Takzhyro was approved by the FDA in August 2018 for prophylaxis to prevent attacks of hereditary angioedema (HAE) in patients 12 years and older. Takzyhro (lanadelumab-flyo) is a non-plasma derived recombinant, fully human, monoclonal antibody that binds plasma kallikrein and inhibits its proteolytic activity. It is supplied as a ready-to-use sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution in a single-dose glass vial for subcutaneous administration.


[INFORMATIONAL NOTES:

• Acute treatment management: According to the 2013 US HAE Association Consensus Guidelines, all patients with HAE due to C1-INH deficiency should have access to at least two standard doses of one“on-demand” treatment for acute HAE attacks (Firazyr, Berinert, Kalbitor, Ruconest). Patients should also have access to a management plan with easy access to their health care provider during an acute attack; On-demand treatment most effective early in the attack when swelling is mild; if self-administering treatment, patients should seek medical attention if ineffective in treating the attack; all attack should be considered for treatment as soon as they are clearly recognized; patients who experience symptoms of laryngeal, tongue or throat swelling should seek immediate medical attention even after initial self-treatment.

• Prophylactic treatment management (Cinryze, Haegarda): Goal is to reduce the likelihood of swelling in a patient undergoing a stressor or procedure likely to precipitate an attack (short-term prophylaxis) ; or to decrease the number and severity of angioedema attacks (long-term prophylaxis);
  • Short-term prophylaxis is indicated prior to medical, surgical or dental procedures
  • Androgens should not be used for long-term prophylaxis if patient does not tolerate (children under 16, pregnant, breast-feeding)
  • Use lowest effective dose that controls disease activity
  • Must also have access to effective on-demand treatment of acute attacks

• According to the 2012 International Consensus Guidelines for HAE, regarding who is appropriate for prophylactic therapy, a portion of the consensus suggested insufficient benefit from on-demand treatment, as patients were having:
  • 24 days per year of HAE symptoms OR
  • 2 severe attacks per year]

• These agents may carry a risk of transmitting infectious agents, e.g. viruses, and theoretically, the Creutzfeldt-Jacob (CJD) agent. As per the FDA approved package insert, all infections thought by a physician to possibly have been transmitted by Cinryze should be reported to Lev Pharmaceuticals, Inc. at 1-877-945-1000. All infections thought by a physician to possibly have been transmitted by Berinert or Haegarda should be reported to the CSL Behring Pharmacovigilance Department at 1-866-915-6958
• Thrombotic events have been reported in association with C1 inhibitor products when used off-label at high doses.
• Severe hypersensitivity reactions may occur. Epinephrine should be immediately available to treat any acute severe hypersensitivity reaction.
• Contraindications: patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis.
• Laryngeal attacks: Following self-administration of Berinert for laryngeal attacks, advise patients to immediately seek medical attention

• Anaphylaxis has been reported after administration of Kalbitor. Because of the risk of anaphylaxis, Kalbitor should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer Kalbitor to patients with known clinical hypersensitivity to Kalbitor. There is a REMS program with Kalbitor.

• Laryngeal attacks: Following treatment of laryngeal attacks with Firazyr, advise patients to immediately seek medical attention.

• Hypersensitivity reactions, including anaphylaxis may occur. Should symptoms occur, discontinue Ruconest and administer appropriate treatment.
• Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Monitor patients with known risk factors for TE events during and after Ruconest administration.

• Hypersensitivity reactions have been observed. In case of a severe hypersensitivity reaction, discontinue. ]

1. Type I HAE:
• Two separate measurements indicating decreased levels of complement component 4 (C4) (<14 mg/dL; normal 14-40 mg/dL) OR
• Low C1 esterase-inhibitor (C1-INH) antigenic level defined as below the lower limit of normal as defined by the laboratory performing the test
• Low C1INH functional level below the lower limit of normal as defined by the laboratory performing the test (<19 mg/dL; normal range 19-37 mg/dL) AND
• Family history of hereditary angioedema; OR
• Acquired angioedema has been ruled out (e.g., patient onset of symptoms occur prior to 30 years old, normal C1q levels, patient does not have underlying disease such as lymphoma or benign monoclonal gammopathy [MGUS], etc. OR
• Onset of HAE symptoms occurred before age 30; OR
2. Type II HAE:
• Low complement component 4 (C4) level (<14 mg/dL; normal 14-40 mg/dL) AND
• Normal to elevated C1 esterase-inhibitor (C1-INH) protein level (normal range 19-37 mg/dL) AND
• Determine C1-INH functional level and repeat C4 and C1-INH levels.
  • Decreased C1-INH functional level confirms a diagnosis of Type II HAE; OR
3. Type III HAE
• Individuals with normal complement component 4 (C4) and C1 esterase-inhibitor (C1-INH) ) antigenic and functional levels both during an attack and at baseline are classified as Type III HAE.
• Patient must have a family history of angioedema
• Demonstration of a Factor XII mutation that is associated with the disease.
AND

4. The prescriber is a specialist in the area of the patients's diagnosis (e.g. allergist, immunologist) or the prescriber has consulted with a specialist in the area of the patient's diagnosis

1. The C1 inhibitor (Cinryze) is medically necessary for the FDA-approved indication of routine prophylaxis against angioedema attacks in adults and adolescents with HAE, when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Member must be at least 6 years of age or older; AND
• For long term prophylaxis, the patient must meet the following (documentation of medical records required):
  • History of at least two severe HAE attacks (i.e. airway swelling, debilitating cutaneous or gastrointestinal episodes) per month OR disability for > 5 days per month due to HAE; OR
  • History of at least one laryngeal attack caused by HAE; AND
  • Treatment of patient with “on demand” therapy (i.e. Kalbitor, Firazyr, Ruconest, or Berinert) did not provide satisfactory control or access to “on demand therapy" is limited OR for short-term prophylaxis if prior to medical, surgical, dental procedure; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member has access to on-demand treatment with either Firazyr, Berinert, Ruconest, or Kalbitor; AND
• Not used in combination with other C1 inhibitor prophylaxis (i.e. Haegarda or Takhzyro)
[INFORMATIONAL NOTE:
In the trial conducted by Zuraw et al., Cinryze was studied in patients who had low functional C1 inhibitor level or had a mutation in the C1 inhibitor gene known to cause HAE. Patients with estrogen-related HAE or high levels of factor XII were not mentioned specifically. Based on these characteristics, the study population for Cinryze included type I and II patients, but not type III. Although the study showed statistically significant improvement in the time from administration of drug to unequivocal relief of symptoms, the applicability of these data is limited to type I and II patients.

Safety and effectiveness of Cinryze have not been established in neonates, infants, or children. Only, 3 of the 24 subjects in the pivotal trial were under the age of 18 years (9, 14, and 16 years of age).]

2. When the C1 inhibitor (Cinryze) is medically necessary, initial therapy will be approved for a period of 12 weeks at the FDA recommended dose of 1,000 units intravenously every 3 or 4 days. For patients who have not responded adequately to initial dosing, doses up to 2,500 U (not exceeding 100 U/kg) every 3 or 4 days may be considered based on individual patient response. Dosing in pediatric patients age 6 to 11 years old is 500 units given intravenously every 3 to 4 days. For patients who have not responded adequately to initial dosing, doses up to 1,000 U every 3 or 4 days may be considered

• Member continues to meet initial criteria; AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions, thrombotic events, laryngeal attacks) AND
  • Significant improvement in severity and duration of attacks have been achieved and sustained (documentation of medical records required); OR
  • Patient requires dose titration due to an inadequate response to therapy (> 1.0 HAE attack/month, regardless of severity/duration) (documentation of medical records required)
4. Other uses of the C1 inhibitor (Cinryze) are considered investigational, including but not limited to:
• Acute ST segment elevation myocardial infarction
• Sepsis
• Streptococcal toxic shock syndrome
• Treatment of an acute attack of hereditary angioedema (HAE)
• Children less than 6 years old.
• [INFORMATIONAL NOTE: Currently, the FDA has not approved any form of HAE prophylactic therapy in the pediatric population. In the phase 3 trial being conducted by Aygören-Pürsün et al., Cinryze was studied in 6 female patients with type I HAE and a median age of 10.5 years. Patients received either a 500 units or 1000 units dose every 3-4 days for 12 weeks. Interim analysis depicted significant improvements in reducing HAE exacerbations per month (500 units: -1.89(-84.8%); 1000 units: -1.89 (-88.1%)). Attacks that did occur were determined to be less severe and required less use of rescue medication. There was a lack of serious drug-related adverse events. This trial reinforced previous clinical data supporting the use of Cinryze as prophylactic therapy in children 6 years old and above. However, the study is still ongoing and the applicability of this data in a larger scale pediatric population is still to be determined. ]

1. C1 inhibitor (Haegarda) is medically necessary for the FDA-approved indication of routine prophylaxis to prevent HAE when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Members must be at least 12 years of age or older; AND
• For long-term prophylaxis, the patient must meet the following (documentation of medical records required):
  • History of at least two severe HAE attacks (i.e. airway swelling, debilitating cutaneous or gastrointestinal episodes) per month OR disability for > 5 days per month due to HAE; OR
  • History of of at least one laryngeal attack caused by HAE; AND
  • Treatment of patient with “on demand” therapy (i.e. Kalbitor, Firazyr, Ruconest, or Berinert) did not provide satisfactory control or access to “on demand therapy" is limited OR for short-term prophylaxis if prior to medical, surgical, dental procedure; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member has access to on-demand treatment with either Firazyr, Berinert, Ruconest, or Kalbitor; AND
• Not used in combination with other C1 inhibitor prophylaxis (i.e. Cinzyre or Takhzyro)

2. When C1 inhibitor (Haegarda) is medically necessary, initial therapy will be approved for a period of 16 weeks at the FDA recommended dose of 60 units/kg subcutaneously twice weekly.

3. Continued therapy will be approved every 6 months after the initial 16-week period:
• Member continues to meet initial criteria;AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions, thrombotic events, laryngeal attacks); AND
  • Member achieved and sustained improvement in severity and duration of attacks (documentation of medical records required); OR
  • Patient requires dose titration due to an inadequate response to therapy (> 1.0 HAE attack/month, regardless of severity/duration) (documentation of medical records required);
4. Other uses of the C1 inhibitor (Haegarda) are considered investigational.

1. Lanadelumab-flyo (Takhzyro) is medically necessary for the FDA-approved indication of prophylaxis to prevent HAE when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Members must be at least 12 years of age or older; AND
• For long-term prophylaxis, the patient must meet the following (documentation of medical records required):
  • History of at least two severe HAE attacks (i.e. airway swelling, debilitating cutaneous or gastrointestinal episodes) per month OR disability for > 5 days per month due to HAE; OR
  • History of at least one laryngeal attack caused by HAE; AND
  • Treatment of patient with “on demand” therapy (i.e. Kalbitor, Firazyr, Ruconest, or Berinert) did not provide satisfactory control or access to “on demand therapy" is limited OR for short-term prophylaxis if prior to medical, surgical, dental procedure; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member has access to on-demand treatment with either Firazyr, Berinert, Ruconest, or Kalbitor; AND
• Not used in combination with other C1 inhibitor prophylaxis (i.e. Cinzyre or Haegarda)
  

2. When lanadelumab-flyo (Takhzyro) is medically necessary, initial therapy will be approved for a period of 6 months at the FDA recommended dose of 300 mg subcutaneously every 2 weeks. A dosing interval of 300 mg every 4 weeks is also effective and may be considered if the patient is well controlled(e.g., attack free) for more than 6 months.

3. Continued therapy will be approved every 6 months after the initial approval period:
• Member continues to meet initial criteria; AND
• Member achieved and sustained improvement in severity and duration of attacks (documentation of medical records required); AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions, thrombotic events, laryngeal attacks)
• A dosing interval of 300 mg every 4 weeks will be required if the patient is well controlled (i.e., attack free) for more than 6 months, unless the prescriber has submitted documentation in support of using the 300mg every 2 weeks dosing (documentation of medical records required).
4. Other uses of the lanadelumab-flyo (Takhzyro) are considered investigational.

1. The C1 inhibitor (Berinert) is medically necessary for the FDA-approved indication of treatment of acute abdominal, facial, or laryngeal attacks of HAE in adult and pediatric patients, when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Member has a known HAE-causing mutation (e.g., mutation of coagulation factor XII gene [F12 mutation], mutation in the angiopoietin-1 gene, mutation in the plasminogen gene, etc.) (documentation of medical records required); AND
• Member must be at least 5 years of age or older; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member will not also be receiving Firazyr, Ruconest, or Kalbitor
[INFORMATIONAL NOTE:
The safety and efficacy of Berinert in the treatment of acute abdominal of facial attacks in HAE was assessed in a placebo-controlled, dose-finding, three-arm clinical study that enrolled 124 adults and pediatric patients with C1 esterase inhibitor deficiency who were experiencing an acute moderate or severe attack, Since only type I and II HAE involves C1-INH deficiency, the study population of this trial did not include type III patients. The applicability of Berinert’s pivotal trial to the type III HAE population is unclear at this time.

[As per FDA approved package insert, safety and efficacy of Berinert have been evaluated in 12 pediatric patients (ages 10 through 16 years) in placebo controlled and open-label extension studies. Berinert was also evaluated in 18 pediatric patients (ages 5 through 11 years) in a Registry Study conducted in US and Europe. The safety profile observed in pediatric population was similar to that observed in adults.]

2. When the C1 inhibitor (Berinert) is medically necessary, initial therapy will be approved for 6 months at 30 days quantity of two doses intravenously at 20 units per kg body weight for storage in anticipation of an acute attack of HAE.

3. Continued therapy will be approved for 6 months at 30 days quantity of 1 or 2 intravenous doses (20 units/kg) per request, provided that the previous dose or doses has been depleted (Member is to have doses available for two attacks) AND
• Member continues to meet initial criteria; AND
• Member achieved and sustained improvement in severity and duration of attacks (documentation of medical records required); AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions)
[INFORMATIONAL NOTE: Berinert is dosed at 20 units per kg body weight. It is administered by intravenous infusion at a rate of approximately 4 mL per minute. Patients can be taught to self-administer which was added December 2011.

Severe hypersensitivity reactions may occur. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction.

When stored at temperatures of 2-25°C (36-77°F), Berinert is stable for the period indicated by the expiration date on the carton and vial label (up to 30 months). Berinert should be kept in its original carton until ready to use. It should not be frozen and should be protected from light.]

4. Other uses of the C1 inhibitor (Berinert) are considered investigational, including but not limited to:
• Acute ST segment elevation myocardial infarction
• Sepsis
• Streptococcal toxic shock syndrome
• Prophylactic therapy against attacks of hereditary angioedema
• Kidney transplantation to prevent rejection
• Acute antibody-mediated rejection (graft rejection)
• ACE inhibitor induced angioedema
[INFORMATIONAL NOTES: The safety and efficacy of Berinert for the treatment of type III HAE was evaluated in a French clinical study. Berinert is already used off-label to treat exacerbations in the HAE type III patient population in Europe. In a retrospective analysis studying data from 2007-2016 in HAE type III diagnosed patients, 35/38 HAE exacerbations were shown to have been treated effectively with the use of Berinert (22 attacks improved within 60 minutes of therapy; 9 attacks improved within 60-180 minutes of therapy; four attacks improved 180 minutes after therapy initiation). There were no serious adverse events reported and the safety profile was similar to previous trials studying Berinert. The applicability of the data to the type III HAE population in the US is unclear at this time.
Pregnancies result in higher estrogen levels which can put patients at a higher risk of HAE exacerbations. However, the FDA has not approved any medications to treat HAE specifically in the pregnant population. The safety of Berinert in the pregnant population was assessed in a recent worldwide study conducted by Fox et al. by considering neonatal health and outcomes. Administration of Berinert was shown to be safe with 8 of 11 patients reporting the birth of a healthy baby with a lack of serious drug-related adverse events (One pregnancy was voluntarily terminated, one patient suffered a spontaneous abortion determined to be unrelated to Berinert therapy, one patient exited registry before due date and was lost for follow up). Applicability of this trial is unclear at this time as the FDA suggests the use of Berinert in the HAE pregnant population only if clearly needed.

1. Ecallantide (Kalbitor) is medically necessary for the FDA-approved indication of treatment of acute attacks of HAE when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Member has a known HAE-causing mutation (e.g., mutation of coagulation factor XII gene [F12 mutation], mutation in the angiopoietin-1 gene, mutation in the plasminogen gene, etc.) (documentation of medical records required); AND
• Member must be at least 12 years of age or older; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member will not also be receiving Firazyr, Ruconest, or Berinert.

[INFORMATIONAL NOTE:
The safety and efficacy of Kalbitor was assessed in two phase III, randomized, double-blind trials, EDEMA3 and EDEMA4. EDEMA3 enrolled 72 patients who were > 10 years old, and had documented diagnosis of hereditary angioedema. Patients were randomized to receive either 30 mg ecallantide or placebo. The primary endpoint, which was treatment score at 4 hours after drug administration due to an HAE acute attack, was found to be significantly in the favor of ecallantide (46.8 vs 21.3 in placebo group; p=0.004). The secondary endpoint, change from baseline in mean symptom complex severity score, was also in favor of ecallantide (-0.88 vs -0.51 in placebo group; p=0.01). The most common adverse events that were reported were headache, nasopharyngitis, and nasal congestion.

EDEMA4 only enrolled HAE patients who presented within 8 hours of a moderate to severe HAE attack. Trial design was identical to EDEMA3, and results were similar in that patients treated with ecallantide were found to have significant improvement in the symptom score at 4 hours after dosing (p=0.01). The benefit with ecallantide was apparent at 24 hour after dosing (treatment outcome score 88.8 vs 55.1 in placebo group; p=0.03).

The FDA approval of the label expansion (include patients 12 years and older) is supported by results from EDEMA3, EDEMA5, and DX88/19, which was ongoing at the time of original approval. The efficacy and safety profile observed in pediatric patients 12 years of age and older is similar to the adult population.

The FDA recommended dose of Kalbitor is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24 hour period.

Kalbitor should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.

Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in
patients treated with Kalbitor. Patients should be observed for an appropriate period of time after drug administration, taking into account the time to onset of anaphylaxis seen in clinical trials (typically less than 30 minutes). Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.

Kalbitor should be kept refrigerated (2ºC to 8ºC/36ºF to 46ºF) and protected from light. Vials removed from refrigeration should be stored below 86ºF/30ºC and used within 14 days or returned to refrigeration until use.]

2. When ecallantide (Kalbitor) is medically necessary, initial therapy will be approved for 6 months at 30 days quantity of 4 subcutaneous doses of 30 mg (6 - 10 mg single use vials per dose).
3. Continued therapy will be approved for 6 months at 30 days quantity of 2 or 4 subcutaneous doses of 30 mg (3 or 6 - 10 mg single use vials per dose) per request, provided that the previous dose or doses has been depleted (Member is to have doses available for two attacks) AND:
• Member continues to meet initial criteria; AND
• Member achieved and sustained improvement in severity and duration of attacks (documentation of medical records required); AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions)

4. Other uses of ecallantide (Kalbitor) are considered investigational, including but not limited to:
• Prophylactic therapy against attacks of hereditary angioedema
• Reduction of surgical blood loss volume.

1. The recombinant C1 inhibitor (Ruconest) is medically necessary for the FDA-approved indication of the treatment of acute angioedema attacks in adult and adolescent patients with HAE, when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Member has a known HAE-causing mutation (e.g., mutation of coagulation factor XII gene [F12 mutation], mutation in the angiopoietin-1 gene, mutation in the plasminogen gene, etc.) (documentation of medical records required); AND
• Member must be at least 13 years of age or older; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member will not also be receiving Berinert, Kalbitor or Firazyr

[INFORMATIONAL NOTE: The safety and efficacy of RUCONEST was evaluated in 17 adolescent patients (13-17 years of age) treated for 52 HAE attacks. Eight out of 17 (47%) adolescent patients experienced adverse reactions.]

2. When recombinant C1 inhibitor (Ruconest) is medically necessary, initial therapy will be approved for 6 months at 30 days quantity of 4 intravenous doses of 50 IU per kg with a maximum of 4200 IU (4 vials) per dose per request.

[INFORMATIONAL NOTE:
The safety and efficacy of Ruconest was studied in the treatment of acute attacks in patients with hereditary angioedema were demonstrated in a placebo controlled, double-blind, randomized study (Study 1). Supportive evidence of effectiveness is provided by two double-blind, randomized, placebo-controlled studies (Studies 2 and 3). Evidence for the efficacy of repeat treatment of HAE attacks is provided from the open-label extensions (OLE) of each of the three randomized studies.

The primary efficacy endpoint was the time to beginning of relief of symptoms, assessed using patient-reported responses to two questions from a Treatment Effect Questionnaire (TEQ). To achieve the primary endpoint, a patient had to have a positive response to both questions along with persistence of improvement at the next assessment time.

Among several planned subgroup analyses, descriptive statistics showed that in US patients a median time to beginning of relief of symptoms with persistence at the primary attack location (based on TEQ) was 98 minutes [95% CI:(45,240), n=22] for those receiving RUCONEST and 90 minutes [95% CI:(50, -), n=16] for those receiving placebo. The hazard ratio for time to the beginning of relief of symptoms in this subpopulation was 1.20 [95%CI 0.48 to 3.01] for patients receiving RUCONEST as compared with patients receiving placebo.

The recommended dose of Ruconest is 50 IU per kg with a maximum of 4200 IU to be administered as a slow intravenous injection over approximately 5 minutes. If the attack symptoms persist, an additional (second) dose can be administered at the recommended dose level. Do not exceed 4200 IU per dose. No more than two doses should be administered within a 24 hour period.

Initiate treatment with Ruconest under the supervision of a qualified healthcare professional experienced in the treatment of HAE. Appropriately trained patients may self-administer upon recognition of an HAE attack.

The Ruconest package insert contains the following warning:
• Severe hypersensitivity reactions may occur. The signs and symptoms of hypersensitivity reactions may include hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and/or anaphylaxis during or after injection of Ruconest. Should symptoms occur, discontinue Ruconest and institute appropriate treatment. Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered.
• Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of plasma derived C1 esterase inhibitor products in patients with risk factors. Risk factors may include the presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens, morbid obesity, and immobility. Monitor patients with known risk factors for TE events during and after Ruconest administration.

Shelf life is 48 months when stored at 2°C to 25°C (36°F to 77°F). Do not freeze. Each vial of RUCONEST should be reconstituted with 14 mL water for injection (not supplied). The reconstituted solution contains 150 IU/mL rhC1INH and is clear and colorless. Each vial of Ruconest is for single use only. Ruconest contains no preservative. Any product that has been reconstituted should be used immediately, or within 8 hours stored at 2°C to8°C (36°F to46°F). Discard partially used vials after treatment.]

3. Continued therapy will be approved for 6 months at 30 days quantity of 2 or 4 intravenous doses of 50 IU per kg with a maximum of 4200 IU (2 or 4 vials) per dose per request, provided that the previous dose or doses has been depleted (Member is to have doses available for two attacks) AND:
• Member continues to meet initial criteria; AND
• Member achieved and sustained improvement in severity and duration of attacks (documentation of medical records required); AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions)
• [INFORMATIONAL NOTE: 50 IU per kg with a maximum of 4200 IU to be administered
  as a slow intravenous injection over approximately 5 minutes. If the attack symptoms persist, an additional second dose can be administered at the recommended dose level. Do not exceed 4200 IU per dose. No more than two doses should be administered within a 24 hour period.
  
  Initiate treatment with Ruconest under the supervision of a qualified healthcare professional experienced in the treatment of HAE. Appropriately trained patients may self-administer upon recognition of an HAE attack.]
4. All other uses of recombinant C1 esterase inhibitor (Ruconest) are considered investigational, including but not limited to:
• HAE in 2 to 12 year olds
• Early antibody-mediated rejection in renal transplantation

1. Icatibant (Firazyr) is medically necessary for the FDA-approved indication of treatment of acute attacks acute attacks of HAE when the following criteria are met.
• Member must meet the criteria in section II (above); AND
• Member has a known HAE-causing mutation (e.g., mutation of coagulation factor XII gene [F12 mutation], mutation in the angiopoietin-1 gene, mutation in the plasminogen gene, etc.) (documentation of medical records required); AND
• The member must be at least 18 years of age or older; AND
• Confirmation that member is avoiding medications that are possible triggers for HAE attacks (e.g. estrogen-containing oral contraceptive agents and hormone replacement therapy, antihypertensive agents containing ACE inhibitors and angiotensin II receptor blockers); AND
• Member will not also be receiving Berinert, Ruconest, or Kalbitor; AND
• If the request is for Firazyr (brand), member must have trial and failure, contraindication, or allergy to generic icatibant (documentation of medical records required)

2. When icatibant (Firazyr) is medically necessary, initial therapy will be approved for 6 months at 30 days quantity of 6 subcutaneous doses of 30 mg (6 - 30 mg/3 mL prefilled syringes).

[INFORMATIONAL NOTE: The safety and efficacy of icatibant was studied in three phase III trials, FAST-1, FAST-2 and FAST-3. All three trials enrolled a total of 228 patients that had a documented diagnosis of HAE. Each patient was randomized to receive either placebo (FAST 1 and FAST 3 trials), tranexamic acid (FAST 2 trial) or icabitant 30 mg SQ within 6 hours after beginning of acute attack. Primary endpoint, defined as median time to clinically significant relief of index symptom (measured by change in visual analog scale (VAS)), was not significant in FAST-1 compared to placebo (2.5 h vs 4.6 h, p=0.14), but was significant in FAST-2 compared to tranexamic acid (2.0 h vs 12.0 h; p<0.001). In FAST-3, the primary endpoint, defined as median time to 50% reduction of pretreatment VAS score (symptom relief), was statistically significant in the icatibant group compared to placebo (2.0 h vs 19.8 h; p<0.001). Secondary endpoints, such as time to almost complete relief and median time to onset of relief for single primary endpoints were also statistically in the favor of icatibant. The overall use of rescue medication was markedly higher in the placebo groups across all three trials compared to icatibant groups.

The recommended dose of Firazyr is 30 mg (or one prefilled syringe) administered by subcutaneous (SC) injection in the abdomen. Patients may self-administer Firazyr upon recognition of symptoms of an HAE attack after training under the guidance of a healthcare professional. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses of Firazyr may be administered in any 24 hour period.

The Firazyr package insert contains the following warning: Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in appropriate healthcare facility immediately in addition to treatment with Firazyr.

No hypersensitivity or anaphylactic reactions have been reported with Firazyr, but given the potential for airway obstruction during HAE attacks, patients should be advised to seek medical attention immediately in addition to treatment with Firazyr. Firazyr should be stored refrigerated or at room temperature 2-25°C (36-77°F) and should be kept in the carton until time of administration]

3. Continued therapy will be approved for 6 months at 30 days quantity of 3 or 6 subcutaneous doses of 30 mg ( 3 or 6 - 30 mg/3 mL prefilled syringes) per request, provided that the previous dose or doses has been depleted (Member is to have doses available for two attacks); AND
• Member continues to meet initial criteria; AND
• Member achieved and sustained improvement in severity and duration of attacks (documentation of medical records required); AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions)

4. All other uses of icatibant (Firazyr) are considered investigational, including but not limited to:
• Prophylactic therapy against attacks of hereditary angioedema
• Knee Osteoarthritis
• Ischemic reperfusion of the myocardium
• In children and adolescents 2 to 17 years of age.
• Use in patients taking ACE-inhibitors
Medicare Coverage

There is no National Coverage Determination (NCD) for Drug Therapy for Hereditary Angioedema. In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has not issued a determination for Drug Therapy for Hereditary Angioedema with [Cinryze, Berinert (Human C1 Inhibitor), Kalbitor (Ecallantide), and Ruconest (C1 Esterase Inhibitor [Recombinant])]. Therefore, Medicare Advantage Products will follow the Horizon BCBSNJ Medical Policy for these drugs. Also see Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

Icatibant (Firazyr),Lanadelumab-flyo (Takhzyro), and Haegarda (Human C1 Inhibitor),

Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Drugs ADMINISTERED subcutaneously are considered to be usually SELF-ADMINISTERED. If a drug is SELF-ADMINISTERED by more than 50 percent of Medicare beneficiaries, the drug is excluded from coverage under Medicare Part B. Therefore, for Medicare Advantage Products, Haegarda (Human C1 Inhibitor), Icatibant (Firazyr) and Lanadelumab-flyo (Takhzyro) administered subcutaneous are noncovered.

For members with a Medicare drug plan (Part D): Haegarda (Human C1 Inhibitor), Icatibant (Firazyr) and Lanadelumab-flyo (Takhzyro) may be covered under that plan.

For additional information, refer to Local Coverage Article: Self-Administered Drug Exclusion List (A53127). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46.

Local Coverage Article: Approved Drugs and Biologicals; Includes Cancer Chemotherapeutic Agents (A53049). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

**Note: Bullet 1 of the policy section referring to Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) does not apply for Medicare Advantage Products.

Medicaid Coverage

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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Drug Therapy for Hereditary Angioedema [Cinryze, Berinert, Haegarda (Human C1 Inhibitor), Kalbitor (Ecallantide), Firazyr (Icatibant), Ruconest (C1 esterase inhibitor [recombinant])]
C1 Inhibitor (Human)
Cinryze
Hereditary Angioedema
Human C1 Inhibitor
Berinert
Kalbitor
Ecallantide
Firazyr
Icatibant
Ruconest
C1 esterase inhibitor [recombinant]
Haegarda
Lanadelumab-flyo
Takhzyro

References:

1. Cinryze IV injection prescribing information. ViroPharma. New York, NY June 2018.

2. U.S. Food and Drug Administration: FDA News. FDA Licenses for Marketing New Therapy for Rare Genetic Disease. October 2008. [Available at: http://www.fda.gov/bbs/topics/NEWS/2008/NEW01903.html]

3. Zuraw, BL. Hereditary Angioedema. NEJM 2008;359:1027-36.

4. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clin Exp Immunol 2005;139 :379-94.

5. Bernstein JA. Hereditary angioedema: a current state-of-the-art review, VIII: current status of emerging therapies. Ann Allergy Asthma Immunol 2008;100(Suppl 2):S41-46.

6. Frank MM, Jiang H. New therapies for hereditary angioedema: Disease outlook changes dramatically. J Allergy Clin Immunol. 2008;121:272-80.

7. Berinert IV injection prescribing information. CSL Behring LLC. Kankakee, IL. April 2019.

8. U.S. Food and Drug Administration: FDA News. FDA Approves Berinert to Treat Abdominal Attacks, Facial Swelling Associated With Hereditary Angioedema. Oct. 9, 2009. [Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm186257.htm].

9. Kalbitor (ecallantide) prescribing information. Dyax Corp. Cambridge, MA. March 2015.

10. U.S. Food and Drug Administration: FDA News. FDA Approves Kalbitor for Treating Potentially Life-Threatening Attacks of Hereditary Angioedema. Dec. 2, 2009. [Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm192687.htm].

11. van Doorn MB, Burggraaf J, van Dam T, et al. A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema. J Allergy Clin Immunol. 2005;116(4):876-83.

12. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124(4):801-8.

13. Fattouch K, Bianco G, Speziale G, et al. Beneficial effects of C1 esterase inhibitor in ST-elevation myocardial infarction in patients who underwent surgical reperfusion: a randomised double-blind study. Eur J Cardiothorac Surg. 2007;32(2):326-32.

14. Thielmann M, Marggraf G, Neuhäuser M, et al. Administration of C1-esterase inhibitor during emergency coronary artery bypass surgery in acute ST-elevation myocardial infarction. Eur J Cardiothorac Surg. 2006;30(2):285-93.

15. Caliezi C, Zeerleder S, Redondo M, et al. C1-inhibitor in patients with severe sepsis and septic shock: beneficial effect on renal dysfunction. Crit Care Med. 2002;30(8):1722-8.

16. Fronhoffs S, Luyken J, Steuer K, et al. The effect of C1-esterase inhibitor in definite and suspected streptococcal toxic shock syndrome. Report of seven patients. Intensive Care Med. 2000;26(10):1566-70.

17. Gompels MM, Lock RJ, Abinun M, et al. C1 inhibitor deficiency: consensus document. Clinical and Experimental Immunology. 2005;139:379-394.

18. Schneider L, Lumry W, Vegh A, et al. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J Allergy Clin Immunol. 2007;120(2):416-22.

19. Firazyr (icatibant) prescribing information. Shire Orphan Therapies, Inc. Lexington, MA. December 2015.

20. Cicardi M, et al. Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy. 2012;67(2):147.

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