Anakinra

Anakinra is a an Antirheumatic Agent belonging to pharmacology class of Interleukin-1 Receptor Antagonist

Anakinra can be used in the treatment of Deficiency of interleukin-1 receptor antagonist, Neonatal-onset multisystem inflammatory disease, Rheumatoid arthritis . It is also used to treat Behçet disease, mucocutaneous, refractory; Calcium pyrophosphate crystal deposition disease (ie, pseudogout); COVID-19, hospitalized patients; Cytokine storm syndromes; Familial Mediterranean fever; Gout, treatment (acute flares); Pericarditis, recurrent; Still disease, adult onset.

The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patient with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3- 7 hours later. The volume of distribution averaged 18.5 L. As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body. Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function

The common side effects associated with Anakinra include erythema, bruising, swelling and pain, headache, nausea.

Anakinra is available in the form of Prefilled syringess.

The molecule is available in India, USA, Japan, Germany.

Anakinra belonging to the Interleukin-1 Receptor Antagonist acts a Antirheumatic Agent.

Anakinra is a recombinant receptor antagonist of interleukin-1 (IL-1). It competitively inhibits IL-1 binding to interleukin-1 type I receptor (IL-1RI) and hence blocks the activity of endogenous IL-1α and IL-1β. IL-1 is involved in inflammatory and immunological responses, cartilage degradation (loss of proteoglycans), stimulates bone resorption and its production is induced by inflammatory stimuli.

Anakinra is available in Prefilled syringes

Subcutaneous: Allow solution to warm to room temperature prior to use (30 minutes). Inject into outer area of upper arms, abdomen (do not use within 2 inches of belly button), front of middle thighs, or upper outer buttocks. Rotate injection sites; do not administer into tender, swollen, bruised, red, or hard skin or skin with scars or stretch marks. If dose is separated into 2 injections, a new syringe should be used for each dose. After proper training, patients may self-inject, or the patient's caregiver may administer anakinra.

Anakinra can be used in the treatment of Deficiency of interleukin-1 receptor antagonist, Neonatal-onset multisystem inflammatory disease, Rheumatoid arthritis. It is also used to treat Behçet disease, mucocutaneous, refractory; Calcium pyrophosphate crystal deposition disease (ie, pseudogout); COVID-19, hospitalized patients; Cytokine storm syndromes; Familial Mediterranean fever; Gout, treatment (acute flares); Pericarditis, recurrent; Still disease, adult onset.

Anakinra is a recombinant, non-glycosylated form of IL-1Ra that competes with and inhibits IL-1 by binding to the IL-1 receptor; therefore, the administration of this drug reduces the inflammatory response in RA patients.

Anakinra is approved for use in the following clinical indications

• Deficiency of interleukin-1 receptor antagonist: Treatment of deficiency of interleukin-1 receptor antagonist.

• Neonatal-onset multisystem inflammatory disease: Treatment of neonatal-onset multisystem inflammatory disease.

• Rheumatoid arthritis: Reduction in signs and symptoms and slowing the progression of structural damage of moderately to severely active rheumatoid arthritis in patients ≥18 years of age in whom 1 or more disease-modifying antirheumatic drugs have failed.

Although not approved there have been certain off labelled uses documented for Anakinra which includes:

Behçet disease, mucocutaneous, refractory; Calcium pyrophosphate crystal deposition disease (ie, pseudogout); COVID-19, hospitalized patients; Cytokine storm syndromes; Familial Mediterranean fever; Gout, treatment (acute flares); Pericarditis, recurrent; Still disease, adult onset.

• Behçet disease, mucocutaneous, refractory (adjunctive agent) (off-label use): SUBQ: Initial: 100 mg once daily in combination with other immunosuppressants (eg, corticosteroids); if ulcers persist, may increase to 200 mg once daily after 1 month and further increase to 300 mg once daily after 6 months.
• Calcium pyrophosphate crystal deposition disease (ie, pseudogout) (alternative agent) (off-label use): SUBQ: 100 mg once daily. Usual duration of therapy for acute attacks is ~3 to 9 days; however, some patients may require long-term treatment to control symptoms after the acute attack.
• COVID-19, hospitalized patients (off-label use): Note: For patients requiring supplemental oxygen who are at risk for progressing to severe respiratory failure and likely to have an elevated plasma soluble urokinase plasminogen activator receptor.
• SUBQ: 100 mg once daily for 10 days.
• Cytokine storm syndromes (adjunctive agent) (off-label use):
• Note: The IV route is preferred for doses >2 mg/kg/day or >100 mg/day, or in patients with platelets <20 × 10⁹/L, presence of significant skin edema, or neurological symptoms.
• IV: 2 mg/kg/hour as a continuous infusion for up to 72 hours, or 2 to 10 mg/kg/day in 2 to 4 divided doses; use in combination with corticosteroids.
• SUBQ: 2 to 10 mg/kg/day in 2 to 4 divided doses; use in combination with corticosteroids.
• Deficiency of interleukin-1 receptor antagonist: SUBQ: Initial: 1 to 2 mg/kg daily; adjust dose in 0.5 to 1 mg/kg increments as needed to a maximum of 8 mg/kg daily.
• Neonatal-onset multisystem inflammatory disease: SUBQ : Initial: 1 to 2 mg/kg daily in 1 to 2 divided doses; adjust dose in 0.5 to 1 mg/kg increments as needed; usual maintenance dose: 3 to 4 mg/kg daily (maximum: 8 mg/kg daily). Note: Once-daily administration is preferred; however, the dose may also be divided and administered twice daily.
• Familial Mediterranean fever (off-label use): SUBQ : 100 mg once daily
• Gout, treatment (acute flares) (alternative agent) (off-label use):
• Note: Reserve use for patients in whom first-line therapies are ineffective, contraindicated, or not tolerated.
• SUBQ: 100 mg once daily until symptom improvement; usual duration: 3 to 5 days.
• Pericarditis, recurrent (off-label use): SUBQ: 100 mg once daily. Usual duration of therapy is ~6 months followed by a taper.
• Rheumatoid arthritis: SUBQ : 100 mg once daily (administer at approximately the same time each day).
• Still disease, adult onset (alternative agent) (off-label use): SUBQ: Initial: 100 mg once daily usually in combination with other immunosuppressants (eg, corticosteroids). In patients with incomplete response, may increase to 200 mg/day in 1 or 2 divided doses.

• Prefilled syringes: 100mg/0.67mL

Prefilled syringes

• Dose Adjustment in Kidney impairment patient:

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute or end-stage renal disease:

COVID-19, hospitalized patients: Consider administering 100 mg every other day for a total of 5 doses over 10 days.

Other indications: Consider administering the prescribed dose every other day.

Hemodialysis: Not dialyzable (<2.5%)

Continuous ambulatory peritoneal dialysis (CAPD): Not dialyzable (<2.5%)

• Dose Adjustment in Pediatric Patient:

Deficiency of interleukin-1 receptor antagonist (DIRA): Infants, Children, and Adolescents: SubQ: Initial: 1 to 2 mg/kg/dose once daily; may titrate in 0.5 to 1 mg/kg increments up to a maximum dose of 8 mg/kg/dose to achieve control of active inflammation

Familial Mediterranean Fever; colchicine-resistant: Limited data available: Children ≥2 years and Adolescents: SubQ: 1 to 2 mg/kg/dose once daily; dose, frequency, and duration of therapy were adjusted as needed based on clinical response; reported range: 1 to 5 mg/kg/dose; maximum dose: 100 mg/dose. One center has reported transitioning to less frequent doses (every other day) in patients who remain attack-free for 6 months; on-demand treatment during times of specific triggers (eg, menstrual cycle) has also been reported

Juvenile idiopathic arthritis (JIA): Limited data available:

Systemic-onset JIA (SOJIA): Children and Adolescents: SubQ: Initial: 1 to 2 mg/kg/dose once daily; maximum initial dose: 100 mg; if no response, may titrate typically at 2-week intervals by doubling dose up to 4 mg/kg/dose once daily; maximum dose: 200 mg . Anakinra was shown efficacious as first-line monotherapy in single-center, prospective cohort trial including 42 pediatric patients (median age: 7.1 years); dosing was initiated at 2 mg/kg/dose if after 3 days fever remained the dose was increased to 4 mg/kg/dose

Polyarticular course JIA: Children ≥2 years and Adolescents: SubQ: 1 mg/kg once daily; maximum dose: 100 mg.

Kawasaki disease, refractory to IVIG: Limited data available; optimal dose, timing, and duration of anakinra therapy has not been defined.

Infants ≥3 months weighing ≥5 kg to <8 months weighing <10 kg: SubQ: Initial: 4 mg/kg/dose once daily; if fever persisted or recurred 24 hours after previous anakinra dose, the dose was increased in 2 mg/kg increments; maximum daily dose: 8 mg/kg/day; anakinra was continued for 14 days total of anakinra therapy.

Infants ≥8 months, Children, and Adolescents weighing ≥10 kg: SubQ: Initial: 2 mg/kg/dose once daily; if fever persisted or recurred 24 hours after previous anakinra dose, the dose was increased in 2 mg/kg increments; maximum daily dose: 6 mg/kg/day;anakinra was continued for 14 days total of anakinra therapy.

Dosing based on the largest trial (KAWAKINRA study), a phase 2, open-labeled, multicenter trial evaluating 16 patients (median age: 31 months; range: 3 to 83 months), which initiated anakinra for recurrent or persistent fever 48 hours after the last dose of IVIG; after the last escalation of dose, 87.5% in the per protocol group were afebrile and 75% in the intent-to-treat group.

Reported dosing from smaller case series and reports: 1 to 10 mg/kg/day in 1 to 2 divided doses; in several reports, doses were initiated at the low to mid-range (1 to 6 mg/kg) and titrated based on response and subsequently tapered to discontinued therapy; the duration of therapy variable, up to 180 days has been reported.

Multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2: Very limited data available: Note: Recommended for intensification therapy in patients who do not improve within 24 hours of initial MIS-C therapy (ie, immune globulin and methylprednisolone); do not use in combination with infliximab.

Infants, Children, and Adolescents: IV, SUBQ: 5 to 10 mg/kg/day in 1 to 4 divided doses; duration varies and is dependent upon clinical course; tapering over at least 2 to 3 weeks has been suggested. Note: While poorly documented, the IV route may be preferred for MIS-C.

Neonatal-onset multisystem inflammatory disease (NOMID) or chronic infantile neurological, cutaneous, and articular syndrome (CINCA) [cryopyrin-associated periodic syndromes (CAPS)]:

Infants, Children, and Adolescents: SubQ: Initial: 1 to 2 mg/kg/day in 1 to 2 divided doses; adjust dose in 0.5 to 1 mg/kg increments as needed to control inflammation; usual maintenance dose: 3 to 4 mg/kg/day; maximum daily dose: 8 mg/kg/day. Note: Once-daily administration is preferred; however, the dose may also be divided and administered twice daily.

Rheumatoid arthritis: Adolescents ≥18 years: SubQ: 100 mg once daily; administer at approximately the same time each day.

The dietary restriction should be individualized as per patient requirements.

Anakinra may be contraindicated in the following conditions:-

Hypersensitivity to E. coli-derived proteins or anakinra. Neutropenia (absolute neutrophil count <1.5 x 10⁹/L). Severe renal impairment (CrCl <30 mL/min).

The treating physician must closely monitor the patient and keep pharmacovigilance as follows

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported. Patients with deficiency of interleukin-1 receptor antagonist (DIRA) may have an increased risk of allergic reactions, especially within the first few weeks of initiating therapy; monitor closely. Discontinue use if severe hypersensitivity occurs; medications for the treatment of hypersensitivity reactions should be available for immediate use.
• Infections: Associated with an increased risk of serious infections in rheumatoid arthritis studies. Anakinra should not be initiated in patients with an active infection. If a patient receiving anakinra for rheumatoid arthritis develops a serious infection, therapy should be discontinued; if a patient receiving anakinra for neonatal-onset multisystem inflammatory disease (NOMID) or DIRA develops a serious infection, the risk of a disease flare should be weighed against the risks associated with continued treatment. Safety and efficacy have not been evaluated in immunosuppressed patients or patients with chronic infections; the impact on active or chronic infections has not been determined. Immunosuppressive therapy (including anakinra) may lead to reactivation of tuberculosis (TB) infection (latent TB) or other atypical or opportunistic infections; test patients for TB infection prior to initiation, and treat TB infection prior to use.
• Injection site reactions: Injection site reactions commonly occur (within first 4 weeks of therapy) and are generally mild with a duration of 14 to 28 days. Patients who do not experience an injection site reaction within the first 4 weeks of therapy are not likely to experience one; the incidence of injection site reactions may be lower in patients on concomitant oral corticosteroids.
• Malignancy: May affect defenses against malignancies; impact on the development and course of malignancies is not fully defined. As compared to the general population, an increased risk of lymphoma has been noted in clinical trials; however, rheumatoid arthritis has been previously associated with an increased rate of lymphoma.

• Neutropenia: A decrease in neutrophil count may occur during treatment. Assess neutrophil count at baseline, monthly for 3 months, then every 3 months for up to 1 year. In a limited number of patients with NOMID, neutropenia resolved over time with continued anakinra administration.

There is no sufficient scientific evidence traceable regarding use and safety of Anakinra in concurrent use with alcohol.

There is no sufficient scientific evidence traceable regarding use and safety of Anakinra in concurrent use with any particular food.

There is no sufficient scientific evidence traceable regarding use and safety of Anakinra in concurrent use with any particular food.

The adverse reactions related to Anakinra can be categorized as

• Common Adverse effects: erythema, bruising, swelling and pain, headache, nausea.
• Less Common Adverse effects: diarrhea, abdominal pain, elevated transaminases, non-infectious hepatitis.
• Rare Adverse effects: allergic reactions e.g. rashes.

The clinically relevant drug interactions of Anakinra is briefly summarized here

Enhanced adverse effects of live vaccines. Co-admin w/ etanercept or other tumour necrosis factor (TNF) inhibitors may induce serious infection and neutropenia.

The common side of Anakinra include the following

Erythema, Bruising, Swelling and Pain, Headache, Nausea.

Pregnancy

Teratogenic effects: Pregnancy Category B: There are no adequate and well-controlled studies of Anakinra in pregnant women. Reproductive studies have been performed in rats and rabbits at doses up to 25 times the maximum recommended human dose (on a mg/kg basis at a maternal dose of 200 mg/kg/day) and have revealed no evidence of impaired fertility or harm to the fetus due to Anakinra. Because animal reproduction studies are not always predictive of human response, Anakinra should be used during pregnancy only if clearly needed.

Nursing Mothers

It is not known whether Anakinra is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised if Anakinra is administered to nursing women.

Pediatric Use

The NOMID study included 36 pediatric patients: 13 below 2 years, 18 between 2 and 11 years, and 5 between 12 and 17 years of age. A subcutaneous Anakinra starting dose of 1–2 mg/kg/day was administered in all age groups. An average maintenance dose of 3–4 mg/kg/day was adequate to maintain clinical response throughout the study irrespective of age but a higher dose was, on occasion, required in severely affected patients. The prefilled syringe does not allow doses lower than 20 mg to be administered. Anakinra was studied in a single randomized, blinded multi-center trial in 86 patients with polyarticular course Juvenile Rheumatoid Arthritis receiving a dose of 1 mg/kg subcutaneously daily, up to a maximum dose of 100 mg. The 50 patients who achieved a clinical response after a 12-week open-label run-in were randomized to Anakinra (25 patients) or placebo (25 patients), administered daily for an additional 16 weeks. A subset of these patients continued open-label treatment with Anakinra for up to 1 year in a companion extension study. An adverse event profile similar to that seen in adult RA patients was observed in these studies. These study data are insufficient to demonstrate efficacy and, therefore, Anakinra is not recommended for pediatric use in Juvenile Rheumatoid Arthritis.

Geriatric Use

A total of 752 RA patients ≥ 65 years of age, including 163 patients ≥ 75 years of age, were studied in clinical trials. No differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Because there is a higher incidence of infections in the elderly population in general, caution should be used in treating the elderly. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Renal Impairment

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function

Hepatic Impairment

No formal studies have been conducted examining the pharmacokinetics of Anakinra administered subcutaneously in patients with hepatic impairment

• Pharmacodynamics:

Anakinra blocks the biologic activity of IL-1 alpha and beta by competitively inhibiting IL-1 binding to the interleukin-1 type I receptor (IL-1RI), which is expressed in a wide variety of tissues and organs. IL-1 production is induced in response to inflammatory stimuli and mediates various physiologic responses including inflammatory and immunological responses. IL-1 has a broad range of activities including cartilage degradation by its induction of the rapid loss of proteoglycans, as well as stimulation of bone resorption. The levels of the naturally occurring IL-1Ra in synovium and synovial fluid from RA patients are not sufficient to compete with the elevated amount of locally produced IL-1. Spontaneous mutations in the CIAS1/NLRP3 gene have been identified in a majority of patients with cryopyrin-associated periodic syndromes such as NOMID. CIAS1/NLRP3 encodes for cryopyrin, a component of the inflammasome. The activated inflammasome results in proteolytic maturation and secretion of IL-1β, which has an important role in the systemic inflammation and manifestations of NOMID.

• Pharmacokinetics:

Absorption:

The bioavailability of anakinra is 95% in healthy subjects administered a 70 mg subcutaneous bolus injection. In patients with rheumatoid arthritis (RA) administered a subcutaneous dose of anakinra, the maximum plasma concentration was detected 3 to 7 hours later.

Distribution The volume of distribution averaged 18.5 L

Metabolism: As a protein-based therapy, anakinra is expected to be metabolized by proteases throughout the body.

Excretion: Anakinra is mostly excreted by the kidney; therefore, the risk of toxic reactions may increase in patients with impaired renal function.

1. https://www.uptodate.com/contents/Anakinra -drug-information?search=Anakinra &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Anakinra _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Anakinra ?type=full&mtype=generic#mechanism-of-action