Pending Policies - Prescription Drugs


Ziconotide (Prialt)

Number:RX501.060

Effective Date:08-15-2017

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, Hayes, 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.

Ziconotide intrathecal infusion (Prialt®) may be considered medically necessary for management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of or refractory to other treatment, including systemic analgesics, adjunctive therapies, and IT morphine.

Ziconotide intrathecal infusion (Prialt®) is considered experimental, investigational and/or unproven for all other indications.

Description:

While acute pain is a normal sensation triggered in the nervous system to alert the individual to possible injury and the need for treatment, chronic pain is different. Chronic pain persists. Pain signals keep firing in the nervous system for weeks, months, even years. There may have been an initial mishap, such as a sprained back, serious infection, or there may be an ongoing cause of pain, such as arthritis, cancer, ear infection, but some individuals suffer chronic pain in the absence of any past injury or evidence of body damage. Many chronic pain conditions affect older adults.

Background

Ziconotide (Prialt®) is a non-opioid analgesic, called an N-type calcium channel blocker, which works by targeting and blocking calcium channels on the nerves that transmit pain signals to the brain. The U.S. Food and Drug Administration (FDA) approved label states ziconotide is for use only in the Medtronic SynchroMed® II Infusion System and the CADD-Micro Ambulatory Infusion Pump. (1) These are programmable pumps that release the drug into the fluid surrounding the spinal cord, through a surgically implanted catheter. In clinical trials, ziconotide helped alleviate pain in most patients over the long term.

Severe psychiatric symptoms and neurological impairment may occur during treatment with Ziconotide. Patients with a pre-existing history of psychosis should not be treated with Ziconotide. All patients should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Ziconotide therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms. Other frequently reported adverse events associated with the drug in clinical trials were asthenia, nausea, vomiting, abnormal gait, ataxia, confusion, dizziness, memory impairment, nystagmus, abnormal vision, and urinary retention.

Regulatory Status

Ziconotide (Prialt®) (distributed by Azur Pharma International Ltd, Philadelphia, PA) received FDA approval on December 28, 2004, for treatment of chronic, severe pain, when administered by intrathecal (IT) infusion only. The FDA issued a warning, included on the approved label, regarding neuropsychiatric adverse reactions during treatment.

As described above, ziconotide is intended for use with the two Medtronic infusion systems, manufactured by Medtronic, Inc., Minneapolis, MN, described above.

Rationale:

The policy was created in 2005, based on the U.S. Food and Drug Administration (FDA) approved label and a search of the MedLine database. Periodic searches of scientific literature have been conducted through July 6, 2016. The following is a summary of the key literature.

The safety and efficacy of intrathecal (IT) ziconotide in the management of severe chronic pain were studied in 3 double-blind, placebo-controlled, multicenter studies in a total of 457 patients (268 ziconotide, 189 placebo) using two different titration schedules. (2) The slow titration schedule tested dose increases two to three times per week with a maximum dose of 19.2 mcg/day (0.8 mcg/hr) at 21 days. The fast titration schedule used daily increases up to a maximum dose of 57.6 mcg/day (2.4 mcg/hr) in five to six days. The FDA based their approval on these 3 unpublished clinical studies.

A randomized, double-blind, placebo-controlled study was conducted at 39 centers to evaluate the efficacy of IT ziconotide administered using a slow titration schedule in 220 patients with severe chronic pain. (1) Patients were randomized 1:1 between ziconotide (112 patients) and placebo (108 patients). At baseline, 97% of these patients reported that their pain was refractory to treatment including IT morphine, IT bupivacaine (an off-label use for this drug) and/or IT clonidine (an off-label use for this drug) in addition to their systemic analgesics and adjunctive therapy. All IT medications were discontinued over a one- to three-week period and patients were maintained on a stable regimen of non-IT analgesics including opiates, for at least seven days prior to randomization. This period was successfully completed by 93% of the patients screened. Dosing with ziconotide was started at 2.4 mcg/day (0.1 mcg/hr) and the dose could be increased by 2.4 mcg/day (0.1 mcg/hr) two to three times/week (minimum titration interval 24 hours) to a maximum dose of 19.2 mcg/day (0.8 mcg/hr). The final mean dose at the end of the trial at 21 days was 6.9 mcg/day (0.29 mcg/hr).

Using a 100 mm Visual Analog Scale of Pain Intensity (VASPI) where 100 mm equals the worst possible pain, mean baseline pain scores were 81 in both the Ziconotide and placebo groups. The primary efficacy variable was the mean percent change in the VASPI score from baseline to day 21. In the intent-to-treat (ITT) efficacy analysis, there was a statistically significant difference between groups in the mean percent change in VASPI score from baseline with the ziconotide group having a 12% mean improvement at Week 3 compared to a 5% mean improvement in the placebo group (p=0.04). The 95% confidence interval for the treatment difference (ziconotide – placebo) was 0.4%, 13%. The effect of IT Ziconotide on pain was variable over the time period of treatment for some patients. Some patients had a reduction in VASPI in the first or second week, but did not maintain pain relief by the end of the third week. Other patients, who did not exhibit a reduction in VASPI early in treatment, did have a reduction in VASPI by the third week.

Patients exhibited various degrees of improvement in pain after three weeks of treatment compared with baseline pain assessment. Patients were monitored for their degree of improvement. Patients who did not have a VASPI score recorded at week 3 (study days 17-23, inclusive) were assigned 0% improvement. The improvement in the proportion of “responders,” defined as having a ≥30% improvement from baseline in VASPI, was 16% in the Ziconotide group compared to 12% in the placebo group, for a net difference of 4%. Non-IT opioid use decreased by 24% in the ziconotide group and by 17% in the placebo group.

Two studies cited by the manufacturer (Wallace et al. in 2006 [3] and Rauck et al. in 2006, [4]) reiterate the pain improvement when conventional therapies have failed and the considerable incidence of ziconotide-associated adverse events with rapid titration to higher doses.

In 2008, Wallace et al. followed up with an open-label, long-term study to assess the safety and tolerability of ziconotide administration in patients who are intolerant of, or refractory to, other pain treatments. (5) In this study of 640 patients, the efficacy was evaluated using VASPI, vital signs, and routine laboratory values. Of the 640 patients, 119 were given ziconotide for ≥360 days. Most patients (99.7%) experienced ≥1 adverse event in the course of treatment, of which 43.5% were mild or 42.3% were moderate in severity. Over half (58.6%) of the adverse events were considered unrelated to the ziconotide therapy. The authors concluded that long-term IT treatment with ziconotide is an option for patients with severe, refractory chronic pain.

More recently in 2014, Saulino et al. reviewed the practical considerations of IT therapy using morphine and ziconotide for patients with chronic pain challenges and as a “last resort”. (6) The authors cite the original clinical evidence used for the FDA approval of 457 patients in 3 double-blinded, placebo-controlled studies and safety assessments of 1254 patients overall with severe chronic cancer pain, noncancer, and acquired immunodeficiency syndrome pain types. The authors concluded that patients should be critically evaluated to determine the most appropriate agent for IT therapy.

Ongoing and Unpublished Clinical Trials

As of July 6, 2016, in ClinicalTrials.gov, there are several studies listed as completed at the time of the FDA approval, without study results posted. One small study, listed in Table 1 below, is ongoing.

Table 1: Summary of Key Trials

NCT Number

Trial Name

Planned Enrollment

Completion Date

Ongoing

NCT00996983

Safety and Activity Study of Intrathecally Administered Ziconotide for Neuropathic Pain in Patients with Cancer (ZIDON)

16

Jul 2017

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements

There were no professional guidelines and position statements identified that would likely influence this review.

Summary of Evidence

The evidence used for the FDA approval suggests an overall benefit for ziconotide intrathecal administration for patients who are intolerant of or refractory to other pain treatments. Despite the adverse events experienced by patients, the benefit of ziconotide IT treatment for chronic severe pain noted in the FDA approved indications outweighs the negative patient experience.

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

J2278

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 – Ziconotide. Product Label and Approval History (2005). U.S. Food and Drug Administration. Available at <http://www.accessdata.fda.gov> (accessed on June 29, 2016).

2. Prialt. Product Information (2004). Dublin, Ireland: Jazz Pharmaceuticals. Available at <http://www.prialt.com> (accessed on July 6, 2016).

3. Wallace MS, Charapata SG, Fisher R, et al. Intrathecal ziconotide in the treatment of chronic nonmalignant pain: a randomized, double-blind, placebo-controlled clinical trial. Neuromodulation. Apr 2006; 9(2):75-86. PMID 22151630

4. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. May 2006; 31(5):393-406. PMID 16716870

5. Wallace MS, Rauck R, Fisher R, et al. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth Analg. Feb 2008; 106(2):628-37. PMID 18227325

6. Saulino M, Kim PS, Shaw E. Practical considerations and patient selection for intrathecal drug delivery in the management of chronic pain. J Pain Res. 2014; 7:627-38. PMID 25419158

7. Ziconotide (Prialt) Intrathecal. Micromedex Drug Summary Information. Truven Health Analytics Microdex Solutions. Available at <www.microdexsolutions.com> (accessed on June 29, 2016).

Policy History:

DateReason
8/15/2017 Reviewed. No changes.
9/1/2016 Document updated with literature review. Coverage unchanged.
7/1/2015 Document updated with literature review. Coverage unchanged.
5/1/2014 Document updated with literature review. Coverage unchanged.
9/1/2012 Document updated with literature review. Coverage unchanged. This policy is no longer scheduled for routine literature review and update.
9/1/2007 Revised/Updated Entire Document
11/1/2006 Revised/Updated Entire Document
9/1/2005 New medical document

Archived Document(s):

Title:Effective Date:End Date:
Ziconotide07-01-202108-14-2022
Ziconotide12-01-202006-30-2021
Ziconotide (Prialt)08-01-201911-30-2020
Ziconotide (Prialt)08-15-201707-31-2019
Ziconotide (Prialt)09-01-201608-14-2017
Zinconotide (Prialt)07-01-201508-31-2016
Zinconotide (Prialt)05-01-201406-30-2015
Zinconotide (Prialt)09-01-201204-30-2014
Zinconotide (Prialt)09-01-200708-31-2012
Zinconotide (Prialt)11-01-200608-31-2007
Zinconotide (Prialt)09-01-200510-31-2006
Zinconotide (Prialt)07-11-200508-31-2005
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