Ziconotide

Pain

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.1,2,3,5

Safety and efficacy of ziconotide have been evaluated in 3 double-blind, placebo-controlled studies using 2 different dosage titration schedules.1 In the slow dosage titration schedule, dosage was increased 2 or 3 times per week (minimum interval between dose escalations: 24 hours) up to a maximum dosage of 19.2 mcg per 24 hours at day 21.1,6 In the fast dosage titration schedule, dosage was increased daily up to a maximum dosage of 57.6 mcg per 24 hours after 5-6 days.1,2

Efficacy of ziconotide administered using the slow dosage titration schedule has been evaluated in one randomized, placebo-controlled, multicenter study in patients with severe chronic pain (mean baseline score of 81 on the 100-mm Visual Analog Scale of Pain Intensity [VASPI]; pain was unresponsive to other analgesic therapy in 97% of patients).1 Prior to randomization, all intrathecal agents were discontinued and patients received a stable regimen of analgesics (including opiates) for at least 7 days.1 The mean improvement in VASPI score from baseline to study completion at day 21 (the primary efficacy measure) was 12% in patients receiving ziconotide and 5% in those receiving placebo.1 The effect of ziconotide on pain was variable over time.1 Some patients experienced pain relief (i.e., improvement in VASPI score) during the first or second week, but improvement was not sustained through the end of the third week.1 Other patients did not show improvement in VASPI score until the third week.1 Sixteen or 12% of those receiving ziconotide or placebo, respectively, were classified as responders (defined as having at least a 30% improvement in VASPI score from baseline).1 Use of systemic opiate analgesics decreased by 24% in patients receiving ziconotide and by 17% in those receiving placebo.1

Although the duration of ziconotide therapy in controlled clinical studies to date has been limited to 21 days, the drug has been used in a substantial number of patients in long-term open-label studies.1

Dosage and Administration ⬆ ⬇

[Section Outline]

Administration
Dosage
Special Populations

Administration

Ziconotide is administered intrathecally using a programmable implanted variable-rate microinfusion device (i.e., Medtronic SynchroMed^® EL or SynchroMed^® II) or an external microinfusion device and catheter (i.e., CADD-Micro^® ambulatory infusion pump) by or under the supervision of a qualified clinician familiar with the drug, the techniques of intrathecal administration, and the device being used.1 The device manufacturer's manual should be consulted for specific instructions and precautions for performing a reservoir rinse, initial filling, refilling the reservoir or replacing the drug cartridge, and programming.1

An appropriate vial strength and final concentration of the drug should be selected in accordance with the manufacturer's instructions.1 The commercially available preparation containing ziconotide 25 mcg/mL may be used undiluted; the preparation containing ziconotide 100 mcg/mL may be used undiluted or may be diluted with 0.9% sodium chloride injection prior to placement in the pump.1 Sodium chloride solutions containing preservatives are not appropriate for intrathecal administration and should not be used to dilute ziconotide.1 Diluted ziconotide solutions should be refrigerated; freezing should be avoided.1 Infusion of diluted ziconotide solutions should be initiated within 24 hours of preparation.1

Ziconotide is not for IV administration.1

Dosage

Ziconotide therapy should be initiated using a slow dosage titration schedule in order to minimize the risk of adverse effects that are serious or require drug discontinuance.1 A faster titration schedule should be used only if an urgent need for analgesia outweighs the risk to patient safety.1

The recommended initial dosage of ziconotide for management of severe chronic pain in adults is 2.4 mcg per 24 hours (0.1 mcg/hour) or less.1 Dosage is then titrated based on patient response.1 Dosage can be increased 2 or 3 times per week in increments of up to 2.4 mcg per 24 hours (0.1 mcg/hour), up to a maximum recommended dosage of 19.2 mcg per 24 hours (0.8 mcg/hour) by day 21.1 In a study that evaluated efficacy of ziconotide using the slow dosage titration schedule, the average dosage at day 21 was 6.9 mcg per 24 hours (0.29 mcg/hour); the maximum dosage was 19.2 mcg per 24 hours.1

Ziconotide therapy can be interrupted or discontinued abruptly without withdrawal effects.1

Special Populations

Initiate ziconotide at the lower end of the dosage range in geriatric patients. (See Specific Populations: Geriatric Use under Cautions: Warnings/Precautions.)

Cautions ⬆ ⬇

[Section Outline]

Contraindications
Warnings/Precautions
Common Adverse Effects

Contraindications

Concomitant treatments or medical conditions (e.g., presence of infection at the microinfusion injection site, uncontrolled bleeding diathesis, spinal canal obstruction that impairs CSF circulation) that make intrathecal therapy hazardous.1

History of psychosis.1

Known hypersensitivity to ziconotide or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Nervous System Effects

Severe psychiatric symptoms and neurologic impairment may occur in patients receiving ziconotide.1 Patients with a history of psychosis should not receive ziconotide.1 (See Contraindications.) Patients should be monitored for cognitive impairment, hallucinations, and changes in mood or consciousness.1 If a severe adverse neurologic or psychiatric event occurs, ziconotide can be temporarily interrupted or abruptly discontinued without withdrawal effects.1

Cognitive impairment (e.g., confusion, memory impairment, speech disorder, aphasia, abnormal thinking, amnesia) has been reported in patients receiving ziconotide.1 Cognitive impairment may appear gradually over several weeks and generally is reversible following discontinuance of the drug.1 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.1

Acute psychiatric disturbances (e.g., hallucinations, paranoid reactions, hostility, delirium, psychosis, manic reactions) have occurred in patients receiving ziconotide.1 Patients with preexisting psychiatric disorders may be at increased risk for these adverse events.1 Ziconotide may cause or worsen depression, resulting in the risk of suicide in certain patients.1 Suicide, suicide attempts, and suicidal ideation have been reported more frequently in ziconotide-treated patients than in placebo-treated patients.1 If psychiatric disturbances occur, ziconotide should be discontinued and the disturbances managed appropriately (e.g., psychotherapeutic agents, hospital admission).1 A decision to reinitiate ziconotide therapy in a patient who has experienced psychiatric symptoms should be made on an individual basis after careful evaluation.1

Patients receiving ziconotide have become unresponsive or stuporous; patients sometimes appear to be conscious, and breathing is not depressed during these events.1 Patients receiving concomitant therapy with anticonvulsants, antipsychotics, sedatives, or diuretics may be at increased risk for this adverse effect.1 If reduced levels of consciousness occur, ziconotide should be discontinued until the event resolves; other etiologies (e.g., meningitis) should be considered.1 In addition, concomitant CNS depressants (e.g., anticonvulsants, antipsychotics, sedatives) should be discontinued as clinically appropriate if altered consciousness occurs.1,6

Opiate Withdrawal

Ziconotide does not prevent or treat the symptoms of opiate withdrawal.1 For patients discontinuing intrathecal opiate therapy, the intrathecal infusion rate should be gradually tapered over a few weeks and replaced with equivalent doses of oral opiates to avoid symptoms of opiate withdrawal.1

Major Toxicities

Meningitis

Meningitis has occurred in patients receiving ziconotide, principally in individuals receiving therapy via an external microinfusion device and catheter.1 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.1 Patients should be monitored for signs and symptoms of meningitis (e.g., fever, headache, stiff neck, altered mental status, nausea or vomiting, seizures).1 Preparation of ziconotide solution and filling of the drug reservoir should be performed under aseptic conditions by trained and qualified personnel.1 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.1

General Precautions

Serum Creatine Kinase

Serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations exceeding the upper limit of normal have been observed in many patients (40%) receiving ziconotide; CK concentrations 3 or more times the upper limit of normal have occurred in 11% of patients.1 These increases generally have been observed during the first 2 months of therapy with ziconotide and have not been associated with treatment-limiting adverse effects.1 Men, patients receiving concomitant therapy with antidepressants or anticonvulsants, and those who had received intrathecal morphine were more likely to have elevated serum CK values. 1

Symptomatic myopathy with electromyographic abnormalities has occurred in at least one patient, and acute renal failure with rhabdomyolysis and markedly elevated CK concentrations (17,000-27,000 IU/L) has been reported in at least 2 patients.1

Serum CK concentrations should be monitored periodically (e.g., every other week during the first month of therapy and then monthly as appropriate).1 If neuromuscular symptoms (e.g., myalgias, myasthenia, muscle cramps, asthenia) develop or a reduction in physical activity occurs, the patient should be evaluated (e.g., clinical evaluation, determination of serum CK concentrations).1 If symptoms persist and CK concentrations remain elevated or continue to rise, dosage reduction or discontinuance of ziconotide should be considered.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

Lactation

Not known whether ziconotide is distributed into milk.1 Discontinue nursing or the drug, taking into account the importance of the drug to the mother.1

Pediatric Use

Safety and efficacy not established in patients younger than 18 years of age.1,6

Geriatric Use

In clinical studies, 22% of patients were 65 years of age or older and 7% were 75 years of age or older.1 In all studies, the incidence of confusion was higher in individuals 65 years of age or older than in younger adults.1 No substantial difference in efficacy in geriatric patients relative to younger adults.1

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.1

Common Adverse Effects

Adverse effects reported in 25% or more of patients receiving ziconotide include dizziness, nausea, confusion, headache, somnolence, nystagmus, asthenia, and pain.1

Drug Interactions ⬆ ⬇

[Section Outline]

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Protein-bound Drugs
CNS Agents
Diuretics
Opiates

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1

Protein-bound Drugs

Pharmacokinetic interaction unlikely.1

CNS Agents

Used concomitantly with anticonvulsants, antidepressants, antipsychotics, anxiolytics, and sedatives in clinical studies.1 Potential interaction with CNS depressants (increased incidence of adverse CNS effects [e.g., dizziness, confusion, reduced levels of consciousness]).1 Dosage adjustment or discontinuance of ziconotide or the concomitant CNS depressant may be needed.1

Potential interaction with antidepressants or anticonvulsants (elevated serum creatine kinase [CK, creatine phosphokinase, CPK]).1

Diuretics

Potential interaction (reduced levels of consciousness).1

Opiates

Used concomitantly with systemically administered opiates in clinical studies; concomitant use of ziconotide with intrathecal opiates has not been evaluated in placebo-controlled studies and is not recommended.1

Potential interaction in patients who previously had received intrathecal morphine (elevated serum CK).1

Other Information ⬆ ⬇

Description

Ziconotide, a synthetic form of a naturally occurring conopeptide found in the venom of the marine snail Conus magus , is a 25-amino acid polybasic peptide containing 3 disulfide bridges.1,2,3 Ziconotide produces potent antinociceptive effects by selectively binding to N-type voltage-sensitive calcium channels on the primary nociceptive afferent nerves in the superficial layers of the spinal cord, thus blocking neurotransmission from primary nociceptive afferents.1,2,3

Ziconotide does not bind to opiate receptors, and the pharmacologic effects of the drug are not blocked by opiate antagonists.1 Ziconotide does not potentiate opiate-induced respiratory depression.1

Intrathecal administration of ziconotide results in little systemic exposure.1,3 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.1

Advice to Patients

Risk of somnolence; avoid driving, operating machinery, or performing hazardous tasks until effects on individual are known.1

Importance of informing clinician if new or worsening muscle pain, soreness, weakness, or brown urine develops.1

Importance of promptly reporting any change in mental status (e.g., lethargy, confusion, disorientation, decreased alertness), mood or perception (e.g., hallucinations, unusual tactile sensations in the mouth), and symptoms of depression or suicidal ideation.1

Importance of promptly informing clinician if symptoms of meningitis (i.e., nausea, vomiting, seizures, fever, headache, stiff neck) occur.1

For patients receiving ziconotide via an external microinfusion device and catheter, importance of proper handling of the device and proper care of the skin at the catheter exit site.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.1 Potential for additive CNS effects if used concomitantly with other CNS depressants.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Parenteral	Injection, for intrathecal administration via compatible microinfusion device only	25 mcg/mL	Prialt^®	Elan
		100 mcg/mL	Prialt^®	Elan

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Ziconotide

Copyright ⬆ ⬇

References ⬆