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.

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.

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 To avoid withdrawal syndrome when opiate withdrawal is necessary, patients must NOT be abruptly withdrawn from opiates. For patients being withdrawn from IT opiates, the IT opiate infusion should be gradually tapered over a few weeks and replaced with a pharmacologically equivalent dose of oral opiates.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.

General

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 the 1254 patients in PRIALT clinical trials with an exposure of 662 patient-years, meningitis occurred at 3% (40 cases) in the PRIALT group using either internal or external microinfusion devices and 1% (1 case) in the placebo group with an exposure of only 5 patient-years. The risk of meningitis with external microinfusion devices and catheters was higher with 93% cases (38/41) occurring with external infusion systems (37 PRIALT, 1 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 should be familiar with the handling of the external microinfusion device and care of the catheter skin exit site at risk of infection. Strict aseptic procedures must be used during the preparation of the PRIALT solution or refilling of the microinfusion device to prevent accidental introduction of any 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 IT space and therefore discontinuation of PRIALT therapy.

Congnitive And Neuropsychiatric Adverse Events

Use of PRIALT has been associated with CNS-related adverse events, including psychiatric symptoms, cognitive impairment, and decreased alertness/unresponsiveness. For the 1254 patients treated, the following cognitive adverse event 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. The PRIALT dose should be reduced or discontinued if signs or symptoms of cognitive impairment develop, but other contributing causes should also be considered. The various cognitive effects of PRIALT are generally reversible within 2 weeks after drug discontinuation. The medians for 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 Geriatric Use)

In placebo-controlled trials, there was a higher incidence of suicide, suicide attempts, and suicide ideations in PRIALT-treated patients (N=3) than in the placebo group (N=1). The incidence was 0.10/patient year for placebo patients and 0.27/patient year for PRIALT patients.

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. If appropriate, management of psychiatric complications should include discontinuation of PRIALT, treatment with psychotherapeutic agents if appropriate, and/or short-term hospitalization. Before drug is reinitiated, careful evaluation must be performed on an individual basis.

Reduced Level Of Consciousness

Patients have become unresponsive or stuporous while receiving PRIALT. The incidence of unresponsiveness or stupor in clinical trials was 2%. During these episodes, the patient sometimes appears to be conscious and breathing is not depressed. If reduced levels of consciousness occur, PRIALT should be discontinued until the event resolves, and other etiologies (e.g., meningitis) should 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, other CNS-depressant drugs should also be discontinued as clinically appropriate.

Elevation Of Serum Creatine Kinase (CK-MM)

In clinical studies (mostly open label), 40% of patients had serum creatine kinase (CK) levels above the upper limit of normal, and 11% had CK levels that were ≥ 3 X 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. Elevated CKs were more often seen in males, in patients who were being treated with anti-depressants or anti-epileptics, and in patients treated with IT morphine. Most patients who experienced elevations in CK, even for prolonged periods of time, did not have limiting side effects. However, 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.

Therefore, it is recommended that physicians monitor serum CK in patients undergoing treatment with PRIALT periodically (e.g., every other week for the first month and monthly as appropriate thereafter). Patients should be clinically evaluated and CK measurements obtained in the setting of new neuromuscular symptoms (e.g., myalgias, myasthenia, muscle cramps, asthenia) or a reduction in physical activity. Should these symptoms continue and CK levels remain elevated or continue to rise, it is recommended that the physician consider PRIALT dose reduction or discontinuation.

Laboratory Tests

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..

Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

Pregnancy

Pregnancy Category C:

Ziconotide was embryolethal in rats when given as a continuous IV 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 (IT) dose of 0.8 mcg/hr (19.2 mcg/day). Ziconotide was not teratogenic in female rats when given as a continuous IV 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 intrathecal (IT) 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 IT 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 IT 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 IV 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 (IT) 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.

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.

Geriatric 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 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.

Hepatic and Renal Impairment

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

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