Medical Policies - Prescription Drugs


Sustol (Granisetron) Extended Release Injection

Number:RX501.090

Effective Date:07-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.

Sustol® (granisetron) extended release injection may be considered medically necessary in adult patients 18 years of age or older when:

Used in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

Sustol® (granisetron) extended release injection is considered experimental, investigational and/or unproven, for all other indications, including use in the following patients:

Under the age of 18; or

Severe renal impairment (creatinine clearance <30 mL/min); or

Nausea and emesis in pregnancy; or

Hypersensitivity to granisetron, any components of granisetron or to any other 5-HT3 receptor antagonists; or

Use more frequently than every 7 days.

NOTE 1: Per the FDA label, Sustol® (granisetron) extended release injection is intended for administration by a healthcare provider. For patients with moderate renal impairment (creatinine clearance 30-59mL/min), do not administer Sustol® (granisetron) extended release injection more frequently than once every 14 days.

NOTE 2: Per the FDA label, Sustol® (granisetron) extended release injection is specifically intended for subcutaneous administration and is not interchangeable with the intravenous formulation.

Description:

Sustol® (granisetron) extended release injection, also known as APF530, is a selective 5-hydroxytryptamine3 (5-HT3) receptor antagonist that acts as a receptor antagonist at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in specific areas of the brain. (1) 5-HT3 antagonists are antiemetics and are considered the gold standard to manage nausea and vomiting produced by chemotherapy agents. (2, 3) Chemotherapy drugs are classified into four different emetogenic categories: high, moderate, low or minimal. The 2017 National Comprehensive Cancer Network (NCCN) Guidelines on antiemesis (4) identifies which specific chemotherapy agents are moderate or high emetogenic risk (refer to Table 1 and Table 2 for specific drug risk level).

Table 1. Emetogenic Potential of Oral Antineoplastic Agents

Risk Level

Agent

Moderate to high emetic risk b (>30% frequency of emesis)

Alretamine

Busulfan (>4 mg/day)

Ceritinib

Crizotinib

Cyclophosphamide (>100 mg/m2/d)

Estramustine

Etoposide

Lenvatinib

Lomustine (single day)

Mitotane

Olaparib

Panobinostat

Procarbizine

Rucaparib

Temozolomide (>75 mg/m2/d)

Trifluridine/tipiracil

Table key:

b Proportion of patients who experience emesis in the absence of effective antiemetic prophylaxis.

Table 2. Emetogenic Potential of Intravenous Antineoplastic Agents

Risk Level

Agent

High emetic risk b, c

(>90% frequency of emesis)

AC combination defined as any chemotherapy regimen that contains anthracycline and cyclophosphamide

Carboplatin areas under the curve >4

Carmustine >250mg/m2

Cisplatin

Cyclophosphamide >1,500 mg/m2

Dacarbazine

Doxorubicin>60 mg/m2

Epirubicin >90 mg/m2

Ifosfamide >2 g/m2 per dose

Mechlorethamine

Streptozocin

Moderate emetic risk b, c

(30-90% frequency of emesis)

Aldesleukin >12-15 million IU/m2

Amifostine >300 mg/m2

Arsenic trixide

Azacitidine

Bendamustine

Busulfan

Carboplatin AUC <4d

Carmustined <250 mg/m2

Clofarabine

Cyclophamide <1500 mg/m2

Cytarabine >200 mg/m2

Dactinomycind

Daunorubicind

Dinutuximab

Doxorubicind <60 mg/m2

Epirubicind <90 mg/m2

Idarubicin

Ifosfamided <2 g/m2 per dose

Interferon alfa >10 million IU/m2

Irinotecand

Melphalan

Methotrexated >250 mg/m2

Oxaliplatind

Temzolomide

Trabectedind

Table key:

b Proportion of patients who experience emesis in the absence of effective antiemetic prophylaxis.

c Continuous infusion may make an agentless emetogenic.

d These agents may be emetogenic in certain patients.

Regulatory Status

Sustol® (granisetron) extended release injection (Heron Therapeutics, Redwood City, CA.) was approved in 1993 by the U.S. Food and Drug Administration(FDA) for the use in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens. Sustol® (granisetron) extended release injection is intended for administration by a healthcare provider. Use of Sustol® (granisetron) extended release injection is not recommended more frequently than once every 7 days. For patients with moderate renal impairment, defined as creatinine clearance 30-59mL/min, do not administer Sustol® (granisetron) extended release injection more frequently than once every 14 days. (1)

Rationale:

This policy was created based on U.S. Food and Drug Administration (FDA) approved labeled indications with literature search through February 2017. Following is a summary of the key literature to date.

In 2015, Gabrail et al. (5) studied the safety and efficacy of APF530, also known as Sustol® (granisetron) extended release injection, in two open-label, single-dose phase II trials (C2005-01 and C2007-01) in patients receiving moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC). In C2005-01, 45 patients received APF530 250, 500, or 750 mg subcutaneous (granisetron 5, 10, or 15 mg, respectively). In C2007-01, 35 patients were randomized to APF530 250 or 500 mg subcutaneously. Injections were given 30 to 60 minutes before single-day MEC or HEC. Plasma granisetron was measured from pre-dose to 168 hours after study drug administration. Safety and efficacy were also evaluated. APF530 pharmacokinetics were dose proportional, with slow absorption and elimination of granisetron after a single subcutaneous dose. Median time to maximum plasma concentration and half-life was similar for APF530 250 and 500 mg in both trials, with no differences between the groups receiving MEC and HEC. Exposure to granisetron was maintained at a therapeutic level over the delayed-onset phase, at least 168 hours. Adverse events in both trials were as expected for granisetron; injection site reactions (e.g., erythema and induration) were predominantly mild and seen in 20% of patients. Complete responses (no emesis, with no rescue medication) were obtained in the acute, delayed, and overall phases in 80% and 75% of patients in both trials with the 250 and 500 mg doses, respectively. The authors concluded that after a single injection of APF530, there were dose-proportional pharmacokinetics and sustained concentrations of granisetron over 168 hours. The 250 and 500 mg doses were well tolerated and the patients maintained therapeutic granisetron levels for 5 days.

In 2015, Raftopoulos and colleagues (6) performed a randomized, double-blind phase III trial comparing extended-release granisetron (APF530) to palonosetron in preventing acute and delayed chemotherapy induced nausea and vomiting (CINV) after MEC or HEC. Patients receiving single day MEC or HEC received single dose APF530 at 250mg or 500 mg subcutaneous (granisetron 5mg or 10 mg) or intravenous palonosetron 0.25 mg. The primary objective was to establish APF530 noninferiority to palonosetron for preventing acute CINV following MEC or HEC and delayed CINV following MEC and to determine APF530 superiority to palonosetron for preventing delayed CINV following HEC. The primary efficacy was complete response (CR [using CI difference for APF530 − palonosetron]). A lower confidence bound greater than 15 % indicated noninferiority. In the modified intent to treat population (MEC = 634; HEC = 707), both APF530 doses were non-inferior to palonosetron in preventing acute CINV after MEC (CRs 74.8 % [−9.8, 9.3] and 76.9 % [−7.5, 11.4], respectively, vs 75.0 % palonosetron) and after HEC (CRs 77.7 % [−11.5, 5.5] and 81.3 % [-7.7, 8.7], respectively, vs. 80.7 % palonosetron). APF530 500 mg was non-inferior to palonosetron in preventing delayed CINV after MEC (CR 58.5 % [−9.5, 12.1] vs. 57.2 % palonosetron) but not superior in preventing delayed CINV after HEC. Adverse events were generally mild and unrelated to treatment, the most common (excluding injection-site reactions) being constipation. The study concluded that a single subcutaneous APF530 injection offers a convenient alternative to palonosetron for preventing acute and delayed CINV after MEC or HEC.

In 2016 Boccia et al. (7) completed a randomized phase III trial of APF530 versus palonosetron in the prevention of CINV in a subset of patients with breast cancer receiving MEC or HEC. Patients were randomized to receive subcutaneous APF530 250mg or 500 mg (granisetron 5 or 10 mg) or intravenous palonosetron 0.25 mg during cycle 1. Palonosetron patients were randomized to APF530 for cycles 2 to 4. The primary efficacy end point was complete response (CR, no emesis or rescue medication) in cycle 1. Among breast cancer patients (n = 423 MEC, n = 185 HEC), > 70 % received anthracycline-containing regimens in each emetogenicity subgroup. There were no significant between-group differences in CRs in cycle 1 for acute (APF530 250 mg: MEC 71 %, HEC 77 %; 500 mg: MEC 73 %, HEC 73 %; palonosetron: MEC 68 %, HEC 66 %) and delayed (APF530 250 mg: MEC 46 %, HEC 58 %; 500 mg: MEC 48 %, HEC 63 %; palonosetron: MEC 52 %, HEC 52 %) CINV. There were no significant differences in within-cycle CRs between APF530 doses for acute and delayed CINV in MEC or HEC in cycles 2 to 4; CRs trended higher in later cycles, with no notable differences in adverse events between breast cancer and overall populations. The study determined that APF530 effectively prevented acute and delayed CINV over 4 chemotherapy cycles in breast cancer patients receiving MEC or HEC.

Professional Guidelines and Position Statements

National Comprehensive Cancer Network (NCCN)

NCCN (v2.2017) highlights the unique, extended-release formulation of Sustol® (granisetron) extended release injection and provides recommendations for antiemetic use during chemotherapy based on the emetogenic potential as follows: (5)

Granisetron extended release injection is a unique formulation of granisetron using polymer-based drug delivery system. This formulation is specifically intended for subcutaneous administration and is not interchangeable with the intravenous formulation

Granisetron has an extended half-life and should not be administered at less than 1 week intervals.

A single subcutaneous dose of granisetron extended release injection (10 mg) was found to be non-inferior to a single intravenous dose of palonosetron 0.25 mg for the prevention of acute and delayed CINV when both are used in combination with dexamethasone.

A single subcutaneous dose of granisetron extended release injection (10 mg) was found to be superior to a single intravenous dose of ondansetron for the prevention of delayed CINV following HEC when both are used in combination with fosaprepitant and dexamethasone.

When palonosetron or granisetron extended release injection is used as part of an antiemetic regimen that does not contain a Neurokinin 1 (NK1) receptorantagonist, Palonosetron or Granisetron extended release injection are the preferred 5-HT3 RA.

Ondansetron, granisetron, and dolasetron are effective in preventing acute emesis but are less effective compared to palonosetron for preventing delayed emesis due to its approximately 100-fold higher binding affinity for the 5-HT3 receptor and subsequent longer half-life.

The American Society of Clinical Oncology (ASCO)

In 2015, ASCO (8) made the following recommendations for the use of antiemetic therapy:

All patients who receive highly emetogenic chemotherapy regimens (including anthracycline plus cyclophosphamide) should be offered a three-drug combination of a neurokinin 1 receptor antagonist, a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, and dexamethasone.

The preferred 5-HT3 receptor antagonist for patients who receive MEC regimens is Palonosetron; antiemetic treatment includes that agent combined with a corticosteroid.

Antiemetic treatment for patients who receive combination chemotherapy should be determined according to the agent with the greatest degree of emetic risk.

Both dexamethasone and a 5-HT3 receptor antagonist are recommended for patients receiving high-dose chemotherapy.

For those treated with highly emetogenic radiation therapy, a 5-HT3 receptor antagonist before each fraction and a 5-day course of dexamethasone are recommended.

A 5-HT3 receptor antagonist before each fraction is also recommended before moderately emetogenic radiation therapy; a 5-day course of dexamethasone is optional.

For patients who receive combination chemotherapy and radiotherapy, antiemetic therapy is dictated by the emetogenicity of chemotherapy, unless the emetic risk of radiation therapy is higher.

Summary Of Evidence

The available studies, FDA label and NCCN guidelines support the use of Sustol® (granisetron) extended release injection in adult patients 18 years of age or older when used in combination with other antiemetics for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy (MEC) or anthracycline and cyclophosphamide (AC) combination chemotherapy regimens.

Per the FDA label, Sustol® (granisetron) extended release injection has not been proven in patients under the age of 18. Sustol® (granisetron) extended release injection is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min), patients with hypersensitivity to granisetron, any of the components of Sustol, or to any other 5-HT3 receptor antagonists. It is not recommended for use in patients more frequently than every 7 days therefore it is considered experimental, investigational and/or unproven in these situations.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

None

HCPCS Codes

C9486, J1627

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.

A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

References:

1. FDA - Sustol (granisetron) extended release injection. Food and Drug Administration (1993). Available at <http://www.fda.gov> (accessed 2017 March 6).

2. Mayo Clinic - Chemotherapy nausea and vomiting: Prevention is best defense (2016). Available at <http://mayoclinic.org> (accessed 2017 March 29).

3. de Wit R, Aapro M, Blower PR, et al. Is there a pharmacological basis for differences in 5-HT3-receptor antagonist efficacy in refractory patients? Cancer Chemother Pharmacol. 2005 Sept; 56(3):231-8. PMID 15838653

4. National Comprehensive Cancer Network. NCCN Clinical Practice Guideline in Oncology. Antiemesis. V.1.2017. Available at <www.nccn.org> (accessed 2017 March 6).

5. Gabrail N, Yanagihara R, Spaczy?ski M, et al. Pharmacokinetics, safety, and efficacy of APF530 (extended-release granisetron) in patients receiving moderately or highly emetogenic chemotherapy: results of two Phase II trials. Cancer Management and Research 2015; 7:83–92

6. Raftopoulos H, Cooper W, Boyle E, et al. Comparison of an extended-release formulation of granisetron (APF530) versus palonosetron for the prevention of chemotherapy-induced nausea and vomiting associated with moderately or highly emetogenic chemotherapy: results of a prospective, randomized, double-blind, noninferiority phase 3 trial. Support Care Cancer. 2015; 23: 723–732.

7. Boccia R, O’Boyle E, Cooper W, et al. Randomized phase III trial of APF530 versus palonosetron in the prevention of chemotherapy-induced nausea and vomiting in a subset of patients with breast cancer receiving moderately or highly emetogenic chemotherapy. BMC Cancer. 2016; 16:166

8. Hesketh P, Bohlke K, Lyman G, et al. Antiemetics: American Society of Clinical Oncology Focused Guideline Update (2015). Available at <http://ascopubs.org> (accessed 2017 March 31).

Policy History:

Date Reason
7/15/2018 Reviewed. No changes.
9/1/2017 New Medical Document. Coverage: Sustol® (Granisetron) extended release injection may be considered medically necessary when specific criteria are met. Sustol® (Granisetron) extended release injection is considered experimental, investigational and/or unproven for all other indications.

Archived Document(s):

Title:Effective Date:End Date:
Sustol (Granisetron) Extended Release Injection09-01-201707-14-2018
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