Pamelor^®
(nortriptyline HCl) capsules, USP
(nortriptyline HCl) oral solution, USP

Rx only

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 nortriptyline hydrochloride 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. Nortriptyline hydrochloride is not approved for use in pediatric patients (seeWARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients,andPRECAUTIONS: Pediatric Use).

Pamelor^® (nortriptyline HCl) is 1-Propanamine, 3-(10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5-ylidene)-N-methyl-, hydrochloride.

The structural formula is as follows:

Active Ingredient: nortriptyline hydrochloride USP.

Inactive Ingredients: D&C Yellow #10, FD&C Yellow #6, gelatin, silicone fluid, starch, and titanium dioxide.

Inactive Ingredients: gelatin, silicone fluid, starch, and titanium dioxide.

Active Ingredient: nortriptyline hydrochloride USP.

Inactive Ingredients: alcohol, benzoic acid, flavoring, purified water, and sorbitol.

The mechanism of mood elevation by tricyclic antidepressants is at present unknown. Pamelor^® (nortriptyline HCl) is not a monoamine oxidase inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that Pamelor^® (nortriptyline HCl) interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that Pamelor^® (nortriptyline HCl) has a combination of stimulant and depressant properties.

Pamelor^® (nortriptyline HCl) is indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states.

The use of Pamelor^® (nortriptyline HCl) or other tricyclic antidepressants concurrently with a monoamine oxidase (MAO) inhibitor is contraindicated. Hyperpyretic crises, severe convulsions, and fatalities have occurred when similar tricyclic antidepressants were used in such combinations. It is advisable to have discontinued the MAO inhibitor for at least two weeks before treatment with Pamelor^® (nortriptyline HCl) is started. Patients hypersensitive to Pamelor^® (nortriptyline HCl) should not be given the drug.

Cross-sensitivity between Pamelor^® (nortriptyline HCl) and other dibenzazepines is a possibility.

Pamelor^® (nortriptyline HCl) is contraindicated during the acute recovery period after myocardial infarction.

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.

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 nortriptyline hydrochloride should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

Safe use of Pamelor^® (nortriptyline HCl) during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results.

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with nortriptyline hydrochloride 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 nortriptyline hydrochloride. 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 spans. Patients should be given the opportunity to discuss the spans of the Medication Guide and to obtain answers to any questions they may have. The complete div 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 nortriptyline hydrochloride.

Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a “stimulating” effect in some depressed patients.

Close supervision and careful adjustment of the dosage are required when Pamelor^® (nortriptyline HCl) is used with other anticholinergic drugs and sympathomimetic drugs.

Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant. The patient should be informed that the response to alcohol may be exaggerated.

A case of significant hypoglycemia has been reported in a type II diabetic patient maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline (125 mg/day).

Safety and effectiveness in the pediatric population have not been established (seeBOX WARNING and WARNINGS - Clinical Worsening and Suicide Risk). Anyone considering the use of nortriptyline hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

Clinical studies of Pamelor^® (nortriptyline HCl) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience indicates that, as with other tricyclic antidepressants, hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes) are observed very rarely in geriatric patients and deaths associated with cholestatic liver damage have been reported in isolated instances. Cardiovascular function, particularly arrhythmias and fluctuations in blood pressure, should be monitored. There have also been reports of confusional states following tricyclic antidepressant administration in the elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic antidepressants, dose selection for an elderly patient should usually be limited to the smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).

Note – Included in the following ul are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when nortriptyline is administered.

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.

Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, 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, restlessness, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute symptoms uled under ADVERSE REACTIONS. There have been reports of patients recovering from nortriptyline overdoses of up to 525 mg.

Pamelor^® (nortriptyline HCl) is not recommended for children.

Pamelor^® (nortriptyline HCl) is administered orally in the form of capsules or liquid. Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalized patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer period of time at the lowest dose that will maintain remission.

If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur.

Pamelor^® (nortriptyline HCl) Capsules USP

Pamelor^® (nortriptyline HCl) Capsules USP, equivalent to 10 mg, 25 mg, 50 mg, and 75 mg base, are available as follows:

10 mg:      Light orange opaque cap printed “PAMELOR 10 mg” in black and white opaque body printed “” in black.

     Bottles of 30..................NDC 0406-9910-03

25 mg:      Light orange opaque cap printed “PAMELOR 25 mg” in black and white opaque body printed ““ in black.

     Bottles of 30..................NDC 0406-9911-03

50 mg:      White opaque cap printed “PAMELOR 50 mg” in black and white opaque body printed “” in black.

     Bottles of 30..................NDC 0406-9912-03

75 mg:      Light orange opaque cap printed “PAMELOR 75 mg” in black and light orange opaque body printed “” SANDOZ” in black.

     Bottles of 100..................NDC 0406-9913-01

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight container (USP) with a child-resistant closure.

Pamelor^® (nortriptyline HCl) oral solution USP, equivalent to 10 mg base per 5 mL, is supplied in 16-fluid-ounce bottles (NDC 0406-9918-16). Alcohol span 4%.

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Dispense in tight, light-resistant container.

Pamelor® and are registered trademarks of Mallinckrodt Inc.

10 mg, 25 mg, and 50 mg Capsules manufactured by:
Patheon Inc.
Whitby, Ontario, Canada
L1N 5Z5

75 mg Capsules manufactured by:
Novartis Pharmaceuticals Corp.
East Hanover, New Jersey 07936

Oral Solution manufactured by:
Novartis Consumer Health, Inc.
Lincoln, Nebraska 68517

Manufactured for:
Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.

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:

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 ul 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.

Mallinckrodt Inc.
Hazelwood, MO 63042 U.S.A.

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Mallinckrodt

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