For use only in the Medtronic SynchroMed® EL, SynchroMed® II Infusion System, and the CADD-Micro ambulatory infusion pump.
WARNING:
Severe psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. Patients with a pre-existing history of psychosis should not be treated with PRIALT. All patients should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. PRIALT therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms.
DESCRIPTION
PRIALT contains ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus. Ziconotide is a 25amino acid, polybasic peptide containing three disulfide bridges with a molecular weight of 2639daltons and a molecular formula of C102H172N36O32S7. Theamino acid sequence and disulfide bridging pattern are given below:
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 (IT) administration using an appropriate microinfusion device (see Dosage and Administration). Each 1, 2, or 5 mL vial of PRIALT (100 mcg/mL) respectively contains 100, 200, or 500 mcg of ziconotide acetate, and the 20 mL vial of PRIALT (25 mcg/mL) contains 500 mcg of ziconotide acetate, with L-methionine and sodium chloride as excipients at pH4.0–5.0. Each vial is intended for single use only, either undiluted or after dilution to the appropriate concentration with 0.9%Sodium Chloride Injection, USP (preservative free).
CLINICAL PHARMACOLOGY
Pharmacodynamics
Mechanism of Action
Ziconotide binds to N-type calcium channels located on the primary nociceptive (A-δ andC) afferent nerves in the superficial layers (Rexed laminae I and II) of the dorsal horn in the spinal cord. Although the mechanism of action of ziconotide has not been established in humans, results in animals suggest that its binding blocks N-type calcium channels, which leads to a blockade of excitatory neurotransmitter release from the primary afferent nerve terminals and antinociception.
Interaction with opioids
Ziconotide does not bind to opioid receptors and its pharmacological effects are not blocked by opioid antagonists. In animal models, IT ziconotide potentiated opioid-induced reduction in gastrointestinal (GI) motility, but did not potentiate morphine-induced respiratory depression. Inrats receiving IT ziconotide, additive analgesic effects were observed with concurrent administration of morphine, baclofen, or clonidine. Concurrent administration of IT ziconotide and morphine did not prevent the development of morphine tolerance in rats.
PHARMACOKINETICS
The cerebrospinal fluid (CSF) pharmacokinetics (PK) of ziconotide have been studied after one-hour IT infusions of 1–10 mcg of PRIALT to patients with chronic pain. The plasma PK following intravenous (IV) infusion (0.3–10 mcg/kg/day) have also been studied. Both IT and IV data are shown below (Table 1).
Table 1: PRIALT PK Parameters (Mean ± SD)
|
Route |
Fluid |
N |
CL (mL/min) |
Vd (mL) |
T1/2elim(hr) |
|
IT |
CSF |
23 |
0.38 ± 0.56 |
155 ± 263 |
4.6 ± 0.9 |
|
IV |
Plasma |
21 |
270 ± 44 |
30,460 ± 6366 |
1.3 ± 0.3 |
Following one-hour IT administration of 1–10mcg of PRIALT, both total exposure (AUC; range: 83.6–608 ng⋅h/mL) and peak exposure (Cmax; range: 16.4–132 ng/mL) values in the CSF were variable and dose-dependent, but appeared approximately dose-proportional. During 5 or 6 days of continuous IT infusions of PRIALT at infusion rates ranging from 0.1 to 7.0 mcg/hr in patients with chronic pain, plasma ziconotide levels could not be quantified in 56% of patients using an assay with a lower limit of detection of approximately 0.04ng/mL. Predictably, patients requiring higher IT infusion dose rates were more likely to have quantifiable ziconotide levels in plasma. Plasma ziconotide levels, when detectable, remain constant after many months of IT PRIALT infusion in patients followed for up to 9 months.
Distribution
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).
Metabolism
Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following passage from the CSF into the systemic circulation during continuous IT administration, ziconotide is expected to be susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus readily degraded to peptide fragments and their individual constituent free amino acids. Human and animal CSF and blood exhibit minimal hydrolytic activity toward ziconotide in vitro. The biological activity of the various expected proteolytic degradation products of ziconotide has not been assessed.
Elimination
Minimal amounts of ziconotide (<1%) were recovered in human urine following IV infusion. The terminal half-life of ziconotide in CSF after an IT administration was around 4.6 hours (range 2.9–6.5 hours). Mean CSF clearance (CL) of ziconotide approximates adult human CSF turnover rate (0.3–0.4 mL/min).
Special populations
No formal studies were conducted to assess the effect of demographic factors (age, race, gender, and weight), renal or hepatic dysfunction, or to assess the effect of concomitant drugs on the pharmacokinetics of ziconotide due to the low systemic exposure of ziconotide following IT administration.
CLINICAL TRIALS
The safety and efficacy of IT PRIALT in the management of severe chronic pain were studied in three double-blind, placebo-controlled, multicenter studies in a total of 457patients (268 PRIALT, 189 placebo) using two different titration schedules. The slow titration schedule tested dose increases 2–3 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 57.6mcg/day (2.4mcg/hr) in 5–6 days. The safety in chronic use was studied in four additional open-label, long-term studies in 977 patients.
A randomized, double-blind, placebo-controlled study was conducted at 39 centers to eva luate the efficacy of IT PRIALT administered using a slow titration schedule in 220 patients with severe chronic pain. Patients were randomized 1:1 between PRIALT (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 7 days prior to randomization. This period was successfully completed by 93% of the patients screened. Dosing with PRIALT 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 (0.8mcg/hr). The final mean dose at the end of the trial at 21 days was 6.9mcg/day (0.29 mcg/hr).
Using a 100mm Visual Analog Scale of Pain Intensity (VASPI) where 100mm=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 (ITT) 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 (p=0.04). The 95% confidence interval for the treatment difference (PRIALT–placebo) was 0.4%, 13%.
The effect of IT PRIALT 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. Figure 1 depicts the fraction of patients by their degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. 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 PRIALT group compared to 12% in the placebo group, for a net difference of 4%. The use of non-IT opioids decreased by 24% in the PRIALT group and by 17% in the placebo group.
INDICATIONS AND USAGE
PRIALT (ziconotide intrathecal infusion) is indicated for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.
CONTRAINDICATIONS
PRIALT is contraindicated in patients with a known hypersensitivity to ziconotide or any of its formulation components and in patients with any other concomitant treatment or medical condition that would render IT administration hazardous.
Patients with a pre-existing history of psychosis should not be treated with ziconotide.
Contraindications to the use of IT analgesia include conditions such as thepresence of infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of CSF.
WARNINGS
