Ziconotide

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# Black Box Warning

# Overview
Ziconotide is an N-type calcium channel antagonist that is FDA approved for the {{{indicationType}}} of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include dizziness, nausea, confusional state, nystagmus.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- PRIALT (ziconotide) solution, intrathecal infusion is indicated for the management of severe chronic pain in adult patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine.
- Dose Initiation
- Initiate dosing with PRIALT via intrathecal device at no more than 2.4 mcg/day (0.1 mcg/hr).
- Dose Titration
- Titrate doses by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2 to 3 times per week based on analgesic response and adverse events. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and less frequently than 2 to 3 times per week may be used. For each dose titration, assess the dosing requirements and adjust the pump infusion flow rate as required to achieve the new dosing.
- The maximum recommended dose is 19.2 mcg/day (0.8 mcg/hr).
- Adjust the dose of intrathecal PRIALT according to the severity of pain, the patients response to therapy, and the occurrence of adverse reactions.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ziconotide in adult patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ziconotide in adult patients.

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Ziconotide in pediatric patients.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ziconotide in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Ziconotide in pediatric patients.

# Contraindications
- PRIALT is contraindicated in patients with a known hypersensitivity to ziconotide or any of its formulation components.
- PRIALT is contraindicated in patients with any other concomitant treatment or medical condition that would render intrathecal administration hazardous. Contraindications to the use of intrathecal analgesia include the presence of infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of CSF.
- PRIALT is contraindicated in patients with a pre-existing history of psychosis.

# Warnings

### Precautions
- Cognitive and Neuropsychiatric Adverse Reactions
- ere psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. PRIALT is contraindicated in patients with a pre-existing history of psychosis. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. PRIALT therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms.
- Events of acute psychiatric disturbances such as hallucinations (12%), paranoid reactions (3%), hostility (2%), delirium (2%), psychosis (1%), and manic reactions (0.4%) have been reported in patients treated with PRIALT. Patients with pretreatment psychiatric disorders may be at an increased risk. PRIALT may cause or worsen depression with the risk of suicide in susceptible patients. In placebo-controlled trials, there was a higher incidence of suicide, suicide attempts, and suicide ideations in PRIALT-treated patients than in the placebo group (0.27/patient year for PRIALT patients and 0.10/patient year for placebo patients).
- Management of psychiatric complications may need to include discontinuation of PRIALT, treatment with psychotherapeutic agents and/or short-term hospitalization. Before drug is reinitiated, careful evaluation must be performed on an individual basis.
- Use of PRIALT has been associated with cognitive impairment and decreased alertness/unresponsiveness. The following cognitive adverse reaction rates were reported: confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), thinking abnormal (8%), and amnesia (1%). Cognitive impairment may appear gradually after several weeks of treatment. Reduce the dose of PRIALT or discontinue the use of PRIALT if signs or symptoms of cognitive impairment develop, but other contributing causes must also be considered. The cognitive effects of PRIALT are generally reversible within 2 weeks after drug discontinuation. The median time to reversal of the individual cognitive effects ranged from 3 to 15 days. The elderly ( 65 years of age) are at higher risk for confusion.
- There may be additive effects on cognitive impairment and decreased alertness when PRIALT is used in conjunction with other CNS-depressant drugs that may necessitate dosage adjustments.
- Meningitis and Other Infections
- Meningitis can occur due to inadvertent contamination of the microinfusion device and other means such as CSF seeding due to hematogenous or direct spread from an infected pump pocket or catheter tract. While meningitis is rare with an internal microinfusion device and surgically-implanted catheter, the incidence increases substantially with external devices. In PRIALT clinical trials, meningitis occurred in 3% (40) of patients in the PRIALT group using either internal or external microinfusion devices and 1% (1 case) of patients in the placebo group.
- The risk of meningitis was particularly high in patients with external microinfusion devices and catheters, occurring in 38 out of 41 patients (93%), 37 of whom received PRIALT and one who received placebo.
- Patients, caregivers, and healthcare providers must be particularly vigilant for the signs and symptoms of meningitis, including but not limited to fever, headache, stiff neck, altered mental status (e.g., lethargy, confusion, disorientation), nausea or vomiting, and occasionally seizures. Serious infection or meningitis can occur within 24 hours of a breach in sterility such as a disconnected catheter, the most common cause of meningitis with external microinfusion devices. The patient and health care provider must be familiar with the handling of the external microinfusion device and care of the catheter skin exit site.
- Strict aseptic procedures must be used during the preparation of the PRIALT solution and refilling of the microinfusion device to decrease the risk of introducing contaminants or other environmental pathogens into the reservoir. In suspected cases (especially in immuno-compromised patients) or in confirmed cases of meningitis, CSF cultures must be obtained and appropriate antibiotic therapy must be promptly instituted. Treatment of meningitis usually requires removal of the microinfusion system, catheter, and any other foreign body materials within the intrathecal space and, therefore, discontinuation of PRIALT therapy.
- Reduced Level of Consciousness
- Patients have become unresponsive or stuporous while receiving PRIALT. The incidence of unresponsiveness or stupor in clinical trials was 2% in PRIALT-treated patients. During these episodes, patients sometimes appear to be conscious and breathing is not depressed. If reduced levels of consciousness occur, discontinue PRIALT until the event resolves, and other etiologies (e.g., meningitis) must be considered. There is no known pharmacologic antagonist for this effect. Patients taking concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness. If altered consciousness occurs, discontinue other CNS-depressant drugs as clinically appropriate.
- Elevation of Serum Creatine Kinase
- In clinical studies, 40% of PRIALT-treated patients had serum creatine kinase (CK) levels above the upper limit of normal (ULN), and 11% had CK levels that were greater than three times the ULN. In cases where CK was fractionated, only the muscle isoenzyme (MM) was elevated. The time to occurrence was sporadic, but the greatest incidence of CK elevation was during the first two months of treatment. One case of symptomatic myopathy with EMG findings, and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations (17,00027,000 IU/L) have been reported in PRIALT-treated patients.
- Therefore, monitor serum CK in patients undergoing treatment with PRIALT periodically (e.g., every other week for the first month and monthly as appropriate thereafter). Evaluate patients clinically and obtain CK measurements in the setting of new neuromuscular symptoms (e.g., myalgias, myasthenia, muscle cramps, asthenia) or a reduction in physical activity. If these symptoms continue and CK levels remain elevated or continue to rise, reduce the dose or discontinue the use of PRIALT.
- Withdrawal From Opiates
- PRIALT is not an opiate and cannot prevent or relieve the symptoms associated with the withdrawal of opiates.
- To avoid withdrawal syndrome when opiate withdrawal is necessary, do not abruptly reduce or withdraw opioid medications.
- For patients being withdrawn from intrathecal opiates or intrathecal opiate infusion, gradually taper over a few weeks and replace with a pharmacologically equivalent dose of oral opiates.
- Driving and Operating Machinery
- Use of PRIALT has been associated with cognitive impairment and decreased alertness/unresponsiveness. Therefore, caution patients against engaging in hazardous activities that require complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle.

# Adverse Reactions

## Clinical Trials Experience
- Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates in clinical practice.
- A total of 1254 adult patients received PRIALT as a continuous infusion in acute and severe chronic pain trials with an exposure of 662 patient-years. The mean duration of treatment was 193 days with 173 patients (14%) treated for at least 1 year. The average final dose was 17.6 mcg/day (0.73 mcg/hr).
- The most frequently reported adverse reactions ( 25%) in clinical trials were dizziness, nausea, confusional state and nystagmus. Slower titration of PRIALT may result in fewer serious adverse reactions and discontinuation of PRIALT for adverse reactions.
- Adverse reactions during the slow titration placebo-controlled trial that occurred in 5% or greater of patients and more commonly with PRIALT than with placebo are summarized in Table 1.
The following adverse reactions assessed as related to PRIALT have been reported in 2% or greater of patients participating in the clinical studies:
Fall, fatigue, lethargy, peripheral edema
Hypotension, orthostatic hypotension
Abdominal pain, constipation, dry mouth, nausea aggravated
Appetite decreased
Muscle cramp, muscle weakness, myalgia, pain in limb
Aphasia, areflexia, balance impaired, burning sensation, coordination abnormal, disturbance in attention, dizziness postural, dysarthria, dysgeusia, hypoaesthesia, mental impairment, paraesthesia, sedation, speech disorder, agitation, anxiety, cognitive disorder, confusional state, depression, depression aggravated, disorientation, hallucination, hallucination auditory, hallucination visual, insomnia, irritability, mood disorder, nervousness, paranoia
Diplopia, visual disturbance
Dysuria, urinary hesitation
Blood creatine phosphokinase increased
- The following medically important adverse reactions occurred in less than 2% of patients were assessed by the clinical investigators as related to PRIALT: acute renal failure, atrial fibrillation, cerebrovascular accident, sepsis, meningitis, psychotic disorder, suicidal ideation, respiratory distress, rhabdomyolysis, electrocardiogram abnormal, stupor, loss of consciousness, clonic convulsion and grand mal convulsion. Fatal aspiration pneumonia and suicide attempt were reported in less than 1% of patients.

## Postmarketing Experience
- The following adverse events have been reported during post-approval use of PRIALT. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Hypersensitivity reactions including angioedema, serious skin reactions including bullous dermatitis, skin ulcers, skin exfoliation, and burning skin sensation.

# Drug Interactions
- Formal PK drug-drug interaction studies have not been performed with PRIALT. As ziconotide is a peptide, it is expected to be completely degraded by endopeptidases and exopeptidases (Phase I hydrolytic enzymes) widely located throughout the body, and not by other Phase I biotransformation processes (including the cytochrome P450 system) or by Phase II conjugation reactions. Thus, intrathecal administration, low plasma ziconotide concentrations, and metabolism by ubiquitous peptidases make metabolic interactions of other drugs with ziconotide unlikely. Further, as ziconotide is not highly bound in plasma (approximately 50%) and has low plasma exposure following intrathecal administration, clinically relevant plasma protein displacement reactions involving ziconotide and co-administered medications are unlikely.
- Over 90% of patients treated with intrathecal PRIALT used systemic opiates and in the slow titration study, 98% of patients received opioids.
- The combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended.
- Interaction with CNS Depressants
- Almost all patients in the PRIALT clinical trials received concomitant non-intrathecal medication. Most patients received several concomitant drugs, including antidepressants (66%), anxiolytics (52%), antiepileptics (47%), neuroleptics (46%), and sedatives (34%). The use of drugs with CNS-depressant activities may be associated with an increased incidence of CNS adverse reactions such as dizziness and confusion.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA):
- Pregnancy Category C
- 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/hr (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/hr (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 dose levels. Maternal toxicity in the rat led to reduced fetal weights and transient, delayed ossification of the pubic bones at doses  15 mg/kg/day, which is approximately 8900-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (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/hr (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 3800-fold higher than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (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.
- No adequate and well-controlled studies have been conducted in pregnant women. Because animal studies are not always predictive of human response, PRIALT should be used during pregnancy only if the potential benefit justifies risk to the fetus.
Pregnancy Category (AUS):
- Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ziconotide in women who are pregnant.

### Labor and Delivery
- The effect of PRIALT on labor and delivery in humans is not known.

### Nursing Mothers
- It is not known whether PRIALT is excreted in human breast milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from PRIALT, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
- Safety and effectiveness in pediatric patients have not been established.

### Geriatic Use
- Of the total number of subjects in clinical studies of PRIALT, 22% were 65 and over, while 7% were 75 and over. In all trials, there was a higher incidence of confusion in older patients (42% for  65 year old versus 29% for < 65 year old subgroups). Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, the dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.

### Gender
There is no FDA guidance on the use of Ziconotide with respect to specific gender populations.

### Race
There is no FDA guidance on the use of Ziconotide with respect to specific racial populations.

### Renal Impairment
There is no FDA guidance on the use of Ziconotide in patients with renal impairment.

### Hepatic Impairment
There is no FDA guidance on the use of Ziconotide in patients with hepatic impairment.

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ziconotide in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Ziconotide in patients who are immunocompromised.

# Administration and Monitoring

### Administration
- Intrathecal

### Monitoring
There is limited information regarding Monitoring of Ziconotide in the drug label.

# IV Compatibility
There is limited information regarding IV Compatibility of Ziconotide in the drug label.

# Overdosage

## Acute Overdose
- The maximum recommended intrathecal PRIALT dose is 19.2 mcg/day. The maximum intrathecal dose of PRIALT in clinical trials was 912 mcg/day. In some patients who received intrathecal doses greater than the maximum recommended dose, exaggerated pharmacological effects (e.g., ataxia, nystagmus, dizziness, stupor, unresponsiveness, spinal myoclonus, confusion, sedation, hypotension, word-finding difficulties, garbled speech, nausea, and vomiting) were observed. There was no indication of respiratory depression. Overdoses may occur due to pump programming errors or incorrect drug concentration preparations. In these cases, patients were observed and ziconotide was either temporarily discontinued or permanently withdrawn. Most patients recovered within 24 hours after withdrawal of drug. In the event of an overdose, elimination of ziconotide from CSF would be expected to remain constant (CSF t12=4.6 hours). Therefore, within 24 hours of stopping therapy, the ziconotide CSF concentration should be less than 5% of peak levels.
- There is no known antidote to ziconotide. General medical supportive measures should be administered to patients who receive an overdose until the exaggerated pharmacological effects of the drug have resolved. Treatment for an overdose is hospitalization, when needed, and symptom-related supportive care. Ziconotide does not bind to opiate receptors and its pharmacological effects are not blocked by opioid antagonists.
- In the event of an inadvertent intravenous or epidural administration, adverse reactions could include severe hypotension, which can be treated with a recumbent posture and blood pressure support as required. The half-life of PRIALT in serum is 1.3 hours.

## Chronic Overdose
There is limited information regarding Chronic Overdose of Ziconotide in the drug label.

# Pharmacology

## Mechanism of Action
- Ziconotide binds to N-type calcium channels located on the primary nociceptive (A- and C) 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.

## Structure
- PRIALT contains ziconotide, a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus. Ziconotide is a 25 amino acid, polybasic peptide containing three disulfide bridges with a molecular weight of 2639 daltons and a molecular formula of C102H172N36O32S7. The amino acid sequence and disulfide bridging pattern are given below:
- Ziconotide is a hydrophilic molecule that is freely soluble in water and is practically insoluble in methyl t-butyl ether.
- PRIALT is formulated as a sterile, preservative-free, isotonic solution for intrathecal administration using an appropriate microinfusion device . Each 1 or 5 mL vial of PRIALT (100 mcg/mL) respectively contains 100 or 500 mcg of ziconotide acetate, and the 20 mL vial of PRIALT (25 mcg/mL) contains 500 mcg of ziconotide acetate, with L-methionine and sodium chloride as excipients at pH 4.05.0. Each vial is intended for single use only, either undiluted or after dilution to the appropriate concentration with 0.9% Sodium Chloride Injection, USP (preservative free).

## Pharmacodynamics
- Interaction with Opioids
- Ziconotide does not bind to opioid receptors and its pharmacological effects are not blocked by opioid antagonists. In animal models, intrathecal ziconotide potentiated opioid-induced reduction in gastrointestinal (GI) motility, but did not potentiate morphine-induced respiratory depression. In rats receiving ziconotide, additive analgesic effects were observed with concurrent administration of morphine, baclofen, or clonidine. Concurrent administration of intrathecal ziconotide and morphine did not prevent the development of morphine tolerance in rats.

## Pharmacokinetics
- The cerebrospinal fluid (CSF) pharmacokinetics (PK) of ziconotide have been studied after one-hour intrathecal infusions of 1 to 10 mcg of PRIALT to patients with chronic pain. The plasma PK following intravenous infusion (0.3 to 10 mcg/kg/day) have also been studied. Both intrathecal and intravenous data are shown below (Table 2).
- Following one-hour intrathecal administration of 1 to 10 mcg of PRIALT, both total exposure (AUC; range: 83.6 to 608 ngh/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 PRIALT at infusion rates ranging from 0.1 to 7.0 mcg/hr in patients with chronic pain, plasma ziconotide levels 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 levels in plasma. Plasma ziconotide levels, when detectable, remain constant after many months of intrathecal PRIALT infusion in patients followed for up to 9 months.
- Distribution
- Ziconotide is about 50% bound to human plasma proteins. The mean CSF volume of distribution (Vd) of ziconotide following intrathecal administration approximates the estimated total CSF volume (140 mL).
- Metabolism
- Ziconotide is cleaved by endopeptidases and exopeptidases at multiple sites on the peptide. Following 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 and animal 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.
- Elimination
- Minimal amounts of ziconotide (< 1%) were recovered in human urine following intravenous infusion. 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 (CL) of ziconotide approximates adult human CSF turnover rate (0.3 to 0.4 mL/min).
- Special Populations
- No formal studies were conducted to assess the effect of demographic factors (age, race, gender, and weight), renal or hepatic dysfunction, or to assess the effect of concomitant drugs on the pharmacokinetics of ziconotide due to the low systemic exposure of ziconotide following intrathecal administration.

## Nonclinical Toxicology
- No carcinogenicity studies have been conducted in animals.
- Ziconotide was negative in the in vitro bacterial reverse mutation assay, in vitro mouse lymphoma assay, in vivo mouse micronucleus assay, and in the in vitro Syrian hamster embryo (SHE) cell transformation assay.
- Ziconotide did not affect male fertility in rats when administered as a continuous intravenous infusion at a dose of up to 10 mg/kg/day when administered for approximately 8 weeks, including a 28-day pre-mating period, or female fertility at a dose of 3 mg/kg/day when administered for approximately 6 weeks, including a 14-day pre-mating period. Estimated exposures for the male and female rats were approximately 6500-fold and 1700-fold higher, respectively, than the expected exposure resulting from the maximum recommended human daily intrathecal dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure.
- Female fertility in rats was significantly affected following continuous intravenous infusion at a dose of 10 mg/kg/day. Significant reductions in corpora lutea, implantation sites, and number of live fetuses were observed.

# Clinical Studies
- The efficacy of intrathecal PRIALT in the management of severe chronic pain was studied in three double-blind, placebo-controlled, multicenter studies in a total of 457 patients (268 PRIALT, 189 placebo) using two different titration schedules. The slow titration schedule tested dose increases 2 to 3 times per week with a maximum dose of 19.2 mcg/day (0.8 mcg/hr) at 21 days. The fast titration schedule used daily increases up to a maximum dose of 57.6 mcg/day (2.4 mcg/hr) in 5 to 6 days but resulted in less tolerability and substantially more frequent adverse events.
- A randomized, double-blind, placebo-controlled study of PRIALT was conducted in adult patients with severe chronic pain not adequately controlled with intrathecally delivered analgesics including morphine, bupivacaine and/or clonidine; or who were intolerant to analgesics and/or systemic analgesics using the 21-day slow titration schedule. All prior intrathecal medications were discontinued over a one to three week period, and patients were maintained on a stable regimen of non-intrathecal analgesics, including opiates, for at least 7 days prior to randomization. Dosing with PRIALT was started at 2.4 mcg/day (0.1 mcg/hr) and the dose was increased by 2.4 mcg/day (0.1 mcg/hr) two to three times/week (minimum titration interval 24 hours) to a maximum dose of 19.2 mcg/day (0.8 mcg/hr) as needed for management of pain. The final mean dose at the end of the trial at 21 days was 6.9 mcg/day (0.29 mcg/hr).
- Using a 100 mm Visual Analog Scale of Pain Intensity (VASPI) where 100 mm represented the worst possible pain, mean baseline pain scores were 81 in both the PRIALT and placebo groups. The primary efficacy variable was the mean percent change in the VASPI score from baseline to day 21. In the intent-to-treat efficacy analysis, there was a statistically significant difference between groups in the mean percent change in VASPI score from baseline with the PRIALT group having a 12% mean improvement at Week 3 compared to a 5% mean improvement in the placebo group. The 95% confidence interval for the treatment difference (PRIALTplacebo) was 0.4%, 13%.
- The effect of intrathecal PRIALT on pain was variable over the time period of treatment for some patients. Patients exhibited various degrees of improvement in pain after three weeks of treatment compared with baseline pain assessment. Figure 1 depicts the fraction of patients by their degree of improvement. The figure is cumulative, so that patients whose change from baseline is, for example, 30%, are also included at every level of improvement below 30%. Patients who did not have a VASPI score recorded at Week 3 (Study days 1723, inclusive) were assigned 0% improvement. The improvement in the proportion of responders, defined as having a  30% improvement from baseline in VASPI, was 16% in the PRIALT group compared to 12% in the placebo group, for a net difference of 4%. The use of non-intrathecal opioids decreased by 24% in the PRIALT group and by 17% in the placebo group.

# How Supplied
- PRIALT is supplied as a 25 mcg/mL solution in a single-use 20 mL glass vial and as a 100 mcg/mL solution in single-use glass vials containing 1 mL or 5 mL of solution. One vial is packaged per carton.
- Presentation (NDC)
- 25 mcg/mL: 20 mL vial (18860-723-10). Only the undiluted 25 mcg/mL formulation should be used for PRIALT naive pump priming.
- 100 mcg/mL:     1 mL vial (18860-720-10) and 5 mL vial (18860-722-10)
- Storage
- Refrigerate PRIALT during transit.
- Store PRIALT at 2C to 8C (36F to 46F).
- PRIALT, once diluted aseptically with saline, may be stored at 2C to 8C for 24 hours.
- Do NOT freeze PRIALT.
- Protect from light.

## Storage
There is limited information regarding Ziconotide Storage in the drug label.

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
- Advise patients that psychiatric symptoms (paranoia, hostility, mania, depressive, suicidal) and cognitive symptoms (confusion, memory problems, speech disorder) may occur during treatment with PRIALT.
- Caution patients against engaging in hazardous activity requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle during treatment with PRIALT.
- Caution patients about possible combined effects with other CNS-depressant drugs. Dosage adjustments may be necessary when PRIALT is administered with such agents because of the potentially additive effects.
- Advise patients to contact a physician if the patient experiences new or worsening muscle pain, soreness, weakness with or without darkened urine.
- Instruct patients and their caregivers to contact a physician immediately if the patient has any of the following
- A change in mental status (e.g., lethargy, confusion, disorientation, decreased alertness)
- A change in mood, perception (hallucinations, including unusual tactile sensations in the oral cavity)
- Symptoms of depression or suicidal ideation
- Nausea, vomiting, seizures, fever, headache, and/or stiff neck, as these may be symptoms of developing meningitis
- Decreased level of consciousness, unresponsiveness or stupor
- New muscular symptoms (e.g., muscle cramps, myalgias)
- Withdrawal symptoms (e.g., nausea, insomnia, flu-like symptoms) as a result of abruptly discontinuing opioid therapy
- Development of serious skin reaction (e.g., bullous dermatitis, skin ulcers, skin exfoliation)
- For use only in the Medtronic SynchroMed II Infusion System and CADD-Micro Ambulatory Infusion Pump.

# Precautions with Alcohol
- Alcohol-Ziconotide interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- PRIALT

# Look-Alike Drug Names
There is limited information regarding Ziconotide Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price