Jane S. Ricciuti, RPh, MS

Disclosures

January 20, 2005

In This Article

Analgesic Agents

Prialt
(ziconotide) Intrathecal Injection

Manufacturer: Elan Pharmaceuticals, Inc.

Drug Approval Classification: Original New Drug Application (Approval Date: 12/28/04)

Indication: Prialt (ziconotide) intrathecal injection (IT) is indicated for the management of severe chronic pain in patients for whom IT therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.

Dosing: Ziconotide via intrathecal injection (IT) should be initiated at no more than 2.4 mcg/day (0.1 mcg/hr) and titrated to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2-3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/hr) by Day 21. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and increases in dose less frequently than 2-3 times per week may be used.

Ziconotide is intended for IT delivery using a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter (see product labeling for detailed information).

Clinical Summary: Ziconotide is the synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus. Ziconotide binds to N-type calcium channels located on the primary nociceptive afferent nerves in the superficial layers of the dorsal horn in the spinal cord. The mechanism of action of ziconotide has not been established in humans, but results in animals suggest that its binding blocks N-type calcium channels, which leads to a blockade of excitatory neurotransmitter release in the primary afferent nerve terminals and antinociception.

Three double-blind, placebo-controlled, multicenter studies in a total of 457 patients were conducted with IT ziconotide. Using a 100 mm Visual Analog Scale of Pain Intensity (VASPI) where 100 mm signified worst possible pain, mean baseline pain scores were 81 in both the IT ziconotide and placebo groups. The primary efficacy endpoint 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 IT ziconotide group having a 12% mean improvement at Week 3 compared with a 5% mean improvement in the placebo group (P = .04). 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. The improvement in the proportion of "responders," defined as having a 30% improvement from baseline in VASPI, was 16% in the IT ziconotide group vs 12% in the placebo group, for a net difference of 4%. The use of non IT opioids decreased by 24% in the IT ziconotide group and by 17% in the placebo group.

Adverse Effects: The ziconotide labeling contains a black box warning for severe psychiatric symptoms:

WARNING:
Severe psychiatric symptoms and neurological impairment may occur during treatment with IT ziconotide. Patients with a pre-existing history of psychosis should not be treated with IT ziconotide. All patients should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. IT ziconotide therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms.

The most frequently reported adverse events (25%) in the 1254 patients in clinical trials were dizziness, nausea, confusion, headache, somnolence, nystagmus, asthenia, and pain.

Pharmacokinetics: Following 1-hour IT administration of 1-10 mcg of ziconotide, both total exposure (AUC; range: 83.6-608 ng h/mL) and peak exposure (Cmax; range: 16.4-132 ng/mL) values in the cerebral spinal fluid (CSF) were variable and dose dependent, but appeared approximately dose proportional. Ziconotide is about 50% bound to human plasma proteins. The mean CSF volume of distribution (Vd) of ziconotide following IT administration approximates the estimated total CSF volume (140 mL).

Ziconotide does not bind to opioid receptors, and its pharmacologic effects are not blocked by opioid antagonists.

Prialt (ziconotide) Intrathecal Injection Labeling

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