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Khedezla

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicidal Thoughts And Behaviors In Adolescents And Young Adults

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 studies 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.

The pooled analyses of placebo-controlled studies in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term studies of 9 antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled studies in adults with MDD or other psychiatric disorders included a total of 295 short-term studies (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality 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 1,000 patients treated) are provided in Table 1.

Table 1

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 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 studies. There were suicides in the adult studies, 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 studies 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 DOSAGE AND ADMINISTRATION].

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 KHEDEZLA 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 studies) 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 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 KHEDEZLA is not approved for use in treating bipolar depression.

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including desvenlafaxine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort), and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of KHEDEZLA with MAOIs intended to treat psychiatric disorders is contraindicated. KHEDEZLA should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking d KHEDEZLA. KHEDEZLA should be discontinued before initiating treatment with the MAOI [see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION].

If concomitant use of KHEDEZLA with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with KHEDEZLA and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Elevated Blood Pressure

Patients receiving KHEDEZLA should have regular monitoring of blood pressure since increases in blood pressure were observed in clinical studies [see ADVERSE REACTIONS]. Pre-existing hypertension should be controlled before initiating treatment with desvenlafaxine. Caution should be exercised in treating patients with pre-existing hypertension, cardiovascular, or cerebrovascular conditions that might be compromised by increases in blood pressure. Cases of elevated blood pressure requiring immediate treatment have been reported with desvenlafaxine.

Sustained blood pressure increases could have adverse consequences. For patients who experience a sustained increase in blood pressure while receiving KHEDEZLA, either dose reduction or discontinuation should be considered [see ADVERSE REACTIONS].

Abnormal Bleeding

SSRIs and SNRIs, including KHEDEZLA, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs have ranged from ecchymosis, hematoma, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of desvenlafaxine and NSAIDs, aspirin, or other drugs that affect coagulation or bleeding.

Angle Closure Glaucoma

Angle-Closure Glaucoma: The pupillary dilation that occurs following the use of many antidepressant drugs including Desvenlafaxine may trigger and angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Activation Of Mania/Hypomania

During all MDD phase 2 and phase 3 studies, mania was reported for approximately 0.02% of patients treated with desvenlafaxine. Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants. As with all antidepressants, KHEDEZLA should be used cautiously in patients with a history or family history of mania or hypomania.

Discontinuation Syndrome

Discontinuation symptoms have been systematically and prospectively evaluated in patients treated with desvenlafaxine during clinical studies in Major Depressive Disorder. Abrupt discontinuation or dose reduction has been associated with the appearance of new symptoms that include dizziness, nausea, headache, irritability, insomnia, diarrhea, anxiety, fatigue, abnormal dreams, and hyperhidrosis. In general, discontinuation events occurred more frequently with longer duration of therapy.

During marketing of SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), and SSRIs (Selective Serotonin Reuptake Inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesia, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. 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 KHEDEZLA. 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 and ADVERSE REACTIONS].

Seizure

Cases of seizure have been reported in pre-marketing clinical studies with desvenlafaxine. Desvenlafaxine has not been systematically evaluated in patients with a seizure disorder. Patients with a history of seizures were excluded from pre-marketing clinical studies. KHEDEZLA should be prescribed with caution in patients with a seizure disorder.

Hyponatremia

Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including KHEDEZLA. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs. Also, patients taking diuretics or who are otherwise volume depleted can be at greater risk [see Use in Specific Populations and CLINICAL PHARMACOLOGY]. Discontinuation of KHEDEZLA should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which can lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

Interstitial Lung Disease And Eosinophilic Pneumonia

Interstitial lung disease and eosinophilic pneumonia associated with venlafaxine (the parent drug of desvenlafaxine) therapy have been rarely reported. The possibility of these adverse events should be considered in patients treated with KHEDEZLA who present with progressive dyspnea, cough, or chest discomfort. Such patients should undergo a prompt medical evaluation, and discontinuation of KHEDEZLA should be considered.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide).

Advise patients, their families, and their caregivers about the benefits and risks associated with treatment with KHEDEZLA and counsel them in its appropriate use.

Advise patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. The complete text of the Medication Guide is reprinted at the end of this document.

Suicide Risk

Advise patients, their families and caregivers to look for the emergence of suicidality, especially early during treatment and when the dose is adjusted up or down [see BOXED WARNING and WARNINGS AND PRECAUTIONS].

Concomitant Medication

Advise patients taking KHEDEZLA Extended-release Tablets not to use concomitantly other products containing desvenlafaxine or venlafaxine. Healthcare professionals should instruct patients not to take KHEDEZLA with an MAOI or within 14 days of stopping an MAOI and to allow 7 days after stopping KHEDEZLA before starting an MAOI [see CONTRAINDICATIONS].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of KHEDEZLA with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John”s Wort supplements) [see WARNINGS AND PRECAUTIONS].

Elevated Blood Pressure

Advise patients that they should have regular monitoring of blood pressure when taking KHEDEZLA [see WARNINGS AND PRECAUTIONS].

Abnormal Bleeding

Patients should be cautioned about the concomitant use of KHEDEZLA and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [seeWARNINGS AND PRECAUTIONS].

Angle Closure Glaucoma

Patients should be advised that taking Desvenlafaxine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitely with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g. iridectomy), if they are susceptible [see WARNINGS AND PRECAUTIONS].

Activation of Mania/Hypomania

Advise patients, their families and caregivers to observe for signs of activation of mania/hypomania [see WARNINGS AND PRECAUTIONS].

Discontinuation

Advise patients not to stop taking KHEDEZLA without talking first with their healthcare professional. Patients should be aware that discontinuation effects may occur when stopping desvenlafaxine [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Switching Patients from Other Antidepressants to KHEDEZLA

Discontinuation symptoms have been reported when switching patients from other antidepressants, including venlafaxine, to desvenlafaxine. Tapering of the initial antidepressant may be necessary to minimize discontinuation symptoms.

Interference with Cognitive and Motor Performance

Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that KHEDEZLA therapy does not adversely affect their ability to engage in such activities.

Alcohol

Advise patients to avoid alcohol while taking KHEDEZLA [see DRUG INTERACTIONS].

Allergic Reactions

Advise patients to notify their physician if they develop allergic phenomena such as rash, hives, swelling, or difficulty breathing.

Pregnancy

Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations].

Nursing

Advise patients to notify their physician if they are breastfeeding an infant [see Use In Specific Populations].

Residual Inert Matrix Tablet

Patients receiving KHEDEZLA may notice an inert matrix tablet passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert matrix tablet.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study.

Mice received desvenlafaxine succinate at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The 300 mg/kg/day dose is 15 times a human dose of 100 mg/day on a mg/m² basis.

Rats received desvenlafaxine succinate at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The highest dose is 29 (males) or 48 (females) times a human dose of 100 mg/day on a mg/m² basis.

Mutagenesis

Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay.

Impairment Of Fertility

When desvenlafaxine succinate was administered orally to male and female rats, fertility was reduced at the high dose of 300 mg/kg/day, which is 30 times a human dose of 100 mg/day (on a mg/m² basis). There was no effect on fertility at 100 mg/kg/day, approximately 10 times a human dose of 100 mg/day (on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk summary

There are no adequate and well-controlled studies of KHEDEZLA in pregnant women. In reproductive developmental studies in rats and rabbits with desvenlafaxine succinate, evidence of teratogenicity was not observed at doses up to 30 times a human dose of 100 mg/day (on a mg/m² basis) in rats, and up to 15 times a human dose of 100 mg/day (on a mg/m² basis) in rabbits. An increase in rat pup deaths was seen during the first 4 days of lactation when dosing occurred during gestation and lactation, at doses greater than 10 times a human dose of 100 mg/day (on a mg/m² basis). KHEDEZLA should be used during pregnancy only if the potential benefits justify the potential risks to the fetus.

Clinical considerations

A prospective longitudinal study of 201 women with history of major depression who were euthymic at the beginning of pregnancy, showed women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

Human data

Neonates exposed to SNRIs (Serotonin and Norepinephrine Reuptake Inhibitors), or SSRIs (Selective Serotonin Reuptake Inhibitors), 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 that, in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS].

Animal data

When desvenlafaxine succinate was administered orally to pregnant rats and rabbits during the period of organogenesis at doses up to 300 mg/kg/day and 75 mg/kg/day, respectively, no teratogenic effects were observed. These doses are 30 times a human dose of 100 mg/day (on a mg/m² basis) in rats and 15 times a human dose of 100 mg/day (on a mg/m² basis) in rabbits. However, fetal weights were decreased and skeletal ossification was delayed in rats in association with maternal toxicity at the highest dose, with a no-effect dose 10 times a human dose of 100 mg/day (on a mg/m² basis).

When desvenlafaxine succinate was administered orally to pregnant rats throughout gestation and lactation, there was a decrease in pup weights and an increase in pup deaths during the first four days of lactation at the highest dose of 300 mg/kg/day. The cause of these deaths is not known. The no-effect dose for rat pup mortality was 10 times a human dose of 100 mg/day (on a mg/m² basis). Post-weaning growth and reproductive performance of the progeny were not affected by maternal treatment with desvenlafaxine succinate at a dose 30 times a human dose of 100 mg/day (on a mg/m² basis).

Nursing Mothers

Desvenlafaxine (O-desmethylvenlafaxine) is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from desvenlafaxine, 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 [see BOXED WARNING and WARNINGS AND PRECAUTIONS]. Anyone considering the use of KHEDEZLA in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

Of the 4,158 patients in clinical studies with desvenlafaxine, 6% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥ 65 years of age compared to patients < 65 years of age treated with desvenlafaxine [see ADVERSE REACTIONS]. For elderly patients, possible reduced renal clearance of KHEDEZLA should be considered when determining dose [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

SSRIs and SNRIs, including desvenlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS].

Renal Impairment

In subjects with renal impairment the clearance of desvenlafaxine was decreased. In subjects with severe renal impairment (24-hr CrCl < 30 mL/min, Cockcroft-Gault) and end-stage renal disease, elimination half-lives were significantly prolonged, increasing exposures to desvenlafaxine; therefore, dosage adjustment is recommended in these patients [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

The mean terminal half life (t½) changed from approximately 10 hours in healthy subjects and subjects with mild hepatic impairment to 13 and 14 hours in moderate and severe hepatic impairment, respectively. The recommended dose in patients with moderate to severe hepatic impairment is 50 mg/day. Dose escalation above 100 mg/day is not recommended [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 8/8/2014
This monograph has been modified to include the generic and brand name in many instances.

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