C1 esterase inhibitor subcutaneous (Haegarda)

C1 esterase inhibitor subcutaneous (Haegarda)
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yashasvi Aryaputra[2], Anmol Pitliya, M.B.B.S. M.D.[3]

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Overview

C1 esterase inhibitor subcutaneous (Haegarda) is a plasma-derived concentrate of C1 esterase inhibitor (human) (C1-INH) that is FDA approved for the prevention of hereditary angioedema (HAE) attacks. Common adverse reactions include injection site reaction, hypersensitivity, nasopharyngitis and dizziness.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications:

• C1 esterase inhibitor subcutaneous is a plasma-derived concentrate of C1 esterase inhibitor (Human) (C1-INH) indicated for routine prophylaxis to prevent hereditary angioedema (HAE) attacks in adolescent and adult patients.

Dosage:

• C1 esterase inhibitor subcutaneous is intended for self-administration after reconstitution at a dose of 60 International Units (IU) per kg body weight by subcutaneous (S.C.) injection twice weekly (every 3 or 4 days). The patient or caregiver should be trained on how to administer C1 esterase inhibitor subcutaneous.

• C1 esterase inhibitor subcutaneous is provided as a freeze-dried powder for reconstitution with sterile water for injection, USP.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding C1 esterase inhibitor subcutaneous Off-Label Guideline-Supported Use and Dosage (Adult) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding C1 esterase inhibitor subcutaneous Off-Label Non-Guideline-Supported Use and Dosage (Adult) in the drug label.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding C1 esterase inhibitor subcutaneous (Haegarda) FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding C1 esterase inhibitor subcutaneous Off-Label Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Non–Guideline-Supported Use

There is limited information regarding C1 esterase inhibitor subcutaneous Off-Label Non-Guideline-Supported Use and Dosage (Pediatric) in the drug label.

Contraindications

• C1 esterase inhibitor subcutaneous is contraindicated in individuals who have experienced life-threatening hypersensitivity reactions, including anaphylaxis, to C1-INH preparations or its excipients.

Warnings

Hypersensitivity

• Severe hypersensitivity reactions may occur. The signs and symptoms of hypersensitivity reactions may include hives (local and generalized), tightness of the chest, difficulty breathing, wheezing, hypotension, and/or anaphylaxis during or after injection of C1 esterase inhibitor subcutaneous. In case of severe hypersensitivity, discontinue C1 esterase inhibitor subcutaneous administration and institute appropriate treatment. Epinephrine should be immediately available for treatment of severe hypersensitivity reaction.

Thromboembolic Events

• At the recommended subcutaneous dose, a causal relationship between thromboembolic events (TEEs) and the use of C1 esterase inhibitor subcutaneous has not been established. Thrombosis has occurred in treatment attempts with high doses of C1-INH intravenous (I.V.) for prevention or therapy of capillary leak syndrome before, during or after cardiac surgery (unapproved indication and dose).

Transmissible Infectious Agents

• Because C1 esterase inhibitor subcutaneous is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by processes demonstrated to inactivate and/or remove certain viruses during manufacturing. Despite these measures, such products may still contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated.

• All infections thought by a physician possibly to have been transmitted by C1 esterase inhibitor subcutaneous should be reported by lot number, by the physician or other healthcare provider, to the CSL Behring Pharmacovigilance Department at 1-866-915-6958.

Adverse Reactions

Clinical Trials Experience

• Because clinical studies 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.

• Of the 90 subjects randomized in the double-blind, placebo-controlled, cross-over study, 86 subjects received at least one dose of C1 esterase inhibitor subcutaneous and 86 subjects received at least one dose of placebo (Table 2). A total of 5081 injections of C1 esterase inhibitor subcutaneous and placebo were administered over a range of 3 to 19 weeks (median of 16.6 weeks for C1 esterase inhibitor subcutaneous; median of 16.3 weeks for placebo).

This image is provided by the National Library of Medicine.

• Of the injection site reactions occurring after treatment with C1 esterase inhibitor subcutaneous, 95% were of mild intensity and 83% resolved within 1 day after onset.

Postmarketing Experience

There is limited information regarding C1 esterase inhibitor subcutaneous (Haegarda) Postmarketing Experience in the drug label.

Drug Interactions

There is limited information regarding C1 esterase inhibitor subcutaneous (Haegarda) Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

Risk Summary

• There are no prospective clinical data from C1 esterase inhibitor subcutaneous use in pregnant women. C1-INH is a normal component of human plasma. Animal developmental or reproduction toxicity studies have not been conducted with C1 esterase inhibitor subcutaneous. In the U.S. general population, the estimated background risk of major birth defects occurs in 2-4% of the general population and miscarriage occurs in 15-20% of clinically recognized pregnancies.

Data

• In a retrospective case collection study, 22 pregnant women with type I HAE and ranging in age from 20 to 38 years received C1-INH doses of 500 or 1000 IU per I.V. administration for the treatment of acute attacks before, during, and/or after pregnancy (total of 35 pregnancies). No adverse events were associated with C1-INH treatment before, during, or after pregnancy.1

• In an observational registry (overall 318 subjects) data were collected on 11 pregnancies in 10 subjects (16 to 40 years old) receiving up to 3000 IU C1-INH (I.V. administration) to treat or prevent HAE attacks. No adverse events were associated with C1-INH treatment.2

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of C1 esterase inhibitor subcutaneous (Haegarda) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of C1 esterase inhibitor subcutaneous (Haegarda) during labor and delivery.

Nursing Mothers

Risk Summary

• There is no information regarding the excretion of C1 esterase inhibitor subcutaneous in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for C1 esterase inhibitor subcutaneous and any potential adverse effects on the breastfed infant from C1 esterase inhibitor subcutaneous or from the underlying maternal condition.

Data

• In a retrospective case collection study, breastfeeding was documented for neonates from 21 of 35 births with a median duration of 4.8 months (ranging from 1 to 34 months). Mothers were treated postpartum with C1-INH doses up to 1000 IU per I.V. administration for the treatment of acute HAE attacks. No adverse events to the mothers were associated with C1-INH treatment after pregnancy. No information regarding the effect on the breastfed infant was reported.1

Pediatric Use

• The safety and effectiveness of C1 esterase inhibitor subcutaneous were evaluated in a subgroup of six patients 12 to <17 years of age in the randomized, double-blind, placebo-controlled, crossover, routine prophylaxis trial. Results of subgroup analysis by age were consistent with overall study results.

Geriatic Use

• The safety and effectiveness of C1 esterase inhibitor subcutaneous were evaluated in a subgroup of eight patients 65 to 72 years of age in the randomized, double-blind, placebo-controlled, crossover, routine prophylaxis trial. Results of subgroup analysis by age were consistent with overall study results.

Gender

There is no FDA guidance on the use of C1 esterase inhibitor subcutaneous (Haegarda) with respect to specific gender populations.

Race

There is no FDA guidance on the use of C1 esterase inhibitor subcutaneous (Haegarda) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of C1 esterase inhibitor subcutaneous (Haegarda) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of C1 esterase inhibitor subcutaneous (Haegarda) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of C1 esterase inhibitor subcutaneous (Haegarda) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of C1 esterase inhibitor subcutaneous (Haegarda) in patients who are immunocompromised.

Administration and Monitoring

Administration

• For subcutaneous injection only.

• Train the patient or caregiver on how to self-administer C1 esterase inhibitor subcutaneous.

• Do not mix C1 esterase inhibitor subcutaneous with other medicinal products.

• Visually inspect the final solution for particles and discoloration prior to administration, and whenever solution and container permit. Do not use if particles or discoloration is observed.

• Attach the syringe containing the reconstituted C1 esterase inhibitor subcutaneous solution to a hypodermic needle or subcutaneous infusion set and administer by subcutaneous injection. Adapt the rate of administration to the comfort level of the patient.

• Inject in the abdominal area or other subcutaneous injection sites. Rotate injection sites so that the same site is not used repeatedly.

• Administer C1 esterase inhibitor subcutaneous at room temperature and within 8 hours after reconstitution. Following administration, discard any unused solution and all administration equipment in an appropriate manner as per local requirements.

Monitoring

• Reduction in number, severity, and duration of swelling attacks.

• Symptoms of hypersensitivity during or after infusion.

• Thromboembolic events, in patients with risk factors; during and after treatment.

IV Compatibility

There is limited information regarding the compatibility of C1 esterase inhibitor subcutaneous (Haegarda) and IV administrations.

Overdosage

• No case of overdose has been reported. Doses corresponding to up to 117 IU/kg S.C. have been administered twice weekly in a fixed-dose clinical study.

Pharmacology

C1 esterase inhibitor subcutaneous (Haegarda)
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Mechanism of Action

• C1-INH is a normal constituent of human plasma and belongs to the group of serine protease inhibitors (serpins) that includes antithrombin III, alpha1-protease inhibitor, alpha2-antiplasmin, and heparin cofactor II. As with the other inhibitors in this group, C1-INH has an important inhibiting potential on several of the major human cascade systems, including the complement, fibrinolytic and coagulation systems. Regulation of these systems is performed through the formation of complexes between the protease and the inhibitor, resulting in inactivation of both and consumption of the C1-INH.

• C1-INH, which is usually activated during the inflammatory process, inactivates its substrate by covalently binding to the reactive site. C1-INH is the only known inhibitor for the C1r and C1s subcomponents of complement component 1 (C1), coagulation factor XIIa, and plasma kallikrein. Additionally, C1-INH is the main inhibitor for coagulation factor XIa of the intrinsic coagulation cascade.

• HAE patients have absence or low levels of endogenous or functional C1-INH. Although the events that cause attacks of angioedema in HAE patients are not well defined, it has been postulated that increased vascular permeability and the clinical manifestation of HAE attacks may be primarily mediated through contact system activation. Suppression of contact system activation by C1-INH through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin. Administration of C1 esterase inhibitor subcutaneous replaces the missing or malfunctioning C1-INH protein in patients with HAE.

Structure

There is limited information regarding C1 esterase inhibitor subcutaneous (Haegarda) Structure in the drug label.

Pharmacodynamics

• In untreated patients, insufficient levels of functional C1-INH lead to increased activation of C1, which results in decreased levels of complement component 4 (C4). The administration of C1 esterase inhibitor subcutaneous increases plasma levels of C1-INH in a dose-dependent manner and subsequently increases plasma concentrations of C4. The C4 plasma concentrations after S.C. administration of 60 IU/kg C1 esterase inhibitor subcutaneous were in the normal range (16 to 38 mg/dL).

Pharmacokinetics

• The pharmacokinetics (PK) of C1-INH were described using population PK analysis.

• The PK parameters of C1-INH following twice weekly subcutaneous 60 IU/kg dosing are shown in Table 4.

This image is provided by the National Library of Medicine.

• The steady state PK of S.C. C1-INH is independent of dose between 20-80 IU/kg in HAE subjects.

• Studies have not been conducted to evaluate the PK of C1-INH in specific patient populations stratified by gender, race, age, or the presence of renal or hepatic impairment. The PK of C1-INH was not influenced at the age range of 12-72 years.

Nonclinical Toxicology

(Description)

Clinical Studies

• The efficacy and safety of C1 esterase inhibitor subcutaneous for routine prophylaxis to prevent HAE attacks were demonstrated in a multicenter, randomized, double-blind, placebo-controlled, crossover study. The study assessed 90 adult and adolescent subjects with symptomatic HAE type I or II. The median (range) age of subjects was 40 (12 to 72) years; 60 subjects were female and 30 subjects were male. Subjects were randomized to receive either 60 IU/kg or 40 IU/kg C1 esterase inhibitor subcutaneous in one 16-week treatment period and placebo in the other 16-week treatment period. Patients self-administered C1 esterase inhibitor subcutaneous or placebo subcutaneously 2 times per week. Efficacy was evaluated for the last 14 weeks of each treatment period.

• Twice per week S.C. doses of 60 IU/kg or 40 IU/kg C1 esterase inhibitor subcutaneous resulted in a significant difference in the time-normalized number of HAE attacks (the rate of attacks) relative to placebo (Table 5). The time normalized number of HAE attacks in subjects dosed with 60 IU/kg was 0.52 attacks per month compared to 4.03 attacks per month while receiving placebo (p <0.001). The time normalized number of HAE attacks in subjects dosed with 40 IU/kg was 1.19 attacks per month compared to 3.61 attacks per month while receiving placebo (p <0.001).

This image is provided by the National Library of Medicine.

• The median (25th, 75th percentile) percentage reduction in the time-normalized number of HAE attacks relative to placebo was 95% (79, 100) on 60 IU/kg C1 esterase inhibitor subcutaneous and 89% (70, 100) on 40 IU/kg C1 esterase inhibitor subcutaneous among subjects with evaluable data in both treatment periods.

• The percentage of responders (95% CI) with a ≥50% reduction in the time-normalized number of HAE attacks on C1 esterase inhibitor subcutaneous relative to placebo was 83% (73%, 90%). Ninety percent (90%) of subjects on 60 IU/kg responded to treatment and 76% of subjects on 40 IU/kg responded to treatment.

• The percentages of subjects (95% CI) with ≥70% and ≥90% reductions in the time-normalized number of HAE attacks on C1 esterase inhibitor subcutaneous relative to placebo were 74% (64%, 83%) and 50% (39%, 61%), respectively. The percentages of subjects with ≥70% and ≥90% reductions in comparison to placebo in the time-normalized number of HAE attacks were 83% and 58% on 60 IU/kg and 67% and 43% on 40 IU/kg. Seventy-one percent (71%) of subjects on 60 IU/kg and 53% of subjects on 40 IU/kg had ≥1 HAE attack per 4 week period on placebo and <1 HAE attack per 4 week period on C1 esterase inhibitor subcutaneous.

• A total of 40% of subjects on 60 IU/kg and 38% of subjects on 40 IU/kg were attack-free, and the median rate of HAE attacks per month was 0.3 on both doses.

• C1 esterase inhibitor subcutaneous resulted in a significant difference in the time-normalized number of uses of rescue medication (the rate of rescue medication use) relative to placebo. A dose of 60 IU/kg resulted in a mean rate of rescue medication of 0.3 uses per month, compared to 3.9 uses per month with placebo. A dose of 40 IU/kg resulted in a mean rate of rescue medication use of 1.1 uses per month, compared to 5.6 uses per month with placebo.

How Supplied

• C1 esterase inhibitor subcutaneous is supplied in a kit containing a lyophilized powder in a single-use vial.

• C1 esterase inhibitor subcutaneous is packaged with Sterile Water for Injection, USP (4 mL for reconstitution of 2000 IU or 6 mL for reconstitution of 3000 IU) and one Mix2Vial filter transfer set. Not made with natural rubber latex.

This image is provided by the National Library of Medicine.

Storage

• When stored at temperatures up to 30°C (86°F), C1 esterase inhibitor subcutaneous is stable for the period indicated by the expiration date on the carton and vial label.

• Keep C1 esterase inhibitor subcutaneous in its original carton until ready to use.

• Do not freeze.

• Protect from light.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

• All risks and benefits of C1 esterase inhibitor subcutaneous should be discussed with the patient/caregiver before prescribing or administering it to the patient.

Inform patients/caregivers to immediately report the following to their physician:

• Signs and symptoms of allergic hypersensitivity reactions, such as hives, tightness of the chest, difficulty breathing, wheezing, hypotension and/or anaphylaxis experienced during or after injection of C1 esterase inhibitor subcutaneous.

• Signs and symptoms of a thromboembolic event, including pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body.

Inform all patients/caregivers:

• C1 esterase inhibitor subcutaneous is indicated for HAE prophylaxis and should not be used for the treatment of acute HAE attacks. Patients/caregivers should be counselled regarding the appropriate course of action if breakthrough HAE attacks occur while on C1 esterase inhibitor subcutaneous, including:

• Individualized rescue treatment for acute HAE attacks.

• Situations in which to seek immediate medical attention, such as acute laryngeal HAE attacks.

• Patients/caregivers must ensure an adequate supply of C1 esterase inhibitor subcutaneous when traveling.

• Because C1 esterase inhibitor subcutaneous is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. Inform patients of the risks and benefits of C1 esterase inhibitor subcutaneous before prescribing or administering it to the patient.

• Patients with known risk factors for thromboembolic events are at an increased risk for these events.

• Ensure that the patient/caregiver has access to and has received training in the administration of subcutaneous epinephrine and/or other appropriate supportive therapy for the treatment of any acute anaphylactic or severe hypersensitivity reaction.

Advise female patients:

• Patients should notify their physician if they become pregnant or intend to become pregnant while taking C1 esterase inhibitor subcutaneous.

• Patients should notify their physician if they are breastfeeding or plan to breastfeed while taking C1 esterase inhibitor subcutaneous.

• Self-administration - Ensure that the patient/caregiver receives clear instructions and training on S.C. administration in the home or other appropriate setting and has demonstrated the ability to perform S.C. injection.

• The patient (or caregiver) has the necessary dexterity and comprehension to be trained to self-administer.

• Instruct patients/caregivers to record the lot number from the C1 esterase inhibitor subcutaneous vial label every time they use C1 esterase inhibitor subcutaneous.

• The attached C1 esterase inhibitor subcutaneous "Patient Product Information (PPI)" contains more detailed instructions for patients/caregivers who will be self-administering C1 esterase inhibitor subcutaneous.

Precautions with Alcohol

Alcohol-C1 esterase inhibitor subcutaneous (Haegarda) interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

• Haegarda

Look-Alike Drug Names

There is limited information regarding C1 esterase inhibitor subcutaneous (Haegarda) Look-Alike Drug Names in the drug label.

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.