WARNINGS AND PRECAUTIONS
Serious Infections
ILARIS may be associated with an increased risk of serious infections. Physicians should exercise caution when administering ILARIS to patients with infections, a history of recurring infections or underlying conditions which may predispose them to infections. ILARIS should not be administered to patients during an active infection requiring medical intervention. Administration of ILARIS should be discontinued if a patient develops a serious infection.
Infections, predominantly of the upper respiratory tract, in some instances serious, have been reported with ILARIS. Generally, the observed infections responded to standard therapy. Isolated cases of unusual or opportunistic infections were reported during ILARIS treatment. In clinical trials, ILARIS has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of another IL-1 blocker in combination with TNF inhibitors. Co-administration of ILARIS with TNF inhibitors is not recommended because this may increase the risk of serious infections [ see Drug Interactions (7.1) ].
Drugs that affect the immune system by blocking TNF have been associated with an increased risk of new tuberculosis and reactivation of latent tuberculosis (TB). It is possible that use of IL-1 inhibitors such as ILARIS increases the risk of reactivation of tuberculosis or of opportunistic infections.
Prior to initiating immunomodulatory therapies, including ILARIS, patients should be evaluated for active and latent tuberculosis infection. Appropriate screening tests should be performed in all patients. ILARIS has not been studied in patients with a positive tuberculosis screen, and the safety of ILARIS in individuals with latent tuberculosis infection is unknown. Patients testing positive in tuberculosis screening should be treated according to standard medical practice prior to therapy with ILARIS. All patients should be instructed to seek medical advice if signs, symptoms, or high risk exposure suggestive of tuberculosis (e.g. persistent cough, weight loss, subfebrile temperature) appear during or after ILARIS therapy.
Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with ILARIS.
Immunosuppression
The impact of treatment with anti-interleukin-1 (IL-1) therapy on the development of malignancies is not known. However, treatment with immunosuppressants, including ILARIS, may result in an increase in the risk of malignancies.
Hypersensitivity
Hypersensitivity reactions have been reported with ILARIS therapy. No anaphylactic reactions have been reported. It should be recognized that symptoms of the underlying disease being treated may be similar to symptoms of hypersensitivity. ILARIS should not be administered to any patients with known clinical hypersensitivity to ILARIS [ see Contraindications (4) and Adverse Reactions (6.3) ].
Immunizations
Live vaccines should not be given concurrently with ILARIS [ see Drug Interactions (7.2) ]. Since no data are available on either the efficacy or on the risks of secondary transmission of infection by live vaccines in patients receiving ILARIS, live vaccines should not be given concurrently with ILARIS. In addition, because ILARIS may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving ILARIS. No data are available on the effectiveness of vaccinations with inactivated (killed) antigens in patients receiving ILARIS. [ see Drug Interactions (7.2) ].
Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with ILARIS, adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. (See current recommended immunization schedules at the website of the Centers for Disease Control, http://www.cdc.gov/vaccines/recs/schedules/).
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category
C
Canakinumab has been shown to produce delays in fetal skeletal development when evaluated in marmoset monkeys using doses 23-fold the maximum recommended human dose (MRHD) and greater (based on a plasma area under the time-concentration curve [AUC] comparison). Doses producing exposures within the clinical exposure range at the MRHD were not evaluated. Similar delays in fetal skeletal development were observed in mice administered a murine analog of canakinumab. There are no adequate and well-controlled studies of ILARIS in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Embryofetal developmental toxicity studies were performed in marmoset monkeys and mice. Pregnant marmoset monkeys were administered canakinumab subcutaneously twice weekly at doses of 15, 50 or 150 mg/kg (representing 23 to 230-fold the human dose based on a plasma AUC comparison at the MRHD) from gestation days 25 to 109 which revealed no evidence of embryotoxicity or fetal malformations. There were increases in the incidence of incomplete ossification of the terminal caudal vertebra and misaligned and/or bipartite vertebra in fetuses at all dose levels when compared to concurrent controls suggestive of delay in skeletal development in the marmoset. Since canakinumab does not cross-react with mouse or rat IL-1, pregnant mice were subcutaneously administered a murine analog of canakinumab at doses of 15, 50, or 150 mg/kg on gestation days 6, 11 and 17. The incidence of incomplete ossification of the parietal and frontal skull bones of fetuses was increased in a dose-dependent manner at all dose levels tested.
Nursing Mothers
It is not known whether canakinumab is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ILARIS is administered to a nursing woman.
Pediatric Use
The CAPS trials with ILARIS included a total of 23 pediatric patients with an age range from 4 years to 17 years (11 adolescents were treated subcutaneously with 150 mg, and 12 children were treated with 2 mg/kg based on body weight greater than or equal to 15 kg and less than or equal to 40 kg). The majority of patients achieved improvement in clinical symptoms and objective markers of inflammation (e.g., Serum Amyloid A and C-Reactive Protein). Overall, the efficacy and safety of ILARIS in pediatric and adult patients were comparable. Infections of the upper respiratory tract were the most frequently reported infection. The safety and effectiveness of ILARIS in patients under 4 years of age has not been established [ see Pharmacokinetics (12.3) ].
Geriatric Use
Clinical studies of ILARIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Patients with Renal Impairment
No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with renal impairment.
Patients with Hepatic Impairment
No formal studies have been conducted to examine the pharmacokinetics of ILARIS administered subcutaneously in patients with hepatic impairment.
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