"The U.S. Food and Drug Administration today approved the first generic versions of Cymbalta (duloxetine delayed-release capsules), a prescription medicine used to treat depression and other conditions.
Aurobindo Pharma Ltd., Dr. Reddy's La"...
WARNINGS TO PHYSICIANS
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 longstanding 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 18-24) 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.
The pooled analyses of placebo-controlled trials of nine antidepressant drugs (SSRIs) and others) in children and adolescents with MDD, Obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk among drugs, but a tendency toward an increase in the younger patients `for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
|Age Range||Drug-Placebo Difference in Number of Cases of Suicidality Per 1000 Patients Treated|
|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|
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 casual 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.
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 if suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for MARPLAN (isocarboxazid) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose
Screening Patients for Bipolar Disorder
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 these symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms 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 MARPLAN (isocarboxazid) is not approved for use in treating bipolar depression.
WARNINGS: Second Line Status
Marplan (isocarboxazid) can cause serious side effects. It is not recommended as initial therapy but should be reserved for patients who have not responded satisfactorily to other antidepressants.
The most important reaction associated with MAO inhibitors is the occurrence of hypertensive crises, which have sometimes been fatal, resulting from the co-administration of MAOIs and certain drugs and foods (see CONTRAINDICATIONS).
These crises are characterized by some or all of the following symptoms: occipital headache which may radiate frontally, palpitation, neck stiffness or soreness, nausea or vomiting, sweating (sometimes with fever and sometimes with cold, clammy skin), and photophobia. Either tachycardia or bradycardia may be present, and associated constricting chest pain and dilated pupils may occur. Intracranial bleeding, sometimes fatal, has been reported in association with the increase in blood pressure.
Blood pressure should be followed closely in patients taking Marplan (isocarboxazid) to detect any pressor response.
Therapy should be discontinued immediately if palpitations or frequent headaches occur during Marplan (isocarboxazid) therapy as these symptoms may be prodromal of a hypertensive crisis.
If a hypertensive crisis occurs, Marplan (isocarboxazid) should be discontinued, and therapy to lower blood pressure should be instituted immediately. Although there has been no systematic study of treatment of hypertensive crisis, phentolamine (available as Regitine®, Novartis) has been used and is recommended at a dosage of 5 mg IV. Care should be taken to administer the drug slowly in order to avoid producing an excessive hypotensive effect. Fever should be managed by means of external cooling. Other symptomatic and supportive measures may be desirable in particular cases. Parenteral reserpine should not be used.
Warnings to the Patient
Patients should be instructed to report promptly the occurrence of headache or other unusual symptoms, i.e., palpitation and/or tachycardia, a sense of constriction in the throat or chest, sweating, dizziness, neck stiffness, nausea, or vomiting. Patients should be warned against eating the foods listed under CONTRAINDICATIONS while on Marplan (isocarboxazid) therapy and should also be told not to drink alcoholic beverages. The patient should also be warned about the possibility of hypotension and faintness, as well as drowsiness sufficient to impair performance of potentially hazardous tasks, such as driving a car or operating machinery.
Patients should also be cautioned not to take concomitant medications, whether prescription or over-the-counter drugs such as cold, hay fever, or weight-reducing preparations, without the advice of a physician. They should be advised not to consume excessive amounts of caffeine in any form. Likewise, they should inform their physicians and their dentist about the use of Marplan (isocarboxazid) .
Limited Experience With Marplan (isocarboxazid) at Higher Doses
Because of the limited experience with systematically monitored patients receiving Marplan (isocarboxazid) at the higher end of the currently recommended dose range of up to 60 mg/day, caution is indicated in patients for whom a dose of 40 mg/day is exceeded (see ADVERSE REACTIONS).
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 Marplan (isocarboxazid) and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medications, Depression and Other Serious Mental Illness, and Suicidal Thoughts and Actions” is available for Marplan (isocarboxazid) . 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 Marplan (isocarboxazid) .
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS-Clinical Worsening and Suicide Risk). Anyone considering the use of Marplan (isocarboxazid) in a child or adolescent must balance the potential risks with the clinical need.
Hypotension has been observed during Marplan (isocarboxazid) therapy. Symptoms of postural hypotension are seen most commonly, but not exclusively, in patients with preexistent hypertension; blood pressure usually returns rapidly to pretreatment levels upon discontinuation of the drug. Dosage increases should be made more gradually in patients showing a tendency toward hypotension at the beginning of therapy. Postural hypotension may be relieved by having the patient lie down until blood pressure returns to normal.
When Marplan (isocarboxazid) is combined with phenothiazine derivatives or other compounds known to cause hypotension, the possibility of additive hypotensive effects should be considered.
Lower Seizure Threshold
Because Marplan (isocarboxazid) lowers the convulsive threshold in some animal experiments, suitable precautions should be taken if epileptic patients are treated. Marplan (isocarboxazid) appears to have varying effects in epileptic patients; while some have a decrease in frequency of seizures, other have more seizures.
Drugs that lower the seizure threshold, including MAO inhibitors, should not be used with Amipaque® (metrizamide, Sanofi Winthrop Pharmaceuticals). As with other MAO inhibitors, Marplan (isocarboxazid) should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
There is a low incidence of altered liver function or jaundice in patients treated with Marplan (isocarboxazid) . In the past, it was difficult to differentiate most cases of drug-induced hepatocellular jaundice from viral hepatitis although this is no longer true. Periodic liver chemistry tests should be performed during Marplan (isocarboxazid) therapy; use of the drug should be discontinued at the first sign of hepatic dysfunction or jaundice.
In depressed patients, the possibility of suicide should always be considered and adequate precautions taken. Exclusive reliance on drug therapy to prevent suicidal attempts is unwarranted, as there may be a delay in the onset of therapeutic effect or an increase in anxiety or agitation. Also, some patients fail to respond to drug therapy or may respond only temporarily. The strictest supervision, and preferably hospitalization, are required.
Use in Patients With Concomitant Illness
MAO inhibitors can suppress anginal pain that would otherwise serve as a warning of myocardial ischemia.
In patients with impaired renal function, Marplan (isocarboxazid) should be used cautiously to prevent accumulation.
Some MAO inhibitors have contributed to hypoglycemic episodes in diabetic patients receiving insulin or glycemic agents. Marplan (isocarboxazid) should therefore be used with caution in diabetics using these drugs.
Marplan (isocarboxazid) may aggravate coexisting symptoms in depression, such as anxiety and agitation.
Use Marplan (isocarboxazid) with caution in hyperthyroid patients because of their increased sensitivity to pressor amines.
Marplan (isocarboxazid) should be used cautiously in hyperactive or agitated patients, as well as in schizophrenic patients, because it may cause excessive stimulation. Activation of mania/hypomania has been reported in a small proportion of patients with major affective disorder who were treated with marketed antidepressants.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies to evaluate carcinogenic potential have not been conducted with this drug, and there is no information concerning mutagenesis or impairment of fertility.
Pregnancy Category C
The potential reproductive toxicity of isocarboxazid has not been adequately evaluated in animals. It is also not known whether isocarboxazid can cause embryo/fetal harm when administered to a pregnant woman or can affect reproductive capacity. Marplan (isocarboxazid) should be given to a pregnant woman only if clearly needed.
Levels of excretion of isocarboxazid and/or its metabolites in human milk have not been determined, and effects on the nursing infant are unknown. Marplan (isocarboxazid) should be used in women who are nursing only if clearly needed.
Marplan (isocarboxazid) is not recommended for use in patients under 16 years of age, as safety and effectiveness in pediatric populations have not been demonstrated.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 9/14/2007
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