Doxepin Hydrochloride - Doxepin Hydrochloride solution Prescribing Information
and Young Adults
In pooled analyses of placebo-controlled trials of antidepressant drugs including tricyclic antidepressants and other antidepressant classes that included approximately 77,000 adult patients and 4,500 pediatric patients (doxepin hydrochloride is not approved for use in pediatric patients), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.
Age Range | Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients Treated |
Increases Compared to Placebo | |
| < 18 years old | 14 additional patients |
| 18-24 years old | 5 additional patients |
Decreases Compared to Placebo | |
| 25-64 years old | 1 fewer patient |
| ≥ 65 years old | 6 fewer patients |
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all doxepin hydrochloride-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of doxepin hydrochloride therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride, in patients who are experiencing emergent suicidal thoughts or behaviors.
The safety and effectiveness of doxepin hydrochloride in pediatric patients have not been established.
Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients
Doxepin hydrochloride is indicated for the treatment of major depressive disorder (MDD) in adults.
Oral solution: Each mL of oral solution contains 10 mg of doxepin as a clear, colorless solution for dilution prior to administration
Oral Solution
- Use the supplied calibrated dropper to measure the amount of Doxepin Hydrochloride Oral Solution needed. The calibrated dropper has markings at 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg.
- Just prior to administration, mix doxepin hydrochloride with 120 mL of water, whole or skimmed milk, or orange, grapefruit, tomato, prune, or pineapple juice. Do not mix with other liquids.
- Administer the dose immediately after mixing.
Doxepin hydrochloride is contraindicated in patients:
- With hypersensitivity to doxepin (hypersensitivity reactions have included tongue edema and urticaria). The possibility of cross sensitivity with other dibenzoxepines should be kept in mind.
- With glaucoma [see Warnings and Precautions (
5.3 Angle-Closure GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride may trigger an angle closure glaucoma attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 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.
Doxepin hydrochloride is contraindicated in patients with glaucoma. Avoid use of doxepin hydrochloride in patients with untreated anatomically narrow angles.
)]. - With current or past urinary retention [see Adverse Reactions (
6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Adverse reactions (≥ 2% of doxepin hydrochloride-treated patients) in 1,635 doxepin hydrochloride-treated patients with MDD in clinical trials included somnolence (17%), dry mouth (15%), dizziness (6%), constipation (5%), fatigue (5%), blurred vision (3%), tachycardia (3%), hypotension (3%), insomnia (2%), tremor (2%), nausea (2%), hyperhidrosis (2%), and increased weight (2%).
Other Adverse Reactions Observed in Clinical TrialsOther adverse reactions that occurred at an incidence of < 2% in patients treated with doxepin hydrochloride in clinical trials were:
- Ear and Labyrinth Disorders: Tinnitus.
- Gastrointestinal Disorders: Diarrhea, dyspepsia, vomiting.
- General Disorders and Administration Site Conditions: Asthenia, edema, chills.
- Metabolism and Nutrition Disorders: Decreased appetite.
- Nervous System Disorders: Ataxia, paresthesia, headache, extrapyramidal disorder.
- Psychiatric Disorders: Agitation, confusional state, libido decreased.
- Pulmonary Disorders: Asthma exacerbation.
- Renal and Urinary Disorders: Urinary retention.
- Reproductive System and Breast Disorders: Breast enlargement.
- Skin & Subcutaneous Tissue Disorders: Rash, pruritus.
- Vascular Disorders: Flushing.
)]. - Taking MAOIs, or within 14 days of stopping MAOIs (including the MAOIs linezolid or intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (
5.2 Serotonin SyndromeTricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue)[see Drug Interactions (7)].Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI[see Dosage and Administration (2.4) and Drug Interactions (7)].Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.) and Drug Interactions (7 DRUG INTERACTIONSTable 2 describe the clinically significant drug interactions of doxepin hydrochloride with other drugs or classes.
Table 2: Clinically Significant Drug Interactions with Doxepin HydrochlorideMonoamine Oxidase InhibitorsPrevention or ManagementDoxepin hydrochloride is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue. The use of doxepin hydrochloride within 14 days of discontinuation of an MAOI or the use of MAOI within 14 days of discontinuation of doxepin hydrochloride is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI is contraindicated. Clinical Effect(s)Concomitant use of doxepin hydrochloride and MAOIs increases the risk of serotonin syndrome [Warnings and Precautions (5.2)].Other Serotonergic Drugs (Besides MAOIs)Prevention or ManagementMonitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of doxepin hydrochloride and/or concomitant serotonergic drugs [see Warnings and Precautions (5.2)].Mechanism and Clinical Effect(s)Concomitant use of doxepin hydrochloride with other serotonergic drugs increases the risk of serotonin syndrome [see Warnings and Precautions (5.2)].Strong CYP2D6 InhibitorsPrevention or ManagementMonitor doxepin plasma concentrations and reduce the doxepin hydrochloride dosage or the strong CYP2D6 inhibitor as appropriate [see Dosage and Administration (2.5)].Mechanism and Clinical Effect(s)Concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase the exposures of doxepin [see Clinical Pharmacology (12.3)]which may increase the risk of doxepin hydrochloride related adverse reactions[see Warnings and Precautions (5) and Adverse Reactions (6)].ExamplesSee www.fda.gov/CYPandTransporterInteractingDrugsfor examples of strong CYP2D6 Inhibitors. CarbamazepinePrevention or ManagementMonitor doxepin plasma concentrations and consider increasing the doxepin hydrochloride dosage in patients taking carbamazepine. Mechanism and Clinical Effect(s)Concomitant use of carbamazepine with doxepin hydrochloride decreases the exposure of doxepin [see Clinical Pharmacology (12.3)]which could lead to reduced treatment effect.CimetidinePrevention or ManagementMonitor doxepin plasma concentrations and consider reducing the doxepin hydrochloride dosage in patients taking cimetidine. Mechanism and Clinical Effect(s)Concomitant use of doxepin hydrochloride with cimetidine may increase the exposures of doxepin [see Clinical Pharmacology (12.3)]which may increase the risk of doxepin hydrochloride-related anticholinergic effects (e.g., dry mouth, blurred vision, constipation)[see Adverse Reactions (6.1)].AlcoholPrevention or ManagementAvoid concomitant use with alcohol. Mechanism and Clinical Effect(s)Doxepin hydrochloride may potentiate the sedative effects of alcohol [see Warnings and Precautions (5.4)].CNS DepressantsPrevention or ManagementDosage reduction of doxepin hydrochloride and/or the CNS depressant may be needed based on clinical response and tolerability. Mechanism and Clinical Effect(s)When concomitantly administered with doxepin hydrochloride, the sedative effects of CNS depressant may be potentiated [see Warnings and Precautions (5.4)].TolazamidePrevention or ManagementMonitor glucose levels and reduce the doxepin hydrochloride dosage as appropriate. Clinical Effect(s)Doxepin hydrochloride may cause severe hypoglycemia when concomitantly used with tolazamide. - Serotonergic Drugs: Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of doxepin hydrochloride and/or concomitant serotonergic drugs.
- Strong CYP2D6 Inhibitors: Concomitant use of TCAs with drugs that can inhibit CYP2D6 may require lower dosages for the TCA or the other drug, and monitor TCA plasma levels.
- Carbamazepine: Monitor doxepin plasma concentrations and increase doxepin hydrochloride dosage in patients taking carbamazepine.
- Cimetidine: Monitor doxepin plasma concentrations and consider reducing the doxepin hydrochloride dosage in patients taking cimetidine.
- Alcohol: Avoid concomitant use.
- CNS Depressants: Dosage reduction may be needed based on clinical response and tolerability.
- Tolazamide: Monitor glucose levels and reduce the doxepin hydrochloride dosage as appropriate.
)].
The following clinically significant adverse reactions are described elsewhere in the labeling:
- Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions (
5.1 Suicidal Thoughts and Behaviors in Adolescents
and Young AdultsIn pooled analyses of placebo-controlled trials of antidepressant drugs including tricyclic antidepressants and other antidepressant classes that included approximately 77,000 adult patients and 4,500 pediatric patients (doxepin hydrochloride is not approved for use in pediatric patients), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1.
Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult PatientsAge RangeDrug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients TreatedIncreases Compared to Placebo< 18 years old 14 additional patients 18-24 years old 5 additional patients Decreases Compared to Placebo25-64 years old 1 fewer patient ≥ 65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all doxepin hydrochloride-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of doxepin hydrochloride therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride, in patients who are experiencing emergent suicidal thoughts or behaviors.
)] - Serotonin Syndrome [see Warnings and Precautions (
5.2 Serotonin SyndromeTricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue)[see Drug Interactions (7)].Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI[see Dosage and Administration (2.4) and Drug Interactions (7)].Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.)] - Angle-Closure Glaucoma [see Warnings and Precautions (
5.3 Angle-Closure GlaucomaThe pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride may trigger an angle closure glaucoma attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 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.
Doxepin hydrochloride is contraindicated in patients with glaucoma. Avoid use of doxepin hydrochloride in patients with untreated anatomically narrow angles.
)] - Sedation and Driving Risks [see Warnings and Precautions (
5.4 Sedation and Driving RisksBecause doxepin hydrochloride can cause sedation, warn patients of the risk of sedation and caution patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride. Also caution patients that their response to alcohol may be potentiated.
Sedating drugs, including doxepin hydrochloride, may cause oversedation in geriatric patients.
)] - Activation of Mania or Hypomania [see Warnings and Precautions (
5.5 Activation of Mania or HypomaniaIn patients with bipolar disorder, treating MDD with doxepin hydrochloride may precipitate a mixed/manic episode. Prior to initiating treatment with doxepin hydrochloride, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. Doxepin hydrochloride is not approved for use in treating bipolar depression.)] - Risk of Seizures [see Warnings and Precautions (
5.6 Risk of SeizuresCaution should be used when doxepin hydrochloride is given to patients with a history of seizure disorder, because this drug may lower the seizure threshold. Patients with a history of seizures should be monitored during doxepin hydrochloride use to identify recurrence of seizures or increase in frequency of seizures.
)] - Psychosis [see Warnings and Precautions (
5.7 PsychosisIn patients with schizophrenia, treatment with doxepin hydrochloride for MDD may activate psychosis. If this occurs, stop doxepin hydrochloride and consider alternative treatment options.
)]
Table 2 describe the clinically significant drug interactions of doxepin hydrochloride with other drugs or classes.
Monoamine Oxidase Inhibitors | |||||||||||||||
Prevention or Management | Doxepin hydrochloride is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs), including MAOIs such as linezolid or intravenous methylene blue. The use of doxepin hydrochloride within 14 days of discontinuation of an MAOI or the use of MAOI within 14 days of discontinuation of doxepin hydrochloride is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI is contraindicated. | ||||||||||||||
Clinical Effect(s) | Concomitant use of doxepin hydrochloride and MAOIs increases the risk of serotonin syndrome [Warnings and Precautions ( Tricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions ( 7 )] .Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )] .Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. )] . | ||||||||||||||
Other Serotonergic Drugs (Besides MAOIs) | |||||||||||||||
Prevention or Management | Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of doxepin hydrochloride and/or concomitant serotonergic drugs [see Warnings and Precautions ( Tricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions ( 7 )] .Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )] .Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. )] . | ||||||||||||||
Mechanism and Clinical Effect(s) | Concomitant use of doxepin hydrochloride with other serotonergic drugs increases the risk of serotonin syndrome [see Warnings and Precautions ( Tricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions ( 7 )] .Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )] .Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. )] . | ||||||||||||||
Strong CYP2D6 Inhibitors | |||||||||||||||
Prevention or Management | Monitor doxepin plasma concentrations and reduce the doxepin hydrochloride dosage or the strong CYP2D6 inhibitor as appropriate [see Dosage and Administration ( Inhibitors Reduce the doxepin hydrochloride dosage based on doxepin plasma concentrations when used concomitantly with strong CYP2D6 inhibitors [see Drug Interactions ( 7 )] .)] . | ||||||||||||||
Mechanism and Clinical Effect(s) | Concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase the exposures of doxepin [see Clinical Pharmacology ( Absorption In healthy volunteers, a single oral doxepin hydrochloride dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between 2 and 4 hours (mean 2.9 hours) after doxepin hydrochloride administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between 2 and 10 hours after doxepin hydrochloride administration. Distribution The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%. Elimination In healthy volunteers, the plasma elimination half-life of doxepin ranged from 8 to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg. Metabolism After oral doxepin hydrochloride administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation.Excretion Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form.Specific Populations Patients with Hepatic Impairment: Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have a greater systemic doxepin exposure than those with normal liver function[see Use in Specific Populations ( 8.6 )] .Patients with Renal Impairment: The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function.Drug Interaction Studies Carbamazepine: After concomitant use of doxepin hydrochloride and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin hydrochloride alone[see Drug Interactions ( 7 )] .Strong CYP2D6 Inhibitors: CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase doxepin exposure[see Drug Interactions ( 7 )] .Cimetidine: Cimetidine is a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with a single 6 mg dose of another oral doxepin product, there was approximately a 2-fold increase in doxepin Cmaxand AUC compared to doxepin without cimetidine[see Drug Interactions ( 7 )] .CYP2D6 Substrates: Concomitant use of doxepin hydrochloride and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.)] which may increase the risk of doxepin hydrochloride related adverse reactions [see Warnings and Precautions (
and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs including tricyclic antidepressants and other antidepressant classes that included approximately 77,000 adult patients and 4,500 pediatric patients (doxepin hydrochloride is not approved for use in pediatric patients), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression. Monitor all doxepin hydrochloride-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of doxepin hydrochloride therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride, in patients who are experiencing emergent suicidal thoughts or behaviors. Tricyclic antidepressants, including doxepin hydrochloride, can precipitate serotonin syndrome, a potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. John’s Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions ( 7 )] .Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride with MAOIs is contraindicated. The use of doxepin hydrochloride within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride in a patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with a MAOI such as linezolid or intravenous methylene blue in a patient taking doxepin hydrochloride, discontinue doxepin hydrochloride before initiating treatment with the MAOI [see Dosage and Administration ( 2.4 ) and Drug Interactions ( 7 )] .Monitor all patients taking doxepin hydrochloride for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. The pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride may trigger an angle closure glaucoma attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 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. Doxepin hydrochloride is contraindicated in patients with glaucoma. Avoid use of doxepin hydrochloride in patients with untreated anatomically narrow angles. Because doxepin hydrochloride can cause sedation, warn patients of the risk of sedation and caution patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride. Also caution patients that their response to alcohol may be potentiated. Sedating drugs, including doxepin hydrochloride, may cause oversedation in geriatric patients. In patients with bipolar disorder, treating MDD with doxepin hydrochloride may precipitate a mixed/manic episode. Prior to initiating treatment with doxepin hydrochloride, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. Doxepin hydrochloride is not approved for use in treating bipolar depression. Caution should be used when doxepin hydrochloride is given to patients with a history of seizure disorder, because this drug may lower the seizure threshold. Patients with a history of seizures should be monitored during doxepin hydrochloride use to identify recurrence of seizures or increase in frequency of seizures. In patients with schizophrenia, treatment with doxepin hydrochloride for MDD may activate psychosis. If this occurs, stop doxepin hydrochloride and consider alternative treatment options. ) and Adverse Reactions ( The following clinically significant adverse reactions are described elsewhere in the labeling:
Most common adverse reactions (incidence ≥ 5%) are somnolence, dry mouth, dizziness, constipation and fatigue. To report SUSPECTED ADVERSE REACTIONS, contact Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions (≥ 2% of doxepin hydrochloride-treated patients) in 1,635 doxepin hydrochloride-treated patients with MDD in clinical trials included somnolence (17%), dry mouth (15%), dizziness (6%), constipation (5%), fatigue (5%), blurred vision (3%), tachycardia (3%), hypotension (3%), insomnia (2%), tremor (2%), nausea (2%), hyperhidrosis (2%), and increased weight (2%). Other Adverse Reactions Observed in Clinical Trials Other adverse reactions that occurred at an incidence of < 2% in patients treated with doxepin hydrochloride in clinical trials were:
The following adverse reactions have been identified during post-approval use of doxepin hydrochloride. 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.
Withdrawal syndrome occurred after stopping doxepin hydrochloride [see Drug Abuse and Dependence ( 9.3 )] .The following adverse reaction has been reported with use with other tricyclic antidepressants: decreased blood glucose. )] . | ||||||||||||||
Examples | See www.fda.gov/CYPandTransporterInteractingDrugs for examples of strong CYP2D6 Inhibitors. | ||||||||||||||
Carbamazepine | |||||||||||||||
Prevention or Management | Monitor doxepin plasma concentrations and consider increasing the doxepin hydrochloride dosage in patients taking carbamazepine. | ||||||||||||||
Mechanism and Clinical Effect(s) | Concomitant use of carbamazepine with doxepin hydrochloride decreases the exposure of doxepin [see Clinical Pharmacology ( Absorption In healthy volunteers, a single oral doxepin hydrochloride dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between 2 and 4 hours (mean 2.9 hours) after doxepin hydrochloride administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between 2 and 10 hours after doxepin hydrochloride administration. Distribution The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%. Elimination In healthy volunteers, the plasma elimination half-life of doxepin ranged from 8 to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg. Metabolism After oral doxepin hydrochloride administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation.Excretion Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form.Specific Populations Patients with Hepatic Impairment: Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have a greater systemic doxepin exposure than those with normal liver function[see Use in Specific Populations ( 8.6 )] .Patients with Renal Impairment: The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function.Drug Interaction Studies Carbamazepine: After concomitant use of doxepin hydrochloride and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin hydrochloride alone[see Drug Interactions ( 7 )] .Strong CYP2D6 Inhibitors: CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase doxepin exposure[see Drug Interactions ( 7 )] .Cimetidine: Cimetidine is a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with a single 6 mg dose of another oral doxepin product, there was approximately a 2-fold increase in doxepin Cmaxand AUC compared to doxepin without cimetidine[see Drug Interactions ( 7 )] .CYP2D6 Substrates: Concomitant use of doxepin hydrochloride and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.)] which could lead to reduced treatment effect. | ||||||||||||||
Cimetidine | |||||||||||||||
Prevention or Management | Monitor doxepin plasma concentrations and consider reducing the doxepin hydrochloride dosage in patients taking cimetidine. | ||||||||||||||
Mechanism and Clinical Effect(s) | Concomitant use of doxepin hydrochloride with cimetidine may increase the exposures of doxepin [see Clinical Pharmacology ( Absorption In healthy volunteers, a single oral doxepin hydrochloride dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between 2 and 4 hours (mean 2.9 hours) after doxepin hydrochloride administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between 2 and 10 hours after doxepin hydrochloride administration. Distribution The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%. Elimination In healthy volunteers, the plasma elimination half-life of doxepin ranged from 8 to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg. Metabolism After oral doxepin hydrochloride administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation.Excretion Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form.Specific Populations Patients with Hepatic Impairment: Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have a greater systemic doxepin exposure than those with normal liver function[see Use in Specific Populations ( 8.6 )] .Patients with Renal Impairment: The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function.Drug Interaction Studies Carbamazepine: After concomitant use of doxepin hydrochloride and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin hydrochloride alone[see Drug Interactions ( 7 )] .Strong CYP2D6 Inhibitors: CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin hydrochloride with strong CYP2D6 inhibitors may increase doxepin exposure[see Drug Interactions ( 7 )] .Cimetidine: Cimetidine is a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with a single 6 mg dose of another oral doxepin product, there was approximately a 2-fold increase in doxepin Cmaxand AUC compared to doxepin without cimetidine[see Drug Interactions ( 7 )] .CYP2D6 Substrates: Concomitant use of doxepin hydrochloride and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.)] which may increase the risk of doxepin hydrochloride-related anticholinergic effects (e.g., dry mouth, blurred vision, constipation) [see Adverse Reactions ( Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions (≥ 2% of doxepin hydrochloride-treated patients) in 1,635 doxepin hydrochloride-treated patients with MDD in clinical trials included somnolence (17%), dry mouth (15%), dizziness (6%), constipation (5%), fatigue (5%), blurred vision (3%), tachycardia (3%), hypotension (3%), insomnia (2%), tremor (2%), nausea (2%), hyperhidrosis (2%), and increased weight (2%). Other Adverse Reactions Observed in Clinical Trials Other adverse reactions that occurred at an incidence of < 2% in patients treated with doxepin hydrochloride in clinical trials were:
)] . | ||||||||||||||
Alcohol | |||||||||||||||
Prevention or Management | Avoid concomitant use with alcohol. | ||||||||||||||
Mechanism and Clinical Effect(s) | Doxepin hydrochloride may potentiate the sedative effects of alcohol [see Warnings and Precautions ( Because doxepin hydrochloride can cause sedation, warn patients of the risk of sedation and caution patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride. Also caution patients that their response to alcohol may be potentiated. Sedating drugs, including doxepin hydrochloride, may cause oversedation in geriatric patients. )] . | ||||||||||||||
CNS Depressants | |||||||||||||||
Prevention or Management | Dosage reduction of doxepin hydrochloride and/or the CNS depressant may be needed based on clinical response and tolerability. | ||||||||||||||
Mechanism and Clinical Effect(s) | When concomitantly administered with doxepin hydrochloride, the sedative effects of CNS depressant may be potentiated [see Warnings and Precautions ( Because doxepin hydrochloride can cause sedation, warn patients of the risk of sedation and caution patients against driving a car or operating dangerous machinery while taking doxepin hydrochloride. Also caution patients that their response to alcohol may be potentiated. Sedating drugs, including doxepin hydrochloride, may cause oversedation in geriatric patients. )] . | ||||||||||||||
Tolazamide | |||||||||||||||
Prevention or Management | Monitor glucose levels and reduce the doxepin hydrochloride dosage as appropriate. | ||||||||||||||
Clinical Effect(s) | Doxepin hydrochloride may cause severe hypoglycemia when concomitantly used with tolazamide. | ||||||||||||||