Prescription Drugs

CLINICAL PHARMACOLOGY Although doxepin HCl does have H1 and H2 histamine receptor blocking actions, the exact mechanism by which doxepin exerts its antipruritic effect is unknown. Zonalon (doxepin) Cream can produce drowsiness in significant numbers of patients, and this sedation may reduce awareness, including awareness of pruritic symptoms. In 19 pruritic eczema patients treated with Zonalon (doxepin) Cream, plasma doxepin concentrations ranged from nondetectable to 47 ng/mL from percutaneous absorption. Plasma levels from topical application of Zonalon (doxepin) Cream can result in CNS and other systemic side effects. Once absorbed into the systemic circulation, doxepin undergoes hepatic metabolism that results in conversion to pharmacologically-active desmethyldoxepin. Further glucuronidation results in urinary excretion of the parent drug and its metabolites. Desmethyldoxepin has a half-life that ranges from 28 to 52 hours and is not affected by multiple dosing. Plasma levels of both doxepin and desmethyldoxepin are highly variable and are poorly correlated with dosage. Wide distribution occurs in body tissues including lungs, heart, brain, and liver. Renal disease, genetic factors, age, and other medications affect the metabolism and subsequent elimination of doxepin. (See PRECAUTIONS - DRUG INTERACTIONS.)

CLINICAL PHARMACOLOGY Actions The mechanism of action of SINEQUAN (doxepin HCl) is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin HCl does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses, norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, SINEQUAN can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these compounds has been reported. SINEQUAN is virtually devoid of euphoria as a side effect. Characteristic of this type of compound, SINEQUAN has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.

CLINICAL PHARMACOLOGY No information provided.

Find Lowest Prices on ZONALON® (doxepin hydrochloride) Cream, 5% FOR TOPICAL DERMATOLOGIC USE ONLY - NOT FOR OPHTHALMIC, ORAL, OR INTRAVAGINAL USE. DESCRIPTION Zonalon (doxepin hydrochloride) Cream, 5% is a topical cream. Each gram contains: 50 mg of doxepin hydrochloride (equivalent to 44.3 mg of doxepin). Doxepin hydrochloride is one of a class of agents known as dibenzoxepin tricyclic antidepressant compounds. It is an isomeric mixture of N,N-dimethyldibenz[b,e]oxepin-Δ11(6H),γ- propylaminehydrochloride. Doxepin hydrochloride has an empirical formula of C19H21NO•HCl and a molecular weight of 316. Zonalon (doxepin) Cream also contains sorbitol, cetyl alcohol, isopropyl myristate, glyceryl stearate, PEG-100 stearate, petrolatum, benzyl alcohol, titanium dioxide and purified water.

SINEQUAN® (doxepin HCl) Capsules and Oral Concentrate Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Sinequan or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Sinequan is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PATIENT INFORMATION, and PRECAUTIONS: Pediatric Use) DESCRIPTION SINEQUAN® (doxepin hydrochloride) is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform. Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch. Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint oil; propylparaben; water. Chemistry SINEQUAN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of: 1-Propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-, hydrochloride.

Find Lowest Prices on PRUDOXIN™ Cream (doxepin hydrochloride) Cream, 5% NDC 0064-3600-45 For Topical Dermatologic Use Only – Not For Ophthalmic, Oral, or Intravaginal Use. DESCRIPTION PRUDOXIN® Doxepin Hydrochloride Cream, 5% is a fast, non-steroidal alternative that provides soothing relief in minutes from moderate pruritus (itching) associated with atopic dermatitis or lichen simplex chronica.

INDICATIONS Zonalon (doxepin) Cream is indicated for the short-term (up to 8 days) management of moderate pruritus in adult patients with atopic dermatitis or lichen simplex chronicus. (See DOSAGE AND ADMINISTRATION) DOSAGE AND ADMINISTRATION A thin film of Zonalon (doxepin) Cream should be applied four times each day with at least a 3 to 4 hour interval between applications. There are no data to establish the safety and effectiveness of Zonalon (doxepin) Cream when used for greater than 8 days. Chronic use beyond eight days may result in higher systemic levels and should be avoided. Use of Zonalon (doxepin) cream for longer than 8 days may result in an increased likelihood of contact sensitization. The risk for sedation may increase with greater body surface area application of Zonalon cream (See WARNINGS section). Clinical experience has shown that drowsiness is significantly more common in patients applying Zonalon (doxepin) Cream to over 10% of body surface area; therefore, patients with greater than 10% of body surface area (see WARNINGS section) affected should be particularly cautioned concerning possible drowsiness and other systemic adverse effects of doxepin. If excessive drowsiness occurs, it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with Zonalon (doxepin) Cream. HOW SUPPLIED Zonalon (doxepin) Cream is available in 30 g (NDC 62436-523-30) and 45 g (NDC 62436-523-45) tubes. Store at or below 27° C (80° F). Manufactured for: Bioglan Pharma, Inc. Malvern, PA 19355 by: DPT Laboratories, Inc. San Antonio, Texas 78215. FDA Rev date: 12/20/2002

INDICATIONS SINEQUAN is recommended for the treatment of: Psychoneurotic patients with depression and/or anxiety. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. The target symptoms of psychoneurosis that respond particularly well to SINEQUAN include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. Clinical experience has shown that SINEQUAN is safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, SINEQUAN is not recommended for use in children under 12 years of age. DOSAGE AND ADMINISTRATION For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day. In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day. In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25–50 mg/day. The total daily dosage of SINEQUAN may be given on a divided or once-a-day dosage schedule. If the once-a-day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment. Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks. HOW SUPPLIED SINEQUAN is available as capsules containing doxepin HCl equivalent to: 10 mg – 100's (NDC 0049-5340-66) 25 mg – 100's (NDC 0049-5350-66) 50 mg – 100's (NDC 0049-5360-66) 75 mg – 100's (NDC 0049-5390-66) 100 mg – 100's (NDC 0049-5380-66) 150 mg – 50's (NDC 0049-5370-50) SINEQUAN Oral Concentrate is available in 120 mL bottles (NDC 0049-5100-47) with an accompanying dropper calibrated at 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. Each mL contains doxepin HCl equivalent to 10 mg doxepin. Just prior to administration, SINEQUAN Oral Concentrate should be diluted with approximately 120 mL of water, whole or skimmed milk, or orange, grapefruit, tomato, prune or pineapple juice. SINEQUAN Oral Concentrate is not physically compatible with a number of carbonated beverages. For those patients requiring antidepressant therapy who are on methadone maintenance, SINEQUAN Oral Concentrate and methadone syrup can be mixed together with Gatorade®, lemonade, orange juice, sugar water, Tang®, or water; but not with grape juice. Preparation and storage of bulk dilutions is not recommended. Distributed by: Roerig, Division of Pfizer Inc, NY, NY 10017. June 2014

INDICATIONS PRUDOXIN (doxepin) Cream is indicated for the short-term (up to 8 days) management of moderate pruritus in adult patients with the following forms of eczematous dermatitis: atopic dermatitis and lichen simplex chronicus. (See DOSAGE AND ADMINISTRATION.) DOSAGE AND ADMINISTRATION A thin film of PRUDOXIN (doxepin) Cream should be applied four times each day with at least a 3 to 4 hour interval between applications. There are no data to establish the safety and effectiveness of PRUDOXIN (doxepin) Cream when used for greater than eight days. Chronic use beyond eight days may result in higher systemic levels. Clinical experience has shown that drowsiness is significantly more common in patients applying PRUDOXIN (doxepin) Cream to over 10% of body surface area; therefore, patients with greater than 10% of body surface area affected should be particularly cautioned concerning possible drowsiness and other systemic adverse effects of doxepin. If excessive drowsiness occurs it may be necessary to do one or more of the following: reduce the body surface area treated, reduce the number of applications per day, reduce the amount of cream applied, or discontinue the drug. Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings with PRUDOXIN (doxepin) Cream should not be utilized. HOW SUPPLIED PRUDOXIN (doxepin) Cream is available in a 45 g (NDC 0064-3600-45) aluminum tube. Store at or below 27° C (80° F). HEALTH POINT® 1-800-441-8227. www.healthpoint.com. FDA Rev date: n/a

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about: all risks and benefits of treatment with antidepressant medicines all treatment choices for depression or other serious mental illness What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions? Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member? Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling very agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mania) other unusual changes in behavior or mood Visual problems eye pain changes in vision swelling or redness in or around the eye Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. What else do I need to know about antidepressant medicines? Never stop an antidepressant medicine without first talking to a healthcare provider.  Stopping an antidepressant medicine suddenly can cause other symptoms. Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants. Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information. This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

PATIENT INFORMATION PRUDOXIN™ (DOXEPIN HYDROCHLORIDE CREAM), 5% Stop the Itch Fast What is PRUDOXIN™ Cream? PRUDOXIN™ Cream (doxepin hydrochloride cream), 5% is a non-steroidal, moisturizing, topical anti-itch cream. How does PRUDOXIN™ Cream (doxepin) relieve itching? The exact way PRUDOXIN™ Cream (doxepin) works to relieve itching is unknown. However, it does have potent histamine-blocking actions. How quickly does PRUDOXIN™ Cream (doxepin) begin to work? PRUDOXIN™ Cream (doxepin) 's targeted delivery begins to relieve itching within minutes. In one clinical study, 75% of patients reported they began to feel relief in 15 minutes.1 How should I use PRUDOXIN™ Cream (doxepin) ? PRUDOXIN™ Cream (doxepin) should be applied in a thin film to the affected areas four times each day with at least a 3 to 4 hour interval between applications. Can I use PRUDOXIN™ Cream (doxepin) with other medications? Studies have not been performed examining drug interactions with PRUDOXIN (doxepin) ™ Cream. However, data are available regarding potentially significant drug interactions regarding the active ingredient, so certain drug interactions could be possible following topical PRUDOXIN™ Cream (doxepin) application. Please see complete prescribing information. To minimize the possibility of any drug interactions, be sure to talk with your doctor about all prescription and/or over-the-counter medications you are taking before you begin using PRUDOXIN™ Cream (doxepin) . What are the possible side effects of PRUDOXIN™ Cream (doxepin) ? Most common side effects, including burning and/or stinging, drowsiness (more common when applied to greater than 10% of body surface area), and dry mouth, are generally mild. Be sure and tell your doctor if you are experiencing any side effects. What are the contraindications of PRUDOXIN™ Cream (doxepin) ? The use of PRUDOXIN™ Cream (doxepin) is contraindicated in patients with untreated narrow angle glaucoma, tendency to urinary retention, and in individuals who have shown previous sensitivity to any of its components. PRUDOXIN™ Cream (doxepin) is for topical dermatologic use only. It should not be used in or around the eyes, the mouth or any mucous membrane. How should I store PRUDOXIN™ Cream (doxepin) ? PRUDOXIN™ Cream (doxepin) should be stored at or below 27° C (80° F). General advice about prescription medicines: This medicine is for your use only. Never give it to other people. It may harm them even if their skin problem appears to be the same as yours. Do not use PRUDOXIN™ Cream (doxepin) for any condition for which it was not prescribed. REFERENCE: 1. Breneman DL, Dunlap FE, Monroe EW, Schupbach CW, Shmunes E, Phillips SB. Doxepin cream relieves eczema-associated pruritus within 15 minutes and is not accompanied by a risk of rebound upon discontinuation. J Dermatol Treat. 1997; 8:161-168.

OVERDOSE Deaths may occur from overdosage with this class of drugs. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations: Should overdosage with topical application of Zonalon (doxepin) Cream occur, the signs and symptoms may include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. General Recommendations General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. 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. Cardiovascular: A maximal limb-lead QRS duration of > /=0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. 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 pCO 2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium 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 tricyclic antidepressant poisoning. CNS: In patients with CNS 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, 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. Pediatric Management: The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. CONTRAINDICATIONS Because doxepin HCl has an anticholinergic effect and because significant plasma levels of doxepin are detectable after topical Zonalon (doxepin) Cream application, the use of Zonalon (doxepin) Cream is contraindicated in patients with untreated narrow angle glaucoma or a tendency to urinary retention. Zonalon (doxepin) Cream is contraindicated in individuals who have shown previous sensitivity to any of its components.

OVERDOSE Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible. Manifestations Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS. Deaths have been reported involving overdoses of doxepin. General Recommendations General Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. 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 tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by 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 the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. 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, bretylium 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 tricyclic antidepressant poisoning. CNS  In patients with CNS 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, 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 overdosage is often 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 overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment. CONTRAINDICATIONS SINEQUAN is contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind. SINEQUAN is contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.

OVERDOSE Overdosage with a topical product is unlikely; should it occur, the signs and symptoms include: Mild: Drowsiness, stupor, blurred vision, excessive dryness of mouth. Severe:Respiratory depression, hypotension, coma, convulsions, cardiac arrhythmias and tachycardias. Also, urinary retention (bladder atony), decreased gastrointestinal motility (paralytic ileus), hyperthermia (or hypothermia), hypertension, dilated pupils, hyperactive reflexes. Management and Treatment Mild: Observation and supportive therapy is all that is usually necessary. It may be necessary to reduce the percent of body surface area treated or the frequency of application or apply a thinner layer of cream. Severe: Medical management of severe doxepin overdosage consists of aggressive supportive therapy. The area covered with doxepin HCI cream should be thoroughly washed. An adequate airway should be established in comatose patients and assisted ventilation used if necessary. EKG monitoring may be required for several days, because relapse after apparent recovery has been reported with oral doxepin HCI. Arrhythmias should be treated with the appropriate antiarrhythmic agent. It has been reported that many of the cardiovascular and CNS symptoms of tricyclic antidepressant poisoning in adults may be reversed by the slow intravenous administration of 1 mg to 3 mg of physostigmine salicylate. Because physostigmine is rapidly metabolized, the dosage should be repeated as required. Convulsions may respond to standard anticonvulsant therapy; however, barbiturates may potentiate any respiratory depression. Dialysis and forced diuresis generally are not of value in the management of overdosage due to high tissue and protein binding of doxepin HCI. CONTRAINDICATIONS Because doxepin HCI has an anticholinergic effect and because significant plasma levels of doxepin are detectable after topical PRUDOXIN (doxepin) Cream application, the use of PRUDOXIN (doxepin) Cream is contraindicated in patients with untreated narrow angle glaucoma or a tendency to urinary retention. PRUDOXIN (doxepin) Cream is contraindicated in individuals who have shown previous sensitivity to any of its components.

SIDE EFFECTS Controlled Clinical Trials Systemic Adverse Effects: In controlled clinical trials of patients treated with Zonalon (doxepin) Cream, the most common systemic adverse event reported was drowsiness. Drowsiness occurred in 71 of 330 (22%) of patients treated with Zonalon (doxepin) Cream compared to 7 of 334 (2%) of patients treated with vehicle cream. Drowsiness resulted in the premature discontinuation of the drug in approximately 5% of patients treated with Zonalon (doxepin) Cream in controlled clinical trials. Local Site Adverse Effects: In controlled clinical trials of patients treated with Zonalon (doxepin) Cream, the most common local site adverse event reported was burning and/or stinging at the site of application. These occurred in 76 of 330 (23%) of patients treated with Zonalon (doxepin) Cream compared to 54 of 334 (16%) of patients treated with vehicle cream. Most of these reactions were categorized as "mild"; however, approximately 25% of patients who reported burning and/or stinging reported the reaction as "severe". Four patients treated with Zonalon (doxepin) Cream withdrew from the study because of the burning and/or stinging. The table below presents the adverse events reported at an incidence of ≥ 1 % in either Zonalon (doxepin) or vehicle cream treatment groups during the trials: Adverse Event Zonalon N=330 Vehicle N=334 Burning /Stinging 76 (23.0%) 54 (16.2%) Drowsiness 71 (21.5%) 7 (2.1%) Dry Mouth1 32 (9.7%) 4 (1.2%) Pruritus2 13 (3.9%) 20 (6.0%) Fatigue/Tiredness 10 (3.0%) 5 (1.5%) Exacerbated Eczema 10 (3.0%) 8 (2.4%) Other Application Site Reaction3 10 (3.0%) 16 (4.8%) Dizziness4 7 (2.1%) 3 (0.9%) Mental Emotional Changes 6 (1.8%) 1 (0.3%) Taste Perversion5 5 (1.5%) 1 (0.3%) Edema 4 (1.2%) 1 (0.3%) Headache 3 (0.9%) 14 (4.2%) 1 Includes reports of "dry lips", "dry throat", and "thirst" 2Includes reports of "Pruritus Exacerbated" 3Includes report of "increased irritation at application site" 4Includes reports of "lightheadedness" and "dizziness/vertigo" 5Includes reports of "bitter taste" and "metallic taste in mouth" Adverse events occurring in 0.5% to < 1.0% of Zonalon (doxepin) Cream treated patients in the controlled clinical trials included: nervousness/anxiety, tongue numbness, fever, and nausea. Post Marketing Experience Twenty-six cases of allergic contact dermatitis have been reported in patients using Zonalon (doxepin) Cream, twenty of which were documented by positive patch test to doxepin 5% cream. DRUG INTERACTIONS Studies have not been performed examining drug interactions with Zonalon (doxepin) Cream. However, since plasma levels of doxepin following topical application of Zonalon Cream can reach levels obtained with oral doxepin HCl therapy, the following drug interactions are possible following topical Zonalon (doxepin) Cream application: Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7-10% of Caucasians are so-called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers 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). 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 dosage regimen of a TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to 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 importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for 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 another drug known to be an inhibitor of P450 2D6. MAO Inhibitors: Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with Zonalon (doxepin) Cream. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine: Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. Alcohol: Alcohol ingestion may exacerbate the potential sedative effects of Zonalon (doxepin) Cream. This is especially important in patients who may use alcohol excessively. Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of oral doxepin (75 mg/day).

SIDE EFFECTS NOTE: Some of the adverse reactions noted below have not been specifically reported with SINEQUAN use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing SINEQUAN (doxepin HCl). Anticholinergic Effects Dry mouth, blurred vision, constipation, and urinary retention have been reported. If they do not subside with continued therapy, or become severe, it may be necessary to reduce the dosage. Central Nervous System Effects Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued. Other infrequently reported CNS side effects are confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor. Cardiovascular Cardiovascular effects including hypotension, hypertension, and tachycardia have been reported occasionally. Allergic Skin rash, edema, photosensitization, and pruritus have occasionally occurred. Hematologic Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura. Gastrointestinal Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and aphthous stomatitis have been reported. (See Anticholinergic Effects.) Endocrine Raised or lowered 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 have been reported with tricyclic administration. Other Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects. Withdrawal Symptoms The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged SINEQUAN administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms. DRUG INTERACTIONS Drugs Metabolized by P450 2D6 The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7–10% of Caucasians are so-called “poor metabolizers”); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African and other populations are not yet available. Poor metabolizers 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). 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 dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram, escitalopram, fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to 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 and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary). Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6. Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated. MAO Inhibitors Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with SINEQUAN. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved. Cimetidine Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional SINEQUAN overdosage. This is especially important in patients who may use alcohol excessively. Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).

SIDE EFFECTS Controlled Clinical Trials Systemic Adverse Effects: In controlled clinical trials of patients treated with Doxepin HCl Cream 5%, the most common systemic adverse effect reported was drowsiness. Drowsiness occurred in 22% of patients treated with Doxepin HCl Cream 5% (and 2% of patients treated with placebo cream) and resulted in the premature discontinuation of the drug in approximately 5% of patients treated. Other systemic adverse effects reported in approximately 1 to 10% of these patients included: Dry mouth, dry lips, thirst, headache, fatigue, dizziness, emotional changes, and taste changes. Other systemic adverse effects reported in less than 1% of these patients included: Nausea, anxiety and fever. Local Site Adverse Effects: In controlled clinical trials of patients treated with Doxepin HCl Cream 5%, the most common local site adverse effect reported was burning and/or stinging at the site of application. These occurred in approximately 21% of these patients. Most of these reactions were categorized as "mild"; however, approximately 25% of patients who reported burning and/or stinging reported the reaction as "severe". Four patients treated with Doxepin HCl Cream 5% withdrew from the study because of the burning and/or stinging. Other local site adverse effects reported in approximately 1 to 10% of these patients included: Pruritus exacerbation, eczema exacerbation, dryness and tightness to skin, paresthesias, and edema. Other local site adverse effects reported in less than 1% of these patients included: Irritation, tingling, scaling, and cracking. Post Marketing Experience Some cases of allergic contact dermatitis have been reported in patients using Doxepin HCl 5% cream. DRUG INTERACTIONS Studies have not been performed examining drug interactions with PRUDOXIN (doxepin) Cream. However, data are available regarding potentially significant drug interactions regarding doxepin. As plasma levels of doxepin similar to therapeutic ranges for antidepressant therapy can be obtained following topical application of PRUDOXIN (doxepin) Cream, it would not be unexpected for the following drug interactions to be possible following topical PRUDOXIN (doxepin) Cream application. MAO Inhibitors: Serious side effects and even death have been reported following the concomitant use of certain orally administered drugs chemically related to doxepin and MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the initiation of treatment with PRUDOXIN (doxepin) Cream. Cimetidine: Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms have been associated with elevations in the serum levels of tricyclic antidepressants when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed in patients already taking cimetidine. In patients who have been reported to be well-controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects. Alcohol: Alcohol ingestion may exacerbate the potential sedative effects of PRUDOXIN (doxepin) Cream. Drugs Metabolized by P450IID6: A subset (3% to 10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isozyme P450IID6. Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. These individuals may have higher than expected plasma concentrations of tricyclic antidepressant when given usual doses. In addition, certain drugs that are metabolized by this isozyme, including many antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isozyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interactions. Concomitant use of tricyclic antidepressants with other drugs metabolized by cytochrome P450IID6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Therefore, co-administration of tricyclic antidepressants with other drugs that are metabolized by this isoenzyme, including other antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution. Concomitant use of PRUDOXIN (doxepin) Cream with drugs metabolized by cytochrome P450IID6 has not been formally studied.

WARNINGS Drowsiness occurs in over 20% of patients treated with Zonalon (doxepin) Cream, especially in patients receiving treatment to greater than 10% of their body surface area. Patients should be warned about the possibility of sedation and cautioned against driving a motor vehicle or operating hazardous machinery while being treated with Zonalon (doxepin) Cream. The sedating effects of alcoholic beverages, antihistamines, and other CNS depressants may be potentiated when Zonalon (doxepin) Cream is used. If excessive drowsiness occurs it may be necessary to reduce the frequency of applications, the amount of cream applied, and/or the percentage of body surface area treated, or discontinue the drug. However, the efficacy with reduced frequency of applications has not been established. Keep this product away from the eyes. PRECAUTIONS General Drowsiness: Since drowsiness may occur with the use of Zonalon (doxepin) Cream, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while using this drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on Zonalon (doxepin) Cream. (See PRECAUTIONS -- Geriatric Use.) Use under occlusion: Occlusive dressings may increase the absorption of most topical drugs; therefore, occlusive dressings should not be utilized with Zonalon (doxepin) Cream. Contact sensitization: Use of Zonalon (doxepin) Cream can cause Type IV hypersensitivity reactions (contact sensitization) to doxepin. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, and impairment of fertility studies have not been conducted with doxepin hydrochloride. Pregnancy Category B Reproduction studies have been performed in which doxepin was orally administered to rats and rabbits at doses up to 0.6 and 1.2 times, respectively, the estimated exposure to doxepin that results from use of 16 grams of Zonalon (doxepin) Cream per day (four applications of four grams of cream per day; dose multiples reflect comparisons made following normalization of the data on the basis of body surface area estimates) and have revealed no evidence of harm to rat or rabbit fetuses due to doxepin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Doxepin is excreted in human milk after oral administration. It is possible that doxepin may also be excreted in human milk following topical application of Zonalon (doxepin) Cream. One case has been reported of apnea and drowsiness in a nursing infant whose mother was taking an oral dosage form of doxepin HCl. Because of the potential for serious adverse reactions in nursing infants from doxepin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The use of Zonalon (doxepin) Cream in pediatric patients is not recommended. Safe conditions for use of Zonalon (doxepin) Cream in children have not been established. One case has been reported of a 2.5 year old child who developed somnolence, grand mal seizure, respiratory depression, ECG abnormalities, and coma after treatment with Zonalon (doxepin) Cream. A total of 27 grams had been applied over three days for eczema. He was treated with supportive care, activated charcoal, and systemic alkalization and recovered. Geriatric Use Clinical studies of Zonalon (doxepin) Cream did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of doxepin has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be observed closely for confusion and oversedation when started on Zonalon (doxepin) Cream. (See WARNINGS.) An 80-year old male nursing home patient developed probable systemic anticholinergic toxicity which included urinary retention and delirium after Zonalon (doxepin) cream had been applied to his arms, legs and back three times daily for two days.

WARNINGS Clinical Worsening And Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children,adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo < 18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case ≥ 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers Such monitoring should include daily observation by families and caregivers. Prescriptions for Sinequan should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Sinequan is not approved for use in treating bipolar depression. Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Sinequan may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Usage in Geriatrics: The use of SINEQUAN on a once-a-day dosage regimen in geriatric patients should be adjusted carefully based on the patient's condition (see PRECAUTIONS-Geriatric Use). Usage in Pregnancy: Reproduction studies have been performed in rats, rabbits, monkeys and dogs and there was no evidence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking SINEQUAN. Usage in Children: The use of SINEQUAN in children under 12 years of age is not recommended because safe conditions for its use have not been established. PRECAUTIONS Information For Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with Sinequan and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for Sinequan. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking Sinequan. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-today basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Patients should be advised that taking Sinequan can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible. Pediatric Use Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS - Clinical Worsening and Suicide Risk). Anyone considering the use of SINEQUAN in a child or adolescent must balance the potential risks with the clinical need. Drowsiness Since drowsiness may occur with the use of this drug, patients should be warned of the possibility and cautioned against driving a car or operating dangerous machinery while taking the drug. Patients should also be cautioned that their response to alcohol may be potentiated. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of SINEQUAN and observed closely. (See PRECAUTIONS - Geriatric Use.) Suicide Since suicide is an inherent risk in any depressed patient and may remain so until significant improvement has occurred, patients should be closely supervised during the early course of therapy. Prescriptions should be written for the smallest feasible amount. Psychosis Should increased symptoms of psychosis or shift to manic symptomatology occur, it may be necessary to reduce dosage or add a major tranquilizer to the dosage regimen. Geriatric Use A determination has not been made whether controlled clinical studies of SINEQUAN included sufficient numbers of subjects aged 65 and over to define a difference in response from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. The extent of renal excretion of SINEQUAN has not been determined. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selections. Sedating drugs may cause confusion and oversedation in the elderly; elderly patients generally should be started on low doses of SINEQUAN and observed closely. (See WARNINGS.)

WARNINGS Drowsiness occurs in over 20% of patients treated with Doxepin HCl Cream 5%, especially in patients receiving treatment to greater than 10% of their body surface area. Patients should be warned of this possibility and cautioned against driving a motor vehicle or operating hazardous machinery while being treated with PRUDOXIN (doxepin) Cream. Patients should also be warned that the effects of alcoholic beverages can be potentiated when using PRUDOXIN (doxepin) Cream. If excessive drowsiness occurs it may be necessary to reduce the number of applications, the amount of cream applied, and/or the percentage of body surface area treated, or discontinue the drug. Keep this product away from the eyes. PRECAUTIONS Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis, mutagenesis, impairment of fertility studies have not been conducted with doxepin hydrochloride. Pregnancy Pregnancy Category B: Teratology studies have been performed in rats and rabbits at oral doses up to 8 times the topical human dose (based on a mg/kg basis) and have revealed no evidence of impaired fertility or harm to the fetus due to doxepin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nursing Mothers Doxepin is excreted in human milk after oral administration. There have been no studies conducted to date to determine if doxepin is excreted in human milk after topical administration; however, it is known that significant systemic levels of doxepin are obtained after topical administration. It is therefore possible that doxepin could be secreted in human milk following topical administration. One case has been reported of apnea and drowsiness in a nursing infant whose mother was taking an oral dosage form of doxepin HCI. Because of the potential for serious adverse reactions in nursing infants from doxepin, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of PRUDOXIN (doxepin) Cream in children have not been established.