Suicidality in Children and Adolescents
Suicidality in Children and Adolescents
DESCRIPTION
CLINICAL PHARMACOLOGY
Pharmacodynamics
Pharmacokinetics
Absorption and Distribution
Metabolism and Excretion
Other Clinical Pharmacology Information
Specific Populations
Drug-Drug Interactions
Clinical Trials
Major Depressive Disorder
Obsessive Compulsive Disorder
| Worse | 14% | 7% | 7% | 3% |
| No Change | 44% | 35% | 22% | 19% |
| Minimally Improved | 24% | 33% | 29% | 34% |
| Much Improved | 11% | 18% | 22% | 24% |
| Very Much Improved | 7% | 7% | 20% | 20% |
Panic Disorder
Generalized Anxiety Disorder
INDICATIONS AND USAGE
Major Depressive Disorder
Obsessive Compulsive Disorder
Panic Disorder
Generalized Anxiety Disorder
CONTRAINDICATIONS
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
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, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
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 Paroxetine Tablets), for a description of the risks of discontinuation of paroxetine.
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, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for paroxetine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
| Increases Compared to Placebo | |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Decreases Compared to Placebo | |
| 25-64 | 1 fewer case |
| ≥65 | 6 fewer cases |
Screening Patients for Bipolar Disorder
Potential for Interaction With Monoamine Oxidase Inhibitors
Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions
Treatment with paroxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.
Potential Interaction With Thioridazine
Usage in Pregnancy
Teratogenic Effects
Animal Findings
Nonteratogenic Effects
Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN). PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality. In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy. There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk. The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.
There have also been postmarketing reports of premature births in pregnant women exposed to paroxetine or other SSRIs.
PRECAUTIONS
General
Activation of Mania/Hypomania
Seizures
Discontinuation of Treatment With Paroxetine Tablets
Akathisia
Hyponatremia
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.
Abnormal Bleeding
Use in Patients With Concomitant Illness
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with paroxetineand should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for paroxetine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking paroxetine.
Clinical Worsening and Suicide Risk
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Interference With Cognitive and Motor Performance
Completing Course of Therapy
Concomitant Medication
Alcohol
Pregnancy
Nursing
Laboratory Tests
There are no specific laboratory tests recommended.
Drug Interactions
Tryptophan
Monoamine Oxidase Inhibitors
Pimozide
Serotonergic Drugs
Thioridazine
Warfarin
Triptans
Drugs Affecting Hepatic Metabolism
Cimetidine
Phenobarbital
Phenytoin
Drugs Metabolized by CYP2D6
Drugs Metabolized by Cytochrome CYP3A4
Tricyclic Antidepressants (TCAs)
Drugs Highly Bound to Plasma Protein
Drugs That Interfere With Hemostasis (e.g., NSAIDs, Aspirin, and Warfarin)
Alcohol
Lithium
Digoxin
Diazepam
Procyclidine
Beta-Blockers
Theophylline
Fosamprenavir/Ritonavir
Electroconvulsive Therapy (ECT)
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Mutagenesis
Impairment of Fertility
Pregnancy
See WARNINGS—Usage in Pregnancy: Teratogenic and Nonteratogenic Effects.
Labor and Delivery
The effect of paroxetine on labor and delivery in humans is unknown.
Nursing Mothers
Pediatric Use
Geriatric Use
ADVERSE REACTIONS
Associated With Discontinuation of Treatment
| CNS | ||||||||
| Somnolence | 2.3% | 0.7% | — | 1.9% | 0.3% | 2% | 0.2% | |
| Insomnia | — | — | 1.7% | 0% | 1.3% | 0.3% | ||
| Agitation | 1.1% | 0.5% | — | |||||
| Tremor | 1.1% | 0.3% | — | |||||
| Anxiety | — | — | — | |||||
| Dizziness | — | — | 1.5% | 0% | 1% | 0.2% | ||
| Gastrointestinal | ||||||||
| Constipation | — | 1.1% | 0% | |||||
| Nausea | 3.2% | 1.1% | 1.9% | 0% | 3.2% | 1.2% | 2% | 0.2% |
| Diarrhea | 1% | 0.3% | — | |||||
| Dry mouth | 1% | 0.3% | — | |||||
| Vomiting | 1% | 0.3% | — | |||||
| Flatulence | ||||||||
| Other | ||||||||
| Asthenia | 1.6% | 0.4% | 1.9% | 0.4% | 1.8% | 0.2% | ||
| Abnormal ejaculation1 | 1.6% | 0% | 2.1% | 0% | 2.5% | 0.5% | ||
| Sweating | 1% | 0.3% | — | 1.1% | 0.2% | |||
| Impotence1 | — | 1.5% | 0% | |||||
| Libido Decreased |
Commonly Observed Adverse Events
Major Depressive Disorder
Obsessive Compulsive Disorder
Panic Disorder
Generalized Anxiety Disorder
Incidence in Controlled Clinical Trials
Major Depressive Disorder
2. Includes mostly “lump in throat” and “tightness in throat.”
3. Percentage corrected for gender.
4. Mostly “ejaculatory delay.”
5. Includes “anorgasmia,” “erectile difficulties,” “delayed ejaculation/orgasm,” and “sexual dysfunction,” and “impotence.”
6. Includes mostly “difficulty with micturition” and “urinary hesitancy.”
7. Includes mostly “anorgasmia” and “difficulty reaching climax/orgasm.”
| Body as a Whole | HeadacheAsthenia | 18% 15% | 17% 6% |
| Cardiovascular | PalpitationVasodilation | 3% 3% | 1% 1% |
| Dermatologic | SweatingRash | 11% 2% | 2% 1% |
| Gastrointestinal | NauseaDry MouthConstipationDiarrheaDecreased AppetiteFlatulenceOropharynx Disorder2Dyspepsia | 26% 18% 14% 12% 6% 4% 2% 2% | 9% 12% 9% 8% 2% 2% 0% 1% |
| Musculoskeletal | MyopathyMyalgiaMyasthenia | 2% 2% 1% | 1% 1% 0% |
| Nervous System | SomnolenceDizzinessInsomniaTremorNervousnessAnxietyParesthesiaLibido DecreasedDrugged FeelingConfusion | 23% 13% 13% 8% 5% 5% 4% 3% 2% 1% | 9% 6% 6% 2% 3% 3% 2% 0% 1% 0% |
| Respiration | Yawn | 4% | 0% |
| Special Senses | Blurred VisionTaste Perversion | 4% 2% | 1% 0% |
| Urogenital System | Ejaculatory Disturbance3,4Other Male Genital Disorders3,5Urinary FrequencyUrination Disorder6Female Genital Disorders3,7 | 13% 10% 3% 3% 2% | 0% 0% 1% 0% 0% |
- Events reported by at least 1% of patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: Abdominal pain, agitation, back pain, chest pain, CNS stimulation, fever, increased appetite, myoclonus, pharyngitis, postural hypotension, respiratory disorder includes mostly “cold symptoms” or “URI”), trauma, and vomiting.
Obsessive Compulsive Disorder and Panic Disorder
| Body as a Whole | Asthenia | 22% | 14% | 14% | 5% |
| Abdominal Pain | — | — | 4% | 3% | |
| Chest Pain | 3% | 2% | — | — | |
| Back Pain | — | — | 3% | 2% | |
| Chills | 2% | 1% | 2% | 1% | |
| Trauma | — | — | — | — | |
| Cardiovascular | Vasodilation | 4% | 1% | — | — |
| Palpitation | 2% | 0% | — | — | |
| Dermatologic | Sweating | 9% | 3% | 14% | 6% |
| Rash | 3% | 2% | — | — | |
| Gastrointestinal | Nausea | 23% | 10% | 23% | 17% |
| Dry Mouth | 18% | 9% | 18% | 11% | |
| Constipation | 16% | 6% | 8% | 5% | |
| Diarrhea | 10% | 10% | 12% | 7% | |
| Decreased Appetite | 9% | 3% | 7% | 3% | |
| Dyspepsia | — | — | — | — | |
| Flatulence | — | — | — | — | |
| Increased Appetite | 4% | 3% | 2% | 1% | |
| Vomiting | — | — | — | — | |
| Musculoskeletal | Myalgia | — | — | — | — |
| Nervous System | Insomnia | 24% | 13% | 18% | 10% |
| Somnolence | 24% | 7% | 19% | 11% | |
| Dizziness | 12% | 6% | 14% | 10% | |
| Tremor | 11% | 1% | 9% | 1% | |
| Nervousness | 9% | 8% | — | — | |
| Libido Decreased | 7% | 4% | 9% | 1% | |
| Agitation | — | — | 5% | 4% | |
| Anxiety | — | — | 5% | 4% | |
| Abnormal Dreams | 4% | 1% | — | — | |
| Concentration Impaired | 3% | 2% | — | — | |
| Depersonalization | 3% | 0% | — | — | |
| Myoclonus | 3% | 0% | 3% | 2% | |
| Amnesia | 2% | 1% | — | — | |
| Respiratory System | Rhinitis | — | — | 3% | 0% |
| Pharyngitis | — | — | — | — | |
| Yawn | — | — | — | — | |
| Special Senses | Abnormal Vision | 4% | 2% | — | — |
| Taste Perversion | 2% | 0% | — | — | |
| Urogenital System | Abnormal Ejaculation2 | 23% | 1% | 21% | 1% |
| Dysmenorrhea | — | — | — | — | |
| Female GenitalDisorder2 | 3% | 0% | 9% | 1% | |
| Impotence2 | 8% | 1% | 5% | 0% | |
| Urinary Frequency | 3% | 1% | 2% | 0% | |
| Urination Impaired | 3% | 0% | — | — | |
| Urinary TractInfection | 2% | 1% | 2% | 1% |
- Events reported by at least 2% of OCD and panic disorder in patients treated with paroxetine are included, except the following events which had an incidence on placebo ≥ paroxetine: [OCD]: Abdominal pain, agitation, anxiety, back pain, cough increased, depression, headache, hyperkinesia, infection, paresthesia, pharyngitis, respiratory disorder, rhinitis, and sinusitis. [panic disorder]: Abnormal dreams, abnormal vision, chest pain, cough increased, depersonalization, depression, dysmenorrhea, dyspepsia, flu syndrome, headache, infection, myalgia, nervousness, palpitation, paresthesia, pharyngitis, rash, respiratory disorder, sinusitis, taste perversion, trauma, urination impaired, and vasodilation.
- Percentage corrected for gender.
Generalized Anxiety Disorder
| Body as a Whole | Asthenia | 14% | 6% |
| Headache | 17% | 14% | |
| Infection | 6% | 3% | |
| Abdominal Pain | |||
| Trauma | |||
| Cardiovascular | Vasodilation | 3% | 1% |
| Dermatologic | Sweating | 6% | 2% |
| Gastrointestinal | Nausea | 20% | 5% |
| Dry Mouth | 11% | 5% | |
| Constipation | 10% | 2% | |
| Diarrhea | 9% | 7% | |
| Decreased Appetite | 5% | 1% | |
| Vomiting | 3% | 2% | |
| Dyspepsia | — | — | |
| Nervous System | Insomnia | 11% | 8% |
| Somnolence | 15% | 5% | |
| Dizziness | 6% | 5% | |
| Tremor | 5% | 1% | |
| Nervousness | 4% | 3% | |
| Libido Decreased | 9% | 2% | |
| Abnormal Dreams | |||
| Respiratory System | Respiratory Disorder | 7% | 5% |
| Sinusitis | 4% | 3% | |
| Yawn | 4% | — | |
| Special Senses | Abnormal Vision | 2% | 1% |
| Urogenital System | Abnormal Ejaculation2 | 25% | 2% |
| Female Genital Disorder2 | 4% | 1% | |
| Impotence2 | 4% | 3% |
- Events reported by at least 2% of GAD in patients treated with paroxetine are included, except the following events whichhad an incidence on placebo ≥ paroxetine [GAD]: Abdominal pain, back pain, trauma, dyspepsia, myalgia, and pharyngitis.
Dose Dependency of Adverse Events
| Body as a Whole | |||||
| Asthenia | 0% | 2.9% | 10.6% | 13.9% | 12.7% |
| Dermatology | |||||
| Sweating | 2% | 1% | 6.7% | 8.9% | 11.8% |
| Gastrointestinal | |||||
| Constipation | 5.9% | 4.9% | 7.7% | 9.9% | 12.7% |
| Decreased Appetite | 2% | 2% | 5.8% | 4% | 4.9% |
| Diarrhea | 7.8% | 9.8% | 19.2% | 7.9% | 14.7% |
| Dry Mouth | 2% | 10.8% | 18.3% | 15.8% | 20.6% |
| Nausea | 13.7% | 14.7% | 26.9% | 34.7% | 36.3% |
| Nervous System | |||||
| Anxiety | 0% | 2% | 5.8% | 5.9% | 5.9% |
| Dizziness | 3.9% | 6.9% | 6.7% | 8.9% | 12.7% |
| Nervousness | 0% | 5.9% | 5.8% | 4.0% | 2.9% |
| Paresthesia | 0% | 2.9% | 1% | 5% | 5.9% |
| Somnolence | 7.8% | 12.7% | 18.3% | 20.8% | 21.6% |
| Tremor | 0% | 0% | 7.7% | 7.9% | 14.7% |
| Special Senses | |||||
| Blurred Vision | 2% | 2.9% | 2.9% | 2% | 7.8% |
| Urogenital System | |||||
| Abnormal Ejaculation | 0% | 5.8% | 6.5% | 10.6% | 13% |
| Impotence | 0% | 1.9% | 4.3% | 6.4% | 1.9% |
| Male Genital Disorders | 0% | 3.8% | 8.7% | 6.4% | 3.7% |
Adaptation to Certain Adverse Events
Male and Female Sexual Dysfunction With SSRIs
| n (males) | 1446 | 1042 |
| Decreased Libido | 6-15% | 0-5% |
| Ejaculatory Disturbance | 13-28% | 0-2% |
| Impotence | 2-9% | 0-3% |
| n (females) | 1822 | 1340 |
| Decreased Libido | 0-9% | 0-2% |
| Orgasmic Disturbance | 2-9% | 0-1% |
Weight and Vital Sign Changes
ECG Changes
Liver Function Tests
Hallucinations
Other Events Observed During the Premarketing Evaluation of Paroxetine
Body as a Whole
Cardiovascular System
Digestive System
Endocrine System
Hemic and Lymphatic Systems
Metabolic and Nutritional
Musculoskeletal System
Nervous System
Respiratory System
Skin and Appendages
Special Senses
Urogenital System
Postmarketing Reports
Voluntary reports of adverse events in patients taking paroxetine that have been received since market introduction and not listed above that may have no causal relationship with the drug include acute pancreatitis, elevated liver function tests (the most severe cases were deaths due to liver necrosis, and grossly elevated transaminases associated with severe liver dysfunction), Guillain-Barré syndrome, toxic epidermal necrolysis, priapism, syndrome of inappropriate ADH secretion, symptoms suggestive of prolactinemia and galactorrhea; extrapyramidal symptoms which have included akathisia, bradykinesia, cogwheel rigidity, dystonia, hypertonia, oculogyric crisis which has been associated with concomitant use of pimozide; tremor and trismus; status epilepticus, acute renal failure, pulmonary hypertension, allergic alveolitis, anaphylaxis, eclampsia, laryngismus, optic neuritis, porphyria, ventricular fibrillation, ventricular tachycardia (including torsade de pointes), thrombocytopenia, hemolytic anemia, events related to impaired hematopoiesis (including aplastic anemia, pancytopenia, bone marrow aplasia, and agranulocytosis), and vasculitic syndromes (such as Henoch-Schönlein purpura). There has been a case report of an elevated phenytoin level after 4 weeks of paroxetine and phenytoin coadministration. There has been a case report of severe hypotension when paroxetine was added to chronic metoprolol treatment.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
Physical and Psychologic Dependence
Paroxetine has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of misuse or abuse of paroxetine (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).
OVERDOSAGE
Human Experience
Overdosage Management
DOSAGE AND ADMINISTRATION
Major Depressive Disorder
Usual Initial Dosage
Maintenance Therapy
Obsessive Compulsive Disorder
Usual Initial Dosage
Maintenance Therapy
Panic Disorder
Usual Initial Dosage
Maintenance Therapy
Generalized Anxiety Disorder
Usual Initial Dosage
Maintenance Therapy
Special Populations
Treatment of Pregnant Women During the Third Trimester
Dosage for Elderly or Debilitated Patients, and Patients With Severe Renal or Hepatic Impairment
Switching Patients to or From a Monoamine Oxidase Inhibitor
Discontinuation of Treatment With Paroxetine Tablets
HOW SUPPLIED
They are supplied by State of Florida DOH Central Pharmacy as follows:
This Product was Repackaged By:
State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 United States
| 53808-0749-1 | 20 mg | 30 Tablets in a Blister Pack | PINK | 65862-155 |
| 53808-0752-1 | 30 mg | 30 Tablets in a Blister Pack | BLUE | 65862-156 |
| 53808-0756-1 | 40 mg | 30 Tablets in a Blister Pack | PINK | 65862-157 |
MEDICATION GUIDE
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
What else do I need to know about antidepressant medicines?
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
- all risks and benefits of treatment with antidepressant medicines
- all treatment choices for depression or other serious mental illness