PRIALT® (ziconotide intrathecal infusion)

For use only in the Medtronic SynchroMed® EL, SynchroMed® II Infusion System, and the CADD-Micro® ambulatory infusion pump.

Severe psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. Patients with a pre-existing history of psychosis should not be treated with PRIALT. All patients should be monitored 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.

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 (IT) administration using an appropriate microinfusion device (see Dosage and Administration). Each 1, 2, or 5 mL vial of PRIALT (100 mcg/mL) respectively contains 100, 200, 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).

The cerebrospinal fluid (CSF) pharmacokinetics (PK) of ziconotide have been studied after one-hour IT infusions of 1–10 mcg of PRIALT to patients with chronic pain. The plasma PK following intravenous (IV) infusion (0.3–10 mcg/kg/day) have also been studied. Both IT and IV data are shown below (Table 1).

Following one-hour IT administration of 1–10 mcg of PRIALT, both total exposure (AUC; range: 83.6–608 ng⋅h/mL) and peak exposure (Cmax; range: 16.4–132 ng/mL) values in the CSF were variable and dose-dependent, but appeared approximately dose-proportional. During 5 or 6 days of continuous IT 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 IT infusion dose rates were more likely to have quantifiable ziconotide levels in plasma. Plasma ziconotide levels, when detectable, remain constant after many months of IT PRIALT infusion in patients followed for up to 9 months.

The safety and efficacy of IT PRIALT in the management of severe chronic pain were 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 2–3 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 5–6 days. The safety in chronic use was studied in four additional open-label, long-term studies in 977 patients.

A randomized, double-blind, placebo-controlled study was conducted at 39 centers to evaluate the efficacy of IT PRIALT administered using a slow titration schedule in 220 patients with severe chronic pain. Patients were randomized 1:1 between PRIALT (112 patients) and placebo (108 patients). At baseline, 97% of these patients reported that their pain was refractory to treatment including IT morphine, IT bupivacaine (an off-label use for this drug), and/or IT clonidine (an off-label use for this drug) in addition to their systemic analgesics and adjunctive therapy. All IT medications were discontinued over a one to three week period, and patients were maintained on a stable regimen of non-IT analgesics, including opiates, for at least 7 days prior to randomization. This period was successfully completed by 93% of the patients screened. Dosing with PRIALT was started at 2.4 mcg/day (0.1 mcg/hr) and the dose could be 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). 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=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 (ITT) 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 (p=0.04). The 95% confidence interval for the treatment difference (PRIALT–placebo) was 0.4%, 13%.

The effect of IT PRIALT on pain was variable over the time period of treatment for some patients. Some patients had a reduction in VASPI in the first or second week but did not maintain pain relief by the end of the third week. Other patients, who did not exhibit a reduction in VASPI early in treatment, did have a reduction in VASPI by the third week.

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 17-23, 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-IT opioids decreased by 24% in the PRIALT group and by 17% in the placebo group.

PRIALT (ziconotide intrathecal infusion) is indicated for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.

PRIALT is contraindicated in 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 IT administration hazardous.

Patients with a pre-existing history of psychosis should not be treated with ziconotide.

Contraindications to the use of IT 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 CSF.

Patients should be cautioned 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. Patients should also be cautioned 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.

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, patients must NOT be abruptly withdrawn from opiates. For patients being withdrawn from IT opiates, the IT opiate infusion should be gradually tapered over a few weeks and replaced with a pharmacologically equivalent dose of oral opiates. PRIALT does not interact with opiate receptors and does not potentiate opiate-induced respiratory depression.

Patients should be cautioned 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. Patients should also be cautioned 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. The physician should be contacted if the patient experiences new or worsening muscle pain, soreness, weakness with or without darkened urine.

PATIENTS AND THEIR CAREGIVERS SHOULD BE INSTRUCTED TO CONTACT A PHYSICIAN IMMEDIATELY IF THE PATIENT HAS

• 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

In clinical studies (mostly open label), up to 40% of patients had serum creatine kinase (CK) levels above the upper limit of normal, and 11% had CK levels that were ≥ 3 times the upper limit of normal (see Elevation of Serum Creatine Kinase). Most cases of CK elevation were not associated with muscle weakness, however one case of myopathy with EMG findings, and two cases of acute renal failure associated with rhabdomyolysis and extreme CK elevations (17,000–27,000 IU/L) were reported.

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, IT 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 IT administration, clinically relevant plasma protein displacement reactions involving ziconotide and co-administered medications are unlikely.

Over 90% of patients treated with IT PRIALT used systemic opiates and in the slow titration study, 98% of patients received opioids.

Combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended.

Almost all patients in the PRIALT clinical trials received concomitant non-IT medication. Of the 1254 patients treated, most 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 events such as dizziness and confusion (see PRECAUTIONS).

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 (IV) 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 (IT) dose of 0.8 mcg/hr (19.2 mcg/day) based on plasma exposure.

Female fertility in rats was significantly affected following continuous IV infusion at a dose of 10 mg/kg/day. Significant reductions in corpora lutea, implantation sites, and number of live fetuses were observed.

The effect of PRIALT on labor and delivery in humans is not known.

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.

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 the 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.

Formal PK studies were not conducted in patients with hepatic or renal impairment.

The safety of IT PRIALT administered as a continuous infusion has been evaluated in 1254 patients participating in acute and severe chronic pain trials. The duration of treatment has ranged from a one-hour IT infusion to treatment lasting for more than 7.5 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 events (≥25%) in the 1254 patients (662  patient years) in clinical trials were dizziness, nausea, confusional state and nystagmus. Serious adverse events and discontinuation of PRIALT for adverse events are less frequent when the drug is slowly titrated over 21 days than with a faster titration schedule. (see CLINICAL TRIALS and DOSAGE and ADMINISTRATION.)

Table 2 summarizes the treatment-emergent adverse events with a frequency of 5% or greater in the PRIALT-treated group from the one placebo-controlled trial using the slow titration schedule in patients with severe chronic pain. All events reported during the initial placebo-controlled period of the studies (21 days in the slow titration schedule) are tabulated, regardless of relationship to PRIALT.

The following adverse events assessed as related to PRIALT have been reported in 2% or greater of patients participating in the clinical studies (MedDRA preferred terms, by system organ class):

EAR AND LABYRINTH DISORDERS: vertigo; EYE DISORDERS: diplopia, vision blurred, visual disturbance NOS; GASTROINTESTINAL DISORDERS: abdominal pain NOS, constipation, diarrhea NOS, dry mouth, nausea, nausea aggravated, vomiting NOS; GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: asthenia, fall, fatigue, gait abnormal, lethargy, edema peripheral, pain NOS, pyrexia, rigors; INVESTIGATIONS: blood creatine phosphokinase increased; METABOLISM AND NUTRITION DISORDERS: anorexia, appetite decreased NOS; MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS: muscle cramp, muscle spasms, muscle weakness NOS, myalgia, pain in limb; NERVOUS SYSTEM DISORDERS: amnesia, aphasia, areflexia, ataxia, balance impaired NOS, burning sensation NOS, coordination abnormal NOS, disturbance in attention, dizziness, dizziness postural, dysarthria, dysgeusia, headache, hypoaesthesia, memory impairment, mental impairment NOS, nystagmus NOS, paraesthesia, sedation, somnolence, speech disorder, tremor; PSYCHIATRIC DISORDERS: agitation, anxiety, cognitive disorder NOS, confusional state, depression, depression aggravated, disorientation, hallucination NOS, hallucination auditory, hallucination visual, insomnia, irritability, mood disorder NOS, nervousness, paranoia; RENAL AND URINARY DISORDERS: dysuria, urinary hesitation, urinary retention; SKIN AND SUBCUTANEOUS TISSUE DISORDERS: pruritus, sweating increased; VASCULAR DISORDERS: hypotension NOS, orthostatic hypotension.

At less than 2%, the following medically important events 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, incoherent, clonic convulsion and grand mal convulsion. Rare instances of fatal pneumonia aspiration and suicide attempt were reported (<1%).

The maximum recommended IT PRIALT dose is 19.2 mcg/day. The maximum IT dose of PRIALT in clinical trials was 912 mcg/day. In some patients who received IT 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 IT 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 events could include 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.

IT PRIALT should be initiated 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. Dose increases in increments of less than 2.4 mcg/day (0.1 mcg/hr) and increases in dose less frequently than 2–3 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. Controlled studies of pain relief have not been conducted for longer than 3 weeks duration, although 977 patients have been treated with IT PRIALT in long-term open-label trials.

The dose of IT PRIALT should be adjusted according to the patient's severity of pain, their response to therapy, and the occurrence of adverse events. The effective dose of PRIALT for analgesia is variable. The average dose level at the end of the 21-day titration used in the slow titration clinical trial (see CLINICAL TRIALS) was 6.9 mcg/day (0.29 mcg/hr) and the maximum dose was 19.2 mcg/day (0.8 mcg/hr) on Day 21. Due to the frequency of adverse events, 19.2 mcg/day (0.8 mcg/hr) is the maximum recommended dose.

Because of the lower incidence of serious adverse events and discontinuations for adverse events associated with the slower titration (see ADVERSE REACTIONS), a faster titration schedule should only be used if there is an urgent need for analgesia that outweighs the risk to patient safety.

In clinical trials, no rebound or other adverse events related to discontinuation of PRIALT were noted, although treatment was almost always discontinued abruptly.

Vials of PRIALT should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

PRIALT should be administered intrathecally (IT) by or under the direction of a physician experienced in the technique of IT administration and who is familiar with the drug and device labeling. PRIALT is not intended for intravenous administration.

PRIALT is intended for IT delivery using a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter (see PRECAUTIONS-Meningitis and Other Infections). Refer to the manufacturer's manual for specific instructions and precautions for programming the microinfusion device and/or refilling the reservoir.

PRIALT is used for therapy undiluted (25 mcg/mL in 20 mL vial) or diluted (100 mcg/mL in 1, 2, or 5 mL vials). Diluted PRIALT is prepared with 0.9% Sodium Chloride Injection, USP (preservative free) using aseptic procedures to the desired concentration prior to placement in the microinfusion pump. The 100 mcg/mL formulation may be administered undiluted once an appropriate dose has been established. SALINE SOLUTIONS CONTAINING PRESERVATIVES ARE NOT APPROPRIATE FOR IT DRUG ADMINISTRATION AND SHOULD NOT BE USED. Refrigerate but do not freeze all PRIALT solutions after preparation and begin infusion within 24 hours. Discard any PRIALT solution with observed particulate matter or discoloration and any unused portion left in the vial.

Refer to the manufacturer's manuals for specific instructions and precautions for performing a reservoir rinse, initial filling, refilling the reservoir, and programming.

Instructions for Use of PRIALT with Pump

1. Naïve Pump Priming (i.e., first time use with PRIALT)
Only the undiluted 25 mcg/mL formulation should be used 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.

2. Initial Pump Fill
Only the undiluted 25 mcg/mL formulation should be used for initial pump fill. Fill the naïve pump after priming as above with the appropriate volume of PRIALT at 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 the 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.

3. 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, it is recommended that the Medtronic refill kit be used. The pump spans should be emptied prior to refill with PRIALT.

If the internal infusion system must be surgically replaced while the person is receiving PRIALT, the replacement pump should be rinsed with PRIALT (No. 1 above), and this initial fill solution must be replaced within 14 days (No. 2 above). Subsequent refills should be done at least every 84 days if PRIALT is used undiluted or at least every 40 days if PRIALT is used diluted.

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. The appropriate external microinfusion device is filled for the first time with PRIALT solution at a concentration of 5 mcg/mL. This solution is prepared by diluting PRIALT with 0.9% Sodium Chloride, USP (preservative free). The flow rate for the external microinfusion device usually starts at 0.02 mL/hr to deliver the initial dose rate of 2.4 mcg/day (0.1 mcg/hr) of PRIALT. Changes in dose rate are made by adjusting the flow rate of the infusion system and/or the concentration of PRIALT solution.

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, 2 mL, or 5 mL of solution. One vial is packaged per carton.

Presentation (NDC)

25 mcg/mL: 20 mL vial (59075-723-10). Only the undiluted 25 mcg/mL formulation should be used for PRIALT naïve pump priming.

100 mcg/mL: 1 mL (59075-720-10)

2 mL (59075-721-10)

5 mL (59075-722-10)

• Refrigerate PRIALT during transit.
• Store PRIALT at 2°C–8°C (36°F–46°F).
• PRIALT, once diluted aseptically with saline, may be stored at 2°C–8°C for 24 hours.
• Do NOT freeze PRIALT.
• Protect from light.

U.S. Patent Nos. 5,364,842, 5,795,864, and 5,859,186

Distributed by:

Elan Pharmaceuticals, Inc.

San Diego, CA 92121

© 2007 Elan Pharmaceuticals, Inc. All rights reserved

PRIALT^® is a registered trademark of Elan Pharmaceuticals, Inc.

SynchroMed^® is a registered trademark of Medtronic, Inc.

CADD-Micro^® is a registered trademark of the Smiths Medical family of companies

6001451-A
Rev. 04/07