Prescription Drug Information: Doxepin Hydrochloride (Page 3 of 5)
8.6. Use in Patients with Hepatic Impairment
Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Initiate Doxepin HCl Tablets treatment with 3 mg in patients with hepatic impairment and monitor closely for adverse daytime effects. [see Clinical Pharmacology (12.3)]
8.7. Use in Patients with Sleep Apnea
Doxepin HCl Tablets 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 HCl Tablets is prescribed to patients with compromised respiratory function. In patients with severe sleep apnea, Doxepin HCl Tablets is ordinarily not recommended for use.
9. DRUG ABUSE AND DEPENDENCE
9.1. Controlled Substance
Doxepin is not a controlled substance.
9.2. Abuse
Doxepin is not associated with abuse potential in animals or in humans. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of doxepin (e.g., incrementation of dose, drug-seeking behavior).
9.3. Dependence
In a brief assessment of adverse events observed during discontinuation of doxepin following chronic administration, no symptoms indicative of a withdrawal syndrome were observed. Thus, doxepin does not appear to produce physical dependence.
10. OVERDOSAGE
Doxepin is routinely administered for indications other than insomnia at doses 10- to 50-fold higher than the highest recommended dose of Doxepin HCl Tablets.
The signs and symptoms associated with doxepin use at doses several-fold higher than the maximum recommended dose (Excessive dose) of Doxepin HCl Tablets for the treatment of insomnia are described [see Overdosage (10.1)] , as are signs and symptoms associated with higher multiples of the maximum recommended dose (Critical overdose) [see Overdosage (10.2)].
10.1. Signs and Symptoms of Excessive Doses
The following adverse effects have been associated with use of doxepin at doses higher than 6 mg.
Anticholinergic Effects: constipation and urinary retention.
Central Nervous System: disorientation, hallucinations, numbness, paresthesias, extrapyramidal symptoms, seizures, tardive dyskinesia.
Cardiovascular: hypotension.
Gastrointestinal: aphthous stomatitis, indigestion.
Endocrine: raised libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels, and syndrome of inappropriate antidiuretic hormone secretion.
Other: tinnitus, weight gain, sweating, flushing, jaundice, alopecia, exacerbation of asthma, and hyperpyrexia (in association with chlorpromazine).
10.2. Signs and Symptoms of Critical Overdose
Manifestations of doxepin critical overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Electrocardiogram changes, particularly in QRS axis or width, are clinically significant indicators of tricyclic compound toxicity. Other signs of overdose may include, but are not limited to: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia.
10.3. Recommended Management
As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. In addition, the possibility of a multiple drug ingestion should be considered.
If an overdose is suspected, an ECG should be obtained and cardiac monitoring should be initiated immediately. The patient’s airway should be protected, an intravenous line should be established, and gastric decontamination should be initiated. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is strongly advised. If signs of toxicity occur at any time during this period, extended monitoring is recommended. There are case reports of patients succumbing to fatal dysrhythmias late after overdose; these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.
Gastrointestinal Decontamination
All patients suspected of overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by administration of activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.
Cardiovascular
A maximal limb-lead QRS duration of ≥0.10 seconds may be the best indication of the severity of an overdose. Serum alkalinization, using intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55 for patients with dysrhythmias and/or QRS widening. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO2 <20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in treatment of tricyclic compound poisoning.
Central Nervous System
In patients with central nervous system depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or, if these are ineffective, other anticonvulsants (e.g., phenobarbital or phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.
Psychiatric Follow-up
Since overdose often is deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
Pediatric Management
The principles of management of child and adult overdoses are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
11. DESCRIPTION
Doxepin HCl Tablets is available in 3 mg and 6 mg strength tablets for oral administration. Each tablet contains 3.39 mg or 6.78 mg doxepin hydrochloride, equivalent to 3 mg and 6mg of doxepin, respectively.
Chemically, doxepin hydrochloride is an (E) and (Z) geometric, isomeric mixture of 1 propanamine, 3-dibenz[b,e] oxepin-11(6H)ylidene-N,N -dimethyl-hydrochloride. It has the following structure:
Doxepin hydrochloride is a white crystalline powder, with a slight amine-like odor, that is readily soluble in water. It has a molecular weight of 315.84 and molecular formula of C19 H21 NO∙HCl.
Each Doxepin HCl Tablets tablet includes the following inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate. The 3 mg tablet also contains FD&C Blue No.1. The 6 mg tablet also contains D&C Yellow No. 10 and FD&C Blue No. 1.
12. CLINICAL PHARMACOLOGY
12.1. Mechanism of Action
The mechanism of action of doxepin in sleep maintenance is unclear; however, doxepin’s effect could be mediated through antagonism of the H1 receptor.
12.2. Pharmacodynamics
Doxepin has high binding affinity to the H1 receptor (Ki < 1 nM)
Cardiac Electrophysiology
In a thorough QTc prolongation clinical study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg.
12.3. Pharmacokinetics
Absorption
The median time to peak concentrations (Tmax ) of doxepin occurred at 3.5 hours postdose after oral administration of a 6 mg dose to fasted healthy subjects. Peak plasma concentrations (Cmax ) of Doxepin HCl Tablets increased in approximately a dose-proportional manner for 3 mg and 6 mg doses. The AUC was increased by 41% and Cmax by 15% when 6 mg Doxepin HCl Tablets was administered with a high fat meal. Additionally, compared to the fasted state, Tmax was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended that Doxepin HCl Tablets not be taken within 3 hours of a meal [see Dosage and Administration (2.3)].
Distribution
Doxepin HCl Tablets is widely distributed throughout the body tissues. The mean apparent volume of distribution following a single 6 mg oral dose of Doxepin HCl Tablets to healthy subjects was 11,930 liters. Doxepin HCl Tablets is approximately 80% bound to plasma proteins.
Metabolism
Following oral administration, Doxepin HCl Tablets is extensively metabolized by oxidation and demethylation. The primary metabolite is N-desmethyldoxepin (nordoxepin).
The primary metabolite undergoes further biotransformation to glucuronide conjugates.
In vitro studies have shown that CYP2C19 and CYP2D6 are the major enzymes involved in doxepin metabolism, and that CYP1A2 and CYP2C9 are involved to a lesser extent.
Doxepin appears not to have inhibitory effects on human CYP enzymes at therapeutic concentrations. The potential of doxepin to induce metabolizing enzymes is not known. Doxepin is not a Pgp substrate.
Excretion
Doxepin 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.The apparent terminal half-life (t ½) of doxepin was 15.3 hours and for nordoxepin was 31 hours.
Drug Interactions
Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of these CYP isozymes may increase the exposure of doxepin.
Cimetidine
The effect of cimetidine, a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4, on Doxepin HCl Tablets plasma concentrations was evaluated in healthy subjects. When cimetidine 300 mg BID was co-administered with a single dose of Doxepin HCl Tablets 6 mg, there was approximately a 2-fold increase in Doxepin HCl Tablets Cmax and AUC compared to Doxepin HCl Tablets given alone. A maximum dose of doxepin in adults and elderly should be 3 mg, when doxepin is co-administered with cimetidine.
Sertraline
The effect of sertraline HCl, a selective serotonin reuptake inhibitor, on doxepin plasma concentrations was evaluated in a daytime study conducted with 24 healthy subjects. Following co-administration of doxepin 6 mg with sertraline 50 mg (at steady-state), the doxepin mean AUC and Cmax estimates were approximately 21% and 32% higher, respectively, than those obtained following administration of doxepin alone. Psychomotor function as measured by the digit symbol substitution test and symbol copy test performance was decreased more at 2-4 hours post dosing for the combination of sertraline and doxepin as compared to doxepin alone, but subjective measures of alertness were comparable for the two treatments.
Special Populations
Renal Impairment
The effects of renal impairment on doxepin pharmacokinetics have not been studied. Because only small amounts of doxepin and nordoxepin are eliminated in the urine, renal impairment would not be expected to result in significantly altered doxepin concentrations.
Hepatic Impairment
The effects of Doxepin HCl Tablets in patients with hepatic impairment have not been studied. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic impairment may display higher doxepin concentrations than healthy individuals.
Poor Metabolizers of CYPs
Poor metabolizers of CYP2C19 and CYP2D6 may have higher doxepin plasma levels than normal subjects.
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