Important Safety Information

WARNING: NEUROPSYCHIATRIC ADVERSE REACTIONS
PRIALT intrathecal infusion 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.

 

CONTRAINDICATIONS
PRIALT is contraindicated in patients with:

  • A known hypersensitivity to ziconotide or any of its formulation components.
  • Any other concomitant treatment or medical condition that would render IT administration hazardous, 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).
  • A pre-existing history of psychosis.

WARNINGS AND PRECAUTIONS
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.

In clinical trials, 12% of patients reported hallucinations; other acute psychiatric events included paranoid reactions (3%), hostility (2%), delirium (2%), psychosis (1%), and manic reactions (0.4%). Patients with pretreatment psychiatric disorders may be at increased risk.

PRIALT may cause or worsen depression, with the risk of suicide in susceptible patients. A higher incidence of suicide, suicide attempts, and suicidal ideations was reported with PRIALT than with placebo (0.27 vs 0.10 per patient-year for PRIALT vs placebo, respectively).

Management of psychiatric complications may need to include discontinuation of PRIALT, treatment with psychotherapeutic agents, and/or short-term hospitalization.

In clinical trials, cognitive adverse reactions included confusion (33%), memory impairment (22%), speech disorder (14%), aphasia (12%), thinking abnormal (8%), and amnesia (1%). Cognitive effects may appear gradually after several weeks of treatment and are generally reversible within 2 weeks after discontinuation. The elderly (≥65 years) are at higher risk for confusion. Concomitant use of central nervous system (CNS) depressants with PRIALT may have additive effects. 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.

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. In clinical trials, the rate of meningitis was 3% (40 cases) in the PRIALT group using either internal or external microinfusion devices and 1% (1 case) with placebo. In patients with external microinfusion devices and catheters, meningitis occurred 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.

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.

Reduced Level of Consciousness

In clinical trials, 2% of PRIALT-treated patients became unresponsive or stuporous. 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.

Elevation of Serum Creatine Kinase

In clinical trials, serum creatine kinase (CK) levels above the upper limit of normal (ULN) were reported in 40% of patients, with 11% of patients having CK levels >3 times ULN. Incidences were higher during the first 2 months of treatment. Serum CK should be monitored periodically (eg, every other week for first month and monthly as appropriate thereafter). In the setting of new neuromuscular symptoms (e.g., myalgias, myasthenia, muscle cramps, asthenia) or a reduction in physical activity, evaluate patients clinically and obtain CK measurements. 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 IT opiates or IT 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. Caution patients against engaging in hazardous activities that require complete mental alertness or motor coordination.

MOST COMMON ADVERSE REACTIONS

The most frequently reported adverse reactions (≥25%) in clinical trials (n=1254 PRIALT-treated patients) were dizziness, nausea, confusional state, and nystagmus. Slower titration of PRIALT may result in fewer serious adverse reactions and discontinuations for adverse reactions.

In a controlled trial using the slow-titration schedule in patients with severe chronic pain (n=112 PRIALT-treated patients, n=108 placebo), the most common adverse reactions (≥5% and more frequent with PRIALT than with placebo) were dizziness (46%), nausea (40%), asthenia (18%), diarrhea (18%), somnolence (17%), vomiting (16%), confusional state (15%), abnormal gait (14%), ataxia (14%), headache (13%), blurred vision (12%), urinary retention (9%), amnesia (8%), anxiety (8%), nystagmus (8%), dysarthria (7%), memory impairment (7%), rigors (7%), tremor (7%), vertigo (7%), anorexia (6%), muscle spasms (6%), pain in limb (5%), pyrexia (5%), and sinusitis (5%).

ADDITIONAL IMPORTANT SAFETY INFORMATION

  • PRIALT should be administered intrathecally (IT) by or under the direction of a physician. PRIALT is not intended for intravenous (IV) administration. See full Prescribing Information for dosing and administration instructions.
  • PRIALT is for use only in the Medtronic SynchroMed® II Infusion System and the CADD-Micro Ambulatory Infusion Pump.
  • Advise patients to contact a physician if they experience new or worsening muscle pain, soreness, or 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 or perception (e.g., 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 discontinuing opioids abruptly
    • Development of serious skin reaction (e.g., bullous dermatitis, skin ulcers, skin exfoliation)

DRUG INTERACTIONS

  • Formal drug-drug interaction studies were not conducted with PRIALT.
  • The combination of PRIALT with intrathecal opiates has not been studied in placebo-controlled clinical trials and is not recommended.
  • Patients taking concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness.

USE IN SPECIFIC POPULATIONS

  • PREGNANCY CATEGORY C. No adequate and well-controlled studies have been conducted in pregnant women. PRIALT should be used during pregnancy only if the potential benefit justifies risk to fetus.
  • 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.
  • Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
  • Geriatric Use: In all trials, there was a higher incidence of confusion in elderly patients. The dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

Please see full Prescribing Information, including BOXED Warning, for additional important safety information.