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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs which have a heightened risk of causing significant patient harm when used in error.
Pronunciation
(zi KOE no tide)
U.S. Brand Names
Generic Available
No
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of severe chronic pain in patients requiring intrathecal (I.T.) therapy and who are intolerant or refractory to other therapies
Pregnancy Risk Factor
C
Pregnancy Considerations
Teratogenic effects were not observed in animal studies, but increased postimplantation pup loss was reported. Maternal toxicity was also noted. There are no adequate and well-controlled studies in pregnant women.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
The manufacturer recommends discontinuing breast-feeding or discontinuing ziconotide.
Contraindications
Hypersensitivity to ziconotide or any component of the formulation; history of psychosis; I.V. administration
I.T. administration is contraindicated in patients with infection at the injection site, uncontrolled bleeding, or spinal canal obstruction that impairs CSF circulation
Warnings/Precautions
Boxed warnings:
• CNS toxicity: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• CNS toxicity: [U.S Boxed Warning]: Severe psychiatric symptoms and neurological impairment have been reported; interrupt or discontinue therapy if cognitive impairment, hallucinations, mood changes, or changes in consciousness occur. May cause or worsen depression and/or risk of suicide. Cognitive impairment may appear gradually during treatment and is generally reversible after discontinuation (may take up to 2 weeks for cognitive effects to reverse). May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving).
• Elevated serum creatine kinase: With use, elevated serum creatine kinase can occur; particularly during the first 2 months of therapy. Consider dose reduction or discontinuing if combined with new neuromuscular symptoms (myalgias, myasthenia, muscle cramps, weakness) or reduction in physical activity.
• Meningitis: May occur with use of I.T. pumps; monitor for signs of meningitis; treatment of meningitis may require removal of system and discontinuation of intrathecal therapy.
Disease-related concerns:
• Hepatic impairment: Safety and efficacy have not been established in patients with hepatic impairment.
• Renal impairment: Safety and efficacy have not been established in patients with renal impairment.
Concurrent drug therapy issues:
• CNS depressants: May have additive effects with CNS-depressant medications.
• Opiates: May have additive CNS effects with opiates and may potentiate opioid-induced decreased GI motility; does not interact with opioid receptors or potentiate opiate-induced respiratory depression.
Special populations:
• Elderly: Use with caution in the elderly; may experience a higher incidence of confusion.
• Pediatrics: Safety and efficacy have not been established in children.
Other warnings/precautions:
• Withdrawal: Will not prevent or relieve symptoms associated with opiate withdrawal; unlike opioids, ziconotide therapy can be interrupted abruptly or discontinued without evidence of withdrawal.
Adverse Reactions
>10%:
Central nervous system: Dizziness (46%), confusion (15% to 33%), memory impairment (7% to 22%), somnolence (17%), ataxia (14%), speech disorder (14%), headache (13%), aphasia (12%), hallucination (12%; including auditory and visual)
Gastrointestinal: Nausea (40%), diarrhea (18%), vomiting (16%)
Neuromuscular & skeletal: Creatine kinase increased (40%; ?3 times ULN: 11%), weakness (18%), gait disturbances (14%)
Ocular: Blurred vision (12%)
2% to 10%:
Cardiovascular: Hypotension, peripheral edema, postural hypotension
Central nervous system: Abnormal thinking (8%), amnesia (8%), anxiety (8%), vertigo (7%), insomnia (6%), fever (5%), paranoid reaction (3%), delirium (2%), hostility (2%), stupor (2%), agitation, attention disturbance, balance impaired, burning sensation, coordination abnormal, depression, disorientation, fatigue, fever, hypoesthesia, irritability, lethargy, mental impairment, mood disorder, nervousness, pain, sedation
Dermatologic: Pruritus (7%)
Gastrointestinal: Anorexia (6%), taste perversion (5%), abdominal pain, appetite decreased, constipation, xerostomia
Genitourinary: Urinary retention (9%), dysuria, urinary hesitance
Neuromuscular & skeletal: Dysarthria (7%), paresthesia (7%), rigors (7%), tremor (7%), muscle spasm (6%), limb pain (5%), areflexia, muscle cramp, muscle weakness, myalgia
Ocular: Nystagmus (8%), diplopia, visual disturbance
Respiratory: Sinusitis (5%)
Miscellaneous: Diaphoresis (5%)
<2%, postmarketing, and/or case reports: Acute renal failure, aspiration pneumonia (<1%), atrial fibrillation, cerebral vascular accident, ECG abnormalities, incoherence, loss of consciousness, mania, meningitis, myoclonus, psychosis (1%), psychotic disorder, respiratory distress, rhabdomyolysis, seizure (clonic and grand mal), sepsis, suicidal ideation, suicide attempt (<1%)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Ethanol: Avoid ethanol (may increase CNS adverse effects).
Storage
Prior to use, store vials at 2°C to 8°C (36°F to 46°F). Once diluted, may be stored at 2°C to 8°C (36°F to 46°F) for 24 hours; refrigerate during transit. Do not freeze. Protect from light.
When using the Medtronic SynchroMed® EL or SynchroMed® II Infusion System, solutions expire as follows:
25 mcg/mL: Undiluted:
Initial fill: Use within 14 days.
Refill: Use within 84 days.
100 mcg/mL:
Undiluted: Refill: Use within 84 days.
Diluted: Refill: Use within 40 days.
Reconstitution
Preservative free NS should be used when dilution is needed.
CADD-Micro® ambulatory infusion pump: Initial fill: Dilute to final concentration of 5 mcg/mL.
Medtronic SynchroMed® EL or SynchroMed® II infusion system: Prior to initial fill, rinse internal pump surfaces with 2 mL ziconotide (25 mcg/mL), repeat twice. Only the 25 mcg/mL concentration (undiluted) should be used for initial pump fill.
Mechanism of Action
Ziconotide selectively binds to N-type voltage-sensitive calcium channels located on the nociceptive afferent nerves of the dorsal horn in the spinal cord. This binding is thought to block N-type calcium channels, leading to a blockade of excitatory neurotransmitter release and reducing sensitivity to painful stimuli.
Pharmacodynamics/Kinetics
Distribution: I.T.: Vd: ?140 mL
Protein binding: ?50%
Metabolism: Metabolized via endopeptidases and exopeptidases present on multiple organs including kidney, liver, lung; degraded to peptide fragments and free amino acids
Half-life elimination: I.V.: 1-1.6 hours (plasma); I.T.: 2.9-6.5 hours (CSF)
Excretion: I.V.: Urine (<1%)
Dosage
I.T.:
Adults: Chronic pain: Initial dose: ?2.4 mcg/day (0.1 mcg/hour)
Dose may be titrated by ?2.4 mcg/day (0.1 mcg/hour) at intervals ?2-3 times/week to a maximum dose of 19.2 mcg/day (0.8 mcg/hour) by day 21; average dose at day 21: 6.9 mcg/day (0.29 mcg/hour). A faster titration should be used only if the urgent need for analgesia outweighs the possible risk to patient safety.
Dosage adjustment for toxicity:
Cognitive impairment: Reduce dose or discontinue. Effects are generally reversible within 3-15 days of discontinuation.
Reduced level of consciousness: Discontinue until event resolves.
CK elevation with neuromuscular symptoms: Consider dose reduction or discontinuation.
Elderly: Refer to adult dosing; use with caution.
Administration: I.V.
Not for I.V. administration
Administration: Other
Not for I.V. administration. For I.T. administration only using Medtronic SynchroMed® EL, SynchroMed® II Infusion System, or CADD-Micro® ambulatory infusion pump.
Medtronic SynchroMed® EL or SynchroMed® II Infusion Systems:
Naive pump priming (first time use with ziconotide): Use 2 mL of undiluted ziconotide 25 mcg/mL solution to rinse the internal surfaces of the pump; repeat twice for a total of 3 rinses
Initial pump fill: Use only undiluted 25 mcg/mL solution and fill pump after priming. Following the initial fill only, adsorption on internal device surfaces will occur, requiring the use of the undiluted solution and refill within 14 days.
Pump refills: Contents should be emptied prior to refill. Subsequent pump refills should occur at least every 40 days if using diluted solution or at least every 84 days if using undiluted solution.
CADD-Micro® ambulatory infusion pump: Refer to manufacturers' manual for initial fill and refill instructions
pH: 4-5
Monitoring Parameters
Monitor for psychiatric or neurological impairment; signs and symptoms of meningitis or other infection; serum CPK (every other week for first month then monthly); pain relief
Patient Education
Avoid alcohol, other prescriptions, or OTC medications (especially sedatives, tranquilizers, antihistamines, and other pain medications) without consulting prescriber. You may experience dizziness, sleepiness, or lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea or vomiting (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); diarrhea (buttermilk, boiled milk, or yogurt may help); or loss of appetite. Report chest pain, swelling of extremities (feet/ankles); muscle weakness and poor coordination; hallucinations, confusion, or extreme weakness. Pregnancy/breast-feeding precaution: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.
Geriatric Considerations
Manufacturer reports that in all trials there was a higher incidence of confusion in the elderly compared to younger adults.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation) and taste perversion.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
Dizziness and sedation are common. May cause hallucinations, mood changes, cognitive impairment, changes in consciousness, anxiety, nervousness, agitation, abnormal dreams, insomnia, or hostility.
Mental Health: Effects on Psychiatric Treatment
Contraindicated in individuals with a history of psychosis. Concomitant use with psychotropic agents may produce additive sedative effects; monitor. GI side effects are common; concomitant use with SSRIs, valproic acid, or lithium may produce additive effects; monitor.
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. This medication is given intrathecally via pump. Monitor for therapeutic response. Monitor for changes in behavior, cognitive impairment, hallucinations, or changes in mood or consciousness. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, solution, as acetate [preservative free]:
Prialt®: 25 mcg/mL (20 mL); 100 mcg/mL (1 mL, 5 mL)
References
Jain KK, “An Evaluation of Intrathecal Ziconotide for the Treatment of Chronic Pain,” Expert Opin Investig Drugs, 2000, 9(10):2403-10.
Miljanich GP, “Ziconotide: Neuronal Calcium Channel Blocker for Treating Severe Chronic Pain,” Curr Med Chem, 2004, 11(23):3029-40.
Staats PS, Yearwood T, Charapata SG, et al, “Intrathecal Ziconotide in the Treatment of Refractory Pain in Patients With Cancer or AIDS: A Randomized Controlled Trial,” JAMA, 2004, 291(1):63-70.
Wermeling D, Drass M, Ellis D, et al, “Pharmacokinetics and Pharmacodynamics of Intrathecal Ziconotide in Chronic Pain Patients,” J Clin Pharmacol, 2003, 43(6):624-36.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
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