Ziconotide acetate

2639.13

2637.098389

C1475

N02BG08|N - Nervous system

1310

-17.05

1.60±0.1 g/cm3(Predicted)

1.710

Freely soluble in water and is practically insoluble in methyl tert-butyl ether

−20°C

Oral-rat TDL0: 50 mg/kg

Combustible, decomposes toxic fluoride, sulfur oxide gas when burning

Hydrophilic

III

6.1(b)

3172

3

Treasury is low temperature, ventilated, dry; stored separately from food raw materials

The results /of stability studies/ justify a retest period of 36 months when stored at -20 deg c in the proposed packaging.

P261-P304 + P340 + P312-P403 + P233

H301 + H331

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ziconotide, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

highly toxic

Ziconotide is a selective, potent and reversible blocker of neuronal N-type voltage-sensitive calcium channels (VSCCs). Morphine is an agonist of mu-opioid receptors and inhibits N-type VSCC channels via a G-protein coupling mechanism. Both agents are antinociceptive when they are administered intrathecally (spinally). The present study investigated the acute and chronic (7-day) interactions of intrathecally administered ziconotide and morphine on nociception in several animal models of pain. In the acute study, intrathecal bolus injections of morphine and ziconotide alone produced dose-dependent inhibition of formalin-induced tonic flinch responses and withdrawal responses to paw pressure. The combination of ziconotide and morphine produced an additive inhibition of formalin-induced tonic flinch responses and a significant leftward shift of the morphine dose-response curve in the paw pressure test. After chronic (7-day) intrathecal infusion, ziconotide enhanced morphine analgesia in the formalin test. In contrast, chronic intrathecal morphine infusion produced tolerance to analgesia, but did not affect ziconotide antinociception. Antinociception produced by ziconotide alone was the same as that observed when the compound was co-administered with morphine to morphine-tolerant rats. In the hot-plate and tail immersion tests, chronic intrathecal infusion of morphine lead to rapid tolerance whereas ziconotide produced sustained analgesia with no loss of potency throughout the infusion period. Although ziconotide in combination with morphine produced an apparent synergistic analgesic effects during the initial phase of continuous infusion, it did not prevent morphine tolerance to analgesia. These results demonstrate that (1) acute intrathecal administrations of ziconotide and morphine produce additive or synergistic analgesic effects; (2) chronic intrathecal morphine infusion results in tolerance to analgesia but does not produce cross-tolerance to ziconotide; (3) chronic intrathecal ziconotide administration produces neither tolerance nor cross-tolerance to morphine analgesia; (4) intrathecal ziconotide does not prevent or reverse morphine tolerance.|Used concomitantly with anticonvulsants, antidepressants, antipsychotics, anxiolytics, and sedatives in clinical studies. Potential interaction with CNS depressants (increased incidence of adverse CNS effects [e.g., dizziness, confusion, reduced levels of consciousness]). Dosage adjustment or discontinuance of ziconotide or the concomitant CNS depressant may be needed. Potential interaction with antidepressants or anticonvulsants (elevated serum creatine kinase [CK, creatine phosphokinase, CPK]).

In clinical studies, 22% of patients were 65 years of age or older and 7% were 75 years of age or older. In all studies, the incidence of confusion was higher in individuals 65 years of age or older than in younger adults. No substantial difference in efficacy in geriatric patients relative to younger adults. Select dosage with caution, starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.|Patients with a history of psychosis should not receive ziconotide.

While data specific to ziconotide were not located(SRC, 2008), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through soils(1).

Ziconotide is indicated for the treatment of severe, chronic pain in patients who require intrathecal (IT) analgesia.

Ziconotide is used intrathecally for the management of severe chronic pain in patients who are intolerant of or do not obtain adequate pain relief from other therapies (e.g., systemic analgesics, adjunctive therapies, intrathecal morphine therapy) when intrathecal therapy is warranted.

/BOXED WARNING/ WARNING: NEUROPSYCHIATRIC ADVERSE REACTIONS. Prialt is contraindicated in patients with a preexisting history of psychosis. Severe psychiatric symptoms and neurological impairment may occur during treatment with Prialt. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Discontinue Prialt therapy in the event of serious neurological or psychiatric signs or symptoms.|Meningitis has occurred in patients receiving ziconotide, principally in individuals receiving therapy via an external microinfusion device and catheter. Meningitis may occur secondary to inadvertent contamination of the microinfusion device or as a result of CSF seeding caused by hematogenous or direct spread from an infected pump pocket or catheter tract. Patients should be monitored for signs and symptoms of meningitis (e.g., fever, headache, stiff neck, altered mental status, nausea or vomiting, seizures). Preparation of ziconotide solution and filling of the drug reservoir should be performed under aseptic conditions by trained and qualified personnel. If meningitis is suspected (especially in immunocompromised patients) or is confirmed, appropriate measures (CSF culture, anti-infective therapy, removal of the microinfusion device and catheter) should be initiated.|Use of Prialt has been associated with CNS-related adverse events, including psychiatric symptoms, cognitive impairment, and decreased alertness/unresponsiveness. For the 1254 patients treated /in clinical trials/, the following cognitive adverse event rates were reported: confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), thinking abnormal (8%), and amnesia (1%). Cognitive impairment may appear gradually after several weeks of treatment. The PRIALT dose should be reduced or discontinued if signs or symptoms of cognitive impairment develop, but other contributing causes should also be considered. The various cognitive effects of Prialt are generally reversible within 2 weeks after drug discontinuation. The medians for time to reversal of the individual cognitive effects ranged from 3 to 15 days. The elderly (> or = 65 years of age) are at higher risk for confusion.|Cognitive impairment (e.g., confusion, memory impairment, speech disorder, aphasia, abnormal thinking, amnesia) has been reported in patients receiving ziconotide. Cognitive impairment may appear gradually over several weeks and generally is reversible following discontinuance of the drug. If cognitive impairment develops, the dose of ziconotide should be reduced or the drug discontinued; other causes that could contribute to cognitive impairment should be considered.|For more Drug Warnings (Complete) data for ZICONOTIDE (17 total), please visit the HSDB record page.

A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS. (See all compounds classified as Analgesics, Non-Narcotic.)|A class of drugs that act by selective inhibition of calcium influx through cellular membranes. (See all compounds classified as Calcium Channel Blockers.)|Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids. (See all compounds classified as Neuroprotective Agents.)

Ziconotide reached a maximal brain concentration of between 0.003 and 0.006% of the injected material per gram of tissue at 3-20 min after i.v. injection, and this decayed to below 0.001%/g after 2 hr. ... The peptide was perfused through in vivo dialysis probes implanted into the hippocampus. Image analysis and serial sectioning showed that diffusion of Ziconotide in the extracellular fluid around the dialysis probe was minimal, with the peptide located within 1 mm of the probe after 2 hr. ... Passage from blood to brain was also verified by in situ perfusion through the carotid artery. A statistically greater amount of radioactivity was found to cross the BBB after perfusion of radioiodinated Ziconotide compared to (14)C inulin.|The pharmacokinetics and pharmacodynamics of ziconotide were assessed over a 48-hour period following intrathecal (i.t.) administration (1, 5, 7.5, or 10 ug) to 22 patients with chronic, nonmalignant pain. Plasma and cerebrospinal fluid samples were obtained over a 24-hour period. Analgesic efficacy was monitored using Visual Analog Scale of Pain Intensity (VASPI) and Category Pain Relief Scores (CPRS) measurements. Pharmacokinetic (PK) parameters were calculated by noncompartmental methods. Plasma ziconotide data were insufficient for pharmacokinetic calculations. In cerebrospinal fluid, the median half-life of ziconotide was 4.5 hours. The median cerebrospinal fluid clearance and volume of distribution were 0.26 mL/min and 99 mL, respectively. Cerebrospinal fluid pharmacokinetics of ziconotide were linear, based on cumulative exposure and peak cerebrospinal fluid concentrations. A dose-related analgesia was observed. ...|Intrathecal administration of ziconotide results in little systemic exposure. Following passage from the CSF into the systemic circulation, ziconotide is expected to be degraded to peptide fragments and their constituent amino acids by endopeptidases and exopeptidases present in most organs.|Ziconotide is about 50% bound to human plasma proteins. The mean cerebrospinal fluid (CSF) volume of distribution (Vd) of ziconotide following intrathecal administration approximates the estimated total CSF volume (140 mL).|For more Absorption, Distribution and Excretion (Complete) data for ZICONOTIDE (6 total), please visit the HSDB record page.

Ziconotide is rapidly distributed and/or metabolized in spinal cerebrospinal fluid (CSF) after intrathecal administration, followed by relatively rapid mass transport of the product from the CSF into the plasma. The relative contributions of mass transport, within and outside the spinal cord, and metabolism within it, are unclear. There is certainly evidence for rapid transport into the blood and metabolism within the spinal cord is likely to have a significant role. Following entry into the blood, the compound is quickly metabolized by normal proteolytic mechanisms, eventually to its constituent amino acids; it can be assumed that these will be further metabolized or incorporated into proteins by normal processes.|Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following passage from the cerebrospinal fluid (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.

The terminal half-life of ziconotide in cerebrospinal fluid after an intrathecal administration was around 4.6 hours (range 2.9-6.5 hours).

/Ziconotide/ is a N-type calcium channel blocker (NCCB). Voltage-sensitive calcium channel (VSCC) conduction plays a major role in the transmission of pain. The N-type VSCC's are found in high concentrations in the dorsal root ganglion cells responsible for the spinal processing of pain. Ziconotide selectively and reversibly binds to and blocks these channels without interacting with other ion channels or cholinergic, monoaminergic or mu and delta-opioid receptors. Ziconotide thus inhibits the spinal signalling of pain.

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.

/SIGNS AND SYMPTOMS/ The maximum recommended intrathecal Prialt dose is 19.2 ug/day. The maximum intrathecal dose of Prialt in clinical trials was 912 ug/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 intrathecal overdose, elimination of ziconotide from cerebrospinal fluid (CSF) would be expected to remain constant (CSF half life = 4.6 hours). Therefore, within 24 hours of stopping therapy, the ziconotide CSF concentration should be less than 5% of peak levels.|/CASE REPORTS/ Symptomatic myopathy with electromyographic abnormalities has occurred in at least one patient, and acute renal failure with rhabdomyolysis and markedly elevated creatine kinase (CK) concentrations (17,000-27,000 IU/L) has been reported in at least 2 patients.|/CASE REPORTS/ Two patients with longstanding neuropathic pain, one with complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) of the leg and one with lumbar radiculitis, achieved temporary but complete pain relief from single 5- and 10-ug epidural test doses /of ziconotide/. In the third case, a patient with longstanding bilateral leg and foot neuropathic pain from acquired immunodeficiency syndrome and antiretroviral drug therapy achieved considerable pain relief from a long-term continuous intrathecal infusion. The patients who received a single dose had mild central nervous system adverse effects such as sedation, somnolence, nausea, headache, and lightheadedness. The patient who received the intrathecal infusion experienced mild-to-severe adverse effects depending on the rate of infusion; these effects included sedation, confusion, memory impairment, slurred speech, and double vision. This patient could sense impending adverse effects and made rate adjustments or suspended infusion to avert untoward symptoms. In all three cases, patients achieved considerable pain relief that was long-lasting and persisted well after dose administration or suspension of infusion.|/OTHER TOXICITY INFORMATION/ Ziconotide intrathecal infusion was recently approved by the United States Food and Drug Administration for the treatment of intractable severe chronic pain. Patients with neuropathic pain make up a significant population among those who experience chronic pain for which there are less than optimal pharmacotherapeutic options. Published clinical trials provide a global view of ziconotide efficacy and safety. A subset of patients in clinical trials obtained complete pain relief, a remarkable finding given the history of drug treatment for neuropathic pain. To provide more information regarding those who respond to ziconotide therapy, we discuss three patients with neuropathic pain who received ziconotide infusion. Two patients with longstanding neuropathic pain, one with complex regional pain syndrome (formerly known as reflex sympathetic dystrophy) of the leg and one with lumbar radiculitis, achieved temporary but complete pain relief from single 5- and 10-microg epidural test doses. In the third case, a patient with longstanding bilateral leg and foot neuropathic pain from acquired immunodeficiency syndrome and antiretroviral drug therapy achieved considerable pain relief from a long-term continuous intrathecal infusion. The patients who received a single dose had mild central nervous system adverse effects such as sedation, somnolence, nausea, headache, and lightheadedness. The patient who received the intrathecal infusion experienced mild-to-severe adverse effects depending on the rate of infusion; these effects included sedation, confusion, memory impairment, slurred speech, and double vision. This patient could sense impending adverse effects and made rate adjustments or suspended infusion to avert untoward symptoms. In all three cases, patients achieved considerable pain relief that was long-lasting and persisted well after dose administration or suspension of infusion.

CYS-LYS-GLY-LYS-GLY-ALA-LYS-CYS-SER-ARG-LEU-MET-TYR-ASP-CYS-CYS-THR-GLY-SER-CYS-ARG-SER-GLY-LYS-CYS-NH2

Parenteral: Injection, for intrathecal administration via compatible microinfusion device only: 25 ug/mL Prialt, (Elan), 100 ug/mL Prialt, (Elan).

... a synthetic equivalent of a naturally occurring conopeptide found in the piscevorous marine snail, Conus magus.

Analyte: ziconotide; matrix: blood (plasma); procedure: immunoaffinity extraction with matrix-assisted laser desorption/ionization mass spectrometry|Analyte: ziconotide; matrix: blood (plasma); procedure: radioimmunoassay|Analyte: ziconotide; matrix: blood (plasma); procedure: immunoaffinity chromatography with capillary liquid chromatography coupled with electrospray ionization mass spectrometry|Analyte: ziconotide; matrix: blood (plasma), tissue (brain); procedure: high-performance liquid chromatography with ultraviolet detection at 220 nm

Human drugs -> Prialt -> EMA Drug Category|Analgesics -> Human pharmacotherapeutic group|Human drugs -> Rare disease (orphan)|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients