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Doxepin | CAS No: 1668-19-5 | GMP-certified suppliers
A medication that treats depressive and anxiety disorders, insomnia, and moderate pruritus, with additional use in managing neuropathic pain through oral and topical administration.
Therapeutic categories
Primary indications
- Oral doxepin is approved for the following indications:
- Treatment of depression and/or anxiety
- Treatment of depression and/or anxiety associated with different conditions, including alcoholism, organic disease and manic-depressive disorders
Product Snapshot
- Doxepin is available in oral solid and liquid formulations as well as topical creams
- It is primarily used for the treatment of depression, anxiety, insomnia, and short-term management of pruritus associated with dermatological conditions
- Doxepin is approved for these indications in key regulatory markets including the US and Canada
Clinical Overview
Clinically, oral doxepin is approved for the treatment of depressive and anxiety disorders, including psychotic depression, manic-depressive disorder, involutional depression, and depression associated with alcoholism or organic disease. It is also approved for management of insomnia characterized by difficulties in sleep maintenance. Topically, doxepin is licensed for short-term treatment (up to 8 days) of moderate pruritus in adult patients with atopic dermatitis, pruritus, or lichen simplex chronicus. Off-label topical use includes management of neuropathic pain.
Pharmacodynamically, doxepin acts primarily as a selective antagonist of histamine H1 receptors, contributing to its sedative and antipruritic properties. Its antidepressant effects are attributed to inhibition of central nervous system norepinephrine and serotonin reuptake, increasing synaptic availability of these monoamines. Additional receptor interaction includes desensitization of serotonin 1A and beta-adrenergic receptors. Doxepin may also enhance dopaminergic transmission in the frontal cortex indirectly via norepinephrine reuptake inhibition. Central nervous system depression and anticholinergic effects become prominent at higher doses, which can limit dosage.
Pharmacokinetics indicates that doxepin exhibits properties typical of tertiary amine antidepressants. It is metabolized extensively via cytochrome P450 isoenzymes including CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP3A4. The compound is a substrate and inhibitor of CYP2D6, indicating potential for drug-drug interactions. Elimination occurs primarily through renal excretion of metabolites. The onset of antidepressant effects generally requires approximately two weeks of treatment, whereas sedative effects manifest rapidly after administration.
Safety considerations involve monitoring for anticholinergic side effects, central nervous system depression, potential QTc interval prolongation, and risks associated with polypharmacy, particularly with other serotonergic or CYP-interacting agents. Use in patients with cardiac conduction abnormalities or a history of arrhythmias requires caution.
Doxepin has been marketed under various brand names since its initial FDA approval in 1969 by Pfizer, with later approvals expanding its indications, notably for insomnia in 2010 under Pernix Therapeutics.
From an API sourcing perspective, quality considerations include ensuring stereoisomeric consistency due to the presence of active (Z) and (E) forms, strict control of impurity profiles related to synthesis of dibenzoxepine frameworks, and compliance with regulatory standards for compounds exhibiting multiple pharmacodynamic activities and complex metabolism. Evaluating batch-to-batch reproducibility and stability is critical to support formulation development and global regulatory submissions.
Identification & chemistry
| Generic name | Doxepin |
|---|---|
| Molecule type | Small molecule |
| CAS | 1668-19-5 |
| UNII | 5ASJ6HUZ7D |
| DrugBank ID | DB01142 |
Pharmacology
| Summary | Doxepin is a tricyclic antidepressant that primarily inhibits the reuptake of norepinephrine and serotonin, enhancing monoaminergic neurotransmission associated with its antidepressant and anxiolytic effects. It also acts as a selective histamine H1 receptor antagonist, contributing to its sedative properties and effectiveness in treating pruritus. At higher concentrations, doxepin exhibits anticholinergic and antiadrenergic activity, impacting multiple receptor systems. |
|---|---|
| Mechanism of action | Doxepin exact mechanism of action is not very clear. However, doxepin is known to be a selective histamine H1 receptor blocker. This effect on histamine receptors indicates effectiveness in skin conditions. Breaking its function according to the different effect, doxepin's antidepressive action is primarily associated with the inhibition of the central nervous system biogenic amine reuptake; more specifically, norepinephrine and serotonin at synaptic nerve terminals. This effect increases the level of monoamines in the synaptic site which in order increases the activity at the post-synaptic neuron receptor sites. It has been suggested that doxepin also desensitizes both serotonin 1A receptors and beta-adrenergic receptors. It is known that the lack of dopamine transporters in the frontal cortex and the transmission of dopamine in this region is largely inactivated by the effect of norepinephrine reuptake. Hence, doxepin action on the frontal cortex is suggested to increase dopamine neurotransmission in this area. |
| Pharmacodynamics | Similar to other tricyclic antidepressants, doxepin was shown, in preclinical trials, to decrease the electrical activity of the brain, prolong the hexobarbital-induced sleep and block avoidance behavior without affecting the conditioned emotional response. At high doses, it also produces symptoms of central nervous system depression. Doxepin is known to cause antidepressant, sedative, and anticholinergic effects. At high doses, its anticholinergic and antiadrenergic properties are the most prevalent which limit its efficacy. These effects are observed at high doses where its affinity for H1 histamine receptor is lost and its binding to other receptors is observed. The maximal antidepressive effects of doxepin are present around two weeks following initiation of therapy. However, the sedative effects of doxepin, usually used for the treatment of insomnia or anxiety, are observed immediately after administration. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Histamine H1 receptor | Humans | antagonist |
| Histamine H2 receptor | Humans | antagonist |
| Sodium-dependent noradrenaline transporter | Humans | inhibitor |
ADME / PK
| Absorption | Doxepin is moderately absorbed following oral ingestion with a bioavailability of 30%. The median peak concentration of doxepin ranges from 8.8-45.8 ng/ml and it is achieved 3.5 hours after initial administration. Its absorption is increased with concomitant administration of a high-fat meal. |
|---|---|
| Half-life | The mean elimination half-life is reported to be of 15 hours. |
| Protein binding | Equilibrium dialysis indicates a mean protein binding of 75.5% for doxepin and 76% for desmethyldoxepin. |
| Metabolism | Doxepin is extensively metabolized to N-desmethyldoxepin which is a biologically active metabolite and other inactive metabolites. The first-pass metabolism accounts for 55-87% of the administered dose. After, the secondary metabolism is driven by the transformation of N-desmethyldoxepin to its glucuronide conjugates. The main metabolic enzymes involved in the transformation of doxepin are the members of the cytochrome P450 family, CYP2C19 and CYP2D6 with minor involvement of CYP1A2 and CYP2C9. |
| Route of elimination | The elimination profile of doxepin is presented as biphasic. It is excreted in the urine mainly in the form of glucuronide conjugates. Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. |
| Volume of distribution | The mean apparent volume of distribution of doxepin is reported to be of 20 L/kg. |
| Clearance | The mean total apparent plasma clearance of a single oral dose of 50 mg doxepin in healthy individuals is 0.93 l/hr/kg. |
Formulation & handling
- Doxepin is a small molecule available for oral and topical administration, with formulations including capsules, tablets, solutions, and creams.
- The drug exhibits low water solubility and moderate lipophilicity (LogP 3.84), impacting formulation dissolution and bioavailability considerations for oral delivery.
- Co-administration with alcohol or St. John's Wort should be avoided due to potential CNS effects and altered serum concentrations, relevant for clinical handling and patient counseling.
Regulatory status
| Lifecycle | The API is currently patented in the United States with key patents expiring between 2027 and 2030, indicating a developing market maturity in the US. It is marketed in both the US and Canada, with ongoing patent protections likely influencing market entry and competition timelines. |
|---|
| Markets | Canada, US |
|---|
Supply Chain
| Supply chain summary | The manufacturing and supply landscape for Doxepin involves numerous packagers, including both originator and generic pharmaceutical companies, indicating a well-established supply chain primarily focused on the US and Canadian markets. Branded products such as Alti-doxepin are available in multiple dosages, reflecting an active branded presence in these regions. Patent expiry dates ranging from 2027 to 2030 suggest that while some patent protections remain, there is potential for ongoing or future generic competition. |
|---|
Safety
| Toxicity | Oral LD50 values of doxepin in mouse and rat are 180 mg/kg and 147 mg/kg, respectively.[MSDS] In an overdose state, symptoms of convulsions, dysrhythmias, coma, severe hypotension, central nervous system depression, changes on electrocardiography results and death have been observed. On fertility studies, doxepin was shown to increase the copulatory interval, decrease the corpora lutea, decrease implantation, decreased the number of viable embryos, decrease litter size, increase the number of abnormal sperm and decrease the sperm motility. There is no evidence indicating carcinogenic and mutagenic potential. |
|---|
- Doxepin exhibits moderate acute toxicity with oral LD50 values of 180 mg/kg in mice and 147 mg/kg in rats
- Overdose may result in convulsions, cardiac dysrhythmias, severe hypotension, CNS depression, and fatality
- Reproductive toxicity studies indicate effects on fertility parameters including increased copulatory interval, reduced corpora lutea, decreased implantation, and impaired sperm quality
Doxepin is a type of Tricyclic antidepressants
Tricyclic antidepressants (TCAs) are a class of pharmaceutical active pharmaceutical ingredients (APIs) widely used in the treatment of various mental health disorders, especially depression and anxiety. TCAs derive their name from their unique molecular structure, which consists of three interconnected rings.
These antidepressants work by inhibiting the reuptake of neurotransmitters such as serotonin and norepinephrine in the brain, thereby increasing their availability and improving mood regulation. Some commonly prescribed TCAs include amitriptyline, imipramine, and nortriptyline.
The efficacy of TCAs in managing depressive symptoms is well-documented, making them a popular choice among healthcare professionals. Additionally, they exhibit analgesic properties, making them useful in treating chronic pain conditions like neuropathic pain and migraines.
It is important to note that TCAs are associated with a range of side effects, including dry mouth, drowsiness, constipation, and blurred vision. Moreover, they require careful monitoring due to their potential for drug interactions, particularly with monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs).
Despite the availability of newer classes of antidepressants, TCAs remain an essential component of the treatment arsenal for various mental health disorders. Their well-established efficacy, along with ongoing research and development in the field, ensures that TCAs will continue to play a significant role in managing these conditions in the foreseeable future.
Doxepin (Tricyclic antidepressants), classified under Antidepressants
Antidepressants are a category of pharmaceutical Active Pharmaceutical Ingredients (APIs) widely used in the treatment of depression and other mood disorders. These medications work by balancing the levels of certain chemicals in the brain called neurotransmitters, such as serotonin, norepinephrine, and dopamine.
There are several types of antidepressants available, each with its own mechanism of action and efficacy. Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed as a first-line treatment for depression. They prevent the reabsorption of serotonin, resulting in increased serotonin levels in the brain. Examples of popular SSRIs include fluoxetine, sertraline, and escitalopram.
Tricyclic antidepressants (TCAs) are another class of antidepressants that work by blocking the reuptake of both serotonin and norepinephrine. They are generally used when SSRIs are ineffective or not well-tolerated. Amitriptyline, nortriptyline, and imipramine are commonly prescribed TCAs.
Other antidepressants include serotonin-norepinephrine reuptake inhibitors (SNRIs), atypical antidepressants, and monoamine oxidase inhibitors (MAOIs). SNRIs, such as venlafaxine and duloxetine, inhibit the reuptake of both serotonin and norepinephrine. Atypical antidepressants, including bupropion and mirtazapine, have diverse mechanisms of action, targeting multiple neurotransmitters. MAOIs, such as phenelzine and tranylcypromine, work by inhibiting the enzyme monoamine oxidase, which breaks down neurotransmitters.
It is important to note that antidepressants may have various side effects and require close monitoring by healthcare professionals. Dosages and treatment duration vary based on individual needs and response. Antidepressants are typically prescribed as part of a comprehensive treatment plan that may include psychotherapy and lifestyle modifications.
In conclusion, antidepressants are a vital category of pharmaceutical APIs used to manage depression and related mood disorders. They act on neurotransmitters in the brain to alleviate symptoms and improve overall well-being. It is crucial to consult with a healthcare provider to determine the most suitable antidepressant and monitor its effects.
Doxepin API manufacturers & distributors
Compare qualified Doxepin API suppliers worldwide. We currently have 1 companies offering Doxepin API, with manufacturing taking place in 1 different countries. Use the table below to review supplier type, countries of origin, certifications, product portfolio and GMP audit availability.
| Supplier | Type | Country | Product origin | Certifications | Portfolio |
|---|---|---|---|---|---|
| SETV Global | Producer | India | India | CoA, FDA, GMP | 515 products |
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