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Ziconotide (Prialt) - Drug Details

Ziconotide (Prialt) is used to treat severe chronic pain. It is used in patients who are either intolerant to other therapies or are refractory to other modalities of pain management such as analgesics, adjunctive therapies, and intrathecal morphine.

Ziconotide dose in Adults

Ziconotide dose in the treatment of refractory Chronic pain:

It should be administered intrathecally.
The initial dose is 2.4 mcg/day (≤0.1 mcg/hour) or less.
However, a more conservative dosing schedule is preferred for better tolerability.
Alternate initial dosing:
- 0.5 - 1.2 mcg/day (0.02 to 0.05 mcg/hour) initially.
- The treatment should not exceed 0.5 mcg/day (0.02 mcg/hour).
Dosage titration:
- The manufacturer recommends titrating the dose by 2.4 mcg/day (≤0.1 mcg/hour) or less every second or third day to a maximum dose of 19.2 mcg/day (0.8 mcg/hour) by day 21.
- The average dose at day 21 is 6.9 mcg/day (0.29 mcg/hour).
- However, experts recommend the upward titration dose should not exceed 0.5 mcg/day per week (based on analgesia and tolerability).
- If there is an urgent need for analgesia, the benefits and risks should be weighed.

Ziconotide dose in Children

Data regarding its use in children is limited.

Pregnancy Risk Factor C

In animal reproduction studies, adverse events and maternal toxicities were found.

Use of ziconotide during breastfeeding

It is unknown if ziconotide is present in breast milk.
It is best to stop breastfeeding because of possible adverse reactions in nursing infants.

Ziconotide dose in Renal Disease:

The manufacturer has not recommended any dose adjustments because of limited data.

Ziconotide dose in Liver Disease:

The manufacturer has not recommended any dose adjustments because of limited data.

Common Side Effects of Ziconotide Include:

Central Nervous System:
- Dizziness
- Confusion
- Memory Impairment
- Drowsiness
- Abnormal gait
- Ataxia
- Speech Disorder
- Headache
- Aphasia
- Hallucination
Gastrointestinal:
- Nausea
- Diarrhea
- Vomiting
Neuromuscular & Skeletal:
- Increased Creatine Phosphokinase
- Weakness
Ophthalmic:
- Blurred Vision

Less Common Side Effects of Ziconotide Include:

Cardiovascular:
- Hypotension
- Orthostatic Hypotension
- Peripheral Edema
Central Nervous System:
- Abnormality In Thinking
- Amnesia
- Anxiety
- Dysarthria
- Paresthesia
- Rigors
- Vertigo
- Insomnia
- Paranoia
- Delirium
- Hostility
- Stupor
- 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
- Diaphoresis
Gastrointestinal:
- Anorexia
- Dysgeusia
- Abdominal Pain
- Constipation
- Decreased Appetite
- Xerostomia
Genitourinary:
- Urinary Retention
- Dysuria
- Urinary Hesitancy
Neuromuscular & Skeletal:
- Tremor
- Muscle Spasm
- Limb Pain
- Muscle Cramps
- Myalgia
Ophthalmic:
- Nystagmus
- Diplopia
- Visual Disturbance
Respiratory:
- Sinusitis
Miscellaneous:
- Fever

Contraindication to Ziconotide Include:

Ziconotide or any other component of the formulation can cause severe allergic reactions
Psychosis: History
Intravenous administration
Patients with the following conditions are not advised to inject intrathecal medication:
- Infection at the injection site
- Uncontrolled bleeding or
- Spinal canal obstruction can cause CSF to not circulate properly.

Warnings and precautions

CNS toxicities: [US Boxed Warning]
- After the use of this medication, patients may experience severe psychiatric symptoms or neurological impairments.
- Interrupt therapy if cognitive impairment, mood changes or hallucinations occur.
- It can also increase depression and be associated with suicidal tendencies.
- Cognitive impairment can develop gradually during treatment and may take up to two weeks for it to resolve.
- CNS depression can occur in patients who perform tasks that require mental alertness.
Creatinine kinase elevated:
- Serum creatine kinase can rise in the first two months of therapy.
- Patients should stop taking the medication if they experience myalgia, muscle cramps, weakness, myasthenia or any other neuromuscular symptoms.
Meningitis
- Monitor the patient for any signs of meningitis, which may be caused by intrathecal pumps.
- Meningitis may result in the need to stop intrathecal therapy or remove the system.
Hepatic impairment
- It has not been proven safe and effective in treating patients with liver impairment.
Renal impairment
- It has not been proven safe and effective in treating patients with kidney impairment.

Ziconotide: Drug Interaction

Risk Factor C (Monitor therapy)
Alcohol (Ethyl)	CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl).
Alizapride	May enhance the CNS depressant effect of CNS Depressants.
Brexanolone	CNS Depressants may enhance the CNS depressant effect of Brexanolone.
Brimonidine (Topical)	May enhance the CNS depressant effect of CNS Depressants.
Bromopride	May enhance the CNS depressant effect of CNS Depressants.
Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Cannabis	May enhance the CNS depressant effect of CNS Depressants.
Chlorphenesin Carbamate	May enhance the adverse/toxic effect of CNS Depressants.
CNS Depressants	May enhance the adverse/toxic effect of other CNS Depressants.
Dimethindene (Topical)	May enhance the CNS depressant effect of CNS Depressants.
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.
Dronabinol	May enhance the CNS depressant effect of CNS Depressants.
Esketamine	May enhance the CNS depressant effect of CNS Depressants.
HydrOXYzine	May enhance the CNS depressant effect of CNS Depressants.
Kava Kava	May enhance the adverse/toxic effect of CNS Depressants.
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.
Magnesium Sulfate	May enhance the CNS depressant effect of CNS Depressants.
MetyroSINE	CNS Depressants may enhance the sedative effect of MetyroSINE.
Minocycline	May enhance the CNS depressant effect of CNS Depressants.
Mirtazapine	CNS Depressants may enhance the CNS depressant effect of Mirtazapine.
Nabilone	May enhance the CNS depressant effect of CNS Depressants.
Piribedil	CNS Depressants may enhance the CNS depressant effect of Piribedil.
Pramipexole	CNS Depressants may enhance the sedative effect of Pramipexole.
ROPINIRole	CNS Depressants may enhance the sedative effect of ROPINIRole.
Rotigotine	CNS Depressants may enhance the sedative effect of Rotigotine.
Rufinamide	May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced.
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.
Tetrahydrocannabinol	May enhance the CNS depressant effect of CNS Depressants.
Tetrahydrocannabinol and Cannabidiol	May enhance the CNS depressant effect of CNS Depressants.
Trimeprazine	May enhance the CNS depressant effect of CNS Depressants.
Risk Factor D (Consider therapy modification)
Blonanserin	CNS Depressants may enhance the CNS depressant effect of Blonanserin.
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.
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.
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.
Flunitrazepam	CNS Depressants may enhance the CNS depressant effect of Flunitrazepam.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Risk Factor X (Avoid combination)
Azelastine (Nasal)	CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal).
Bromperidol	May enhance the CNS depressant effect of CNS Depressants.
Orphenadrine	CNS Depressants may enhance the CNS depressant effect of Orphenadrine.
Oxomemazine	May enhance the CNS depressant effect of CNS Depressants.
Paraldehyde	CNS Depressants may enhance the CNS depressant effect of Paraldehyde.
Thalidomide	CNS Depressants may enhance the CNS depressant effect of Thalidomide.

Monitor:

Monitor for neurological or psychiatric impairment.
Meningitis symptoms and other infections.
Serum CPK (everyother week for the first and second months, then monthly). Pain relief.

How to administer Ziconotide (Prialt)?

Intrathecal It should not be given intravenously. It should not be administered intravenously.
Medtronic SynchroMed (r) EL or Medtronic SychroMed(r), II Infusion Systems
Naive pump-priming (first time use of ziconotide). To clean the internal surfaces of your pump, use 2 mL undiluted ziconotide 25, mcg/mL solution. For a total of three rinses, repeat the process twice more. Pump filling: After priming, only use undiluted 25 mg/mL solution. After the initial fill, there will be adsorption of water on the internal surfaces of the pump.
This should be addressed immediately and the pump must then be refilled within 14 days.
Pump refills Before refilling, empty the contents. If you use a diluted solution, refills should be done every 40 days or every 84 days.
CADD-Micro(r), ambulatory infusion pump
Refer to the manual for refill and initial fill instructions.

Mechanism of action of Ziconotide:

Ziconotide (Prialt), selectively binds N-type voltage-sensitive Calcium channels.
These receptors are found on the spinal cord's nociceptive and afferent nerves.
This binding causes N-type calcium channels to become blocked, resulting in a blockade and decreased sensitivity to pain stimuli.

Distribution:

Intrathecal: V : ~140 mL

Protein binding is about 50%

Metabolism:

It is metabolized via endopeptidases and exopeptidases that are present on multiple organs including kidney, liver, lung. It is degraded to peptide fragments and free amino acids.

Half-life elimination after intravenous administration: 1 - 1.6 hours and 2.9 - 6.5 hours after intrathecal administration.

Excretion: