Peginterferon alfa-2a is approved for the treatment of chronic hepatitis C virus (HCV) infections in patients 5 years and older, and for the treatment of chronic hepatitis B virus (HBV) infections in patients 3 years and older. The drug is a highly purified protein containing 165 amino acids (recombinant interferon alfa-2a) that is covalently conjugated with bis-monomethoxy polyethylene glycol (PEG). Interferon alfa-2a represents only one specific subtype of alpha interferon (i.e., interferon alpha-2) and is produced by recombinant DNA technology that uses a genetically engineered Escherichia coli bacterium containing DNA that codes for the protein. By increasing the size of the molecule with PEG (average molecular weight of 60,000 daltons), the absorption and half-life are prolonged, and the clearance is decreased. The safety of peginterferon alfa-2a is comparable to interferon alfa-2a; however, the tolerability is increased.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Variations in dosage and adverse reactions exist among different subtypes of interferon alfa. Therefore, do not use different brands of interferon in a single treatment regimen. Also, the vials and prefilled syringes of peginterferon alfa-2a are not directly interchangeable. The same amount of drug will not be provided by equal volumes.
NOTE: Due to possible severe central nervous system reactions and severe hematologic reactions, baseline neuropsychiatric monitoring and complete blood count assessment of all patients are recommended. Pregnancy screening, liver function tests, serum creatinine, and thyroid function tests are also recommended prior to initiating therapy.
NOTE: Patients should be well hydrated before drug receipt, if clinically appropriate.
Route-Specific Administration
Injectable Administration
-Administer subcutaneously. Do not inject intradermally, intramuscularly, or intravenously.
-Only an individual trained in subcutaneous drug delivery should administer the injection. The initial injection should be given by a trained health care professional. A patient that is properly trained in subcutaneous injection technique may self-inject, if appropriate.
-Premedication with acetaminophen or ibuprofen may decrease the incidence of administration-related reactions (i.e., fever). Bedtime administration may increase patient tolerance of therapy.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. The solution should be clear and colorless or a light yellow. Do not use if the solution has visible particles, flakes, color, or is cloudy.
Subcutaneous Administration
Do not use the vials and prefilled syringes interchangeably without noting the drug concentration difference. The volume to be administered will vary based on the product. All preparations are single-dose only; discard any unused solution.
-180 mcg dose: 1 mL from 180 mcg/mL vial; 0.5 mL from 180 mcg/ 0.5 mL prefilled syringe.
-135 mcg dose: 0.75 mL from 180 mcg/mL vial; 0.375 mL from 180 mcg/0.5 mL prefilled syringe.
-90 mcg dose: 0.5 mL from 180 mcg/mL vial; 0.25 mL from 180 mcg/ 0.5 mL prefilled syringe.
Preparation of subcutaneous dosage immediately prior to injection:
-Gently warm the refrigerated medicine to room temperature. Accomplish this by rolling the vial in the palms of your hands for about 1 minute prior to injection. Warm the syringe by placing it on a clean flat surface and waiting until it reaches room temperature. Wait for any condensation on the outside of the syringe to disappear prior to use.
-Do not shake the vial or prefilled syringe as foaming may occur.
-If using the vial, flip the plastic top off the vial and clean the rubber stopper with an alcohol pad. Obtain a sterile needle and syringe to withdraw and administer the drug solution. If needed, attach the needle to the end of the syringe. Pull the plunger back to the needed dosage mark on the syringe. While keeping the vial upright, insert the needle into the vial and slowly inject all the air into the airspace of the vial; DO NOT inject air into the fluid. Invert the vial and syringe to withdraw the needed amount of drug solution by slowly pulling the plunger back to the needed dosage mark on the syringe. The vials are single-use only; discard any unused portion.
-For pediatric patients, prepare dose using ONLY the 180 mcg/mL vial. The weight-based dose should be drawn from the 180 mcg/mL vial using a sterile 1 mL tuberculin syringe.
-If using the prefilled syringe, attach the needle by removing the rubber cap from the syringe barrel and placing the needle onto the end of the syringe barrel. Do not remove the clear needle shield until immediately before the injection of the product.
-With the needle in the upright position, tap the syringe barrel lightly. Press the plunger slightly to eliminate any air bubbles that may be present. If using the prefilled syringe, you may need to push some medicine out of the syringe to deliver the correct amount. The prefilled syringe is marked for 90 mcg, 135 mcg, and 180 mcg dosage amounts. The edge of the plunger stopper needs to be on the correct dosage line.
Subcutaneous (SC) injection technique:
-Clean the injection area (upper thigh or abdominal area beside the navel or waistline) with an alcohol swab. Choose a new location for each subsequent injection.
-Pinch an area of skin and insert the needle with the bevel up subcutaneously as far as it will go by using a quick dart-like motion.
-Release the skin and gently pull back on the syringe before delivering the drug to ensure it is not injected into a blood vessel. If blood appears in the barrel of the syringe, remove the needle and discard the syringe. Do not reuse syringes and needles. If no blood appears, slowly push down on the plunger to deposit the medicine.
-After removal of the needle, place an alcohol swab over the injection site and press slightly.
-Do not recap the needle. If using a syringe with a needle-stick protection device, place the free end of the orange cap on a flat surface and push down until the cap covers the needle. A click will be heard. Discard the syringe and needle into a sharps container.
Life-threatening or fatal neuropsychiatric events have occurred in patients with and without previous psychiatric disorders during peginterferon alfa-2a therapy. Depression was reported in 18% of 559 patients that received peginterferon alfa-2a (180 mcg/week SC) during clinical trials. Depression development during peginterferon alfa-2a receipt warrants careful monitoring of the disorder and possible peginterferon alfa-2a dose reduction or discontinuation. Discontinue peginterferon alfa-2a if the condition is persistently severe or if associated signs and symptoms worsen. Clinicians should monitor for unusual changes in mood and behavior, including emotional lability. In many, but not all cases, the disorder resolves after peginterferon alfa-2a withdrawal. Other neuropsychiatric adverse effects reported during clinical trials included insomnia (19%), dizziness (6% to 16%), irritability or nervousness (19%), anxiety (19%), impaired cognition or concentration (8%), memory impairment (5%), and mood alteration (3% to 9%). Adverse events reported in less than 1% of patients include suicide, suicidal ideation, relapse of drug addiction or drug abuse, drug overdose, aggression, anxiety, psychosis, hallucinations, and coma. Homicidal ideation has also been reported. Seizures have been noted in postmarketing reports.
The most common adverse reactions to alfa interferons are constitutional symptoms or flu-like symptoms. Patients who received peginterferon alfa-2a during clinical trials experienced fatigue and asthenia (8% to 65%), headache (21% to 64%), fever (37% to 54%), myalgia (26% to 40%), arthralgia (22% to 28%), rigors (25% to 35%), pain (11%), and diaphoresis (6%). If fever is high or persistent, rule out other causes such as infection, especially in patients with low neutrophil counts. Serious and severe infections of bacterial, viral, and fungal origin that have sometimes been fatal have been reported during alpha interferon treatment including peginterferon alfa-2a. Bacterial infection was reported in patients during trials and included sepsis (up to 5%), osteomyelitis (3% to 5%), endocarditis (3% to 5%), pyelonephritis (3% to 5%), pneumonia, naso-pharyngitis (6%), and upper respiratory tract infections (3% to 8%), appendicitis (less than 1%), tuberculosis (less than 1%), and influenza-like symptoms (up to 14%). During postmarketing use, cases of limb abscess have been associated with peginterferon alfa-2a treatment. If infection occurs, immediately start appropriate anti-infective therapy, and consider peginterferon alfa-2a discontinuation. Fatigue may be dose-limiting and chronic; it can be severe in elderly patients or patients with poor performance status. Varying degrees of tolerance to fatigue may develop.
An injection site reaction occurred in 22% to 45% of patients that received peginterferon alfa-2a. Other dermatologic adverse effects included alopecia (6% to 28%), dermatitis (8% to 16%), rash (5% to 15%), xerosis (4% to 10%), eczema (1% to 5%), and pruritus (11% to 19%). Slight to moderate hair loss (alopecia) has been reported in patients receiving alpha interferon therapy for an extended period of time (i.e., more than 4 months). Hair loss is temporary and hair growth should return with peginterferon alfa-2a cessation.
Severe acute hypersensitivity reactions including urticaria, angioedema, bronchoconstriction (bronchospasm), and anaphylaxis such as anaphylactic shock and anaphylactoid reactions have been observed during alpha interferon and ribavirin therapy. If such reaction occurs, discontinue peginterferon alfa-2a and ribavirin and immediately institute appropriate medical therapy. Serious skin reactions including vesiculobullous eruptions (vesicular rash/bullous rash), reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Discontinue peginterferon alfa-2a if signs or symptoms of a severe skin reaction develop.
Gastrointestinal effects reported by patients that received peginterferon alfa-2a include nausea (9% to 25%), vomiting (15% to 25%), diarrhea (11% to 16%), xerostomia or dry mouth (4% to 6%), anorexia (6% to 24%), weight loss (4% to 16%), and abdominal pain (8% to 17%). Severe or fatal GI bleeding, pancreatitis, hemorrhagic or ischemic colitis, dyspepsia, and peptic ulcer have been reported in less than 1% of patients treated with peginterferon alfa-2a. Dehydration and tongue discoloration (tongue pigmentation) were noted in postmarketing reports. Most patients that received peginterferon alfa-2a either alone or with ribavirin developed elevated triglyceride serum concentrations. Random concentrations greater than 400 mg/dL occurred in about 20% of chronic hepatitis C patients and severe elevations (greater than 1000 mg/dL) were reported in 2% of chronic hepatitis C patients. In HCV and HIV coinfected patients, fasting triglyceride concentrations 400 mg/dL or more were reported in up to 36% of patients with severe increases (greater than 1000 mg/dL) occurred in 7% of patients. As hypertriglyceridemia can cause pancreatitis, periodic serum triglyceride concentration determination is recommended during drug receipt. Colitis has been observed within 12 weeks of starting alfa interferon therapy. Patients who develop signs and symptoms of colitis (e.g., abdominal pain, bloody diarrhea, fever) or pancreatitis during peginterferon alfa-2a receipt should discontinue the drug. Colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon therapy.
Cardiac and pulmonary adverse reactions have been reported during peginterferon alfa-2a therapy. Cardiac arrhythmias (less than 1%) including supraventricular arrhythmias (i.e., supraventricular tachycardia (SVT)), angina (less than 1%), chest pain (unspecified), myocardial infarction, and hypertension have been reported. Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension and sarcoidosis (less than 1%), some resulting in respiratory failure and patient deaths, may be induced or aggravated by peginterferon alfa-2a or alpha interferon therapy. Recurrence of respiratory failure has been observed with interferon rechallenge. Patients who received peginterferon alfa-2a during clinical trials developed epistaxis (9%), dyspnea (4% to 13%), and a cough (4% to 15%). Exertional dyspnea and pulmonary embolism each occurred in less than 1% of patients. Suspend peginterferon alfa-2a combination treatment in patients who develop pulmonary infiltrates or pulmonary function impairment. Closely monitor patients who resume interferon treatment.
Peginterferon alfa-2a suppresses bone marrow function and may result in severe neutropenia. Ribavirin may potentiate this in patients. Decreased neutrophils below normal occurs in most patients (95%) who receive peginterferon alfa-2a alone or in combination with ribavirin and may necessitate dosage reduction (see Dosage). Neutropenia was reported in 21% to 40% of patients. Severe and potentially life-threatening neutropenia (less than 0.5 x109/L) was reported in 5% to 12% of patients. Neutropenia generally improves with dosage adjustment. In clinical trials, the median neutrophil count returned to pretreatment concentrations within 4 to 8 weeks after stopping therapy. Seventeen to twenty-seven percent of patients needed dosage adjustment because of neutropenia development. Although permanent dosage reduction was required for 2% to 10% of patients, less than 1% of patients had to permanently discontinue the drug.
Receipt of peginterferon alfa-2a has been associated with anemia. Hemoglobin concentrations dropped below 12 g/dL in 17% of patients with a median drop in the hemoglobin concentration of 2.2 g/dL. Anemia was reported in 2% of chronic hepatitis C (CHC) patients 14% of CHC patients that were coinfected with HIV. Severe anemia (less than 10 g/dL) was reported in 2% of CHC patients and in 8% of patients coinfected with CHC and HIV. Dosage modifications for anemia occurred in 22% of CHC patients and 16% of CHC and HIV coinfected patients. Very rarely alpha interferons may be associated with aplastic anemia (less than 1% of patients).
Hyperglycemia, hypoglycemia, and diabetes mellitus (less than 1%) have been observed to develop in patients treated peginterferon alfa-2a. Patients with diabetes mellitus at baseline whose diabetes cannot be effectively treated by medication should not begin peginterferon alfa-2a. Patients with diabetes mellitus may require antidiabetic medication dosage adjustment during therapy with peginterferon alfa-2a; patients whose diabetes cannot be controlled may require peginterferon alfa-2a discontinuation.
Thrombocytopenia is an adverse effect associated with peginterferon alfa-2a and may necessitate dosage reduction. Of the chronic hepatitis C (CHC) patients, 5% had thrombocytopenia, 4% had a moderate to severe platelet count reduction (less than 50,000/mm3) and 52% had a reduction in their platelet count with the median drop from baseline was 41%. Of the CHC and HIV coinfected patients, 8% had thrombocytopenia (including moderate to severe) and 51% had a reduction in their platelet count (median decrease from baseline was 35%). Cessation of peginterferon alfa-2a caused a return to median pretreatment platelet counts within 4 weeks. Cerebral hemorrhage occurred in less than 1% of patients that received peginterferon alfa-2a during clinical trials.
Lymphopenia occurs in many patients (3% to 81%) that receive peginterferon alfa-2a monotherapy. A lymphocyte count below 0.5 x109/L occurred in approximately 5% of patients. Cessation of peginterferon alfa-2a caused a return to median pretreatment lymphocyte counts within 4 to 12 weeks. The clinical significance of lymphopenia is not known.
Development or exacerbation of autoimmune disease including myositis, thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), psoriasis, rheumatoid arthritis, interstitial nephritis, thyroiditis, and lupus-like symptoms or systemic lupus erythematosus have been observed in patients treated with alpha interferons and may occur in less than 1% of patients. In very rare cases, the autoimmune event resulted in fatality. Autoimmune disorder development during peginterferon alfa-2a receipt warrants careful monitoring of the autoimmune disorder and possible peginterferon alfa-2a discontinuation. Discontinue peginterferon alfa-2a if the condition is persistently severe or if associated signs and symptoms worsen. In many, but not all cases, the disorder resolves after peginterferon alfa-2a withdrawal. Liver or renal graft rejection has been noted in postmarketing reports.
Low-titer neutralizing antibody formation developed in 3% of 835 chronic hepatitis C (CHC) patients that received peginterferon alfa-2a with or without ribavirin. Nine percent of CHC patients developed binding antibodies to peginterferon alfa-2a, as assessed by an ELISA assay. Low-titer neutralizing antibody formation developed in 13% of 143 hepatitis B patients that received peginterferon alfa-2a with or without ribavirin. Twenty-nine percent of CHC patients developed binding antibodies to peginterferon alfa-2a, as assessed by an ELISA assay. The clinical and pathologic significance of the appearance of serum neutralizing antibodies is unknown. No apparent correlation of antibody development to clinical response or adverse events was observed. Additionally, the incidence observed in these assays may be influence by several factors.
Hemorrhagic and ischemic cerebrovascular events such as stroke (less than 1%) have been observed in patients treated with interferon alfa-based therapies including peginterferon alfa-2a. The cerebrovascular events occurred in patients with few or no reported risk factors for stroke; some events occurred in patients less than 45 years of age. A causal relationship between peginterferon alfa-2a and stroke has not been established. Health care providers are encouraged to report to the manufacturer any adverse events thought to be related to peginterferon alfa-2a.
Hyperthyroidism (less than 1%) and hypothyroidism (up to 3%) have been reported and may be a result of autoimmune exacerbations. Peginterferon alfa-2a may also causes or aggravate existing hypothyroidism and hyperthyroidism. TSH and T4 within normal limits or adequately controlled thyroid function was an entrance criteria used for the clinical studies and may be considered as a guideline to acceptable baseline values for peginterferon alfa-2a initiation. In hepatitis C trials, the rates of clinically relevant hypothyroidism or hyperthyroidism (requiring treatment, dose modification, or discontinuation) were 4% and 1%, respectively. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Among patients who developed new onset thyroid abnormalities during peginterferon alfa-2a therapy, approximately half still had abnormalities during the follow-up period. The TSH serum concentration needs to be within the normal range during peginterferon alfa-2a receipt. Patients with hypothyroidism or hyperthyroidism who cannot be controlled with medication may require peginterferon alfa-2a discontinuation.
A decrease in vision or loss of vision, retinopathy, macular edema, retinal hemorrhage, cotton-wool spots, retinal thrombosis (artery or vein), optic neuritis, serous retinal detachment, and papilledema are induced or aggravated by treatment with peginterferon alfa-2a and other alpha interferons; discontinue peginterferon alfa-2a if patients develop new or worsening ophthalmic disorders. Of 559 patients who received peginterferon 180 mcg weekly, 4% developed blurred vision and less than 1% developed a corneal ulcer (corneal erosion). Prior to starting peginterferon alfa-2a, all patients should receive a baseline eye examination. Patients with preexisting ophthalmologic disorders, such as hypertensive or diabetic retinopathy, should receive periodic ophthalmologic exams during therapy. Also, any patient complaining of visual impairment, including changes in visual acuity or visual field, or other ophthalmologic symptoms during peginterferon alfa-2a treatment should have a prompt and complete eye exam.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation (hepatic failure) and death when treated with alpha interferons, include peginterferon alfa-2a. Elevated hepatic enzymes have been noted in both hepatitis C and hepatitis B patients. One percent of CHC patients had a 5- to 10-fold increase in their ALT serum concentration from the baseline value and were occasionally associated with hyperbilirubinemia. The elevations were generally transient and were not associated with deterioration of other liver function tests. However, when the increase in ALT concentrations is progressive despite dose reduction or is accompanied by hyperbilirubinemia, peginterferon alfa-2a therapy should be discontinued. Exacerbations of hepatitis during hepatitis B therapy are not uncommon and are characterized by transient and possible severe increases in serum ALT which may be greater than 10-fold higher than the upper limit of normal (ULN) during treatment (12% to 18%) or after treatment (7% to 12%). Increases in ALT of 25% to 27% of these patients. These flares have been accompanied by elevations in total bilirubin, elevated alkaline phosphatase, prolonged PT, and reduced albumin concentrations. ALT flares in hepatitis B patients of 5 to 10-times ULN were reported in 13% to 16% of patients and greater than 10-times ULN in 7% to 12% of patients. Fatty liver (steatosis) and cholangitis have been reported in less than 1% of patients treated with peginterferon alfa-2a.
Peripheral neuropathy has been reported in less than 1% of patients receiving peginterferon alfa-2a. When alpha interferons were administered in combination with telbivudine, and increased risk and severity of peripheral neuropathy was observed with the combination as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons has not been demonstrated.
Back pain was reported in 9% of hepatitis C patients during peginterferon alfa-2a clinical trials.
Pure red cell aplasia was noted in postmarketing reports with peginterferon alfa-2a. Pancytopenia has been reported patients receiving pegylated interferon and ribavirin in combination with azathioprine, which was reversible within 4 to 6 weeks upon discontinuation of therapy.
Hearing impairment or hearing loss has been noted in postmarketing reports with peginterferon alfa-2a.
Use of peginterferon alfa-2a with ribavirin has been associated with growth inhibition in children and adolescents 3 years of age and older; monitor growth carefully in these patients. During a 48-week hepatitis C virus study, 43% of peginterferon alfa-2a and ribavirin-treated pediatric patients (5 to 17 years) experienced weight percentile decreases of 15 percentiles or more and 25% experienced height percentile decreases of at least 15 percentiles on normative growth curves. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight and height; 16% of subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve. The available longer-term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients. Growth inhibition was also observed in a 48-week chronic hepatitis B virus study involving pediatric patients ages 3 to 17 years. At 24 weeks post-treatment, 12% of drug recipients were more than 15 percentiles below their baseline weight and height curve. At 5 years post-treatment the percentage of subjects with decrease of more than 15 percentiles from baseline was 29% for weight and 18% for height.
Peginterferon alfa-2a is contraindicated in patients with known hypersensitivity reactions to alpha interferons, including peginterferon alfa-2a or any of its components. There is a risk of serious hypersensitivity reactions or anaphylaxis with peginterferon alfa-2a, including angioedema, acute bronchospasm, urticaria, or other allergic-type events. Such reactions have also been observed during alpha interferon and ribavirin therapy. Serious rash, including vesiculobullous eruptions, reactions in the spectrum of Stevens-Johnson Syndrome (erythema multiforme major) with varying degrees of skin and mucosal involvement and exfoliative dermatitis (erythroderma) have been reported in patients receiving peginterferon alfa-2a with and without ribavirin. Patients developing signs or symptoms of severe skin reactions or severe hypersensitivity must discontinue therapy. Institute appropriate medical treatment. Peginterferon alfa-2a is produced using recombinant DNA technology using Escherichia coli; do not use in patients with E. coli protein hypersensitivity. Peginterferon alfa-2a injection contains benzyl alcohol and is contraindicated in any patient with benzyl alcohol hypersensitivity.
Alpha interferons, including peginterferon alfa-2a, may cause or aggravate a psychiatric event or disorder. Patients should be monitored closely with periodic clinical and laboratory evaluations. It is recommended to monitor and evaluate for these conditions every 3 weeks during the first 8 weeks of treatment and every 6 months thereafter and for at least 6 months after the last dose. Permanently discontinue peginterferon alfa-2a therapy for homicidal or suicidial ideation, aggressive behavior towards others, severe depression, or other severe or persistent psychiatric symptoms; institute psychiatric intervention and follow-up as appropriate. In many, but not all cases, these disorders may resolve after stopping therapy. Patients should be warned to report changes in moods or behaviors, depression, suicidal ideation or other symptoms promptly to their health care provider. Any patient with a history of substance abuse (e.g., alcoholism), encephalopathy, depression or severe psychiatric disorder (e.g., bipolar disorder, mania, psychosis) should receive peginterferon alfa-2a with extreme caution, since these conditions may worsen or relapse. Former drug addicts may fall back into drug addiction or overdose. Although dose reduction or cessation of therapy may lead to resolution of the symptoms, depression or other psychiatric symptoms may persist and suicides have occurred even after withdrawing therapy, and continued psychiatric intervention may be needed. Neurologic events have also been reported with use. Because dizziness and drowsiness are common, patients should also be warned against driving or operating machinery until they know how peginterferon alfa-2a therapy will affect them. EEG abnormalities and seizures have been reported in post-market use and peginterferon alfa-2a should be used with caution in patients with a pre-existing seizure disorder. Peripheral neuropathy has been reported when alpha interferons were given in combination with telbivudine. In one clinical trial, an increased risk and severity of peripheral neuropathy was observed with the combination use of telbivudine and peginterferon alfa-2a as compared to telbivudine alone. The safety and efficacy of telbivudine in combination with interferons for the treatment of chronic hepatitis B have not been demonstrated.
Alpha interferons, including peginterferon alfa-2a, may cause or aggravate fatal or life-threatening infections. Serious and severe infections (bacterial infection, viral infection, or fungal infection), some fatal, have been reported during treatment with alpha interferons, including peginterferon alfa-2a. Suppression of the bone marrow due to peginterferon alfa-2a increases the risk for serious infections, but such infections may also occur in the absence of decreased neutrophil counts. Patients should be monitored closely with baseline and periodic monitoring and clinical and laboratory evaluations. While fever may be associated with the flu-like syndrome reported commonly during interferon therapy, other causes of high or persistent fever must be ruled out, particularly in patients with reduced neutrophil counts. Appropriate anti-infective therapy should be started immediately and discontinuation of peginterferon alfa-2a therapy should be considered.
Peginterferon alfa-2a suppresses bone marrow function and may result in severe cytopenias, including anemia, neutropenia, lymphopenia, and thrombocytopenia. Peginterferon alfa-2a is associated with decreases in white cell, neutrophil, and platelet counts during the first 2 weeks of therapy. Very rarely, alpha interferons may be associated with aplastic anemia. Complete blood counts (CBC) should be obtained pretreatment and monitored routinely during therapy. Peginterferon alfa-2a should be discontinued, at least temporarily, in patients who develop severe decreases in neutrophil and/or platelet counts. Bleeding or serious infectious disorders may occur due to bone marrow suppression. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a. Anemia from peginterferon alfa-2a may complicate the management of other blood disorders, such as thalassemia or sickle cell disease. Patients who develop neutropenia or thrombocytopenia during treatment require dosage adjustment of peginterferon alfa-2a therapy; patients that develop severe decreases in neutrophil or platelet counts should discontinue peginterferon alfa-2a treatment, at least temporarily. Severe neutropenia and thrombocytopenia occur with a greater incidence in those with human immunodeficiency virus (HIV) infection and may place them at greater infectious and bleeding risk; use cautiously if the CD4 cell count is less than 350 cells/mcL. Safety and efficacy have not been established in patients with liver or other organ transplant. Patients receiving immunosuppressive therapy due to an organ transplant may have increased risk for bone marrow suppression. As with other alpha interferons, liver and renal graft rejections have been reported in patients receiving peginterferon alfa-2a. Certain medications may increase the risk for severe bone marrow suppression. Ribavirin co-therapy may potentiate the neutropenia and lymphopenia induced by alpha interferons. Peginterferon alfa-2a/ribavirin combination therapy should be used with caution in patients with baseline neutrophil counts less than 1500/mm3, platelet counts less than 90,000/mm3, or anemia (hemoglobin less than 10 grams/dL). Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of peginterferon/ribavirin combination treatment and azathioprine. Myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both peginterferon/ribavirin therapy and concomitant azathioprine and did not recur upon reintroduction of either treatment alone. Discontinue therapy for pancytopenia, and do not re-introduce peginterferon/ribavirin treatment with azathioprine.
Peginterferon alfa-2a is contraindicated for use in patients with autoimmune hepatitis, in patients with hepatic decompensation due to cirrhotic hepatic disease before treatment, or those cirrhotic chronic hepatitis C and HIV coinfection with hepatic decompensation and Child-Pugh score greater than or equal to 6 before treatment. Patients with non-compensated cirrhosis may experience worsening hepatic disease including, but not limited to, jaundice, hepatic failure, and death after peginterferon alfa-2a treatment. Serum ALT concentrations should be evaluated at baseline, 2 weeks after treatment initiation, and monthly thereafter in order to determine clinical response. Any patient developing liver function test (LFT) abnormalities during peginterferon alfa-2a therapy should receive more frequent monitoring of liver function; consider dose reduction. Flares have been accompanied by other LFT abnormalities. Hepatitis B exacerbation (flares) during hepatitis B therapy are not uncommon and are characterized by transient and potentially severe increases in serum ALT. In patients with chronic hepatitis B and ALT values greater than 5-times the upper limit of normal (ULN), dose reduction, temporary drug discontinuation, or permanent drug discontinuation may be appropriate. Patients with hepatitis C who experience progressive ALT increases above baseline concentrations require dosage adjustment. If ALT increases are progressive despite reduction of peginterferon alfa-2a dose or are accompanied by hyperbilirubinemia or evidence of hepatic decompensation, immediately discontinue peginterferon alfa-2a. HIV treatment guidelines recommend all adult and adolescent patients presenting with HIV infection undergo routine screening for hepatitis C virus (HCV). Additionally, perform HCV screening in any child whose mother is known to have HCV infection. For HCV seronegative individuals who are at continued high risk of acquiring hepatitis C, specifically men who have sex with men (MSM) or persons who inject drugs, additional HCV screening is recommended annually or as indicated by clinical presentation (e.g., unexplained ALT elevation), risk activities, or exposure. Similarly, the AASLD/IDSA HCV guidelines and the CDC preexposure prophylaxis (PrEP) guidelines recommend HCV serologic testing at baseline and every 12 months for MSM, transgender women, and persons who inject drugs. Use an FDA-approved immunoassay licensed for detection of HCV antibodies (anti-HCV); in settings where acute HCV infection is suspected or in persons with known prior infection that cleared spontaneously or after treatment, use of nucleic acid testing for HCV RNA is recommended. If hepatitis C and HIV coinfection is identified, consider treating both viral infections concurrently. It is recommended to use a fully suppressive antiretroviral therapy and an HCV regimen in all patients with coinfection regardless of CD4 count, as lower CD4 counts do not appear to compromise the efficacy of HCV treatment. In most patients, a simplified pangenotypic HCV regimen (i.e., glecaprevir; pibrentasvir or sofosbuvir; velpatasvir) may be an appropriate choice; however, these regimens are NOT recommended for use in persons with HCV and HIV coinfection who: are treatment-experience with HCV relapse (reinfection after successful therapy is not an exclusion); have decompensated cirrhosis; on a tenofovir disoproxil fumarate containing regimen with eGFR less than 60 mL/minute; on efavirenz, etravirine, nevirapine, or boosted protease inhibitor; have untreated chronic hepatitis B; are pregnant. Patients with HCV and HIV coinfection who meet these exclusion criteria should be treated for HCV following standard approaches as described in the AASLD/IDSA HCV guidelines. Treatment of HCV infection in children younger than 3 years is not usually recommended; however, treatment should be considered for all children 3 years and older with HCV and HIV coinfection who have no contraindications to treatment. Instruct patients with coinfection to avoid ethanol ingestion, limit use of potentially hepatotoxic medications, avoid iron supplementation in the absence of documented iron deficiency, and receive vaccinations against hepatitis A and hepatitis B as appropriate.
Peginterferon alfa-2a should be used with caution in patients with a history of autoimmune disease. Peginterferon alfa-2a is contraindicated for use in patients with autoimmune hepatitis. Development or exacerbation of autoimmune diseases (e.g., myositis, hepatitis, thrombotic thrombocytopenic purpura (TTP), immune thrombocytopenic purpura (ITP), thyroiditis, thrombocytopenia, rheumatoid arthritis, interstitial nephritis, systemic lupus erythematosus (SLE), or psoriasis) has been observed in patients receiving alpha interferons. Patients should be monitored closely with periodic clinical and laboratory evaluations. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a.
Patients with thyroid disease (e.g., hyperthyroidism or hypothyroidism) whose thyroid stimulating hormone (TSH) serum concentration cannot be maintained in the normal range by medication should not be treated with peginterferon alfa-2a. If the TSH concentration can be maintained within the normal range, TSH concentration assessment is recommended before treatment and every 3 months following initiation of peginterferon alfa-2a therapy. If the TSH concentration cannot be controlled with medications, peginterferon alfa-2a should be discontinued. Also, the development or exacerbation of autoimmune thyroid diseases (e.g., Graves' disease, thyroiditis) has been observed in patients receiving peginterferon alfa-2a. Patients should be monitored closely with periodic clinical and laboratory evaluations. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of autoimmune thyroid disease. In many, but not all cases, autoimmune disorders resolve after stopping peginterferon alfa-2a.
Hyperglycemia, hypoglycemia, and diabetes mellitus have been observed to develop in patients treated with peginterferon alfa-2a. Patients with these conditions at baseline who cannot be effectively treated by medication should not begin peginterferon alfa-2a therapy. Patients who develop these conditions during treatment and cannot be controlled with medication may require discontinuation of peginterferon alfa-2a therapy.
Ischemic and other cerebrovascular and cardiovascular events (e.g., hypertension, supraventricular arrhythmias, cardiomyopathy, chest pain, unstable angina pectoris, myocardial infarction, stroke) have been observed in patients treated with peginterferon alfa-2a. Some events occurred in patients with few or no reported risk factors. The drug should be used cautiously in patients with cardiac disease (including coronary artery disease) or cerebrovascular disease. Common adverse effects of peginterferon alfa-2a such as fever and chills may exacerbate preexisting cardiac conditions. Patients with a history of myocardial infarction and cardiac arrhythmias should be closely monitored, with baseline and periodic monitoring and clinical and laboratory evaluations. An electrocardiogram (ECG) is recommended prior to initiating therapy in such patients. Ischemic and hemorrhagic cerebrovascular events (e.g., strokes) have been observed in patients treated with interferon alfa-based therapies, including peginterferon alfa-2a. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made, and a causal relationship between interferon alfa-based therapies and these events is difficult to establish. Peginterferon alfa-2a should be discontinued in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping peginterferon alfa-2a. Because cardiac disease may be worsened by ribavirin-induced hemolytic anemia, patients with a history of significant or unstable cardiac disease should not receive combination therapy with ribavirin.
Dyspnea, pulmonary infiltrates, pneumonia, bronchiolitis obliterans, interstitial pneumonitis, pulmonary hypertension, and sarcoidosis, some resulting in respiratory failure or patient deaths, may be induced or aggravated by peginterferon alfa-2a or alpha interferon therapy. Recurrence of respiratory insufficiency and failure has been observed with interferon rechallenge. Peginterferon alfa-2a combination treatment should be suspended in patients who develop pulmonary infiltrates or pulmonary function impairment. Patients who resume interferon treatment should be closely monitored. Use with caution in patients with known pulmonary disease.
Estimate the patient's creatinine clearance (CrCl) before peginterferon alfa-2a initiation. Peginterferon alfa-2a initial dose reduction is needed for patients with renal impairment as evidenced by a CrCl less than 30 mL/min. Dose reductions are also needed for including patients patients with end-stage renal disease or renal failure who require dialysis. Closely monitor patients with moderate to severe renal impairment (e.g., CrCl less than 50 mL/min) for adverse reactions and laboratory abnormalities, especially decreased hemoglobin. If severe adverse reactions or laboratory abnormalities develop, or if adverse reactions persist after dose adjustment, discontinue peginterferon alfa-2a and/or ribavirin. Peginterferon alfa-2a was well tolerated among 25 adults with chronic hepatitis C on hemodialysis; patients were naive to interferon-based therapy. Peginterferon alfa-2a was started at the recommended dose for hemodialysis patients. During the 24-week treatment period, 3 patients had a dose reduction for a platelet count less than 50,000/mm3, but no patient had to stop treatment because of an adverse event.
Ulcerative colitis and hemorrhagic or ischemic colitis events, sometimes fatal, have been observed within 12 weeks of starting alpha interferon treatment. Abdominal pain, bloody diarrhea, and fever are the typical manifestations of colitis. Peginterferon alfa-2a therapy should be discontinued immediately if these symptoms develop. The colitis usually resolves within 1 to 3 weeks of discontinuation of alpha interferon.
Pancreatitis, sometimes fatal, has occurred during alpha interferon and ribavirin treatment. Peginterferon alfa-2a/ribavirin combination treatment should be suspended if symptoms or signs suggestive of pancreatitis are observed. Discontinue in patients who are diagnosed with pancreatitis. Triglyceride levels are commonly elevated in subjects receiving alpha interferon therapy and were elevated in the majority of subjects participating in clinical studies receiving either peginterferon alfa-2a alone or in combination with ribavirin. Hypertriglyceridemia may occur or worsen; monitor triglycerides during therapy and watch for pancreatitis symptoms in at-risk patients.
Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal bleeding and cotton wool spots, optic neuritis, papilledema and serous retinal detachment are induced or aggravated by treatment with peginterferon alfa-2a or other alpha interferons. All patients should receive an eye examination at baseline. Patients with pre-existing ocular disease (e.g., hypertensive or diabetic retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. Any patient who develops ocular symptoms or visual disturbance should receive a prompt and complete eye examination. Discontinue treatment in patients who develop new or worsening ophthalmologic disorders.
Younger adult patients typically have higher virologic response rates than older patients. Clinical studies of peginterferon alfa-2a alone or in combination with ribavirin did not include sufficient numbers of subjects 65 years of age or over to determine whether they respond differently from younger adults. Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (e.g., flu-like) effects may be more severe in the geriatric patient. Also, peginterferon alfa-2a is excreted by the kidney, and the risk of toxic reactions may be greater in patients with impaired renal function, including geriatric patients. Use with caution in geriatric patients with creatinine clearance less than or equal to 50 mL/min; reduce the dose in geriatric patients with a creatinine clearance less than 30 mL/min.
There are no adequate and well-controlled studies evaluating use of peginterferon alfa-2a in pregnant women. Peginterferon alfa-2a should be assumed to have abortifacient potential based on studies in pregnant Rhesus monkeys, which showed a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. Peginterferon alfa-2a monotherapy may be administered to women of childbearing potential only after a confirmed negative pregnancy test. Advise female patients to use effective contraception requirements during therapy. Ribavirin use with peginterferon alfa-2a poses additional risks during pregnancy, and clinicians should be fully aware of the contraindications, as well as the proper use and monitoring for ribavirin therapy. Peginterferon alfa-2a use with ribavirin is contraindicated in women who are pregnant and men whose female partners are pregnant. Ribavirin may cause birth defects and death of the unborn child (intrauterine fetal death), and is genotoxic and mutagenic. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients if ribavirin is prescribed. Females drug recipients and female partners of male drug recipients must undergo pregnancy testing before starting peginterferon alfa-2a and ribavirin combination therapy, every month while being treated, and every month for the 6 months after treatment is discontinued. Contraceptive requirements exist for both males and females of childbearing potential in whom both ribavirin and peginterferon alfa-2a are prescribed. Both men and women of childbearing potential must use 2 forms of effective contraception during treatment and for 6 months after combination treatment discontinuation. If a female or the female sexual partner of a treated male becomes pregnant while taking peginterferon alfa-2a and ribavirin or within 6 months after discontinuation of treatment, the healthcare provider should be informed right away. The Ribavirin Pregnancy Registry (1-800-593-2214) should be contacted.
Peginterferon alfa-2a may cause menstrual irregularity and infertility in women. Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17-beta-estradiol and progesterone levels following administration of peginterferon alfa-2a at approximately 60-times the recommended human dose to female cynomolgus monkeys. A return to normal menstrual rhythm followed cessation of treatment. Every other day dosing with peginterferon alfa-2a at a dose equivalent to approximately 30 times the recommended human dose had no effects on cycle duration or reproductive hormone status. The effects of peginterferon alfa-2a on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys.
It is not known if peginterferon alfa-2a is excreted in breast milk and any effect of orally ingested interferon on a nursing infant has not been evaluated. Because of the potential for adverse reactions from the drug in a nursing infant, the manufacturer recommends that a decision be made to discontinue breast-feeding or to discontinue the drug. Patients should not do both. One case report involving two pregnant women receiving interferon alfa treatment has been published. An analysis immediately postpartum, found interferon concentrations in the breast milk (1.4 Units/mL and 6 Units/mL) to be considerably lower than the maternal serum concentrations (20.8 Units/mL and 58 Units/mL, respectively). Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
Peginterferon alfa-2 is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications which are sometimes fatal in neonates and infants. Use of peginterferon alfa-2a with ribavirin has been associated with growth inhibition in children and adolescents 3 years of age and older; monitor growth carefully in these patients. During a 48-week hepatitis C virus study, 43% of peginterferon alfa-2a and ribavirin-treated pediatric patients (5 to 17 years) experienced weight percentile decreases of 15 percentiles or more and 25% experienced height percentile decreases of at least 15 percentiles on normative growth curves. At the end of 2 years follow-up after treatment, most subjects had returned to baseline normative curve percentiles for weight and height; 16% of subjects were more than 15 percentiles below their baseline weight curve and 11% were more than 15 percentiles below their baseline height curve. The available longer-term data on subjects who were followed up to 6 years post-treatment are too limited to determine the risk of reduced adult height in some patients. Growth inhibition was also observed in a 48-week chronic hepatitis B virus study involving pediatric patients ages 3 to 17 years. At 24 weeks post-treatment, 12% of drug recipients were more than 15 percentiles below their baseline weight and height curve. At 5 years post-treatment the percentage of subjects with decrease of more than 15 percentiles from baseline was 29% for weight and 18% for height.
Dental disease and periodontal disorders have been reported in patients receiving peginterferon alfa and ribavirin combination therapy. Dry mouth due to peginterferon alfa/ribavirin combination therapy can impact oral health. Patients should check with their healthcare provider before having any dental work completed. Myelosuppressive effects of peginterferon alfa-2a may increase the risk of infection and bleeding during dental procedures. However, it is important for treated patients to receive regular dental care and emergency treatment when necessary. Patients should report any signs of oral infection or unusual bleeding. Patients should be instructed in proper oral hygiene, including gentle brushing and flossing of teeth and receiving regular dental exams.
Vaccination with live vaccines should be avoided due to the risk of neutropenia and myelotoxicity during peginterferon alfa-2a therapy.
Initiation of therapy for HCV infection:
-HCV screening (i.e., HCV-antibody for initial screening, HCV-RNA for confirmation of active infection) recommended for:
-All persons 18 years and older (a 1-time, routine, opt-out test)
-All persons younger than 18 years with any of the below activities, exposures, or conditions and circumstances associated with an increased risk of HCV infection (a 1-time test)
-Each pregnancy (testing as part of routine prenatal care)
-All persons with any of the below activities, exposures, or conditions and circumstances associated with an increased risk of HCV infection (periodic repeat testing)
-All persons who inject drugs (annual testing)
-Men with HIV who have unprotected sex with men, and men who have sex with men taking HIV pre-exposure prophylaxis (annual testing)
-HCV risk-associated activities, exposures, or conditions and circumstances include:-Activities: injection drug use (current or ever, including those who injected only once); intranasal illicit drug use; use of glass crack pipes; engagement in chem sex (i.e., combining sex with nonprescription drugs to facilitate or enhance sexual encounter); men who have sex with men.
-Exposures: persons on long-term hemodialysis (ever); persons with percutaneous or parenteral exposures in an unregulated setting; healthcare, emergency medical, and public safety workers after needlestick, sharps, or mucosal exposure to HCV-infected blood; children born to mothers with HCV; persons who were ever incarcerated; certain recipients of a prior transfusion or organ transplant (i.e., received blood from a donor who later tested positive for HCV; received a blood transfusion or blood component, or underwent an organ transplant before July 1992; received clotting factor concentrates produced before 1987).
-Conditions and Circumstances: HIV infection; sexually active persons about to start pre-exposure prophylaxis for HIV; chronic hepatic disease or chronic hepatitis, including unexplained elevated ALT concentrations; solid organ donors and recipients.
-Treatment is recommended for all patients with acute or chronic HCV infection, except those with short life expectancy.
-Laboratory tests recommended prior to initiating antiviral therapy: quantitative HCV-RNA test to document baseline viral load; HCV genotype and subtype test (if starting a non-pan-genotypic direct-acting antiviral [DAA]); HBsAg test for active HBV coinfection, and anti-HBs and anti-HBc test for prior HBV coinfection (if starting DAA); test for HIV coinfection (if starting DAA).
Place in therapy for HCV infection:
-Interferon-based therapies are no longer recommended as part of preferred or alternative treatment regimens.
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: hepatitis C virus
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
This drug may also have activity against the following microorganisms: adenovirus, encephalomyocarditis virus, hepatitis B virus, hepatitis D virus, herpes simplex virus type 1, herpes simplex virus type 2, human immunodeficiency virus (HIV), human papillomavirus (HPV), human T-lymphotropic virus type I (HTLV-I), poliovirus, rhinovirus, varicella-zoster virus, variola virus (smallpox), vesicular stomatitis virus
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.
For the treatment of chronic hepatitis C infection in patients with compensated cirrhosis:
NOTE: The vials and prefilled syringes are not directly interchangeable. The same amount of drug will not be provided by equal volumes. The 1 mL vial and the 0.5 mL prefilled syringe both provide 180 mcg peginterferon alfa-2a.
NOTE: Patients who have failed other alfa interferon treatments, must receive peginterferon alfa-2a in combination with BOTH ribavirin AND an HCV direct-acting antiviral (DAA).
NOTE: Safety and efficacy have not been established in patients who are liver or other organ transplant recipients, are coinfected with hepatitis B, or are coinfected with HIV with a CD4 cell count less than 100 cells/mm3.
-for the treatment of chronic hepatitis C genotypes 1 or 4 infection in treatment-naive persons as part of combination therapy with ribavirin and sofosbuvir:
Subcutaneous dosage:
Adults: 180 mcg subcutaneously once weekly for 12 weeks in combination with ribavirin and sofosbuvir.
-for the treatment of chronic hepatitis C genotypes 1 and 4 infection as part of combination therapy with ribavirin:
Subcutaneous dosage:
Adults: 180 mcg subcutaneously once weekly for 48 weeks in combination with ribavirin. This includes persons living with HIV. Consider treatment discontinuation if there is not at least a 2 log10 reduction in HCV RNA from baseline by 12 weeks or if the HCV RNA is detectable after 24 weeks.
Children and Adolescents 5 to 17 years: 180 mcg/1.73 m2 x BSA (Max: 180 mcg/dose) subcutaneously once weekly for 48 weeks in combination with ribavirin. Consider treatment discontinuation if there is not at least a 2 log10 reduction in HCV RNA from baseline by 12 weeks or if the HCV RNA is detectable after 24 weeks. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen.
-for the treatment of chronic hepatitis C genotypes 2 and 3 infection as part of combination therapy with ribavirin in persons without HIV:
Subcutaneous dosage:
Adults: 180 mcg subcutaneously once weekly for 24 weeks in combination with ribavirin. Consider treatment discontinuation if there is not at least a 2 log10 reduction in HCV RNA from baseline by 12 weeks or if the HCV RNA is detectable after 24 weeks.
Children and Adolescents 5 to 17 years: 180 mcg/1.73 m2 x BSA (Max: 180 mcg/dose) subcutaneously once weekly for 24 weeks in combination with ribavirin. Consider treatment discontinuation if there is not at least a 2 log10 reduction in HCV RNA from baseline by 12 weeks or if the HCV RNA is detectable after 24 weeks. Patients who reach their 18th birthday while on therapy should remain on the pediatric dosing regimen.
-for the treatment of chronic hepatitis C genotypes 2 and 3 infection as part of combination therapy with ribavirin in persons living with HIV:
Subcutaneous dosage:
Adults: 180 mcg subcutaneously once weekly for 48 weeks in combination with ribavirin. Consider treatment discontinuation if there is not at least a 2 log10 reduction in HCV RNA from baseline by 12 weeks or if the HCV RNA is detectable after 24 weeks.
-for the treatment of chronic hepatitis C infection as monotherapy in persons without HIV:
NOTE: Monotherapy is not recommended unless there are contraindications or substantial intolerance to other HCV antiviral therapies. The efficacy of peginterferon alfa-2a is enhanced when used in combination with other HCV therapies.
Subcutaneous dosage:
Adults: 180 mcg subcutaneously once weekly for 48 weeks. Consider treatment discontinuation if there is not at least a 2 log10 reduction in HCV RNA from baseline by 12 weeks or if the HCV RNA is detectable after 24 weeks.
For the treatment of chronic hepatitis B infection:
Subcutaneous dosage:
Adults: 180 mcg subcutaneously once weekly for 48 weeks. Peginterferon alfa-2a is FDA-approved for the treatment of adults with HBeAg-positive and HBeAg-negative chronic hepatitis B infection who have compensated liver disease with evidence of viral replication and liver inflammation.
Children and Adolescents 3 to 17 years: 180 mcg/1.73 m2 x BSA (Max: 180 mcg/dose) subcutaneously once weekly for 48 weeks. Maintain the recommended pediatric dosage throughout the entire duration of therapy in children who turn 18 years during treatment. Peginterferon alfa-2a is FDA-approved for the treatment of HBeAg-positive chronic hepatitis B infection in non-cirrhotic children with evidence of viral replication and elevations in serum alanine aminotransferase.
Therapeutic Drug Monitoring:
Dosage adjustments based on adverse reactions and hematologic parameters:
NOTE: Also see dosage adjustment modifications for renal and hepatic alterations during treatment.
-For moderate to serious adverse reactions (clinical and/or laboratory): In adults, decrease the dose to 135 mcg SC once weekly. In some cases, dose reduction to 90 mcg SC once weekly may be required. After improvement of the adverse reaction, re-escalation of the dose may be considered. If the reaction persists despite dosage reduction, discontinue therapy. In children and adolescents, decrease the dose to 135 mcg/1.73 m2 x BSA SC once weekly. In some cases, a dose reduction to 90 mcg/1.73 m2 x BSA once weekly may be needed.
-For mild depression in adults, adolescents, and children: No dosage change necessary; evaluate once weekly by visit and/or phone for 4-8 weeks. If depression remains stable, continue weekly visit schedule, or if depression improved, resume normal visit schedule. If depression worsens, use the recommendations for moderate depression.
-For moderate depression in adults: Decrease dose to 135 mcg SC once weekly. In some cases, dose reduction to 90 mcg SC once weekly may be required; evaluate once weekly, including an office visit at least every other week. If depression remains stable, consider psychiatric consultation and continue with the reduced dosage. If symptoms improve and are stable for 4 weeks, normal visit schedule may be resumed; continue with the reduced dosing or consider return to normal dose. If depression worsens, discontinue treatment immediately and permanently; obtain immediate psychiatric consultation.
-For moderate depression in children and adolescents: Decrease dose to 135 mcg/1.73 m2 x BSA SC once weekly. In some cases, dose reduction to 90 mcg/1.73 m2 x BSA SC once weekly may be required; evaluate once weekly, including an office visit at least every other week. If depression remains stable, consider psychiatric consultation and continue with the reduced dosage. If symptoms improve and are stable for 4 weeks, normal visit schedule may be resumed; continue with the reduced dosing or consider return to normal dose. If depression worsens, discontinue treatment immediately and permanently; obtain immediate psychiatric consultation.
-For severe depression in adults, adolescents, and children: Discontinue treatment immediately and permanently; obtain immediate psychiatric consultation.
-For neutrophil count 750-999/mm3 in children and adolescents: If during treatment weeks 1-2, reduce dose to 135 mcg/1.73 m2 x BSA SC once weekly. If during treatment weeks 3-48, no dose modification is needed.
-For neutrophil count 500-749/mm3: In adults, reduce dose to 135 mcg SC once weekly. In children and adolescents during treatment weeks 1-2, hold dose until > 750/mm3 then resume at 135 mcg/1.73 m2 x BSA SC once weekly. Reassess weekly x 3 weeks to ensure WBC's remain > 750 cells/mm3. In children and adolescents during treatment weeks 3-48, reduce dose to 135 mcg/1.73 m2 x BSA SC once weekly.
-For neutrophil count < 500/mm3 in adults: Suspend treatment until neutrophil count > 1000/mm3; reinstitute at 90 mcg SC once weekly; monitor neutrophil count.
-For neutrophil count 250-499/mm3 in children and adolescents: If during treatment weeks 1-2, hold dose until > 750/mm3 then resume at 90 mcg/1.73 m2 x BSA SC once weekly. If during treatment weeks 3-48, hold dose until > 750/mm3 then resume at 135 mcg/1.73 m2 x BSA SC once weekly.
-For neutrophil count < 250/mm3 (or febrile neutropenia) in children and adolescents: Discontinue treatment.
-For platelet count < 50,000/mm3: In adults, reduce dose to 90 mcg SC once weekly. In children and adolescents, reduce dose to 90 mcg/1.73 m2 x BSA SC once weekly.
-For platelet count < 25,000/mm3 in adults: Discontinue treatment.
Maximum Dosage Limits:
-Adults
180 mcg/week subcutaneously.
-Geriatric
180 mcg/week subcutaneously.
-Adolescents
180 mcg/1.73 m2 x BSA subcutaneously once weekly (Max: 180 mcg/week).
-Children
5 to 12 years: 180 mcg/1.73 m2 x BSA subcutaneously once weekly (Max: 180 mcg/week).
3 to 4 years: 180 mcg/1.73 m2 x BSA subcutaneously once weekly (Max: 180 mcg/week).
1 to 2 years: Safety and efficacy have not been established.
-Infants
Use not recommended.
-Neonates
Use not recommended.
Patients with Hepatic Impairment Dosing
Patients with decompensated hepatic disease (e.g., Child-Pugh class B or C) should not be treated with peginterferon alfa-2a. Peginterferon alfa-2a is also contraindicated for use in patients with autoimmune hepatitis. If ALT increases are progressive despite dose reduction or are accompanied by increased bilirubin or evidence of hepatic decompensation, immediately discontinue therapy.
Adult patients with chronic hepatitis C: In patients with progressive ALT increases above baseline values, reduce the dose to 135 mcg SC once weekly and perform more frequent liver function monitoring. Peginterferon alfa-2a may be resumed after the ALT flare has subsided.
Adult patients with chronic hepatitis B: In patients with ALT values greater than 5 times the upper limit of normal, consider dose reduction to 135 mcg SC once weekly or temporary drug discontinuation and perform more frequent liver function monitoring. Peginterferon alfa-2a may be resumed after ALT flares subside. Therapy discontinuation may be appropriate for patients with persistent ALT elevations more than 10 times the upper limit of normal.
Children and Adolescents with chronic hepatitis C:
-For alanine transaminase (ALT) > 5 but < 10 x upper limit of normal (ULN) in children and adolescents: Reduce dose to 135 mcg/1.73 m2 x BSA SC once weekly. If necessary, further modify dose until stable or ALT concentrations decrease.
-For persistent alanine transaminase (ALT) > 10 x ULN in children and adolescents: Discontinue treatment.
Patients with Renal Impairment Dosing
NOTE: In all patients, estimate the creatinine clearance before peginterferon alfa-2a initiation. Due to a lack of data, dosage recommendations cannot be made for pediatric patients with renal impairment.
CrCl >= 30 ml/min: No dosage adjustment needed.
CrCl < 30 ml/min (Adults): Reduce dose to 135 mcg SC once weekly and closely monitor for signs and symptoms of interferon toxicity. If severe adverse reactions or laboratory abnormalities develop, the dose may be further reduced to 90 mcg SC once weekly until the adverse reactions abate. If intolerance persists after dose adjustment, discontinue peginterferon alfa-2a.
Intermittent hemodialysis
Adults: 135 mcg SC once weekly. Monitor patients closely for the potential for reduced efficacy and for signs and symptoms of interferon toxicity. If severe adverse reactions or laboratory abnormalities develop, the dose may be reduced to 90 mcg SC once weekly until the adverse reactions abate. If intolerance persists after dose adjustment, discontinue peginterferon alfa-2a.
*non-FDA-approved indication
Abacavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Alemtuzumab: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Alteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Arsenic Trioxide: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Atazanavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Atazanavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Azathioprine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Basiliximab: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Cabotegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Chikungunya Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Chloroquine: (Moderate) Concurrent use of chloroquine and interferons is not recommended as there is an increased risk of retinal toxicity.
Cladribine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Darunavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Darunavir; Cobicistat: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Delavirdine: (Major) The concomitant use of interferons and anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs) should be done with caution as both can cause hepatic damage. NNRTIs may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Many studies demonstrate that nevirapine is more hepatotoxic than efavirenz. Underlying chronic HCV infection enhances the risk of developing liver enzyme elevations in patients receiving nevirapine. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Dolutegravir; Lamivudine: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Dolutegravir; Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Efavirenz: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6). (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and efavirenz can both cause hepatotoxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Tenofovir alafenamide: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Entecavir: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Estramustine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Filgrastim, G-CSF: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Fludarabine: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Folate analogs: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Fosamprenavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Hydroxyurea: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Ibritumomab Tiuxetan: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Imatinib: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Indinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Lamivudine, 3TC: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine, 3TC; Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance. (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Monitor for treatment-associated toxicities, especially hepatic decompensation, during coadministration of interferons (with or without ribavirin) and lamivudine. Dose reduction or discontinuation of interferon, ribavirin, or both should be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Lomustine, CCNU: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Lopinavir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Mercaptopurine, 6-MP: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Methadone: (Major) Addition of peginterferon alfa-2a 180 mcg SC once weekly to methadone maintenance therapy resulted in 10 to 15% higher mean methadone pharmacokinetic parameter values after 4 weeks of dual therapy as compared with baseline values. The pharmacokinetic parameter values of peginterferon alfa-2a were not altered by methadone. Patients received a median methadone dose of 95 mg (range, 30150 mg). If both drugs will be used concomitantly, the dosage of methadone may need to be lowered. Patients need to be cautioned to not drive or operate machinery until the effects of both drugs on them are known.
Methotrexate: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Methoxsalen: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Methylprednisolone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Mitoxantrone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Nelfinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Nevirapine: (Major) The concomitant use of interferons and nevirapine should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Nevirapine may cause liver damage in the context of hypersensitivity reactions or by direct toxic effects. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Patients with signs or symptoms of hepatitis, or with increased transaminases combined with rash or other systemic symptoms, must discontinue nevirapine and seek medical evaluation immediately.
Nirmatrelvir; Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Pegfilgrastim: (Major) Pegfilgrastim induces the proliferation of neutrophil-progenitor cells, and because antineoplastic agents exert toxic effects against rapidly growing cells, pegfilgrastim should not be given 14 days before or for 24 hours after cytotoxic chemotherapy.
Pemetrexed: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Pentostatin: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Pexidartinib: (Moderate) Monitor for evidence of hepatotoxicity if pexidartinib is coadministered with peginterferon alfa-2a. Avoid concurrent use in patients with increased serum transaminases, total bilirubin, or direct bilirubin (more than ULN) or active liver or biliary tract disease.
Pralatrexate: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Prednisolone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Prednisone: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Pretomanid: (Major) Avoid coadministration of pretomanid with peginterferon alfa-2a, especially in patients with impaired hepatic function, due to increased risk for hepatotoxicity. Monitor for evidence of hepatotoxicity if coadministration is necessary. If new or worsening hepatic dysfunction occurs, discontinue hepatotoxic medications.
Protease inhibitors: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Purine analogs: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Rilpivirine: (Moderate) Use together with caution and monitor for hepatic decompensation. Interferons and rilpivirine can both cause hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving antiretroviral agents and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART.
Riluzole: (Moderate) Monitor for signs and symptoms of hepatic injury during coadministration of riluzole and peginterferon alfa-2a. Concomitant use may increase the risk for hepatotoxicity. Discontinue riluzole if clinical signs of liver dysfunction are present.
Ritonavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Saquinavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Stavudine, d4T: (Major) Patients receiving stavudine with interferons (with or without ribavirin) should be closely monitored for treatment-associated toxicities, especially hepatic decompensation. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation compared to patients not receiving HAART. Additionally, stavudine has been associated with fatal and nonfatal lactic acidosis and hepatomegaly with or without steatosis and should be used cautiously in patients with hepatic disease. Discontinuation of stavudine should be considered as medically appropriate. Dose reduction or discontinuation of interferon, ribavirin, or both should also be considered if worsening clinical toxicities are observed, including hepatic decompensation (e.g., Child-Pugh score greater than 6).
Tbo-Filgrastim: (Major) Filgrastim induces the proliferation of neutrophil-progenitor cells, and, because antineoplastic agents exert toxic effects against rapidly growing cells, filgrastim is contraindicated for use during the 24 hours before or after cytotoxic chemotherapy.
Tenecteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Theophylline, Aminophylline: (Major) Alpha interferons, when administered systemically, may decrease the clearance of aminophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced aminophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated. (Major) Alpha interferons, when administered systemically, may decrease the clearance of theophylline resulting in increased plasma concentrations. Concomitant use may result in a significant increase in theophylline concentrations due to reduced theophylline clearance. In studies, increases in theophylline levels of 25% up to 100% have occurred. Reductions in CYP1A2 activity have been noted with various alpha interferons, and likely provide a mechanism for the interaction. Monitor theophylline concentrations and for signs and symptoms of theophylline toxicity when interferons are used concomitantly; consider appropriate dose adjustments as clinically indicated.
Thioguanine, 6-TG: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
Tipranavir: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. The HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART.
Tretinoin, ATRA: (Moderate) Use of alpha interferons are associated with myelosuppression; additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Vigabatrin: (Major) Vigabatrin is associated with vision loss. The drug should not be used with interferons, which are associated with a potential for serious ophthalmic effects (e.g., retinopathy, optic neuritis, visual impairment), unless the benefit of treatment clearly outweighs the risks.
Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient, including those receiving Interferon therapy. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
Zidovudine, ZDV: (Major) Use interferons and zidovudine together with caution. Closely monitor patients for treatment-associated toxicities, especially hematologic effects and hepatic decompensation, and manage as recommended for the individual therapies. Coadministration of alpha interferons may increase the hematologic toxicity of zidovudine. Interferons and anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs) are also associated with hepatotoxicity. Patients with chronic, cirrhotic HCV co-infected with HIV receiving NRTIs and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. Interferon therapy may also reduce zidovudine clearance.
The active component of peginterferon alfa-2a is the interferon alfa-2a moiety. Interferon alfa-2a acts similarly to native interferon alpha. Endogenous alpha-interferons (IFNs) are secreted by leukocytes (e.g., macrophages, B lymphocytes, and non-B non-T lymphocytes) in response to viral infection or various synthetic and biological inducers. All alpha-IFNs share common biologic activities generated by the binding of interferon to the cell-surface receptor. Although the exact mechanism of action is not fully understood, interferon binding to the cell surface receptor is followed by activation of tyrosine kinases, which leads to the production of several IFN-stimulated enzymes such as 2'-5'-oligoadenylate synthetase (2'-5'-OAS) and beta2-microglobulin. These and possibly other IFN-stimulated enzymes are thought to be responsible for the pleiotropic biologic effects of alpha-IFNs, which include antiviral, antiproliferative and immunomodulatory effects, cellular differentiation, regulation of cell surface major histocompatibility antigen expression (HLA class I), and cytokine induction.
-Antiviral effects: Interferon exerts antiviral effects by augmenting the production and/or release of specific enzymes. Interferon-induced intracellular enzymes such as 2'5'-OAS and protein kinase contribute to inhibition of viral replication by activating endoribonucleases that cleave single-stranded viral RNA. Thus, translation of viral proteins is inhibited. The activity of IFN-induced enzymes depends on the presence of double-stranded RNA (dsRNA) formed during viral replication. It has been suggested that the antiviral activity of IFNs may be related, in part, to an effect on dsRNA. Interferon-induced enzymes may also inhibit viral penetration and uncoating, and/or viral assembly and release. Expression of major histocompatibility antigens by IFNs may also contribute to antiviral activity by enhancing the lytic effects of cytotoxic T lymphocytes.
A wide range of viruses, particularly RNA viruses, are sensitive to the antiviral actions of IFN. Alpha interferons are generally active against the following viruses in vitro: adenovirus; coronavirus; encephalomyocarditis virus; hepatitis B virus; hepatitis C virus (HCV); hepatitis D virus; herpes simplex virus type 1; herpes simplex virus type 2; human immunodeficiency virus (HIV); papillomavirus; poliovirus; rhinovirus; vaccinia virus; varicella-zoster virus; vesicular stomatitis virus; human T-lymphotropic virus type I (HTLV-I). In chronic hepatitis C, INF treatment is associated with normalization of ALT and reduction of serum HCV RNA, as well as improvement in liver histopathology, in responding patients. The HCV genotype 1 is more resistant to interferon alfa treatment than other viral genotypes; 75% of persons in the United States infected with HCV carry this genotype. Many patients with a biochemical and virologic response relapse 1-2 months after stopping IFN therapy.
-Effect on hepatic microsomal enzymes: Alpha interferons may inhibit microsomal enzymes involved in the hepatic cytochrome P-450 system. The effect of interferon on the CYP450 system may be related to increased enzyme degradation, suppressed enzyme synthesis, or inhibition of cytochrome P-450. Implications of this effect have not been fully evaluated, but the metabolism of certain drugs may be affected (see Drug Interactions).
Peginterferon alfa-2a is given subcutaneously (SC). In patients with hepatitis C infection, the mean elimination half-life of peginterferon alfa-2a (i.e., Pegasys) is 80 hours (range 50-140 hours) as compared with 5.1 hours (range 3.7-8.5 hours) for interferon alfa-2a (i.e., Roferon-A). When compared to interferon alfa-2a in healthy patients, the mean systemic clearance of peginterferon alfa-2a is approximately 100-fold lower, allowing for a reduced dosing frequency.
-Route-Specific Pharmacokinetics
Subcutaneous Route
Following a single SC dose, the mean absorption half-life is 4.6 hours. Maximal concentrations occur between 72 and 96 hours post dose and are sustained for 168 hours. With multiple dosing there is an increase in peginterferon alfa-2a bioavailability. Steady-state serum concentrations are reached within 5-8 weeks of once weekly dosing. Mean trough concentrations (16 ng/ml) at week 48 of treatment are roughly 2-fold higher than the trough concentrations (8 ng/ml) at week 1 of treatment.
-Special Populations
Renal Impairment
Similar peginterferon alfa-2a plasma exposures after a 180 mcg once weekly dose were obtained from patients with a CrCl of 30-50 ml/min as compared with values obtained from patients with a CrCl > 80 ml/min. No peginterferon alfa-2a dose adjustment is required for patients with a CrCl > 30 ml/min. In contrast, peginterferon alfa-2a dose reduction is needed for patients with CrCl < 30 ml/min including patients with end-stage renal disease requiring hemodialysis (see Dosage). Among patients with a CrCl < 30 ml/min, the peginterferon alfa-2a apparent clearance was 43% lower as compared with values obtained from patients with normal renal function. Despite use of a reduced dose of 135 mcg once weekly, a 30% higher peginterferon alfa-2a exposure compared to that of the recommended dose for patients with normal renal function may occur. Among patients on chronic hemodialysis who received peginterferon alfa-2a 135 mcg once weekly, the apparent clearance of peginterferon alfa-2a was similar as compared with values from patients with normal renal function who received 180 mcg once weekly. However, despite a lower exposure to peginterferon alfa-2a with the 135 mcg dose, patients on chronic hemodialysis had a high rate of adverse events and discontinuations. Specifically, among 18 patients on chronic hemodialysis who received peginterferon alfa-2a 135 mcg once weekly, up to 22% had dose reductions and temporary interruptions of peginterferon alfa-2a due to drug-related adverse reactions, and 17% of these patients discontinued peginterferon alfa-2a due to drug-related adverse reactions. Only one-third of patients on hemodialysis received peginterferon alfa-2a for 48 weeks.
Pediatrics
The pharmacokinetic parameters of peginterferon alfa-2a (180 mcg/1.73 m2 x BSA given subcutaneously) were evaluated in a study involving 14 children, aged 2-8 years, with chronic hepatitis C. Peginterferon alfa-2a steady-state trough concentrations were similar to those observed in adults receiving 180 mcg fixed dosing; however, the time to reach steady state (Tmax) was longer in the pediatric group (approximately 12 weeks) when compared to the adult population (5-8 weeks). Additionally, the pediatric group experienced a 4-fold lower clearance of peginterferon alfa-2a compared to the clearance reported in adults. Based on this decreased clearance, the mean exposure (AUC) is predicted to be 25-70% higher in children receiving BSA adjusted dosing than in adults receiving fixed dosing. Safety and efficacy of peginterferon alfa-2a have not been established in neonates, infants, or children < 5 years of age.
Geriatric
The AUC was slightly increased in elderly subjects > 62 years of age taking 180 mcg SC per week of peginterferon alfa-2a, but peak concentrations were similar in these patients as compared with younger adults.