- ACRONYMS AND DEFINITIONS
- AASLD - American Association for the Study of Liver Diseases
- GCSF - Granulocyte colony-stimulating factor
- HCV - Hepatitis C virus
- PegIFN - Pegylated interferon
- PI - Protease inhibitors
- RBV - Ribavirin
- DRUGS IN CLASS
- Pegylated interferon
- Peginterferon alfa-2b (PegIntron®)
- Peginterferon alfa-2a (Pegasys®)
- MECHANISM OF ACTION
- Interferon
- Interferons are natural chemicals produced by a person's immune system in response to infections by viruses and bacteria
- Interferons block viral replication inside cells, and they stimulate the immune system to attack viruses
- Interferons also stimulate the immune system to attack cancer cells, and some are used to treat cancer
- Pegylated interferon (PegIFN)
- Pegylated interferon is a synthetic version of human interferon that has been slightly modified
- "Pegylated" means that a polyethylene glycol molecule has been attached to the interferon molecule
- This gives the interferon a longer half-life (amount of time it stays active before it is eliminated)
- When synthetic interferons were first introduced, they were not pegylated and had to be dosed three times a week
- Pegylated interferons are dosed once a week
- They have also been shown to be more effective than standard interferon in clinical trials
- HEPATITIS C VIRUS
- Hepatitis C
- With the advent of next generation, highly-effective, hepatitis C drugs, PegIFN-based regimens are no longer recommended
- See hepatitis C treatment for current treatment regimens
- See the AASLD website for treatment recommendations
- PEGASYS® VS PEGINTRON®
- A large study (N=3070) published in 2009 randomized patients with treatment-naïve HCV genotype 1 to ribavirin + PegIntron or Pegasys. Cure rates between the groups were not significantly different (∼40%). [PMID 19625712]
- SIDE EFFECTS
- Neutropenia
- PegIFN typically causes a decrease in white blood cells. The decrease in white blood cells may be worsened by ribavirin and possibly protease inhibitors.
- White blood cell effects are typically monitored by following the neutrophil count. A neutrophil count < 1500 cells/mm³ is considered low. Some patients may require granulocyte colony-stimulating factor (GCSF) while on therapy to increase their neutrophil production.
- See monitoring therapy for recommendations on monitoring and managing hematological side effects of pegylated interferon therapy
- Neutrophil effects from the SPRINT-2 trial are presented in the table below. Numbers represent the percent of patients in each treatment group who experienced at least one neutrophil count in the given range.
| Neutrophil count(cells/mm³) | PegIFN + RBV | PegIFN + RBV + PI |
|---|---|---|
| > 1500 | 23% | 15% |
| 1000 - 1500 | 35% | 27% |
| 750 - 999 | 23% | 27% |
| 500 - 749 | 14% | 24% |
| < 500 | 4% | 7% |
| GCSF use (% of patients) |
6% | 10% |
- Thrombocytopenia (low platelets)
- PegIFN typically causes a decrease in the platelet count. The decrease in platelets may be worsened by protease inhibitors.
- See monitoring therapy for recommendations on monitoring and managing hematological side effects of pegylated interferon therapy
- Platelet effects in the SPRINT-2 trial are presented in the table below. Numbers represent the percent of patients in each treatment group who experienced at least one platelet count in the given range.
| Platelet count (#/mm³) | PegIFN + RBV | PegIFN + RBV + PI |
|---|---|---|
| > 100,000 | 87% | 69% |
| 70,000 - 100,000 | 11% | 18% |
| 50,000 - 69,999 | 1% | 8% |
| 25,000 - 49,999 | 1% | 3% |
| < 25,000 | 0% | < 1% |
- Pancytopenia (decrease in all blood cells)
- Pancytopenia has been reported in a small number of patients when PegIFN was coadministered with ribavirin and boceprevir
- Pancytopenia has also occurred when PegIFN was coadministered with ribavirin and azathioprine (Imuran®)
- Flu-like symptoms
- During a viral infection, interferon release causes the flu-like symptoms (fever, aching, fatigue, nausea) that a person experiences. PegIFN will cause these same type of symptoms when used to treat HCV.
- The majority of patients who receive PegIFN (> 60%) experience some sort of flu-like side effect
- Around 10 - 20% of patients will discontinue treatment because of these side effects [1]
- Depression and psychiatric symptoms
- Depression and psychiatric symptoms (insomnia, irritability, anxiety) are common in patients receiving PegIFN
- Symptoms may occur in anywhere from 21 - 58% of patients [4]
- Hair loss
- Hair loss or thinning is common during treatment (20 - 40% of patients)
- It typically resolves when therapy is over
- Injection site reactions
- PegIFN Injection site reactions including redness, swelling, and itching are common and may occur in up to 75% of patients [1]
- Rashes and hyperpigmentation
- Rashes are common during PegIFN and ribavirin therapy (up to 25% of patients)
- PegIFN has also been known to cause hyperpigmentation of the face, oral mucosa, and nail bed in some patients [12]
- Liver function worsening
- Liver function tests may worsen and hepatic decompensation may occur when patients are treated with combinations of PegIFN, ribavirin, and protease inhibitors
- Thyroid dysfunction
- PegIFN may cause or aggravate hypothyroidism and hyperthyroidism
- Patients with pre-existing thyroid disease should have their condition controlled before therapy is started [1]
- See monitoring therapy for recommendations on monitoring thyroid function during pegylated interferon therapy
- Visual changes
- Rarely, visual changes including retinopathy, macular edema, retinal hemorrhages, and optic neuritis have occurred in patients receiving PegIFN
- Patients with visual changes during therapy should have an eye exam as soon as possible [1]
- CONTRAINDICATIONS
- Known hypersensitivity
- Autoimmune hepatitis
- Child-Pugh B or C before or during treatment
- PRECAUTIONS
- Kidney disease
- Peginterferon alfa-2b (PegIntron®)
- CrCl 30 - 50 ml/min: reduce dose by 25%
- CrCl 10 - 29 ml/min: reduce dose by 50%
- Peginterferon alfa-2a (Pegasys®)
- CrCl 30 - 50 ml/min: no adjustment necessary
- CrCl < 30 ml/min: dose is 135 mcg a week
- Liver disease
- Child-Pugh A: no dose adjustment necessary
- Child-Pugh B or C before or during treatment: DO NOT USE
- Autoimmune diseases (rheumatoid arthritis, lupus, autoimmune hepatitis, psoriasis, ITP, TTP, etc.)
- PegIFN has been shown to exacerbate autoimmune disorders in some patients
- PegIFN should be used with caution in patients with autoimmune disorders [1,11]
- PegIFN should not be given to patients with autoimmune hepatitis [1,11]
- Colitis
- Cases of colitis or worsening of pre-existing colitis (ex. ulcerative colitis) have been observed in patients treated with PegIFN [1,11]
- Depression and psychiatric disorders
- PegIFN may cause worsening depression and anxiety in a significant number of patients (up to 60%)
- Patients with unstable depression or other psychiatric illness should not use PegIFN until their condition is well-controlled
- All patients should be aware of the risk when being treated [1,11]
- Eye disease
- PegIFN may cause eye disease including retinopathy, optic neuritis, retinal hemorrhages, etc.
- Patients with pre-existing eye diseases should monitor their vision closely and receive an eye exam if vision changes [1,11]
- Hematological disorders (ex. thalassemia major, sickle cell disease, cirrhosis, HIV disease)
- PegIFN typically causes a decrease in white blood cells (neutropenia) and platelets (thrombocytopenia)
- Many patients with cirrhosis have hematological abnormalities
- Caution should be exercised when choosing to treat patients with pre-existing blood disorders
- Patients with pre-existing blood disorders should be monitored closely while undergoing treatment [1,11]
- Thyroid disease
- PegIFN may cause or aggravate hypothyroidism and hyperthyroidism
- Patients with pre-existing thyroid disease should have their condition controlled before therapy is started [1,11]
- MONITORING THERAPY
- Lab monitoring
- Check CBC, CMP, and uric acid at baseline, 2 weeks, 4 weeks, 8 weeks, and 12 weeks. From then on, check at 6-week intervals, or more frequently if abnormalities develop.
- Check TSH levels at baseline and every 12 weeks during the treatment period
| Adjusting therapy for neutropenia |
|---|
|
For Neutrophil count 500 - 750 cells/mm³
|
For Neutrophil count < 500 cells/mm³
|
| Adjusting therapy for thrombocytopenia |
|---|
|
For platelet count 25,000 - 50,000/mm³
|
For platelet count < 25,000/mm³
|
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Pegasys and PegIntron
- CYP1A2 substrates - PegIFN alfa-2b and alfa-2a are CYP1A2 inhibitors. Use caution and monitor for toxicity when administering with sensitive CYP1A2 substrates.
- Methadone - PegIFN may increase methadone blood levels. Patients on methadone should be monitored for toxicity when taking PegIFN.
- PegIntron (PegIFN alfa-2b)
- CYP2D6 substrates (PegIFN alfa-2b) - PegIFN alfa-2b is a CYP2D6 inhibitor. Use caution and monitor for toxicity when administering with sensitive CYP2D6 substrates
- LONG-TERM SAFETY
- PegIFN was approved by the FDA in 2001
- Standard interferon has been used since the 1980s
- PegIFN is only used for a short period during which it can have many side effects
- No long-term adverse effects have been identified
- DOSING
- See the PegIntron® PI and Pegasys® PI for dosing information
- BIBLIOGRAPHY
- 1 - PegIntron PI
- 2 - PMID 12324553
- 3 - PMID 19625712
- 4 - PMID 19330875
- 5 - PMID 21898493
- 6 - PMID 21316497
- 7 - PMID 21449783
- 8 - Telaprevir PI
- 9 - Boceprevir PI
- 10 - Ribavirin PI
- 11 - Pegasys PI
- 12 - PMID 23553009