Included as part of the PRECAUTIONS section.
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 PRIALTtreated 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]
There may be additive effects on cognitive impairment and
decreased alertness when PRIALT is used in conjunction with other CNSdepressant
drugs that may necessitate dosage adjustments.
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.
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.
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
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.
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.
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
Carcinogenesis, Mutagenesis, Impairment Of Fertility
No carcinogenicity studies have been conducted in
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 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.
Use In Specific Populations
Pregnancy Category C
Ziconotide was embryolethal 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 embryolethality 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 was not teratogenic in female rats when given as a continuous
intravenous 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
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.
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
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
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.