Interferon Beta (Monograph)

Brand names: Avonex, Betaseron, Extavia, Rebif
Drug class: Interferons

Introduction

Biosynthetic (recombinant DNA origin) form of endogenous human interferon beta with immunomodulatory and disease-modifying activity in multiple sclerosis (MS).^{1 4 8 9 19 20 21 26} Available as interferon beta-1a^{19 20} and interferon beta-1b.^{1 70}

Uses for Interferon Beta

Multiple Sclerosis (MS)

Management of relapsing forms of MS, including clinically isolated syndrome (CIS), relapsing-remitting disease, and active secondary-progressive disease, in adults.^{1 19 20 48 49 50 51 70 76}

The American Academy of Neurology (AAN) recommends that disease-modifying therapy be offered to patients with relapsing-remitting MS who have had recent relapses and/or MRI activity.⁷⁶ Clinicians should consider adverse effects, tolerability, method of administration, safety, efficacy, and cost of the drugs in addition to patient preferences when selecting an appropriate therapy.^{76 77}

Interferon Beta Dosage and Administration

General

Patient Monitoring

• Monitor complete blood counts (CBC), including differential, and liver function tests at regular intervals (e.g., 1, 3, and 6 months) following initiation of therapy, and then periodically in the absence of symptoms.^{1 19 20 70} Patients experiencing myelosuppression should undergo more frequent monitoring.^{1 19 20 70}

• Thyroid function tests are recommended every 6 months in patients with a history of thyroid dysfunction, or as clinically indicated.^{1 19 20 70}

• Periodically evaluate patient's understanding and use of aseptic technique and proper procedures for self administration.^{1 19 20 70}

• Monitor patients for any new or increasing fatigue or shortness of breath during therapy.^{1 19 20}

Premedication and Prophylaxis

• Consider premedication with analgesic and/or antipyretic agents on treatment days to prevent or reduce flu-like symptoms.^{1 19 20 40 42 43 70}

• Administer interferon beta doses in the evening to make some adverse effects (e.g., flu-like syndrome) more tolerable since this avoids peak serum concentrations of the drug during the day.⁴⁰

Dispensing and Administration Precautions

• May be self-administered if the clinician determines that the patient and/or their caregiver is competent to prepare and safely administer the drug after appropriate training and with medical follow-up.^{1 19 20 60 70} Perform initial injection under the supervision of a qualified clinician.^{1 19 20 70}

• Give patients a copy of the manufacturer’s patient information (medication guide and instructions for use) for the specific preparation of interferon beta-1a (Avonex or Rebif) or interferon beta-1b (Betaseron or Extavia) used.^{1 19 20 70}

Other General Considerations

• Patients may feel worse or experience a temporary worsening of MS symptoms immediately following initiation of interferon beta therapy;⁴⁰ these effects often abate with continued therapy and should not be interpreted as an indication of treatment failure.⁴²

Administration

Administer by IM¹⁹ or sub-Q injection depending on preparation.^{1 19 20 70}

Interferon beta-1a is commercially available as a once-weekly IM injection (Avonex) or a 3-times-weekly sub-Q injection (Rebif).^{19 20} Interferon beta-1b is commercially available as a sub-Q alternate-day injection (Betaseron, Extavia);^{1 70} the 2 currently available interferon beta-1b preparations are identical except for some packaging components (e.g., needle size).⁶⁹

Sub-Q administration associated with higher rates of injection site reactions than IM administration.^{1 19 20 29} Prefilled syringes and auto-injectors are for single use only; do not re-use.^{1 19 20 70}

IM Administration

Interferon Beta-1a (Avonex)

Administer Avonex once weekly by IM injection into thigh or upper arm.¹⁹ Administer Avonex Pen once weekly into upper outer thigh.¹⁹ Rotate injection sites and avoid injecting into sites that appear irritated, reddened, bruised, infected, or scarred.¹⁹ Inspect injection site for any redness, swelling, or tenderness 2 hours after administration.¹⁹

Commercially available as prefilled syringe or prefilled auto-injector (i.e., Avonex Pen).¹⁹

The prefilled syringes are packaged with a 23-gauge, 1¼-inch needle supplied by the manufacturer; a 25-gauge, 1-inch needle for IM injection may be substituted by the clinician if appropriate.¹⁹ The prefilled auto-injector must be used with the supplied 25-gauge, (5/8)-inch needle; do not substitute with any other needle.¹⁹

Remove prefilled syringes and auto-injectors from refrigerator about 30 minutes prior to use to allow solution to reach room temperature; do not use external heat sources (e.g., hot water) to warm solution.¹⁹

Sub-Q Administration

Interferon Beta-1a (Rebif)

Administer 3 times weekly by sub-Q injection into the abdomen (avoiding waistline or areas within 2 inches of navel), thigh, upper arm, or buttock.²⁰ Administer on the same 3 days (e.g., Monday, Wednesday, and Friday) at least 48 hours apart each week and at the same time (preferably in the late afternoon or evening) each day.²⁰

Rotate injection sites and avoid injecting into sites that appear irritated, reddened, bruised, infected, or abnormal in any way.^{20 40}

Remove the drug from refrigerator 30 minutes prior to use.²⁰

Commercially available as a prefilled syringe or prefilled auto-injector (i.e., Rebidose).²⁰

Interferon Beta-1b (Betaseron, Extavia)

Administer by sub-Q injection every other day into the abdomen (except areas near the waistline and navel), thigh, upper arm, or buttocks.^{1 70}

Rotate injection sites and avoid injecting into sites that appear reddened, bruised, infected, or abnormal in any way.^{1 70}

Available as a lyophilized powder that must be reconstituted prior to use.^{1 70} An optional auto-injector (Betaconnect) is commercially available and may be obtained through the manufacturer's patient support program by calling 1-800-788-1467.¹

Reconstitution of Betaseron and Extavia Lyophilized Powder

Reconstitute vial containing 0.3 mg of interferon-beta-1b (Betaseron, Extavia) lyophilized powder by attaching the manufacturer-supplied prefilled syringe containing 1.2 mL of 0.54% sodium chloride to the vial; slowly inject entire contents of syringe to provide a solution containing 0.25 mg of interferon beta-1b per 1 mL.^{1 70}

Gently swirl vial to ensure complete dissolution; do not shake.^{1 70}

Reconstituted solutions contain no preservatives; solutions preferably should be prepared immediately before use.^{1 70} Vials are for single use only; discard any residual solution.^{1 70}

Dosage

Available as interferon beta-1a or interferon beta-1b; dosage expressed in terms of mg.^{1 19 20 70}

Potency of interferon beta also has been expressed in terms of international units.^{1 19 20 70} Each mg of interferon beta-1a is equivalent to approximately 200 million units (for Avonex) and 270 million units (for Rebif);^{19 20} each mg of interferon beta-1b is equivalent to approximately 32 million units (for Betaseron and Extavia).^{1 70}

Adults

Multiple Sclerosis

Interferon beta-1a (Avonex)

IM

30 mcg once weekly.¹⁹ To reduce incidence and severity of flu-like symptoms, initiate at a low dosage of 7.5 mcg once weekly, and then increase by 7.5 mcg each week for the next 3 weeks up to recommended dosage.¹⁹

Interferon beta-1a (Rebif)

Sub-Q

Gradually titrate dosage over a 4-week period to 22 or 44 mcg 3 times weekly using the schedule in Table 1.²⁰ When titrating to the 22-mcg dose, use only the prefilled syringes (not auto-injectors).²⁰

Interferon beta-1b (Betaseron, Extavia)

Sub-Q

Gradually titrate dosage over a 6-week period to 0.25 mg every other day using the schedule in Table 2.^{1 61 70}

If a dose is missed, administer as soon as possible; administer next scheduled dose approximately 48 hours later.^{1 70} Do not administer on 2 consecutive days.^{1 70}

Special Populations

Hepatic Impairment

Manufacturer of Rebif states to consider dosage reduction in patients whose serum ALT concentrations increase to >5 times ULN.²⁰ May gradually re-escalate dosage when serum ALT concentrations have returned to normal.²⁰

Renal Impairment

No specific dosage recommendations.^{1 19 20 70}

Geriatric Patients

No specific dosage adjustments required;^{1 19 20 70} however, select dosage with caution, usually initiating therapy at the low end of the dosage range due to possible age-related decreases in hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.²⁰

Cautions for Interferon Beta

Contraindications

• Avonex and Rebif are contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, albumin, or any other component of the formulation.^{19 20}

• Betaseron and Extavia are contraindicated in patients with a history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation.^{1 70}

Warnings/Precautions

Hepatotoxicity

Serious hepatic injury including autoimmune hepatitis and possibly severe, fulminant hepatic failure requiring liver transplantation reported.^{1 19 20 60 62 70}

Use with caution in patients with active liver disease, alcohol abuse, increased serum ALT concentrations (>2.5 times ULN), or history of clinically important liver disease.²⁰ Consider potential risks when interferon beta used concomitantly with other drugs associated with hepatic injury (including alcohol) or when other drugs are added to an existing interferon beta treatment regimen.^{1 19 20 70}

Monitor for manifestations of hepatic injury.^{1 19} Perform liver function tests at regular intervals (e.g., 1, 3, and 6 months) following initiation of therapy and then periodically thereafter in the absence of clinical symptoms.^{1 19 20 70}

Some manufacturers recommend discontinuance of therapy if substantial elevations in serum aminotransferase concentrations or clinical manifestations of liver dysfunction (e.g., jaundice) occur.^{1 19 20 70}

Asymptomatic elevations in serum aminotransferase concentrations (particularly ALT) reported commonly with interferon beta therapy.^{1 19 20 70}

Latex Sensitivity

Some packaging components of certain formulations (e.g., Avonex prefilled syringe pen cap, Extavia prefilled diluent syringe cap) contain natural rubber latex;^{19 70} individuals sensitive to latex should not handle these packaging components.^{124 125 126} Safety of Extavia reconstituted using the prefilled diluent syringe in latex-sensitive individuals not evaluated.⁷⁰

Hypersensitivity Reactions

Possible anaphylaxis or anaphylactoid reactions.^{1 19 20 70}

If acute, serious hypersensitivity reactions occur, discontinue immediately and initiate appropriate therapy.^{1 19 20 70}

Depression and Suicide

Possible depression, suicidal ideation, and suicide.^{1 19 20 70}

Some manufacturers state to use with caution in patients with depression or other mood disorders.²⁰ Monitor patients closely for evidence of depression or other psychiatric symptoms; consider discontinuance of therapy if any such symptoms occur.^{1 19 20 42 70}

Because of a high prevalence of mood disorders in patients with MS, a history of depression is not an absolute contraindication to use of interferon beta.⁴² It may be difficult to separate neuropsychiatric symptoms related to interferon beta therapy from those related to MS.^{60 61 62}

Congestive Heart Failure

Congestive heart failure (CHF), cardiomyopathy (with or without CHF),^{1 19 70} palpitations,^{1 70} and tachycardia,^{1 70} reported with some preparations of interferon beta during post marketing surveillance.^{1 19 70} In some cases, these events were temporally related to the administration of interferon beta-1b; recurrence upon rechallenge was observed in some patients.^{1 19 70}

Monitor patients with preexisting CHF for clinical worsening during therapy.^{1 19 70} Some manufacturers state to consider discontinuance of therapy if worsening CHF occurs without any other etiology.^{1 70}

Necrosis

Severe injection site necrosis reported following sub-Q and IM administration, sometimes requiring dermal debridement or skin grafting.^{1 20 70 19} Usually occurs within the first 3–4 months of therapy.^{1 20 61 70}

Factors that may be associated with development of skin necrosis include nonsterile injection techniques, administering cold interferon beta solutions, failure to rotate injection sites, and exposure of recent injection sites to UV light.^{40 42}

Injection-site Reactions

Mild to moderate injection site reactions (e.g., hemorrhage, hypersensitivity, inflammation, mass, pain, edema, atrophy, redness, induration) reported in some patients following sub-Q or IM administration.^{1 20 70}

Injection site abscess or cellulitis, possibly requiring surgical intervention, rarely reported during post marketing surveillance.^{1 19} Local reactions following IM or sub-Q injection generally are more severe with more frequent and higher doses of interferon beta.^{60 62}

Hematologic Effects

Decreased peripheral blood cell counts in all cell lines, including rare pancytopenia, leukopenia, thrombocytopenia, reported.^{1 19 20 70}

Monitor patients for signs and symptoms of decreased blood counts.^{19 20} Perform CBCs, platelet counts, and appropriate blood chemistry tests prior to initiation of therapy and periodically thereafter.^{1 19 20} Patients with myelosuppression may require more intensive monitoring.^{1 19 20 70}

Thrombotic Microangiopathy

Thrombotic microangiopathy (TMA), including sometimes fatal thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, reported.^{1 19 20 70} Onset ranged from several weeks to years after the drug was initiated.^{1 19 20 70} If TMA occurs, discontinue treatment and manage as clinically indicated.^{1 19 20 70}

Flu-like syndrome

Flu-like syndrome occurs commonly.^{1 19 20 40 61 70} Although there is considerable interindividual variation, symptoms occur most frequently during initiation of therapy (e.g., within hours or days after injection)^{19 62} and usually subside within a few months.^{40 42}

Consider premedication with analgesic and/or antipyretic agents.^{1 19 20 70}

Seizures

Possible seizures, including in patients with no history of seizure;¹⁹ not known whether related to preexisting seizure disorder, effects of MS alone, use of interferon beta, or other potential risk factors (e.g., fever).^{1 19 20 70} Use with caution in patients with preexisting seizure disorders.²⁰

If patients with no seizure history develop seizures during therapy, establish an etiologic basis and institute appropriate anticonvulsant therapy prior to considering resumption of therapy.^{60 62}

Drug-Induced Lupus Erythematosus

Autoimmune disorders of multiple target organs, including idiopathic thrombocytopenia, hyperthyroidism, hypothyroidism, and autoimmune hepatitis, reported.^{19 20 70}

Discontinue interferon beta therapy if a new autoimmune disorder develops, or if patients develop any manifestations of lupus (e.g., rash, serositis, polyarthritis, nephritis, Raynaud phenomenon).¹

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) reported even in the absence of other contributory factors.^{1 19 20} Many cases required hospitalization; one patient underwent lung transplant.^{1 19 20} May occur at varying time points during therapy including several years after treatment initiation.^{1 19 20}

Assess patients who develop new onset dyspnea or increasing fatigue for PAH.^{1 19 20} If alternative causes have been ruled out and a PAH diagnosis confirmed, discontinue interferon beta therapy and manage as clinically indicated.^{1 19 20}

Immunogenicity

Potential for immunogenicity.^{1 19 20 70} Possible development of binding or neutralizing antibodies to interferon beta following long-term therapy.^{21 54 55}

The presence of neutralizing antibodies, particularly in persistently high titers, associated with reductions in radiographic and clinical efficacy of interferon beta therapy.⁷⁴ Neutralizing antibodies generally develop 6–24 months after initiation of therapy.⁷⁴

Risk of antibody development may vary based on preparation, dosing frequency, total dose,⁶¹ and route of administration.^{21 55 56 57 58 74}

Specific Populations

Pregnancy

No well-controlled studies in pregnant women; however, available data have generally not identified drug-associated risk of major birth defects.^{1 19 20 70} Findings regarding a potential risk for low birth weight or miscarriage with the use of interferon beta in pregnancy inconsistent.^{20 70} In animal studies, administration during pregnancy resulted in increased rate of abortion at doses greater than those used clinically; however, unclear whether, as a class of products, administration to pregnant animals at doses greater than those used clinically results in an increased rate of abortion.^{19 20 70} Use during pregnancy only if the potential benefits justify the possible risks to the fetus.^{1 19 20 70}

Lactation

Limited data suggest that interferon beta-1a distributes into human milk.^{19 20} No data on the presence of interferon beta-1b in human milk.^{1 70} Not known whether interferon beta has any effects on the breastfed infant or on milk production.^{1 19 20 70}

Consider developmental and health benefits of breastfeeding along with the mother's clinical need for interferon beta and any potential adverse effects on the breastfed child from the drug or underlying maternal condition.^{1 19 20 70}

Females and Males of Reproductive Potential

Studies not conducted to determine whether interferon beta affects fertility in humans.^{19 20} Menstrual irregularities, anovulation, and decreased serum progesterone concentrations observed in some animal studies at dosages higher than recommended in humans.¹⁹

Pediatric Use

Although the safety and efficacy of interferon beta in children <18 years of age have not been established,^{1 19 20 70} the drug has been used with variable results for the management of childhood onset MS.^{22 77 80}

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults; select dosage with caution.^{1 19 20 70}

Hepatic Impairment

Safety and efficacy not evaluated in hepatic impairment.^{1 19 20 70} Discontinue if serum ALT levels significantly increase.^{1 70}

Renal Impairment

Safety and efficacy not evaluated in renal impairment.²⁰

Common Adverse Effects

Interferon beta-1a (Avonex): The most common adverse reactions (≥5%) in clinical studies were flu-like symptoms including chills, fever, myalgia, and asthenia.¹⁹

Interferon beta-1a (Rebif): The most common adverse reactions in controlled clinical trials were injection site disorders, influenza-like symptoms, abdominal pain, depression, elevation of liver enzymes, and hematologic abnormalities.²⁰

Interferon beta-1b (Betaseron): The most common adverse reactions (≥5%) in clinical studies were injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia.¹

Interferon beta-1b (Extavia): The most common adverse reactions (≥5%) in clinical studies were injection site reaction, lymphopenia, flu-like symptoms, myalgia, leukopenia, neutropenia, increased liver enzymes, headache, hypertonia, pain, rash, insomnia, abdominal pain, and asthenia.⁷⁰

Drug Interactions

No formal drug interaction studies to date.^{1 19 20 70}

Interferon Beta Pharmacokinetics

Absorption

Bioavailability

Bioavailability of interferon beta-1b (Betaseron, Extavia) following sub-Q administration is approximately 50%.^{1 70}

Distribution

Limited data after sub-Q administration due to small doses used.^{1 70}

Elimination

Half-life

Elimination half-life of interferon beta-1a (Avonex) following a single IM dose is 19 hours.¹⁹

Plasma half-life of interferon beta-1a (Rebif) following a single sub-Q dose is approximately 69 hours.²⁰

Elimination half-life of interferon beta-1b ranges from 8 minutes to 4.3 hours in healthy individuals.¹

Gender

Gender-related effects on pharmacokinetic parameters have not been observed in studies using interferon beta-1a (Rebif).²⁰

Stability

Storage

Parenteral

Injection

Interferon beta-1a (Avonex) prefilled syringes or auto-injectors: 2–8°C (excursions permitted to ≤25°C for up to 7 days).¹⁹ Protect from heat and light; do not freeze.¹⁹ Discard if exposed to >25°C or to conditions other than those recommended.¹⁹

Interferon beta-1a (Rebif) prefilled syringes or auto-injectors: 2–8°C (excursions permitted to ≤25°C for up to 30 days).²⁰ Protect from heat and light; do not freeze.²⁰

Powder for Injection

Interferon beta-1b (Betaseron, Extavia) lyophilized powder: 20–25°C (excursions permitted to 15–30°C for up to 3 months).^{1 70} Following reconstitution, store at 2–8°C and use within 3 hours.^{1 70} Do not freeze.^{1 70}

Actions

• Has complex antiviral, antineoplastic, and immunomodulating activities.^{1 2 3 4 5 19 26}

• Mechanisms of action in the treatment of MS have not been fully elucidated,^{1 19 20 26 70} but may involve immunomodulating effects, including anti-inflammatory effects.^{4 8 9 37}

• Potency of interferon beta has been expressed in international units (IU, units) of antiviral activity using reference standards established by WHO.^{1 19 20 70} Avonex has a specific activity of approximately 200 million units of antiviral activity per mg.¹⁹ Rebif has a specific activity of approximately 270 million units of antiviral activity per mg.²⁰ Betaseron and Extavia have a specific action of approximately 32 million units of antiviral activity per mg.^{1 70}

Advice to Patients

• Advise patients to read the manufacturer's patient information (medication guide) and instructions for use before initiating treatment and each time the prescription is refilled.^{1 19 20 70}

• Importance of taking interferon beta exactly as prescribed.^{1 19 20 60 70} Advise patients not to change interferon beta preparations during a single regimen of therapy without consulting their clinician.^{1 19 20 60 62 70}

• Importance of not missing doses of interferon beta.^{1 70} If a dose of interferon beta-1b (Betaseron, Extavia) is missed, the missed dose should be administered as soon as possible and the next scheduled dose should be administered approximately 48 hours later.^{1 70} The drug should not be administered on 2 consecutive days.^{1 70} If two doses are administered on consecutive days, or more than the prescribed dose is administered, the prescriber should be contacted immediately.^{1 70}

• Instruct patients and/or caregivers regarding proper methods of preparation and administration, including the use of aseptic technique.^{1 19 20 70} Importance of rotating injection sites.^{1 19 20 70} Importance of providing instructions on the appropriate use, storage, and disposal of syringes and needles.^{1 19 20 70}

• Risk of developing depression, suicidal ideation, or psychotic disorders.^{1 19 20 60 70} Importance of patients notifying their clinician immediately if symptoms of depression or other psychiatric effects occur.^{1 19 20 60 70}

• Potential for temporary worsening of symptoms immediately following initiation of therapy;⁴⁰ advise patients that these symptoms often abate with continued therapy and should not be interpreted as an indication of treatment failure.⁴²

• Risk of hepatotoxicity; advise patients to immediately inform their clinician if they experience any symptoms of liver injury (e.g., jaundice, nausea, loss of appetite, fatigue, unusual bleeding, confusion, somnolence, dark-colored urine, pale stools).^{1 19 20 70}

• Risk of hypersensitivity reactions, including anaphylaxis.^{1 19 20} Advise patients to seek immediate medical attention if any symptoms of hypersensitivity occur.^{1 19 20 70}

• Importance of informing patients that flu-like symptoms (e.g., fever, muscle aches, chills, fatigue) are common following initiation of interferon beta therapy, and that pretreatment with analgesics and/or antipyretics may minimize these symptoms.^{1 19 20 70}

• Risk of seizures.^{1 19 20 70} Importance of patients immediately informing their clinician if a seizure occurs during therapy.^{1 19 20 70}

• Risk of injection site reactions, including necrosis.^{1 19 20 70} Importance of patients immediately informing their clinician if any blue-black discoloration, swelling, or fluid drainage occurs in conjunction with skin breakage at the injection site.^{1 20 70}

• Risk of decreased peripheral blood counts, which may increase the risk of infections, anemia, or bleeding.^{19 20 70}

• Risk of pulmonary arterial hypertension. Advise patients to promptly report any new or increasing fatigue or shortness of breath to a clinician.^{1 19 20}

• Inform patients that worsening CHF has been reported with interferon beta therapy.¹ Inform patients of the symptoms of worsening heart failure and to immediately report any such symptoms to their clinician.^{1 19 70}

• Some packaging components may contain natural rubber latex; advise patients to inform their clinician if they have an allergy to latex.^{19 70}

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.^{1 19 20 70}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{1 19 20 70}

• Inform patients of other important precautionary information.^{1 19 20 70}

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Betaseron, Avonex, Rebif, Extavia are available through specialty pharmacy networks.^{1 19 20 70} Clinicians may consult the respective manufacturer websites at [Web], [Web], [Web], or [Web] for specific availability information.^{1 19 20 70}

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