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Systemic Adverse Effects from Topical Doxepin Cream

TO THE EDITOR:We report a case of anticholinergic toxicity associated with topically applied doxepin in an elderly man. Case Report. An 80-year-old white male nursing home patient with moderately severe dementia was treated for several months for excoriations on both arms from frequent scratching. No skin rash was evident. Initially, the areas were kept clean and covered with a dressing; however, the scratching continued. Over several months, attempts at management included long-sleeve shirts, gloves, taped arm wraps, and nonmedicated moisturizing lotions. The scratching and excoriations persisted. Considering the scratching as a neurodermatitis and perhaps a manifestation of the patient’s dementia, empiric treatment was begun with haloperidol 1 mg at bedtime. This was discontinued after a two-week trial without benefit. He was then started on carbamazepine 100 mg twice daily, and the dosage was increased to 100 mg in the morning and 200 mg at bedtime after one week. No benefit was seen after three weeks of treatment; therefore, the carbamazepine was discontinued. Additionally, as empiric treatment for possible atopic dermatitis, hydroxyzine 25 mg twice daily for two weeks and loratadine 10 mg/d for five weeks were given in separate trials. The antihistamine therapy produced no changes in the scratching behavior. A trial of acetaminophen was initiated and continued through the time of doxepin therapy; this agent was also ineffective. Therapy with doxepin 5% topical cream was initiated, which was applied to both arms as well as areas on his legs and back three times daily. After two days, the nurses noted the patient was more confused and was yelling. On the third day, he began having difficulty voiding and over the next several days required frequent catheterizations. He also became “thick-tongued.” On day 6 of doxepin therapy, he required treatment for a stool impaction. On day 14 of treatment, the patient began having visual hallucinations, reaching for objects in the air. Doxepin was discontinued at that time. Most of a 30-g tube of doxepin cream had been used. Over the next few days, the patient voided more easily without the need for catheterizations. One week later, the yelling and hallucinations decreased significantly, but persisted. He continued to exhibit some increased confusion compared with that before doxepin was started. Risperidone 0.5 mg at bedtime was initiated. Three weeks later, the nursing staff indicated the patient had returned to his condition prior to initiation of doxepin. The scratching had not diminished over the course of doxepin treatment. The patient’s past medical history included mild chronic obstructive pulmonary disease, type 2 diabetes mellitus, and chronic constipation. Routine medications included glyburide 2.5 mg/d, casanthranol 30 mg with docusate 100 mg, and acetaminophen 650 mg four times daily. He had used an albuterol inhaler, but had not required this in the past two years. Fasting blood glucose during the time he received doxepin was unchanged from previous measurements (103–211 mg/dL). The patient had no history of urinary retention. During the time he was treated for scratching behavior, he twice received courses of sertraline, initiated because of agitation with nursing care, decreasing social interaction, a sad mood, and spending more time in his room. Sertraline was never used concurrently with the previously outlined therapeutic trials and was last discontinued six weeks before the doxepin trial; it also had no effect on his scratching. Discussion.This case represents probable systemic anticholinergic toxicity from topical doxepin administration. 1 Symptoms began on day 2 of therapy; we did not associate doxepin with this reaction until day 14. Symptoms significantly improved over the following weeks. Doxepin has significant antihistaminic properties, and the topical formulation is marketed as an antipruritic. Systemic absorption from topically administered doxepin is well documented. The manufacturer 2 states that serum concentrations from undetectable to 47 ng/mL were found in 19 patients with eczema treated with topical doxepin for eight days. Drake et al. 3 treated 24 adults with acute atopic dermatitis for eight days. On day 8, serum concentrations were undetectable (<5 μg/L) in five patients. In the remaining patients, concentrations varied from 5 to 67 μg/L. The therapeutic serum concentrations of doxepin for depression are 30–150 μg/L. The prescribing information 2,4 for topical doxepin indicates drowsiness as the most common systemic adverse effect. Other possible anticholinergic adverse effects described included dry mouth and emotional changes. Delirium, urinary retention, and constipation are not mentioned. Sedation from topical doxepin has been reported during clinical trials. Additionally, two case reports 5,6 of severe doxepin toxicity in children from topical application have been published. Toxic symptoms with anticholinergic agents may include dry mouth, blurred vision, sinus tachycardia, constipation, urinary retention, and delirium. Our patient demonstrated urinary retention and delirium. He also had a stool impaction during doxepin therapy; however, he had a history of chronic constipation. The nurses’ observation of “thick-tongued” may have represented dry mouth. The patient’s blood pressure and heart rate were never elevated. The patient’s age and dementia may have predisposed him to these reactions. His skin was abraded, which may have enhanced drug absorption. The events described here suggest that topical doxepin was the cause of the hallucinations and aggressive behavior, although we cannot support this with more objective information. Unfortunately, we did not obtain a doxepin concentration during the time our patient was experiencing toxic symptoms. Rechallenge with doxepin was not considered clinically appropriate. The fact that his confusion did not resolve completely after the doxepin is difficult to evaluate because of the unpredictable course of dementia. Possible systemic adverse events must be considered when topical doxepin cream is used. Increased adverse drug reaction monitoring of patients using doxepin cream is recommended.