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PRIALT(ziconotide)injection, solution

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use PRIALT safely and effectively. See full prescribing information for PRIALT. PRIALT (ziconotide) solution, intrathecal infusion Initial U.S. Approval: 2004
WARNING: NEUROPSYCHIATRIC ADVERSE REACTIONS See full prescribing information for complete boxed warning Severe psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. Do not treat patients with a pre-existing history of psychosis with PRIALT
INDICATIONS AND USAGE
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)
DOSAGE AND ADMINISTRATION
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 24hours. (2.1) Initiate PRIALT at no more than 2.4 mcg/day (0.1mcg/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)
DOSAGE FORMS AND STRENGTHS
Intrathecal solution (3): 25 mcg/mL 100 mcg/mL
CONTRAINDICATIONS
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)
WARNINGS AND PRECAUTIONS
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)
ADVERSE REACTIONS
The most frequently reported adverse reactions (≥ 25%) in clinical trials were dizziness, nausea, confusional state, nystagmus (6) To report SUSPECTED ADVERSE REACTIONS, contact Azur at (800) 890-3098 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
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)
USE IN SPECIFIC POPULATIONS
Pregnancy: No adequate and well-controlled studies have been conducted in pregnant women. Use PRIALT during pregnancy only if the potential benefit justifies the risk to the fetus. (8.1) Nursing Mothers: It is not known whether PRIALT is excreted in human breast milk. (8.3) Pediatric Use: Safety and effectiveness in pediatric patients have not been established. (8.4) Geriatric Use: There is a higher incidence of confusion in elderly patients. The dose selection for an elderly patient should be cautious, starting at the low end of the dosing range. (8.5)
See 17 for PATIENT COUNSELING INFORMATION
Revised: 09/2011

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FULL PRESCRIBING INFORMATION: CONTENTS*

* Sections or subsections omitted from the full prescribing information are not listed

WARNING: NEUROPSYCHIATRIC ADVERSE REACTIONS

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 General Information

2.2 Dosing

2.3 Instructions for Use with the Medtronic SynchroMed II Infusion System

2.4 Instructions for Use in the CADD-Micro Ambulatory Infusion Pump

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Cognitive and Neuropsychiatric Adverse Reactions

5.2 Meningitis and Other Infections

5.3 Reduced Level of Consciousness

5.4 Elevation of Serum Creatine Kinase

5.5 Withdrawal From Opiates

5.6 Driving and Operating Machinery

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Interaction with CNS Depressants

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Laboratory Tests

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

PRINCIPAL DISPLAY PANEL - 20 mL Carton

PRINCIPAL DISPLAY PANEL - 20 mL Carton - Sample

PRINCIPAL DISPLAY PANEL - 1 mL Carton

PRINCIPAL DISPLAY PANEL - 5 mL Carton

FULL PRESCRIBING INFORMATION

WARNING: NEUROPSYCHIATRIC ADVERSE REACTIONS

PRIALT is contraindicated in patients with a preexisting history of psychosis. Severe psychiatric symptoms and neurological impairment may occur during treatment with PRIALT. Monitor all patients frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Discontinue PRIALT therapy in the event of serious neurological or psychiatric signs or symptoms.

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

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 Infusion System and CADD-Micro Ambulatory Infusion Pump [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 (25mcg/mL in 20 mL vial) or diluted (100mcg/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 24hours.

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 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,intrathecalinfusion	InitialFill 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

2.4 Instructions for Use in the CADD-Micro Ambulatory Infusion Pump

Refer to the manufacturer's manuals for specific instructions and precautions for performing the initial filling, refilling of the reservoir or replacement of the drug cartridge, and operation. The CADD-Micro Ambulatory Infusion Pump 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 recommended initial flow rate for the external microinfusion is 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. [seeWarnings and Precautions (5.2)]

3 DOSAGE FORMS AND STRENGTHS

PRIALT (ziconotide) solution, intrathecal infusion is supplied as a 25 mcg/mL concentration in single-use 20 mL glass vials and as a 100 mcg/mL concentration in single-use glass vials containing 1 mL or 5 mL of solution.

4 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.

5 WARNINGS AND PRECAUTIONS

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 eva luation 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 therap