Desvenlafaxine: Package Insert and Label Information (Page 3 of 6)

6.2 Postmarketing Experience

The following adverse reaction has been identified during post-approval use of desvenlafaxine extended-release tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Skin and subcutaneous tissue disorders – Stevens-Johnson syndrome Gastrointestinal disorders – Pancreatitis acute

Cardiovascular system – Takotsubo cardiomyopathy

7 DRUG INTERACTIONS

7.1 Drugs Having Clinically Important Interactions with Desvenlafaxine Extended-Release Tablets

Table 8: Clinically Important Drug Interactions with Desvenlafaxine Extended-Release Tablets

Monoamine Oxidase Inhibitors (MAOI)

Clinical Impact

The concomitant use of SSRIs and SNRIs including desvenlafaxine extended-release tablets with MAOIs increases the risk of serotonin syndrome.

Intervention

Concomitant use of desvenlafaxine extended-release tablets is contraindicated:

• With an MAOI intended to treat psychiatric disorders or within 7 days of stopping treatment with desvenlafaxine extended-release tablets.

• Within 14 days of stopping an MAOI intended to treat psychiatric disorders.

• In a patient who is being treated with linezolid or intravenous methylene blue. [see Dosage and Administration ( 2.7), Contraindications ( 4) and Warnings and Precautions ( 5.2)].

Examples

selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue

Other Serotonergic Drugs

Clinical Impact

Concomitant use of desvenlafaxine extended-release tablets with other serotonergic drugs increases the risk of serotonin syndrome.

Intervention

Monitor for symptoms of serotonin syndrome when desvenlafaxine extended-release tablets is used concomitantly with other drugs that may affect the serotonergic neurotransmitter systems. If serotonin syndrome occurs, consider discontinuation of desvenlafaxine extended-release tablets and/or concomitant serotonergic drugs [see Warnings and Precautions ( 5.2)].

Examples

other SNRIs, SSRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, amphetamines, tryptophan, and St. John’s Wort

Drugs that Interfere with Hemostasis

Clinical Impact

Concomitant use of desvenlafaxine extended-release tablets with an antiplatelet or anticoagulant drug may potentiate the risk of bleeding. This may be due to the effect of desvenlafaxine extended-release tablets on the release of serotonin by platelets.

Intervention

Closely monitor for bleeding for patients receiving an antiplatelet or anticoagulant drug when desvenlafaxine extended-release tablets is initiated or discontinued [see Warnings and Precautions ( 5.4)] .

Examples

NSAIDs, aspirin, and warfarin

Drugs that are Primarily Metabolized by CYP2D6

Clinical Impact

Concomitant use of desvenlafaxine extended-release tablets increases Cmax and AUC of a drug primarily metabolized by CYP2D6 which may increase the risk of toxicity of the CYP2D6 substrate drug [see Clinical Pharmacology ( 12.3)] .

Intervention

Original dose should be taken when co-administered with desvenlafaxine extended-release tablets 100 mg or lower. Reduce the dose of these drugs by up to one-half if co-administered with 400 mg of desvenlafaxine extended-release tablets.

Examples

desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine

7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Extended-Release Tablets

Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine extended-release tablets [see Clinical Pharmacology ( 12.3)].

7.3 Alcohol

A clinical study has shown that desvenlafaxine extended-release tablets do not increase the impairment of mental and motor skills caused by ethanol. However, as with all CNS-active drugs, patients should be advised to avoid alcohol consumption while taking desvenlafaxine extended-release tablets.

7.4 Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for phencyclidine (PCP) and amphetamine have been reported in patients taking desvenlafaxine. This is due to lack of specificity of the screening tests. False positive test results may be expected for several days following discontinuation of desvenlafaxine therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish desvenlafaxine from PCP and amphetamine.

8 USE IN SPECIFIC POPULATIONS

8.1 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 desvenlafaxine extended-release tablets 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 desvenlafaxine extended-release tablets, 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 desvenlafaxine extended-release tablets 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 to 1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg/day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10 to 20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg/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 to 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 in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64 to 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 ( 5.2)] .

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.

8.2 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 desvenlafaxine extended-release tablets and any potential adverse effects on the breastfed child from desvenlafaxine extended-release tablets or from the underlying maternal condition.

Data

A lactation study was conducted in 10 breastfeeding women (at a mean of 4.3 months postpartum) who were being treated with a 50 to 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 to 8.1%). No adverse reactions were seen in the infants.

8.4 Pediatric Use

The safety and effectiveness of desvenlafaxine extended-release tablets have not been established in pediatric patients for the treatment of MDD.

Antidepressants, such as desvenlafaxine extended-release tablets, increase the risk of suicidal thoughts and behaviors in pediatric patients [see the Boxed Warning and Warnings and Precautions ( 5.1)] .

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/day.

In a second juvenile animal study, male and female rats were administered desvenlafaxine (75, 225 or 675 mg/kg/day) for 8-9 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/day. These findings were reversed at the end of a 4-week recovery period.The relevance of these findings to humans is not known.

DrugInserts.com provides trustworthy package insert and label information about marketed drugs as submitted by manufacturers to the US Food and Drug Administration. Package information is not reviewed or updated separately by DrugInserts.com. Every individual package label entry contains a unique identifier which can be used to secure further details directly from the US National Institutes of Health and/or the FDA.

As the leading independent provider of trustworthy medication information, we source our database directly from the FDA's central repository of drug labels and package inserts under the Structured Product Labeling standard. Our material is not intended as a substitute for direct consultation with a qualified health professional.

Terms of Use | Copyright © 2021. All Rights Reserved.