Prialt

Other Analgesics

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any ziconotide solution with observed particulate matter or discoloration and any unused portion left in the vial.

Ziconotide is intended for administration by or under the direction of a physician experienced in the technique of intrathecal administration and who is familiar with the drug and device labeling.
Ziconotide is intended for intrathecal delivery using the Medtronic SynchroMed II Infusion System and CADD-Micro Ambulatory Infusion Pump. Refer to the manufacturer's manual for specific instructions and precautions for programming the microinfusion device and/or refilling the reservoir.
Ziconotide may be used for therapy undiluted (25 mcg/mL) or diluted (100 mcg/mL). The 100 mcg/mL formulation may be administered undiluted once an appropriate dose has been established.
 
Dilution
Dilute ziconotide with preservative free 0.9% Sodium Chloride Injection using aseptic procedures to the desired concentration prior to placement in the microinfusion pump.
Storage: Refrigerate but do not freeze all ziconotide solutions after preparation and begin infusion within 24 hours.
 
Continuous intrathecal infusion with the Medtronic SynchroMed II Infusion System
Naive pump priming: Use only the undiluted 25 mcg/mL formulation for naive pump priming. Rinse the internal surfaces of the pump with 2 mL of ziconotide at 25 mcg/mL. Repeat twice for a total of 3 rinses.
Initial pump fill: Use only the undiluted 25 mcg/mL formulation for the initial pump fill. Fill the naive pump after priming with the appropriate volume of ziconotide 25 mcg/mL. In a naive pump, ziconotide is lost due to 2 factors that do not occur upon subsequent refills: adsorption on internal device surfaces, such as titanium, and by dilution in the residual space of the device. Consequently, refill the pump reservoir with ziconotide within 14 days of the initial fill to ensure appropriate dose administration.
Pump refills: For subsequent pump refills, fill the pump at least every 40 days if ziconotide is used diluted. For undiluted ziconotide, fill the pump at least every 84 days. To ensure aseptic transfer of ziconotide into the device, use the Medtronic refill kit. Empty the pump contents prior to refill with ziconotide.
If the internal infusion system must be surgically replaced while the person is receiving ziconotide, rinse the replacement pump with ziconotide according to naive pump priming, and replace the initial fill solution within 14 days according to initial pump fill.
 
Continuous intrathecal infusion with the CADD-Micro Ambulatory Infusion Pump
Refer to the manufacturer's manuals for specific instructions and precautions for performing the initial filling, refilling of the reservoir or replacement of the drug cartridge, and operation.
Initial pump fill: The CADD-Micro Ambulatory Infusion Pump is filled for the first time with ziconotide solution at a concentration of 5 mcg/mL. This solution is prepared by diluting ziconotide with preservative free 0.9% Sodium Chloride.

seizures / Delayed / 0-2.0
stroke / Early / 0-2.0
suicidal ideation / Delayed / 0-2.0
rhabdomyolysis / Delayed / 0-2.0
renal failure / Delayed / 0-2.0
atrial fibrillation / Early / 0-2.0
angioedema / Rapid / Incidence not known
exfoliative dermatitis / Delayed / Incidence not known

confusion / Early / 15.0-33.0
memory impairment / Delayed / 7.0-22.0
ataxia / Delayed / 14.0-14.0
aphasia / Delayed / 12.0-12.0
hallucinations / Early / 12.0-12.0
blurred vision / Early / 12.0-12.0
urinary retention / Early / 9.0-9.0
amnesia / Delayed / 1.0-8.0
nystagmus / Delayed / 8.0-8.0
dysarthria / Delayed / 7.0-7.0
meningitis / Delayed / 3.0-3.0
delirium / Early / 2.0-2.0
hostility / Early / 2.0-2.0
psychosis / Early / 1.0-1.0
mania / Early / 0.4-0.4
myopathy / Delayed / 0.1-0.1
depression / Delayed / 2.0
constipation / Delayed / 2.0
peripheral edema / Delayed / 2.0
myasthenia / Delayed / 2.0
orthostatic hypotension / Delayed / 2.0
hypotension / Rapid / 2.0
dysuria / Early / 2.0
loss of consciousness / Rapid / Incidence not known
impaired cognition / Early / Incidence not known
skin ulcer / Delayed / Incidence not known
bullous rash / Early / Incidence not known

dizziness / Early / 46.0-46.0
nausea / Early / 40.0-40.0
diarrhea / Early / 18.0-18.0
asthenia / Delayed / 18.0-18.0
drowsiness / Early / 17.0-17.0
vomiting / Early / 16.0-16.0
gait disturbance / Delayed / 14.0-14.0
headache / Early / 13.0-13.0
anxiety / Delayed / 8.0-8.0
tremor / Early / 7.0-7.0
vertigo / Early / 7.0-7.0
pruritus / Rapid / 7.0-7.0
insomnia / Early / 6.0-6.0
anorexia / Delayed / 6.0-6.0
dysgeusia / Early / 5.0-5.0
fever / Early / 5.0-5.0
sinusitis / Delayed / 5.0-5.0
diaphoresis / Early / 5.0-5.0
paranoia / Early / 3.0-3.0
paresthesias / Delayed / 2.0
hypoesthesia / Delayed / 2.0
agitation / Early / 2.0
abdominal pain / Early / 2.0
xerostomia / Early / 2.0
lethargy / Early / 2.0
fatigue / Early / 2.0
muscle cramps / Delayed / 2.0
myalgia / Early / 2.0
diplopia / Early / 2.0
infection / Delayed / Incidence not known

Ziconotide is contraindicated for use in patients with a pre-existing history of psychosis. A severe, adverse psychiatric event and neurologic events may occur during treatment with ziconotide. Patients with pretreatment psychiatric disorders may be at an increased risk. Ziconotide may cause or worsen depression with the risk of suicidal ideation in susceptible patients. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness.

Prialt

Rx

Intrathecal N-type calcium channel antagonist
Used for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment
Associated with severe psychiatric symptoms and neurological impairment

2.4 mcg/day (0.1 mcg/hour) continuous intrathecal infusion, initially. Titrate by up to 2.4 mcg/day (0.1 mcg/hour) at intervals of no more than 2 to 3 times per week based on severity of pain, the patient's response to therapy, and the occurrence of adverse reactions. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hour) and less frequently than 2 to 3 times per week may be used. Max: 19.2 mcg/day (0.8 mcg/hour).

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) CNS depressant medications, such as dichloralphenazone, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Dosage adjustments may be necessary if ziconotide is used with dichloralphenazone.
Amoxapine: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as amoxapine. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide. If altered consciousness occurs, consider discontinuation of either agent.
Anxiolytics; Sedatives; and Hypnotics: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as anxiolytics, sedatives, and hypnotics. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Patients taking sedatives with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of sedative cessation is warranted in addition to ziconotide discontinuation.
Aspirin, ASA; Carisoprodol: (Moderate) CNS depressant medications, such as carisoprodol, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) CNS depressant medications, such as carisoprodol, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects.
Barbiturates: (Moderate) CNS depressant medications, such as barbiturates, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Dosage adjustments may be necessary if ziconotide is used with a barbiturate.
Buprenorphine: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Buprenorphine; Naloxone: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Buspirone: (Moderate) CNS depressant medications, such as buspirone, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Dosage adjustments may be necessary if ziconotide is used with buspirone.
Butorphanol: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Carisoprodol: (Moderate) CNS depressant medications, such as carisoprodol, may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects.
Clozapine: (Moderate) Clozapine has CNS depressant effects and may increase drowsiness, dizziness, and confusion that are associated with ziconotide if coadministered.
Droperidol: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as droperidol. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Haloperidol: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as haloperidol. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Loop diuretics: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
Mannitol: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
Maprotiline: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as maprotiline. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Methocarbamol: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as methocarbamol. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Mirtazapine: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as mirtazipine. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Molindone: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as molindone. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Nalbuphine: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Nefazodone: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as nefazodone. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Olanzapine: (Moderate) Olanzapine is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. If altered consciousness occurs, consider treatment discontinuation.
Olanzapine; Fluoxetine: (Moderate) Olanzapine is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. If altered consciousness occurs, consider treatment discontinuation.
Olanzapine; Samidorphan: (Moderate) Olanzapine is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. If altered consciousness occurs, consider treatment discontinuation.
Opiate Agonists: (Moderate) Concurrent use of ziconotide and opiate agonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Opiate Agonists-Antagonists: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Pentazocine: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Pentazocine; Naloxone: (Moderate) Concurrent use of ziconotide and opiate agonists-antagonists may result in an increased incidence of dizziness and confusion. Ziconotide neither interacts with opiate receptors nor potentiates opiate-induced respiratory depression. However, in animal models, ziconotide did potentiate gastrointestinal motility reduction by opioid agonists.
Phenothiazines: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as phenothiazines. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Pimozide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as pimozide. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Potassium-sparing diuretics: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
Pramipexole: (Moderate) Pramipexole is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects.
Quetiapine: (Moderate) Quetiapine is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide. Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects.
Risperidone: (Moderate) Risperidone is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Ropinirole: (Moderate) Ropinirole is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Sedating H1-blockers: (Moderate) Sedating H1-blockers are CNS depressant medications that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Thiazide diuretics: (Moderate) Patients taking diuretics with ziconotide may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, consideration of diuretic cessation is warranted in addition to ziconotide discontinuation.
Trazodone: (Moderate) Trazodone is a CNS depressant medication that may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
Tricyclic antidepressants: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as tricyclic antidepressants. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.

Prialt/Ziconotide Intrathecal Inj Sol: 1mL, 25mcg, 100mcg

19.2 mcg/day (0.8 mcg/hour) intrathecally.

19.2 mcg/day (0.8 mcg/hour) intrathecally.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Ziconotide binds to N-type calcium channels located on the primary nociceptive afferent nerves in the superficial layers (Rexed laminae I and II) 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 from the primary afferent nerve terminals and antinociception.

Ziconotide is administered by continuous intrathecal infusion. Ziconotide is about 50% bound to human plasma proteins. The mean cerebrospinal fluid (CSF) Vd of ziconotide after intrathecal administration approximates the estimated total CSF volume (140 mL). Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. After passage from the CSF into the systemic circulation during continuous intrathecal administration, ziconotide is expected to be susceptible to proteolytic cleavage by various ubiquitous peptidases/proteases present in most organs (e.g., kidney, liver, lung, muscle, etc.), and thus readily degraded to peptide fragments and their individual constituent free amino acids. Human CSF and blood exhibit minimal hydrolytic activity toward ziconotide in vitro. The biological activity of the various expected proteolytic degradation products of ziconotide has not been assessed. The terminal half-life of ziconotide in CSF after an intrathecal administration was around 4.6 hours (range 2.9 to 6.5 hours). Mean CSF clearance of ziconotide approximates adult human CSF turnover rate (0.3 to 0.4 mL/minute).

Intrathecal Route
The cerebrospinal fluid (CSF) pharmacokinetics of ziconotide have been studied after 1-hour intrathecal infusions of 1 to 10 mcg of ziconotide to patients with chronic pain; Vd was 155 +/- 263 mL, clearance was 0.38 +/- 0.56 mL/minute, and half-life was 4.6 +/- 0.9 hours. Both total exposure (AUC; range: 83.6 to 608 ng x hour/mL) and peak exposure (Cmax; range: 16.4 to 132 ng/mL) values in the CSF were variable and dose-dependent, but appeared approximately dose-proportional. During 5 or 6 days of continuous intrathecal infusions of ziconotide at infusion rates ranging from 0.1 to 7 mcg/hour in patients with chronic pain, plasma ziconotide concentrations could not be quantified in 56% of patients using an assay with a lower limit of detection of approximately 0.04 ng/mL. Predictably, patients requiring higher intrathecal infusion dose rates were more likely to have quantifiable ziconotide concentrations in plasma. Plasma ziconotide concentrations, when detectable, remain constant after many months of intrathecal ziconotide infusion in patients followed for up to 9 months.

Use ziconotide during pregnancy only if the potential benefit to the mother justifies risk to the fetus. No adequate and well-controlled studies with ziconotide have been conducted in pregnant women. Ziconotide was embryolethal in rats when given as a continuous intravenous infusion during the major period of organogenesis as evidenced by significant increases in post-implantation loss because of an absence or a reduced number of live fetuses. Estimated exposure for embryolethality in the rat was approximately 700-fold above the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hour (19.2 mcg/day). Ziconotide was not teratogenic in female rats when given as a continuous intravenous infusion at doses up to 30 mg/kg/day or in female rabbits up to 5 mg/kg/day during the major period of organ development. Estimated exposures in the female rat and rabbit were approximately 26,000-fold and 940-fold higher than the expected exposure resulting from the maximum recommended human daily dose of 0.8 mcg/hour (19.2 mcg/day) based on plasma exposure. Maternal toxicity in the rat and rabbit, as evidenced by decreased body weight gain and food consumption, was present at all doses. Maternal toxicity in the rat led to reduced fetal weights and transient, delayed ossification of the pubic bones at doses of 15 mg/kg/day or more, which is approximately 8,900-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hour (19.2 mcg/day) based on plasma exposure. The no observable adverse effect level (NOAEL) for embryo-fetal development in rats was 0.5 mg/kg/day and in rabbits was 5 mg/kg/day. Estimated NOAEL exposures in the rat and rabbit were approximately 400-fold and 940-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hour (19.2 mcg/day) based on plasma exposure. In a pre- and post-natal study in rats, ziconotide given as a continuous intravenous infusion did not affect pup development or reproductive performance up to a dose of 10 mg/kg/day, which is approximately 3,800-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hour (19.2 mcg/day) based on plasma exposure. Maternal toxicity, as evidenced by clinical observations, and decreases in body weight gain and food consumption were observed at all doses.

Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ziconotide and any potential adverse effects on the breast-fed infant from ziconotide or the underlying maternal condition. Monitor infants exposed to ziconotide through breast milk for sedation, which may result in respiratory depression and/or feeding problems. There are no data on the presence of ziconotide in human milk, the effects on the breast-fed infant, or the effects on milk production.