Rilonacept regeneron

Overdose

There have been no reports of overdose with Rilonacept Regeneron. Maximum weekly doses of up to 320 mg have been administered subcutaneously for up to approximately 18 months in a small number of patients with CAPS and up to 6 months in patients with an unapproved indication in clinical trials without evidence of dose-limiting toxicities. In addition, Rilonacept Regeneron given intravenously at doses up to 2000 mg monthly in another patient population for up to six months were tolerated without dose-limiting toxicities. The maximum amount of Rilonacept Regeneron that can be safely administered has not been determined.

In case of overdose, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects, and appropriate symptomatic treatment instituted immediately.

Contraindications

None.

Pharmaceutical form

Undesirable effects

Six serious adverse reactions were reported by four patients during the clinical program. These serious adverse reactions were Mycobacterium intracellulare infection; gastrointestinal bleeding and colitis; sinusitis and bronchitis; and Streptococcus pneumoniae meningitis.

The most commonly reported adverse reaction associated with Rilonacept Regeneron was injection-site reaction (ISR). The next most commonly reported adverse reaction was upper respiratory infection.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described herein reflect exposure to Rilonacept Regeneron in 600 patients, including 85 exposed for at least 6 months and 65 exposed for at least one year. These included patients with CAPS, patients with other diseases, and healthy volunteers. Approximately 60 patients with CAPS have been treated weeklywith 160 mg of Rilonacept Regeneron. The pivotal trial population included 47 patients with CAPS. These patients were between the ages of 22 and 78 years (average 51 years). Thirty-one patients were female and 16 were male. All of the patients were White/Caucasian. Six pediatric patients (12-17 years) were enrolled directly into the open-label extension phase.

Part A of the clinical trial was conducted in patients with CAPS who were naïve to treatment with Rilonacept Regeneron. Part A of the study was a randomized, double-blind, placebo-controlled, six-week study comparing Rilonacept Regeneron to placebo. Table 1 reflects the frequency of adverse events reported by at least two patients during Part A.

Table 1: Most Frequent Adverse Reactions (Part A, Reported by at Least Two Patients )

In patients with CAPS, the most common and consistently reported adverse event associated with Rilonacept Regeneron was injection-site reaction (ISR). The ISRs included erythema, swelling, pruritus, mass, bruising, inflammation, pain, edema, dermatitis, discomfort, urticaria, vesicles, warmth and hemorrhage. Most injection-site reactions lasted for one to two days. No ISRs were assessed as severe, and no patient discontinued study participation due to an ISR.

During Part A, the incidence of patients reporting infections was greater with Rilonacept Regeneron (48%) than with placebo (17%). In Part B, randomized withdrawal, the incidence of infections were similar in the Rilonacept Regeneron (18%) and the placebo patients (22%). Part A of the trial was initiated in the winter months, while Part B was predominantly performed in the summer months.

In placebo-controlled studies across a variety of patient populations encompassing 360 patients treated with rilonacept and 179 treated with placebo, the incidence of infections was 34% and 27% (2.15 per patient-exposure year and 1.81 per patient-exposure year), respectively, for rilonacept and placebo.

Serious Infections: One patient receiving Rilonacept Regeneron for an unapproved indication in another study developed an infection in his olecranon bursa with Mycobacterium intracellulare. The patient was on chronic glucocorticoid treatment. The infection occurred after an intraarticular glucocorticoid injection into the bursa with subsequent local exposure to a suspected source of mycobacteria. The patient recovered after the administration of the appropriate antimicrobial therapy. One patient treated for another unapproved indication developed bronchitis/sinusitis, which resulted in hospitalization. One patient died in an open-label study of CAPS from Streptococcus pneumoniae meningitis.

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One patient in a study in an unapproved indication developed transient neutropenia (ANC < 1 x 109/L) after receiving a large dose (2000 mg intravenously) of Rilonacept Regeneron. The patient did not experience any infection associated with the neutropenia.

Antibodies directed against the receptor domains of rilonacept were detected by an ELISA assay in patients with CAPS after treatment with Rilonacept Regeneron. Nineteen of 55 patients (35%) who had received Rilonacept Regeneron for at least 6 weeks tested positive for treatment-emergent binding antibodies on at least one occasion. Of the 19, seven tested positive at the last assessment (Week 18 or 24 of the open-label extension period), and five patients tested positive for neutralizing antibodies on at least one occasion. There was no correlation of antibody activity and either clinical effectiveness or safety.

The data reflect the percentage of patients whose test results were positive for antibodies to the rilonacept receptor domains in specific assays, and are highly dependent on the sensitivity and specificity of the assays. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to rilonacept with the incidence of antibodies to other products may be misleading.

Cholesterol and lipid levels may be reduced in patients with chronic inflammation. Patients with CAPS treated with Rilonacept Regeneron experienced increases in their mean total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides. The mean increases from baseline for total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were 19 mg/dL, 2 mg/dL, 10 mg/dL, and 57 mg/dL respectively after 6 weeks of open-label therapy. Physicians should monitor the lipid profiles of their patients (for example after 2-3 months) and consider lipid-lowering therapies as needed based upon cardiovascular risk factors and current guidelines.

Therapeutic indications

Rilonacept Regeneron® (rilonacept) is an interleukin-1 blocker indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS)and Muckle-Wells Syndrome (MWS) in adults and children 12 and older.

Pharmacodynamic properties

C-Reactive Protein (CRP) and Serum Amyloid A (SAA) are indicators of inflammatory disease activity that are elevated in patients with CAPS. Elevated SAA has been associated with the development of systemic amyloidosis in patients with CAPS. Compared to placebo, treatment with Rilonacept Regeneron resulted in sustained reductions from baseline in mean serum CRP and SAA to normal levels during the clinical trial. Rilonacept Regeneron also normalized mean SAA from elevated levels.

Pharmacokinetic properties

The average trough levels of rilonacept were approximately 24 mcg/mL at steady-state following weekly subcutaneous doses of 160 mg for up to 48 weeks in patients with CAPS. The steady-state appeared to be reached by 6 weeks.

No pharmacokinetic data are available in patients with hepatic or renal impairment.

No study was conducted to evaluate the effect of age, gender, or body weight on rilonacept exposure. Based on limited data obtained from the clinical study, steady state trough concentrations were similar between male and female patients. Age (26-78 years old) and body weight (50-120 kg) did not appear to have a significant effect on trough rilonacept concentrations. The effect of race could not be assessed because only Caucasian patients participated in the clinical study, reflecting the epidemiology of the disease.

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Interleukin-1 (IL-1) blockade may interfere with the immune response to infections. Treatment with another medication that works through inhibition of IL-1 has been associated with an increased risk of serious infections, and serious infections have been reported in patients taking Rilonacept Regeneron. There was a greater incidence of infections in patients on Rilonacept Regeneron compared with placebo. In the controlled portion of the study, one infection was reported as severe, which was bronchitis in a patient on Rilonacept Regeneron.

In an open-label extension study, one patient developed bacterial meningitis and died. Rilonacept Regeneron should be discontinued if a patient develops a serious infection. Treatment with Rilonacept Regeneron should not be initiated in patients with an active or chronic infection.

In clinical studies, Rilonacept Regeneron has not been administered concomitantly with tumor necrosis factor (TNF) inhibitors. An increased incidence of serious infections has been associated with administration of an IL-1 blocker in combination with TNF inhibitors. Taking Rilonacept Regeneron with TNF inhibitors is not recommended because this may increase the risk of serious infections.

Drugs that affect the immune system by blocking TNF have been associated with an increased risk of reactivation of latent tuberculosis (TB). It is possible that taking drugs such as Rilonacept Regeneron that block IL-1 increases the risk of TB or other atypical or opportunistic infections. Healthcare providers should follow current CDC guidelines both to evaluate for and to treat possible latent tuberculosis infections before initiating therapy with Rilonacept Regeneron.

The impact of treatment with Rilonacept Regeneron on active and/or chronic infections and the development of malignancies is not known. However, treatment with immunosuppressants, including Rilonacept Regeneron, may result in an increase in the risk of malignancies.

Since no data are available on either the efficacy of live vaccines or on the risks of secondary transmission of infection by live vaccines in patients receiving Rilonacept Regeneron, live vaccines should not be given concurrently with Rilonacept Regeneron. In addition, because Rilonacept Regeneron may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving Rilonacept Regeneron. No data are available on the effectiveness of vaccination with inactivated (killed) antigens in patients receiving Rilonacept Regeneron.

Because IL-1 blockade may interfere with immune response to infections, it is recommended that prior to initiation of therapy with Rilonacept Regeneron adult and pediatric patients receive all recommended vaccinations, as appropriate, including pneumococcal vaccine and inactivated influenza vaccine. (See current Recommended Immunizations schedules at the website of the Centers for Disease Control and Prevention. http://www.cdc.gov/vaccines/schedules/index.html).

Patients should be monitored for changes in their lipid profiles and provided with medical treatment if warranted.

Hypersensitivity reactions associated with Rilonacept Regeneron administration in the clinical studies were rare. If a hypersensitivity reaction occurs, administration of Rilonacept Regeneron should be discontinued and appropriate therapy initiated.

See FDA-approved patient labeling.

The first injection of Rilonacept Regeneron should be performed under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer Rilonacept Regeneron, he/she should be instructed on aseptic reconstitution of the lyophilized product and injection technique. The ability to inject subcutaneously should be assessed to ensure proper administration of Rilonacept Regeneron, including rotation of injection sites. (See PATIENT INFORMATION Leaflet for Rilonacept Regeneron®). Rilonacept Regeneron should be reconstituted with preservative-free Sterile Water for Injection to be provided by the pharmacy. A puncture-resistant container for disposal of vials, needles and syringes should be used. Patients or caregivers should be instructed in proper vial, syringe, and needle disposal, and should be cautioned against reuse of these items.

Physicians should explain to patients that almost half of the patients in the clinical trials experienced a reaction at the injection site. Injection-site reactions may include pain, erythema, swelling, pruritus, bruising, mass, inflammation, dermatitis, edema, urticaria, vesicles, warmth, and hemorrhage. Patients should be cautioned to avoid injecting into an area that is already swollen or red. Any persistent reaction should be brought to the attention of the prescribing physician.

Patients should be cautioned that Rilonacept Regeneron has been associated with serious, lifethreatening infections, and not to initiate treatment with Rilonacept Regeneron if they have a chronic or active infection. Patients should be counseled to contact their healthcare professional immediately if they develop an infection after starting Rilonacept Regeneron. Treatment with Rilonacept Regeneron should be discontinued if a patient develops a serious infection. Patients should be counseled not to take any IL-1 blocking drug, including Rilonacept Regeneron, if they are also taking a drug that blocks TNF such as etanercept, infliximab, or adalimumab. Use of Rilonacept Regeneron with other IL-1 blocking agents, such as anakinra, is not recommended.

Prior to initiation of therapy with Rilonacept Regeneron physicians should review with adult and pediatric patients their vaccination history relative to current medical guidelines for vaccine use, including taking into account the potential of increased risk of infection during treatment with Rilonacept Regeneron.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of rilonacept. The mutagenic potential of rilonacept was not evaluated.

Male and female fertility was evaluated in a mouse surrogate model using a murine analog of rilonacept. Male mice were treated beginning 8 weeks prior to mating and continuing through female gestation day 15. Female mice were treated for 2 weeks prior to mating and on gestation days 0, 3, and 6. The murine analog of rilonacept did not alter either male or female fertility parameters at doses up to 200 mg/kg (this dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area).

There are no adequate and well-controlled studies of Rilonacept Regeneron in pregnant women. Based on animal data, Rilonacept Regeneron may cause fetal harm. An embryo-fetal developmental toxicity study was performed in cynomolgus monkeys treated with 0, 5, 15 or 30 mg/kg given twice a week (highest dose is approximately 3.7-fold higher than the human doses of 160 mg based on body surface area). The fetus of the only monkey with exposure to rilonacept during the later period of gestation showed multiple fusion and absence of the ribs and thoracic vertebral bodies and arches. Exposure to rilonacept during this time period was below that expected clinically. Likewise, in the cynomolgus monkey, all doses of rilonacept reduced serum levels of estradiol up to 64% compared to controls and increased the incidence of lumbar ribs compared to both control animals and historical control incidences. In perinatal and postnatal developmental toxicology studies in the mouse model using a murine analog of rilonacept (0, 20, 100 or 200 mg/kg), there was a 3-fold increase in the number of stillbirths in dams treated with 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Rilonacept Regeneron should be used during pregnancy only if the benefit justifies the potential risk to the fetus.

A peri- and post-natal reproductive toxicology study was performed in which mice were subcutaneously administered a murine analog of rilonacept at doses of 20, 100, 200 mg/kg three times per week (the highest dose is approximately 6-fold higher than the 160 mg maintenance dose based on body surface area). Results indicated an increased incidence in unscheduled deaths of the F1 offspring during maturation at all doses tested.

It is not known whether rilonacept is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Rilonacept Regeneron is administered to a nursing woman.

Six pediatric patients with CAPS between the ages of 12 and 16 were treated with Rilonacept Regeneron at a weekly, subcutaneous dose of 2.2 mg/kg (up to a maximum of 160 mg) for 24-weeks during the openlabel extension phase. These patients showed improvement from baseline in their symptom scores and in objective markers of inflammation (e.g. Serum Amyloid A and C-Reactive Protein). The adverse events included injection site reactions and upper respiratory symptoms as were commonly seen in the adult patients.

The trough drug levels for four pediatric patients measured at the end of the weekly dose interval (mean 20 mcg/mL, range 3.6 to 33 mcg/mL) were similar to those observed in adult patients with CAPS (mean 24 mcg/mL, range 7 to 56 mcg/mL).

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

When administered to pregnant primates, rilonacept treatment may have contributed to alterations in bone ossification in the fetus. It is not known if Rilonacept Regeneron will alter bone development in pediatric patients. Pediatric patients treated with Rilonacept Regeneron should undergo appropriate monitoring for growth and development.

In the placebo-controlled clinical studies in patients with CAPS and other indications, 70 patients randomized to treatment with Rilonacept Regeneron were ≥ 65 years of age, and 6 were ≥ 75 years of age. In the CAPS clinical trial, efficacy, safety and tolerability were generally similar in elderly patients as compared to younger adults; however, only ten patients ≥ 65 years old participated in the trial. In an open-label extension study of CAPS, a 71 year old woman developed bacterial meningitis and died. Age did not appear to have a significant effect on steady-state trough concentrations in the clinical study.

No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with renal impairment.

No formal studies have been conducted to examine the pharmacokinetics of rilonacept administered subcutaneously in patients with hepatic impairment.

Dosage (Posology) and method of administration

Injection for Subcutaneous Use Only.

Adult patients 18 years and older: Treatment should be initiated with a loading dose of 320 mg delivered as two, 2-mL, subcutaneous injections of 160 mg each given on the same day at two different sites. Dosing should be continued with a once-weekly injection of 160 mg administered as a single, 2-mL, subcutaneous injection. Rilonacept Regeneron should not be given more often than once weekly. Dosage modification is not required based on advanced age or gender.

Pediatric patients aged 12 to 17 years: Treatment should be initiated with a loading dose of 4.4 mg/kg, up to a maximum of 320 mg, delivered as one or two subcutaneous injections with a maximum singleinjection volume of 2 mL. Dosing should be continued with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 mL. If the initial dose is given as two injections, they should be given on the same day at two different sites. Rilonacept Regeneron should not be given more often than once weekly.

Each single-use vial of Rilonacept Regeneron contains a sterile, white to off-white, preservative-free, lyophilized powder. Reconstitution with 2.3 mL of preservative-free Sterile Water for Injection (supplied separately) is required prior to subcutaneous administration of the drug.

Using aseptic technique, withdraw 2.3 mL of preservative-free Sterile Water for Injection through a 27- gauge, ½-inch needle attached to a 3-mL syringe and inject the preservative-free Sterile Water for Injection into the drug product vial for reconstitution. The needle and syringe used for reconstitution with preservative-free Sterile Water for Injection should then be discarded and should not be used for subcutaneous injections. After the addition of preservative-free Sterile Water for Injection, the vial contents should be reconstituted by shaking the vial for approximately one minute and then allowing it to sit for one minute. The resulting 80-mg/mL solution is sufficient to allow a withdrawal volume of up to 2 mL for subcutaneous administration. The reconstituted solution is viscous, clear, colorless to pale yellow, and essentially free from particulates. Prior to injection, the reconstituted solution should be carefully inspected for any discoloration or particulate matter. If there is discoloration or particulate matter in the solution, the product in that vial should not be used.

Using aseptic technique, withdraw the recommended dose volume, up to 2 mL (160 mg), of the solution with a new 27-gauge, ½-inch needle attached to a new 3-mL syringe for subcutaneous injection. EACH VIAL SHOULD BE USED FOR A SINGLE DOSE ONLY. Discard the vial after withdrawal of drug.

Sites for subcutaneous injection, such as the abdomen, thigh, or upper arm, should be rotated. Injections should never be made at sites that are bruised, red, tender, or hard.

The lyophilized Rilonacept Regeneron product is to be stored refrigerated at 2° to 8°C (36° to 46°F) inside the original carton to protect it from light. Do not use beyond the date stamped on the label. After reconstitution, Rilonacept Regeneron may be kept at room temperature, should be protected from light, and should be used within three hours of reconstitution. Rilonacept Regeneron does not contain preservatives; therefore, unused portions of Rilonacept Regeneron should be discarded.