Antril

Active Rheumatoid Arthritis

Antril is indicated for the reduction in signs and symptoms and slowing the progression of structural damage in moderately to severely active rheumatoid arthritis (RA), in patients 18 years of age or older who have failed 1 or more disease modifying antirheumatic drugs (DMARDs). Antril can be used alone or in combination with DMARDs other than Tumor Necrosis Factor (TNF) blocking agents.

Cryopyrin-Associated Periodic Syndromes (CAPS)

Antril is indicated for the treatment of Neonatal-Onset Multisystem Inflammatory Disease (NOMID).

Antril reduces the actions of chemicals in the body that are involved in inflammatory and immune responses.

Antril is used to treat the symptoms of moderate to severe rheumatoid arthritis in adults. Antril may also help slow the progress of the disease. Antril is usually given after other arthritis medications have been tried without successful treatment of symptoms.

Antril is also used in newborn babies to treat a rare genetic condition called neonatal onset multisystem inflammatory disease (NOMID). NOMID is a form of cryopyrin-associated periodic syndromes (CAPS). This condition causes uncontrolled inflammation in many parts of the body, including the skin, joints, and central nervous system.

Antril may also be used for purposes not listed in this medication guide.

Active Rheumatoid Arthritis

The recommended dose of Antril for the treatment of patients with rheumatoid arthritis is 100 mg/day administered daily by subcutaneous injection. Higher doses did not result in a higher response. The dose should be administered at approximately the same time every day.

Cryopyrin-Associated Periodic Syndromes (CAPS)

The recommended starting dose of Antril is 1-2 mg/kg for NOMID patients. The dose can be individually adjusted to a maximum of 8 mg/kg daily to control active inflammation.

Adjust doses in 0.5 to 1.0 mg/kg increments. Once daily administration is generally recommended, but the dose may be split into twice daily administrations. Each syringe is intended for a single use. A new syringe must be used for each dose. Any unused portion after each dose should be discarded.

Renal Impairment

Physicians should consider administration of the prescribed dose of Antril every other day for patients who have severe renal insufficiency or end stage renal disease (defined as creatinine clearance < 30 mL/min, as estimated from serum creatinine levels).

Administration

Instructions on appropriate use should be given by the healthcare provider to the patient or caregiver. Patients or caregivers should not be allowed to administer Antril until the patient or caregiver has demonstrated a thorough understanding of procedures and an ability to inject the product correctly. The prescribed dose of Antril should be administered according to the instructions for use and any unused portions discarded. After administration of Antril it is essential to follow the proper procedure for disposal of syringes and any residual drug. See the “PATIENT INFORMATION” insert for detailed instructions on the handling and injection of Antril.

Do not use Antril beyond the expiration date shown on the carton. Visually inspect the solution for particulate matter and discoloration before administration. There may be trace amounts of small, translucent-to-white amorphous particles of protein in the solution. The prefilled syringe should not be used if the solution is discolored or cloudy, or if foreign particulate matter is present. If the number of translucent-to-white amorphous particles in a given syringe appears excessive, do not use this syringe.

How supplied

Dosage Forms And Strengths

100 mg/0.67 mL solution for subcutaneous injection. Graduated syringe allows for doses between 20 and 100 mg.

Storage And Handling

Antril is supplied in single-use preservative free, prefilled glass syringes with 27 gauge needles. Each prefilled glass syringe contains 100 mg of Antril per 0.67 mL. The full syringe contains 100 mg Antril. Antril is dispensed in a 4 x 7 syringe dispensing pack containing 28 syringes (NDC 66658-234-28). Antril is also dispensed in a 1 x 7 syringe dispensing pack containing 7 syringes (NDC 66658-234-07).

Storage

Antril should be stored in the refrigerator at 2° to 8°C (36° to 46°F). DO NOT FREEZE OR SHAKE. Protect from light.

Manufactured by: Swedish Orphan Biovitrum AB (publ) SE-112 76 Stockholm, Sweden License No. 1859. Revised Date: 10/2013

See also:
What is the most important information I should know about Antril?

You should not use this medication if you are allergic to Antril or to other medicines that contain E. coli bacteria proteins. You also should not use Antril if you have an active infection.

Before using Antril, tell your doctor if you have asthma, kidney disease, a latex allergy, a weak immune system, an active or chronic infection, or signs of infection such as fever, chills, or open sores on your skin.

Antril can lower blood cells that help your body fight infections. Your blood may need to be tested often. Avoid being near people who are sick or have infections. Stop using this medicine and call your doctor right away if you have signs of infection such as: fever, chills, flu symptoms, mouth sores, weight loss, or feeling tired or short of breath.

You may have a higher risk of infection if you are also using adalimumab (Humira), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), adalimumab (Humira), cancer medicines, steroids, or medicines to prevent organ transplant rejection.

Do not give this medication to anyone under 18 years old without medical advice.

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

• An extra patient leaflet is available with Antril. It also comes with detailed instructions for use. Read them carefully. Read them again each time you get Antril refilled. Ask your doctor, nurse, or pharmacist any questions that you may have about this information.
• Antril may be administered as an injection at your doctor's office, hospital, or clinic. If you are using Antril at home, carefully follow the injection procedures taught to you by your health care provider. Ask your doctor or other health care provider if you have any questions about how to administer Antril.
• Use the proper technique taught to you by your doctor. Inject deep under the skin, NOT into muscle or a vein.
• Rotate injection sites. Do not inject Antril into an area that is irritated, bruised, red, infected, scarred, or has stretch marks.
• Antril should be administered at the same time each day.
• Wash your hands thoroughly with soap and warm water before using Antril.
• Before using Antril, take it out of the refrigerator and leave it at room temperature for 30 minutes.
• Use a new syringe every day. Use the prefilled syringe only once. Throw away any unused portion of the medicine. Do not save for future use.
• If Antril contains particles or is discolored, or if the container is cracked or damaged in any way, do not use it.
• Do not use a syringe that has been dropped or broken. Properly dispose of the damaged syringe and replace it with the syringe that would be used on the last day of the week in your current box. For example, if you start on Wednesday, the last day of the week in your series is Tuesday. After using all of the remaining syringes in your current box, start your next box.
• Do not use Antril beyond the expiration date on the container.
• Keep this product, as well as syringes and needles, out of the reach of children and away from pets. Do not reuse needles, syringes, or other materials. Dispose of properly after use. Ask your doctor or pharmacist to explain local regulations for proper disposal.
• If you miss a dose of Antril, use it as soon as possible. If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not use 2 doses on the same day.

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

Use: Labeled Indications

Neonatal-onset multisystem inflammatory disease: Treatment of neonatal-onset multisystem inflammatory disease (NOMID).

Rheumatoid arthritis: Reduction in signs and symptoms and slowing the progression of structural damage of moderately to severely active rheumatoid arthritis (RA) in patients 18 years and older who have failed 1 or more disease-modifying antirheumatic drugs (DMARDs).

Off Label Uses

Familial Mediterranean fever

Evidence from a small number of patients in a short-term controlled trial and noncontrolled trials suggests that Antril may reduce the frequency of attacks in patients with familial Mediterranean fever (FMF) who are resistant or intolerant to colchicine. Additional data are necessary to further define the role of Antril in this condition.

Based on European League Against Rheumatism (EULAR) guidelines for the management of FMF, interleukin-1 (IL-1) blockers are recommended for patients unresponsive or resistant to the maximum dose of colchicine.

Gout, treatment of acute flares (when conventional therapy is ineffective, contraindicated, or not tolerated)

Data from a case series and several retrospective chart reviews have suggested Antril may be beneficial for the treatment of acute flare of gout in patients who are refractory to, intolerant of, or have contraindications to conventional therapy (eg, colchicine, NSAIDs, corticosteroids). Additional data may be necessary to further define the role of Antril in this condition.

Based on European League Against Rheumatism (EULAR) evidence-based recommendations for the management of gout, interleukin-1 (IL-1) blockers (eg, Antril) may be considered for treating acute gout flares in patients with frequent flares and who have contraindications to other anti-gout therapies including colchicine, NSAIDS, and corticosteroids. Following flare treatment with interleukin-1 (IL-1) blockers, urate-lowering therapy should be adjusted to meet uricemia target levels.

Pericarditis, recurrent

Evidence from small controlled and noncontrolled trials and several case reports/series indicates that Antril may be effective in preventing recurrences in patients with recurrent pericarditis refractory to conventional therapy.

European Society of Cardiology (ESC) guidelines on the diagnosis and management of pericardial diseases recommend that intravenous immunoglobulin, Antril, or azathioprine be considered in cases of infection-negative, corticosteroid-dependent recurrent pericarditis in patients not responsive to colchicine.

See also:
What other drugs will affect Antril?

TNF-Blocking Agents:

An increased incidence of serious infections and an increased risk of neutropenia have been seen when Antril and etanercept were used concomitantly in patients with rheumatoid arthritis. Similar interactions can be anticipated for the combination therapy of Antril together with other agents blocking TNF (alpha) (e.g., adalimumab, infliximab). Therefore, combined drug therapy with Antril and any TNF-blocking agent is not recommended and should be avoided. Moreover, in a 24-week clinical study a regime with Antril and etanercept did not provide any additional benefit to the patients.

Methotrexate:

Methotrexate has been coadministered with Antril in quite extended clinical studies. Neither specific drug interactions nor increased toxicity of Antril and/or methotrexate have been noticed. In animal models (rats) studying the effects of both drugs when coadminstered, no effects on clearing of both drugs form plasma or on the respective toxicologic properties have been seen. Therefore, the concomitant use of both disease modifiers in patients with rheumatoid arthritis can be regarded as safe.

Vaccines:

Live-virus vaccines should not be given to patients during Antril treatment. Information is not available, if Antril would affect the rate of secondary transmission of vaccine virus (e.g., measles or poliomyelitis viruses) following administration of a live virus vaccine or regarding any other effect of vaccination on patients receiving the drug. Due to the fact that Antril decreases the immune response to antigens in general, vaccine efficacy may be reduced in patients receiving Antril.

See also:
What are the possible side effects of Antril?

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 clinical practice.

Clinical Studies Experience in RA

The most serious adverse reactions were:

• Serious Infections –
• Neutropenia, particularly when used in combination with TNF blocking agents

The most common adverse reaction with Antril is injection-site reactions. These reactions were the most common reason for withdrawing from studies.

The data described herein reflect exposure to Antril in 3025 patients, including 2124 exposed for at least 6 months and 884 exposed for at least one year. Studies 1 and 4 used the recommended dose of 100 mg per day. The patients studied were representative of the general population of patients with rheumatoid arthritis.

Injection-site Reactions

The most common and consistently reported treatment-related adverse event associated with Antril is injection-site reaction (ISR). In Studies 1 and 4, 71% of patients developed an ISR, which was typically reported within the first 4 weeks of therapy. The majority of ISRs were reported as mild (72.6% mild, 24.1% moderate and 3.2% severe). The ISRs typically lasted for 14 to 28 days and were characterized by 1 or more of the following: erythema, ecchymosis, inflammation, and pain.

Infections

In Studies 1 and 4 combined, the incidence of infection was 39% in the Antril-treated patients and 37% in placebo-treated patients during the first 6 months of blinded treatment. The incidence of serious infections in Studies 1 and 4 was 2% in Antril-treated patients and 1% in patients receiving placebo over 6 months. The incidence of serious infection over 1 year was 3% in Antril-treated patients and 2% in patients receiving placebo. These infections consisted primarily of bacterial events such as cellulitis, pneumonia, and bone and joint infections. Majority of patients (73%) continued on study drug after the infection resolved. No serious opportunistic infections were reported. Patients with asthma appeared to be at higher risk of developing serious infections when treated with Antril (8 of 177 patients, 4.5%) compared to placebo (0 of 50 patients, 0%).

In open-label extension studies, the overall rate of serious infections was stable over time and comparable to that observed in controlled trials. In clinical studies and postmarketing experience, cases of opportunistic infections have been observed and included fungal, mycobacterial and bacterial pathogens. Infections have been noted in all organ systems and have been reported in patients receiving Antril alone or in combination with immunosuppressive agents.

In patients who received both Antril and etanercept for up to 24 weeks, the incidence of serious infections was 7%. The most common infections consisted of bacterial pneumonia (4 cases) and cellulitis (4 cases). One patient with pulmonary fibrosis and pneumonia died due to respiratory failure.

Malignancies

Among 5300 RA patients treated with Antril in clinical trials for a mean of 15 months (approximately 6400 patient years of treatment), 8 lymphomas were observed for a rate of 0.12 cases/100 patient years. This is 3.6 fold higher than the rate of lymphomas expected in the general population, based on the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) database.3 An increased rate of lymphoma, up to several fold, has been reported in the RA population, and may be further increased in patients with more severe disease activity. Thirty-seven malignancies other than lymphoma were observed. Of these, the most common were breast, respiratory system, and digestive system. There were 3 melanomas observed in Study 4 and its long-term open-label extension, greater than the 1 expected case. The significance of this finding is not known. While patients with RA, particularly those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the role of IL-1 blockers in the development of malignancy is not known.

Hematologic Events

In placebo-controlled studies with Antril, 8% of patients receiving Antril had decreases in total white blood counts of at least one WHO toxicity grade, compared with 2% of placebo patients. Nine Antril-treated patients (0.4%) developed neutropenia (ANC < 1 x 109/L). 9 % of patients receiving Antril had increases in eosinophil differential percentage of at least one WHO toxicity grade, compared with 3 % of placebo patients. Of patients treated concurrently with Antril and etanercept 2% developed neutropenia (ANC < 1 x 109/L). While neutropenic, one patient developed cellulitis which recovered with antibiotic therapy. 2% of patients receiving Antril had decreases in platelets, all of WHO toxicity grade one, compared to 0% of placebo patients.

Hypersensitivity Reactions

Hypersensitivity reactions including anaphylactic reactions, angioedema, urticaria, rash, and pruritus have been reported with Antril.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. In Studies 1 and 4, from which data is available for up to 36 months, 49% of patients tested positive for anti-Antril binding antibodies at one or more time points using a biosensor assay. Of the 1615 patients with available data at Week 12 or later, 30 (2%) tested positive for neutralizing antibodies in a cell-based bioassay. Of the 13 patients with available follow-up data, 5 patients remained positive for neutralizing antibodies at the end of the studies. No correlation between antibody development and adverse events was observed.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assays. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Antril with the incidence of antibodies to other products may be misleading.

Lipids

Cholesterol elevations were observed in some patients treated with Antril.

Other Adverse Events

Table 1 reflects adverse events in Studies 1 and 4, that occurred with a frequency of ≥ 5% in Antril-treated patients over a 6-month period.

Clinical Study Experience in NOMID

The data described herein reflect an open-label study in 43 NOMID patients exposed to Antril for up to 60 months adding up to a total exposure of 159.8 patient years.

Patients were treated with a starting dose of 1 to 2 mg/kg/day and an average maintenance dose of 3-4 mg/kg/day adjusted depending on the severity of disease. Among pediatric NOMID patients, doses up to 7.6 mg/kg/day have been maintained for up to 15 months.

There were 24 serious adverse events (SAEs) reported in 14 of the 43 treated patients. The most common type of SAEs reported were infections. Five SAEs were related to lumbar puncture, which was part of the study procedure.

There were no permanent discontinuations of study drug treatment due to AEs. Doses were adjusted in 5 patients because of AEs; all were dose increases in connection with disease flares.

The reporting frequency of AEs was highest during the first 6 months of treatment. The incidence of AEs did not increase over time, and no new types of AEs emerged.

The most commonly reported AEs during the first 6 months of treatment (incidence >10%) were injection site reaction (ISR), headache, vomiting, arthralgia, pyrexia, and nasopharyngitis (Table 2).

The most commonly reported AEs during the 60-month study period, calculated as the number of events/patient years of exposure, were arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.

The AE profiles for different age groups <2 years, 2-11 years, and 12-17 years corresponded to the AE profile for patients ≥18 years, with the exception of infections and related symptoms being more frequent in patients <2 years.

Infections

The reporting rate for infections was higher during the first 6 months of treatment (2.3 infections/patient-year) compared to after the first 6 months (1.7 infections/patient year). The most common infections were upper respiratory tract infection, sinusitis, ear infections, and nasopharyngitis.

There were no deaths or permanent treatment discontinuations due to infections. In one patient Antril administration was temporarily stopped during an infection and in 5 patients the dose of Antril was increased due to disease flares in connection with infections. Thirteen infections in 7 patients were classified as serious, the most common being pneumonia and gastroenteritis occurring in 3 and 2 patients, respectively. No serious opportunistic infections were reported.

The reporting frequency for infections was highest in patients <12 years of age.

Hematologic Events

After start of Antril treatment neutropenia was reported in 2 patients. One of these patients experienced an upper respiratory tract infection and an otitis media infection. Both episodes of neutropenia resolved over time with continued Antril treatment.

Injection Site Reactions

In total, 17 injection site reactions (ISRs) were reported in 10 patients during the 60-month study period. Out of the 17 ISRs, 11 (65%) occurred during the first month and 13 (76%) were reported during the first 6 months. No ISR was reported after Year 2 of treatment. The majority of ISRs were reported as mild (76% mild, 24% moderate). No patient permanently or temporarily discontinued Antril treatment due to injection site reactions.

Immunogenicity

The immunogenicity of Antril in NOMID patients was not evaluated.

The most common adverse reactions occurring after the first 6-month period of treatment with Antril (up to 60 months of treatment) included: arthralgia, headache, pyrexia, upper respiratory tract infection, nasopharyngitis, and rash.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Antril. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepato-biliary disorders:

• elevations of transaminases,
• non-infectious hepatitis

Hematologic events:

• thrombocytopenia, including severe thrombocytopenia (i.e platelet counts <10x109/L)