A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Paxil Warnings, Precautions, Pregnancy, Nursing, Abuse - Paroxetine Hydrochloride
Paxil Warnings, Precautions, Pregnancy, Nursing, Abuse - Paroxetine Hydrochloride
WARNINGS
Potential for Interaction With Monoamine Oxidase Inhibitors:
In patients receiving another serotonin reuptake inhibitor drug in combination
with a monoamine oxidase inhibitor (MAOI), there have been reports of serious,
sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic
instability with possible rapid fluctuations of vital signs, and mental status
changes that include extreme agitation progressing to delirium and coma. These
reactions have also been reported in patients who have recently discontinued
that drug and have been started on an MAOI. Some cases presented with features
resembling neuroleptic malignant syndrome. While there are no human data showing
such an interaction with PAXIL, limited animal data on the effects of combined
use of paroxetine and MAOIs suggest that these drugs may act synergistically
to elevate blood pressure and evoke behavioral excitation. Therefore, it is
recommended that PAXIL not be used in combination with an MAOI, or within 14
days of discontinuing treatment with an MAOI. At least 2 weeks should be allowed
after stopping PAXIL before starting an MAOI.
Potential Interaction With Thioridazine: Thioridazine administration
alone produces prolongation of the QTc interval, which is associated with serious
ventricular arrhythmias, such as torsade de pointes–type arrhythmias,
and sudden death. This effect appears to be dose related.
An in vivo study suggests that drugs which inhibit P450IID6,
such as paroxetine, will elevate plasma levels of thioridazine. Therefore, it
is recommended that paroxetine not be used in combination with thioridazine
(see CONTRAINDICATIONS and PRECAUTIONS).
Clinical Worsening and Suicide Risk
Patients with major depressive disorder, both adult and pediatric,
may experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality), whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Although
there has been a longstanding concern that antidepressants may have a role in
inducing worsening of depression and the emergence of suicidality in certain
patients, a causal role for antidepressants in inducing such behaviors has not
been established. Nevertheless, patients being treated with antidepressants
should be observed closely for clinical worsening and suicidality, especially
at the beginning of a course of drug therapy, or at the time of dose changes,
either increases or decreases.
Consideration should be given to changing the therapeutic regimen,
including possibly discontinuing the medication, in patients whose depression
is persistently worse or whose emergent suicidality is severe, abrupt in onset,
or was not part of the patient's presenting symptoms.
Because of the possibility of co-morbidity between major depressive
disorder and other psychiatric and nonpsychiatric disorders, the same precautions
observed when treating patients with major depressive disorder should be observed
when treating patients with other psychiatric and nonpsychiatric disorders.
The following symptoms, anxiety, agitation, panic attacks,
insomnia, irritability, hostility (aggressiveness), impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania, have been reported in adult and pediatric
patients being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric. Although
a causal link between the emergence of such symptoms and either the worsening
of depression and/or the emergence of suicidal impulses has not been established,
consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients for whom such symptoms are
severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants
for major depressive disorder or other indications, both psychiatric and nonpsychiatric,
should be alerted about the need to monitor patients for the emergence of agitation,
irritability, and the other symptoms described above, as well as the emergence
of suicidality, and to report such symptoms immediately to health care providers.
Prescriptions for PAXIL should be written for the smallest quantity of tablets
consistent with good patient management, in order to reduce the risk of overdose.
If the decision has been made to discontinue treatment, medication
should be tapered, as rapidly as is feasible, but with recognition that abrupt
discontinuation can be associated with certain symptoms (see PRECAUTIONS
and DOSAGE AND
ADMINISTRATION—Discontinuation of Treatment With PAXIL, for a description
of the risks of discontinuation of PAXIL).
It should be noted that PAXIL is not approved for use in treating
any indications in the pediatric population.
A major depressive episode may be the initial presentation
of bipolar disorder. It is generally believed (though not established in controlled
trials) that treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a mixed/manic episode in patients at risk
for bipolar disorder. Whether any of the symptoms described above represent
such a conversion is unknown. However, prior to initiating treatment with an
antidepressant, patients should be adequately screened to determine if they
are at risk for bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder, and depression.
It should be noted that PAXIL is not approved for use in treating bipolar depression.
PRECAUTIONS
General
Activation of Mania/Hypomania
During premarketing testing, hypomania or mania occurred in
approximately 1.0% of unipolar patients treated with PAXIL compared to 1.1%
of active-control and 0.3% of placebo-treated unipolar patients. In a subset
of patients classified as bipolar, the rate of manic episodes was 2.2% for PAXIL
and 11.6% for the combined active-control groups. As with all drugs effective
in the treatment of major depressive disorder, PAXIL should be used cautiously
in patients with a history of mania.
Seizures
During premarketing testing, seizures occurred in 0.1% of patients
treated with PAXIL, a rate similar to that associated with other drugs effective
in the treatment of major depressive disorder. PAXIL should be used cautiously
in patients with a history of seizures. It should be discontinued in any patient
who develops seizures.
Discontinuation of Treatment With PAXIL
Recent clinical trials supporting the various approved indications
for PAXIL employed a taper-phase regimen, rather than an abrupt discontinuation
of treatment. The taper-phase regimen used in GAD and PTSD clinical trials involved
an incremental decrease in the daily dose by 10 mg/day at weekly intervals.
When a daily dose of 20 mg/day was reached, patients were continued on this
dose for 1 week before treatment was stopped.
With this regimen in those studies, the following adverse events
were reported at an incidence of 2% or greater for PAXIL and were at least twice
that reported for placebo: Abnormal dreams, paresthesia, and dizziness. In the
majority of patients, these events were mild to moderate and were self-limiting
and did not require medical intervention.
During marketing of PAXIL and other SSRIs and SNRIs (serotonin
and norepinephrine reuptake inhibitors), there have been spontaneous reports
of adverse events occurring, upon the discontinuation of these drugs (particularly
when abrupt), including the following: Dysphoric mood, irritability, agitation,
dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations),
anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.
While these events are generally self-limiting, there have been reports of serious
discontinuation symptoms.
Patients should be monitored for these symptoms when discontinuing
treatment with PAXIL. A gradual reduction in the dose rather than abrupt cessation
is recommended whenever possible. If intolerable symptoms occur following a
decrease in the dose or upon discontinuation of treatment, then resuming the
previously prescribed dose may be considered. Subsequently, the physician may
continue decreasing the dose but at a more gradual rate (see DOSAGE
AND ADMINISTRATION).
Hyponatremia
Several cases of hyponatremia have been reported. The hyponatremia
appeared to be reversible when PAXIL was discontinued. The majority of these
occurrences have been in elderly individuals, some in patients taking diuretics
or who were otherwise volume depleted.
Abnormal Bleeding
Published case reports have documented the occurrence of bleeding
episodes in patients treated with psychotropic agents that interfere with serotonin
reuptake. Subsequent epidemiological studies, both of the case-control and cohort
design, have demonstrated an association between use of psychotropic drugs that
interfere with serotonin reuptake and the occurrence of upper gastrointestinal
bleeding. In 2 studies, concurrent use of a nonsteroidal anti-inflammatory drug
(NSAID) or aspirin potentiated the risk of bleeding (see Drug
Interactions). Although these studies focused on upper gastrointestinal
bleeding, there is reason to believe that bleeding at other sites may be similarly
potentiated. Patients should be cautioned regarding the risk of bleeding associated
with the concomitant use of paroxetine with NSAIDs, aspirin, or other drugs
that affect coagulation.
Use in Patients With Concomitant Illness
Clinical experience with PAXIL in patients with certain concomitant
systemic illness is limited. Caution is advisable in using PAXIL in patients
with diseases or conditions that could affect metabolism or hemodynamic responses.
As with other SSRIs, mydriasis has been infrequently reported
in premarketing studies with PAXIL. A few cases of acute angle closure glaucoma
associated with paroxetine therapy have been reported in the literature. As
mydriasis can cause acute angle closure in patients with narrow angle glaucoma,
caution should be used when PAXIL is prescribed for patients with narrow angle
glaucoma.
PAXIL has not been evaluated or used to any appreciable extent
in patients with a recent history of myocardial infarction or unstable heart
disease. Patients with these diagnoses were excluded from clinical studies during
the product’s premarket testing. Evaluation of electrocardiograms of 682 patients
who received PAXIL in double-blind, placebo-controlled trials, however, did
not indicate that PAXIL is associated with the development of significant ECG
abnormalities. Similarly, PAXIL does not cause any clinically important changes
in heart rate or blood pressure.
Increased plasma concentrations of paroxetine occur in patients
with severe renal impairment (creatinine clearance <30 mL/min.) or severe
hepatic impairment. A lower starting dose should be used in such patients (see
DOSAGE AND ADMINISTRATION).
INFORMATION FOR PATIENTS
Physicians are advised to discuss the following issues with
patients for whom they prescribe PAXIL: Patients and their families should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, impulsivity, akathisia, hypomania, mania,
worsening of depression, and suicidal ideation, especially early during antidepressant
treatment.
Such symptoms should be reported to the patient's physician,
especially if they are severe, abrupt in onset, or were not part of the patient's
presenting symptoms.
Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, Warfarin,
etc.)
Patients should be cautioned about the concomitant use of paroxetine
and NSAIDs, aspirin, or other drugs that affect coagulation since the combined
use of psychotropic drugs that interfere with serotonin reuptake and these agents
has been associated with an increased risk of bleeding.
Interference With Cognitive and Motor Performance
Any psychoactive drug may impair judgment, thinking, or motor
skills. Although in controlled studies PAXIL has not been shown to impair psychomotor
performance, patients should be cautioned about operating hazardous machinery,
including automobiles, until they are reasonably certain that therapy with PAXIL
does not affect their ability to engage in such activities.
Completing Course of Therapy
While patients may notice improvement with treatment with PAXIL
in 1 to 4 weeks, they should be advised to continue therapy as directed.
Concomitant Medication
Patients should be advised to inform their physician if they
are taking, or plan to take, any prescription or over-the-counter drugs, since
there is a potential for interactions.
Alcohol
Although PAXIL has not been shown to increase the impairment
of mental and motor skills caused by alcohol, patients should be advised to
avoid alcohol while taking PAXIL.
Pregnancy
Patients should be advised to notify their physician if they
become pregnant or intend to become pregnant during therapy.
Nursing
Patients should be advised to notify their physician if they
are breast-feeding an infant (see PRECAUTIONS—Nursing
Mothers).
Laboratory Tests
There are no specific laboratory tests recommended.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Two-year carcinogenicity studies were conducted in rodents
given paroxetine in the diet at 1, 5, and 25 mg/kg/day (mice) and 1, 5, and
20 mg/kg/day (rats). These doses are up to 2.4 (mouse) and 3.9 (rat) times the
maximum recommended human dose (MRHD) for major depressive disorder, social
anxiety disorder, GAD, and PTSD on a mg/m2 basis. Because the MRHD
for major depressive disorder is slightly less than that for OCD (50 mg versus
60 mg), the doses used in these carcinogenicity studies were only 2.0 (mouse)
and 3.2 (rat) times the MRHD for OCD. There was a significantly greater number
of male rats in the high-dose group with reticulum cell sarcomas (1/100, 0/50,
0/50, and 4/50 for control, low-, middle-, and high-dose groups, respectively)
and a significantly increased linear trend across dose groups for the occurrence
of lymphoreticular tumors in male rats. Female rats were not affected. Although
there was a dose-related increase in the number of tumors in mice, there was
no drug-related increase in the number of mice with tumors. The relevance of
these findings to humans is unknown.
Mutagenesis
Paroxetine produced no genotoxic effects in a battery of 5
in vitro and 2 in vivo assays that included the following: Bacterial mutation
assay, mouse lymphoma mutation assay, unscheduled DNA synthesis assay, and tests
for cytogenetic aberrations in vivo in mouse bone marrow and in vitro in human
lymphocytes and in a dominant lethal test in rats.
Impairment of Fertility
A reduced pregnancy rate was found in reproduction studies
in rats at a dose of paroxetine of 15 mg/kg/day, which is 2.9 times the MRHD
for major depressive disorder, social anxiety disorder, GAD, and PTSD or 2.4
times the MRHD for OCD on a mg/m2 basis. Irreversible lesions occurred
in the reproductive tract of male rats after dosing in toxicity studies for
2 to 52 weeks. These lesions consisted of vacuolation of epididymal tubular
epithelium at 50 mg/kg/day and atrophic changes in the seminiferous tubules
of the testes with arrested spermatogenesis at 25 mg/kg/day (9.8 and 4.9 times
the MRHD for major depressive disorder, social anxiety disorder, and GAD; 8.2
and 4.1 times the MRHD for OCD and PD on a mg/m2 basis).
Pregnancy
Teratogenic Effects
Pregnancy Category C. Reproduction studies were performed at
doses up to 50 mg/kg/day in rats and 6 mg/kg/day in rabbits administered during
organogenesis. These doses are equivalent to 9.7 (rat) and 2.2 (rabbit) times
the maximum recommended human dose (MRHD) for major depressive disorder, social
anxiety disorder, GAD, and PTSD (50 mg) and 8.1 (rat) and 1.9 (rabbit) times
the MRHD for OCD, on an mg/m2 basis. These studies have revealed
no evidence of teratogenic effects. However, in rats, there was an increase
in pup deaths during the first 4 days of lactation when dosing occurred during
the last trimester of gestation and continued throughout lactation. This effect
occurred at a dose of 1 mg/kg/day or 0.19 times (mg/m2) the MRHD
for major depressive disorder, social anxiety disorder, GAD, and PTSD; and at
0.16 times (mg/m2) the MRHD for OCD. The no-effect dose for rat pup
mortality was not determined. The cause of these deaths is not known. There
are no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, this drug
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
Nonteratogenic Effects
Neonates exposed to PAXIL and other SSRIs or SNRIs, late in
the third trimester have developed complications requiring prolonged hospitalization,
respiratory support, and tube feeding. Such complications can arise immediately
upon delivery. Reported clinical findings have included respiratory distress,
cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting,
hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability,
and constant crying. These features are consistent with either a direct toxic
effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It
should be noted, in some cases, the clinical picture is consistent with serotonin
syndrome (see WARNINGS—Potential for
Interaction With Monoamine Oxidase Inhibitors). When treating a pregnant woman
with paroxetine during the third trimester, the physician should carefully consider
the potential risks and benefits of treatment (see DOSAGE
AND ADMINISTRATION).
Labor and Delivery
The effect of paroxetine on labor and delivery in humans is
unknown.
Nursing Mothers
Like many other drugs, paroxetine is secreted in human milk,
and caution should be exercised when PAXIL is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have not
been established (see WARNINGS—Clinical
Worsening and Suicide Risk).
Geriatric Use
In worldwide premarketing clinical trials with PAXIL, 17% of
patients treated with PAXIL (approximately 700) were 65 years of age or older.
Pharmacokinetic studies revealed a decreased clearance in the elderly, and a
lower starting dose is recommended; there were, however, no overall differences
in the adverse event profile between elderly and younger patients, and effectiveness
was similar in younger and older patients (see CLINICAL
PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
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