PRIALT (ziconotide) solution, intrathecal infusion is indicated for the management of severe chronic pain in adult 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.

PRIALT (ziconotide) solution, intrathecal infusion is supplied as a 25 mcg/mL concentration in single-use 20 mL glass vials and as a 100 mcg/mL concentration in single-use glass vials containing 1 mL or 5 mL of solution.

Formal PK drug-drug interaction studies have not been performed with PRIALT. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, intrathecal administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Further, as ziconotide is not highly bound in plasma (approximately 50%) and has low plasma exposure following intrathecal administration, clinically relevant plasma protein displacement reactions involving ziconotide and co-administered medications are unlikely.

Over 90% of patients treated with intrathecal PRIALT used systemic opiates and in the slow titration study, 98% of patients received opioids.

The combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended.

The maximum recommended intrathecal PRIALT dose is 19.2 mcg/day. The maximum intrathecal dose of PRIALT in clinical trials was 912 mcg/day. In some patients who received intrathecal doses greater than the maximum recommended dose, exaggerated pharmacological effects (e.g., ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, sedation, hypotension, word-finding difficulties, garbled speech, nausea, and vomiting) were observed. There was no indication of respiratory depression. Overdoses may occur due to pump programming errors or incorrect drug concentration preparations. In these cases, patients were observed and ziconotide was either temporarily discontinued or permanently withdrawn. Most patients recovered within 24 hours after withdrawal of drug. In the event of an overdose, elimination of ziconotide from CSF would be expected to remain constant (CSF t

There is no known antidote to ziconotide. General medical supportive measures should be administered to patients who receive an overdose until the exaggerated pharmacological effects of the drug have resolved. Treatment for an overdose is hospitalization, when needed, and symptom-related supportive care. Ziconotide does not bind to opiate receptors and its pharmacological effects are not blocked by opioid antagonists.

In the event of an inadvertent intravenous or epidural administration, adverse reactions could include severe hypotension, which can be treated with a recumbent posture and blood pressure support as required. The half-life of PRIALT in serum is 1.3 hours.

PRIALT contains ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail,

Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in methyl t-butyl ether.

PRIALT is formulated as a sterile, preservative-free, isotonic solution for intrathecal administration using an appropriate microinfusion device [

The efficacy of intrathecal PRIALT in the management of severe chronic pain was studied in three double-blind, placebo-controlled, multicenter studies in a total of 457 patients (268 PRIALT, 189 placebo) using two different titration schedules. The slow titration schedule tested dose increases 2 to 3 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 5 to 6 days but resulted in less tolerability and substantially more frequent adverse events.

A randomized, double-blind, placebo-controlled study of PRIALT was conducted in adult patients with severe chronic pain not adequately controlled with intrathecally delivered analgesics including morphine, bupivacaine and/or clonidine; or who were intolerant to analgesics and/or systemic analgesics using the 21-day slow titration schedule. All prior intrathecal medications were discontinued over a one to three week period, and patients were maintained on a stable regimen of non-intrathecal analgesics, including opiates, for at least 7 days prior to randomization. Dosing with PRIALT was started at 2.4 mcg/day (0.1 mcg/hr) and the dose was 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) as needed for management of pain. 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 represented the worst possible pain, mean baseline pain scores were 81 in both the PRIALT 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 efficacy analysis, there was a statistically significant difference between groups in the mean percent change in VASPI score from baseline with the PRIALT group having a 12% mean improvement at Week 3 compared to a 5% mean improvement in the placebo group. The 95% confidence interval for the treatment difference (PRIALT–placebo) was 0.4%, 13%.

The effect of intrathecal PRIALT on pain was variable over the time period of treatment for some patients. Patients exhibited various degrees of improvement in pain after three weeks of treatment compared with baseline pain assessment.

For use only in the Medtronic SynchroMed

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