Intermax

Contraindications

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What is the most important information I should know about Intermax?

Intermax (Intermax, recombinant) is contraindicated in patients with:

• Hypersensitivity to Intermax (Intermax, recombinant) or any of its components
• Autoimmune hepatitis
• Hepatic decompensation (Child-Pugh class B and C) before or during treatment

Intermax (Intermax, recombinant) 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.

Undesirable effects

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What are the possible side effects of Intermax?

Depressive illness and suicidal behavior, including suicidal ideation, suicide attempt, 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.

The most frequent adverse experiences were reported to be possibly or probably related to therapy with 3 MIU tiw Intermax (Intermax, recombinant), 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 Intermax (Intermax, recombinant).

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 Intermax (Intermax, recombinant) 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.

Triglyceride levels were not evaluated in the clinical trials. However, hypertriglyceridemia has been reported postmarketing in patients receiving Intermax (Intermax, recombinant) therapy for chronic hepatitis C.

For patients with chronic myelogenous leukemia, the percentage of adverse events, whether related to drug therapy or not, experienced by patients treated with rIFNα-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 Intermax (Intermax, recombinant), 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.

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.

The following infrequent adverse events have been reported with the investigational use of Intermax (Intermax, recombinant).

Gastrointestinal: Pancreatitis, colitis, gastrointestinal hemorrhage, stomatitis ( < 5%); constipation ( < 3%); hepatitis, abdominal fullness, hypermotility, excessive salivation, gastric distress ( < 1%).

Cardiovascular: Palpitations ( < 3%); myocardial infarction, congestive heart failure, ischemic retinopathy, Raynaud's phenomenon, hot flashes ( < 1%).

Pulmonary: Pneumonitis, some cases responded to interferon cessation and corticosteroid therapy ( < 5%); chest congestion ( < 3%); tachypnea ( < 1%).

Central Nervous System and Psychiatric: Stroke, coma, encephalopathy, transient ischemic attacks, dysphasia, hallucinations, gait disturbance, psychomotor retardation, apathy, sedation, irritability, hyperactivity, claustrophobia, loss of libido, ataxia, neuropathy, poor coordination, dysarthria, aphasia, aphonia, amnesia ( < 1%).

Autoimmune Disease: Vasculitis, arthritis, hemolytic anemia and lupus erythematosus syndrome ( < 3%).

Other: Thyroid dysfunction including hypothyroidism and hyperthyroidism, diabetes requiring insulin therapy in some patients ( < 5%); anaphylactic reactions, eye irritation, earache, cyanosis, flushing of skin ( < 1%).

The percentage of patients with chronic hepatitis C, hairy cell leukemia, 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 Intermax (Intermax, recombinant) is shown in Table 2:

Table 2 - Significant Abnormal Laboratory Test Values

Elevated triglyceride levels have been observed in patients receiving interferon therapy, including Intermax (Intermax, recombinant).

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%).

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 rIFNα-2a in clinical studies. Severe cytopenias led to discontinuation of therapy in 4% of all Intermax (Intermax, recombinant) treated patients.

Transient increases in liver transaminases or alkaline phosphatase of any intensity were seen in up to 50% of patients during treatment with Intermax (Intermax, recombinant). 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.

Increases in serum phosphorus ( ≥ 1.6 mmol/L) and serum uric acid ( ≥ 9.1 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.

Central and Peripheral Nervous System: Somnolence, hearing impairment, hearing loss.

Vision: Retinopathy including retinal hemorrhages and cotton-wool spots, papilledema, retinal artery and vein thrombosis and optic neuropathy.

Skin: Injection site necrosis.

Blood: Idiopathic thrombocytopenic purpura, cyanosis.

Renal and Urinary System: Increased blood urea and serum creatinine, decreased renal function and acute renal failure.

Endocrine: Hyperglycemia.

Immune System Disorder: Sarcoidosis.

Respiratory: Pulmonary edema.

Metabolic and Nutritional: Cases of hypertriglyceridemia/hyperlipidemia have been reported including some occurring in association with pancreatitis.

Therapeutic indications

Intermax (Intermax, recombinant) is indicated for the treatment of chronic hepatitis C and hairy cell leukemia in patients 18 years of age or older. In addition, it is indicated for chronic phase, Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML) patients who are minimally pretreated (within 1 year of diagnosis).

Intermax (Intermax, recombinant) is indicated for use in patients with chronic hepatitis C diagnosed by HCV antibody and/or a history of exposure to hepatitis C who have compensated liver disease and are 18 years of age or older. A liver biopsy and a serum test for the presence of antibody to HCV should be performed to establish the diagnosis of chronic hepatitis C. Other causes of hepatitis, including hepatitis B, should be excluded prior to therapy with Intermax (Intermax, recombinant).

Intermax is a protein. Interferons are released in the body in response to viral infections. Interferons are important for fighting viruses in the body, regulating reproduction of cells, and regulating the immune system.

Intermax is used to treat chronic hepatitis C, hairy cell leukemia, AIDS-related Kaposi's sarcoma, and some types of chronic myelogenous leukemia (CML).

Intermax may also be used for purposes other than those listed in this medication guide.

Name of the medicinal product

Qualitative and quantitative composition

Recombinant protein of 165 residues, prepared from E. coli, has K23 as part of the native sequence

Special warnings and precautions for use

Use Intermax solution as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Intermax solution comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Intermax solution refilled.
• Intermax solution is sometimes given as an injection at your doctor's office, hospital, or clinic. If you are using Intermax solution at home, a health care provider will teach you how to use it. Be sure you understand how to use Intermax solution. Follow the procedures you are taught when you use a dose. Contact your health care provider if you have questions.
• Inject Intermax solution deep under the skin, NOT into muscle.
• Do NOT shake Intermax solution.
• Do not use Intermax solution if it contains particles, is cloudy or discolored, or if the vial is cracked or damaged.
• Intermax solution may cause flu-like side effects. Talk to your doctor if these effects become bothersome. Use it at bedtime or take a fever reducer to help decrease these effects.
• Drinking extra fluids while you are using Intermax solution is recommended. Check with your doctor for instructions.
• Keep this product, as well as syringes and needles, out the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.
• If you miss a dose of the medicine, use the missed dose as soon as you remember then go back to your regular dosing schedule. If several days go by after you miss a dose, check with your doctor about what to do. Do not use 2 doses at once. Do not use more than 1 dose per week without talking to your doctor.

Ask your health care provider any questions you may have about how to use Intermax solution.

Dosage (Posology) and method of administration

Intermax (Intermax, recombinant) recommended dosing regimens are different for each of the following indications as described below.

Note:

Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

Intermax (Intermax, recombinant) is administered subcutaneously.

The recommended dosage of Intermax (Intermax, recombinant) for the treatment of chronic hepatitis C is 3 MIU three times a week (tiw) administered subcutaneously for 12 months (48 to 52 weeks). As an alternative, patients may be treated with an induction dose of 6 MIU tiw for the first 3 months (12 weeks) followed by 3 MIU tiw for 9 months (36 weeks). Normalization of serum ALT generally occurs within a few weeks after initiation of treatment in responders. Approximately 90% of patients who respond to Intermax (Intermax, recombinant) do so within the first 3 months of treatment; however, patients responding to Intermax (Intermax, recombinant) with a reduction in ALT should complete 12 months of treatment. Patients who have no response to Intermax (Intermax, recombinant) within the first 3 months of therapy are not likely to respond with continued treatment; treatment discontinuation should be considered in these patients.

Patients who tolerate and partially or completely respond to therapy with Intermax (Intermax, recombinant) but relapse following its discontinuation may be re-treated. Re-treatment with either 3 MIU tiw or with 6 MIU tiw for 6 to 12 months may be considered. Please see ADVERSE REACTIONS regarding the increased frequency of adverse reactions associated with treatment with higher doses.

Temporary dose reduction by 50% is recommended in patients who do not tolerate the prescribed dose. If adverse events resolve, treatment with the original prescribed dose can be re-initiated. In patients who cannot tolerate the reduced dose, cessation of therapy, at least temporarily, is recommended.

For patients with Ph-positive CML in chronic phase: Prior to initiation of therapy, a diagnosis of Philadelphia chromosome positive CML in chronic phase by the appropriate peripheral blood, bone marrow and other diagnostic testing should be made. Monitoring of hematologic parameters should be done regularly (e.g., monthly). Since significant cytogenetic changes are not readily apparent until after hematologic response has occurred, and usually not until several months of therapy have elapsed, cytogenetic monitoring may be performed at less frequent intervals. Achievement of complete cytogenetic response has been observed up to 2 years following the start of Intermax (Intermax, recombinant) treatment.

The recommended initial dose of Intermax (Intermax, recombinant) is 9 MIU daily administered as a subcutaneous injection. Based on clinical experience.

Prior to initiation of therapy, tests should be performed to quantitate peripheral blood hemoglobin, platelets, granulocytes and hairy cells and bone marrow hairy cells. These parameters should be monitored periodically (e.g., monthly) during treatment to determine whether response to treatment has occurred. If a patient does not respond within 6 months, treatment should be discontinued. If a response to treatment does occur, treatment should be continued until no further improvement is observed and these laboratory parameters have been stable for about 3 months. Patients with hairy cell leukemia have been treated for up to 24 consecutive months. The optimal duration of treatment for this disease has not been determined.

The induction dose of Intermax (Intermax, recombinant) is 3 MIU daily for 16 to 24 weeks, administered as a subcutaneous injection. The recommended maintenance dose is 3 MIU, tiw. Dose reduction by one-half or withholding of individual doses may be needed when severe adverse reactions occur. The use of doses higher than 3 MIU is not recommended in hairy cell leukemia.

(for subcutaneous administration)

3 million IU Intermax (Intermax, recombinant) per syringe — Each 0.5 mL contains 3 MIU of Intermax, recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385 mg ammonium acetate. Boxes of 1 (NDC 0004-2015-09); Boxes of 6 (NDC 0004-2015-07).

6 million IU Intermax (Intermax, recombinant) per syringe — Each 0.5 mL contains 6 MIU of Intermax, recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385 mg ammonium acetate. Boxes of 1 (NDC 0004-2016-09); Boxes of 6 (NDC 0004-2016-07).

9 million IU Intermax (Intermax, recombinant) per syringe — Each 0.5 mL contains 9 MIU of Intermax, recombinant, 3.605 mg sodium chloride, 0.1 mg polysorbate 80, 5 mg benzyl alcohol as a preservative and 0.385 mg ammonium acetate. Boxes of 1 (NDC 0004-2017-09); Boxes of 6 (NDC 0004-2017-07).

Storage

The prefilled syringe should be stored in the refrigerator at 36° to 46°F (2° to 8°C). Do not freeze or shake. Protect Intermax (Intermax, recombinant) from light during storage.

REFERENCES

12. Maybee D, et al. Proc Annu Meet Am Soc Clin Oncol. 1992; 11:A950.

Revised: January 2008. Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey. NJ 07110-1199. FDA revision date: 8/29/2006

Interaction with other medicinal products and other forms of interaction

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What other drugs will affect Intermax?

Intermax (Intermax, recombinant) has been reported to reduce the clearance of theophylline. The clinical relevance of this interaction is presently unknown. Caution should be exercised when administering Intermax (Intermax, recombinant) in combination with other potentially myelosuppressive agents. Synergistic toxicity has been observed when Intermax (Intermax, recombinant) is administered in combination with zidovudine (AZT).

In transplant recipients, therapeutic immunosuppression may be weakened because interferons also exert an immunostimulatory action.

Alpha-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 Intermax (Intermax, recombinant) in conjunction with interleukin-2 may potentiate risks of renal failure.