Ziconotide

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intrathecal, as acetate [preservative free]:

Prialt: 500 mcg/20 mL (20 mL); 100 mcg/mL (1 mL); 500 mcg/5 mL (5 mL)

Pharmacology

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.

Pharmacokinetics/Pharmacodynamics

Distribution

Intrathecal: V_d: ~140 mL

Metabolism

Metabolized via endopeptidases and exopeptidases present on multiple organs including kidney, liver, lung; degraded to peptide fragments and free amino acids

Excretion

IV: Urine (<1%)

Half-Life Elimination

IV: 1 to 1.6 hours (plasma); Intrathecal: 2.9 to 6.5 hours (CSF)

Protein Binding

~50%

Use: Labeled Indications

Management of severe chronic pain in patients requiring intrathecal therapy and who are intolerant or refractory to other therapies (eg, systemic analgesics, adjunctive therapies, intrathecal morphine)

Contraindications

Hypersensitivity to ziconotide or any component of the formulation; history of psychosis; IV administration

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

Dosage and Administration

Dosing: Adult

Chronic pain (intolerant or refractory to other therapies): Intrathecal: Initial dose: ≤2.4 mcg/day (≤0.1 mcg/hour). Note: Initiating with more conservative dosing (see Alternate initial dosing) is preferred due to improved tolerability (McDowell 2016; Prager 2014).

Alternate initial dosing: Initial: 0.5 to 1.2 mcg/day (0.02 to 0.05 mcg/hour) (McDowell 2016). Initiating with no more than 0.5 mcg/day (0.02 mcg/hour) may be preferred (Prager 2014).

Dosage titration: According to the manufacturer, dose may be titrated by ≤2.4 mcg/day (≤0.1 mcg/hour) at intervals ≤2 to 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). However, expert consensus recommends upward titration (based on analgesia and tolerability) in increments of no more than 0.5 mcg/day (≤0.02 mcg/hour) and not more often than once weekly (McDowell 2016; Prager 2014). A faster titration should be used only if the urgent need for analgesia outweighs the possible risk to patient safety.

Dosing: Geriatric

Higher incidence of confusion in elderly patients. Use with caution and start at the low end of the dosing range. Refer to adult dosing.

Dosing: 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.

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 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.

Administration

Intrathecal: Not for IV administration. For intrathecal administration only using Medtronic SynchroMed II Infusion System, or CADD-Micro ambulatory infusion pump.

Medtronic 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 manufacturer's manual for initial fill and refill instructions

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 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.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%:

Central nervous system: Dizziness (46%), confusion (15% to 33%), memory impairment (7% to 22%), drowsiness (17%), abnormal gait (14%), ataxia (14%), speech disorder (14%), headache (13%), aphasia (12%), hallucination (12%; including auditory and visual)

Gastrointestinal: Nausea (40%), diarrhea (18%), vomiting (16%)

Neuromuscular & skeletal: Increased creatine phosphokinase (40%; ≥3 x ULN: 11%), weakness (18%)

Ophthalmic: Blurred vision (12%)

2% to 10%:

Cardiovascular: Hypotension, orthostatic hypotension, peripheral edema

Central nervous system: Abnormality in thinking (8%), amnesia (8%), anxiety (8%), dysarthria (7%), paresthesia (7%), rigors (7%), vertigo (7%), insomnia (6%), paranoia (3%), delirium (2%), hostility (2%), stupor (2%), absent reflexes, agitation, burning sensation, decreased mental acuity, depression, disorientation, disturbance in attention, fatigue, hypoesthesia, irritability, lethargy, loss of balance, mood disorder, myasthenia, nervousness, pain, sedation

Dermatologic: Pruritus (7%), diaphoresis (5%)

Gastrointestinal: Anorexia (6%), dysgeusia (5%), abdominal pain, constipation, decreased appetite, xerostomia

Genitourinary: Urinary retention (9%), dysuria, urinary hesitancy

Neuromuscular & skeletal: Tremor (7%), muscle spasm (6%), limb pain (5%), muscle cramps, myalgia

Ophthalmic: Nystagmus (8%), diplopia, visual disturbance

Respiratory: Sinusitis (5%)

Miscellaneous: Fever (5%)

<2%, postmarketing, and/or case reports: Acute renal failure, aspiration pneumonia (<1%), atrial fibrillation, attempted suicide (<1%), cerebrovascular accident, ECG abnormality, incoherence, loss of consciousness, mania, meningitis, myoclonus, psychosis (1%), respiratory distress, rhabdomyolysis, seizure (clonic and grand mal), sepsis, suicidal ideation

Warnings/Precautions

Concerns related to adverse effects:

• CNS toxicity: [US 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 intrathecal 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 ethanol and CNS-depressant medications.
• Opioids: May have additive CNS effects with opioids and may potentiate opioid-induced decreased GI motility; does not interact with opioid receptors or potentiate opioid-induced respiratory depression.

Special populations:

• Elderly: Use with caution in the elderly; may experience a higher incidence of confusion.
• Pediatric: Safety and efficacy have not been established in children.

Other warnings/precautions:

• Withdrawal: Will not prevent or relieve symptoms associated with opioid withdrawal; unlike opioids, ziconotide therapy can be interrupted abruptly or discontinued without evidence of withdrawal.

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

Pregnancy

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events and maternal toxicity were observed in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience dizziness, loss of strength and energy, fatigue, diarrhea, sinusitis, headache, or lack of appetite. Have patient report immediately to prescriber thoughts of suicide, confusion, sensing things that seem real but are not, trouble with memory, mood changes, behavioral changes, change in speech, change in alertness, signs of meningitis (headache with fever, stiff neck, nausea, confusion, or sensitivity to light), signs of pneumonia (fever, chest pain, cough, dyspnea, or wheezing), seizures, change in balance, anxiety, severe nausea, vomiting, feeling sluggish, muscle pain, muscle weakness, muscle cramps, muscle spasms, dark urine, involuntary eye movements, vision changes, abnormal gait, tremors, difficult urination, painful extremities, skin ulcers, or severe skin irritation (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.