WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicidal Thoughts And Behaviors In Pediatric And Young
Adult Patients
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 to 24 |
5 additional cases |
Decreases Compared to Placebo |
25 to 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 and Discontinuation Syndrome].
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
Serotonin-norepinephrine reuptake inhibitors (SNRIs) and
selective-serotonin reuptake inhibitors (SSRIs), including KHEDEZLA, can
precipitate serotonin syndrome, a potentially life-threatening condition. The
risk is increased with concomitant use of other serotonergic drugs (including
triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan,
buspirone, amphetamines, and St. John's Wort), and with drugs that impair
metabolism of serotonin i.e., MAOIs [see CONTRAINDICATIONS and DRUG
INTERACTIONS]. Serotonin syndrome can also occur when these drugs are used
alone.
Serotonin syndrome signs and 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 gastrointestinal symptoms
(e.g., nausea, vomiting, diarrhea).
The concomitant use of KHEDEZLA with MAOIs is
contraindicated. In addition, do not initiate KHEDEZLA in a patient 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. If it is necessary
to initiate treatment with an MAOI such as linezolid or intravenous methylene
blue in a patient taking KHEDEZLA, discontinue KHEDEZLA before initiating
treatment with the MAOI [see CONTRAINDICATIONS and DRUG INTERACTIONS].
Monitor all patients taking KHEDEZLA for the emergence of
serotonin syndrome. Discontinue treatment with KHEDEZLA and any concomitant
serotonergic agents immediately if the above symptoms occur, and initiate
supportive symptomatic treatment. If concomitant use of KHEDEZLA with other
serotonergic drugs is clinically warranted, inform patients of the increased
risk for serotonin syndrome and monitor for symptoms.
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].
Increased Risk Of Bleeding
Drugs that interfere with serotonin reuptake inhibition,
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. Inform patients about the risk of bleeding associated with the
concomitant use of KHEDEZLA and antiplatelet agents or anticoagulants. For
patients taking warfarin, carefully monitor coagulation indices when
initiating, titrating, or discontinuing KHEDEZLA.
Angle Closure Glaucoma
The pupillary dilation that occurs following use of many
antidepressant drugs including KHEDEZLA may trigger an angle closure attack in
a patient with anatomically narrow angles who does not have a patent
iridectomy. Avoid use of antidepressants, including KHEDEZLA, in patients with
untreated anatomically narrow angles.
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
Adverse reactions after discontinuation of serotonergic
antidepressants, particularly after abrupt discontinuation, include: nausea,
sweating, dysphoric mood, irritability, agitation, dizziness, sensory
disturbances (e.g., paresthesia, such as electric shock sensations), tremor,
anxiety, confusion, headache, lethargy, emotional lability, insomnia,
hypomania, tinnitus, and seizures. A gradual reduction in dosage rather than
abrupt cessation is recommended whenever possible [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
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Suicidal Thoughts And Behaviors
Advise patients and caregivers to look for the emergence
of suicidality, especially early during treatment and when the dose is adjusted
up or down, and instruct them to report such symptoms to the healthcare
provider [see BOXED WARNING and WARNINGS AND PRECAUTIONS].
Concomitant Medication
Advise patients taking KHEDEZLA 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, amphetamines, 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].
Increased Risk Of Bleeding
Inform patients about the concomitant use of KHEDEZLA
with NSAIDs, aspirin, other antiplatelet drugs, warfarin, or other coagulants
because the combined use of has been associated with an increased risk of
bleeding. Advise patients to inform their healthcare providers if they are
taking or planning to take any prescription or over-the-counter medications that
increase the risk of bleeding [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 abruptly stop taking KHEDEZLA
without talking first with their healthcare professional. Patients should be
aware that discontinuation effects may occur when stopping KHEDEZLA [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. Advise patients that
there is a pregnancy exposure registry that monitors pregnancy outcomes in
women exposed to desvenlafaxine during pregnancy [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 AUC exposure
at 300 mg/kg/day dose is estimated at 10-times the AUC exposure at an adult
human dose of 100 mg per day.
Rats received desvenlafaxine succinate at dosages up to
300 mg/kg/day (males) or 500 mg/kg/day (females). The AUC exposure at the
highest dose is estimated at 11 (males) or 26 (females) times the AUC exposure
at an adult human dose of 100 mg per day.
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 10 (males) and 19 (females) times the AUC exposure at an adult human
dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day,
which is 3 (males) or 5 (females) times the AUC exposure at an adult human dose
of 100 mg per day. These studies did not address reversibility of the effect on
fertility. The relevance of these findings to humans is not known.
Use In Specific Populations
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors
pregnancy outcomes in women exposed to antidepressants during pregnancy.
Healthcare providers are encouraged to register patients by calling the
National Pregnancy Registry for Antidepressants at 1-844-405-6185.
Risk summary
There are no published studies on KHEDEZLA in pregnant
women; however published epidemiologic studies of pregnant women exposed to
venlafaxine, the parent compound, have not reported a clear association with adverse
developmental outcomes (see Data). There are risks associated with
untreated depression in pregnancy and with exposure to SNRIs and SSRIs,
including KHEDEZLA, during pregnancy (see Clinical Considerations).
In reproductive developmental studies in rats and rabbits
treated with desvenlafaxine succinate, there was no evidence of teratogenicity
at a plasma exposure (AUC) that is up to 19-times (rats), and 0.5-times
(rabbits) the exposure at an adult human dose of 100 mg per day. However,
fetotoxicity and pup deaths were observed in rats at 4.5-times the AUC exposure
observed with an adult human dose of 100 mg per day.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. All pregnancies have a
background risk of birth defect, loss, or other adverse outcomes. In the U.S.
general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%,
respectively.
Clinical Considerations
Disease-Associated Maternal And/Or Embryo/Fetal Risk
A prospective longitudinal study of 201 women with a
history of major depression who were euthymic at the beginning of pregnancy,
showed that women who discontinued antidepressant medication during pregnancy
were more likely to experience a relapse of major depression than women who
continued antidepressant medication.
Maternal Adverse Reactions
Exposure to SNRIs in mid to late pregnancy may increase
the risk for preeclampsia, and exposure to SNRIs near delivery may increase the
risk for postpartum hemorrhage.
Fetal/Neonatal Adverse Reactions
Exposure to SNRIs or SSRIs in late pregnancy may lead to
an increased risk for neonatal complications requiring prolonged hospitalization,
respiratory support, and tube feeding. Monitor neonates who were exposed to
KHEDEZLA in the third trimester of pregnancy for drug discontinuation syndrome (see
Data).
Data
Human Data
Published epidemiological studies of pregnant women
exposed to the parent compound venlafaxine have not reported a clear
association with major birth defects or miscarriage. Methodological limitations
of these observational studies include possible exposure and outcome
misclassification, lack of adequate controls, adjustment for confounders, and confirmatory
studies; therefore, these studies cannot establish or exclude any
drug-associated risk during pregnancy.
Retrospective cohort studies based on claims data have
shown an association between venlafaxine use and preeclampsia, compared to
depressed women who did not take an antidepressant during pregnancy. One study
that assessed venlafaxine exposure in the second trimester or first half of the
third trimester and preeclampsia showed an increased risk compared to unexposed
depressed women (adjusted (adj) RR 1.57, 95% CI 1.29-1.91). Preeclampsia was
observed at venlafaxine doses equal to or greater than 75 mg per day and a
duration of treatment >30 days. Another study that assessed venlafaxine exposure
in gestational weeks 10-20 and preeclampsia showed an increased risk at doses
equal to or greater than 150 mg per day. Available data are limited by possible
outcome misclassification and possible confounding due to depression severity
and other confounders.
Retrospective cohort studies based on claims data have
suggested an association between venlafaxine use near the time of delivery or
through delivery and postpartum hemorrhage. One study showed an increased risk
for postpartum hemorrhage when venlafaxine exposure occurred through delivery,
compared to unexposed depressed women (adj RR 2.24 (95% CI 1.69-2.97). There
was no increased risk in women who were exposed to venlafaxine earlier in
pregnancy. Limitations of this study include possible confounding due to
depression severity and other confounders. Another study showed an increased
risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days
in the last month of pregnancy or through delivery, compared to unexposed women
(adj RR 1.64-1.76). The results of this study may be confounded by the effects
of depression.
Neonates exposed to SNRIs or SSRIs, 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 were associated with a plasma exposure (AUC) 19-times (rats) and
0.5-times (rabbits) the AUC exposure at an adult human dose of 100 mg per day.
However, fetal weights were decreased and skeletal ossification was delayed in
rats in association with maternal toxicity at the highest dose, with an AUC
exposure at the no-effect dose that is 4.5-times the AUC exposure at an adult
human dose of 100 mg per day.
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 AUC exposure at the no-effect dose for rat pup mortality was 4.5-times the
AUC exposure at an adult human dose of 100 mg per day. Post-weaning growth and
reproductive performance of the progeny were not affected by maternal treatment
with desvenlafaxine succinate at exposures 19-times the AUC exposure at an
adult human dose of 100 mg per day.
Lactation
Risk Summary
Available limited data from published literature show low
levels of desvenlafaxine in human milk, and have not shown adverse reactions in
breastfed infants (see Data). There are no data on the effects of
desvenlafaxine on milk production.
The developmental and health benefits of breastfeeding
should be considered along with the mother's clinical need for KHEDEZLA and any
potential adverse effects on the breastfed child from KHEDEZLA or from the
underlying maternal condition.
Data
A lactation study was conducted in 10 breastfeeding women
(at a mean of 4.3 months post-partum) who were being treated with a 50-150 mg
daily dose of desvenlafaxine for postpartum depression. Sampling was performed
at steady state (up to 8 samples) over a 24 hour dosing period, and included
foremilk and hindmilk. The mean relative infant dose was calculated to be 6.8%
(range of 5.5-8.1%). No adverse reactions were seen in the infants.
Pediatric Use
The safety and effectiveness of KHEDEZLA have not been
established in pediatric patients for the treatment of MDD.
Antidepressants, such as KHEDEZLA, increase the risk of
suicidal thoughts and behaviors in pediatric patients [see BOXED WARNING
and WARNINGS AND PRECAUTIONS].
Additional information describing clinical studies in
which efficacy was not demonstrated in pediatric patients is approved for Wyeth
Pharmaceuticals Inc., a subsidiary of Pfizer Inc.’s Pristiq® (desvenlafaxine)
Extended-Release Tablets. However, due to Wyeth Pharmaceuticals Inc., a
subsidiary of Pfizer Inc.’s marketing exclusivity rights, this product is not
labeled with that pediatric information.
Juvenile Animal Studies
In a juvenile animal study, male and female rats were
treated with desvenlafaxine (75, 225 and 675 mg/kg/day) starting on postnatal
day (PND) 22 through 112. Behavioral deficits (longer time immobile in a motor
activity test, longer time swimming in a straight channel test, and lack of
habituation in an acoustic startle test) were observed in males and females but
were reversed after a recovery period. A No Adverse Effect Level (NOAEL) was
not identified for these deficits. The Low Adverse Effect Level (LOAEL) was 75
mg/kg/day which was associated with plasma exposure (AUC) twice the levels
measured with a pediatric dose of 100 mg per day.
In a second juvenile animal study, male and female rats
were administered desvenlafaxine (75, 225 or 675 mg/kg/day) for 8 to 9 weeks
starting on PND 22 and were mated with naïve counterparts. Delays in sexual
maturation and decreased fertility, number of implantation sites and total live
embryos were observed in treated females at all doses. The LOAEL for these
findings is 75 mg/kg/day which was associated with an AUC twice the levels
measured with a pediatric dose of 100 mg per day. These findings were reversed
at the end of a 4-week recovery period. The relevance of these findings to humans
is not known.
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
Adjust the maximum recommended dosage in patients with
moderate or severe renal impairment (ClCr 15 to 50 mL/min, C-G), or end-stage
renal disease (ClCr < 15 mL/min, C-G) [see DOSAGE AND ADMINISTRATION and
CLINICAL PHARMACOLOGY].
Hepatic Impairment
Adjust the maximum recommended dosage in patients with
moderate to severe hepatic impairment (Child-Pugh score 7 to 15) [see DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY].