Doxepin Hydrochloride

Doxepin tablets are indicated for the treatment of insomnia characterized by difficulty with sleep maintenance. The clinical trials performed in support of efficacy were up to 3 months in duration.

The dose of doxepin tablets should be individualized.

Doxepin tablets are an immediate-release, oval-shaped, tablet for oral administration available in strengths of 3 mg and 6 mg. The tablets are white (3 mg) or light yellow (6 mg) and are debossed with “134” or “135”, respectively, on one side and “m” on the other side. Doxepin tablets are

• Pregnancy: Third trimester use may increase the risk for symptoms of poor adaptation (respiratory distress, temperature instability, feeding difficulties, hypotonia, tremor, irritability) in the neonate. (
  8.1 Pregnancy

  
  
  

  Risk Summary

  
  
  Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage

  (see Data).

  There are risks of poor neonatal adaptation with exposure to tricyclic antidepressants (TCAs), including doxepin, during pregnancy

  (see Clinical Considerations).

  In animal reproduction studies, oral administration of doxepin to rats and rabbits during the period of organogenesis caused adverse developmental effects at doses 65 and 23 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC, respectively. Oral administration of doxepin to pregnant rats during pregnancy and lactation resulted in decreased pup survival and a delay in pup growth at doses 60 times the MRHD based on AUC

  (see Data).

  
  
  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major 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

  
  
  

  Fetal/Neonatal adverse reactions

  
  
  Neonates exposed to TCAs, including doxepin, 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, hyperreflexia, tremor, jitteriness, irritability and constant crying. These findings are consistent with either direct toxic effects of TCAs or possibly a drug discontinuation syndrome. Monitor neonates who were exposed to doxepin in the third trimester of pregnancy for poor neonatal adaptation syndrome.
  
  

  Data

  
  
  

  Human Data

  
  
  Published epidemiologic studies of pregnant women exposed to TCAs, including doxepin, have not established an association with major birth defects, miscarriage or adverse maternal outcomes. Methodological limitations of these observational studies include small sample size and lack of adequate controls.
  
  

  Animal Data

  
  
  When doxepin (30, 100, and 150 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, developmental toxicity (increased incidences of fetal structural abnormalities consisting of non-ossified bones in the skull and sternum and decreased fetal body weights) and maternal toxicity were noted at ≥100 mg/kg/day, which produced plasma exposures (AUCs) of doxepin and nordoxepin (the primary metabolite in humans) approximately 65 and 53 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for embryo-fetal developmental toxicity in rats (30 mg/kg/day) are approximately 6 and 5 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. When doxepin (10, 30, and 60 mg/kg/day) was administered orally to pregnant rabbits during the period of organogenesis, fetal body weights were reduced at the highest dose in the absence of maternal toxicity, which produced plasma AUCs of doxepin and nordoxepin approximately 23 and 56 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for developmental effects (30 mg/kg/day) are approximately 8 and 25 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. Oral administration of doxepin (10, 30, and 100 mg/kg/day) to rats throughout pregnancy and lactation resulted in decreased pup survival and transient growth delay at the highest dose, which produced plasma AUCs of doxepin and nordoxepin approximately 60 and 39 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for adverse effects on pre-and postnatal development in rats (30 mg/kg/day) are approximately 2 and 1 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD.
  )
• Lactation: Breastfeeding not recommended. (
  8.2 Lactation

  Risk Summary

  
  
  Data from the published literature report the presence of doxepin and nordoxepin in human milk. There are reports of excess sedation, respiratory depression, poor sucking and swallowing, and hypotonia in breastfed infants exposed to doxepin. There are no data on the effects of doxepin on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, clinicians should advise patients that breastfeeding is not recommended during treatment with doxepin.
  
  

  Clinical Considerations

  
  
  Infants exposed to doxepin through breast milk should be monitored for excess sedation, respiratory depression and hypotonia.

  
  
  
  )
• Pediatric Use: Safety and effectiveness have not been evaluated. (
  8.4 Pediatric Use

  The safety and effectiveness of doxepin in pediatric patients have not been evaluated.
  )
• Geriatric Use: The recommended starting dose is 3 mg. Monitor prior to considering dose escalation. (
  2.2 Dosing in the Elderly

  The recommended starting dose of doxepin tablets in elderly patients (≥65 years old) is 3 mg once daily. The daily dose can be increased to 6 mg, if clinically indicated.
  ,
  8.5 Geriatric Use

  A total of 362 subjects who were ≥ 65 years and 86 subjects who were ≥ 75 years received doxepin in controlled clinical studies. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects. Greater sensitivity of some older individuals cannot be ruled out.
  
  Sleep-promoting drugs may cause confusion and over-sedation in the elderly. A starting dose of 3 mg is recommended in this population and evaluation prior to considering dose escalation is recommended

  [ see Dosage and Administration (2.2)].

  
  
  
  )
• Use in Patients with Comorbid Illness: Initiate treatment with 3 mg in patients with hepatic impairment or tendency to urinary retention. (
  8.6 Use in Patients with Hepatic Impairment

  Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Initiate doxepin treatment with 3 mg in patients with hepatic impairment and monitor closely for adverse daytime effects.

  [see Clinical Pharmacology (12.3)]
  ,
  4.3 Glaucoma and Urinary Retention

  Doxepin is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.
  )

• Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use. (
  5.1 Need to Evaluate for Comorbid Diagnoses

  Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.

  The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.

  Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with hypnotic drugs.
  )
• Abnormal thinking, behavioral changes, complex behaviors: May include “Sleep-driving” and hallucinations. Immediately evaluate any new onset behavioral changes. (
  5.2 Abnormal Thinking and Behavioral Changes

  Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics. These events can occur in hypnotic-naive as well as in hypnotic-experienced persons. Although behaviors such as “sleep-driving” may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of doxepin should be strongly considered for patients who report a “sleep-driving” episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic. As with “sleep-driving”, patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.
  )
• Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least amount feasible to avoid intentional overdose. (
  5.3 Suicide Risk and Worsening of Depression

  In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics.
  
  Doxepin, the active ingredient in doxepin tablets, is an antidepressant at doses 10- to 100-fold higher than in doxepin. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Risk from the lower dose of doxepin in doxepin tablets can not be excluded.
  
  It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
  )
• CNS-depressant effects: Use can impair alertness and motor coordination. Avoid engaging in hazardous activities such as operating a motor vehicle or heavy machinery after taking drug. (
  5.4 CNS Depressant Effects

  After taking doxepin, patients should confine their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking doxepin, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion.
  
  When taken with doxepin, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.3, 7.4)].

  Patients should not consume alcohol with doxepin

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.3)].

  Patients should be cautioned about potential additive effects of doxepin used in combination with CNS depressants or sedating antihistamines

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.4)].
  ) Do not use with alcohol. (
  5.4 CNS Depressant Effects

  After taking doxepin, patients should confine their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking doxepin, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion.
  
  When taken with doxepin, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.3, 7.4)].

  Patients should not consume alcohol with doxepin

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.3)].

  Patients should be cautioned about potential additive effects of doxepin used in combination with CNS depressants or sedating antihistamines

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.4)].
  ,
  7.3 Alcohol

  When taken with doxepin, the sedative effects of alcohol may be potentiated

  [ see Warnings and Precautions (5.2, 5.4)].
  )
• Potential additive effects when used in combination with CNS depressants or sedating antihistamines. Dose reduction may be needed. (
  5.4 CNS Depressant Effects

  After taking doxepin, patients should confine their activities to those necessary to prepare for bed. Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking doxepin, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion.
  
  When taken with doxepin, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.3, 7.4)].

  Patients should not consume alcohol with doxepin

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.3)].

  Patients should be cautioned about potential additive effects of doxepin used in combination with CNS depressants or sedating antihistamines

  [ see Warnings and Precautions (5.2)and Drug Interactions (7.4)].
  ,
  7.4 CNS Depressants and Sedating Antihistamines

  When taken with doxepin, the sedative effects of sedating antihistamines and CNS depressants may be potentiated [

  see Warnings and Precautions (5.2

  ,

  5.4

  )

  ].
  )
• Patients with severe sleep apnea: Doxepin is ordinarily not recommended for use in this population. (
  8.7 Use in Patients with Sleep Apnea

  Doxepin has not been studied in patients with obstructive sleep apnea. Since hypnotics have the capacity to depress respiratory drive, precautions should be taken if doxepin is prescribed to patients with compromised respiratory function. In patients with severe sleep apnea, doxepin is ordinarily not recommended for use.
  )