating antibodies; thus, the patient’s health and age must be considered. 4. Note that measuring T4 alone could lead to missing a diagnosis of compensated hypothyroidism, since the T4 level could be normal only because the TSH has been stimulating the thyroid into additional production. Compensated hypothyroidism cannot persist for long without progressing to overt hypothyroidism. 5. Note that T3 is measured, but is less meaningful; may be lower than normal in up to 70% of all hospitalized patients. SYMPTOMS OF HYPOTHYROIDISM1 SYMPTOMS OF HYPERTHYROIDISM2 SUBCLINICAL: · Restlessness · Easily fatigued · Anxiety · Mood alterations/mild depression · Heat intolerance · Inability to lose weight · Palpitations CLINICAL: · Declining mental function · CHF · Increased fatigue · Increased appetite · Dry skin/myalgias · Emotional lability · Constipation · Weight loss · Irregular/heavy menses · Thyroid enlargement · Pallor, yellow skin tone · Infertility · Hoarseness · Gynecomastia in males · Tremors in fingers/hands Side Effects Management Handbook • VI. Endocrine • p. 6 TREATMENT FOR HYPOTHYROIDISM1 1. Check medical history for possible etiology. Two widely used drugs, lithium carbonate (Eskalith®) and amiodarone (Cordarone®, Pacerone®), are known to cause hypothyroidism. 2. Continue anti-HCV therapy while therapy for hypothyroidism is instituted. 3. Thyroid hormone replacement: levothyroxine (Levothroid®, Levoxyl®, Synthroid®, Unithroid™) preferred. Age <50 years: 75–100 µg with 25–50 µg dose adjustment every 2 to 3 weeks. Age >50 years: 25 to 50 µg, increases in 25 µg increments. Do not interchange brands; bioequivalence problems between manufacturers. Peak therapeutic effect: 4 to 6 weeks. 4. Adverse reactions of thyroid hormone replacement: a. CNS: nervousness, insomnia, tremor b. CV: tachycardia, angina c. Gastrointestinal: diarrhea, vomiting d. General: weight loss, fever, heat intolerance, menstrual irregularities 5. Recheck thyroid panel in 4 weeks. If there are persistent abnormalities, consider referral to endocrinologist. 6. Be aware that antidiabetic agents may have to be increased when thyroid medications are initiated, and patients taking estrogen (hormone replacement therapy) may need to increase the amount when beginning thyroid medications. Patients should be instructed to1: 1. Take medication at the same time every day to maintain hormone levels. A single morning dose before breakfast decreases the chance of insomnia; tablets may be crushed. Do not adjust the dose. 2. Take iron preparations, antacids, and cholesterol-lowering drugs 4 to 5 hours apart from thyroxine. 3. Notify their healthcare provider of symptoms of intolerance: palpitations, chest pain, anxiety, and sudden increase in size of thyroid gland. 4. Know that symptoms should begin to abate within 2 weeks of therapy initiation. 5. Be aware that thyroid hormone replacement is usually permanent, and they should tell all healthcare providers that they are taking this therapy. 6. Store medications in cool, dark, dry place. 7. Avoid changing dose/brand or discontinuing treatment without physician approval. 8. Limit consumption of high iodine foods (especially kelp preparations), since thyroid medications may increase toxicity to iodine. 9. Inform their radiologist about thyroid medication before any iodine contrast is given for imaging studies. TREATMENT FOR HYPERTHYROIDISM 1. Upon diagnosis of hyperthyroidism, strongly consider referral to the primary physician and/or endocrinologist. 2. Antithyroid drugs: Methimazole (MMI; Tapazole®) and propylthiouracil (PTU). Indications: Grave’s disease, hyperthyroidism in children and adolescents, hyperthyroidism in pregnancy. Side Effects Management Handbook • VI. Endocrine • p. 7 3. Iodide: Reserved for severe hyperthyroidism following iodine-131 (131I) therapy or as preparation for surgery.2 4. Beta-adrenergic drugs: Propranolol (Inderal®, Inderide®). Indications: between interval that 131I therapy becomes effective or prior to surgery. 5. Radioactive iodine. Indications: long-term antithyroid drug failures. 6. Surgery. Indications: hyperthyroid pregnant women who cannot tolerate antithyroid drugs and those with large goiters to relieve symptoms locally. Patients should be instructed: 1. That medications are generally taken for at least 2 years and should not be abruptly discontinued 2. To contact healthcare professional with first signs of infection or fever 3. That the therapeutic effect of medication is not usually evident for about 3 weeks THYROID DYSFUNCTION AND HCV INFECTION CONSIDERATIONS The prevalence of antithyroid antibodies and autoimmune thyroid disease is higher in the HCV-infected population than in control groups.5 A proportion of patients with antithyroid antibodies will develop clinical thyroid dysfunction. Hypothyroidism is seen more frequently than hyperthyroidism. Hyperthyroidism may transform over time into hypothyroidism. The incidence of antithyroid antibodies and thyroid dysfunction is enhanced by interferon alfa treatment. Thyroid dysfunction is reversible only in a minority of patients following discontinuation of interferon alfa treatment. Antithyroid autoantibodies have a 4.6% to 15% prevalence in untreated HCV-infected patients. Latent AI thyroiditis is more frequent in untreated hepatitis C patients than in controls. Risk factors for developing antithyroid antibodies include5: • Age • Female sex • Increased TSH levels • Hypoechogenic pattern of thyroid gland on ultrasound5 THYROID DYSFUNCTION IN HCV-INFECTED PATIENTS TREATED WITH INTERFERON ALFA • Study of 308 patients treated with interferon alfa therapy, including 211 with HCV infection, who underwent thyroid function evaluation before and after interferon6 • 14% of patients had antithyroid peroxidase antibodies (ATPO); 3.7% had detectable thyroid dysfunction prior to onset of therapy.6 • Interferon alfa led to increase in ATPO in 73% of patients with positive baseline levels; 10.8% of patients developed de novo ATPO. • Increased prevalence of ATPO following therapy was more frequent in women.6 • Patients with high baseline ATPO titers had a higher rate of thyroid dysfunction at end of treatment. • Six months posttherapy, an increased rate of thyroid dysfunction persisted in 8% of patients. • 5.8% of euthyroid patients with undetectable ATPO prior to therapy developed thyroid dysfunction; 11/15 developed hypothyroidism and 4/15 hyperthyroidism. Side Effects Management Handbook • VI. Endocrine • p. 8 • 15.2% of euthyroid patients with detectable ATPO prior to treatment developed hypothyroidism. • Six months posttherapy, normal thyroid function was observed in 3/15 patients (20%) who developed hypothyroidism and 4/7 patients who developed hyperthyroidism. • 3/7 remaining patients who developed hyperthyroidism during treatment progressed to hypothyroidism during follow-up. • Clinical recommendation: interferon-based therapy can continue unless the patient is symptomatic or unstable.
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Thyroid Autoimmunity Associated With Interferon-Alpha May Be IrreversibleA DGReview of :"Long-Term
Outcome of Interferon-(alpha)-Induced Thyroid Autoimmunity and Prognostic
Influence of Thyroid Autoantibody Pattern at the End of Treatment"
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Shortness of breath is seen in up to 14% of patients: Shortness of breath may be from anemia and this must be monitored for
patients with normal Hgb, pulmonary function is usually normal in spite of
symptoms, Patients who have had their asthma under control, but have been taking interferon for the suppression of hepatitis C, have suffered enough to be hospitalized for the return of asthma symptoms. Hepatitis C therapy with interferon-alpha can lead to severe asthma exacerbation in patients with previously mild asthma. Interferon-alpha therapy has previously been associated with pulmonary complications, and now we have evidence of asthma exacerbation as well. (Mayo Clinic Proceedings 1999; 74:367-370) Pulmonary and Renal WARNING: Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, and sarcoidosis, some resulting in respiratory failure and/or patient deaths, may be induced or aggravated by peginterferon or interferon alfa therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. The etiology has yet to be established. Side Effects Management Handbook • XII. Pulmonary & Renal • p. 2 XII. Pulmonary and Renal COUGH Cough of unexplained etiology can occur in patients receiving interferon or peginterferon alone or in combination with ribavirin. Nonproductive cough is sometimes seen in association with throat irritation accompanying postnasal drip. The cough may be worse at night or may become a nervous cough. ASSESSMENT Providers should perform physical examination, WBC, chest x-ray, etc, as needed to rule out other possible etiologies before diagnosing cough secondary to peginterferon and/or ribavirin. MANAGEMENT STRATEGIES Patients should be instructed to: 1. Maintain adequate hydration1 (consumption in fluid ounces = one half body weight in pounds; eg, a 160-lb person should drink 80 fl oz/d). 2. Humidify air. 3. Use two pillows for sleep. 4. Use a saline nebulizer. 5. Suck on cough drops/hard candy/lozenges. 6. Try Cepacol® spray. 7. Take antihistamines at bedtime. 8. Try expectorants, especially during the day. Providers should: 1. Follow absolute ANC and CBC with differential. 2. Perform chest x-ray as needed. If x-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be closely monitored, and, if appropriate, treatment should be discontinued. Patients who resume interferon treatment should be closely monitored. 3. Administer flu/pneumonia vaccinations if not contraindicated. Administer other vaccinations (eg, hepatitis A and B vaccinations if susceptible) in accordance with Centers for Disease Control and Prevention (CDC) recommendations. 4. Recommend pharmacologic therapies. Consider prescription therapies if over-thecounter agents are not helping. a. Dextromethorphan hydrobromide – try before prescribing narcotics b. Guaifenesin (Organidin®) with or without codeine; 30 cc as directed around the clock for 2 to 3 days. Guaifenesin can be prescribed in capsule and extendedrelease forms at 600 mg, 800 mg,1200 mg REFERENCE 1. Rieger PT. Clinical Handbook for Biotherapy. Boston: Jones & Bartlett; 1999:60-90. Side Effects Management Handbook • XII. Pulmonary & Renal • p. 3
Pulmonary DYSPNEA Dyspnea, defined as difficult or labored breathing,1 may be seen as part of pulmonary edema or as part of pulmonary symptoms of unexplained etiology in patients receiving peginterferon/ribavirin. Shortness of breath may occur only on exertion or, in some patients, may be present even at rest. In most cases, dyspnea is secondary to ribavirininduced anemia. Pulmonary symptoms, that is, pulmonary infiltrates, pneumonitis, and pneumonia, including fatality, have been observed in patients treated with interferon. The etiology of these pulmonary findings has not been established. Acute serious hypersensitivity reactions (eg, urticaria, angioedema, bronchoconstriction, anaphylaxis) have been observed rarely in patients on interferon. It is important to rule out the following: • Hypersensitivity (wheezing, bronchospasm2) to interferon or other medications patient may be taking • Pneumonia (infection) or pulmonary infiltrates • Anemia • Allergies • Pulmonary embolism MANAGEMENT STRATEGIES 1. Measure CBC with differential, Hgb, and ANC, and perform chest x-ray, STAT. a. If x-ray shows pulmonary infiltrates or there is evidence of pulmonary function impairment, the patient should be closely monitored, and, if appropriate, treatment should be discontinued. Patients who resume interferon treatment should be closely monitored. b. Treat anemia, if present, with epoetin and/or dose reduction (see “Hematologic” section). 2. Prescribe inhalers (eg, albuterol [Proventil®, Ventolin®]), which may relieve dyspnea even in the absence of wheezing. 3. Advise patients to modify ADL and conserve energy. Recommend that patients avoid smoke, sudden inspiration of cold air, allergens, and dust. 4. Hospitalize and administer oxygen as needed. 5. Discontinue interferon immediately if hypersensitivity occurs. Initiate appropriate medical therapy. REFERENCES 1. Harwood KV. Dyspnea. In: Groenwald SL, Frogge MH, Goodman M, Yarbro CH, eds. Cancer Symptom Management. Boston, Mass: Jones and Bartlett, 1996;45-53. 2. Camp-Sorrell D. Surviving the cancer, surviving the treatment: acute cardiac and pulmonary toxicity. Oncol Nurs Forum. 1999;26:983-990. Side Effects Management Handbook • XII. Pulmonary & Renal • p. 5
Interferon: The Great Initiator (of Side Effects)IFN alfa can lead to a surprising variety of rare but very severe side effects, often in the form of autoimmune syndromes. For example, sarcoidosis, a rare IFN-associated side effect, can progress to life-threatening illness, as illustrated by a 47-year-old woman with HCV genotype 3a infection in whom fever and respiratory failure developed 20 days after completion of a course of treatment with PEG IFN alfa-2b and ribavirin. Chest x-ray films showed "atypical pneumonia" (Figure 3), and transbronchial biopsy demonstrated granulomatous inflammation (Figure 4). Corticosteroids were given concomitantly with antituberculous medication (until PCR testing for Mycobacterium tuberculosis complex showed negative results), and the patient slowly recovered after 9 days on mechanical ventilation. The HCV response to IFN was sustained.
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Ribavirin has also been found to cause itching and nasal stuffiness. These are histamine-like side effects; they occur in 10 to 20 percent of patients and are usually mild to moderate in severity. In some patients, however, sinusitis, recurrent bronchitis, or asthma-like symptoms become prominent. It is important that these symptoms be recognized as attributable to ribavirin, because dose modification (by 200 mg per day) or early discontinuation of treatment may be necessary.
SINUSITIS Sinusitis is caused by inflammation of the lining membrane of any sinus, especially one of the paranasal sinuses.1 It may be acute, caused by the extension of inflammation from the nasal mucosa, or chronic, as a sequela of the acute inflammation, because of incomplete resolution of infection or recurrent acute complications. Symptoms may include postnasal drip, pain, throat irritation, and/or cough. Sinusitis is more common in coinfected patients. Treatment Strategies 1. Adequate hydration (consumption in fluid ounces = one half body weight in pounds; eg, a 160-lb person should drink 80 fl oz/d) 2. Humidifier1 3. Oral care with saline gargle1 4. Topical decongestant spray1 5. Cough drops/hard candy/lozenges 6. Antihistamines 7. Nasal saline spray 8. Antibiotics, if bacterial etiology REFERENCE 1. Sinusitis. In: Nettina SM, ed. Lippincott’s Pocket Manual of Nursing Practice. Philadelphia, Pa: Lippincott; 1997:798-802.
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Weight
Loss Weight loss occurs frequently with treatment: Weight loss is usually due to decreased intake, ANOREXIA PATHOPHYSIOLOGY Anorexia has been demonstrated in mammals after exogenous administration of cytokines, such as interferon. The extent of anorexia seen varies depending on the dose, duration, timing, underlying pathology, and nutritional status of the patient. Cytokineinduced anorexia involves both the peripheral system and the CNS. Cytokines modulate gastrointestinal activities, affect the endocrine system, and exert their effects on the hypothalamus. Cytokines can inhibit appetite by causing a delay in gastric motility and emptying. Cytokine-induced changes can also cause nausea and vomiting. Hormonally, IL-1 may be responsible for alterations in corticotropin-releasing factor, cholecystokinin, glucagon, and insulin. IL-1, interferon, and TNF act directly as well as synergistically on the hypothalamus, altering neurotransmitters (eg, serotonin) and contributing to taste aversions. These same cytokines can increase the rate of lipolysis, increase serum triglyceride levels, and alter carbohydrate and protein metabolism. Cachexia is a risk with long-term cytokine therapy due to muscle wasting secondary to skeletal muscle protein breakdown.1 ASSESSMENT 1. Assess the patient’s current nutritional status. 2. Determine ideal body weight (IBW): Women: Add 100 lb for the first 60 inches of height, 5 lb for each inch over 60 inches, divide by 2.2 to obtain IBW in kilograms (kg). Men: Add 106 lb for the first 60 inches of height, 6 lb for each inch over 60 inches, divide by 2.2 to obtain IBW in kg.2 3. Determine caloric needs: Women: Multiply IBW kg calculation x 24 hours x 0.9 calorie = resting needs. Men: Multiply IBW kg calculation x 24 hours x 1.0 calorie = resting needs.2 Note: Immunotherapy-related febrile reactions are associated with an approximate 10% increase in metabolic requirements per degree above 37°C.3 4. Review the patient’s dietary intake diary. 5. Assess for significant weight loss: ³1–2 lb/wk, 5% weight loss over the past month, and loss of >10% IBW indicate significant weight loss. Assess for signs of anorexia/malnutrition, including hair loss, scaling skin, brittle nails, and impaired skin integrity. 6. Assess serum albumin levels (may be influenced by hydration, infection, position, or activity, and/or decompensated cirrhosis) and electrolytes. 7. Assess transferrin levels (influenced by bone marrow suppression and iron deficiency). Fluctuations in transferrin reflect changes in nutritional state more rapidly than albumin, as it is less affected by factors that affect serum albumin concentrations. 8. Perform CBC and assess for macrocytosis (possible folate or vitamin B12 deficiency). 9. Assess total lymphocyte count. Levels <1200/mm3 suggest nutritional deficiency. Side Effects Management Handbook • VIII. Gastrointestinal • p. 11 10. Oral cavity examination: rule out oral candida and ulcers, which may contribute to anorexia. 11. Rule out other causes, such as nausea, vomiting, diagnostic studies, biochemical abnormalities, thyroid dysfunction, diarrhea, constipation, lactase deficiency, dysphagia, surgery, tumor presence, mechanical obstruction, chemotherapy, radiation, psychosocial effects (depression, social isolation, fatigue, etc). 12. Monitor thyroid function every 3 months. PREVENTIVE STRATEGIES 1. Educate the patient regarding anorexia as a potential side effect of interferon and ribavirin and provide suggestions for its management. 2. Determine living conditions: Does the patient have social support, including significant relationships? There is a potential risk for increased malnutrition if patients live alone, prepare their own meals, etc. 3. Suggest packing snacks and fluids in a thermal bag to facilitate eating on the run. 4. Suggest that patients exercise moderately (walking, biking, swimming) on injection days to counter the potential for muscle catabolism with interferon. TREATMENT STRATEGIES The management of anorexia for patients on interferon has not been extensively studied. The following interventions may facilitate food intake in those patients experiencing anorexia. Patients should be instructed to: 1. Increase oral hygiene (avoid smoking if possible). 2. Eat smaller, more frequent meals; small helpings look less overwhelming on smaller plates. 3. Add spices and herbs when experiencing alterations in taste perception. Avoid spicy foods when experiencing nausea. 4. Eat foods chilled or at room temperature rather than hot. 5. Eat foods that are calorically dense, such as peanut butter, granola, and cheese. 6. Consider supplementation with Carnation Instant Breakfast®, Ensure®, Boost®, and instant breakfast bars (watch for iron content, as iron intake should be limited in patients infected with HCV). 7. Consume protein throughout the day. Take advantage of easy sources, such as peanut butter and cold cuts. To boost protein intake, add protein powder and/or powdered milk to cereal, shakes, or any food (1/3 c powdered milk = 80 cal and 8 g protein. The nutritional content of protein powders varies). 8. Avoid carbonated beverages and gas-forming foods, such as broccoli or cabbage, as they may contribute to early satiety. Providers should: 1. Provide a nutrition consultation to determine optimal diet for the patient. 2. Consider megestrol acetate (Megace®) 800 mg (20 mL)/d via suspension; or 40 mg PO QID as tablets; AM administration preferred. Some evidence suggests that low-dose megestrol acetate may assist with cytokine-induced anorexia. One of its Side Effects Management Handbook • VIII. Gastrointestinal • p. 12 mechanisms is to inhibit cytokine production and activity. Further research in this area is needed to prevent potential interference with the therapeutic effects of interferon. Availability: suspension 40 mg/mL: less expensive, easier to swallow, increased patient preference versus tablets. Tablets: 20-mg and 40-mg strengths. Average 5 kg weight gain; it may take 4 to 12 weeks to see weight gain. 3. Consider metoclopramide (Reglan®) 10 mg PO before meals and QHS for relief of anorexia, nausea, and early satiety. 4. If other options fail, consider dronabinol (Marinol®): Initially, 2.5 mg PO BID (before lunch, dinner). Range: 2.5 to 20 mg/d. Dronabinol is indicated for treatment of anorexia associated with weight loss in patients with AIDS and for the treatment of nausea and vomiting associated with cancer chemotherapy, but its use has not been studied in patients on interferon. Dronabinol may be problematic for patients with a history of drug abuse, as its active ingredient, synthetic delta9-THC, is a component of Cannabis sativa (marijuana). 5. Consider antidepressants if anorexia is caused by depression. Note: Although there was initial concern that methylphenidate (Concerta™, Metadate®, Methylin®, Ritalin®) may cause anorexia in patients, a number of studies have shown that patients prescribed methylphenidate for profound depression or fatigue may experience improved appetite from this medication.4 In one study, 54% of patients experienced appetite stimulation; 13% had minimal improvement in appetite, 29% reported moderate improvement, and 12% were noted to have a marked improvement.5 REFERENCES 1. Plata-Salamįn CR. Cytokines and anorexia: a brief overview. Semin Oncol. 1998;25 (1 suppl l):64-72. 2. Foltz AT. Nutritional disturbances. In: Groenwald SL, Frogge-Hansen M, Goodman M, Yarbro CH, eds. Cancer Nursing: Principles and Practice. 4th ed. Boston, Mass: Jones and Bartlett; 1997:655-683. 3. National Cancer Institute. PDQ, Supportive Care for Health Professionals: Nutrition: 1-14. Available at: http://cancernet.nci.nih.gov/cgibin/ srchcgi.exe?DBID=pdq&TYP…/0&Z208=208_04467. Updated July 1997. 4. Plutchik L, Snyder S, Drooker M, Chodoff L, Sheiner P. Methylphenidate in post liver transplant patients. Psychosomatics. 1998;39:118-123. 5. Olin J, Masand P. Psychostimulants for depression in hospitalized cancer patients. Psychosomatics. 1996;37:57-62. Side Effects Management Handbook • VIII. Gastrointestinal • p. 13 |
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Neutropenia refers to the presence of abnormally low levels of neutrophils in the circulating blood. Neutrophils are a specific kind of white blood cell that help prevent and fight infections. The most common reason that cancer patients experience neutropenia is as a side effect of chemotherapy. Blood Cell Growth Factors Improve Adherence and SVR RatesBy Liz Highleyman Neutropenia (low white blood cell count), anemia (low red blood cell count or hemoglobin level), and thrombocytopenia (low platelet count) are potentially dose-limiting side effects of interferon and ribavirin, respectively. Because reduced doses impair treatment response, adjunct therapies may be required. G-CSF for NeutropeniaAn open-label study assessed the use of granulocyte colony-stimulating factor (G-CSF or filgrastim) versus interferon dose reduction in 39 patients with genotype 1 hepatitis C who developed severe neutropenia (absolute neutrophil count [ANC] < 1000/L) while being treated with 1.5 mcg/kg/week pegylated interferon-alpha 2b (Peg-Intron) plus 800-1400 mg/day ribavirin. Subjects were assigned to receive either a flexible dose scheme of 150-300 mcg G-CSF by subcutaneous injection twice weekly (one day after and two days before peginterferon injection), or else had their peginterferon dose reduced for two weeks (or discontinued for 1-2 weeks if neutropenia did not resolve). Results
The researchers concluded that use of G-CSF is safe and enables adherence to full-dose peginterferon in patients with chronic hepatitis C who develop neutropenia during therapy. Use of G-CSF was also associated with higher early and sustained virological response rates. Growth Factors vs Dose ReductionIn a related study, 160 patients with chronic genotype 1 hepatitis C and compensated liver disease were treated with Peg-Intron plus weight-based ribavirin. Participants were randomly assigned to either have their doses reduced in the case of hematological toxicity, or else were pre-emptively treated with adjunct therapy as follows:
ResultsAt the time of abstract submission, 63 patients had been treated for at least 12 weeks. About one in 10 were African-American, a population that normally has lower average neutrophil counts compared with whites.
ConclusionThe authors concluded that the use of growth factors prevents dose reductions of pegylated interferon and ribavirin and “maintains more physiologic hemoglobin levels” in patients receiving treatment for hepatitis C. The study will continue in order to determine whether use of growth factors allows for higher SVR rates. Neutropenia and Infections Finally, a study reported recently in the journal Clinical of Infection Diseases suggests that low neutrophil counts in patients receiving hepatitis C treatment are not associated with an increased risk of infection. Researchers followed 192 patients who received 211 courses of therapy for HCV; none used G-CSF. After a median 17 weeks of therapy, 57 patients (30%) experienced 67 instances of infectious complications. Infection rate did not differ based on patient age, sex, race, body weight, HIV serostatus, extent of liver disease, or type of interferon used. The rates of fungal, viral, and bacterial infections did not correlate with nadir (lowest ever) neutrophil count or magnitude of decline from baseline. The authors concluded that, “Neutrophil count is not correlated with infection rate in recipients of interferon-based therapy for hepatitis C,” and suggested that, “Reduction in interferon dose and/or dosing with granulocyte colony-stimulating factor in those with neutropenia is not supported by this analysis.” 6/06/06 References G. Zacharakis, J. Koskinas, J. Sidiropoulos, and others. G-CSF is safe and improves adherence and SVR in HCV patients with genotype 1 who develop Peg-IFNa-2b related severe neutropenia. Abstract T1828. Digestive Disease Week 2006 (DDW 2006). May 20-25, 2006. Los Angeles, CA. M. Kugelmas, A.L. Sabel-Soteres, G. Spiegelman. The impact of growth factors on Peg-Intron and Rebetol dose reduction in patients treated for genotype 1 chronic hepatitis C. Abstract S1058. DDW 2006. May 20-25, 2006. Los Angeles, CA. C.L. Cooper, S. Al-Bedwawi, C. Lee, and others. Rate of infectious complications during interferon-based therapy for hepatitis C is not related to neutropenia. Clinical Infectious Diseases 42(12): 1674-1678. June 15, 2006.
Hematologic NEUTROPENIA Neutropenia is the most common hematologic side effect of peginterferon therapy. Neutropenia is defined as an absolute neutrophil count (ANC) of <1000/mm3. The ANC is calculated by multiplying the white blood cell (WBC) count by the percentage of bands and segmented neutrophils.1 There is a theoretic concern that neutropenia will increase the propensity to develop opportunistic infections. However, peginterferon alfa-2b has been in use for over 2 years, and collective experience has not demonstrated a clinically significant association between neutropenia and infection in patients treated for hepatitis C. PATHOPHYSIOLOGY Interferon elicits secondary cytokines, such as interleukin-8, which promotes migration of neutrophils to outside the peripheral vascular space and into tissue spaces. There, they become sequestered and reach their nadir. THE NATIONAL CANCER INSTITUTE COMMON TOXICITY CRITERIA GRADING FOR NEUTROPENIA3 • Grade 1: ³1.5 to <2.0 x 109/L neutrophils • Grade 2: ³1.0 to <1.5 x 109/L neutrophils • Grade 3: ³0.5 to <1.0 x 109/L neutrophils • Grade 4: ³0.5 x 109/L neutrophils PREVENTIVE STRATEGIES 1. Assess for neutropenia by monitoring the WBC count with differential at baseline and weeks 2 and 4 and then monthly in all patients receiving anti–HCV-treatment. Note: lower neutrophil counts will be recorded if the blood for the CBC is drawn within 24 to 72 hours of peginterferon administration. Consider drawing the CBC 1 to 2 days before peginterferon administration. 2. In the HIV coinfected patient on anti-HCV combination therapy, monitor the WBC/differential biweekly for the first 3 months. After 3 months, monitor WBC/differential monthly and as clinically necessary. A more frequent schedule may be necessary depending on the immune status of the individual patient. 3. Teach patient signs and symptoms of infection (fever, chills, etc) to report to the healthcare provider.1 TREATMENT STRATEGIES 1. Consider granulocyte colony-stimulating factor therapy (filgrastim [Neupogen®] 300 µg SQ once to thrice weekly and then titrated to maintain an ANC >750/mm3) if ANC is <1000/mm3 on peginterferon-based therapy. For maximum effect, give at least 24 hours before peginterferon administration. Granulocyte macrophage colonystimulating factor (sargramostim [Leukine®, Prokine®, Leukomax®]) is also used to treat neutropenic patients. Side Effects Management Handbook • IX. Hematologic • p. 4 2. Institute dose reduction/discontinuation guidelines per package inserts. A 50% reduction in peginterferon alfa-2b dose is recommended if WBC becomes <1500/mm3, and both peginterferon and ribavirin should be discontinued if WBC is <1000/mm3. Dose reduction to 135 µg peginterferon alfa-2a is recommended if the neutrophil count is <750/mm3, and treatment should be discontinued if ANC falls below 500/mm3. 3. Monitor for signs of infection; treat appropriately.1 REFERENCES 1. Groenwald SL, Frogge MH, Goodman M, Yarbro CH, eds. Cancer Symptom Management. Boston, Mass: Jones and Bartlett Publishers; 1996:292-300. 2. Rieger PT. Biotherapy: A Comprehensive Overview. 2nd ed. Boston, Mass: Jones and Bartlett Publishers; 2000:129-132. 3. National Cancer Institute. Common Toxicity Criteria: Version 2.0. National Institutes of Health; 1999. Side Effects Management Handbook • IX. Hematologic • p. 5
Neutropenia ( Low White Cells )Associated with HCV Therapy May Not Be Associated with Serious Adverse Events By Brian Boyle, MDNeutropenia is a common event in patients treated with pegylated interferon and ribavirin; however, the clinical importance of the neutropenia is uncertain. In a study presented at Digestive Disease Week 2003 (DDW), investigators evaluated whether the neutropenia induced in patients treated with pegylated interferon and ribavirin led to any clinically serious adverse events, such as infections. The investigators obtained data regarding adverse events from the WIN-R Trial, a study that enrolled 4,243 patients and compared fixed (800mg) versus weight based (800-1400mg) daily dosing of Rebetol (ribavirin) in combination with PEG-Intron (pegylated interferon alfa-2b). The investigators reviewed the adverse event data collected throughout the 48 weeks of therapy. The investigators found that 30 (0.7%) of the patients developed infectious serious adverse events while on the PEG-Intron + Rebetol therapy. The infections included 10 patients with pneumonia, 3 with urinary tract infections, 3 with cellulitis, 2 with upper respiratory tract infections, 4 with an abscess, and one each with cat scratch disease, salmonella colitis, furuncle, meningitis, appendicitis with perforation, tibial hardware infection, bacteremia, and invasive C. jejuni diarrhea. Of these patients, 24 received antibiotics, 27 were hospitalized, and 7 required surgical intervention. One patient died of pneumonia. Examining the absolute neutrophil counts, the investigators found that the ANC fell below 1000 at some point in 14 of 25 (56%) of the patients that developed a serious infection. Further, they found that overall mean nadir ANCs in patients with a serious adverse event and all treated patients were not significantly different, 1198 and 1318, respectively (p=0.46). Finally, the mean nadir ANC for the serious adverse event patients also did not significantly differ from that of the rest of the patients and the proportion of patients who developed an ANC <750 were similar in both groups (20%). Based upon these data the authors conclude, “(1) Patients who develop serious infections while on combination therapy with pegylated interferon alfa-2b and ribavirin do not have significantly lower mean nadir ANCs. (2) Infectious [serious adverse events] generally did not occur at the time of nadir ANC. (3) Criteria and utility for dose reduction of peginterferon and the use of granulocyte stimulating factor to treat neutropenia require further assessment.” 05/28/03
Reference
Date: Apr 5, 2001 (Thu, 8:42:0) What is NEUPOGEN®?
Combo Survival Guide from A to Z. http://www.hepatitiscaware.org/pdf/comboguide.pdf
The Hepatitis C Treatment Series: Part III
Common Questions About Finishing Hepatitis C Treatment What
should I know after I finish my hepatitis C treatment?
http://www.va.gov/hepatitisc/pted/treatment_3.htm When you finish your treatment, your doctor will give you advice based on the type of drugs you took, and whether they worked. Below are suggestions on what you should do after you have finished your treatment. Talk with your doctor if you have any questions about hepatitis C or the treatments you took.
What should I do if my treatment didn't clear the
virus from my blood? What other kinds of treatment are being made? Recently, a long-acting interferon (called pegylated interferon) was approved by the FDA to treat people who have never been treated. Other kinds of pegylated interferon are also being tested by the FDA. So far, it seems that the interferon/ribavirin combination treatment works best for most patients with hepatitis C. There are also several new types of treatments that try to clear the virus or decrease the amount of liver damage. These new treatments work in different ways, and may do the following things:
If treatment didn't clear the virus
from my blood, are there any herbal remedies that I can take?
If my viral test was negative six months at the end
of treatment, will I stay negative?
Everyone has a slightly different experience with hepatitis C treatments. Side effects are different for everyone, and we can never predict how well a drug will work for a certain person. It always helps to know as much as you can, and to keep yourself healthy by eating well, getting plenty of rest, and not using alcohol or drugs that can damage your liver. At all stages - before, during, and after treatment - talk with your doctor or nurse to learn as much as possible about your disease and your treatment. Your doctor will give you advice after you finish treatment. You must understand that the risks and side effects of treatment may last even after you have finished treatment. For example, ribavirin can cause serious birth defects and you or your partner should NOT get pregnant while on combination treatment and for six months after your last dose. You must practice two effective forms of birth control, one for you and one for your partner (an example is a condom, plus a diaphragm or birth control pill). Try to find health care providers who know about hepatitis C, and can give you up-to-date information and advice. With support from your family and friends, and a doctor that you trust, you can have a better treatment experience. If you have tried a treatment that didn't work, don't be discouraged. New and better treatments are becoming available as we learn more about hepatitis C every day.
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