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importance, sufficient time must elapse before initiating TCA treatment in a 1 Includes reports of "dry lips", "dry throat", and "thirst" patient being withdrawn from fluoxetine, given the long halflife of the parent 2 Includes reports of "pruritus exacerbated" and active metabolite (at least 5 weeks may be necessary).
3 Includes report of "increased irritation at application site" Concomitant use of tricyclic antidepressants with drugs that can inhibit 4 Includes reports of "lightheadedness" and "dizziness/vertigo" cytochrome P450 2D6 may require lower doses than usually prescribed for 5 Includes reports of "bitter taste" and "metallic taste in mouth" either the tricyclic antidepressant or the other drug. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with Adverse events occurring in 0.5% to < 1.0% of PRUDOXIN™ Cream another drug known to be an inhibitor of P450 2D6.
treated patients in the controlled clinical trials included: nervousness/ PRUDOXIN™ (doxepin hydrochloride) CREAM, 5%
anxiety, tongue numbness, fever, and nausea.
FOR TOPICAL DERMATOLOGIC USE ONLY — MAO Inhibitors: Serious side effects and even death have been reported fol- NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE.
lowing the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cau- Twenty-six cases of allergic contact dermatitis have been reported in tious initiation of therapy with PRUDOXIN™ Cream. The exact length of time patients using PRUDOXIN™ Cream, twenty of which were documented may vary and is dependent upon the particular MAO inhibitor being used, the by positive patch test to doxepin 5% cream.
PRUDOXIN™ (doxepin hydrochloride) Cream, 5% is a topical cream. Each gram length of time it has been administered, and the dosage involved.
contains: 50 mg of doxepin hydrochloride (equivalent to 44.3 mg of doxepin).
Cimetidine: Serious anticholinergic symptoms (i.e., severe dry mouth, Deaths may occur from overdosage with this class of drugs. As the management is complex and changing, it is recommended that the Doxepin hydrochloride is one of a class of agents known as dibenzoxepin tricyclic urinary retention and blurred vision) have been associated with elevations in physician contact a poison control center for current information on antidepressant compounds. It is an isomeric mixture of N,N-dimethyldibenz[b,e] the serum levels of tricyclic antidepressants when cimetidine therapy is initi- treatment. Signs and symptoms of toxicity develop rapidly after tricyclic oxepin-Δ11(6H),γ-propylamine hydrochloride. Doxepin hydrochloride has an ated. Additionally, higher than expected tricyclic antidepressant levels have antidepressant overdose; therefore, hospital monitoring is required as empirical formula of C19H21NO•HCl and a molecular weight of 316.
been observed when they are begun in patients already taking cimetidine.
soon as possible.
Alcohol: Alcohol ingestion may exacerbate the potential sedative effects of PRUDOXIN™ Cream. This is especially important in patients who may use Should overdosage with topical application of PRUDOXIN™ Cream occur, the signs and symptoms may include: cardiac dysrhythmias, Tolazamide: A case of severe hypoglycemia has been reported in a type severe hypotension, convulsions, and CNS depression, including coma. II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the Changes in the electrocardiogram, particularly in QRS axis or width, are addition of oral doxepin (75 mg/day).
clinically significant indicators of tricyclic antidepressant toxicity.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Other signs of overdose may include: confusion, disturbed concentra- Carcinogenesis, mutagenesis, and impairment of fertility studies have not tion, transient visual hallucinations, dilated pupils, agitation, hyperactive been conducted with doxepin hydrochloride.
reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hy- PRUDOXIN™ Cream also contains sorbitol, cetyl alcohol, isopropyl myristate, Pregnancy Category B: Reproduction studies have been performed in which perpyrexia, or any of the symptoms listed under ADVERSE REACTIONS.
glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide doxepin was orally administered to rats and rabbits at doses up to 0.6 and and purified water.
1.2 times, respectively, the estimated exposure to doxepin that results from General: Obtain an ECG and immediately initiate cardiac monitoring. use of 16 grams of PRUDOXIN™ Cream per day (four applications of four grams Protect the patient's airway, establish an intravenous line and initiate Although doxepin HCl does have H of cream per day; dose multiples reflect comparisons made following nor- gastric decontamination. A minimum of six hours of observation with 1 and H2 histamine receptor blocking actions, the exact mechanism by which doxepin exerts its antipruritic effect is unknown. malization of the data on the basis of body surface area estimates) and have cardiac monitoring and observation for signs of CNS or respiratory de- PRUDOXIN™ Cream can produce drowsiness which may reduce awareness, includ- revealed no evidence of harm to rat or rabbit fetuses due to doxepin. There pression, hypotension, cardiac dysrhythmias and/or conduction blocks, ing awareness of pruritic symptoms. In 19 pruritic eczema patients treated with are, however, no adequate and well-controlled studies in pregnant women. and seizures is strongly advised. If signs of toxicity occur at any time PRUDOXIN™ Cream, plasma doxepin concentrations ranged from nondetectable to Because animal reproduction studies are not always predictive of human during this period, extended monitoring is recommended. There are case 47 ng/mL from percutaneous absorption. Plasma levels from topical application of response, this drug should be used during pregnancy only if clearly needed.
reports of patients succumbing to fatal dysrhythmias late after overdose; PRUDOXIN™ Cream can result in CNS and other systemic side effects.
these patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Once absorbed into the systemic circulation, doxepin undergoes hepatic metabolism Doxepin is excreted in human milk after oral administration. It is possible Monitoring of plasma drug levels should not guide management of the that results in conversion to pharmacologically-active desmethyldoxepin. Further that doxepin may also be excreted in human milk following topical applica- glucuronidation results in urinary excretion of the parent drug and its metabolites. tion of PRUDOXIN™ Cream.
Desmethyldoxepin has a half-life that ranges from 28 to 52 hours and is not One case has been reported of apnea and drowsiness in a nursing infant Cardiovascular: A maximal limb-lead QRS duration of ≥ 0.10 seconds affected by multiple dosing. Plasma levels of both doxepin and desmethyldoxepin whose mother was taking an oral dosage form of doxepin HCl.
may be the best indication of the severity of the overdose. Intravenous are highly variable and are poorly correlated with dosage. Wide distribution occurs sodium bicarbonate should be used to maintain the serum pH in the in body tissues including lungs, heart, brain, and liver. Renal disease, genetic Because of the potential for serious adverse reactions in nursing infants range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation factors, age, and other medications affect the metabolism and subsequent from doxepin, a decision should be made whether to discontinue nursing may also be used. Concomitant use of hyperventilation and sodium elimination of doxepin. (See PRECAUTIONS - Drug Interactions.) or to discontinue the drug, taking into account the importance of the drug bicarbonate should be done with extreme caution, with frequent pH to the mother.
monitoring. A pH >7.60 or a pCO INDICATIONS AND USAGE
2 < 20 mm Hg is undesirable. Dysrhyth- mias unresponsive to sodium bicarbonate therapy/hyperventilation may PRUDOXIN™ Cream is indicated for the short-term (up to 8 days) management respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiar- of moderate pruritus in adult patients with atopic dermatitis or lichen simplex The use of PRUDOXIN™ Cream in pediatric patients is not recommended. rhythmics are generally contraindicated (e.g., quinidine, disopyramide, chronicus. (See DOSAGE AND ADMINISTRATION.) Safe conditions for use of PRUDOXIN™ Cream in children have not been established. One case has been reported of a 2.5-year-old child who and procainamide).
developed somnolence, grand mal seizure, respiratory depression, ECG In rare instances, hemoperfusion may be beneficial in acute refractory Because doxepin HCl has an anticholinergic effect and because significant plasma abnormalities, and coma after treatment with PRUDOXIN™ Cream. A total of cardiovascular instability in patients with acute toxicity. However, hemo- levels of doxepin are detectable after topical PRUDOXIN™ Cream application, the 27 grams had been applied over three days for eczema. He was treated with dialysis, peritoneal dialysis, exchange transfusions, and forced diuresis use of PRUDOXIN™ Cream is contraindicated in patients with untreated narrow supportive care, activated charcoal, and systemic alkalization and recovered.
generally have been reported as ineffective in tricyclic antidepressant angle glaucoma or a tendency to urinary retention.
PRUDOXIN™ Cream is contraindicated in individuals who have shown previous Clinical studies of PRUDOXIN™ Cream did not include sufficient numbers CNS: In patients with CNS depression, early intubation is advised sensitivity to any of its components.
of subjects aged 65 and over to determine whether they respond differently because of the potential for abrupt deterioration. Seizures should from younger subjects. Other reported clinical experience has not identified be controlled with benzodiazepines, or if these are ineffective, other Drowsiness occurs in over 20% of patients treated with PRUDOXIN™ Cream, differences in responses between the elderly and younger patients. In anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not especially in patients receiving treatment to greater than 10% of their body surface general, dose selection for an elderly patient should be cautious, usually recommended except to treat life-threatening symptoms that have been area. Patients should be warned about the possibility of sedation and cautioned
starting at the low end of the dosing range, reflecting the greater frequency unresponsive to other therapies, and then only in consultation with a against driving a motor vehicle or operating hazardous machinery while being
of decreased hepatic, renal or cardiac function, and of concomitant disease poison control center.
treated with PRUDOXIN™ Cream.
or other drug therapy.
Pediatric Management: The principles of management of child and adult The sedating effects of alcoholic beverages, antihistamines, and other CNS depres- The extent of renal excretion of doxepin has not been determined. Because overdosages are similar. It is strongly recommended that the physician sants may be potentiated when PRUDOXIN™ Cream is used.
elderly patients are more likely to have decreased renal function, care should contact the local poison control center for specific pediatric treatment.
be taken in dose selections.
If excessive drowsiness occurs it may be necessary to reduce the frequency of DOSAGE AND ADMINISTRATION
applications, the amount of cream applied, and/or the percentage of body surface Sedating drugs may cause confusion and oversedation in the elderly; elderly A thin film of PRUDOXIN™ Cream should be applied four times each area treated, or discontinue the drug. However, the efficacy with reduced frequency patients generally should be observed closely for confusion and overseda- day with at least a 3 to 4 hour interval between applications. There of applications has not been established.
tion when started on PRUDOXIN™ Cream. (See WARNINGS.) An 80-year-old are no data to establish the safety and effectiveness of PRUDOXIN™ male nursing home patient developed probable systemic anticholinergic tox- Keep this product away from the eyes.
Cream when used for greater than 8 days. Chronic use beyond eight icity which included urinary retention and delirium after PRUDOXIN™ Cream days may result in higher systemic levels and should be avoided. Use of had been applied to his arms, legs and back three times daily for two days.
PRUDOXIN™ Cream for longer than 8 days may result in an increased likelihood of contact sensitization.
Drowsiness: Since drowsiness may occur with the use of PRUDOXIN™ Cream,
Controlled Clinical Trials
patients should be warned of the possibility and cautioned against driving a car The risk for sedation may increase with greater body surface area Systemic Adverse Effects: In controlled clinical trials of patients treated with or operating dangerous machinery while using this drug. Patients should also be application of PRUDOXIN™ Cream (See WARNINGS section). Clinical PRUDOXIN™ Cream, the most common systemic adverse event reported cautioned that their response to alcohol may be potentiated.
experience has shown that drowsiness is significantly more common was drowsiness. Drowsiness occurred in 71 of 330 (22%) of patients treated in patients applying PRUDOXIN™ Cream to over 10% of body surface Sedating drugs may cause confusion and oversedation in the elderly; elderly with PRUDOXIN™ Cream compared to 7 of 334 (2%) of patients treated with area; therefore, patients with greater than 10% of body surface area patients generally should be observed closely for confusion and oversedation when vehicle cream. Drowsiness resulted in the premature discontinuation of the (see WARNINGS section) affected should be particularly cautioned started on PRUDOXIN™ Cream. (See PRECAUTIONS - Geriatric Use.) drug in approximately 5% of patients treated with PRUDOXIN™ Cream in concerning possible drowsiness and other systemic adverse effects of controlled clinical trials.
Use under occlusion: Occlusive dressings may increase the absorption of
doxepin. If excessive drowsiness occurs, it may be necessary to do one most topical drugs; therefore, occlusive dressings should not be utilized with Local Site Adverse Effects: In controlled clinical trials of patients treated with or more of the following: reduce the body surface area treated, reduce PRUDOXIN™ Cream.
PRUDOXIN™ Cream, the most common local site adverse event reported the number of applications per day, reduce the amount of cream applied, was burning and/or stinging at the site of application. These occurred in 76 or discontinue the drug.
Contact sensitization: Use of PRUDOXIN™ Cream can cause Type IV hypersensitiv-
of 330 (23%) of patients treated with PRUDOXIN™ Cream compared to 54 ity reactions (contact sensitization) to doxepin.
Occlusive dressings may increase the absorption of most topical drugs; of 334 (16%) of patients treated with vehicle cream. Most of these reactions therefore, occlusive dressings should not be utilized with PRUDOXIN™ were categorized as "mild"; however, approximately 25% of patients who Studies have not been performed examining drug interactions with PRUDOXIN™ reported burning and/or stinging reported the reaction as "severe". Four Cream. However, since plasma levels of doxepin following topical application of patients treated with PRUDOXIN™ Cream withdrew from the study because HOW SUPPLIED
PRUDOXIN™ Cream can reach levels obtained with oral doxepin HCl therapy, the of the burning and/or stinging.
PRUDOXIN™ Cream is available in a 45 g (NDC 40076-511-45) tube. following drug interactions are possible following topical PRUDOXIN™ Cream application: The table below presents the adverse events reported at an incidence of ≥1% Store at or below 27°C (80°F).
Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing in either PRUDOXIN™ or vehicle cream treatment groups during the trials: isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7-10% of Caucasians are so-called "poor metabo- PRUDOXIN™
Manufactured for: lizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers Burning/Stinging have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8-fold increase in plasma AUC of the TCA).
Prestium Pharma, Inc., Newtown, PA 18940 In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given Fatigue/Tiredness Manufactured by: dosage regimen of a TCA may become abruptly toxic when given one of these Exacerbated Eczema DPT Laboratories, Ltd. inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 San Antonio, Texas 78215 Other Application Site Reaction3 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) PRUDOXIN™ is a registered trademark of Delcor Asset Corporation, and many that are substrates for P450 2D6 (many other antidepressants, phe- an affiliate of Prestium Pharma, Inc.
nothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all Mental/Emotional Changes the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and 2015 Prestium Pharma, Inc.
paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to Taste Perversion5 which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCAs with any of the SSRIs. Of particular

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