Drug Criteria & Outcomes
Ziconotide (Prialt) Formulary Evaluation
Part 2 of 2: Overdose, Patient/Staff Education, Clinical Trial Summary, Summary and Recommendations
By Tiffany Gilmer, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University
Overdose
In patients who received intrathecal (IT) doses of ziconotide greater than the maximum recommended dose (19.2 mcg/day), exaggerated pharmacological effects such as ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, sedation, hypotension, word-finding difficulties, garbled speech, nausea, and vomiting were observed. There is no known antidote for ziconotide.
Overdosage of morphine is characterized by respiratory depression, with or without concomitant CNS depression. The narcotic antagonist, naloxone, should be administered at an initial dose of 0.4 to 2 mg IV, simultaneously with respiratory resuscitation if respiratory arrest occurs.
Overdoses may occur due to pump programming errors or incorrect drug concentration preparations.
Patient education (special)
Patients receiving ziconotide should be cautioned against engaging in hazardous activity requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. The physician should be contacted if the patient experiences new or worsening muscle pain, soreness, or weakness with or without darkened urine.
IT morphine may cause physical and/or psychological dependence. While using this medication, patients should not use alcohol and other prescription or over-the-counter medications without consulting their prescriber. Patients should maintain adequate hydration (2-3 L/day of fluids). Unless instructed to restrict fluid intake, IT morphine may cause hypotension, dizziness, drowsiness, impaired coordination, or blurred vision; loss of appetite, nausea, or vomiting; or constipation. Patients should report chest pain, slow or rapid heartbeat, acute dizziness, or persistent headache; changes in mental status; swelling of extremities or unusual weight gain; changes in urinary elimination or pain on urination; acute headache; back or flank pain; muscle spasms; blurred vision; skin rash; or shortness of breath.
Clinical trial summary
Trial 1: Staats PS, Yearwood T, Charapata SG, et al. Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS. JAMA 2004;291:63-70.
Objective: To assess the safety and efficacy of intrathecal ziconotide in patients with pain that is refractory to conventional treatment.
Study design: Double-blind, placebo-controlled, randomized trial.
Outcomes measured
- Primary efficacy outcome
- Mean percentage change in VASPI score
- Secondary outcomes
- Mean percentage change in the CPRS, the WBPI, and the KPSS
- Change in opioid use
- Change in responder status from baseline to the end of the maintenance and crossover phases
- Efficacy outcomes
- Adverse events, vital signs, and cognitive assessments
Inclusion criteria
- Patients with cancer or AIDS
- Mean VASPI score of 50 mm or greater
Exclusion criteria
- Pregnancy
- Sepsis or inadequately treated infection
- Investigational drug use
- Palliative surgical procedure(s) within the preceding 30 days
- Dementia
- Untreated affective disorders
- Severe asthma
- Cardiac failure
- Bradyarrhythmias
- Neurocardiogenic syncope
Patient population
- One hundred twelve patients ages 24-85 years enrolled at 32 study centers
- Seventy-one patients randomized to ziconotide; three patients excluded because of insufficient VASPI data, leaving 68 patients
- Forty patients randomized to placebo
- Mean KPSS score near 60
- Thirty-six patients had received IT morphine
- Median oral morphine equivalent dosage of 300 mg/day in the ziconotide group and 600 mg/day in the placebo group
- Comparable demographic and clinical characteristics, including mean VASPI scores between the two groups
Regimen
- All IT medications were discontinued at least three days prior to study enrollment and systemic and oral medications to control pain were maximized during this period.
- Patients were randomized in a 2:1 ratio to receive ziconotide or placebo treatment for five days.
- Responders received an additional five days of medication.
- Nonresponders were crossed over to the opposite group for 5-6 days.
- Responders could then enroll in a long-term open-label study.
Dosage
- Initial dose of 5 ng/kg/hr used during early stage of enrollment.
- Dose changed to 0.4 ng/hr "for consistency purposes."
- Dosage increases every 12 hours to a maximum tolerated dose.
Statistical analysis
- Ninety-six percent power to detect a greater than 30% change in the two treatment groups
- Two-way ANOVA of the mean percentage change in VASPI and KPSS scores
- Cochran-Mantel-Haenszel test
- Cochran-Mantel-Haenszel general association test
- Fisher exact test
- All statistical tests were two-sided
- P < 0.05 considered statistically significant
- Intention-to-treat analysis
Results
- Efficacy.
- From baseline to the end of titration phase, mean VASPI scores improved 53.1% (95% confidence interval [CI] 44-62.2%) in the ziconotide group and 18.1% (95% CI 4.8-31.4%) in the placebo group (P < 0.001).
- Pain relief based on CPRS scores was moderate to complete in 52.9% of the ziconotide group and in the same range but never reaching complete in 17.5% of the placebo group (P < 0.001).
- Opioid use decreased in the ziconotide group by 9.9% but increased in the placebo group by 5.1%
- Ziconotide maintained efficacy in the maintenance phase.
- No significant difference in WBPI subsets or KPSS scores at the end of the initial titration between the two groups.
- Thirty-four patients receiving ziconotide and seven patients receiving placebo were considered responders based on the protocol.
- One patient from each group did not continue to the maintenance phase.
- An additional 15 patients receiving ziconotide and seven receiving placebo were considered responders by the investigators and proceeded into the maintenance phase.
- Ziconotide maintained efficacy in the maintenance phase.
- 44.9% mean reduction in VASPI score in patients receiving placebo who crossed over to ziconotide (n = 26).
- 4.2% mean reduction in VASPI score in patients receiving ziconotide who crossed over to the placebo group (n = 12).
Safety
- Four patients receiving placebo (10%) and 22 patients receiving ziconotide (30.6%) experienced a serious adverse event.
- Fourteen adverse events were thought to be related to the ziconotide.
- The most common serious adverse events for ziconotide were confusion, somnolence, and urinary retention. Other adverse events that occurred at a higher rate than placebo include fever, postural hypotension, nausea, vomiting, abnormal gait, confusion, and dizziness.
- Adverse events lead to early discontinuation in 12 patients receiving ziconotide and four receiving placebo. Fifteen patients in ziconotide and five in placebo group discontinued therapy for other reasons.
- Five cases of meningitis were reported in the ziconotide group and two in the placebo group.
- Thirteen patient deaths were reported during the study period and two after follow-up; death rates were not significantly different between the two groups.
- No significant changes in vital signs, laboratory analyses, or cognitive function test scores between the two groups.
Strengths
- Randomized, double-blind, controlled study
- Thirty-two study centers
Weaknesses
- Compared to placebo
- Protocol violations
- The sponsor designed, conducted the study, and performed the analysis and interpretation of the data.
- Median oral equivalent dose of morphine higher in the placebo group before initiation of treatment.
- Dose was changed in the study.
Authors’ conclusion: IT ziconotide provided clinically and statistically significant analgesia in patients with pain from cancer or AIDS.
Trial 2 was an unpublished trial conducted at 39 centers, randomized, double-blind, and placebo-controlled. Patients (n = 220) were randomized to receive IT placebo or ziconotide 2.4 mcg/day (0.1 mcg/hr), and the dose could be increased by 2.4 mcg/day 2-3 times per 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).
Compared to placebo, patients receiving ziconotide showed a significant difference in the mean percent change in VASPI score from baseline at week three, 12% mean improvement for ziconotide and 5% with placebo (P = 0.04; 95% CI 0.4-13%).
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. In addition, the use of non-IT opioids decreased by 24% with ziconotide, compared to 17% with placebo.
Summary and recommendations
Ziconotide is a nonopioid IT pain medication with no evidence of tolerance. Both ziconotide and IT morphine can cause serious adverse events; however, there is more experience and more post-marketing data available on IT morphine. Ziconotide can be stopped without evidence of withdrawal effects in the event of serious neurological or psychiatric signs and symptoms.
IT morphine has an antidote (naloxone) in case of respiratory depression due to morphine overdose, but withdrawal effects can occur.
Ziconotide can be given only by the Medtronic SynchroMed EL, SynchroMed II Infusion System, and Simms Deltec Cadd Micro External Microinfusion Device and Catheter. IT morphine can be given by any of the intrathecal pumps or by intrathecal injection.
Ziconotide is not a scheduled drug, whereas intrathecal morphine is a Schedule II medication. Ziconotide is only indicated for the management of severe chronic pain in patients who are intolerant of or refractory to other treatment, such as systemic analgesic, adjunctive therapies, or intrathecal morphine.
Ziconotide should not be used in place of intrathecal morphine, but only after intrathecal morphine has been initiated and the dose titrated to the highest tolerated dose or in patients allergic to morphine that have tried other systemic analgesics and adjunctive therapies.
Cost comparisons
Ziconotide: $3,041.67 for a 20 mL vial of 25 mcg/mL, or $608.33 for a 1 mL vial of 100 mcg/mL
- Initial daily dose: 2.4 mcg/day = $14.00
- Average daily dose: 6.9 mcg/day = $42
- Maximum daily dose: 19.2 mcg/day = $116
Infumorph: $45.85 for a 20 mL ampule of 10 mg/mL
- Initial maximum IT dose in patients without opioid tolerance ~1 mg/day = 22 cents.
- Maximum IT dose ~ 20 mg/day = $4.58.
Duramorph: $17.50 for 10 mL ampule of 0.5 mg/mL
- Initial maximum IT dose in patients without opioid tolerance ~1 mg/day = $3.50
- Maximum IT dose ~ 20 mg/day = $70
Place in therapy/advantages
Ziconotide should only be used for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine.
Although ziconotide does not produce respiratory depression, and is not classified as a C-II like IT morphine, it should not be used in its place.
Formulary recommendation
Since this medication is for chronic pain relief and will be administered through an IT pump containing a drug reservoir, this drug will not be stocked in the hospital.
Patients will mainly be started in the outpatient setting and their chronic pump reservoir supply used when admitted to the hospital.
If under unusual circumstances the patient must start on the drug in the hospital and has no drug supply, the drug must be ordered by a pain specialist.
Use should be restricted to the following groups of patients:
- failed oral or systemic therapy;
- failed adjunctive therapies and intrathecal morphine;
- allergies or intolerance to morphine or morphine derivatives and have failed other therapies.
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