The P-I-E-N-O Parkinsn's List Drug Database
doxepin / SinequanTM , AdapinTM , ZonalonTM
ANTIDEPRESSANT:
tricyclic
Description: Doxepin is a tricyclic antidepressant of the dibenzoxepin type. In addition to depression, doxepin has been used in the treatment of peptic ulcer disease; to treat chronic, severe neurogenic pain; and to treat pruritus in idiopathic cold pruritus. Doxepin was originally approved by the FDA in 1969. A topical formulation of doxepin (Zonalon) was approved for pruritus associated with eczema in 1994.
Mechanism of Action: The concise action of tricyclic antidepressants is not fully understood, but it is believed that their most important effect is to enhance the actions of norepinephrine and serotonin by blocking the reuptake of various neurotransmitters at the neuronal membrane. Doxepin most closely resembles amitriptyline in mechanism of action: both agents exert effects on norepinephrine and serotonin. Recent evidence suggests that the upset of monoamine output seen in depressed patients may be regulated by long-term treatment with antidepressants due to their action on œ-adrenergic receptors. This action on œ-receptors may be a better explanation than the reuptake theory of these agents' antidepressant effects.
Monoamine oxidase is not inhibited by tricyclic drugs. Tricyclic antidepressants do not affect dopamine reuptake. Varying degrees of sedation can be produced, being high with doxepin, due to strong binding affinity for histamine HA-receptors, and the seizure threshold can be lowered. The antipruritic action of doxepin is thought to be secondary to blockade of HA-receptors. Anticholinergic activity is moderate and may be responsible for the inhibition of urination in the treatment of enuresis. Cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function combined with anticholinergic activity and norepinephrine potentiation. Changes in sex hormone concentrations and blood glucose can result from doxepin's effect on the endocrine system.
Pharmacokinetics: Doxepin appears to be well absorbed from the gut following oral administration, and peak plasma concentration is achieved in about 2 hours. There is wide distribution throughout the body. The full antidepressant effects can take 2 or more weeks to stabilize, but adverse effects may be seen within a few hours. Tricyclic antidepressants are highly protein-bound in plasma and tissues. Because the tricyclic antidepressants are long-acting, a single daily dose may be given to improve patient compliance.
Following topical administration doxepin is absorbed through the skin. The amount of absorption is increased by use of occlusive dressings. Plasma concentrations are highly variable and range from negligible to about one third the concentration seen after an oral dose of doxepin taken for treatment of depression.
Metabolism takes place in the liver to produce an active metabolite, N-demethyldoxepin, which is known to be distributed into breast milk. Enterohepatic circulation may occur as well as secretion of both unchanged drug and metabolites into gastric juice. Lipophilic metabolites, such as the N-monodemethylated derivatives, are most likely to be reabsorbed and further metabolized. Primary excretion is in the urine, and the halflife of doxepin is 6-8 hours.
CONTRAINDICATIONS/PRECAUTIONS: Anticholinergic effects of tricyclic antidepressants contraindicate their use in patients with decreased GI motility. Tricyclic antidepressants can induce or exacerbate hiatal hernia, and can cause paralytic ileus or constipation. Patients who have increased intraocular pressure or angle-closure glaucoma, benign prostatic hypertrophy, GI disease, gastroesophageal reflux disease (GERD), or urinary retention should be treated with caution because of the anticholinergic activity of tricyclic antidepressants. Anticholinergic effects appear most frequently and cause the greatest morbidity in geriatric patients.
Following prolonged therapy in high doses, abrupt discontinuation of the tricyclic antidepressant should be avoided because this can precipitate symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea. This is particularly true for the tertiary amine tricyclic antidepressants: amitriptyline, imipramine, clomipramine, trimipramine, and doxepin.
Tricyclic antidepressants should be used with caution in patients who have a history of alcoholism or who may use alcohol or other sedative medications because the depressant effects on the CNS can be potentiated. Decreased mental alertness can occur.
Tricyclic antidepressants can exacerbate schizophrenia or manic symptoms of bipolar disorder because of the drugs' effects on the CNS. Bipolar disorder patients who are not concomitantly treated with an anticyclic medication are likely to switch from depression to mania, and some schizophrenic patients can experience exacerbation of psychosis.
Tricyclic antidepressants should be used with extreme caution in patients with a preexisting seizure disorder because the seizure threshold may be lowered.
Tricyclic antidepressants should be used with caution in patients with Parkinson's disease. Tricyclic antidepressants rarely can induce or worsen extrapyramidal symptoms. In addition, involuntary movements, which appear to be tardive dyskinesia, can occur.
Patients with respiratory depression should be treated cautiously with tricyclic antidepressants because of additive CNSdepressant effects.
Tricyclic antidepressants should be used with caution in patients (especially children and elderly) with cardiac disease because of the alterations in ECG patterns. Many adverse cardiovascular effects are associated with the use of tricyclic antidepressant drugs, and they could lead to complete cardiac collapse and sudden death. While these events are more likely to occur after acute overdose, patients with cardiovascular disease should be closely monitored and regular ECG tracings made. Tricyclic antidepressants should not be given to patients who are in the acute recovery phase following myocardial infarction; sudden death is possible.
Asthma can be aggravated by administering tricyclic antidepressants to patients with the disease, especially to patients with a known sulfite hypersensitivity. Sulfites in the tablet may be responsible for allergic reactions.
Tricyclic antidepressants are known to produce an allergic response in some patients. There appears to be crosssensitivity, so caution should be used when changing from one tricyclic antidepressant to another. Alternative therapy should be considered. Alternative therapy should be considered. Tricyclic antidepressants can also display cross-sensitivity to carbamazepine, maprotiline, or trazodone.
Tricyclic antidepressant therapy should be discontinued for several days prior to elective surgery because of the risk of hypertensive episodes.
On rare occasions, agranulocytosis, thrombocytopenia, eosinophilia, leukopenia, or purpura have been reported with tricyclic antidepressants. Any patient with symptoms of a blood dyscrasia (sore throat, fever, bruising, etc.) should have immediate laboratory studies performed and suitable therapy initiated. Use tricyclic antidepressants cautiously in patients with preexisting hematological disease.
Intramuscular injections should be administered cautiously to patients receiving doxepin. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to doxepin therapy.
Tricyclic antidepressants should be used with caution in patients with hepatic disease. Use of tricyclic antidepressants has caused hepatitis and jaundice, which are reversible on discontinuation of the drug. Hepatic failure and death have occurred when tricyclic antidepressants were continued. Liverfunction tests should be performed and the drug discontinued if there is persistent elevation of enzymes. Metabolism of tricyclic antidepressants may be altered in patients with hepatic impairment.
Patients may be more prone to sunburn during therapy with a tricyclic antidepressant. Suitable precautions should be taken such as wearing long-sleeved clothing and a hat, and routinely applying a sunblock with an SPF "15.
Tricyclic antidepressants should be used with caution in patients who have hyperthyroidism or are receiving thyroid drugs. Concomitant use with thyroid drugs can produce cardiac arrhythmias. Hypothyroidism that is untreated will prevent adequate response to antidepressant therapy. Thyroid agents also can accelerate the onset of the response to tricyclic antidepressants.
Tricyclic antidepressants affect blood glucose concentrations because of their effect on the endocrine system, so they should be used with caution in patients with diabetes mellitus.
Doxepin is classified as a pregnancy category C drug. Tricyclic antidepressants are not recommended for use during pregnancy, unless the possible benefits outweigh the risks. Patients should be made aware of the risks to the neonate: possible fetal abnormality, delayed development, or withdrawal symptoms. , Because the drugs are excreted into breast milk, the benefits and risks of breast-feeding should be carefully weighed if tricyclic antidepressants are needed in the mother.
DRUG INTERACTIONS: Concurrent use of tricyclic antidepressants and monoamine oxidase inhibitors (MAOIs), such as furazolidone, isocarboxazid, phenelzine, procarbazine, selegiline, or tranylcypromine, can cause hyperpyrexia, hypertension, or seizures. In the rare patients who need this combination therapy, the interaction can be minimized by initiating therapy with a tricyclic antidepressant and then beginning MAOI therapy at low doses, followed by a very gradual increase. The tricyclic antidepressant should inhibit the uptake of tyramine from food in the GI tract; the subsequent addition of an MAOI should not lead to high levels of tyramine. Conversely, tricyclic antidepressants should not be added to an exisiting MAOI regimen because the reuptake blockade will be unopposed due to the existing inhibition of the main elimination pathway. An interval of 14 days is recommended between cessation of an irreversible MAOI agent and initiation of tricyclic antidepressant therapy.
Tricyclic antidepressants (with the exception of doxepin in doses <150 mg/day) block the uptake of guanadrel, guanethidine, and methyldopa into norepinephrine neurons, preventing the expected antihypertensive effects. Reserpine and other rauwolfia alkaloids can have decreased antihypertensive effects in the presence of tricyclic antidepressants. Guanabenz use can increase the circulation of catecholamines. Concomitant use of tricyclic antidepressants can lead to hypertension, especially during the second week of tricyclic antidepressant therapy. Occasionally, the hypertension will occur within the first few days of tricyclic antidepressant therapy.
Labetalol, when used with tricyclic antidepressants, has been reported to cause an increased incidence of tremor.
Clonidine's antihypertensive effect can be reduced by tricyclic antidepressants (reported with imipramine and desipramine). Concomitant use of tricyclic antidepressants can lead to hypertension, especially during the second week of tricyclic antidepressant therapy. Occasionally, the hypertension will occur within the first few days of tricyclic antidepressant therapy. In addition, concurrent administration of a tricyclic antidepressant (amitriptyline) and clonidine in rats has produced corneal lesions within 5 days.
Ethanol or other CNS depressants should be combined cautiously with tricyclic antidepressants because this could cause additive depressant effects and possible respiratory depression or hypotension. Barbiturates and carbamazepine induce hepatic microsomal enzymes and increase the metabolism of tricyclic antidepressants. The tricyclic antidepressants' plasma concentrations are reduced and may require an increase in dosage to achieve equivalent therapeutic effects.
Benzodiazepines (alprazolam and diazepam) have been reported to increase the concentrations of tricyclic antidepressants (imipramine and amitriptyline) or metabolites (desipramine and nortriptyline) when coadministered. This is a commonly used drug combination and is considered to be safe, as long as patients are monitored for excessive adverse effects from either agent. Benzodiazepines and tricyclic antidepressants will produce additive CNS depression.
Serotonin specific reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, paroxetine, and fluvoxamine, are another class of antidepressants that have been reported to cause symptoms of tricyclic antidepressant toxicity when used with a tricyclic antidepressant. The mechanism of this interaction is poorly understood, but it is believed to involve specific isoenzymes of the cytochrome P-450 mixed-function oxidase system. The most critical and well-studied pathway is 2D6. Cytochrome P-450 2D6 is impaired most by fluoxetine and least by sertraline. Patients receiving an SSRI and tricyclic antidepressant should be monitored closely for excessive adverse effects from either agent.
Tricyclic antidepressants can lower the seizure threshold. Concomitant use with anticonvulsants may require increased concentrations of the anticonvulsant to achieve equivalent effects.
Cholestyramine can decrease the serum concentrations of imipramine. While it is logical to conclude that staggering the times of administration may avoid this interaction, doing so did not prevent a similar interaction between cholestyramine and doxepin even when the doses were separated by 6 hours. Until more data are available, clinicians should avoid using cholestyramine in patients stabilized on doxepin or imipramine.
Tricyclic antidepressants used concomitantly with disulfiram or ethchlorvynol can produce transient delirium.
Tricyclic antidepressants used concomitantly with strong anticholinergic agents, such as anticholinergics; HA-blockers; cyclobenzaprine; antipsychotics (haloperidol, loxapine, molindone, phenothiazines, or thioxanthenes); amoxapine; or metoclopramide, will increase the anticholinergic and sedative effects. Concomitant therapy should be avoided whenever possible. If coadministration is necessary, doses of both drugs should be started lower and increased cautiously with careful monitoring.
Tricyclic antidepressants can potentiate cardiac arrhythmias if used concurrently with pimozide.
Pressor effects of ophthalmic or nasal vasoconstrictors (naphazoline, oxymetazoline, phenylephrine, or xylometazoline) can be potentiated by tricyclic antidepressants. Concomitant use of tricyclic antidepressants with sympathomimetics (isoproterenol, phenylephrine, norepinephrine, epinephrine, or amphetamines) can cause adverse cardiovascular effects such as arrhythmias, tachycardia, or severe hypertension or hyperpyrexia.
Tricyclic antidepressant metabolism can be inhibited by cimetidine or ranitidine, resulting in increased plasma levels of the tricyclic antidepressant and, possibly, toxicity. Patients should be closely observed for toxic effects such as orthostatic hypotension or sedation.
Oral contraceptives, fluoxetine, erythromycin, or methylphenidate can inhibit the hepatic metabolism of tricyclic antidepressants and can increase the risk of tricyclic antidepressant toxicity if used concurrently.
The risk of developing agranulocytosis is increased if tricyclic antidepressant drugs are used concurrently with antithyroid agents.
Tricyclic antidepressants used concomitantly with thyroid hormones can increase the therapeutic and toxic effects, such as arrhythmias and CNS stimulation, of both medicines.
The anticholinergic activity of tricyclic antidepressants can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
The prothrombin time (and presumably INR) of patients stabilized on warfarin has been reported to increase from tricyclic antidepressants (amitriptyline). Similarly, dicumarol plasma concentrations have been observed to increase when tricyclic antidepressants (amitriptyline and nortriptyline) were added. The mechanism is not understood, but it may be due to anticholinergic effects decreasing gastrointestinal motility, leading to increased bioavailability of the oral anticoagulant.
ADVERSE REACTIONS: A wide variety of cardiovascular side effects can result from the use of tricyclic antidepressants due to their direct quinidinelike action, their potent anticholinergic properties, and their ability to potentiate norepinephrine. Ventricular tachycardia, palpitations, hypertension, and orthostatic hypotension all can be precipitated, with the possibility of more severe reactions occurring such as myocardial infarction, congestive heart failure, or stroke. Imipramine, and possibly other tricyclic antidepressants, can cause both PR prolongation and QT prolongation. Imipramine and nortriptyline are known to prolong the QRS interval. Other tricyclics would be expected to produce similar ECG changes. The cardiovascular response to tricyclic antidepressants depends on the specific agent and the dose. Although all tricyclic antidepressants are thought to be proarrhythmic after acute overdoses, at therapeutic doses, their actions on the conducting system of the heart may vary. Imipramine has been utilized therapeutically for its antiarrhythmic effect. The cardiovascular response to tricyclic antidepressants is varied, and patients most at risk have preexisting cardiovascular disease. Some reviews consider the association between doxepin and either QT prolongation or torsade de pointes at therapeutic doses to be rare.
Drowsiness is the most frequent adverse CNS effect during therapy with tricyclic antidepressants. Sedation can be made into a desirable effect by administering the tricyclic antidepressant at bedtime, minimizing any undesirable drowsiness and sedation during the day. Dizziness usually is due to orthostatic hypotension and can be reduced by having the patient change positions more slowly. Sedation is the most commonly reported systemic effect from topical application of doxepin, occuring in about 22% of patients. Some patients exhibit excitation and anxiety. Confusion is most apparent in the elderly. Topical application occasionally causes emotional changes, fatigue, headace and thirst.
Peripheral nervous system adverse reactions can occur during therapy with tricyclic antidepressants. Tremor can result from norepinephrine reuptake blockade. Rarely, extrapyramidal symptoms can occur in both young and elderly patients. Parkinsonism is more likely to occur in the elderly, especially if they are receiving high doses.
Seizures and EEG changes have been observed more commonly in children than in adults during therapy with tricyclic antidepressants. Patients that have a preexisting seizure disorder may require increased concentrations of their anticonvulsant to maintain seizure control.
Ocular manifestations of the anticholinergic actions of tricyclic antidepressants include blurred vision due to cycloplegia, mydriasis, and increased intraocular pressure. Increased intraocular pressure can precipitate a crisis in patients with angle-closure glaucoma. Ophthalmological examination is recommended when there are visual changes.
Gastrointestinal manifestations of tricyclic antidepressants' anticholinergic activity include dry mouth (xerostomia), constipation, urinary retention, adynamic ileus, abdominal pain or cramps, nausea/vomiting, anorexia, diarrhea, and jaundice. Constipation is more commonly observed in elderly patients. If these symptoms become severe, withdrawal of the drug may be necessary. Topical application also produces xerostomia in between 1-10% of patients.
Allergic reactions to tricyclic antidepressants can include photosensitivity, vasculitis, erythema, urticaria, fever, and/or pruritus. Fever also can indicate a blood dyscrasia. Topical application of doxepin frequently causes burning or stinging at the application site (21% of patients). Less frequently (1-10% of patients) exacerbation of eczema or pruritus, and increased dryness or tightness of the skin have been reported. Paresthesias and edema were evident in 1-10% of patients. Less than 1% of patients reported irritation, tingling, scaling, and cracking of skin at the application site.
The effects of tricyclic antidepressants on the endocrine system can cause sexual dysfunction including libido decrease, testicular swelling, ejaculation dysfunction, breast enlargement, and galactorrhea in females or gynecomastia in males. The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) has been reported. Glucose metabolism can be altered and should be monitored in patients with diabetes mellitus.
Doxepin may cause hematologic adverse reactions. These effects inclue agranulocytosis, eosinophilia, purpura, thrombocytopenia, and leukopenia.
PATIENT INFORMATION:
What do doxepin capsules do?
Doxepin (SinequanTM ) belongs to a group of medicines called tricyclic antidepressants. Doxepin can lift your spirits and relieve your depression. Generic doxepin capsules are available.
What should my doctor, dentist, and pharmacist know before I take doxepin?
They need to know if you have any of these conditions:
How should I take this medicine?
Take doxepin capsules by mouth. Follow the directions on the prescription label. Swallow the capsules with a drink of water. Take your doses at regular intervals. Do not take your medicine more often than directed. Do not stop taking except on your doctor's advice.
Special precautions for use in children:
This medicine is not for children under 12 years old.
Elderly patients over 65 years old may have a stronger reaction to this medicine and need smaller doses.
What if I miss a dose?
If you miss a dose, take it as soon as you can. If it is almost time for your next dose, take only that dose. Do not take double or extra doses. If you are only taking doxepin once a day at bedtime and forget your dose, check with your doctor before taking it in the morning.
What other medicines can interact with doxepin?
Doxepin can interact with many other medicines. An interaction can be very important or fairly insignificant. Make sure your doctor knows about all other medicines you are taking.
The most important medicines are listed below:
Tell your doctor or pharmacist: about all other medicines you are taking including non-prescription medicines; if you are a frequent user of drinks with caffeine or alcohol; if you smoke; or if you use illegal drugs. These can affect the way your medicine works. Check before stopping or starting any of your medicines.
What side effects might I notice from taking doxepin?
Serious side effects with doxepin include:
Call your doctor as soon as you can if you get any of these side effects.
Minor side effects with doxepin include:
Let your doctor know about these side effects if they do not go away or if they annoy you.
What do I need to watch for while I take doxepin?
Visit your doctor for regular checks on your progress. It can take several days before you feel the full effect of doxepin. If you have been taking doxepin regularly for some time, do not suddenly stop taking it. Ask your doctor for advice. Even after you stop taking doxepin it can still affect your body for several days.
If you are going to have surgery, tell your doctor or dentist that you are taking doxepin well before the scheduled date of surgery.
You may get dizzy, drowsy or have blurred vision; until you know how doxepin affects you, do not drive, use machinery, or do anything that needs mental alertness. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can increase the side effects of doxepin; avoid alcoholic drinks. Doxepin can make your skin more sensitive to the sun or UV light. Keep out of the sun, or wear protective clothing outdoors and use a sunscreen. Do not use sun lamps or sun tanning beds or booths.
If you are diabetic, check your blood sugar levels more often than usual, especially during the first few weeks of treatment with doxepin. Doxepin can affect your blood sugar levels. Call your doctor for advice if you notice a change in the results of your urine or blood sugar tests.
Where should I keep my medicine?
Keep out of the reach of children in a container that small children cannot open.
Store at room temperature between 15 and 30C (59 and 86F). Throw away any unused medicine after the expiration date.
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