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ZICONOTIDE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ziconotide is a non-opioid analgesic that acts as a neuron-specific calcium channel blocker. It is the synthetic equivalent of a naturally occurring conopeptide found in Conus magus, a piscivorous marine snail.

Specific Substances

    1) Ziconotida
    2) Omega-conotoxin MVIIA
    3) CI-1009
    4) SNX-111
    1.2.1) MOLECULAR FORMULA
    1) C102H172N36O32S7

Available Forms Sources

    A) FORMS
    1) Ziconotide is available, for intrathecal administration, in a 1 and 5 mL vial (100 mcg/mL) containing 100 and 500 mcg of ziconotide acetate, respectively, and in a 20 mL vial (25 mcg/mL) containing 500 mcg of ziconotide acetate (Prod Info PRIALT(R) intrathecal injection, 2010).
    B) USES
    1) Ziconotide is indicated for the management of severe chronic pain in patients who are intolerant or refractory to other treatment, including systemic analgesics, or adjunctive therapies, and in whom intrathecal therapy is warranted (Prod Info PRIALT(R) intrathecal injection, 2010).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ziconotide is indicated for the management of severe chronic pain in patients who are intolerant or refractory to other treatment, including systemic analgesics, or adjunctive therapies, and in whom intrathecal therapy is warranted.
    B) PHARMACOLOGY: Ziconotide is bound to N-type voltage-sensitive calcium channels located on the primary nociceptive afferent nerves in the superficial layers of the dorsal horn in the spinal cord. It blocks depolarization-induced increases in presynaptic intracellular calcium, which controls excitatory neurotransmitter release into the synaptic cleft. Ziconotide is derived from the venom of the marine snail Conus magus.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Dizziness, nausea, confusion, somnolence, nystagmus, and asthenia. Fever may be a common occurrence with intrathecal ziconotide therapy. OTHERS: Nausea, vomiting, anorexia, constipation, diarrhea, taste perversion, cognitive impairment, agitation, stupor, headache, dizziness, asthenia, ataxia, delirium, dysarthria, tremor, hallucinations, urinary retention, hypotension, peripheral edema, atrial fibrillation, abnormal ECG, blurred vision, elevated liver enzymes, muscle spasm, pain in limb, rhabdomyolysis, sinusitis, and fever.
    E) WITH POISONING/EXPOSURE
    1) Ziconotide overdose information is limited. Exaggerated pharmacologic effects (ie, ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, hypotension, nausea, and vomiting) are expected to occur following ziconotide intrathecal doses greater than the maximum recommended dose of 19.2 mcg/day.
    0.2.20) REPRODUCTIVE
    A) Ziconotide is classified as FDA pregnancy category C.

Laboratory Monitoring

    A) Monitor vital signs and liver enzymes.
    B) Monitor for delirium and mental status depression.
    C) Monitor CK in patients with prolonged agitation or coma.
    D) Obtain serial ECGs; institute continuous cardiac monitoring.
    E) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Ziconotide does not bind to opiate receptors, therefore the pharmacological effects of ziconotide are NOT blocked by opioid antagonists. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. After large overdose, removal of CSF should be considered. Treat hypotension with IV fluids and pressors (norepinephrine preferred) if needed.
    C) INTRATHECAL OVERDOSE
    1) Following an intrathecal overdose, elimination of ziconotide from CSF will remain constant (CSF half-life: 4.6 hours); therefore, the ziconotide CSF concentration should be less than 5% of peak levels within 24 hours of ziconotide discontinuation. Immediate attempts to remove as much ziconotide as possible are recommended for very large intrathecal overdoses. Clinical experience is limited, the following information is derived from experience with intrathecal overdose from a variety of xenobiotics. Keep the patient upright if possible. Immediately drain AT LEAST 20 mL CSF; drainage of up to 70 mL has been tolerated in adults. For a very large overdose, follow with CSF exchange (remove serial 20 mL aliquots CSF and replace with equivalent volumes of warmed, preservative free normal saline or lactated ringers).
    D) DECONTAMINATION
    1) GI decontamination is not helpful as ziconotide is administered intrathecally.
    E) AIRWAY MANAGEMENT
    1) Endotracheal intubation may be necessary if life-threatening cardiac dysrhythmias or significant CNS depression develop.
    F) ANTIDOTE
    1) None.
    G) RHABDOMYOLYSIS
    1) Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
    H) ENHANCED ELIMINATION
    1) Ziconotide is administered intrathecally, methods to enhance systemic elimination are not useful.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: There is no data to support home management.
    2) OBSERVATION CRITERIA: Symptomatic patients need to be monitored for several hours. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted. Patients with significant persistent central nervous depression should be admitted to the hospital. Patients with coma, dysrhythmias, or delirium should be admitted to an intensive care setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) Consider the possibility of pump malfunction, or inadvertent epidural or intravenous administration.
    K) PHARMACOKINETICS
    1) Bioavailability (intrathecal): 100% in cerebrospinal fluid; protein binding: 50%. The mean CSF Vd: 140 mL following intrathecal administration. Excretion: Less than 1% recovered in urine. Elimination half-life in CSF (intrathecal): Approximately 4.6 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Overdose with other sedating agents (eg, ethanol, benzodiazepine/barbiturate, antipsychotics); CNS infection; intracranial hemorrhage; hypoglycemia or hypoxia.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose of ziconotide has not been established. In clinical trials, the maximum intrathecal dose of ziconotide was 912 mcg/day. Exaggerated pharmacologic effects (ie, ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, hypotension, nausea, and vomiting) are expected to occur following ziconotide intrathecal doses greater than the maximum recommended dose of 19.2 mcg/day. No respiratory depression is expected.
    B) THERAPEUTIC DOSE: ADULTS: Intrathecal ziconotide should be initiated at no more than 2.4 mcg/day (0.1 mcg/hour) and titrated to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/hour) at intervals of no more than 2 to 3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/hour) by day 21. CHILDREN: The safety and efficacy of ziconotide in pediatric patients have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Ziconotide is indicated for the management of severe chronic pain in patients who are intolerant or refractory to other treatment, including systemic analgesics, or adjunctive therapies, and in whom intrathecal therapy is warranted.
    B) PHARMACOLOGY: Ziconotide is bound to N-type voltage-sensitive calcium channels located on the primary nociceptive afferent nerves in the superficial layers of the dorsal horn in the spinal cord. It blocks depolarization-induced increases in presynaptic intracellular calcium, which controls excitatory neurotransmitter release into the synaptic cleft. Ziconotide is derived from the venom of the marine snail Conus magus.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: Dizziness, nausea, confusion, somnolence, nystagmus, and asthenia. Fever may be a common occurrence with intrathecal ziconotide therapy. OTHERS: Nausea, vomiting, anorexia, constipation, diarrhea, taste perversion, cognitive impairment, agitation, stupor, headache, dizziness, asthenia, ataxia, delirium, dysarthria, tremor, hallucinations, urinary retention, hypotension, peripheral edema, atrial fibrillation, abnormal ECG, blurred vision, elevated liver enzymes, muscle spasm, pain in limb, rhabdomyolysis, sinusitis, and fever.
    E) WITH POISONING/EXPOSURE
    1) Ziconotide overdose information is limited. Exaggerated pharmacologic effects (ie, ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, hypotension, nausea, and vomiting) are expected to occur following ziconotide intrathecal doses greater than the maximum recommended dose of 19.2 mcg/day.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER
    a) Fever has been frequently reported following intrathecal ziconotide therapy (Prod Info PRIALT(R) intrathecal injection, 2010; Staats et al, 2003; Levin et al, 2002).
    b) INCIDENCE: During a randomized, placebo-controlled ziconotide safety and efficacy trial, fever was reported in 25% of patients (n=72) who received ziconotide intrathecally as compared with 7.5% of patients (n=40) of the placebo group (Staats et al, 2003).
    c) Pyrexia was reported in 5% of ziconotide-treated patients (n=112) compared with 3% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) NYSTAGMUS
    a) Nystagmus was reported in 8% of ziconotide-treated patients (n=112) compared with 0% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    b) CASE REPORT: In one case, nystagmus developed at a dose of 0.6 mcg/hour. Ziconotide was stopped for 24 hours and the nystagmus resolved; however, when ziconotide was restarted at 0.4 mcg/hour and increased to 0.6 mcg/hour, the patient again developed nystagmus that continued despite a dose reduction to 0.5 mcg/hour (Penn & Paice, 2000).
    c) CASE REPORT: Nystagmus and blurred vision occurred in a 43-year-old man following therapeutic administration of intrathecal ziconotide at a dose of 3 ng/kg/hour. Decreasing the dose resulted in resolution of the nystagmus (Brose et al, 1997).
    d) CASE SERIES: Four of 6 patients, who received high-dose (7 mcg/hour) intrathecal ziconotide therapy during a clinical trial, developed nystagmus and blurred vision. The symptoms resolved following discontinuation of the drug (Atanassoff et al, 2000).
    2) BLURRED VISION
    a) Blurred vision was reported in 12% of ziconotide-treated patients (n=112) compared with 3% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    B) WITH POISONING/EXPOSURE
    1) NYSTAGMUS: Nystagmus occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) ORTHOSTATIC HYPOTENSION
    1) WITH THERAPEUTIC USE
    a) Postural hypotension was reported in 17 of 72 patients (23.6%) who received ziconotide intrathecally during a randomized placebo-controlled efficacy trial as compared with 2 of 40 patients (5%) in the placebo group (Staats et al, 2003).
    b) Symptomatic orthostatic hypotension and syncope have been reported in 2 healthy subjects (McGuire et al, 1996; Luther et al, 1994)
    c) CASE REPORT: A patient with neuropathic back pain developed orthostatic hypotension within 6 hours of receiving ziconotide 0.9 mcg/hour (Penn & Paice, 2000).
    B) HYPOTENSIVE EPISODE
    1) WITH POISONING/EXPOSURE
    a) Hypotension occurred in patients who received intrathecal ziconotide, during clinical trials, at doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    C) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) The incidence of peripheral edema related to ziconotide therapy was greater in patients 60 years of age or older compared with younger patients less than age 60 years (24.3% vs 17.1%, respectively) in an open-label, long-term, outpatient study (n=644) of ziconotide for severe chronic pain. Peripheral edema was considered serious in one patient (0.2%). Patients received a mean dose at the last infusion of ziconotide 8.4 mcg/day intrathecally (range, 0.048 to 240 mcg/day) for a median duration of 67.5 days (range, 1.2 to 1215.5 days), with 119 (18.5%) patients receiving ziconotide for 360 days or longer (Wallace et al, 2008).
    D) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) Abnormal ECG has been reported in less than 2% of patients being treated with ziconotide in clinical trials (Prod Info PRIALT(R) intrathecal injection, 2010). Sinus tachycardia, nonspecific T-wave changes, and long systolic pauses have been reported (Penn & Paice, 2000).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) SINUSITIS
    1) WITH THERAPEUTIC USE
    a) Sinusitis was reported in 5% of ziconotide-treated patients (n=112) compared with 2% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) IMPAIRED COGNITION
    1) WITH THERAPEUTIC USE
    a) Confusion and cognitive impairment have been frequently reported in 33% and 22% of patients (n=1254), respectively, who received ziconotide intrathecally during randomized placebo-controlled clinical trials. Cognitive impairment may occur gradually during ziconotide therapy and appears to be reversible following ziconotide discontinuation. The median time for reversal of individual cognitive effects have ranged from 3 to 15 days after cessation of ziconotide (Prod Info PRIALT(R) intrathecal injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Confusion and cognitive impairment occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    b) CASE REPORT: A 34-year-old woman, with severe spasticity following a spinal cord injury, began intrathecal ziconotide therapy in increasingly higher doses (2.4 mcg/day to 144 mcg/day) and subsequently developed intermittent confusion, amnesia, and sedation (Ridgeway et al, 2000).
    B) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence was reported in 17% of ziconotide-treated patients (n=112) compared with 10% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    C) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness is a frequent occurrence following therapeutic administration of intrathecal ziconotide (Prod Info PRIALT(R) intrathecal injection, 2010; Staats et al, 2003; Wermeling et al, 2003) and appears to be dose-dependent (Brose et al, 1997).
    b) Dizziness was reported in 46% of ziconotide-treated patients (n=112) compared with 13% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Dizziness occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    b) Four of six patients, who received high-dose (7 mcg/hour) intrathecal ziconotide therapy during a clinical trial, developed dizziness and sedation. The symptoms resolved following discontinuation of the drug (Atanassoff et al, 2000).
    D) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headaches are frequent occurrences following initiation of intrathecal ziconotide therapy (Staats et al, 2003; Wermeling et al, 2003).
    b) Headache was reported in 13% of ziconotide-treated patients (n=112) compared with 11% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    E) DELIRIUM
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: A 38-year-old man, with a psychiatric history of hallucinations and delirium, presented to the ED with increasing agitation, confusion, and delirium, which was associated with intrathecal ziconotide therapy for management of peripheral neuropathic pain, and required intubation, physical restraints, chemical sedation and neuromuscular paralysis with propofol and cisatracurium infusions. Prior to presentation at the ED, the patient began experiencing periods of anxiety and intermittent memory loss corresponding to an increase in ziconotide dosage. Laboratory analyses showed normocytic, normochromic anemia and an elevated serum creatine phosphokinase (1,557 units/liter on admission decreasing to a persistent 500 units/liter thereafter). Several attempts at weaning the patient from the ventilator and decreasing the propofol and cisatracurium infusions were unsuccessful. The agitation was so severe that the patient fractured two toes despite immobilization with restraints. Due to the patient's intractable delirium, electroconvulsive therapy (ECT) was initiated on hospital day 18. The patient was treated with ECT five times over 3 consecutive days. Three hours after his last ECT session, the patient was successfully weaned from neuromuscular paralysis and subsequently extubated. Although the patient initially continued to experience disorientation and retrograde amnesia, he gradually recovered completely without neurologic sequelae (Levin et al, 2002).
    2) WITH POISONING/EXPOSURE
    a) Severe agitation, disorientation, and periods of unresponsiveness, in which the patient was unable to verbally respond but would squeeze the examiner's hand when instructed, were reported at an intrathecal ziconotide dose of 5.3 mcg/hour. Unresponsiveness (to all but painful stimulation) also occurred eight days after a patient was begun on a dose of ziconotide 0.75 mcg/hour. Following ziconotide discontinuation and supportive care, the patient became intermittently responsive with agitation over a 48-hour period before becoming alert but agitated. Over 3 to 7 days, the agitation and shakiness resolved (Penn & Paice, 2000).
    F) COMA
    1) WITH POISONING/EXPOSURE
    a) Stupor and unresponsiveness occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    b) Severe agitation, disorientation, and periods of unresponsiveness, in which the patient was unable to verbally respond but would squeeze the examiner's hand when instructed, were reported at an intrathecal ziconotide dose of 5.3 mcg/hour. Unresponsiveness (to all but painful stimulation) also occurred eight days after a patient was begun on a dose of ziconotide 0.75 mcg/hour. Following ziconotide discontinuation and supportive care, the patient became intermittently responsive with agitation over a 48-hour period before becoming alert but agitated. Over 3 to 7 days, the agitation and shakiness resolved (Penn & Paice, 2000).
    G) ATAXIA
    1) WITH THERAPEUTIC USE
    a) Ataxia and abnormal gait were reported in several patients following initiation of intrathecal ziconotide therapy (Prod Info PRIALT(R) intrathecal injection, 2010; Staats et al, 2003; Levin et al, 2002; Penn & Paice, 2000).
    b) Ataxia was reported in 14% of ziconotide-treated patients (n=112) compared with 1% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Ataxia occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    H) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia may frequently occur with intrathecal ziconotide therapy (Prod Info PRIALT(R) intrathecal injection, 2010; Staats et al, 2003).
    b) Asthenia was reported in 18% of ziconotide-treated patients (n=112) compared with 6% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    I) MYOCLONUS
    1) WITH POISONING/EXPOSURE
    a) Spinal myoclonus occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    J) DYSARTHRIA
    1) WITH THERAPEUTIC USE
    a) Dysarthria was reported in 7% of ziconotide-treated patients (n=112) compared with 0% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    K) TREMOR
    1) WITH THERAPEUTIC USE
    a) Tremor was reported in 7% of ziconotide-treated patients (n=112) compared with 3% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    L) ABNORMAL GAIT
    1) WITH THERAPEUTIC USE
    a) Abnormal gait was reported in 14% of ziconotide-treated patients (n=112) compared with 2% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    M) ANXIETY
    1) WITH THERAPEUTIC USE
    a) Anxiety was reported in 8% of ziconotide-treated patients (n=112) compared with 3% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea is a frequent occurrence following intrathecal administration of ziconotide (Prod Info PRIALT(R) intrathecal injection, 2010; Staats et al, 2003; Wermeling et al, 2003; Penn & Paice, 2000; Ridgeway et al, 2000).
    b) Nausea was reported in 40% of ziconotide-treated patients (n=112) compared with 29% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Nausea occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    B) VOMITING
    1) WITH THERAPEUTIC USE
    a) Vomiting was reported in 16% of ziconotide-treated patients (n=112) compared with 14% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    2) WITH POISONING/EXPOSURE
    a) Vomiting occurred in patients who received intrathecal ziconotide, during clinical trials, in doses greater than the maximum recommended dose of 19.2 mcg/day (Prod Info PRIALT(R) intrathecal injection, 2010).
    C) LOSS OF APPETITE
    1) WITH THERAPEUTIC USE
    a) Anorexia was reported in 6% of ziconotide-treated patients (n=112) compared with 2% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    D) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation has been reported in 2% or greater of patients being treated with ziconotide in clinical trials (Prod Info PRIALT(R) intrathecal injection, 2010).
    E) TASTE SENSE ALTERED
    1) WITH THERAPEUTIC USE
    a) The incidence of taste perversion related to ziconotide therapy was 8.4% (54/644) in patients treated with intrathecal ziconotide for severe chronic pain in an open-label, long-term, outpatient study. Patients received a mean dose at the last infusion of ziconotide 8.4 mcg/day intrathecally (range, 0.048 to 240 mcg/day) for a median duration of 67.5 days (range, 1.2 to 1215.5 days), with 119 (18.5%) patients receiving ziconotide for 360 days or longer (Wallace et al, 2008).
    F) DIARRHEA
    1) WITH THERAPEUTIC USE
    a) Diarrhea was reported in 18% of ziconotide-treated patients (n=112) compared with 15% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: In one case, 2 weeks after discontinuing ziconotide, significant liver enzyme elevations were noted (serum gamma glutamyl transpeptidase (463 units/L), lactate dehydrogenase (444 units/L), aspartate aminotransferase (529 units/L), alanine aminotransferase (373 units/L), and total bilirubin (5.7 mg/dL)) in a 62-year-old man with multiple sclerosis. Another patient showed lesser but significant, increases in liver enzymes (Penn & Paice, 2000).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) RETENTION OF URINE
    1) WITH THERAPEUTIC USE
    a) Urinary retention was reported in 9% of ziconotide-treated patients (n=112) compared with 0% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    b) CASE REPORT - A 38-year-old man experienced several episodes of urinary retention after beginning intrathecal ziconotide therapy. The urinary retention appeared to be dose-dependent (Levin et al, 2002).
    B) URINARY TRACT INFECTIOUS DISEASE
    1) WITH THERAPEUTIC USE
    a) The incidence of urinary tract infection related to ziconotide therapy was 5.1% in male patients and 16.7% in female patients treated with intrathecal ziconotide for severe chronic pain in an open-label, long-term, outpatient study. Patients received a mean dose at the last infusion of ziconotide 8.4 mcg/day intrathecally (range, 0.048 to 240 mcg/day) for a median duration of 67.5 days (range, 1.2 to 1215.5 days), with 119 (18.5%) patients receiving ziconotide for 360 days or longer (Wallace et al, 2008).
    C) DIFFICULTY PASSING URINE
    1) WITH THERAPEUTIC USE
    a) The incidence of impaired urination related to ziconotide therapy was 9.9% (64/644) in patients treated with intrathecal ziconotide for severe chronic pain in an open-label, long-term, outpatient study. Patients received a mean dose at the last infusion of ziconotide 8.4 mcg/day intrathecally (range, 0.048 to 240 mcg/day) for a median duration of 67.5 days (range, 1.2 to 1215.5 days), with 119 (18.5%) patients receiving ziconotide for 360 days or longer (Wallace et al, 2008).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) Up to 40% of patients had serum creatine kinase (CK) levels above the upper limit of normal, and 11% had CK levels that were greater than or equal to 3 times the upper limit of normal, during clinical studies with ziconotide. In cases where CK was fractionated, only the muscle isoenzyme was elevated. Elevated CKs were more often seen in males, in patients who were being treated with antidepressants or anti-epileptics, and in patients treated with intrathecal morphine. One case of myopathy with electromyogram findings, and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations (17,000 to 27,000 International Units/L) were reported (Prod Info PRIALT(R) intrathecal injection, 2010).
    B) SPASM
    1) WITH THERAPEUTIC USE
    a) Muscle spasm was reported in 6% of ziconotide-treated patients (n=112) compared with 4% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).
    C) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) Pain in limb was reported in 5% of ziconotide-treated patients (n=112) compared with 2% of placebo-treated patients (n=108) in a clinical trial using a slow titration schedule (21 days) for severe chronic pain (Prod Info PRIALT(R) intrathecal injection, 2010).

Reproductive

    3.20.1) SUMMARY
    A) Ziconotide is classified as FDA pregnancy category C.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) Ziconotide was not teratogenic in rats and rabbits following continuous intravenous infusion at doses up to 30 mg/kg/day and up to 5 mg/kg/day, respectively. Estimated exposures in the rat and rabbit were approximately 26,000-fold and 940-fold higher, respectively, than the expected exposure resulting from the maximum recommended human intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) (Prod Info PRIALT, 2004).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Ziconotide is classified by the manufacturer as FDA pregnancy category C (Prod Info PRIALT, 2004).
    B) ANIMAL STUDIES
    1) Reduced fetal weights and delayed ossification of the pubic bones occurred in female rats following maternal administration of ziconotide at doses of greater than 15 mg/kg/day. This is approximately 8900-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hour (19.2 mcg/day) (Prod Info PRIALT, 2004).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether ziconotide is excreted in human breast milk (Prod Info PRIALT, 2004).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS107452-89-1 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed

Genotoxicity

    A) Ziconotide was negative in the in vitro bacterial reverse mutation assay, in vitro mouse lymphoma assay, in vivo mouse micronucleus assay, and in the in vitro Syrian hamster embryo cell transformation assay (Prod Info PRIALT, 2004).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs and liver enzymes.
    B) Monitor for delirium and mental status depression.
    C) Monitor CK in patients with prolonged agitation or coma.
    D) Obtain serial ECGs; institute continuous cardiac monitoring.
    E) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted. Patients with significant persistent central nervous depression should be admitted to the hospital. Patients with coma, dysrhythmias, or delirium should be admitted to an intensive care setting.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) There is no data to support home management.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Symptomatic patients need to be monitored for several hours. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Monitor vital signs and liver enzymes.
    B) Monitor for delirium and mental status depression.
    C) Monitor CK in patients with prolonged agitation or coma.
    D) Obtain serial ECGs; institute continuous cardiac monitoring.
    E) Monitor serum electrolytes in patients with significant vomiting and/or diarrhea.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI decontamination is not helpful as ziconotide is administered intrathecally.
    6.5.2) PREVENTION OF ABSORPTION
    A) GI decontamination is not necessary; ziconotide is administered intrathecally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Ziconotide is administered intrathecally; refer to parenteral section for information on specific treatment.

Enhanced Elimination

    A) SUMMARY
    1) Ziconotide is administered intrathecally, methods to enhance systemic elimination are not indicated.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose of ziconotide has not been established. In clinical trials, the maximum intrathecal dose of ziconotide was 912 mcg/day. Exaggerated pharmacologic effects (ie, ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, hypotension, nausea, and vomiting) are expected to occur following ziconotide intrathecal doses greater than the maximum recommended dose of 19.2 mcg/day. No respiratory depression is expected.
    B) THERAPEUTIC DOSE: ADULTS: Intrathecal ziconotide should be initiated at no more than 2.4 mcg/day (0.1 mcg/hour) and titrated to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/hour) at intervals of no more than 2 to 3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/hour) by day 21. CHILDREN: The safety and efficacy of ziconotide in pediatric patients have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) INTRATHECAL: INITIAL: Initiate at no more than 2.4 mcg/day (0.1 mcg/hour) and titrate to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/hour) at intervals of no more than 2 to 3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 microgram/hour) by day 21 (Prod Info Prialt(R) intrathecal injection, 2013).
    B) It is NOT for intravenous administration (Prod Info Prialt(R) intrathecal injection, 2013)
    7.2.2) PEDIATRIC
    A) The safety and efficacy in pediatric patients have not been established (Prod Info Prialt(R) intrathecal injection, 2013).

Maximum Tolerated Exposure

    A) In clinical trials, the maximum intrathecal dose of ziconotide was 912 mcg/day. Exaggerated pharmacologic effects (ie, ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, hypotension, nausea, and vomiting) are expected to occur following ziconotide intrathecal doses greater than the maximum recommended dose of 19.2 mcg/day. No respiratory depression is expected (Prod Info PRIALT(R) intrathecal injection, 2010).

Workplace Standards

    A) ACGIH TLV Values for CAS107452-89-1 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Not Listed

    B) NIOSH REL and IDLH Values for CAS107452-89-1 (National Institute for Occupational Safety and Health, 2007):
    1) Not Listed

    C) Carcinogenicity Ratings for CAS107452-89-1 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
    2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS107452-89-1 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Not Listed

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ziconotide is the synthetic omega conopeptide MVIIA, a 25-amino-acid-residue peptide derived from the venom of the piscivorous marine snail, Conus magus. Ziconotide is bound to N-type voltage-sensitive calcium channels located on the primary nociceptive afferent nerves in the superficial layers of the dorsal horn in the spinal cord. Animal studies indicate that ziconotide blocks depolarization-induced increases in presynaptic intracellular calcium, which controls excitatory neurotransmitter release into the synaptic cleft (Prod Info PRIALT, 2004; Jain, 2000; McGuire et al, 1996).
    B) The pharmacologic effects of ziconotide are not blocked by opioid antagonists, as ziconotide does not bind to opioid receptors. However, in animal models, intrathecal ziconotide potentiated opioid-induced reduction in gastrointestinal motility, but did not potentiate morphine-induced respiratory depression. Additive analgesic effects were observed with concurrent administration of morphine, baclofen, or clonidine in rats receiving intrathecal ziconotide. Furthermore, development of morphine tolerance in rats was not prevented when intrathecal ziconotide and morphine were administered concomitantly (Prod Info PRIALT, 2004).

Physicochemical

Physical Characteristics

    A) ZICONOTIDE is a hydrophilic molecule that is freely soluble in water and practically insoluble in methyl t-butyl ether (Prod Info PRIALT(R) intrathecal infusion solution, 2011).

Ph

    A) 4 to 5 (Prod Info PRIALT(R) intrathecal infusion solution, 2011)

Molecular Weight

    A) 2639 daltons (Prod Info PRIALT(R) intrathecal infusion solution, 2011)

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