AVSOLA (infliximab-axxq) for injection

AVSOLA (infliximab-axxq) for injection

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AVSOLA (infliximab-axxq) for injection

Infliximab-axxq, the active ingredient in AVSOLA, is a chimeric IgG1κ monoclonal antibody (composed of human constant and murine variable regions) specific for human tumor necrosis factor-alpha (TNFα). It has a molecular weight of approximately 149.1 kilodaltons. Infliximab-axxq is produced in a recombinant Chinese Hamster Ovary (CHO) cell line cultured by continuous perfusion and is purified by a series of steps that includes measures to inactivate and remove viruses.

AVSOLA is supplied as a sterile, white to slightly yellow, lyophilized powder for intravenous infusion. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is approximately 7.2. Each single-dose vial contains 100 mg infliximab-axxq, dibasic sodium phosphate, anhydrous (4.9 mg), monobasic sodium phosphate, monohydrate (2.2 mg), polysorbate 80 (0.5 mg), and sucrose (500 mg).

No preservatives are present.

Indications and usage

AVSOLA is a tumor necrosis factor (TNF) blocker indicated for:

Crohn’s Disease:

  • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
  • reducing the number of draining enterocutaneous and rectovaginal fistulas and maintaining fistula closure in adult patients with fistulizing disease.

Pediatric Crohn’s Disease: reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Ulcerative Colitis: reducing signs and symptoms, inducing and maintaining clinical remission and mucosal healing, and eliminating corticosteroid use in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Pediatric Ulcerative Colitis: reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active disease who have had an inadequate response to conventional therapy.

Rheumatoid Arthritis in combination with methotrexate: reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active disease.

Ankylosing Spondylitis: reducing signs and symptoms in patients with active disease.

Psoriatic Arthritis: reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function.

Plaque Psoriasis: treatment of adult patients with chronic severe (i.e., extensive and/or disabling) plaque psoriasis who are candidates for systemic therapy and when other systemic therapies are medically less appropriate.

Mechanism of Action

Infliximab products neutralize the biological activity of TNFα by binding with high affinity to the soluble and transmembrane forms of TNFα and inhibit binding of TNFα with its receptors. Infliximab products do not neutralize TNFβ (lymphotoxin-α), a related cytokine that utilizes the same receptors as TNFα.

Biological activities attributed to TNFα include: induction of pro-inflammatory cytokines such as interleukins (IL) 1 and 6, enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes, activation of neutrophil and eosinophil functional activity, induction of acute phase reactants and other liver proteins, as well as tissue degrading enzymes produced by synoviocytes and/or chondrocytes. Cells expressing transmembrane TNFα bound by infliximab products can be lysed in vitro or in vivo. Infliximab products inhibit the functional activity of TNFα in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils, B and T-lymphocytes and epithelial cells.

The relationship of these biological response markers to the mechanism(s) by which infliximab products exert their clinical effects is unknown. Anti-TNFα antibodies reduce disease activity in the cotton-top tamarin colitis model, and decrease synovitis and joint erosions in a murine model of collagen-induced arthritis. Infliximab products prevent disease in transgenic mice that develop polyarthritis as a result of constitutive expression of human TNFα, and when administered after disease onset, allow eroded joints to heal.

Dosage and administration

AVSOLA is administered by intravenous infusion over a period of not less than 2 hours.

Crohn’s Disease: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some adult patients who initially respond to treatment may benefit from increasing the dose to 10 mg/kg if they later lose their response.

Pediatric Crohn’s Disease: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Ulcerative Colitis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Pediatric Ulcerative Colitis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Rheumatoid Arthritis: In conjunction with methotrexate, 3 mg/kg at 0, 2 and 6 weeks, then every 8 weeks. Some patients may benefit from increasing the dose up to 10 mg/kg or treating as often as every 4 weeks.

Ankylosing Spondylitis: 5 mg/kg at 0, 2 and 6 weeks, then every 6 weeks.

Psoriatic Arthritis and Plaque Psoriasis: 5 mg/kg at 0, 2 and 6 weeks, then every 8 weeks.

Contraindications

  • AVSOLA at doses >5 mg/kg should not be administered to patients with moderate to severe heart failure. In a randomized study evaluating infliximab in patients with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV), infliximab treatment at 10 mg/kg was associated with an increased incidence of death and hospitalization due to worsening heart failure
  • AVSOLA should not be re-administered to patients who have experienced a severe hypersensitivity reaction to infliximab products. Additionally, AVSOLA should not be administered to patients with known hypersensitivity to inactive components of the product or to any murine proteins.

Adverse reactions

Most common adverse reactions (>10%) – infections (e.g., upper respiratory, sinusitis, and pharyngitis), infusion-related reactions, headache, and abdominal pain.

Warnings and precautions

Serious Infections: Patients treated with infliximab products are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death.

Treatment with AVSOLA should not be initiated in patients with an active infection, including clinically important localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection.

Tuberculosis: Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving infliximab products, including patients who have previously received treatment for latent or active tuberculosis. Cases of active tuberculosis have also occurred in patients being treated with infliximab products during treatment for latent tuberculosis.

Invasive Fungal Infections: For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy.

Malignancies: Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤18 years of age), including infliximab products. Approximately half of these cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of malignancies, including rare malignancies that are usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months (range 1 to 84 months) after the first dose of TNF-blocker therapy. Most of the patients were receiving concomitant immunosuppressants. These cases were reported postmarketing and are derived from a variety of sources, including registries and spontaneous postmarketing reports.

Hepatitis B Virus Reactivation: Use of TNF-blockers, including infliximab products, has been associated with reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients should be tested for HBV infection before initiating TNF-blocker therapy, including AVSOLA.

Hepatotoxicity: Severe hepatic reactions, including acute liver failure, jaundice, hepatitis and cholestasis, have been reported in postmarketing data in patients receiving infliximab products. Autoimmune hepatitis has been diagnosed in some of these cases. Severe hepatic reactions occurred between 2 weeks to more than 1 year after initiation of infliximab; elevations in hepatic aminotransferase levels were not noted prior to discovery of the liver injury in many of these cases. Some of these cases were fatal or necessitated liver transplantation. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. If jaundice and/or marked liver enzyme elevations (e.g., ≥5 times the upper limit of normal) develop, AVSOLA should be discontinued, and a thorough investigation of the abnormality should be undertaken. In clinical trials, mild or moderate elevations of ALT and AST have been observed in patients receiving infliximab products without progression to severe hepatic injury.

Patients with Heart Failure: Infliximab products have been associated with adverse outcomes in patients with heart failure, and should be used in patients with heart failure only after consideration of other treatment options. The results of a randomized study evaluating the use of infliximab in patients with heart failure (NYHA Functional Class III/IV) suggested higher mortality in patients who received 10 mg/kg infliximab, and higher rates of cardiovascular adverse events at doses of 5 mg/kg and 10 mg/kg. There have been postmarketing reports of worsening heart failure, with and without identifiable precipitating factors, in patients taking infliximab. There have also been postmarketing reports of new onset heart failure, including heart failure in patients without known pre-existing cardiovascular disease. Some of these patients have been under 50 years of age. If a decision is made to administer AVSOLA to patients with heart failure, they should be closely monitored during therapy, and AVSOLA should be discontinued if new or worsening symptoms of heart failure appear

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Hematologic Reactions: Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia, some with a fatal outcome, have been reported in patients receiving infliximab products. The causal relationship to infliximab product therapy remains unclear. Although no high-risk group(s) has been identified, caution should be exercised in patients being treated with AVSOLA who have ongoing or a history of significant hematologic abnormalities. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever) while on AVSOLA. Discontinuation of AVSOLA therapy should be considered in patients who develop significant hematologic abnormalities.

Hypersensitivity: Infliximab products have been associated with hypersensitivity reactions that vary in their time of onset and required hospitalization in some cases. Most hypersensitivity reactions, which include anaphylaxis, urticaria, dyspnea, and/or hypotension, have occurred during or within 2 hours of infusion.

AVSOLA should be discontinued for severe hypersensitivity reactions. Medications for the treatment of hypersensitivity reactions (e.g., acetaminophen, antihistamines, corticosteroids and/or epinephrine) should be available for immediate use in the event of a reaction

Cardiovascular and Cerebrovascular Reactions: During and After Infusion Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal), hypotension, hypertension, and arrhythmias have been reported during and within 24 hours of initiation of infliximab product infusion. Cases of transient visual loss have been reported during or within 2 hours of infusion of infliximab products. Monitor patients during infusion and if serious reaction occurs, discontinue infusion. Further management of reactions should be dictated by signs and symptoms

Neurologic Reactions: Agents that inhibit TNF have been associated with CNS manifestation of systemic vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and optic neuritis, and peripheral demyelinating disorders, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of AVSOLA in patients with these neurologic disorders and should consider discontinuation of AVSOLA if these disorders develop.

Use with Anakinra: Serious infections and neutropenia were seen in clinical studies with concurrent use of anakinra and another TNFα-blocking agent, etanercept, with no added clinical benefit compared to etanercept alone. Because of the nature of the adverse reactions seen with the combination of etanercept and anakinra therapy, similar toxicities may also result from the combination of anakinra and other TNFα-blocking agents. Therefore, the combination of AVSOLA and anakinra is not recommended.

Use with Abatacept: In clinical studies, concurrent administration of TNF-blocking agents and abatacept have been associated with an increased risk of infections including serious infections compared with TNF-blocking agents alone, without increased clinical benefit. Therefore, the combination of AVSOLA and abatacept is not recommended

Concurrent Administration with Other Biological Therapeutics: There is insufficient information regarding the concomitant use of infliximab products with other biological therapeutics used to treat the same conditions as AVSOLA. The concomitant use of AVSOLA with these biologics is not recommended because of the possibility of an increased risk of infection

Switching Between Biological Disease-Modifying Antirheumatic Drugs (DMARDs): Care should be taken when switching from one biologic to another, since overlapping biological activity may further increase the risk of infection.

Autoimmunity: Treatment with infliximab products may result in the formation of autoantibodies and in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with AVSOLA, treatment should be discontinued

Live Vaccines/Therapeutic Infectious: Agents In patients receiving anti-TNF therapy, limited data are available on the response to vaccination with live vaccines or on the secondary transmission of infection by live vaccines. Use of live vaccines can result in clinical infections, including disseminated infections. The concurrent administration of live vaccines with AVSOLA is not recommended.

It is recommended that all pediatric patients be brought up to date with all vaccinations prior to initiating AVSOLA therapy. The interval between vaccination and initiation of AVSOLA therapy should be in accordance with current vaccination guidelines.

Drug interactions

Use with Anakinra or Abatacept: An increased risk of serious infections was seen in clinical studies of other TNFα-blocking agents used in combination with anakinra or abatacept, with no added clinical benefit. Because of the nature of the adverse reactions seen with these combinations with TNF-blocker therapy, similar toxicities may also result from the combination of anakinra or abatacept with other TNFα-blocking agents. Therefore, the combination of AVSOLA and anakinra or abatacept is not recommended

Use with Tocilizumab: The use of tocilizumab in combination with biological DMARDs such as TNF antagonists, including AVSOLA, should be avoided because of the possibility of increased immunosuppression and increased risk of infection.

Use with Other Biological Therapeutics: The combination of AVSOLA with other biological therapeutics used to treat the same conditions as AVSOLA is not recommended

Methotrexate (MTX) and Other Concomitant Medications: Specific drug interaction studies, including interactions with MTX, have not been conducted. The majority of patients in rheumatoid arthritis or Crohn’s disease clinical studies received one or more concomitant medications. In rheumatoid arthritis, concomitant medications besides MTX were non-steroidal anti-inflammatory agents (NSAIDs), folic acid, corticosteroids and/or narcotics. Concomitant Crohn’s disease medications were antibiotics, antivirals, corticosteroids, 6-MP/AZA and aminosalicylates. In psoriatic arthritis clinical trials, concomitant medications included MTX in approximately half of the patients as well as NSAIDs, folic acid and corticosteroids. Concomitant MTX use may decrease the incidence of anti-drug antibody production and increase infliximab product concentrations.

Immunosuppressants: Patients with Crohn’s disease who received immunosuppressants tended to experience fewer infusion reactions compared to patients on no immunosuppressants. Serum infliximab concentrations appeared to be unaffected by baseline use of medications for the treatment of Crohn’s disease including corticosteroids, antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.

Cytochrome P450 Substrates: The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-1, IL-6, IL-10, IFN) during chronic inflammation. Therefore, it is expected that for a molecule that antagonizes cytokine activity, such as infliximab products, the formation of CYP450 enzymes could be normalized. Upon initiation or discontinuation of AVSOLA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.

Live Vaccines/Therapeutic Infectious: Agents It is recommended that live vaccines not be given concurrently with AVSOLA. It is also recommended that live vaccines not be given to infants after in utero exposure to infliximab products for at least 6 months following birth

Use in specific populations

Pregnancy: Available data from published literature on the use of infliximab products during pregnancy have not reported a clear association with infliximab products and adverse pregnancy outcomes. Infliximab products cross the placenta and infants exposed in utero should not be administered live vaccines for at least 6 months after birth. In a development study conducted in mice using an analogous antibody, no evidence of maternal toxicity, embryotoxicity or teratogenicity was observed.

Fetal/neonatal adverse reactions: Infliximab products cross the placenta, and have been detected in the serum of infants up to 6 months following birth. Consequently, these infants may be at increased risk of infection, including disseminated infection which can become fatal. At least a six-month waiting period following birth is recommended before the administration of live vaccines (e.g. BCG vaccine or other live vaccines, such as the rotavirus vaccine) to these infants. Cases of agranulocytosis in infants exposed in utero have also been reported.

Lactation: Available information is insufficient to inform the amount of infliximab products present in human milk, and the effects on the breastfed infant. There are no data on the effects of infliximab products on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for an infliximab product and any potential adverse effects on the breastfed infant from infliximab products or from the underlying maternal condition.

Pediatric Use: The safety and effectiveness of infliximab products have been established in pediatric patients 6 to 17 years of age for induction and maintenance treatment of Crohn’s disease or ulcerative colitis. However, infliximab products have not been studied in children with Crohn’s disease or ulcerative colitis <6 years of age.

Geriatric Use: In rheumatoid arthritis and plaque psoriasis clinical trials, no overall differences were observed in effectiveness or safety in 181 patients with rheumatoid arthritis and 75 patients with plaque psoriasis, aged 65 or older who received infliximab, compared to younger patients-although the incidence of serious adverse reactions in patients aged 65 or older was higher in both infliximab and control groups compared to younger patients. In Crohn’s disease, ulcerative colitis, ankylosing spondylitis and psoriatic arthritis studies, there were insufficient numbers of patients aged 65 and over to determine whether they respond differently from patients aged 18 to 65. There is a greater incidence of infections in the elderly population in general. The incidence of serious infections in infliximab-treated patients 65 years and older was greater than in those under 65 years of age; therefore caution should be used in treating the elderly

Overdosage

Single doses up to 20 mg/kg of infliximab have been administered without any direct toxic effect. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

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