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Roferon-A Side Effects, and Drug Interactions - Interferon alfa-2a, Recombinant

Roferon-A Side Effects, and Drug Interactions - Interferon alfa-2a, Recombinant

SIDE EFFECTS

Depressive illness and suicidal behavior, including suicidal ideation and suicides, have been reported in association with the use of alfa-interferon products. The incidence of reported depression has varied substantially among trials, possibly related to the underlying disease, dose, duration of therapy and degree of monitoring, but has been reported to be 15% or higher (see WARNINGS).

For Patients With Chronic Hepatitis C

The most frequent adverse experiences were reported to be possibly or probably related to therapy with 3 MIU tiw Roferon-A, were mostly mild to moderate in severity and manageable without the need for discontinuation of therapy. A relative increase in the incidence, severity and seriousness of adverse events was observed in patients receiving doses above 3 MIU tiw.

Adverse reactions associated with the 3 MIU dose include:

Flu-like Symptoms: Fatigue (58%), myalgia/arthralgia (51%), flu-like symptoms (33%), fever (28%), chills (23%), asthenia (6%), sweating (5%), leg cramps (3%) and malaise (1%).
Central and Peripheral Nervous System: Headache (52%), dizziness (13%), paresthesia (7%), confusion (7%), concentration impaired (4%) and change in taste or smell (3%).
Gastrointestinal: Nausea/vomiting (33%), diarrhea (20%), anorexia (14%), abdominal pain (12%), flatulence (3%), liver pain (3%), digestion impaired (2%) and gingival bleeding (2%).
Psychiatric: Depression (16%), irritability (15%), insomnia (14%), anxiety (5%) and behavior disturbances (3%).
Pulmonary and Cardiovascular: Dryness or inflammation of oropharynx (6%), epistaxis (4%), rhinitis (3%), arrhythmia (1%) and sinusitis (<1%).
Skin: Injection site reaction (29%), partial alopecia (19%), rash (8%), dry skin or pruritus (7%), hematoma (1%), psoriasis (<1%), cutaneous eruptions (<1%), eczema (<1%) and seborrhea (<1%).
Other: Conjunctivitis (4%), menstrual irregularity (2%) and visual acuity decreased (<1%).

Patients receiving 6 MIU tiw experienced a higher incidence of severe psychiatric events (9%) than those receiving 3 MIU tiw (6%) in two large US studies. In addition, more patients withdrew from these studies when receiving 6 MIU tiw (11%) than when receiving 3 MIU tiw (7%). Up to half of patients receiving 3 MIU or 6 MIU tiw withdrawing from the study experienced depression or other psychiatric adverse events. At higher doses anxiety, sleep disorders, and irritability were observed more frequently. An increased incidence of fatigue, myalgia/arthralgia, headache, fever, chills, alopecia, sleep disturbances and dry skin or pruritus was also generally observed during treatment with higher doses of Roferon-A.

Generally there were fewer adverse events reported in the second 6 months of treatment than in the first 6 months for patients treated with 3 MIU tiw. Patients tolerant of initial therapy with Roferon-A generally tolerate re-treatment at the same dose, but tend to experience more adverse reactions at higher doses.

Infrequent adverse events (>1% but <3% incidence) included: cold feeling, cough, muscle cramps, diaphoresis, dyspnea, eye pain, reactivation of herpes simplex, lethargy, edema, sexual dysfunction, shaking, skin lesions, stomatitis, tooth disorder, urinary tract infection, weakness in extremities.

For Patients With Chronic Myelogenous Leukemia

For patients with chronic myelogenous leukemia, the percentage of adverse events, whether related to drug therapy or not, experienced by patients treated with rIFNalpha -2a is given below. Severe adverse events were observed in 66% and 31% of patients on study DM84-38 and MI400, respectively. Dose reduction and temporary cessation of therapy were required frequently. Permanent cessation of Roferon-A, due to intolerable side effects, was required in 15% and 23% of patients on studies DM84-38 and MI400, respectively.

Flu-like Symptoms: Fever (92%), asthenia or fatigue (88%), myalgia (68%), chills (63%), arthralgia/bone pain (47%) and headache (44%).
Gastrointestinal: Anorexia (48%), nausea/vomiting (37 %) and diarrhea (37%).
Central and Peripheral Nervous System: Headache (44%), depression (28%), decreased mental status (16%), dizziness (11%), sleep disturbances (11%), paresthesia (8%), involuntary movements (7%) and visual disturbance (6%).
Pulmonary and Cardiovascular: Coughing (19%), dyspnea (8%) and dysrhythmia (7%).
Skin: Hair changes (including alopecia) (18%), skin rash (18%), sweating (15%), dry skin (7%) and pruritus (7%).

Uncommon adverse events (< 4%) reported in clinical studies included chest pain, syncope, hypotension, impotence, alterations in taste or hearing, confusion, seizures, memory loss, disturbances of libido, bruising and coagulopathy. Miscellaneous adverse events that were rarely observed included Coombs' positive hemolytic anemia, aplastic anemia, hypothyroidism, cardiomyopathy, hypertriglyceridemia and bronchospasm.

For Patients With Hairy Cell Leukemia

Constitutional (100%): Fever (92%), fatigue (86%), headache (64%), chills (64%), weight loss (33%), dizziness (21%) and flu-like symptoms (16%).
Integumentary (79%): Skin rash (44%), diaphoresis (22%), partial alopecia (17%), dry skin (17%) and pruritus (13%).
Musculoskeletal (73%): Myalgia (71%), joint or bone pain (25%) and arthritis or polyarthritis (5%).
Gastrointestinal (69%): Anorexia (43%), nausea/vomiting (39%) and diarrhea (34%).
Head and Neck (45%): Throat irritation (21%), rhinorrhea (12%) and sinusitis (11%).
Pulmonary (40%): Coughing (16%), dyspnea (12%) and pneumonia (11%).
Central Nervous System (39%): Dizziness (21%), depression (16%), sleep disturbance (10%), decreased mental status (10%), anxiety (6%), lethargy (6%), visual disturbance (6%) and confusion (5%).
Cardiovascular (39%): Chest pain (11%), edema (11%) and hypertension (11%).
Pain (34%): Pain (24%) and pain in back (16%).
Peripheral Nervous System (23%): Paresthesia (12%) and numbness (12%).

Rarely (<5%), central nervous system effects including gait disturbance, nervousness, syncope and vertigo, as well as cardiac adverse events including murmur, thrombophlebitis and hypotension were reported. Adverse experiences that occurred rarely, and may have been related to underlying disease, included ecchymosis, epistaxis, bleeding gums and petechiae. Urticaria and inflammation at the site of injection were also rarely observed.

For Patients With AIDS-Related Kaposi's Sarcoma

Flu-like Symptoms: Fatigue (95%), fever (74%), myalgia (69%), headache (66%), chills (41%) and arthralgia (24%).
Gastrointestinal: Anorexia (65%), nausea (51%), diarrhea (42%), emesis (17%) and abdominal pain (15%).
Central and Peripheral Nervous System: Dizziness (40%), decreased mental status (17%), depression (16%), paresthesia (8%), confusion (8%), diaphoresis (7%), visual disturbances (5%), sleep disturbances (5%) and numbness (3%).
Pulmonary and Cardiovascular: Coughing (27%), dyspnea (11%), edema (9%), chest pain (4%) and hypotension (4%).
Skin: Partial alopecia (22%), rash (11%) and dry skin or pruritus (5%).
Other: Weight loss (25%), change in taste (25%), dryness or inflammation of the oropharynx (14%), night sweats (8%) and rhinorrhea (4%).

Occasionally (<3%) nervous system effects including anxiety, nervousness, emotional lability, vertigo and forgetfulness, as well as cardiac adverse events, including palpitations and arrhythmia, were reported. Other adverse experiences that occurred occasionally (<3%) and may have been related to underlying disease, included sinusitis, constipation, chest congestion, pneumonia, urticaria and flatulence. Adverse experiences which occurred rarely (<1%) included ataxia, seizures, cyanosis, gastric distress, bronchospasm, pain at injection site, earache, eye irritation and rhinitis. Miscellaneous adverse experiences such as poor coordination, lethargy, muscle contractions, neuropathy, tremor, involuntary movement, syncope, aphasia, aphonia, dysarthria, amnesia, weakness and flushing of skin were observed in less than 0.5% of patients. Cases of cardiomyopathy have been observed on rare occasions in patients treated with alfa interferons.

In Other Investigational Studies of Roferon-A

The following infrequent adverse events have been reported in one or more of the approved clinical indications as well as with the investigational use of Roferon-A (<5%): pancreatitis, colitis, gastrointestinal hemorrhage, stomatitis, thyroid dysfunction (including hypothyroidism and hyperthyroidism), diabetes (in some patients requiring insulin therapy), and pneumonitis (some cases responding to interferon cessation and corticosteroid therapy). In addition to the adverse experiences noted above, other adverse experiences that occurred included: abdominal fullness, hypermotility, hepatitis, gait disturbance, hallucinations, encephalopathy, psychomotor retardation, coma, stroke, transient ischemic attacks, dysphasia, sedation, apathy, irritability, hyperactivity, claustrophobia, loss of libido, congestive heart failure, myocardial infarction, Raynaud's phenomenon, hot flashes, tachypnea, ischemic retinopathy, excessive salivation and anaphylactic reactions. These adverse experiences occurred rarely (<1%).

The following events have been rarely observed (<3%) in some patients receiving Roferon-A: autoimmune diseases, ie, vasculitis, arthritis, hemolytic anemia and lupus erythematosus syndrome. The mechanism by which these events develop and their relationship to Roferon-A therapy are unclear. Similar events have been reported for other types of interferon.

Abnormal Laboratory Test Values: The percentage of patients with chronic hepatitis C, hairy cell leukemia, with AIDS-related Kaposi's sarcoma, and with chronic myelogenous leukemia who experienced a significant abnormal laboratory test value (NCI or WHO grades III or IV) at least once during their treatment with Roferon-A is shown in the following table:

Chronic Hepatitis C: The incidence of neutropenia (WHO grades III or IV) was over twice as high in those treated with 6 MIU tiw (21%) as those treated with 3 MIU tiw (10%).

Chronic Myelogenous Leukemia: In the two clinical studies, a severe or life-threatening anemia was seen in up to 15% of patients. A severe or life-threatening leukopenia and thrombocytopenia were observed in up to 20% and 27% of patients, respectively. Changes were usually reversible when therapy was discontinued. One case of aplastic anemia and one case of Coombs' positive hemolytic anemia were seen in 310 patients treated with rIFNalpha -2a in clinical studies. Severe cytopenias led to discontinuation of therapy in 4% of all Roferon-A treated patients.

Transient increases in liver transaminases or alkaline phosphatase of any intensity were seen in up to 50% of patients during treatment with Roferon-A. Only 5% of patients had a severe or life-threatening increase in SGOT. In the clinical studies, such abnormalities required termination of therapy in less than 1% of patients.

Hairy Cell Leukemia: Increases in serum phosphorus (³1.6 mmol/L) and serum uric acid (³9.1 mg/dL) were observed in 9% and 10% of patients, respectively. The increase in serum uric acid is likely to be related to the underlying disease. Decreases in serum calcium (£1.9 mmol/L) and serum phosphorus (£0.9 mmol/L) were seen in 28% and 22% of patients, respectively.

DRUG INTERACTIONS

Roferon-A has been reported to reduce the clearance of theophylline.^11,12 The clinical relevance of this interaction is presently unknown. Interactions between Roferon-A and other drugs have not been fully evaluated. Caution should be exercised when administering Roferon-A in combination with other potentially myelosuppressive agents (see WARNINGS).

Alfa interferons may affect the oxidative metabolic process by reducing the activity of hepatic microsomal cytochrome enzymes in the P450 group. Although the clinical relevance is still unclear, this should be taken into account when prescribing concomitant therapy with drugs metabolized by this route.

The neurotoxic, hematotoxic or cardiotoxic effects of previously or concurrently administered drugs may be increased by interferons. Interactions could occur following concurrent administration of centrally acting drugs. Use of Roferon-A in conjunction with interleukin-2 may potentiate risks of renal failure.

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