Ziconotide

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 C 102 H 172 N 36 O 32 S 7 . 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 [ see Dosage and Administration ( 2 ) ]. 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 4.0–5.0. 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). Figure

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. PRIALT (ziconotide) solution, intrathecal infusion is an N-type calcium channel antagonist indicated for the management of severe chronic pain in patients for whom intrathecal therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or intrathecal morphine. ( 1 )

16.1 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 (70720-723-10). Only the undiluted 25 mcg/mL formulation should be used for PRIALT naïve pump priming. 100 mcg/mL: 1 mL vial (70720-720-10) 5 mL vial (70720-722-10) 16.2 Storage Refrigerate PRIALT during transit. Store PRIALT at 2°C to 8°C (36°F to 46°F). PRIALT, once diluted aseptically with saline, may be stored at 2°C to 8°C for 24 hours. Do NOT freeze PRIALT. Protect from light.

PRIALT is a non-opioid and non-NSAID analgesic agent used for the management of severe and chronic pain. Administer PRIALT intrathecally 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. ( 2 ) PRIALT is not for intravenous administration. ( 2.1 ) PRIALT is delivered using a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter. ( 2.1 ) PRIALT 25 mcg/mL is used undiluted. The 100 mcg/mL formulation must be used diluted until an appropriate dose has been established. ( 2.1 ) Saline solutions containing preservatives must not be used. ( 2.1 ) Refrigerate but do not freeze all PRIALT solutions after preparation. Begin infusion within 24 hours. ( 2.1 ) Initiate PRIALT at no more than 2.4 mcg/day (0.1 mcg/hr) and titrated to patient response. Doses may be titrated upward by up to 2.4 mcg/day (0.1 mcg/hr) at intervals of no more than 2–3 times per week, up to a recommended maximum of 19.2 mcg/day (0.8 mcg/hr) by Day 21. ( 2 ) 2.1 General Information PRIALT 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. PRIALT is not intended for intravenous administration. PRIALT is intended for intrathecal delivery using the Medtronic SynchroMed ® II and SynchroMed ® III Infusion System [ see Warnings and Precautions ( 5.2 ) ]. Refer to the manufacturer's manual for specific instructions and precautions for programming the microinfusion device and/or refilling the reservoir. PRIALT may be used for therapy undiluted (25 mcg/mL in 20 mL vial) or diluted (100 mcg/mL in 1 or 5 mL vials). The 100 mcg/mL formulation may be administered undiluted once an appropriate dose has been established. Dilute PRIALT with 0.9% Sodium Chloride Injection, USP (preservative free) using aseptic procedures to the desired concentration prior to placement in the microinfusion pump. Saline solutions containing preservatives are not appropriate for intrathecal drug administration and should not be used due to risk of neurotoxicity. Refrigerate but do not freeze all PRIALT solutions after preparation and begin infusion within 24 hours. Inspect vials of PRIALT visually for particulate matter and discoloration prior to administration whenever solution and container permit. Discard any PRIALT solution with observed particulate matter or discoloration and any unused portion left in the vial. 2.2 Dosing 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 patient's response to therapy, and the occurrence of adverse reactions. 2.3 Instructions for Use with the Medtronic SynchroMed II and SynchroMed III Infusion System Refer to the manufacturer's manuals for specific instructions and precautions for performing a reservoir rinse, initial filling, refilling the reservoir, and programming. [ see Warnings and Precautions ( 5.2 ) ] Naïve Pump Priming (i.e., first time use with PRIALT) Use only the undiluted 25 mcg/mL formulation for naïve pump priming. Rinse the internal surfaces of the pump with 2 mL of PRIALT at 25 mcg/mL. Repeat twice for a total of three rinses. Initial Pump Fill Use only the undiluted 25 mcg/mL formulation for the initial pump fill . Fill the naïve pump after priming with the appropriate volume of PRIALT 25 mcg/mL. Begin dosing at a delivery rate no higher than 2.4 mcg/day (0.1 mcg/hr). In a naïve pump, PRIALT is lost due to two 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, the pump reservoir should be refilled with PRIALT 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 PRIALT is used diluted. For undiluted PRIALT, fill the pump at least every 84 days. To ensure aseptic transfer of PRIALT into the device, use the Medtronic refill kit. Empty the pump contents prior to refill with PRIALT. If the internal infusion system must be surgically replaced while the person is receiving PRIALT, rinse the replacement pump with PRIALT according to Naïve Pump Priming [ see Dosage and Administration ( 2.4 ) ], and replace the initial fill solution within 14 days according to Initial Pump Fill [ see Dosage and Administration ( 2.4 ) ]. PRIALT (ziconotide) solution, intrathecal infusion Initial Fill Expiry Refill Expiry 25 mcg/mL, undiluted 14 Days 84 Days 100 mcg/mL, undiluted N/A 84 Days 100 mcg/mL, diluted N/A 40 Days

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. Patients with a known hypersensitivity to ziconotide or any of its formulation components and in patients with any other concomitant treatment or medical condition that would render intrathecal administration hazardous. ( 4 ) Patients with a pre-existing history of psychosis with ziconotide. ( 4 ) Contraindications to the use of intrathecal analgesia include conditions such as the presence of infection at the microinfusion injection site, uncontrolled bleeding diathesis, and spinal canal obstruction that impairs circulation of cerebrospinal fluid (CSF). ( 4 )

Cognitive and neuropsychiatric adverse reactions – Cognitive impairment and severe neuropsychiatric symptoms may occur with PRIALT use. ( 5.1 ) Meningitis and other infections – Patients, caregivers, and healthcare providers must be aware of 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. ( 5.2 ) Reduced level of consciousness – Patients may become unresponsive or stuporous while receiving PRIALT. ( 5.3 ) Elevation of serum creatine kinase – Patients taking PRIALT may experience elevations in creatine kinase. Monitor serum CK in patients undergoing treatment with PRIALT periodically. ( 5.4 ) Withdrawal from opiates : Patients must not be abruptly withdrawn from opiates and must be gradually tapered over a few weeks and replaced with a pharmacologically equivalent dose of oral opiates. ( 5.5 ) 5.1 Cognitive and Neuropsychiatric Adverse Reactions Severe 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. [ see Use in Specific Populations ( 8.5 ) ] 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. 5.2 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. 5.3 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. 5.4 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 (17,000–27,000 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. 5.5 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. 5.6 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.

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) Lactation: Advise mothers who have been administered PRIALT to monitor neonates for signs of sedation which may result in respiratory depression and/or feeding problems [ see Use in Specific Populations ( 8.2 ) ] For use only in the Medtronic SynchroMed ® II and SynchroMed ® III Infusion System. Distributed by: Esteve Pharmaceuticals, S.A. Barcelona, Spain © 2026 Esteve Pharmaceuticals, S.A. PRIALT ® is a registered trademark of Esteve Pharmaceuticals, S.A.. SynchroMed ® is a registered trademark of Medtronic, Inc. U.S. Patent Nos. 5,364,842; 5,795,864; and 5,891,849

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.

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. Combination of PRIALT with intrathecal opiates is not recommended. ( 7 ) Patients taking concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness. ( 5.3 ) The use of PRIALT may be associated with an increased incidence of CNS adverse reactions such as dizziness and confusion. ( 7.1 ) 7.1 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 [ see Warnings and Precautions ( 5 ) ].

Carcinogenesis No carcinogenicity studies have been conducted in animals. Mutagenesis 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. Impairment of Fertility 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.

Risk Summary Available data from postmarketing reports are insufficient to identify a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In an animal reproduction study, ziconotide did not cause embryo-fetal toxicity when administered to pregnant rats and rabbits during the period of organogenesis by continuous intravenous infusion at 400- and 940-times, respectively, the maximum recommended human dose (MRHD) of 19.2 mcg/day. In a pre- and post-natal development study, ziconotide did not affect pup development or reproductive performance when administered to rats by continuous intravenous infusion at 3800-times the MRHD (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Ziconotide caused embryo-fetal mortality 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 embryo-fetal mortality 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 did not result in malformations when administered to pregnant rats by continuous intravenous infusion at doses up to 30 mg/kg/day or to pregnant 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.

Safety and effectiveness in pediatric patients have not been established.

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.

The most frequently reported adverse reactions (≥ 25%) in clinical trials were dizziness, nausea, confusional state, nystagmus. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics at 1-844-344-4035 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 [ see Clinical Studies ( 14 ) and Dosage and Administration ( 2 ) ]. 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 . Table 1. Incidence of Adverse Reactions in Slow Titration Placebo-Controlled Trial by Percent (Events That Occurred in ≥ 5% of Patients and More Commonly with PRIALT than with Placebo) MedDRA System Organ Class MedDRA Preferred term PRIALT N=112 Placebo N=108 Percentage of Patients Any AE 93 82 Ear and Labyrinth Disorders Vertigo 7 0 Eye Disorders Vision Blurred 12 3 Gastrointestinal Disorders Diarrhea 18 15 Nausea 40 29 Vomiting 16 14 General Disorders and Administration Site Conditions Asthenia 18 6 Gait Abnormal 14 2 Pyrexia 5 3 Rigors 7 5 Infections and Infestations Sinusitis 5 2 Metabolism and Nutrition Disorders Anorexia 6 2 Musculoskeletal and Connective Tissue Disorders Muscle Spasms 6 4 Pain in Limb 5 2 Nervous System Disorders Amnesia 8 0 Ataxia 14 1 Dizziness 46 13 Dysarthria 7 0 Dysgeusia 5 5 Headache 13 11 Memory Impairment 7 1 Nystagmus 8 0 Somnolence 17 10 Tremor 7 3 Psychiatric Disorders Anxiety 8 3 Confusional State 15 5 Insomnia 6 9 Renal and Urinary Disorders Urinary Retention 9 0 Skin and Subcutaneous Disorders Pruritis 7 7 Sweating Increased 5 6 Other Adverse Reactions Observed During Clinical Studies of PRIALT The following adverse reactions assessed as related to PRIALT have been reported in 2% or greater of patients participating in the clinical studies: EYE DISORDERS: diplopia, visual disturbance GASTROINTESTINAL DISORDERS: abdominal pain, constipation, dry mouth, nausea aggravated GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: fall, fatigue, lethargy, edema peripheral INVESTIGATIONS: blood creatine phosphokinase increased METABOLISM AND NUTRITION DISORDERS: appetite decreased MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: muscle cramp, muscle weakness, myalgia, pain in limb NERVOUS SYSTEM DISORDERS: aphasia, areflexia, balance impaired, burning sensation, coordination abnormal, disturbance in attention, dizziness postural, dysarthria, dysgeusia, hypoaesthesia, mental impairment, paraesthesia, sedation, speech disorder PSYCHIATRIC DISORDERS: agitation, anxiety, cognitive disorder, confusional state, depression, depression aggravated, disorientation, hallucination, hallucination auditory, hallucination visual, insomnia, irritability, mood disorder, nervousness, paranoia RENAL AND URINARY DISORDERS: dysuria, urinary hesitation VASCULAR DISORDERS: hypotension, orthostatic hypotension. 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. 6.2 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.

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 t ½ =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.