Drug Criteria & Outcomes

Ziconotide (Prialt) Formulary Evaluation

Part 1 of 2: Similar Drugs in Class, Comparative Agent, Mechanism of Action, Strengths/Dosage, Indications, Off-Label Uses, Preparation and Storage, Special Populations, ADEs, Drug-Drug/Food Interactions, Warnings and Precautions, Contraindications, Pregnancy/Lactation Information

By Tiffany Gilmer, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University

Ziconotide (Prialt) is a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail used intrathecally for severe chronic pain relief, and administered only in the Medtronic SynchroMed EL, SynchroMed II Infusion System, and Simms Deltec Cadd Micro External Microinfusion Device and Catheter. It does not bind to opioid receptors, and there is no evidence of tolerance observed with this medication.

Similar drugs in class

No other drugs in this class.

Comparative agent

Infumorph is a preservative-free concentrated morphine sulfate injection intended for intrathecal (IT) use in continuous controlled-microinfusion devices. Duramorph is a preservative-free morphine sulfate intended for intravenous, epidural, or intrathecal administration. Morphine sulfate is a Schedule II drug.

Mechanism of action

Ziconotide binds to N-type calcium channels located on the primary nociceptive afferent nerves in the superficial layers 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 in the primary afferent nerve terminals and antinociception. Intrathecal morphine binds to opiate receptors found on the terminal axons of primary afferent nerves within laminae I and II of the spinal cord and in the trigeminal nerve, causing inhibition of ascending pain pathways, altering the perception of and response to pain.

Strengths/dosage forms available

Ziconotide is available as a preservative-free 100 mcg/1 mL in a 1 mL, 2 mL, and 5 mL vial, and 25 mcg/mL in a 20 mL vial, for intrathecal administration via Medtronic SynchroMed EL, SynchroMed II Infusion System, and Simms Deltec Cadd Micro External Microinfusion Device and Catheter.

Infumorph is available as a preservative-free 200 mg/20 mL (10 mg/mL) and 500 mg/20mL (25 mg/mL) ampule for epidural and intrathecal administration via a continuous microinfusion device. Duramorph is available as a preservative-free 5 mg/10 mL (0.5 mg/mL) and 10 mg/10 mL (1 mg/1 mL) ampule.

Indications (FDA-approved)

Ziconotide is indicated for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatments, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. Infumorph and Duramorph are indicated for intrathecal or epidural infusion in the treatment of intractable chronic pain.

Table: Pharmacokinetics
Kinetic parameter

Ziconotide

Infumorph and Duramorph (IT)
Absorption

Plasma ziconotide levels could not be quantified in 56% of patients.

Diffusion into the systemic circulation occurs slowly, accounting for the long duration of action.
Distribution Peak concentration unknown.
Distribution in cerebrospinal fluid (CSF) = 155 mL.
Plasma protein binding = 50%.
Peak plasma concentration = 5-10 minutes.
Distribution in IT space = 22 mL.
Plasma protein binding = 36%.
Metabolism Cleaved by endopeptidases and exopeptidases at multiple sites on the peptide to their individual constituent-free amino acids following passage from CSF into general circulation. Glucuronidation in the liver to morphine-3-glucuronide, which is inactive.
Excretion Less than 1% of ziconotide is excreted in the urine.
Terminal half-life = 4.6 hours.
Dosed by continuous infusion — duration of action not available.

Metabolite excreted through the kidneys, with 10% in the feces. Twelve percent excreted unchanged in the urine.
CSF terminal half-life = 90 minutes.
Dosed by continuous infusion into intrathecal space or one-time IT injection.
Duration of action of one-time IT injection = 24 hours.

Off-label uses

No off-label uses of ziconotide or Infumorph and Duramorph for intrathecal administration have been identified.

Preparation and storage

Ziconotide should be stored at 2-8° C (36-46° F) and refrigerated during transit, but not frozen. It should be protected from light. Once diluted with 0.9% sodium chloride, it may be stored at 2-8° C (36-46° F) for 24 hours.

Infumorph and Duramorph should be protected from light. They should be stored at room temperature, but not frozen. Discard any unused portion. They may require dilution with 0.9% sodium chloride before use as dictated by the characteristics of the device and the dosage requirements of the individual patient.

Dosing and administration

Ziconotide should be initiated at no more than 2.4 mcg/day (0.1 mcg/hr) by continuous infusion and titrated to patient response. Doses may be titrated upward in increments of up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2-3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/hr) by day 21. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and increases in dose less frequently than 2-3 times per week may be used. No test dose is required. Ziconotide is intended for IT delivery using only a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter.

Intrathecal morphine is given at approximately 1/10 of the epidural dose. The starting dose must be individualized, based on in-hospital evaluation of the response to serial single-dose intrathecal bolus injections of regular Duramorph.

For patients who are not tolerant to opiates, adequate pain relief may be achieved by a single 0.2 mg to 1 mg intrathecal dose for up to 24 hours, or an intrathecal infusion of 0.2 mg/day to 1 mg/day.

The safety of injecting repeated intermittent dose of morphine intrathecally, other than for establishing initial dosage when continuous intrathecal infusion is contemplated, has not been determined. Intrathecal infusions for patients with opioid tolerance vary from 1 mg/day to 10 mg/day.

Intrathecal dosages exceeding 20 mg/day should be employed with caution since they may be associated with an increased likelihood of serious toxicity, including myoclonic spasms.

Special populations

Geriatric patients
Geriatric patients on ziconotide may experience a higher incidence of confusion. In general, dose selection for an elderly patient should be done with caution, usually starting at the low end of the dosing range. The pharmacokinetics of intrathecal morphine are more variable in geriatric patients and caution should be used when initiating therapy.

Pediatric patients
Safety and efficacy in children has not been established in ziconotide or Infumorph.

Renal impairment
Ziconotide has no safety or efficacy data in patients with renal impairment. Infumorph should be used with caution in patients with renal impairment.

Hepatic impairment
Ziconotide has no safety or efficacy data in patients with hepatic impairment. Infumorph should be used with caution in patients with renal impairment.

Adverse drug events

Adverse drug events of ziconotide include:

  • Central nervous system (CNS): dizziness (47%), somnolence (22%), confusion (18%), ataxia (16%), headache (15%), abnormal gait (15%), memory impairment (12%), pain (11%), anxiety (9%), speech disorder (9%), aphasia (8%), dysesthesia (7%), fever (7%), hallucinations (7%), nervousness (7%), vertigo (7%), agitation, chills, depression, abnormal dreams, emotional lability, hostility, hyperesthesia, insomnia, malaise, neuralgia, paranoid reaction, and stupor.
  • Gastrointestinal: nausea (41%), diarrhea (19%), vomiting (15%), anorexia (10%), abdominal pain, constipation, dehydration, dyspepsia, taste perversion, weight loss, and xerostomia.
  • Neuromuscular and skeletal: weakness (22%), gait disturbances (15%), hypertonia (11%), paresthesia (7%), arthralgia, arthritis, back pain, incoordination, leg cramps, myalgia, myasthenia, neck pain, neck rigidity, decreased reflexes, and tremor.
  • Cardiovascular: chest pain, edema, hyper- or hypotension, postural hypotension, tachycardia, and vasodilation.
  • Dermatologic: bruising, cellulitis, diaphoresis, dry skin, pruritus, and rash.
  • Endocrine and metabolic: hypokalemia.
  • Genitourinary: urinary retention (9%), dysuria, urinary incontinence, urinary tract infection, and impaired urination.
  • Hematologic: anemia.
  • Local: catheter complications, catheter site pain, pump site complications, pump site mass, and pump site pain.

Because of the risk of severe adverse effects, patients on intrathecal morphine must be observed for at least 24 hours after the initial test dose and, as appropriate, for the first several days after catheter implantation. The most serious adverse events have been respiratory depression and myoclonus.

Other adverse effects include sympathetic hyperactivitiy, which may result in convulsions; dysphoric reactions; toxic psychoses; pruritus; urinary retention; constipation; headache; peripheral edema; dizziness; euphoria; anxiety; depression of cough reflex; interference with thermal regulation; and oliguria. Evidence of histamine release such as urticaria, wheals, and/or local tissue irritation may occur. Pruritus, nausea/vomiting, and urinary retention, if associated with continuous infusion therapy, may respond to intravenous administration of a low dose of naloxone (0.2 mg).

Drug-drug interactions

No pharmacokinetic drug-drug interactions studies have been conducted with ziconotide. IT administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs unlikely. Combination of ziconotide with intrathecal opiates has not been studied and is not recommended. The use of ziconotide with central nervous system depressants may be associated with an increased incidence of CNS adverse events such as dizziness and confusion.

The depressant effects of morphine are potentiated by the presence of other CNS depressants such as alcohol, sedatives, antihistamines, or psychotropic drugs. Use of neuroleptics may increase the risk of respiratory depression.

Drug-food interactions

There are no known drug-food interactions for ziconotide or Infumorph.

Warnings and precautions

Black box warning: Severe psychiatric symptoms and neurological impairment may occur during treatment with ziconotide. Patients with a pre-existing history of psychosis should not be treated with ziconotide. All patients should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Ziconotide therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs and symptoms.

Use ziconotide with caution in the elderly; patients may experience confusion. Patients should be instructed to use caution in performing tasks that require alertness (e.g., operating machinery or driving). Ziconotide may have additive effects with opiates or other CNS-depressant medications and does not potentiate opiate-induced respiratory depression. Ziconotide will not prevent or relieve symptoms associated with opiate withdrawal, and opiates should not be abruptly discontinued. Unlike opioids, ziconotide therapy can be interrupted abruptly or discontinued without evidence of withdrawal. Meningitis may occur with use of IT pumps and treatment may require removal of system and discontinuation of therapy. Safety and efficacy have not been established with renal or hepatic dysfunction, or in pediatric patients.

Infumorph is for use in continuous microinfusion devices only. Some patients may require unusual accelerations of their intrathecal morphine dose. Myoclonic-like spasms of the lower extremities have been reported. Use in extreme caution in patients with head injury or increased intracranial pressure.

Infumorph may cause respiratory depression; use with caution in patients with impaired respiratory function or severe hepatic dysfunction and in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, hydromorphone, levorphanol, oxycodone, oxymorphone). Use caution in renal impairment (metabolite accumulation). Infumorph is a Schedule II narcotic that possesses an addiction-forming or addiction-sustaining liability.

Contraindications

Contraindications to ziconotide include hypersensitivity to ziconotide or any component of the formulation; history of psychosis; and intravenous (IV) administration.

The only contraindication for intrathecal morphine is a known allergy to morphine.

IT administration is contraindicated in patients with infection at the injection site, uncontrolled bleeding, or spinal canal obstruction that impairs CSF circulation.

Pregnancy/lactation information

Ziconotide is pregnancy Category C and should only be used during pregnancy if the potential benefit justifies risk to the fetus. It is not known whether ziconotide is excreted in human breast milk.

Morphine is pregnancy Category C, and should only be given to pregnant women when no other method of controlling pain is available and means are at hand to manage the delivery and prenatal care of the opiate-dependent infant. Morphine is excreted in breast milk and effects on nursing infants are unknown.