Pegasys (Hoffman-La Roche Inc)

Pegasys (Hoffman-La Roche Inc) - General Information

Human interferon 2a, is a covalent conjugate of recombinant alfa-2a interferon with a single branched bis-monomethoxy polyethylene glycol (PEG) chain. The PEG moiety is linked at a single site to the interferon alfa moiety via a stable amide bond to lysine. Pegasys (Hoffman-La Roche Inc) has an approximate molecular weight of 60,000 daltons. Interferon alfa-2a is produced using recombinant DNA technology in which a cloned human leukocyte interferon gene is inserted into and expressed in Escherichia coli. 165 amino acids. PEGylated to extend serum half life

 

Pharmacology of Pegasys (Hoffman-La Roche Inc)

Upregulates the expression of MHC I proteins, allowing for increased presentation of peptides derived from viral antigens. This enhances the activation of CD8+ T cells that are the precursors for cytotoxic T lymphocytes (CTLs) and makes the macrophage a better target for CTL-mediated killing. Interferon alpha also induce the synthesis of several key antiviral mediators, including 2'-5' oligoadenylate synthetase (2'-5' A synthetase) and protein kinase R.

 

Pegasys (Hoffman-La Roche Inc) for patients

Patients receiving PEGASYS alone or in combination with COPEGUS should be directed in its appropriate use, informed of the benefits and risks associated with treatment, and referred to the PEGASYS and, if applicable, COPEGUS (ribavirin) MEDICATION GUIDES.

PEGASYS and COPEGUS combination therapy must not be used by women who are pregnant or by men whose female partners are pregnant. COPEGUS therapy should not be initiated until a report of a negative pregnancy test has been obtained immediately before starting therapy. Female patients of childbearing potential and male patients with female partners of childbearing potential must be advised of the teratogenic/embryocidal risks and must be instructed to practice effective contraception during COPEGUS therapy and for 6 months post-therapy. Patients should be advised to notify the physician immediately in the event of a pregnancy.

Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded; routine monthly pregnancy tests must be performed during this time.

If pregnancy does occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. To monitor maternal-fetal outcomes of pregnant women exposed to COPEGUS, the COPEGUS Pregnancy Registry has been established. Physicians and patients are strongly encouraged to register by calling 1-800-526-6367.

Patients should be advised that laboratory evaluations are required before starting therapy and periodically thereafter. Patients should be instructed to remain well hydrated, especially during the initial stages of treatment. Patients should be advised to take COPEGUS with food.

Patients should be informed that it is not known if therapy with PEGASYS alone or in combination with COPEGUS will prevent transmission of HCV infection to others or prevent cirrhosis, liver failure or liver cancer that might result from HCV infection. Patients who develop dizziness, confusion, somnolence, and fatigue should be cautioned to avoid driving or operating machinery.

If home use is prescribed, a puncture-resistant container for the disposal of used needles and syringes should be supplied to the patients. Patients should be thoroughly instructed in the importance of proper disposal and cautioned against any reuse of any needles and syringes. The full container should be disposed of according to the directions provided by the physician.

Laboratory Tests

Before beginning PEGASYS or PEGASYS and COPEGUS combination therapy, standard hematological and biochemical laboratory tests are recommended for all patients. Pregnancy screening for women of childbearing potential must be performed. After initiation of therapy, hematological tests should be performed at 2 weeks and 4 weeks and biochemical tests should be performed at 4 weeks. Additional testing should be performed periodically during therapy. In the clinical studies, the CBC (including hemoglobin level and white blood cell and platelet counts) and chemistries (including liver function tests and uric acid) were measured at 1, 2, 4, 6, and 8, and then every 4 weeks or more frequently if abnormalities were found. Thyroid stimulating hormone (TSH) was measured every 12 weeks. Monthly pregnancy testing should be performed during combination therapy and for 6 months after discontinuing therapy.

The entrance criteria used for the clinical studies of PEGASYS may be considered as a guideline to acceptable baseline values for initiation of treatment:

· Platelet count ³ 90,000 cells/mm³ (as low as 75,000 cells/mm³ in patients with cirrhosis)

· Caution should be exercised in initiating treatment in any patient with baseline risk of severe anemia (eg, spherocytosis, history of GI bleeding).

· Absolute neutrophil count (ANC) ³1500 cells/mm³

· Serum creatinine concentration <1.5 x upper limit of normal

· TSH and T₄ within normal limits or adequately controlled thyroid function

PEGASYS treatment was associated with decreases in WBC, ANC, lymphocytes and platelet counts often starting within the first 2 weeks of treatment. Dose reduction is recommended in patients with hematologic abnormalities. While fever is commonly caused by PEGASYS therapy, other causes of persistent fever must be ruled out, particularly in patients with neutropenia.

Transient elevations in ALT (2-fold to 5-fold above baseline) were observed in some patients receiving PEGASYS, and were not associated with deterioration of other liver function tests. When the increase in ALT levels is progressive despite dose reduction or is accompanied by increased bilirubin, PEGASYS therapy should be discontinued.

 

Pegasys (Hoffman-La Roche Inc) Interactions

Treatment with PEGASYS once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC. Theophylline serum levels should be monitored and appropriate dose adjustments considered for patients given both theophylline and PEGASYS. There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. In patients with chronic hepatitis C treated with PEGASYS in combination with COPEGUS, PEGASYS treatment did not affect ribavirin distribution or clearance.

Nucleoside Analogues

Didanosine

Co-administration of COPEGUS and didanosine is not recommended. Reports of fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in clinical trials.

Stavudine and Zidovudine

Ribavirin can antagonize the in vitro antiviral activity of stavudine and zidovudine against HIV. Therefore, concomitant use of ribavirin with either of these drugs should be avoided.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

PEGASYS has not been tested for its carcinogenic potential.

Mutagenesis

PEGASYS did not cause DNA damage when tested in the Ames bacterial mutagenicity assay and in the in vitro chromosomal aberration assay in human lymphocytes, either in the presence or absence of metabolic activation.

Use With Ribavirin

Ribavirin is genotoxic and mutagenic. The carcinogenic potential of ribavirin has not been fully determined. In a p53 (+/-) mouse carcinogenicity study at doses up to the maximum tolerated dose of 100 mg/kg/day ribavirin was not oncogenic. However, on a body surface area basis, this dose was 0.5 times maximum recommended human 24-hour dose of ribavirin. A study in rats to assess the carcinogenic potential of ribavirin is ongoing.

Mutagenesis

Impairment of Fertility

PEGASYS may impair fertility in women. Prolonged menstrual cycles and/or amenorrhea were observed in female cynomolgus monkeys given sc injections of 600 m g/kg/dose (7200 m g/m²/dose) of PEGASYS every other day for one month, at approximately 180 times the recommended weekly human dose for a 60 kg person (based on body surface area). Menstrual cycle irregularities were accompanied by both a decrease and delay in the peak 17b -estradiol and progesterone levels following administration of PEGASYS to female monkeys. A return to normal menstrual rhythm followed cessation of treatment. Every other day dosing with 100m g/kg (1200m g/m²) PEGASYS (equivalent to approximately 30 times the recommended human dose) had no effects on cycle duration or reproductive hormone status.

The effects of PEGASYS on male fertility have not been studied. However, no adverse effects on fertility were observed in male Rhesus monkeys treated with non-pegylated interferon alfa-2a for 5 months at doses up to 25 x 10⁶ IU/kg/day.

Pregnancy

Pregnancy: Category C

PEGASYS has not been studied for its teratogenic effect. Non-pegylated interferon alfa-2a treatment of pregnant Rhesus monkeys at approximately 20 to 500 times the human weekly dose resulted in a statistically significant increase in abortions. No teratogenic effects were seen in the offspring delivered at term. PEGASYS should be assumed to have abortifacient potential. There are no adequate and well-controlled studies of PEGASYS in pregnant women. PEGASYS is to be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. PEGASYS is recommended for use in women of childbearing potential only when they are using effective contraception during therapy.

Pregnancy: Category X: Use With Ribavirin (see CONTRAINDICATIONS) Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. COPEGUS therapy is contraindicated in women who are pregnant and in the male partners of women who are pregnant .

If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment cessation, such cases should be reported to the COPEGUS Pregnancy Registry at 1-800-526-6367.

Nursing Mothers

It is not known whether peginterferon or ribavirin or its components are excreted in human milk. The effect of orally ingested peginterferon or ribavirin from breast milk on the nursing infant has not been evaluated. Because of the potential for adverse reactions from the drugs in nursing infants, a decision must be made whether to discontinue nursing or discontinue PEGASYS and COPEGUS treatment.

Pediatric Use

The safety and effectiveness of PEGASYS, alone or in combination with COPEGUS in patients below the age of 18 years have not been established.

PEGASYS contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal.

Geriatric Use

Younger patients have higher virologic response rates than older patients. Clinical studies of PEGASYS alone or in combination with COPEGUS did not include sufficient numbers of subjects aged 65 or over to determine whether they respond differently from younger subjects. Adverse reactions related to alpha interferons, such as CNS, cardiac, and systemic (eg, flu-like) effects may be more severe in the elderly and caution should be exercised in the use of PEGASYS in this population. PEGASYS and COPEGUS are excreted by the kidney, and the risk of toxic reactions to this therapy may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. PEGASYS should be used with caution in patients with creatinine clearance <50 mL/min and COPEGUS should not be administered to patients with creatinine clearance <50 mL/min.

 

Pegasys (Hoffman-La Roche Inc) Contraindications

PEGASYS is contraindicated in patients with:

· hypersensitivity to PEGASYS or any of its components

· autoimmune hepatitis

· hepatic decompensation (Child-Pugh class B and C) before or during treatment PEGASYS is contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurologic and other complications in neonates and infants, which are sometimes fatal.

PEGASYS and COPEGUS combination therapy is additionally contraindicated in:

· Patients with known hypersensitivity to COPEGUS or to any component of the tablet.

· Women who are pregnant.

· Men whose female partners are pregnant.

· Patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).

 

Additional information about Pegasys (Hoffman-La Roche Inc)

Pegasys (Hoffman-La Roche Inc) Indication: For treatment of hairy cell leukemia, malignant melanoma, and AIDS-related Kaposi's sarcoma
Mechanism Of Action: Interferon alpha binds to type I interferon receptors (IFNAR1 and IFNAR2c) which, upon dimerization, activate two Jak (Janus kinase) tyrosine kinases (Jak1 and Tyk2). These transphosphorylate themselves and phosphorylate the receptors. The phosphorylated INFAR receptors then bind to Stat1 and Stat2 (signal transducers and activators of transcription) which dimerize and activate multiple (~100) immunomodulatory and antiviral proteins. Interferon alpha binds less stably to type I interferon receptors than interferon beta.
Drug Interactions: Aminophylline Interferon increases the effect and toxicity of theophylline
Dyphylline Interferon increases the effect and toxicity of theophylline
Oxtriphylline Interferon increases the effect and toxicity of theophylline
Theophylline Interferon increases the effect and toxicity of theophylline
Food Interactions: Not Available
Generic Name: Peginterferon alfa-2a
Synonyms: Interferon alpha-2 precursor; Interferon alpha-A; LeIF A
Drug Category: Antineoplastic Agents; Antiviral Agents; Immunomodulatory Agents
Drug Type: Biotech; Approved; Investigational

Other Brand Names containing Peginterferon alfa-2a: Pegasys (Hoffman-La Roche Inc);
Absorption: Not Available
Toxicity (Overdose): Not Available
Protein Binding: Not Available
Biotransformation: Not Available
Half Life: 50-140 hrs
Dosage Forms of Pegasys (Hoffman-La Roche Inc): Solution Subcutaneous
Chemical IUPAC Name: PEGylated human interferon alpha 2a
Chemical Formula: C860H1353N227O255S9
Peginterferon alfa-2a on Wikipedia: https://en.wikipedia.org/wiki/Peginterferon_alfa-2a
Organisms Affected: Not Available