Clomipramine Hydrochloride 50 MG Oral Capsule

Generic Name: CLOMIPRAMINE HYDROCHLORIDE
Brand Name: CLOMIPRAMINE HYDROCHLORIDE
  • Substance Name(s):
  • CLOMIPRAMINE HYDROCHLORIDE

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 to 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 healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for clomipramine hydrochloride should be written for the smallest quantity of capsules 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 clomipramine hydrochloride is not approved for use in treating bipolar depression.

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including clomipramine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St.

John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of clomipramine with MAOIs intended to treat psychiatric disorders is contraindicated.

Clomipramine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking clomipramine.

Clomipramine should be discontinued before initiating treatment with the MAOI ( see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ).

If concomitant use of clomipramine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with clomipramine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including clomipramine may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Seizures During premarket evaluation, seizure was identified as the most significant risk of clomipramine use.

The observed cumulative incidence of seizures among patients exposed to clomipramine at doses up to 300 mg/day was 0.64% at 90 days, 1.12% at 180 days, and 1.45% at 365 days.

The cumulative rates correct the crude rate of 0.7%, (25 of 3519 patients) for the variable duration of exposure in clinical trials.

Although dose appears to be a predictor of seizure, there is a confounding of dose and duration of exposure, making it difficult to assess independently the effect of either factor alone.

The ability to predict the occurrence of seizures in subjects exposed to doses of CMI greater than 250 mg is limited, given that the plasma concentration of CMI may be dose-dependent and may vary among subjects given the same dose.

Nevertheless, prescribers are advised to limit the daily dose to a maximum of 250 mg in adults and 3 mg/kg (or 200 mg) in children and adolescents ( see DOSAGE AND ADMINISTRATION ).

Caution should be used in administering clomipramine to patients with a history of seizures or other predisposing factors, e.g., brain damage of varying etiology, alcoholism, and concomitant use with other drugs that lower the seizure threshold.

Rare reports of fatalities in association with seizures have been reported by foreign postmarketing surveillance, but not in U.S.

clinical trials.

In some of these cases, clomipramine had been administered with other epileptogenic agents; in others, the patients involved had possibly predisposing medical conditions.

Thus a causal association between clomipramine treatment and these fatalities has not been established.

Physicians should discuss with patients the risk of taking clomipramine while engaging in activities in which sudden loss of consciousness could result in serious injury to the patient or others, e.g., the operation of complex machinery, driving, swimming, climbing.

DRESS Rare cases of drug rash with eosinophilia and systemic symptoms (DRESS) have been reported with the use of clomipramine.

In the event of severe acute reactions such as DRESS, discontinue clomipramine therapy immediately and institute appropriate treatment.

DRUG INTERACTIONS

Drug Interactions The risks of using clomipramine in combination with other drugs have not been systematically evaluated.

Given the primary CNS effects of clomipramine, caution is advised in using it concomitantly with other CNS-active drugs ( see Information for Patients ).

Clomipramine should not be used with MAO inhibitors ( see CONTRAINDICATIONS ).

Close supervision and careful adjustment of dosage are required when clomipramine is administered with anticholinergic or sympathomimetic drugs.

Several tricyclic antidepressants have been reported to block the pharmacologic effects of guanethidine, clonidine, or similar agents, and such an effect may be anticipated with CMI because of its structural similarity to other tricyclic antidepressants.

The plasma concentration of CMI has been reported to be increased by the concomitant administration of haloperidol; plasma levels of several closely related tricyclic antidepressants have been reported to be increased by the concomitant administration of methylphenidate or hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decreased by the concomitant administration of hepatic enzyme inducers (e.g., barbiturates, phenytoin), and such an effect may be anticipated with CMI as well.

Administration of CMI has been reported to increase the plasma levels of phenobarbital, if given concomitantly ( see CLINICAL PHARMACOLOGY, 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% to 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., fluoxetine, sertraline, paroxetine, and fluvoxamine, inhibit P450 2D6, they may vary in the extent of inhibition.

Fluvoxamine has also been shown to inhibit P450 1A2, an isoform also involved in TCA metabolism.

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 agents in the tricyclic antidepressant class (which includes clomipramine) with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant agent or the other drug.

Furthermore, whenever one of these drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant agent may be required.

It is desirable to monitor TCA plasma levels whenever an agent of the tricyclic antidepressant class including clomipramine is going to be co-administered with another drug known to be an inhibitor of P450 2D6 (and/or P450 1A2).

Because clomipramine is highly bound to serum protein, the administration of clomipramine to patients taking other drugs that are highly bound to protein (e.g., warfarin, digoxin) may cause an increase in plasma concentrations of these drugs, potentially resulting in adverse effects.

Conversely, adverse effects may result from displacement of protein-bound clomipramine by other highly bound drugs ( see CLINICAL PHARMACOLOGY, Distribution ).

Monoamine Oxidase Inhibitors (MAOIs) ( see CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .

) Serotonergic Drugs ( see CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .

)

OVERDOSAGE

Deaths may occur from overdosage with this class of drugs.

Multiple drug ingestion (including alcohol) is common in deliberate tricyclic 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 overdose.

Therefore, hospital monitoring is required as soon as possible.

Human Experience In U.S.

clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with clomipramine either alone or in combination with other drugs.

One death involved a patient suspected of ingesting a dose of 7000 mg.

The second death involved a patient suspected of ingesting a dose of 5750 mg.

The 10 nonfatal cases involved doses of up to 5000 mg, accompanied by plasma levels of up to 1010 ng/mL.

All 10 patients completely recovered.

Among reports from other countries of clomipramine overdose, the lowest dose associated with a fatality was 750 mg.

Based upon postmarketing reports in the United Kingdom, CMI’s lethality in overdose is considered to be similar to that reported for closely related tricyclic compounds marketed as antidepressants.

Manifestations Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion.

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 toxicity.

Other CNS manifestations may include drowsiness, stupor, ataxia, restlessness, agitation, delirium, severe perspiration, hyperactive reflexes, muscle rigidity, and athetoid and choreiform movements.

Cardiac abnormalities may include tachycardia, signs of congestive heart failure, and in very rare cases, cardiac arrest.

Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis and oliguria or anuria, may also be present.

Management Obtain an ECG and immediately initiate cardiac monitoring.

Protect the patient’s airway, establish an intravenous line, and initiate gastric decontamination.

A minimum of 6 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 necessary.

If signs of toxicity occur at any time during this period, extended monitoring is required.

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 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 pCO 2 < 20 mmHg 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 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.

DESCRIPTION

Clomipramine hydrochloride capsules USP is an antiobsessional drug that belongs to the class (dibenzazepine) of pharmacologic agents known as tricyclic antidepressants.

Clomipramine hydrochloride is available as capsules of 25, 50 and 75 mg for oral administration.

Clomipramine hydrochloride USP is 3-chloro-5-[3-(dimethylamino)propyl]-10,11-dihydro-5 H -dibenz[ b,f ] azepine monohydrochloride, and its structural formula is: C 19 H 23 ClN 2 ∙ HCl Molecular weight: 351.31 Clomipramine hydrochloride USP is a white to off-white crystalline powder.

It is freely soluble in water, in methanol, and in methylene chloride, and insoluble in ethyl ether and in hexane.

Inactive Ingredients : black iron oxide (25 mg capsules only), colloidal silicon dioxide, D&C yellow No.

10 (25 mg capsules only), FD&C blue No.

2 (25 mg capsules only), FD&C red No.

3 (25 mg capsules only), gelatin, magnesium stearate, pregelatinized maize starch, titanium dioxide, yellow iron oxide (50 mg capsules only).

Structural Formula

HOW SUPPLIED

Clomipramine Hydrochloride Capsules USP are supplied as follows: 25 mg – Dark blue cap/light blue body capsules, size 2, with black printing of CLOM 25 on both cap and body of capsule Unit dose packages of 30 (5 x 6) NDC 68084-790-25 50 mg – Yellow opaque capsules, size 1, with black printing of CLOM 50 on both cap and body of capsule Unit dose packages of 30 (5 x 6) NDC 68084-818-25 Store at 20° t o 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Protect from moisture.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

GERIATRIC USE

Geriatric Use Clinical studies of clomipramine did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects; 152 patients at least 60 years of age participating in various U.S.

clinical trials received clomipramine for periods of several months to several years.

No unusual age-related adverse events were identified in this population.

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.

Clomipramine has been associated with cases of clinically significant hyponatremia.

Elderly patients may be at greater risk for this adverse reaction ( see PRECAUTIONS, Hyponatremia ).

INDICATIONS AND USAGE

Clomipramine hydrochloride capsules USP are indicated for the treatment of obsessions and compulsions in patients with Obsessive-Compulsive Disorder (OCD).

The obsessions or compulsions must cause marked distress, be time-consuming, or significantly interfere with social or occupational functioning, in order to meet the DSM-III-R (circa 1989) diagnosis of OCD.

Obsessions are recurrent, persistent ideas, thoughts, images, or impulses that are ego-dystonic.

Compulsions are repetitive, purposeful, and intentional behaviors performed in response to an obsession or in a stereotyped fashion, and are recognized by the person as excessive or unreasonable.

The effectiveness of clomipramine for the treatment of OCD was demonstrated in multicenter, placebo-controlled, parallel-group studies, including two 10-week studies in adults and one 8-week study in children and adolescents 10 to 17 years of age.

Patients in all studies had moderate-to-severe OCD (DSM-III), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS) ranging from 26 to 28 and a mean baseline rating of 10 on the NIMH Clinical Global Obsessive Compulsive Scale (NIMH-OC).

Patients taking CMI experienced a mean reduction of approximately 10 on the YBOCS, representing an average improvement on this scale of 35% to 42% among adults and 37% among children and adolescents.

CMI-treated patients experienced a 3.5 unit decrement on the NIMH-OC.

Patients on placebo showed no important clinical response on either scale.

The maximum dose was 250 mg/day for most adults and 3 mg/kg/day (up to 200 mg) for all children and adolescents.

The effectiveness of clomipramine for long-term use (i.e., for more than 10 weeks) has not been systematically evaluated in placebo-controlled trials.

The physician who elects to use clomipramine for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient ( see DOSAGE AND ADMINISTRATION ).

PEDIATRIC USE

Pediatric Use Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established ( see BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk ).

Anyone considering the use of clomipramine in a child or adolescent must balance the potential risks with the clinical need.

In a controlled clinical trial in children and adolescents (10 to 17 years of age), 46 outpatients received clomipramine for up to 8 weeks.

In addition, 150 adolescent patients have received clomipramine in open-label protocols for periods of several months to several years.

Of the 196 adolescents studied, 50 were 13 years of age or less and 146 were 14 to 17 years of age.

The adverse reaction profile in this age group ( see ADVERSE REACTIONS ) is similar to that observed in adults.

The risks, if any, that may be associated with clomipramine’s extended use in children and adolescents with OCD have not been systemically assessed.

The evidence supporting the conclusion that clomipramine is safe for use in children and adolescents is derived from relatively short term clinical studies and from extrapolation of experience gained with adult patients.

In particular, there are no studies that directly evaluate the effects of long term clomipramine use on the growth, development, and maturation of children and adolescents.

Although there is no evidence to suggest that clomipramine adversely affects growth, development or maturation, the absence of such findings is not adequate to rule out a potential for such effects in chronic use.

The safety and effectiveness in pediatric patients below the age of 10 have not been established.

Therefore, specific recommendations cannot be made for the use of clomipramine in pediatric patients under the age of 10.

PREGNANCY

Pregnancy Category C No teratogenic effects were observed in studies performed in rats and mice at doses up to 100 mg/kg, which is 24 times the maximum recommended human daily dose (MRHD) on a mg/kg basis and 4 times (rats) and 2 times (mice) the MRHD on a mg/m 2 basis.

Slight nonspecific embryo/fetotoxic effects were seen in the offspring of treated rats given 50 and 100 mg/kg and of treated mice given 100 mg/kg.

There are no adequate or well-controlled studies in pregnant women.

Withdrawal symptoms, including jitteriness, tremor, and seizures, have been reported in neonates whose mothers had taken clomipramine until delivery.

Clomipramine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

NUSRING MOTHERS

Nursing Mothers Clomipramine hydrochloride has been found in human milk.

Because of the potential for adverse reactions, 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.

BOXED WARNING

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 clomipramine 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.

Clomipramine hydrochloride is not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD) ( see WARNINGS, Clinical Worsening and Suicide Risk ; PRECAUTIONS, Information for Patients ; and PRECAUTIONS, Pediatric Use ).

INFORMATION FOR PATIENTS

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 clomipramine 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 clomipramine 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 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 clomipramine hydrochloride.

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-to-day 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.

Physicians are advised to discuss the following issues with patients for whom they prescribe clomipramine hydrochloride capsules: The risk of seizure ( see WARNINGS ); The relatively high incidence of sexual dysfunction among males ( see Sexual Dysfunction ); Since clomipramine may impair the mental and/or physical abilities required for the performance of complex tasks, and since clomipramine is associated with a risk of seizures, patients should be cautioned about the performance of complex and hazardous tasks ( see WARNINGS ); Patients should be cautioned about using alcohol, barbiturates, or other CNS depressants concurrently, since clomipramine may exaggerate their response to these drugs; Patients should notify their physician if they become pregnant or intend to become pregnant during therapy; Patients should notify their physician if they are breast-feeding.

Patients should be advised that taking clomipramine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma.

Preexisting 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.

DOSAGE AND ADMINISTRATION

The treatment regimens described below are based on those used in controlled clinical trials of clomipramine in 520 adults, and 91 children and adolescents with OCD.

During initial titration, clomipramine should be given in divided doses with meals to reduce gastrointestinal side effects.

The goal of this initial titration phase is to minimize side effects by permitting tolerance to side effects to develop or allowing the patient time to adapt if tolerance does not develop.

Because both CMI and its active metabolite, DMI, have long elimination half-lives, the prescriber should take into consideration the fact that steady-state plasma levels may not be achieved until 2 to 3 weeks after dosage change ( see CLINICAL PHARMACOLOGY ).

Therefore, after initial titration, it may be appropriate to wait 2 to 3 weeks between further dosage adjustments.

Initial Treatment/Dose Adjustment (Adults) Treatment with clomipramine should be initiated at a dosage of 25 mg daily and gradually increased, as tolerated, to approximately 100 mg during the first 2 weeks.

During initial titration, clomipramine should be given in divided doses with meals to reduce gastrointestinal side effects.

Thereafter, the dosage may be increased gradually over the next several weeks, up to a maximum of 250 mg daily.

After titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Initial Treatment/Dose Adjustment (Children and Adolescents) As with adults, the starting dose is 25 mg daily and should be gradually increased (also given in divided doses with meals to reduce gastrointestinal side effects) during the first 2 weeks, as tolerated, up to a daily maximum of 3 mg/kg or 100 mg, whichever is smaller.

Thereafter, the dosage may be increased gradually over the next several weeks up to a daily maximum of 3 mg/kg or 200 mg, whichever is smaller ( see PRECAUTIONS, Pediatric Use ).

As with adults, after titration, the total daily dose may be given once daily at bedtime to minimize daytime sedation.

Maintenance/Continuation Treatment (Adults, Children, and Adolescents) While there are no systematic studies that answer the question of how long to continue clomipramine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient.

Although the efficacy of clomipramine after 10 weeks has not been documented in controlled trials, patients have been continued in therapy under double-blind conditions for up to 1 year without loss of benefit.

However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.

During maintenance, the total daily dose may be given once daily at bedtime.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with clomipramine.

Conversely, at least 14 days should be allowed after stopping clomipramine before starting an MAOI intended to treat psychiatric disorders ( see CONTRAINDICATIONS ).

Use of Clomipramine With Other MAOIs, Such as Linezolid or Methylene Blue Do not start clomipramine in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered ( see CONTRAINDICATIONS ).

In some cases, a patient already receiving clomipramine therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, clomipramine should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with clomipramine may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue ( see WARNINGS ).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with clomipramine is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use ( see WARNINGS ).

dimethicone 180 MG Oral Capsule

Generic Name: SIMETHICONE
Brand Name: Ultra Strength Gas Relief
  • Substance Name(s):
  • DIMETHICONE

WARNINGS

Warnings Stop use and ask a doctor if condition persists Keep out of reach of children .

INDICATIONS AND USAGE

Uses relieves bloating, pressure or fullness commonly referred to as gas

INACTIVE INGREDIENTS

Inactive ingredients FD&C yellow#6, gelatin, glycerin, purified water and white edible ink

PURPOSE

Purpose Anti-gas

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children .

DOSAGE AND ADMINISTRATION

Directions swallow 1 or 2 softgels as needed after a meal do not exceed two softgels per day except under the advice and supervision of a physician

STOP USE

Stop use and ask a doctor if condition persists

ACTIVE INGREDIENTS

Active ingredient (in each softgel) Simethicone 180 mg

Lotensin 20 MG Oral Tablet

WARNINGS

Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lotensin) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin-converting enzyme inhibitors.

In U.S.

clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Lotensin.

Angioedema associated with laryngeal edema can be fatal.

If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Lotensin should be discontinued and appropriate therapy instituted immediately.

Where there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptly administered (see ADVERSE REACTIONS).

Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.

These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption (a procedure dependent upon devices not approved in the United States).

Hypotension Lotensin can cause symptomatic hypotension.

Like other ACE inhibitors, benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients.

Symptomatic hypotension is most likely to occur in patients who have been volume-and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

Volume-and/or salt-depletion should be corrected before initiating therapy with Lotensin.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death.

In such patients, Lotensin therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased.

If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline.

Lotensin treatment usually can be continued following restoration of blood pressure and volume.

Neutropenia/Agranulocytosis Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma.

Available data from clinical trials of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar rates.

Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.

Fetal toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue Lotensin as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intra-amniotic environment.

If oligohydramnios is observed, discontinue Lotensin, unless it is considered lifesaving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to Lotensin for hypotension, oliguria, and hyperkalemia.

[see Precautions, Pediatric Use] No teratogenic effects of Lotensin were seen in studies of pregnant rats, mice, and rabbits.

On a mg/m2 basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50-kg woman).

On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice), and more than 3 times (in rabbits) the maximum recommended human dose.

Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death.

The mechanism of this syndrome is not understood.

Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

DRUG INTERACTIONS

Drug Interactions Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Lotensin.

The possibility of hypotensive effects with Lotensin can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Lotensin.

If this is not possible, the starting dose should be reduced (see DOSAGE AND ADMINISTRATION).

Potassium Supplements and Potassium-Sparing Diuretics: Lotensin can attenuate potassium loss caused by thiazide diuretics.

Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia.

Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient’s serum potassium should be monitored frequently.

Oral Anticoagulants: Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants.

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors (including benazepril) during therapy with lithium.

These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

If a diuretic is also used, the risk of lithium toxicity may be increased.

Gold: Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

Anti-diabetics : In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral anti-diabetics may develop hypoglycemia.

Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure.

These effects are usually reversible.

Monitor renal function periodically in patients receiving benazepril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.

Other: No clinically important pharmacokinetic interactions occurred when Lotensin was administered concomitantly with hydrochlorothiazide, chlorthalidone, furosemide, digoxin, propranolol, atenolol, or cimetidine.

Lotensin has been used concomitantly with beta-adrenergic-blocking agents, calcium-channel-blocking agents, diuretics, digoxin, and hydralazine, without evidence of clinically important adverse interactions.

Benazepril, like other ACE inhibitors, has had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.

OVERDOSAGE

Single oral doses of 3 g/kg benazepril were associated with significant lethality in mice.

Rats, however, tolerated single oral doses of up to 6 g/kg.

Reduced activity was seen at 1 g/kg in mice and at 5 g/kg in rats.

Human overdoses of benazepril have not been reported, but the most common manifestation of human benazepril overdosage is likely to be hypotension.

Laboratory determinations of serum levels of benazepril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of benazepril overdose.

No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of benazepril and its metabolites.

Benazepril is only slightly dialyzable, but dialysis might be considered in overdosed patients with severely impaired renal function (see WARNINGS).

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of benazepril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities.

Because the hypotensive effect of benazepril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat benazepril overdose by infusion of normal saline solution.

DESCRIPTION

Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol.

Its chemical name is 3-[[1-(ethoxy-carbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1 H -1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is Its empirical formula is C 24 H 28 N 2 O 5 •HCl, and its molecular weight is 460.96.

Benazeprilat, the active metabolite of benazepril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor.

Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.

Lotensin is supplied as tablets containing 5 mg, 10 mg, 20 mg, and 40 mg of benazepril hydrochloride for oral administration.

The inactive ingredients are colloidal silicon dioxide, crospovidone, hydrogenated castor oil (5-mg, 10-mg, and 20-mg tablets), hypromellose, iron oxides, lactose, magnesium stearate (40-mg tablets), microcrystalline cellulose, polysorbate 80, propylene glycol (5-mg and 40-mg tablets), starch, talc, and titanium dioxide.

Benazepril hydrochloride structural formula.

HOW SUPPLIED

Lotensin is available in tablets of 20 mg, packaged with a desiccant in bottles of 30 tablets.

Each tablet is imprinted with LOTENSIN on one side and the tablet strength “20,” on the other.

Storage: Do not store above 30°C (86°F).

Protect from moisture.

Dispense in tight container (USP).

GERIATRIC USE

Geriatric Use Of the total number of patients who received benazepril in U.S.

clinical studies of Lotensin, 18% were 65 or older while 2% were 75 or older.

No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Benazepril and benazeprilat are substantially excreted by the kidney.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

MECHANISM OF ACTION

Mechanism of Action Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals.

ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II.

Angiotensin II also stimulates aldosterone secretion by the adrenal cortex.

Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion.

The latter decrease may result in a small increase of serum potassium.

Hypertensive patients treated with Lotensin alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L.

Similar patients treated with Lotensin and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium (see PRECAUTIONS).

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.

In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin.

Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotensin remains to be elucidated.

While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension (see INDICATIONS AND USAGE).

INDICATIONS AND USAGE

Lotensin is indicated for the treatment of hypertension.

It may be used alone or in combination with thiazide diuretics.

In using Lotensin, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease.

Available data are insufficient to show that Lotensin does not have a similar risk (see WARNINGS).

Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.

It should also be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in nonblacks.

PEDIATRIC USE

Pediatric Use Neonates with a history of in utero exposure to Lotensin: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACE inhibitor, but experience is limited.

The antihypertensive effects of Lotensin have been evaluated in a double-blind study in pediatric patients 7 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacodynamics, Hypertension).

The pharmacokinetics of Lotensin have been evaluated in pediatric patients 6 to 16 years of age (see CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism).

Lotensin was generally well tolerated and adverse effects were similar to those described in adults.

(See ADVERSE REACTIONS: Pediatric Patients ).

Treatment with Lotensin is not recommended in pediatric patients less than 6 years of age (see ADVERSE REACTIONS), and in children with glomerular filtration rate <30 mL/min as there are insufficient data available to support a dosing recommendation in these groups.

(See CLINICAL PHARMACOLOGY: Pharmacokinetics and Metabolism, In Pediatric Patients and DOSAGE AND ADMINISTRATION.)

NUSRING MOTHERS

Nursing Mothers Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril.

A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat.

BOXED WARNING

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue Lotensin as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

See Warnings: Fetal Toxicity

INFORMATION FOR PATIENTS

Information for Patients Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to Lotensin during pregnancy.

Discuss treatment options with women planning to become pregnant.

Patients should be asked to report pregnancies to their physicians as soon as possible.

Angioedema: Angioedema, including laryngeal edema, can occur at any time with treatment with ACE inhibitors.

Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.

Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician.

Patients should be told that if syncope occurs, Lotensin should be discontinued until the prescribing physician has been consulted.

All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

DOSAGE AND ADMINISTRATION

Hypertension Adults The recommended initial dose for patients not receiving a diuretic is 10 mg once a day.

The usual maintenance dosage range is 20-40 mg per day administered as a single dose or in two equally divided doses.

A dose of 80 mg gives an increased response, but experience with this dose is limited.

The divided regimen was more effective in controlling trough (pre-dosing) blood pressure than the same dose given as a once-daily regimen.

Dosage adjustment should be based on measurement of peak (2-6 hours after dosing) and trough responses.

If a once-daily regimen does not give adequate trough response, an increase in dosage or divided administration should be considered.

If blood pressure is not controlled with Lotensin alone, a diuretic can be added.

Total daily doses above 80 mg have not been evaluated.

Concomitant administration of Lotensin with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS).

In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Lotensin.

To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued two to three days prior to beginning therapy with Lotensin (see WARNINGS).

Then, if blood pressure is not controlled with Lotensin alone, diuretic therapy should be resumed.

If the diuretic cannot be discontinued, an initial dose of 5 mg Lotensin should be used to avoid excessive hypotension.

Pediatrics In children, doses of Lotensin between 0.1 and 0.6 mg/kg once daily have been studied, and doses greater than 0.1 mg/kg were shown to reduce blood pressure (see Pharmacodynamics).

Based on this, the recommended starting dose of Lotensin is 0.2 mg/kg once per day as monotherapy.

Doses above 0.6 mg/kg (or in excess of 40 mg daily) have not been studied in pediatric patients.

For pediatric patients who cannot swallow tablets, or for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths for Lotensin, follow the suspension preparation instructions below to administer benazepril HCl as a suspension.

Treatment with Lotensin is not advised for children below the age of 6 years (see PRECAUTIONS, Pediatric Use) and in pediatric patients with glomerular filtration rate <30 mL, as there are insufficient data available to support a dosing recommendation in these groups.

For Hypertensive Patients with Renal Impairment For patients with a creatinine clearance 3 mg/dL), the recommended initial dose is 5 mg Lotensin once daily.

Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 40 mg (see WARNINGS).

Preparation of Suspension (for 150 mL of a 2 mg/mL suspension) Add 75 mL of Ora-Plus ® * oral suspending vehicle to an amber polyethylene terephthalate (PET) bottle containing fifteen Lotensin 20 mg tablets, and shake for at least 2 minutes.

Allow the suspension to stand for a minimum of 1 hour.

After the standing time, shake the suspension for a minimum of 1 additional minute.

Add 75 mL of Ora-Sweet ® * oral syrup vehicle to the bottle and shake the suspension to disperse the ingredients.

The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days in the PET bottle with a child-resistant screw-cap closure.

Shake the suspension before each use.

*Ora-Plus ® and Ora-Sweet ® are registered trademarks of Paddock Laboratories, Inc.

Ora-Plus ® contains carrageenan, citric acid, methylparaben, microcrystalline cellulose, carboxymethylcellulose sodium, potassium sorbate, simethicone, sodium phosphate monobasic, xanthan gum, and water.

Ora-Sweet ® contains citric acid, berry citrus flavorant, glycerin, methylparaben, potassium sorbate, sodium phosphate monobasic, sorbitol, sucrose, and water.

Sucralfate 100 MG/ML Oral Suspension [Carafate]

DRUG INTERACTIONS

Drug Interactions Some studies have shown that simultaneous sucralfate administration in healthy volunteers reduced the extent of absorption (bioavailability) of single doses of the following: cimetidine, digoxin, fluoroquinolone antibiotics, ketoconazole, l-thyroxine, phenytoin, quinidine, ranitidine, tetracycline, and theophylline.

Subtherapeutic prothrombin times with concomitant warfarin and sucralfate therapy have been reported in spontaneous and published case reports.

However, two clinical studies have demonstrated no change in either serum warfarin concentration or prothrombin time with the addition of sucralfate to chronic warfarin therapy.

The mechanism of these interactions appears to be nonsystemic in nature, presumably resulting from sucralfate binding to the concomitant agent in the gastrointestinal tract.

In all cases studied to date (cimetidine, ciprofloxacin, digoxin, norfloxacin, ofloxacin, and ranitidine), dosing the concomitant medication 2 hours before sucralfate eliminated the interaction.

Because of the potential of CARAFATE to alter the absorption of some drugs, CARAFATE should be administered separately from other drugs when alterations in bioavailability are felt to be critical.

In these cases, patients should be monitored appropriately.

OVERDOSAGE

Due to limited experience in humans with overdosage of sucralfate, no specific treatment recommendations can be given.

Acute oral studies in animals, however, using doses up to 12 g/kg body weight, could not find a lethal dose.

Sucralfate is only minimally absorbed from the gastrointestinal tract.

Risks associated with acute overdosage should, therefore, be minimal.

In rare reports describing sucralfate overdose, most patients remained asymptomatic.

Those few reports where adverse events were described included symptoms of dyspepsia, abdominal pain, nausea, and vomiting.

DESCRIPTION

CARAFATE ® Suspension contains sucralfate and sucralfate is an α-D-glucopyranoside, β-D-fructofuranosyl-, octakis-(hydrogen sulfate), aluminum complex.

CARAFATE ® Suspension for oral administration contains 1 g of sucralfate per 10 mL.

CARAFATE ® Suspension also contains: colloidal silicon dioxide NF, FD&C Red #40, flavor, glycerin USP, methylcellulose USP, methylparaben NF, microcrystalline cellulose NF, purified water USP, simethicone USP, and sorbitol solution USP.

Therapeutic category: antiulcer.

Carafate suspension structure

CLINICAL STUDIES

CLINICAL TRIALS Error: java.security.PrivilegedActionException: net.sf.saxon.xpath.DynamicError: org.xml.sax.SAXParseException: The end-tag for element type “col” must end with a ‘>’ delimiter.

HOW SUPPLIED

CARAFATE ® (sucralfate) Suspension 1 g/10 mL is a pink suspension supplied in bottles of 14 fl oz (NDC 54868-3735-0).

Dispense as is.

SHAKE WELL BEFORE USING.

AVOID FREEZING.

Store at controlled room temperature 20-25°C (68-77°F)[see USP].

Rx Only Prescribing Information as of December 2010 Aptalis Pharma US, Inc.

100 Somerset Corporate Boulevard Bridgewater, NJ 08807 www.aptalispharma.com Carafate ® is a reg istered trademark of Aptalis Pharma Canada Inc.

Distributed by: Physicians Total Care, Inc.

Tulsa, OK 74146

GERIATRIC USE

Geriatric Use Clinical studies of CARAFATE ® Suspension 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.

(See DOSAGE AND ADMINISTRATION ) This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

(See PRECAUTIONS Special Populations: Chronic Renal Failure and Dialysis Patients ) Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

INDICATIONS AND USAGE

CARAFATE ® (sucralfate) Suspension is indicated in the short-term (up to 8 weeks) treatment of active duodenal ulcer.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

PREGNANCY

Pregnancy Teratogenic effects.

Pregnancy Category B.

Teratogenicity studies have been performed in mice, rats, and rabbits at doses up to 50 times the human dose and have revealed no evidence of harm to the fetus due to sucralfate.

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.

NUSRING MOTHERS

Nursing Mothers It is not known whether this drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should be exercised when sucralfate is administered to a nursing woman.

DOSAGE AND ADMINISTRATION

Active Duodenal Ulcer.

The recommended adult oral dosage for duodenal ulcer is 1 g (10 mL/2 teaspoonfuls) four times per day.

CARAFATE ® should be administered on an empty stomach.

Antacids may be prescribed as needed for relief of pain but should not be taken within one-half hour before or after sucralfate.

While healing with sucralfate may occur during the first week or two, treatment should be continued for 4 to 8 weeks unless healing has been demonstrated by x-ray or endoscopic examination.

Elderly: 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.

(See PRECAUTIONS Geriatric Use ) Call your doctor for medical advice about side effects.

You may report side effects to FDA at 1-800-FDA-1088.

Acitretin 10 MG Oral Capsule

Generic Name: ACITRETIN
Brand Name: Acitretin
  • Substance Name(s):
  • ACITRETIN

WARNINGS

(See also boxed CONTRAINDICATIONS AND .) Hepatotoxicity: Of the 525 subjects treated in U.S.

clinical trials, 2 had clinical jaundice with elevated serum bilirubin and transaminases considered related to treatment with acitretin capsules.

Liver function test results in these subjects returned to normal after acitretin capsules were discontinued.

Two of the 1,289 subjects treated in European clinical trials developed biopsy-confirmed toxic hepatitis.

A second biopsy in one of these subjects revealed nodule formation suggestive of cirrhosis.

One subject in a Canadian clinical trial of 63 subjects developed a 3-fold increase of transaminases.

A liver biopsy of this subject showed mild lobular disarray, multifocal hepatocyte loss, and mild triaditis of the portal tracts compatible with acute reversible hepatic injury.

The subject’s transaminase levels returned to normal 2 months after acitretin capsules were discontinued.

The potential of therapy with acitretin capsules to induce hepatotoxicity was prospectively evaluated using liver biopsies in an open-label trial of 128 subjects.

Pretreatment and posttreatment biopsies were available for 87 subjects.

A comparison of liver biopsy findings before and after therapy revealed 49 (58%) subjects showed no change, 21 (25%) improved, and 14 (17%) subjects had a worsening of their liver biopsy status.

For 6 subjects, the classification changed from class 0 (no pathology) to class I (normal fatty infiltration; nuclear variability and portal inflammation; both mild); for 7 subjects, the change was from class I to class II (fatty infiltration, nuclear variability, portal inflammation, and focal necrosis; all moderate to severe); and for 1 subject, the change was from class II to class IIIb (fibrosis, moderate to severe).

No correlation could be found between liver function test result abnormalities and the change in liver biopsy status, and no cumulative dose relationship was found.

Elevations of AST (SGOT), ALT (SGPT), GGT (GGTP), or LDH have occurred in approximately 1 in 3 subjects treated with acitretin capsules.

Of the 525 subjects treated in clinical trials in the U.S., treatment was discontinued in 20 (3.8%) due to elevated liver function test results.

If hepatotoxicity is suspected during treatment with acitretin capsules, the drug should be discontinued and the etiology further investigated.

Ten of 652 subjects treated in U.S.

clinical trials of etretinate, of which acitretin is the active metabolite, had clinical or histologic hepatitis considered to be possibly or probably related to etretinate treatment.

There have been reports of hepatitis-related deaths worldwide; a few of these subjects had received etretinate for a month or less before presenting with hepatic symptoms or signs.

Skeletal Abnormalities In adults receiving long-term treatment with acitretin capsules, appropriate examinations should be periodically performed in view of possible ossification abnormalities (see ADVERSE REACTIONS ).

Because the frequency and severity of iatrogenic bony abnormality in adults is low, periodic radiography is only warranted in the presence of symptoms or long-term use of acitretin capsules.

If such disorders arise, the continuation of therapy should be discussed with the patient on the basis of a careful risk/benefit analysis.

In clinical trials with acitretin capsules, subjects were prospectively evaluated for evidence of development or change in bony abnormalities of the vertebral column, knees, and ankles.

Of 380 subjects treated with acitretin capsules, 15% had preexisting abnormalities of the spine which showed new changes or progression of preexisting findings.

Changes included degenerative spurs, anterior bridging of spinal vertebrae, diffuse idiopathic skeletal hyperostosis, ligament calcification, and narrowing and destruction of a cervical disc space.

De novo changes (formation of small spurs) were seen in 3 subjects after 1½ to 2½ years.

Six of 128 subjects treated with acitretin capsules showed abnormalities in the knees and ankles before treatment that progressed during treatment.

In 5, these changes involved the formation of additional spurs or enlargement of existing spurs.

The sixth subject had degenerative joint disease which worsened.

No subjects developed spurs de novo .

Clinical complaints did not predict radiographic changes.

Lipids and Possible Cardiovascular Effects Blood lipid determinations should be performed before acitretin capsules are administered and again at intervals of 1 to 2 weeks until the lipid response to the drug is established, usually within 4 to 8 weeks.

In subjects receiving acitretin capsules during clinical trials, 66% and 33% experienced elevation in triglycerides and cholesterol, respectively.

Decreased high density lipoproteins (HDL) occurred in 40% of subjects.

These effects of acitretin capsules were generally reversible upon cessation of therapy.

Subjects with an increased tendency to develop hypertriglyceridemia included those with disturbances of lipid metabolism, diabetes mellitus, obesity, increased alcohol intake, or a familial history of these conditions.

Because of the risk of hypertriglyceridemia, serum lipids must be more closely monitored in high-risk patients and during long-term treatment.

Hypertriglyceridemia and lowered HDL may increase a patient’s cardiovascular risk status.

Although no causal relationship has been established, there have been postmarketing reports of acute myocardial infarction or thromboembolic events in patients on therapy with acitretin capsules.

In addition, elevation of serum triglycerides to greater than 800 mg per dL has been associated with fatal fulminant pancreatitis.

Therefore, dietary modifications, reduction in dose of acitretin capsules, or drug therapy should be employed to control significant elevations of triglycerides.

If, despite these measures, hypertriglyceridemia and low HDL levels persist, the discontinuation of acitretin capsules should be considered.

Ophthalmologic Effects The eyes and vision of 329 subjects treated with acitretin capsules were examined by ophthalmologists.

The findings included dry eyes (23%), irritation of eyes (9%), and brow and lash loss (5%).

The following were reported in less than 5% of subjects: Bell’s Palsy, blepharitis and/or crusting of lids, blurred vision, conjunctivitis, corneal epithelial abnormality, cortical cataract, decreased night vision, diplopia, itchy eyes or eyelids, nuclear cataract, pannus, papilledema, photophobia, posterior subcapsular cataract, recurrent sties, and subepithelial corneal lesions.

Any patient treated with acitretin capsules who is experiencing visual difficulties should discontinue the drug and undergo ophthalmologic evaluation.

Pancreatitis Lipid elevations occur in 25% to 50% of subjects treated with acitretin capsules.

Triglyceride increases sufficient to be associated with pancreatitis are much less common, although fatal fulminant pancreatitis has been reported.

There have been rare reports of pancreatitis during therapy with acitretin capsules in the absence of hypertriglyceridemia.

Pseudotumor Cerebri Acitretin capsules and other retinoids administered orally have been associated with cases of pseudotumor cerebri (benign intracranial hypertension).

Some of these events involved concomitant use of isotretinoin and tetracyclines.

However, the event seen in a single patient receiving acitretin capsules was not associated with tetracycline use.

Early signs and symptoms include papilledema, headache, nausea and vomiting, and visual disturbances.

Patients with these signs and symptoms should be examined for papilledema and, if present, should discontinue acitretin capsules immediately and be referred for neurological evaluation and care.

Since both acitretin capsules and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS ).

Capillary Leak Syndrome Capillary leak syndrome, a potential manifestation of retinoic acid syndrome, has been reported in patients receiving acitretin capsules.

Features of this syndrome may include localized or generalized edema with secondary weight gain, fever, and hypotension.

Rhabdomyolysis and myalgias have been reported in association with capillary leak syndrome, and laboratory tests may reveal neutrophilia, hypoalbuminemia, and an elevated hematocrit.

Discontinue acitretin capsules if capillary leak syndrome develops during therapy.

Exfoliative Dermatitis/Erythroderma Exfoliative dermatitis/erythroderma has been reported in patients receiving acitretin capsules.

Discontinue acitretin capsules if exfoliative dermatitis/erythroderma occurs during therapy.

DRUG INTERACTIONS

Drug Interactions Ethanol Clinical evidence has shown that etretinate can be formed with concurrent ingestion of acitretin and ethanol (see boxed CONTRAINDICATIONS AND WARNINGS and CLINICAL PHARMACOLOGY: Pharmacokinetics ).

Glyburide In a trial of 7 healthy male volunteers, acitretin treatment potentiated the blood glucose-lowering effect of glyburide (a sulfonylurea similar to chlorpropamide) in 3 of the 7 subjects.

Repeating the trial with 6 healthy male volunteers in the absence of glyburide did not detect an effect of acitretin on glucose tolerance.

Careful supervision of diabetic patients under treatment with acitretin capsules is recommended (see CLINICAL PHARMACOLOGY: Pharmacokinetics and DOSAGE AND ADMINISTRATION ).

Hormonal Contraceptives It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives.

However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin “minipill” preparations.

Microdosed “minipill” progestin preparations are not recommended for use with acitretin capsules (see CLINICAL PHARMACOLOGY: Pharmacokinetic Drug Interactions ).

It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.

Methotrexate An increased risk of hepatitis has been reported to result from combined use of methotrexate and etretinate.

Consequently, the combination of methotrexate with acitretin is also contraindicated (see CONTRAINDICATIONS ).

Phenytoin If acitretin is given concurrently with phenytoin, the protein binding of phenytoin may be reduced.

Tetracyclines Since both acitretin and tetracyclines can cause increased intracranial pressure, their combined use is contraindicated (see CONTRAINDICATIONS and WARNINGS: Pseudotumor Cerebri ).

Vitamin A and Oral Retinoids Concomitant administration of vitamin A and/or other oral retinoids with acitretin must be avoided because of the risk of hypervitaminosis A.

Other There appears to be no pharmacokinetic interaction between acitretin and cimetidine, digoxin, or glyburide.

Investigations into the effect of acitretin on the protein binding of anticoagulants of the coumarin type (warfarin) revealed no interaction.

OVERDOSAGE

In the event of acute overdosage, acitretin capsules must be withdrawn at once.

Symptoms of overdose are identical to acute hypervitaminosis A (e.g., headache and vertigo).

The acute oral toxicity (LD 50 ) of acitretin in both mice and rats was greater than 4,000 mg per kg.

In one reported case of overdose, a 32-year-old male with Darier’s disease took 21 x 25-mg capsules (525-mg single dose).

He vomited several hours later but experienced no other ill effects.

All female patients of childbearing potential who have taken an overdose of acitretin capsules must: 1) Have a pregnancy test at the time of overdose; 2) Be counseled as per the boxed CONTRAINDICATIONS AND WARNINGS and PRECAUTIONS sections regarding birth defects and contraceptive use for at least 3 years’ duration after the overdose.

DESCRIPTION

Acitretin capsules, USP (acitretin), a retinoid, are available in 10 mg or 25 mg gelatin capsules for oral administration.

Chemically, acitretin, USP is ( all-E )-9-(4-Methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid.

It is a metabolite of etretinate and is related to both retinoic acid and retinol (vitamin A).

It is a yellow or greenish crystalline powder with a molecular weight of 326.44.

The structural formula is: Each capsule contains acitretin, edetate disodium, gelatin, maltodextrin, microcrystalline cellulose, poloxamer 407, red iron oxide, sodium ascorbate and titanium dioxide.

The 25 mg capsules also contain black iron oxide and yellow iron oxide.

The black imprinting ink for the 10 mg capsules contains black iron oxide, potassium hydroxide, propylene glycol, shellac and strong ammonia solution.

The white imprinting ink for the 25 mg capsules contains povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide.

Acitretin structural formula

CLINICAL STUDIES

In 2 double-blind, placebo-controlled trials, acitretin capsules were administered once daily to subjects with severe psoriasis (e.g., covering at least 10% to 20% of the body surface area).

At 8 weeks (see Table 1) subjects treated in Trial A with 50 mg of acitretin capsules per day showed significant improvements ( P ≤ 0.05) relative to baseline and to placebo in the physician’s global evaluation and in the mean ratings of severity of psoriasis (scaling, thickness, and erythema).

In Trial B, differences from baseline and from placebo were statistically significant ( P ≤ 0.05) for all variables at both the 25-mg and 50-mg doses; it should be noted for Trial B that no statistical adjustment for multiplicity was carried out.

Table 1.

Summary of the Efficacy Results of the 8-Week Double-Blind Phase of Trials A and B of Acitretin Capsules Efficacy Variables Trial A Trial B Total Daily Dose Total Daily Dose Placebo (N = 29) 50 mg (N = 29) Placebo (N = 72) 25 mg (N = 74) 50 mg (N = 71) Physician’s Global Evaluation Baseline 4.62 4.55 4.43 4.37 4.49 Mean Change After 8 Weeks -0.29 -2.00 Values were statistically significantly different from placebo and from baseline ( P ≤ 0.05).

No adjustment for multiplicity was done for Trial B.

-0.06 -1.06 -1.57 Scaling Baseline 4.10 3.76 3.97 4.11 4.10 Mean Change After 8 Weeks -0.22 -1.62 -0.21 -1.50 -1.78 Thickness Baseline 4.10 4.10 4.03 4.11 4.20 Mean Change After 8 Weeks -0.39 -2.10 -0.18 -1.43 -2.11 Erythema Baseline 4.21 4.59 4.42 4.24 4.45 Mean Change After 8 Weeks -0.33 -2.10 -0.37 -1.12 -1.65 The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease.

Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe).

A subset of 141 subjects from both pivotal Trials A and B continued to receive acitretin capsules in an open fashion for up to 24 weeks.

At the end of the treatment period, all efficacy variables, as indicated in Table 2, were significantly improved ( P ≤ 0.01) from baseline, including extent of psoriasis, mean ratings of psoriasis severity, and physician’s global evaluation.

Table 2.

Summary of the First Course of Therapy with Acitretin Capsules (24 Weeks) Variables Trial A Trial B Mean Total Daily Dose of Acitretin Capsules (mg) 42.8 43.1 Mean Duration of Therapy (Weeks) 21.1 22.6 Physician’s Global Evaluation N = 39 N = 98 Baseline 4.51 4.43 Mean Change from Baseline -2.26 Indicates that the difference from baseline was statistically significant ( P ≤ 0.01).

The efficacy variables consisted of: the mean severity rating of scale, lesion thickness, erythema, and the physician’s global evaluation of the current status of the disease.

Ratings of scaling, erythema, and lesion thickness, and the ratings of the global assessments were made using a 7-point scale (0 = none, 1 = trace, 2 = mild, 3 = mild-moderate, 4 = moderate, 5 = moderate-severe, 6 = severe).

-2.60 Scaling N = 59 N = 132 Baseline 3.97 4.07 Mean Change from Baseline -2.15 -2.42 Thickness N = 59 N = 132 Baseline 4.00 4.12 Mean Change from Baseline -2.44 -2.66 Erythema N = 59 N = 132 Baseline 4.35 4.33 Mean Change from Baseline -2.31 -2.29 All efficacy variables improved significantly in a subset of 55 subjects from Trial A treated for a second, 6-month maintenance course of therapy (for a total of 12 months of treatment); a small subset of subjects (n = 4) from Trial A continued to improve after a third 6-month course of therapy (for a total of 18 months of treatment).

HOW SUPPLIED

Acitretin Capsules, USP are available containing 10 mg or 25 mg of acitretin, USP.

The 10 mg capsules are hard shell gelatin capsules with a swedish orange opaque cap and swedish orange opaque body filled with yellow granular powder.

The capsules are axially printed with MYLAN over AC I 02 in black ink on the cap and body.

They are available as follows: NDC 0378-7020-93 bottles of 30 capsules The 25 mg capsules are hard shell gelatin capsules with a brown opaque cap and yellow opaque body filled with yellow granular powder.

The capsules are axially printed with MYLAN over AC I 13 in white ink on the cap and body.

They are available as follows: NDC 0378-7023-93 bottles of 30 capsules Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Protect from light.

Avoid exposure to high temperatures and humidity after the bottle is opened.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

PHARMACIST: Dispense a Medication Guide with each prescription.

GERIATRIC USE

Geriatric Use Clinical trials of acitretin capsules did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently than younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

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.

A 2-fold increase in acitretin plasma concentrations was seen in healthy elderly subjects compared with young subjects, although the elimination half-life did not change (see CLINICAL PHARMACOLOGY: Special Populations ).

INDICATIONS AND USAGE

Acitretin capsules are indicated for the treatment of severe psoriasis in adults.

Because of significant adverse effects associated with its use, acitretin capsules should be prescribed only by those knowledgeable in the systemic use of retinoids.

In females of reproductive potential, acitretin capsules should be reserved for non-pregnant patients who are unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments (see boxed CONTRAINDICATIONS AND WARNINGS – Acitretin capsules can cause severe birth defects).

Most patients experience relapse of psoriasis after discontinuing therapy.

Subsequent courses, when clinically indicated, have produced efficacy results similar to the initial course of therapy.

PEDIATRIC USE

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

No clinical trials have been conducted in pediatric subjects.

Ossification of interosseous ligaments and tendons of the extremities, skeletal hyperostoses, decreases in bone mineral density, and premature epiphyseal closure have been reported in children taking other systemic retinoids, including etretinate, a metabolite of acitretin capsules.

A causal relationship between these effects and acitretin capsules has not been established.

While it is not known that these occurrences are more severe or more frequent in children, there is special concern in pediatric patients because of the implications for growth potential (see WARNINGS: Hyperostosis ).

PREGNANCY

Pregnancy Teratogenic Effects Pregnancy Category X (See boxed CONTRAINDICATIONS AND WARNINGS .) In a study in which acitretin was administered to male rats only at a dosage of 5 mg per kg per day for 10 weeks (approximate duration of one spermatogenic cycle) prior to and during mating with untreated female rats, no teratogenic effects were observed in the progeny (see boxed CONTRAINDICATIONS AND WARNINGS for information about male use of acitretin capsules).

Nonteratogenic Effects In rats dosed at 3 mg per kg per day (approximately one-half the maximum recommended therapeutic dose based on a mg-per-m 2 comparison), slightly decreased pup survival and delayed incisor eruption were noted.

At the next lowest dose tested, 1 mg per kg per day, no treatment-related adverse effects were observed.

NUSRING MOTHERS

Nursing Mothers Studies on lactating rats have shown that etretinate is excreted in the milk.

There is one prospective case report where acitretin is reported to be excreted in human milk.

Therefore, nursing mothers should not receive acitretin capsules prior to or during nursing because of the potential for serious adverse reactions in nursing infants.

BOXED WARNING

CONTRAINDICATIONS AND WARNINGS Pregnancy: Acitretin capsules must not be used by females who are pregnant, or who intend to become pregnant during therapy or at any time for at least 3 years following discontinuation of therapy.

Acitretin capsules also must not be used by females who may not use reliable contraception while undergoing treatment and for at least 3 years following discontinuation of treatment.

Acitretin is a metabolite of etretinate (TEGISON), and major human fetal abnormalities have been reported with the administration of acitretin and etretinate.

Potentially, any fetus exposed can be affected.

Clinical evidence has shown that concurrent ingestion of acitretin and ethanol has been associated with the formation of etretinate, which has a significantly longer elimination half-life than acitretin.

Because the longer elimination half-life of etretinate would increase the duration of teratogenic potential for female patients, ethanol must not be ingested by female patients of childbearing potential either during treatment with acitretin capsules or for 2 months after cessation of therapy.

This allows for elimination of acitretin, thus removing the substrate for transesterification to etretinate.

The mechanism of the metabolic process for conversion of acitretin to etretinate has not been fully defined.

It is not known whether substances other than ethanol are associated with transesterification.

Acitretin has been shown to be embryotoxic and/or teratogenic in rabbits, mice, and rats at oral doses of 0.6, 3, and 15 mg per kg, respectively.

These doses are approximately 0.2, 0.3, and 3 times the maximum recommended therapeutic dose, respectively, based on a mg-per-m 2 comparison.

Major human fetal abnormalities associated with acitretin and/or etretinate administration have been reported including meningomyelocele; meningoencephalocele; multiple synostoses; facial dysmorphia; syndactyly; absence of terminal phalanges; malformations of hip, ankle, and forearm; low-set ears; high palate; decreased cranial volume; cardiovascular malformation; and alterations of the skull and cervical vertebrae.

Acitretin capsules should be prescribed only by those who have special competence in the diagnosis and treatment of severe psoriasis, are experienced in the use of systemic retinoids, and understand the risk of teratogenicity.

Because of the teratogenicity of acitretin, a program called the MyMAC program, My M ylan A citretin C ommitment, has been developed to educate women of childbearing potential and their healthcare providers about the serious risks associated with acitretin and to help prevent pregnancies from occurring with the use of this drug and for 3 years after its discontinuation.

The MyMAC program requirements are described below and program materials are available at www.acitretincommitment.com or may be requested by calling 1-877-446-3679 (1-877-4-INFO-RX) (see also PRECAUTIONS section).

Important Information for Women of Childbearing Potential: Acitretin capsules should be considered only for women with severe psoriasis unresponsive to other therapies or whose clinical condition contraindicates the use of other treatments.

Females of reproductive potential must not be given a prescription for acitretin capsules until pregnancy is excluded.

Acitretin capsules are contraindicated in females of reproductive potential unless the patient meets ALL of the following conditions: • Must have had 2 negative urine or serum pregnancy tests with a sensitivity of at least 25 mIU per mL before receiving the initial prescription for acitretin capsules.

The first test (a screening test) is obtained by the prescriber when the decision is made to pursue therapy with acitretin capsules.

The second pregnancy test (a confirmation test) should be done during the first 5 days of the menstrual period immediately preceding the beginning of therapy with acitretin capsules.

For patients with amenorrhea, the second test should be done at least 11 days after the last act of unprotected sexual intercourse (without using 2 effective forms of contraception [birth control] simultaneously).

If the second pregnancy test is negative, initiation of treatment with acitretin capsules should begin within 7 days of the specimen collection.

Acitretin capsules should be limited to a monthly supply.

• Must have a pregnancy test with a sensitivity of at least 25 mIU per mL repeated every month during treatment with acitretin capsules.

The patient must have a negative result from a urine or serum pregnancy test before receiving a prescription for acitretin capsules.

To encourage compliance with this recommendation, a monthly supply of the drug should be prescribed.

For at least 3 years after discontinuing therapy with acitretin capsules, a pregnancy test must be repeated every 3 months.

• Must have selected and have committed to use 2 effective forms of contraception (birth control) simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method, or the patient has undergone a hysterectomy or is clearly postmenopausal.

• Patients must use 2 effective forms of contraception (birth control) simultaneously for at least 1 month prior to initiation of therapy with acitretin capsules, during therapy with acitretin capsules, and for at least 3 years after discontinuing therapy with acitretin capsules.

A Contraception Counseling Referral Form is available so that patients can receive an initial free contraception counseling session and pregnancy testing.

Counseling about contraception and behaviors associated with an increased risk of pregnancy must be repeated on a monthly basis by the prescriber during therapy with acitretin capsules and every 3 months for at least 3 years following discontinuation of acitretin capsules.

Effective forms of contraception include both primary and secondary forms of contraception.

Primary forms of contraception include: tubal ligation, partner’s vasectomy, intrauterine devices, birth control pills, and injectable/implantable/insertable/topical hormonal birth control products.

Secondary forms of contraception include condoms (with or without spermicide), diaphragms and cervical caps (which must be used with a spermicide), and vaginal sponges (contains spermicide).

Any birth control method can fail.

Therefore, it is critically important that women of childbearing potential use 2 effective forms of contraception (birth control) simultaneously.

It has not been established if there is a pharmacokinetic interaction between acitretin and combined oral contraceptives.

However, it has been established that acitretin interferes with the contraceptive effect of microdosed progestin preparations.

1 Microdosed “minipill” progestin preparations are not recommended for use with acitretin capsules.

It is not known whether other progestin-only contraceptives, such as implants and injectables, are adequate methods of contraception during acitretin therapy.

Prescribers are advised to consult the package insert of any medication administered concomitantly with hormonal contraceptives, since some medications may decrease the effectiveness of these birth control products.

Patients should be prospectively cautioned not to self-medicate with the herbal supplement St.

John’s wort because a possible interaction has been suggested with hormonal contraceptives based on reports of breakthrough bleeding on oral contraceptives shortly after starting St.

John’s wort.

Pregnancies have been reported by users of combined hormonal contraceptives who also used some form of St.

John’s wort (see PRECAUTIONS ).

• Must have signed a Patient Agreement/Informed Consent for Female Patients that contains warnings about the risk of potential birth defects if the fetus is exposed to acitretin capsules, about contraceptive failure, about the fact that they must not ingest beverages or products containing ethanol while taking acitretin capsules and for 2 months after treatment with acitretin capsules has been discontinued, and about preventing pregnancy while taking acitretin capsules and for at least 3 years after discontinuing acitretin capsules.

If pregnancy does occur during therapy with acitretin capsules or at any time for at least 3 years following discontinuation of acitretin capsules, the prescriber and patient should discuss the possible effects on the pregnancy.

The available information is as follows: Acitretin, the active metabolite of etretinate, is teratogenic and is contraindicated during pregnancy.

The risk of severe fetal malformations is well established when systemic retinoids are taken during pregnancy.

Pregnancy must also be prevented after stopping acitretin therapy, while the drug is being eliminated to below a threshold blood concentration that would be associated with an increased incidence of birth defects.

Because this threshold has not been established for acitretin in humans and because elimination rates vary among patients, the duration of posttherapy contraception to achieve adequate elimination cannot be calculated precisely.

It is strongly recommended that contraception be continued for at least 3 years after stopping treatment with acitretin, based on the following considerations: • In the absence of transesterification to form etretinate, greater than 98% of the acitretin would be eliminated within 2 months, assuming a mean elimination half-life of 49 hours.

• In cases where etretinate is formed, as has been demonstrated with concomitant administration of acitretin and ethanol, • greater than 98% of the etretinate formed would be eliminated in 2 years, assuming a mean elimination half-life of 120 days.

• greater than 98% of the etretinate formed would be eliminated in 3 years, based on the longest demonstrated elimination half-life of 168 days.

However, etretinate was found in plasma and subcutaneous fat in one patient reported to have had sporadic alcohol intake, 52 months after she stopped acitretin therapy.

2 • Severe birth defects have been reported where conception occurred during the time interval when the patient was being treated with acitretin and/or etretinate.

In addition, severe birth defects have also been reported when conception occurred after the mother completed therapy.

These cases have been reported both prospectively (before the outcome was known) and retrospectively (after the outcome was known).

The events below are listed without distinction as to whether the reported birth defects are consistent with retinoid-induced embryopathy or not.

• There have been 318 prospectively reported cases involving pregnancies and the use of etretinate, acitretin, or both.

In 238 of these cases, the conception occurred after the last dose of etretinate (103 cases), acitretin (126), or both (9).

Fetal outcome remained unknown in approximately one-half of these cases, of which 62 were terminated and 14 were spontaneous abortions.

Fetal outcome is known for the other 118 cases and 15 of the outcomes were abnormal (including cases of absent hand/wrist, clubfoot, GI malformation, hypocalcemia, hypotonia, limb malformation, neonatal apnea/anemia, neonatal ichthyosis, placental disorder/death, undescended testicle, and 5 cases of premature birth).

In the 126 prospectively reported cases where conception occurred after the last dose of acitretin only, 43 cases involved conception at least 1 year but less than 2 years after the last dose.

There were 3 reports of abnormal outcomes out of these 43 cases (involving limb malformation, GI tract malformations, and premature birth).

There were only 4 cases where conception occurred at least 2 years after the last dose but there were no reports of birth defects in these cases.

• There is also a total of 35 retrospectively reported cases where conception occurred at least 1 year after the last dose of etretinate, acitretin, or both.

From these cases there are 3 reports of birth defects when the conception occurred at least 1 year but less than 2 years after the last dose of acitretin (including heart malformations, Turner’s Syndrome, and unspecified congenital malformations) and 4 reports of birth defects when conception occurred 2 or more years after the last dose of acitretin (including foot malformation, cardiac malformations [2 cases], and unspecified neonatal and infancy disorder).

There were 3 additional abnormal outcomes in cases where conception occurred 2 or more years after the last dose of etretinate (including chromosome disorder, forearm aplasia, and stillbirth).

• Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON.

TEGISON is no longer marketed in the U.S.; for information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

• Patients should not donate blood during and for at least 3 years following the completion of therapy with acitretin capsules because women of childbearing potential must not receive blood from patients being treated with acitretin capsules.

Important Information for Males Taking Acitretin Capsules: Patients should not donate blood during and for at least 3 years following therapy with acitretin capsules because women of childbearing potential must not receive blood from patients being treated with acitretin capsules.

• Samples of seminal fluid from 3 male patients treated with acitretin and 6 male patients treated with etretinate have been assayed for the presence of acitretin.

The maximum concentration of acitretin observed in the seminal fluid of these men was 12.5 ng per mL.

Assuming an ejaculate volume of 10 mL, the amount of drug transferred in semen would be 125 ng, which is 1/200,000 of a single 25-mg capsule.

Thus, although it appears that residual acitretin in seminal fluid poses little, if any, risk to a fetus while a male patient is taking the drug or after it is discontinued, the no-effect limit for teratogenicity is unknown and there is no registry for birth defects associated with acitretin.

The available data are as follows: There have been 25 cases of reported conception when the male partner was taking acitretin.

The pregnancy outcome is known in 13 of these 25 cases.

Of these, 9 reports were retrospective and 4 were prospective (meaning the pregnancy was reported prior to knowledge of the outcome).

3 Timing of Paternal Acitretin Treatment Delivery of Spontaneous Induced Total Relative to Conception Healthy Abortion Abortion Neonate At time of conception 5* 5 1 11 Discontinued ~ 4 weeks prior 0 0 1† 1 Discontinued ~ 6 to 8 months prior 0 1 0 1 * Four of 5 cases were prospective.

† With malformation pattern not typical of retinoid embryopathy (bilateral cystic hygromas of neck, hypoplasia of lungs bilateral, pulmonary atresia, VSD with overriding truncus arteriosus).

For All Patients: AN ACITRETIN CAPSULES MEDICATION GUIDE MUST BE GIVEN TO THE PATIENT EACH TIME ACITRETIN CAPSULES ARE DISPENSED, AS REQUIRED BY LAW.

INFORMATION FOR PATIENTS

Information for Patients (See Medication Guide for all patients and Patient Agreement/Informed Consent for Female Patients at end of professional labeling).

• Patients should be instructed to read the Medication Guide supplied as required by law when acitretin capsules are dispensed.

DOSAGE AND ADMINISTRATION

There is intersubject variation in the pharmacokinetics, clinical efficacy, and incidence of side effects with acitretin capsules.

A number of the more common side effects are dose-related.

Individualization of dosage is required to achieve sufficient therapeutic response while minimizing side effects.

Therapy with acitretin capsules should be initiated at 25 to 50 mg per day, given as a single dose with the main meal.

Maintenance doses of 25 to 50 mg per day may be given dependent upon an individual patient’s response to initial treatment.

Relapses may be treated as outlined for initial therapy.

When acitretin capsules are used with phototherapy, the prescriber should decrease the phototherapy dose, dependent on the patient’s individual response (see PRECAUTIONS: General ).

Females who have taken TEGISON (etretinate) must continue to follow the contraceptive recommendations for TEGISON.

TEGISON is no longer marketed in the U.S.; for information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).

Information for Pharmacists Acitretin capsules must only be dispensed in no more than a monthly supply.

An acitretin capsules Medication Guide must be given to the patient each time acitretin capsules are dispensed, as required by law.

Diamode 2 MG Oral Tablet

Generic Name: LOPERAMIDE HYDROCHLORIDE
Brand Name: MEDIQUE Diamode
  • Substance Name(s):
  • LOPERAMIDE HYDROCHLORIDE

WARNINGS

Warnings Allery alert: Do not use if you have ever had a rash or other allergic reaction to Loperamide HCl.

Heart alert: Taking more than directed can cause serious heart problems or death.

Do not use if you have bloody or black stool Ask a doctor before use if you have a fever mucus in the stool a history of liver disease a history of abnormal heart rythm Ask a doctor or pharmacist before use if you are taking a precription drug.

Loperamide may interect with certain prescription drugs.

When using this product tiredness, drowsiness or dizziness may occur.

Be careful when driving or operating machinery.

Stop use and ask a doctor if symptoms get worse diarrhea lasts more than 2 days you get abdominal swelling or bulging.

These may be signs of a serious condition.

If pregnant or breast feeding , ask a health professional before use.

Keep out of the reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

INDICATIONS AND USAGE

Uses Controls symptoms of diarrhea, including Travelers’ Diarrhea.

INACTIVE INGREDIENTS

Inactive ingredients anhydrous lactose, croscarmellose sodium, crospovidone, D&C Yellow # 10 aluminum lake, FD&C Blue # 1 aluminum lake, hydrogenated vegetable oil, magnesium stearate, powdered cellulose, pregelatinized starch

PURPOSE

Purpose Anti-diarrheal

KEEP OUT OF REACH OF CHILDREN

Keep out of the reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

ASK DOCTOR

Ask a doctor before use if you have a fever mucus in the stool a history of liver disease a history of abnormal heart rythm

OTHER SAFETY INFORMATION

Other information store between 68º – 77ºF (20º – 25ºC) tamper-evident sealed packets do not use any opened or torn packet see back of packet for lot number and expiration date

DOSAGE AND ADMINISTRATION

Directions drink plenty of clear fluids to help prevent dehydration caused by diarrhea Adults and children (12 years and over): Take 2 caplets after the first loose stool; 1 caplet after each subsequent loose stool; but no more than 4 caplets in 24 hours.

Children under 12 years: ask a doctor

PREGNANCY AND BREAST FEEDING

If pregnant or breast feeding , ask a health professional before use.

DO NOT USE

Do not use if you have bloody or black stool

STOP USE

Stop use and ask a doctor if symptoms get worse diarrhea lasts more than 2 days you get abdominal swelling or bulging.

These may be signs of a serious condition.

ACTIVE INGREDIENTS

Active ingredient (in each caplet) Loperamide HCl USP, 2mg

ASK DOCTOR OR PHARMACIST

Ask a doctor or pharmacist before use if you are taking a precription drug.

Loperamide may interect with certain prescription drugs.

DRUG INTERACTIONS

7 Drug Interactions (not described in Contraindications or Warnings And Precautions) include the following: Drugs Inhibiting or Metabolized by Cytochrome P450: Fluvoxamine inhibits several cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP3A4, and CYP2C19).

Carbamazepine: Elevated carbamazepine levels and symptoms of toxicity with coadministration ( 7.2 ).

Sumatriptan: Rare postmarketing reports of weakness, hyperreflexia, and incoordination following use of an SSRI and sumatriptan.

Monitor appropriately if concomitant treatment is clinically warranted ( 7.2 ).

Tacrine: Coadministration increased tacrine C max and AUC five-and eight-fold and caused nausea, vomiting, sweating, and diarrhea ( 7.2 ).

Tricyclic Antidepressants (TCAs): Coadministration significantly increased plasma TCA levels.

Use caution; monitor plasma TCA levels; reduce TCA dose if indicated ( 7.2 ).

Tryptophan: Severe vomiting with coadministration ( 7.2 ).

Diltiazem: Bradycardia with coadministration ( 7.3 ).

Propranolol or metoprolol: Reduce dose if coadministered and titrate more cautiously ( 7.3 ).

7.1 Potential Interactions with Drugs that Inhibit or are Metabolized by Cytochrome P450 Isoenzymes Multiple hepatic cytochrome P450 isoenzymes are involved in the oxidative biotransformation of a large number of structurally different drugs and endogenous compounds.

The available knowledge concerning the relationship of fluvoxamine and the cytochrome P450 isoenzyme system has been obtained mostly from pharmacokinetic interaction studies conducted in healthy volunteers, but some preliminary in vitro data are also available.

Based on a finding of substantial interactions of fluvoxamine with certain of these drugs [see later parts of this section and also WARNINGS AND PRECAUTIONS (5) ] and limited in vitro data for CYP3A4, it appears that fluvoxamine inhibits several cytochrome P450 isoenzymes that are known to be involved in the metabolism of other drugs such as: CYP1A2 (e.g., warfarin, theophylline, propranolol, tizanidine), CYP2C9 (e.g., warfarin), CYP3A4 (e.g., alprazolam), and CYP2C19 (e.g., omeprazole).

In vitro data suggest that fluvoxamine is a relatively weak inhibitor of CYP2D6.

Approximately 7% of the normal population has a genetic code that leads to reduced levels of activity of CYP2D6.

Such individuals have been referred to as “poor metabolizers” (PM) of drugs such as debrisoquin, dextromethorphan, and tricyclic antidepressants.

While none of the drugs studied for drug interactions significantly affected the pharmacokinetics of fluvoxamine, an in vivo study of fluvoxamine single-dose pharmacokinetics in 13 PM subjects demonstrated altered pharmacokinetic properties compared to 16 “extensive metabolizers” (EM): mean C max , AUC, and half-life were increased by 52%, 200%, and 62%, respectively, in the PM compared to the EM group.

This suggests that fluvoxamine is metabolized, at least in part, by CYP2D6.

Caution is indicated in patients known to have reduced levels of CYP2D6 activity and those receiving concomitant drugs known to inhibit this cytochrome P450 isoenzyme (e.g., quinidine).

The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied.

A clinically significant fluvoxamine interaction is possible with drugs having a narrow therapeutic ratio such as pimozide, warfarin, theophylline, certain benzodiazepines, omeprazole and phenytoin.

If fluvoxamine maleate tablets are to be administered together with a drug that is eliminated via oxidative metabolism and has a narrow therapeutic window, plasma levels and/or pharmacodynamic effects of the latter drug should be monitored closely, at least until steady-state conditions are reached.

[see CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5) .] 7.2 CNS Active Drugs Antipsychotics See WARNINGS AND PRECAUTIONS (5.2).

Benzodiazepines See WARNINGS AND PRECAUTIONS (5.8).

Alprazolam See WARNINGS AND PRECAUTIONS (5.8).

Diazepam See WARNINGS AND PRECAUTIONS (5.8).

Lorazepam A study of multiple doses of fluvoxamine maleate (50 mg b.i.d.) in healthy male volunteers (N=12) and a single dose of lorazepam (4 mg single dose) indicated no significant pharmacokinetic interaction.

On average, both lorazepam alone and lorazepam with fluvoxamine produced substantial decrements in cognitive functioning; however, the coadministration of fluvoxamine and lorazepam did not produce larger mean decrements compared to lorazepam alone.

Alcohol Studies involving single 40 g doses of ethanol (oral administration in one study and intravenous in the other) and multiple dosing with fluvoxamine maleate (50 mg b.i.d.) revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of the other.

As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.

Carbamazepine Elevated carbamazepine levels and symptoms of toxicity have been reported with the coadministration of fluvoxamine maleate and carbamazepine.

Clozapine See WARNINGS AND PRECAUTIONS (5.8).

Lithium As with other serotonergic drugs, lithium may enhance the serotonergic effects of fluvoxamine and, therefore, the combination should be used with caution.

Seizures have been reported with the coadministration of fluvoxamine maleate and lithium.

Methadone See WARNINGS AND PRECAUTIONS (5.8).

Monoamine Oxidase Inhibitors See DOSAGE AND ADMINISTRATION ( 2.5 and 2.6 ), CONTRAINDICATIONS (4.2) and WARNINGS AND PRECAUTIONS (5.2) .

Pimozide See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.6) .

Ramelteon See WARNINGS AND PRECAUTIONS (5.8) .

Serotonergic Drugs See DOSAGE AND ADMINISTRATION ( 2.5 and 2.6 ), CONTRAINDICATIONS (4.2) and WARNINGS AND PRECAUTIONS (5.2) .

Tacrine In a study of 13 healthy, male volunteers, a single 40 mg dose of tacrine added to fluvoxamine 100 mg/day administered at steady-state was associated with five-and eight-fold increases in tacrine C max and AUC, respectively, compared to the administration of tacrine alone.

Five subjects experienced nausea, vomiting, sweating, and diarrhea following coadministration, consistent with the cholinergic effects of tacrine.

Thioridazine See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.4) .

Tizanidine See CONTRAINDICATIONS (4.1) and WARNINGS AND PRECAUTIONS (5.5) .

Tricyclic Antidepressants (TCAs) Significantly increased plasma TCA levels have been reported with the coadministration of fluvoxamine maleate and amitriptyline, clomipramine or imipramine.

Caution is indicated with the coadministration of fluvoxamine maleate tablets and TCAs; plasma TCA concentrations may need to be monitored, and the dose of TCA may need to be reduced.

Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.

If concomitant treatment of fluvoxamine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS (5.2) ].

Sumatriptan There have been rare postmarketing reports describing patients with weakness, hyperreflexia, and incoordination following the use of a selective serotonin reuptake inhibitor (SSRI) and sumatriptan.

If concomitant treatment with sumatriptan and an SSRI (e.g., fluoxetine, fluvoxamine, paroxetine, sertraline) is clinically warranted, appropriate observation of the patient is advised.

Tryptophan Tryptophan may enhance the serotonergic effects of fluvoxamine, and the combination should, therefore, be used with caution.

Severe vomiting has been reported with the coadministration of fluvoxamine maleate and tryptophan [see WARNINGS AND PRECAUTIONS (5.2) ].

7.3 Other Drugs Alosetron See CONTRAINDICATIONS (4.1) , WARNINGS AND PRECAUTIONS (5.7) , and Lotronex TM (alosetron) package insert.

Digoxin Administration of fluvoxamine maleate 100 mg daily for 18 days (N=8) did not significantly affect the pharmacokinetics of a 1.25 mg single intravenous dose of digoxin.

Diltiazem Bradycardia has been reported with the coadministration of fluvoxamine maleate and diltiazem.

Mexiletine See WARNINGS AND PRECAUTIONS (5.8).

Propranolol and Other Beta-Blockers Coadministration of fluvoxamine maleate 100 mg per day and propranolol 160 mg per day in normal volunteers resulted in a mean five-fold increase (range 2 to 17) in minimum propranolol plasma concentrations.

In this study, there was a slight potentiation of the propranolol-induced reduction in heart rate and reduction in the exercise diastolic pressure.

One case of bradycardia and hypotension and a second case of orthostatic hypotension have been reported with the coadministration of fluvoxamine maleate and metoprolol.

If propranolol or metoprolol is coadministered with fluvoxamine maleate tablets, a reduction in the initial beta-blocker dose and more cautious dose titration are recommended.

No dosage adjustment is required for fluvoxamine maleate tablets.

Coadministration of fluvoxamine maleate 100 mg per day with atenolol 100 mg per day (N=6) did not affect the plasma concentrations of atenolol.

Unlike propranolol and metoprolol which undergo hepatic metabolism, atenolol is eliminated primarily by renal excretion.

Theophylline See WARNINGS AND PRECAUTIONS (5.8) .

Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.) See WARNINGS AND PRECAUTIONS ( 5.8 and 5.10 ).

7.4 Effects of Smoking on Fluvoxamine Metabolism Smokers had a 25% increase in the metabolism of fluvoxamine compared to nonsmokers.

7.5 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefits or risks of combined use of ECT and fluvoxamine maleate.

OVERDOSAGE

10 10.1 Human Experience Worldwide exposure to fluvoxamine includes over 45,000 patients treated in clinical trials and an estimated exposure of 50,000,000 patients treated during worldwide marketing experience (end of 2005).

Of the 539 cases of deliberate or accidental overdose involving fluvoxamine reported from this population, there were 55 deaths.

Of these, 9 were in patients thought to be taking fluvoxamine alone and the remaining 46 were in patients taking fluvoxamine along with other drugs.

Among non-fatal overdose cases, 404 patients recovered completely.

Five patients experienced adverse sequelae of overdosage, to include persistent mydriasis, unsteady gait, hypoxic encephalopathy, kidney complications (from trauma associated with overdose), bowel infarction requiring a hemicolectomy, and vegetative state.

In 13 patients, the outcome was provided as abating at the time of reporting.

In the remaining 62 patients, the outcome was unknown.

The largest known ingestion of fluvoxamine involved 12,000 mg (equivalent to 2 to 3 months’ dosage).

The patient fully recovered.

However, ingestions as low as 1,400 mg have been associated with lethal outcome, indicating considerable prognostic variability.

Commonly (≥5%) observed adverse events associated with fluvoxamine maleate overdose include gastrointestinal complaints (nausea, vomiting and diarrhea), coma, hypokalemia, hypotension, respiratory difficulties, somnolence, and tachycardia.

Other notable signs and symptoms seen with fluvoxamine maleate overdose (single or multiple drugs) include bradycardia, ECG abnormalities (such as heart arrest, QT interval prolongation, first degree atrioventricular block, bundle branch block, and junctional rhythm), convulsions, dizziness, liver function disturbances, tremor, and increased reflexes.

10.2 Management of Overdosage Treatment should consist of those general measures employed in the management of overdosage with any antidepressant.

Ensure an adequate airway, oxygenation, and ventilation.

Monitor cardiac rhythm and vital signs.

General supportive and symptomatic measures are also recommended.

Induction of emesis is not recommended.

Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered.

Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit.

No specific antidotes for fluvoxamine are known.

A specific caution involves patients taking, or recently having taken, fluvoxamine who might ingest excessive quantities of a tricyclic antidepressant.

In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation.

[see DRUG INTERACTIONS (7.2) .] In managing overdosage, consider the possibility of multiple drug involvement.

The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR).

DESCRIPTION

11 Fluvoxamine maleate is a selective serotonin (5-HT) reuptake inhibitor (SSRI) belonging to the chemical series, the 2-aminoethyl oxime ethers of aralkylketones.

It is chemically unrelated to other SSRIs and clomipramine.

It is chemically designated as 5-methoxy-4′-(trifluoromethyl) valerophenone (E)-O-(2-aminoethyl) oxime maleate (1:1) and has the molecular formula C 15 H 21 O 2 N 2 F 3 •C 4 H 4 O 4 .

Its molecular weight is 434.4.

The structural formula is: Fluvoxamine maleate is a white to off-white, odorless, crystalline powder which is sparingly soluble in water, freely soluble in ethanol and chloroform and practically insoluble in diethyl ether.

Fluvoxamine maleate tablets, USP are available in 25 mg, 50 mg and 100 mg strengths for oral administration.

In addition to the active ingredient, fluvoxamine maleate, each tablet contains the following inactive ingredients: hydroxyethyl cellulose, magnesium stearate, mannitol, polyethylene glycol and titanium dioxide.

The 50 mg and 100 mg tablets also contain synthetic iron oxides.

Chemical Structure

CLINICAL STUDIES

14 14.1 Adult OCD Studies The effectiveness of fluvoxamine maleate tablets for the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 10-week multicenter, parallel group studies of adult outpatients.

Patients in these trials were titrated to a total daily fluvoxamine maleate dose of 150 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 100-300 mg/day (on a b.i.d.

schedule), on the basis of response and tolerance.

Patients in these studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), total score of 23.

Patients receiving fluvoxamine maleate experienced mean reductions of approximately 4 to 5 units on the Y-BOCS total score, compared to a 2 unit reduction for placebo patients.

Table 6 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impressions (CGI) scale for both studies combined.

TABLE 6 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN POOL OF TWO ADULT OCD STUDIES Outcome Classification Fluvoxamine (N=120) Placebo (N=134) Very Much Improved 13% 2% Much Improved 30% 10% Minimally Improved 22% 32% No Change 31% 51% Worse 4% 6% Exploratory analyses for age and gender effects on outcomes did not suggest any differential responsiveness on the basis of age or sex.

14.2 Adult OCD Maintenance Study In a maintenance trial of adult outpatients with OCD, 114 patients meeting DSM-IV criteria for OCD and with a Yale-Brown Obsessive Compulsive Scale (Y-BOCS) score ≥18 were titrated to an effective dose of fluvoxamine maleate tablets 100 to 300 mg/day as part of an initial 10-week single-blind treatment phase.

Treatment response during this single-blind phase was defined as Y-BOCS scores at least 30% lower than baseline at the end of weeks 8 and 10.

Of the patients who responded, their average duration of response was 4 weeks.

Patients who responded during this initial phase were randomized either to continuation of fluvoxamine maleate tablets (N=56) or to placebo (N=58) in a double-blind phase for observation of relapse.

Relapse during the double-blind phase was defined as an increase in the Y-BOCS score of at least 30% over the baseline for that phase or patient refusal to continue treatment due to a substantial increase in OCD symptoms.

In the double-blind phase, patients receiving continued fluvoxamine maleate tablets treatment experienced, on average, a significantly lower relapse rate than those receiving placebo.

An examination of population subgroups from this trial did not reveal any clear evidence of a differential maintenance effect on the basis of age or gender.

14.3 Pediatric OCD Study The effectiveness of fluvoxamine maleate tablets for the treatment of OCD was also demonstrated in a 10-week multicenter, parallel group study in a pediatric outpatient population (children and adolescents, ages 8 to 17).

Patients in this study were titrated to a total daily fluvoxamine dose of approximately 100 mg/day over the first two weeks of the trial, following which the dose was adjusted within a range of 50 to 200 mg/day (on a b.i.d.

schedule) on the basis of response and tolerance.

All patients had moderate to severe OCD (DSM-III-R) with mean baseline ratings on the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) total score of 24.

Patients receiving fluvoxamine maleate experienced mean reductions of approximately six units on the CY-BOCS total score, compared to a three-unit reduction for placebo patients.

Table 7 provides the outcome classification by treatment group on the Global Improvement item of the Clinical Global Impression (CGI) scale for the pediatric study.

TABLE 7 OUTCOME CLASSIFICATION (%) ON CGI-GLOBAL IMPROVEMENT ITEM FOR COMPLETERS IN PEDIATRIC STUDY Outcome Classification Fluvoxamine (N=38) Placebo (N=36) Very Much Improved 21% 11% Much Improved 18% 17% Minimally Improved 37% 22% No Change 16% 44% Worse 8% 6% Post hoc exploratory analyses for gender effects on outcomes did not suggest any differential responsiveness on the basis of gender.

Further exploratory analyses revealed a prominent treatment effect in the 8 to 11 age group and essentially no effect in the 12 to 17 age group.

While the significance of these results is not clear, the 2 to 3 fold higher steady-state plasma fluvoxamine concentrations in children compared to adolescents [see CLINICAL PHARMACOLOGY -Pediatric Subjects (12.3) ] is suggestive that decreased exposure in adolescents may have been a factor, and dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.

HOW SUPPLIED

16 /STORAGE AND HANDLING 16.1 How Supplied Fluvoxamine maleate tablets, USP are available in the following strengths, colors, imprints, and presentations: Tablets 50 mg: Golden, round, scored, film coated tablets, imprinted “APO” on one side and “F50” with a partial bisect on the other side.

Unit dose packages of 30 (3 × 10) NDC 68084-837-21 16.2 Storage Keep out of reach of children.

Fluvoxamine maleate tablets, USP should be protected from high humidity and stored at 20° to 25°C (68° to 77°F); excursions permitted from 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

RECENT MAJOR CHANGES

Warnings and Precautions ( 5.3 ) 7/2014

GERIATRIC USE

8.5 Geriatric Use Approximately 230 patients participating in controlled premarketing studies with fluvoxamine maleate tablets were 65 years of age or over.

No overall differences in safety were observed between these patients and younger patients.

Other reported clinical experience has not identified differences in response between the elderly and younger patients.

However, SSRIs and SNRIs, including fluvoxamine maleate tablets, have been associated with several cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see WARNINGS AND PRECAUTIONS (5.13) ] .

Furthermore, the clearance of fluvoxamine is decreased by about 50% in elderly compared to younger patients [see CLINICAL PHARMACOLOGY-Elderly (12.3) ] , and greater sensitivity of some older individuals also cannot be ruled out.

Consequently, a lower starting dose should be considered in elderly patients and fluvoxamine maleate tablets should be slowly titrated during initiation of therapy.

DOSAGE FORMS AND STRENGTHS

3 Fluvoxamine maleate tablets are available as: Tablets 25 mg: White to off-white, round, unscored, film coated tablets, imprinted “APO” on one side and “F25” on the other side.

Tablets 50 mg: Golden, round, scored, film coated tablets, imprinted “APO” on one side and “F50” with a partial bisect on the other side.

Tablets 100 mg: Reddish-brown, pillow shaped, scored, film coated tablets, imprinted “APO” on one side and “FLU” bisect “100” on the other side.

25 mg, 50 mg, and 100 mg Tablets ( 3 )

MECHANISM OF ACTION

12.1 Mechanism of Action The mechanism of action of fluvoxamine maleate in obsessive compulsive disorder is presumed to be linked to its specific serotonin reuptake inhibition in brain neurons.

Fluvoxamine has been shown to be a potent inhibitor of the serotonin reuptake transporter in preclinical studies, both in vitro and in vivo .

INDICATIONS AND USAGE

1 Fluvoxamine maleate tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD) ( 1 ).

1.1 Obsessive-Compulsive Disorder Fluvoxamine maleate tablets, USP are indicated for the treatment of obsessions and compulsions in patients with obsessive compulsive disorder (OCD), as defined in DSM-III-R or DSM-IV.

The obsessions or compulsions cause marked distress, are time-consuming, or significantly interfere with social or occupational functioning.

Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful, and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable.

The efficacy of fluvoxamine maleate tablets, USP was established in four trials in outpatients with OCD: two 10-week trials in adults, one 10-week trial in pediatric patients (ages 8 to 17) and one maintenance trial in adults.

[see CLINICAL STUDIES (14).

]

PEDIATRIC USE

8.4 Pediatric Use The efficacy of fluvoxamine maleate for the treatment of obsessive compulsive disorder was demonstrated in a 10-week multicenter placebo controlled study with 120 outpatients ages 8 to 17.

In addition, 99 of these outpatients continued open-label fluvoxamine maleate treatment for up to another one to three years, equivalent to 94 patient years.

The adverse event profile observed in that study was generally similar to that observed in adult studies with fluvoxamine.

[see ADVERSE REACTIONS (6.3) and DOSAGE AND ADMINISTRATION (2.2) .] Decreased appetite and weight loss have been observed in association with the use of fluvoxamine as well as other SSRIs.

Consequently, regular monitoring of weight and growth is recommended if treatment of a child with an SSRI is to be continued long term.

The risks, if any, that may be associated with fluvoxamine’s extended use in children and adolescents with OCD have not been systematically assessed.

The prescriber should be mindful that the evidence relied upon to conclude that fluvoxamine is safe for use in children and adolescents derives from relatively short term clinical studies and from extrapolation of experience gained with adult patients.

In particular, there are no studies that directly evaluate the effects of long term fluvoxamine use on the growth, cognitive behavioral development, and maturation of children and adolescents.

Although there is no affirmative finding to suggest that fluvoxamine possesses a capacity to adversely affect growth, development or maturation, the absence of such findings is not compelling evidence of the absence of the potential of fluvoxamine to have adverse effects in chronic use [see WARNINGS AND PRECAUTIONS-Clinical Worsening and Suicide Risk (5.1) ].

Safety and effectiveness in the pediatric population other than pediatric patients with OCD have not been established.

[see BOXED WARNING and WARNINGS AND PRECAUTIONS -Clinical Worsening and Suicide Risk (5.1) .] Anyone considering the use of fluvoxamine maleate tablets in a child or adolescent must balance the potential risks with the clinical need.

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy Category C When pregnant rats were given oral doses of fluvoxamine (60, 120, or 240 mg/kg) throughout the period of organogenesis, developmental toxicity in the form of increased embryofetal death and increased incidences of fetal eye abnormalities (folded retinas) was observed at doses of 120 mg/kg or greater.

Decreased fetal body weight was seen at the high dose.

The no effect dose for developmental toxicity in this study was 60 mg/kg (approximately 2 times the MRHD on a mg/m 2 basis).

In a study in which pregnant rabbits were administered doses of up to 40 mg/kg (approximately 2 times the MRHD on a mg/m 2 basis) during organogenesis, no adverse effects on embryofetal development were observed.

In other reproduction studies in which female rats were dosed orally during pregnancy and lactation (5, 20, 80, or 160 mg/kg), increased pup mortality at birth was seen at doses of 80 mg/kg or greater and decreases in pup body weight and survival were observed at all doses (low effect dose approximately 0.1 times the MRHD on a mg/m 2 basis).

Nonteratogenic Effects Neonates exposed to fluvoxamine maleate tablets and other SSRIs or serotonin and norepinephrine reuptake inhibitors (SNRIs), late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see WARNINGS AND PRECAUTIONS (5.2) ].

Infants exposed to SSRIs in pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).PPHN occurs in 1 to 2 per 1,000 live births in the general population and is associated with substantial neonatal morbidity and mortality.

Several recent epidemiologic studies suggest a positive statistical association between SSRI use (including fluvoxamine maleate tablets) in pregnancy and PPHN.

Other studies do not show a significant statistical association.

Physicians should also note in the results of a prospective longitudinal study of 201 pregnant women with a history of major depression, who were either on antidepressants or had received antidepressants less than 12 weeks prior to their last menstrual period, and were in remission.

Women who discontinued antidepressant medication during pregnancy showed a significant increase in relapse of their major depression compared to those women who remained on antidepressant medication throughout pregnancy.

When treating a pregnant woman with fluvoxamine maleate tablets, the physician should carefully consider both the potential risks of taking an SSRI, along with the established benefits of treating depression with an antidepressant.

This decision can only be made on a case by case basis .

[see DOSAGE AND ADMINISTRATION (2.4) .]

NUSRING MOTHERS

8.3 Nursing Mothers As for many other drugs, fluvoxamine is secreted in human breast milk.

The decision of whether to discontinue nursing or to discontinue the drug should take into account the potential for serious adverse effects from exposure to fluvoxamine in the nursing infant as well as the potential benefits of fluvoxamine maleate tablets therapy to the mother.

BOXED WARNING

Suicidality and AntidepressantS 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 fluvoxamine maleate tablets 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.

Fluvoxamine maleate tablets are not approved for use in pediatric patients except for patients with obsessive compulsive disorder (OCD).

[see WARNINGS AND PRECAUTIONS-Clinical Worsening and Suicide Risk (5.1) .] Warning: Suicidality and Antidepressants See full prescribing information for complete boxed warning.

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for major depressive disorder and other psychiatric disorders.

Fluvoxamine maleate tablets are not approved for use in pediatric patients except those with obsessive compulsive disorder ( 5.1 ).

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Suicidality: Monitor for clinical worsening and suicide risk ( 5.1 ).

Bipolar disorder: Screen for bipolar disorder ( 5.1 ).

S erotonin Syndrome: Serotonin syndrome has been reported with SSRIs, and SNRIs including fluvoxamine maleate tablets, both when taken alone, but especially when co-administered with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St.

John’s Wort).

If such symptoms occur, discontinue fluvoxamine maleate tablets and initiate supportive treatment.

If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

( 5.2 ).

Angle Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants ( 5.3 ).

Other potentially important drug interactions.

Benzodiazepines: Use with caution.

Coadministration with diazepam is generally not advisable ( 5.8 ).

Clozapine: Clozapine levels may be increased and produce orthostatic hypotension or seizures ( 5.9 ).

Methadone : Coadministration may produce opioid intoxication.

Discontinuation of fluvoxamine may produce opioid withdrawal ( 5.8 ).

Mexiletine: Monitor serum mexiletine levels ( 5.9 ).

Ramelteon: Should not be used in combination with fluvoxamine ( 5.8 ).

Theophylline: Clearance decreased; reduce theophylline dose by one-third ( 5.8 ).

Warfarin: Plasma concentrations increased and prothrombin times prolonged; monitor prothrombin time and adjust warfarin dose accordingly ( 5.8 ).

Other Drugs Affecting Hemostasis: Increased risk of bleeding with concomitant use of NSAIDs, aspirin, or other drugs affecting coagulation ( 5.8 , 5.10 ).

See Contraindications (4) .

Discontinuation: Symptoms associated with discontinuation have been reported ( 5.9 ).

Abrupt discontinuation not recommended.

See Dosage And Administration (2.8) .

Activation of mania/hypomania has occurred ( 5.11 ).

Seizures: Avoid administering fluvoxamine in patients with unstable epilepsy; monitor patients with controlled epilepsy; discontinue treatment if seizures occur or frequency increases ( 5.12 ).

Hyponatremia: May occur with SSRIs and SNRIs, including fluvoxamine maleate tablets.

The elderly may be at increased risk.

Consider discontinuing in patients with symptomatic hyponatremia ( 5.13 ).

Concomitant illness: Use caution in patients with diseases or conditions that affect hemodynamic responses or metabolism ( 5.14 ).

Patients with impaired liver function may require a lower starting dose and slower titration ( 2.3 ).

5.1 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 to 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 DRUG-PLACEBO DIFFERENCES IN NUMBER OF CASES OF SUICIDALITY PER 1000 PATIENTS TREATED Age Range Increases Compared to Placebo <18 14 Additional Cases 18-24 5 Additional Cases Age Range 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 the 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.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see DOSAGE AND ADMINISTRATION – Discontinuation of Treatment with fluvoxamine maleate tablets (2.8) , for a description of the risks of discontinuation of fluvoxamine maleate tablets] .

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 healthcare providers.

Such monitoring should include daily observation by families and caregivers.

Prescriptions for fluvoxamine maleate tablets 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 fluvoxamine maleate tablets are not approved for use in treating bipolar depression.

5.2 Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including fluvoxamine maleate tablets, alone but particularly with concomitant use of serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, busipirone, and St.

John’s Wort) and with drugs that impair metabolism of serotonin ( in particular MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular aberrations (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of fluvoxamine maleate tablets with MAOIs intended to treat psychiatric disorders is contraindicated.

Fluvoxamine maleate tablets should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking fluvoxamine maleate tablets.

Fluvoxamine maleate tablets should be discontinued before initiating treatment with the MAOI.

[see CONTRAINDICATIONS (4.2) and DOSAGE AND ADMINISTRATION ( 2.5 and 2.6 ).] If concomitant use of fluvoxamine maleate tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with fluvoxamine maleate tablets and any concomitant serotonergic agents, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

5.3 Angle Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including Fluvoxamine Maleate Tablets may trigger an angle closure attack in a patient with anatomically narrow angles who do not have a patent iridectomy.

5.4 Potential Thioridazine Interaction The effect of fluvoxamine (25 mg b.i.d.

for one week) on thioridazine steady-state concentrations was evaluated in 10 male inpatients with schizophrenia.

Concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, increased threefold following coadministration of fluvoxamine.

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death.

It is likely that this experience underestimates the degree of risk that might occur with higher doses of thioridazine.

Moreover, the effect of fluvoxamine may be even more pronounced when it is administered at higher doses.

Therefore, fluvoxamine and thioridazine should not be coadministered.

[see CONTRAINDICATIONS (4.1) .] 5.5 Potential Tizanidine Interaction Fluvoxamine is a potent inhibitor of CYP1A2 and tizanidine is a CYP1A2 substrate.

The effect of fluvoxamine (100 mg daily for 4 days) on the pharmacokinetics and pharmacodynamics of a single 4 mg dose of tizanidine has been studied in 10 healthy male subjects.

Tizanidine C max was increased approximately 12-fold (range 5-fold to 32-fold), elimination half-life was increased by almost 3-fold, and AUC increased 33-fold (range 14-fold to 103-fold).

The mean maximal effect on blood pressure was a 35 mm Hg decrease in systolic blood pressure, a 20 mm Hg decrease in diastolic blood pressure, and a 4 beat/min decrease in heart rate.

Drowsiness was significantly increased and performance on the psychomotor task was significantly impaired.

Fluvoxamine and tizanidine should not be used together.

[see CONTRAINDICATIONS (4.1) .] 5.6 Potential Pimozide Interaction Pimozide is metabolized by the cytochrome P4503A4 isoenzyme, and it has been demonstrated that ketoconazole, a potent inhibitor of CYP3A4, blocks the metabolism of this drug, resulting in increased plasma concentrations of parent drug.

An increased plasma concentration of pimozide causes QT prolongation and has been associated with torsades de pointes-type ventricular tachycardia, sometimes fatal.

As noted below, a substantial pharmacokinetic interaction has been observed for fluvoxamine in combination with alprazolam, a drug that is known to be metabolized by CYP3A4.

Although it has not been definitively demonstrated that fluvoxamine is a potent CYP3A4 inhibitor, it is likely to be, given the substantial interaction of fluvoxamine with alprazolam.

Consequently, it is recommended that fluvoxamine not be used in combination with pimozide.

[see CONTRAINDICATIONS (4.1) .] 5.7 Potential Alosetron Interaction Because alosetron is metabolized by a variety of hepatic CYP drug metabolizing enzymes, inducers or inhibitors of these enzymes may change the clearance of alosetron.

Fluvoxamine is a known potent inhibitor of CYP1A2 and also inhibits CYP3A4, CYP2C9, and CYP2C19.

In a pharmacokinetic study, 40 healthy female subjects received fluvoxamine in escalating doses from 50 mg to 200 mg a day for 16 days, with coadministration of alosetron 1 mg on the last day.

Fluvoxamine increased mean alosetron plasma concentration (AUC) approximately 6-fold and prolonged the half-life by approximately 3-fold.

[see CONTRAINDICATIONS (4.1) and Lotronex TM (alosetron) package insert.] 5.8 Other Potentially Important Drug Interactions Benzodiazepines- Benzodiazepines metabolized by hepatic oxidation (e.g., alprazolam, midazolam, triazolam, etc.) should be used with caution because the clearance of these drugs is likely to be reduced by fluvoxamine.

The clearance of benzodiazepines metabolized by glucuronidation (e.g., lorazepam, oxazepam, temazepam) is unlikely to be affected by fluvoxamine.

Alprazolam When fluvoxamine maleate (100 mg q.d.) and alprazolam (1 mg q.i.d.) were coadministered to steady state, plasma concentrations and other pharmacokinetic parameters (AUC, C max , T ½ ) of alprazolam were approximately twice those observed when alprazolam was administered alone; oral clearance was reduced by about 50%.

The elevated plasma alprazolam concentrations resulted in decreased psychomotor performance and memory.

This interaction, which has not been investigated using higher doses of fluvoxamine, may be more pronounced if a 300 mg daily dose is coadministered, particularly since fluvoxamine exhibits non-linear pharmacokinetics over the dosage range 100 to 300 mg.

If alprazolam is coadministered with fluvoxamine maleate tablets, the initial alprazolam dosage should be at least halved and titration to the lowest effective dose is recommended.

No dosage adjustment is required for fluvoxamine maleate tablets.

Diazepam The coadministration of fluvoxamine maleate tablets and diazepam is generally not advisable.

Because fluvoxamine reduces the clearance of both diazepam and its active metabolite, N-desmethyldiazepam, there is a strong likelihood of substantial accumulation of both species during chronic coadministration.

Evidence supporting the conclusion that it is inadvisable to coadminister fluvoxamine and diazepam is derived from a study in which healthy volunteers taking 150 mg/day of fluvoxamine were administered a single oral dose of 10 mg of diazepam.

In these subjects (N=8), the clearance of diazepam was reduced by 65% and that of N-desmethyldiazepam to a level that was too low to measure over the course of the 2 week long study.

It is likely that this experience significantly underestimates the degree of accumulation that might occur with repeated diazepam administration.

Moreover, as noted with alprazolam, the effect of fluvoxamine may even be more pronounced when it is administered at higher doses.

Accordingly, diazepam and fluvoxamine should not ordinarily be coadministered.

Clozapine Elevated serum levels of clozapine have been reported in patients taking fluvoxamine maleate and clozapine.

Since clozapine-related seizures and orthostatic hypotension appear to be dose related, the risk of these adverse events may be higher when fluvoxamine and clozapine are coadministered.

Patients should be closely monitored when fluvoxamine maleate and clozapine are used concurrently.

Methadone Significantly increased methadone (plasma level: dose) ratios have been reported when fluvoxamine maleate was administered to patients receiving maintenance methadone treatment, with symptoms of opioid intoxication in one patient.

Opioid withdrawal symptoms were reported following fluvoxamine maleate discontinuation in another patient.

Mexiletine The effect of steady-state fluvoxamine (50 mg b.i.d.

for 7 days) on the single dose pharmacokinetics of mexiletine (200 mg) was evaluated in 6 healthy Japanese males.

The clearance of mexiletine was reduced by 38% following coadministration with fluvoxamine compared to mexiletine alone.

If fluvoxamine and mexiletine are coadministered, serum mexiletine levels should be monitored.

Ramelteon When fluvoxamine 100 mg twice daily was administered for 3 days prior to single-dose coadministration of ramelteon 16 mg and fluvoxamine, the AUC for ramelteon increased approximately 190-fold and the C max increased approximately 70-fold compared to ramelteon administered alone.

Ramelteon should not be used in combination with fluvoxamine.

Theophylline The effect of steady-state fluvoxamine (50 mg b.i.d) on the pharmacokinetics of a single dose of theophylline (375 mg as 442 mg aminophylline) was evaluated in 12 healthy non-smoking, male volunteers.

The clearance of theophylline was decreased approximately 3-fold.

Therefore, if theophylline is coadministered with fluvoxamine maleate, its dose should be reduced to one-third of the usual daily maintenance dose and plasma concentrations of theophylline should be monitored.

No dosage adjustment is required for fluvoxamine maleate tablets.

Warfarin and Other Drugs That Interfere With Hemostasis (NSAIDs, Aspirin, etc.) Serotonin release by platelets plays an important role in hemostasis.

Epidemiological studies of the case-control and cohort design have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding.

These studies have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.

Thus, patients should be cautioned about the use of such drugs concurrently with fluvoxamine [see WARNINGS AND PRECAUTIONS, Abnormal Bleeding (5.9)] .

Warfarin When fluvoxamine maleate (50 mg t.i.d.) was administered concomitantly with warfarin for two weeks, warfarin plasma concentrations increased by 98% and prothrombin times were prolonged.

Thus patients receiving oral anticoagulants and fluvoxamine maleate tablets should have their prothrombin time monitored and their anticoagulant dose adjusted accordingly.

No dosage adjustment is required for fluvoxamine maleate tablets.

5.9 Discontinuation of Treatment with Fluvoxamine Maleate Tablets During marketing of fluvoxamine maleate tablets and other SSRIs and SNRIs (serotonin and norepinephrine reuptake inhibitors), there have been spontaneous reports of adverse events occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias, such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these events are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with fluvoxamine maleate tablets.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

[see DOSAGE AND ADMINISTRATION (2.8) .] 5.10 Abnormal Bleeding SSRIs and SNRIs, including fluvoxamine maleate tablets, may increase the risk of bleeding events.

Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anticoagulants may add to this risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Bleeding events related to SSRIs and SNRIs have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluvoxamine maleate tablets and NSAIDs, aspirin, or other drugs that affect coagulation (see WARNINGS AND PRECAUTIONS [5.8] ).

5.11 Activation of Mania/Hypomania During premarketing studies involving primarily depressed patients, hypomania or mania occurred in approximately 1% of patients treated with fluvoxamine.

In a ten week pediatric OCD study, 2 out of 57 patients (4%) treated with fluvoxamine experienced manic reactions, compared to none of 63 placebo patients.

Activation of mania/hypomania has also been reported in a small proportion of patients with major affective disorder who were treated with other marketed antidepressants.

As with all antidepressants, fluvoxamine maleate tablets should be used cautiously in patients with a history of mania.

5.12 Seizures During premarketing studies, seizures were reported in 0.2% of fluvoxamine-treated patients.

Caution is recommended when the drug is administered to patients with a history of convulsive disorders.

Fluvoxamine should be avoided in patients with unstable epilepsy and patients with controlled epilepsy should be carefully monitored.

Treatment with fluvoxamine should be discontinued if seizures occur or if seizure frequency increases.

5.13 Hyponatremia Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including fluvoxamine maleate tablets.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported.

Elderly patients may be at greater risk of developing hyponatremia with SSRIs and SNRIs [see USE IN SPECIFIC POPULATION, Geriatric Use (8.5) ] .

Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk.

Discontinuation of fluvoxamine maleate tablets should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.14 Use in Patients with Concomitant Illness Closely monitored clinical experience with fluvoxamine maleate tablets in patients with concomitant systemic illness is limited.

Caution is advised in administering fluvoxamine maleate tablets to patients with diseases or conditions that could affect hemodynamic responses or metabolism.

Fluvoxamine maleate tablets have not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were systematically excluded from many clinical studies during the product’s premarketing testing.

Evaluation of the electrocardiograms for patients with depression or OCD who participated in premarketing studies revealed no differences between fluvoxamine and placebo in the emergence of clinically important ECG changes.

Patients with Hepatic Impairment In patients with liver dysfunction, fluvoxamine clearance was decreased by approximately 30%.

Patients with liver dysfunction should begin with a low dose of fluvoxamine maleate tablets and increase it slowly with careful monitoring.

5.15 Laboratory Tests There are no specific laboratory tests recommended.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluvoxamine maleate tablets and should counsel them in the appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for fluvoxamine maleate tablets.

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 Medication Guide is provided as a pull-out in the middle of this booklet.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluvoxamine maleate tablets.

17.1 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-to-day 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 the need for very close monitoring and possibly changes in the medication [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1) ].

17.2 Serotonin Syndrome Patients should be cautioned about the risk of serotonin syndrome particularly with the concomitant use of fluvoxamine with other serotonergic agents (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone and St.

John’s Wort) [see WARNINGS AND PRECAUTIONS-Serotonin Syndrome (5.2) ].

17.3 Angle Closure Glaucoma Patients should be advised that taking Fluvoxamine Maleate Tablets 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 [see WARNINGS AND PRECAUTIONS (5.3) ] .

17.4 Interference with Cognitive or Motor Performance Since any psychoactive drug may impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are certain that fluvoxamine maleate tablets therapy does not adversely affect their ability to engage in such activities.

17.5 Pregnancy Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy with fluvoxamine maleate tablets [see USE IN SPECIFIC POPULATIONS (8.1) .] 17.6 Nursing Patients receiving fluvoxamine maleate tablets should be advised to notify their physicians if they are breast-feeding an infant.

[ see USE IN SPECIFIC POPULATIONS-Nursing Mothers (8.3) .] 17.7 Concomitant Medication Patients should be advised to notify their physicians if they are taking, or plan to take, any prescription or over-the-counter drugs, since there is a potential for clinically important interactions with fluvoxamine maleate tablets.

Patients should be cautioned about the concomitant use of fluvoxamine and NSAIDs, aspirin, or other drugs that affect coagulation since the combined use of psychotropic drugs that interfere with serotonin reuptake and these agents has been associated with an increased risk of bleeding [see WARNINGS AND PRECAUTIONS-Warfarin and Other Drugs That Interfere With Hemostasis (5.8) ].

Because of the potential for the increased risk of serious adverse reactions including severe lowering of blood pressure and sedation when fluvoxamine and tizanidine are used together, fluvoxamine should not be used with tizanidine [see WARNINGS AND PRECAUTIONS (5.5) ] .

Because of the potential for the increased risk of serious adverse reactions when fluvoxamine and alosetron are used together, fluvoxamine should not be used with Lotronex TM (alosetron) [see WARNINGS AND PRECAUTIONS (5.7) ].

17.8 Alcohol As with other psychotropic medications, patients should be advised to avoid alcohol while taking fluvoxamine maleate tablets.

17.9 Allergic Reactions Patients should be advised to notify their physicians if they develop a rash, hives, or a related allergic phenomenon during therapy with fluvoxamine maleate tablets.

PACKAGING INFORMATION American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Apotex Corp.

as follows: (50 mg / 30 UD) NDC 68084-837-25 packaged from NDC 60505-0165 Distributed by: American Health Packaging Columbus, OH 43217 8283721/1015OS 17.10 FDA Approved Medication Guide 8283721/1015OS

DOSAGE AND ADMINISTRATION

2 Adults: Recommended starting dose is 50 mg at bedtime, with increases of 50 mg every 4 to 7 days as tolerated to maximum effect, not to exceed 300 mg/day.

Daily doses over 100 mg should be divided ( 2.1 ).

Children and adolescents (8 to 17 years): Recommended starting dose is 25 mg at bedtime, with increases of 25 mg every 4 to 7 days as tolerated to maximum effect, not to exceed 200 mg/day (8 to 11 years) or 300 mg/day (12 to 17 years).

Daily doses over 50 mg should be divided ( 2.2 ).

Hepatically impaired: Decreased clearance may require modified dose and titration ( 2.3 ).

Extended treatment: Adjust dose to maintain lowest effective dose; reassess patients periodically ( 2.7 ).

Discontinuation: Gradual dose reduction is recommended ( 2.8 , see Warnings And Precautions [5.9] ).

2.1 Adults The recommended starting dose for fluvoxamine maleate tablets in adult patients is 50 mg, administered as a single daily dose at bedtime.

In the controlled clinical trials establishing the effectiveness of fluvoxamine maleate tablets in OCD, patients were titrated within a dose range of 100 to 300 mg/day.

Consequently, the dose should be increased in 50 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved, not to exceed 300 mg per day.

It is advisable that a total daily dose of more than 100 mg should be given in two divided doses.

If the doses are not equal, the larger dose should be given at bedtime.

2.2 Pediatric Population (children and adolescents) The recommended starting dose for fluvoxamine maleate tablets in pediatric populations (ages 8 to 17 years) is 25 mg, administered as a single daily dose at bedtime.

In a controlled clinical trial establishing the effectiveness of fluvoxamine maleate tablets in OCD, pediatric patients (ages 8 to 17) were titrated within a dose range of 50 to 200 mg/day.

Physicians should consider age and gender differences when dosing pediatric patients.

The maximum dose in children up to age 11 should not exceed 200 mg/day.

Therapeutic effect in female children may be achieved with lower doses.

Dose adjustment in adolescents (up to the adult maximum dose of 300 mg) may be indicated to achieve therapeutic benefit.

The dose should be increased in 25 mg increments every 4 to 7 days, as tolerated, until maximum therapeutic benefit is achieved.

It is advisable that a total daily dose of more than 50 mg should be given in two divided doses.

If the two divided doses are not equal, the larger dose should be given at bedtime.

2.3 Elderly or Hepatically Impaired Patients Elderly patients and those with hepatic impairment have been observed to have a decreased clearance of fluvoxamine maleate.

Consequently, it may be appropriate to modify the initial dose and the subsequent dose titration for these patient groups.

2.4 Pregnant Women During the Third Trimester Neonates exposed to fluvoxamine maleate tablets and other SSRIs or SNRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding and may be at risk for persistent pulmonary hypertension of the newborn (PPHN).

[see USE IN SPECIFIC POPULATIONS (8.1) .] When treating pregnant women with fluvoxamine maleate tablets during the third trimester, the physician should carefully consider the potential risks and benefits of treatment.

2.5 Switching Patients To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with fluvoxamine maleate tablets.

Conversely, at least 14 days should be allowed after stopping fluvoxamine maleate tablets before starting an MAOI intended to treat psychiatric disorders.

[see CONTRAINDICATIONS (4.2) .] 2.6 Use of Fluvoxamine Maleate Tablets with Other MAOIs such as Linezolid or Methylene Blue Do not start fluvoxamine maleate tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered.

[see CONTRAINDICATIONS (4.2) .] In some cases, a patient already receiving fluvoxamine maleate tablets therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, fluvoxamine maleate tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with fluvoxamine maleate tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.

[See WARNINGS AND PRECAUTIONS (5.2) .] The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with fluvoxamine maleate tablets is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use.

[See WARNINGS AND PRECAUTIONS (5.2) .] 2.7 Maintenance/Continuation Extended Treatment It is generally agreed that obsessive compulsive disorder requires several months or longer of sustained pharmacologic therapy.

The benefit of maintaining patients with OCD on fluvoxamine maleate tablets after achieving a response for an average duration of about 4 weeks in a 10-week single-blind phase during which patients were titrated to effect was demonstrated in a controlled trial [ see CLINICAL TRIALS (14.2) ].

The physician who elects to use fluvoxamine maleate tablets for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

2.8 Discontinuation of Treatment with Fluvoxamine Maleate Tablets Symptoms associated with discontinuation of other SSRIs or SNRIs have been reported.

[see WARNINGS AND PRECAUTIONS (5.9) .] Patients should be monitored for these symptoms when discontinuing treatment.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Generic Name: FLUOXETINE HYDROCHLORIDE
Brand Name: Fluoxetine Hydrochloride
  • Substance Name(s):
  • FLUOXETINE HYDROCHLORIDE

DRUG INTERACTIONS

7 As with all drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic drug inhibition or enhancement, etc.) is a possibility.

Monoamine Oxidase Inhibitors (MAOI): Fluoxetine is contraindicated for use with MAOI’s, or within 14 days of discontinuing an MAOI due to risk of drug interaction.

At least 5 weeks should be allowed after stopping fluoxetine before starting treatment with an MAOI ( 4 , 7.1 ) Pimozide: Fluoxetine is contraindicated for use with pimozide due to risk of drug interaction or QTc prolongation ( 4 , 7.9 ) Thioridazine: Fluoxetine is contraindicated for use with thioridazine due to QTc interval prolongation or potential for elevated thioridazine plasma levels.

Do not use thioridazine within 5 weeks of discontinuing fluoxetine ( 4 , 7.9 ) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway ( 7.9 ) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued ( 7.9 ) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs ( 7.2 ) Benzodiazepines: Diazepam – increased t½ , alprazolam – further psychomotor performance decrement due to increased levels ( 7.9 ) Antipsycotics: Potential for elevation of haloperidol and clozapine levels ( 7.9 ) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity ( 7.9 ) Serotonergic Drugs: Potential for Serotonin Syndrome ( 5.2 , 7.3 ) Triptans: There have been rare postmarketing reports of Serotonin Syndrome with use of an SSRI and a triptan ( 5.2 , 7.4 ) Tryptophan: Concomitant use with tryptophan is not recommended ( 5.2 , 7.5 ) Drugs that Interfere with Hemostasis (e.g.

NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding ( 7.6 ) Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations ( 7.8 , 7.9 ) Olanzapine: When used in combination with fluoxetine, also refer to the Drug Interactions section of the package insert for Symbyax ( 7.9 ) 7.1 Monoamine Oxidase Inhibitors (MAOI) There have been reports of serious, sometimes fatal, reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) in patients receiving fluoxetine in combination with a monoamine oxidase inhibitor (MAOI), and in patients who have recently discontinued fluoxetine and are then started on an MAOI.

Some cases presented with features resembling neuroleptic malignant syndrome.

Therefore, fluoxetine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see CONTRAINDICATIONS ( 4 ) ].

Since fluoxetine and its major metabolite have very long elimination half-lives, at least 5 weeks perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses should be allowed after stopping fluoxetine before starting an MAOI [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

7.2 CNS Acting Drugs Caution is advised if the concomitant administration of fluoxetine and such drugs is required.

In evaluating individual cases, consideration should be given to using lower initial doses of the concomitantly administered drugs, using conservative titration schedules, and monitoring of clinical status [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

7.3 Serotonergic Drugs Based on the mechanism of action of SNRIs and SSRIs, including fluoxetine, and the potential for serotonin syndrome, caution is advised when fluoxetine is coadministered with other drugs that may affect the serotonergic neurotransmitter systems, such as triptans, linezolid (an antibiotic which is a reversible non-selective MAOI), lithium, tramadol, or St.

John’s Wort [see WARNINGS AND PRECAUTIONS ( 5.2 ) ].

The concomitant use of fluoxetine with SNRIs, SSRIs, or tryptophan is not recommended [see ( 7.4 ), ( 7.5 ) ].

7.4 Triptans There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan.

If concomitant treatment of fluoxetine with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see WARNINGS AND PRECAUTIONS ( 5.2 ) and ( 7.3 ) ].

7.5 Tryptophan Five patients receiving fluoxetine in combination with tryptophan experienced adverse reactions, including agitation, restlessness, and gastrointestinal distress.

The concomitant use with tryptophan is not recommended [see WARNINGS AND PRECAUTIONS ( 5.2 ) and ( 7.3 ) ].

7.6 Drugs that Interfere with Hemostasis (e.g., NSAIDS, Aspirin, Warfarin) Serotonin release by platelets plays an important role in hemostasis.

Epidemiological studies of the case-control and cohort design that have demonstrated an association between use of psychotropic drugs that interfere with serotonin reuptake and the occurrence of upper gastrointestinal bleeding have also shown that concurrent use of an NSAID or aspirin may potentiate this risk of bleeding.

Altered anticoagulant effects, including increased bleeding, have been reported when SNRIs or SSRIs are coadministered with warfarin.

Patients receiving warfarin therapy should be carefully monitored when fluoxetine is initiated or discontinued [see WARNINGS AND PRECAUTIONS ( 5.7 ) ].

7.7 Electroconvulsive Therapy (ECT) There are no clinical studies establishing the benefit of the combined use of ECT and fluoxetine.

There have been rare reports of prolonged seizures in patients on fluoxetine receiving ECT treatment.

7.8 Potential for Other Drugs to affect Fluoxetine Drugs Tightly Bound to Plasma Proteins – Because fluoxetine is tightly bound to plasma protein, adverse effects may result from displacement of protein-bound fluoxetine by other tightly-bound drugs [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

7.9 Potential for Fluoxetine to affect Other Drugs Pimozide – Concomitant use in patients taking pimozide is contraindicated.

Clinical studies of pimozide with other antidepressants demonstrate an increase in drug interaction or QTc prolongation.

While a specific study with pimozide and fluoxetine has not been conducted, the potential for drug interactions or QTc prolongation warrants restricting the concurrent use of pimozide and fluoxetine [see CONTRAINDICATIONS ( 4 ) ].

Thioridazine – Thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see CONTRAINDICATIONS ( 4 ) ].

In a study of 19 healthy male subjects, which included 6 slow and 13 rapid hydroxylators of debrisoquin, a single 25 mg oral dose of thioridazine produced a 2.4-fold higher C max and a 4.5-fold higher AUC for thioridazine in the slow hydroxylators compared with the rapid hydroxylators.

The rate of debrisoquin hydroxylation is felt to depend on the level of CYP2D6 isozyme activity.

Thus, this study suggests that drugs which inhibit CYP2D6, such as certain SSRIs, including fluoxetine, will produce elevated plasma levels of thioridazine.

Thioridazine administration produces a dose-related prolongation of the QTc interval, which is associated with serious ventricular arrhythmias, such as torsades de pointes-type arrhythmias, and sudden death.

This risk is expected to increase with fluoxetine-induced inhibition of thioridazine metabolism.

Drugs Metabolized by CYP2D6 – Fluoxetine inhibits the activity of CYP2D6, and may make individuals with normal CYP2D6 metabolic activity resemble a poor metabolizer.

Coadministration of fluoxetine with other drugs that are metabolized by CYP2D6, including certain antidepressants (e.g., TCAs), antipsychotics (e.g., phenothiazines and most atypicals), and antiarrhythmics (e.g., propafenone, flecainide, and others) should be approached with caution.

Therapy with medications that are predominantly metabolized by the CYP2D6 system and that have a relatively narrow therapeutic index (see list below) should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks.

Thus, his/her dosing requirements resemble those of poor metabolizers.

If fluoxetine is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need for decreased dose of the original medication should be considered.

Drugs with a narrow therapeutic index represent the greatest concern (e.g., flecainide, propafenone, vinblastine, and TCAs).

Due to the risk of serious ventricular arrhythmias and sudden death potentially associated with elevated plasma levels of thioridazine, thioridazine should not be administered with fluoxetine or within a minimum of 5 weeks after fluoxetine has been discontinued [see CONTRAINDICATIONS ( 4 ) ].

Tricyclic Antidepressants (TCAs) – In 2 studies, previously stable plasma levels of imipramine and desipramine have increased greater than 2- to 10-fold when fluoxetine has been administered in combination.

This influence may persist for 3 weeks or 6 longer after fluoxetine is discontinued.

Thus, the dose of TCAs may need to be reduced and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

Benzodiazapines – The half-life of concurrently administered diazepam may be prolonged in some patients [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Antipsychotics – Some clinical data suggests a possible pharmacodynamic and/or pharmacokinetic interaction between SSRIs and antipsychotics.

Elevation of blood levels of haloperidol and clozapine has been observed in patients receiving concomitant fluoxetine.

[see CONTRAINDICATIONS ( 4 ) ].

Anticonvulsants – Patients on stable doses of phenytoin and carbamazepine have developed elevated plasma anticonvulsant concentrations and clinical anticonvulsant toxicity following initiation of concomitant fluoxetine treatment.

Lithium – There have been reports of both increased and decreased lithium levels when lithium was used concomitantly with fluoxetine.

Cases of lithium toxicity and increased serotonergic effects have been reported.

Lithium levels should be monitored when these drugs are administered concomitantly.

Drugs Tightly Bound to Plasma Proteins – Because fluoxetine is tightly bound to plasma protein, the administration of fluoxetine to a patient taking another drug that is tightly bound to protein (e.g., Coumadin, digitoxin) may cause a shift in plasma concentrations potentially resulting in an adverse effect.

[see CLINICAL PHARMACOLOGY ( 12.3 ) ].

Drugs Metabolized by CYP3A4 – In an in vivo interaction study involving coadministration of fluoxetine with single doses of terfenadine (a CYP3A4 substrate), no increase in plasma terfenadine concentrations occurred with concomitant fluoxetine.

Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

These data indicate that fluoxetine’s extent of inhibition of CYP3A4 activity is not likely to be of clinical significance.

Olanzapine – Fluoxetine (60 mg single dose or 60 mg daily dose for 8 days) causes a small (mean 16%) increase in the maximum concentration of olanzapine and a small (mean 16%) decrease in olanzapine clearance.

The magnitude of the impact of this factor is small in comparison to the overall variability between individuals, and therefore dose modification is not routinely recommended.

When using fluoxetine and olanzapine and in combination, also refer to the Drug Interactions section of the package insert for Symbyax.

OVERDOSAGE

10 10.1 Human Experience Worldwide exposure to fluoxetine hydrochloride is estimated to be over 38 million patients (circa 1999).

Of the 1578 cases of overdose involving fluoxetine hydrochloride, alone or with other drugs, reported from this population, there were 195 deaths.

Among 633 adult patients who overdosed on fluoxetine hydrochloride alone, 34 resulted in a fatal outcome, 378 completely recovered, and 15 patients experienced sequelae after overdosage, including abnormal accommodation, abnormal gait, confusion, unresponsiveness, nervousness, pulmonary dysfunction, vertigo, tremor, elevated blood pressure, impotence, movement disorder, and hypomania.

The remaining 206 patients had an unknown outcome.

The most common signs and symptoms associated with non-fatal overdosage were seizures, somnolence, nausea, tachycardia, and vomiting.

The largest known ingestion of fluoxetine hydrochloride in adult patients was 8 grams in a patient who took fluoxetine alone and who subsequently recovered.

However, in an adult patient who took fluoxetine alone, an ingestion as low as 520 mg has been associated with lethal outcome, but causality has not been established.

Among pediatric patients (ages 3 months to 17 years), there were 156 cases of overdose involving fluoxetine alone or in combination with other drugs.

Six patients died, 127 patients completely recovered, 1 patient experienced renal failure, and 22 patients had an unknown outcome.

One of the six fatalities was a 9-year-old boy who had a history of OCD, Tourette’s syndrome with tics, attention deficit disorder, and fetal alcohol syndrome.

He had been receiving 100 mg of fluoxetine daily for 6 months in addition to clonidine, methylphenidate, and promethazine.

Mixed-drug ingestion or other methods of suicide complicated all 6 overdoses in children that resulted in fatalities.

The largest ingestion in pediatric patients was 3 grams which was nonlethal.

Other important adverse reactions reported with fluoxetine overdose (single or multiple drugs) include coma, delirium, ECG abnormalities (such as QT interval prolongation and ventricular tachycardia, including torsades de pointes-type arrhythmias), hypotension, mania, neuroleptic malignant syndrome-like reactions, pyrexia, stupor, and syncope.

10.2 Animal Experience Studies in animals do not provide precise or necessarily valid information about the treatment of human overdose.

However, animal experiments can provide useful insights into possible treatment strategies.

The oral median lethal dose in rats and mice was found to be 452 and 248 mg/kg, respectively.

Acute high oral doses produced hyperirritability and convulsions in several animal species.

Among 6 dogs purposely overdosed with oral fluoxetine, 5 experienced grand mal seizures.

Seizures stopped immediately upon the bolus intravenous administration of a standard veterinary dose of diazepam.

In this short-term study, the lowest plasma concentration at which a seizure occurred was only twice the maximum plasma concentration seen in humans taking 80 mg/day, chronically.

In a separate single-dose study, the ECG of dogs given high doses did not reveal prolongation of the PR, QRS, or QT intervals.

Tachycardia and an increase in blood pressure were observed.

Consequently, the value of the ECG in predicting cardiac toxicity is unknown.

Nonetheless, the ECG should ordinarily be monitored in cases of human overdose [see ( 10.3 ) ].

10.3 Management of Overdose Treatment should consist of those general measures employed in the management of overdosage with any drug effective in the treatment of Major Depressive Disorder.

Ensure an adequate airway, oxygenation, and ventilation.

Monitor cardiac rhythm and vital signs.

General supportive and symptomatic measures are also recommended.

Induction of emesis is not recommended.

Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.

Activated charcoal should be administered.

Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be of benefit.

No specific antidotes for fluoxetine are known.

A specific caution involves patients who are taking or have recently taken fluoxetine and might ingest excessive quantities of a TCA.

In such a case, accumulation of the parent tricyclic and/or an active metabolite may increase the possibility of clinically significant sequelae and extend the time needed for close medical observation [see DRUG INTERACTIONS ( 7.9 ) ].

Based on experience in animals, which may not be relevant to humans, fluoxetine-induced seizures that fail to remit spontaneously may respond to diazepam.

In managing overdosage, consider the possibility of multiple drug involvement.

The physician should consider contacting a poison control center for additional information on the treatment of any overdose.

Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR) .

For specific information about overdosage with olanzapine and fluoxetine in combination, refer to the Overdosage section of the Symbyax package insert.

DESCRIPTION

11 Fluoxetine capsules are a psychotropic drug for oral administration.

They are also marketed for the treatment of premenstrual dysphoric disorder (Sarafem®, fluoxetine hydrochloride).

They are designated (±)-N-methyl-3-phenyl-3-[(α,α,α-trifluoro- p -tolyl)oxy]propylamine hydrochloride and have the empirical formula of C 17 H 18 F 3 NO•HCl.

The molecular weight is 345.79.

The structural formula is: Fluoxetine hydrochloride is a white to off-white crystalline solid with a solubility of 14 mg/mL in water.

Each capsule, for oral administration, contains fluoxetine hydrochloride equivalent to 10 mg (32.3 µmol), 20 mg (64.7 µmol), or 40 mg (129.3 µmol) of fluoxetine.

The inactive ingredients are: corn starch, gelatin, magnesium stearate, pregelatinized starch, propylene glycol, silicon dioxide, sodium lauryl sulfate, and titanium dioxide.

The 10 and 20 mg capsules also contain D&C Yellow #10 Aluminum Lake, FD&C Blue #1 Aluminum Lake, and pharmaceutical glaze; the 20 mg capsule also contains Black Iron Oxide, FD&C Blue #2 Aluminum Lake, and FD&C Red #40 Aluminum Lake; the 40 mg capsule also contains Red Iron Oxide, shellac, and Yellow Iron Oxide.

Fluoxetine Hydrochloride Chemical Structure

CLINICAL STUDIES

14 When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax.

14.1 Major Depressive Disorder Daily Dosing Adult – The efficacy of fluoxetine was studied in 5- and 6-week placebo-controlled trials with depressed adult and geriatric outpatients (≥18 years of age) whose diagnoses corresponded most closely to the DSM-III (currently DSM-IV) category of Major Depressive Disorder.

Fluoxetine was shown to be significantly more effective than placebo as measured by the Hamilton Depression Rating Scale (HAM-D).

Fluoxetine was also significantly more effective than placebo on the HAM-D subscores for depressed mood, sleep disturbance, and the anxiety subfactor.

Two 6-week controlled studies (N=671, randomized) comparing fluoxetine 20 mg and placebo have shown fluoxetine 20 mg daily to be effective in the treatment of elderly patients (≥60 years of age) with Major Depressive Disorder.

In these studies, fluoxetine produced a significantly higher rate of response and remission as defined, respectively, by a 50% decrease in the HAM-D score and a total endpoint HAM-D score of ≤8.

fluoxetine was well tolerated and the rate of treatment discontinuations due to adverse reactions did not differ between fluoxetine (12%) and placebo (9%).

A study was conducted involving depressed outpatients who had responded (modified HAMD-17 score of ≤7 during each of the last 3 weeks of open-label treatment and absence of Major Depressive Disorder by DSM-III-R criteria) by the end of an initial 12-week open-treatment phase on fluoxetine 20 mg/day.

These patients (N=298) were randomized to continuation on double-blind fluoxetine 20 mg/day or placebo.

At 38 weeks (50 weeks total), a statistically significantly lower relapse rate (defined as symptoms sufficient to meet a diagnosis of Major Depressive Disorder for 2 weeks or a modified HAMD-17 score of ≥14 for 3 weeks) was observed for patients taking fluoxetine compared with those on placebo.

Pediatric (children and adolescents) – The efficacy of fluoxetine 20 mg/day in children and adolescents (N=315 randomized; 170 children ages 8 to <13, 145 adolescents ages 13 to ≤18) was studied in two 8- to 9-week placebo-controlled clinical trials in depressed outpatients whose diagnoses corresponded most closely to the DSM-III-R or DSM-IV category of Major Depressive Disorder.

In both studies independently, fluoxetine produced a statistically significantly greater mean change on the Childhood Depression Rating Scale-Revised (CDRS-R) total score from baseline to endpoint than did placebo.

Subgroup analyses on the CDRS-R total score did not suggest any differential responsiveness on the basis of age or gender.

14.2 Obsessive Compulsive Disorder Adult – The effectiveness of fluoxetine for the treatment of Obsessive Compulsive Disorder (OCD) was demonstrated in two 13-week, multicenter, parallel group studies (Studies 1 and 2) of adult outpatients who received fixed fluoxetine doses of 20, 40, or 60 mg/day (on a once-a-day schedule, in the morning) or placebo.

Patients in both studies had moderate to severe OCD (DSM-III-R), with mean baseline ratings on the Yale-Brown Obsessive Compulsive Scale (YBOCS, total score) ranging from 22 to 26.

In Study 1, patients receiving fluoxetine experienced mean reductions of approximately 4 to 6 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients.

In Study 2, patients receiving fluoxetine experienced mean reductions of approximately 4 to 9 units on the YBOCS total score, compared with a 1-unit reduction for placebo patients.

While there was no indication of a dose-response relationship for effectiveness in Study 1, a dose-response relationship was observed in Study 2, with numerically better responses in the 2 higher dose groups.

The following table provides the outcome classification by treatment group on the Clinical Global Impression (CGI) improvement scale for Studies 1 and 2 combined: Table 6.

Outcome Classification (%) on CGI Improvement Scale for Completers in Pool of Two OCD Studies Fluoxetine Outcome Classification Placebo 20 mg 40 mg 60 mg Worse 8% 0% 0% 0% No change 64% 41% 33% 29% Minimally improved 17% 23% 28% 24% Much improved 8% 28% 27% 28% Very much improved 3% 8% 12% 19% Exploratory analyses for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or sex.

Pediatric (children and adolescents) – In one 13-week clinical trial in pediatric patients (N=103 randomized; 75 children ages 7 to <13, 28 adolescents ages 13 to <18) with OCD (DSM-IV), patients received fluoxetine 10 mg/day for 2 weeks, followed by 20 mg/day for 2 weeks.

The dose was then adjusted in the range of 20 to 60 mg/day on the basis of clinical response and tolerability.

Fluoxetine produced a statistically significantly greater mean change from baseline to endpoint than did placebo as measured by the Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS).

Subgroup analyses on outcome did not suggest any differential responsiveness on the basis of age or gender.

14.3 Bulimia Nervosa The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8-week and one 16-week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia.

Patients in the 8-week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning.

Patients in the 16-week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo.

Patients in these 3 studies had moderate to severe bulimia with median binge-eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively.

In these 3 studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge-eating and vomiting episodes per week.

The statistically significantly superior effect of 60 mg versus placebo was present as early as Week 1 and persisted throughout each study.

The fluoxetine-related reduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale.

In each of these 3 studies, the treatment effect, as measured by differences between fluoxetine 60 mg and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge-eating and 2 to 4 episodes per week for vomiting.

The size of the effect was related to baseline frequency, with greater reductions seen in patients with higher baseline frequencies.

Although some patients achieved freedom from binge-eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge-eating and purging.

In a longer-term trial, 150 patients meeting DSM-IV criteria for Bulimia Nervosa, purging subtype, who had responded during a single-blind, 8-week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse.

Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline.

Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgment that the patient had relapsed.

Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.

14.4 Panic Disorder The effectiveness of fluoxetine in the treatment of Panic Disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of Panic Disorder (DSM-IV), with or without agoraphobia.

Study 1 (N=180 randomized) was a 12-week flexible-dose study.

Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability.

A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% versus 28%, respectively.

Study 2 (N=214 randomized) was a 12-week flexible-dose study.

Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability.

A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% versus 44%, respectively.

HOW SUPPLIED

16 /STORAGE AND HANDLING Repackaged by Aphena Pharma Solutions – TN.

See Repackaging Information for available configurations.

Fluoxetine capsules USP, 10 mg, 20 mg, and 40 mg are available as: 10 mg: white capsules, imprinted GG 575 with single green ink bands, filled with white powder and supplied as: NDC 0781-2823-31 bottles of 30 NDC 0781-2823-01 bottles of 100 NDC 0781-2823-10 bottles of 1000 NDC 0781-2823-13 unit dose packages of 100 20 mg: white capsules, imprinted GG 550 with green and black ink bands, filled with white powder and supplied as: NDC 0781-2822-31 bottles of 30 NDC 0781-2822-01 bottles of 100 NDC 0781-2822-10 bottles of 1000 NDC 0781-2822-13 unit dose packages of 100 40 mg: white capsules, imprinted GG 540 with single orange ink bands, filled with white powder and supplied as: NDC 0781-2824-31 bottles of 30 NDC 0781-2824-01 bottles of 100 NDC 0781-2824-10 bottles of 1000 Store at 20°-25°C (68°-77°F) (see USP Controlled Room Temperature).

Protect from light.

RECENT MAJOR CHANGES

Indications and Usage, fluoxetine and olanzapine in combination: Depressive Episodes Associated with Bipolar I Disorder ( 1.5 ) 03/2009 Dosage and Administration, fluoxetine and olanzapine in combination: Depressive Episodes Associated with Bipolar I Disorder ( 2.

5 ) 03/2009 Warnings and Precautions: Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions ( 5.2 ) 01/2009

GERIATRIC USE

8.5 Geriatric Use US fluoxetine clinical trials included 687 patients ≥65 years of age and 93 patients ≥75 years of age.

The efficacy in geriatric patients has been established [see CLINICAL STUDIES ( 14.1 ) ].

For pharmacokinetic information in geriatric patients, [see CLINICAL PHARMACOLOGY ( 12.4 ) ].

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

SNRIs and SSRIs, including fluoxetine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction [see WARNINGS AND PRECAUTIONS ( 5.8 ) ].

Clinical studies of olanzapine and fluoxetine in combination did not include sufficient numbers of patients ≥ 65 years of age to determine whether they respond differently from younger patients.

DOSAGE FORMS AND STRENGTHS

3 10 mg fluoxetine capsules USP is a white capsule, imprinted GG 575 with single green ink bands 20 mg fluoxetine capsules USP is a white capsule, imprinted GG 550 with green and black ink bands 40 mg fluoxetine capsules USP is a white capsule, imprinted GG 540 with single orange ink bands Capsules: 10 mg, 20 mg, 40 mg (3)

MECHANISM OF ACTION

12.1 Mechanism of Action Although the exact mechanism of fluoxetine is unknown, it is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin.

INDICATIONS AND USAGE

1 Fluoxetine is a selective serotonin reuptake inhibitor indicated for: Acute and maintenance treatment of Major Depressive Disorder (MDD) in adult and pediatric patients aged 8 to 18 years ( 1.1 ) Acute and maintenance treatment of Obsessive Compulsive Disorder (OCD) in adult and pediatric patients aged 7 to 17 years ( 1.2 ) Acute and maintenance treatment of Bulimia Nervosa in adult patients ( 1.3 ) Acute treatment of Panic Disorder, with or without agoraphobia, in adult patients ( 1.4 ) Fluoxetine and olanzapine in combination for: Acute treatment of Depressive Episodes Associated with Bipolar I Disorder in adults ( 1.5 ) 1.1 Major Depressive Disorder Fluoxetine hydrochloride is indicated for the acute and maintenance treatment of Major Depressive Disorder in adult patients and in pediatric patients aged 8 to18 years [see CLINICAL STUDIES ( 14.1 ) ].

The usefulness of the drug in adult and pediatric patients receiving fluoxetine for extended periods, should periodically be reevaluated [see DOSAGE AND ADMINISTRATION ( 2.1 ) ].

1.2 Obsessive Compulsive Disorder Fluoxetine is indicated for the acute and maintenance treatment of obsessions and compulsions in adult patients and in pediatric patients aged 7 to 17 years with Obsessive Compulsive Disorder (OCD) [see CLINICAL STUDIES ( 14.2 ) ].

The effectiveness of fluoxetine in long-term use, i.e., for more than 13 weeks, has not been systematically evaluated in placebo-controlled trials.

Therefore, the physician who elects to use fluoxetine for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION ( 2.2 ) ].

1.3 Bulimia Nervosa Fluoxetine is indicated for the acute and maintenance treatment of binge-eating and vomiting behaviors in adult patients with moderate to severe Bulimia Nervosa [see CLINICAL STUDIES ( 14.3 ) ].

The physician who elects to use fluoxetine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION ( 2.3 ) ].

1.4 Panic Disorder Fluoxetine is indicated for the acute treatment of Panic Disorder, with or without agoraphobia, in adult patients [see CLINICAL STUDIES ( 14.4 ) ].

The effectiveness of fluoxetine in long-term use, i.e., for more than 12 weeks, has not been established in placebo-controlled trials.

Therefore, the physician who elects to use fluoxetine for extended periods, should periodically re-evaluate the long-term usefulness of the drug for the individual patient [see DOSAGE AND ADMINISTRATION ( 2.4 ) ].

1.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax ® .

Fluoxetine and olanzapine in combination is indicated for the acute treatment of depressive episodes associated with Bipolar I Disorder in adult patients.

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

PEDIATRIC USE

8.4 Pediatric Use The efficacy of fluoxetine for the treatment of Major Depressive Disorder was demonstrated in two 8- to 9-week placebo-controlled clinical trials with 315 pediatric outpatients ages 8 to ≤18 [see CLINICAL STUDIES ( 14.1 ) ].

The efficacy of fluoxetine for the treatment of OCD was demonstrated in one 13-week placebo-controlled clinical trial with 103 pediatric outpatients ages 7 to <18 [see CLINICAL STUDIES ( 14.2 )].

The safety and effectiveness in pediatric patients <8 years of age in Major Depressive Disorder and <7 years of age in OCD have not been established.

Fluoxetine pharmacokinetics were evaluated in 21 pediatric patients (ages 6 to ≤18) with Major Depressive Disorder or OCD [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

The acute adverse reaction profiles observed in the 3 studies (N=418 randomized; 228 fluoxetine-treated, 190 placebo-treated) were generally similar to that observed in adult studies with fluoxetine.

The longer-term adverse reaction profile observed in the 19-week Major Depressive Disorder study (N=219 randomized; 109 fluoxetine-treated, 110 placebo-treated) was also similar to that observed in adult trials with fluoxetine [see ADVERSE REACTIONS ( 6.1 ) ].

Manic reaction, including mania and hypomania, was reported in 6 (1 mania, 5 hypomania) out of 228 (2.6%) fluoxetine-treated patients and in 0 out of 190 (0%) placebo-treated patients.

Mania/hypomania led to the discontinuation of 4 (1.8%) fluoxetine-treated patients from the acute phases of the 3 studies combined.

Consequently, regular monitoring for the occurrence of mania/hypomania is recommended.

As with other SSRIs, decreased weight gain has been observed in association with the use of fluoxetine in children and adolescent patients.

After 19 weeks of treatment in a clinical trial, pediatric subjects treated with fluoxetine gained an average of 1.1 cm less in height and 1.1 kg less in weight than subjects treated with placebo.

In addition, fluoxetine treatment was associated with a decrease in alkaline phosphatase levels.

The safety of fluoxetine treatment for pediatric patients has not been systematically assessed for chronic treatment longer than several months in duration.

In particular, there are no studies that directly evaluate the longer-term effects of fluoxetine on the growth, development and maturation of children and adolescent patients.

Therefore, height and weight should be monitored periodically in pediatric patients receiving fluoxetine.

[see WARNINGS AND PRECAUTIONS ( 5.6 ) ].

Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box Warning and WARNINGS AND PRECAUTIONS ( 5.1 ) ].

Anyone considering the use of fluoxetine in a child or adolescent must balance the potential risks with the clinical need.

Significant toxicity, including myotoxicity, long-term neurobehavioral and reproductive toxicity, and impaired bone development, has been observed following exposure of juvenile animals to fluoxetine.

Some of these effects occurred at clinically relevant exposures.

In a study in which fluoxetine (3, 10, or 30 mg/kg) was orally administered to young rats from weaning (Postnatal Day 21) through adulthood (Day 90), male and female sexual development was delayed at all doses, and growth (body weight gain, femur length) was decreased during the dosing period in animals receiving the highest dose.

At the end of the treatment period, serum levels of creatine kinase (marker of muscle damage) were increased at the intermediate and high doses, and abnormal muscle and reproductive organ histopathology (skeletal muscle degeneration and necrosis, testicular degeneration and necrosis, epididymal vacuolation and hypospermia) was observed at the high dose.

When animals were evaluated after a recovery period (up to 11 weeks after cessation of dosing), neurobehavioral abnormalities (decreased reactivity at all doses and learning deficit at the high dose) and reproductive functional impairment (decreased mating at all doses and impaired fertility at the high dose) were seen; in addition, testicular and epididymal microscopic lesions and decreased sperm concentrations were found in the high dose group, indicating that the reproductive organ effects seen at the end of treatment were irreversible.

The reversibility of fluoxetine-induced muscle damage was not assessed.

Adverse effects similar to those observed in rats treated with fluoxetine during the juvenile period have not been reported after administration of fluoxetine to adult animals.

Plasma exposures (AUC) to fluoxetine in juvenile rats receiving the low, intermediate, and high dose in this study were approximately 0.1 to 0.2, 1 to 2, and 5 to 10 times, respectively, the average exposure in pediatric patients receiving the maximum recommended dose (MRD) of 20 mg/day.

Rat exposures to the major metabolite, norfluoxetine, were approximately 0.3 to 0.8, 1 to 8, and 3 to 20 times, respectively, pediatric exposure at the MRD.

A specific effect of fluoxetine on bone development has been reported in mice treated with fluoxetine during the juvenile period.

When mice were treated with fluoxetine (5 or 20 mg/kg, intraperitoneal) for 4 weeks starting at 4 weeks of age, bone formation was reduced resulting in decreased bone mineral content and density.

These doses did not affect overall growth (body weight gain or femoral length).

The doses administered to juvenile mice in this study are approximately 0.5 and 2 times the MRD for pediatric patients on a body surface area (mg/m 2 ) basis.

In another mouse study, administration of fluoxetine (10 mg/kg intraperitoneal) during early postnatal development (Postnatal Days 4 to 21) produced abnormal emotional behaviors (decreased exploratory behavior in elevated plus-maze, increase shock avoidance latency) in adulthood (12 weeks of age).

The dose used in this study is approximately equal to the pediatric MRD on a mg/m 2 basis.

Because of the early dosing period in this study, the significance of these findings to the approved pediatric use in humans is uncertain.

Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 18 years of age have not been established.

PREGNANCY

8.1 Pregnancy Teratogenic Effects Pregnancy Category C In embryo-fetal development studies in rats and rabbits, there was no evidence of teratogenicity following administration of up to 12.5 and 15 mg/kg/day, respectively (1.5 and 3.6 times, respectively, the MRHD of 80 mg on a mg/m 2 basis) throughout organogenesis.

However, in rat reproduction studies, an increase in stillborn pups, a decrease in pup weight, and an increase in pup deaths during the first 7 days postpartum occurred following maternal exposure to 12 mg/kg/day (1.5 times the maximum recommended human dose (MRHD) on a mg/m 2 basis) during gestation or 7.5 mg/kg/day (0.9 times the MRHD on a mg/m 2 basis) during gestation and lactation.

There was no evidence of developmental neurotoxicity in the surviving offspring of rats treated with 12 mg/kg/day during gestation.

The no-effect dose for rat pup mortality was 5 mg/kg/day (0.6 times the MRHD on a mg/m 2 basis).

Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Treatment of Pregnant Women During the Third Trimester – Neonates exposed to fluoxetine, SNRIs, or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

Such complications can arise immediately upon delivery.

Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying.

These features are consistent with either a direct toxic effect of SNRIs and SSRIs or, possibly, a drug discontinuation syndrome.

It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome.

Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN).

PPHN occurs in 1 to 2 per 1000 live births in the general population and is associated with substantial neonatal morbidity and mortality.

In a retrospective case-control study of 377 women whose infants were born with PPHN and 836 women whose infants were born healthy, the risk for developing PPHN was approximately six-fold higher for infants exposed to SSRIs after the 20th week of gestation compared to infants who had not been exposed to antidepressants during pregnancy.

There is currently no corroborative evidence regarding the risk for PPHN following exposure to SSRIs in pregnancy; this is the first study that has investigated the potential risk.

The study did not include enough cases with exposure to individual SSRIs to determine if all SSRIs posed similar levels of PPHN risk.

When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider both the potential risks and potential benefits of treatment.

Physicians should note that in a prospective longitudinal study of 201 women with a history of major depression who were euthymic at the beginning of pregnancy, women who discontinued antidepressant medication during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressant medication.

The physician may consider tapering fluoxetine in the third trimester.

NUSRING MOTHERS

8.3 Nursing Mothers Because fluoxetine is excreted in human milk, nursing while on fluoxetine is not recommended.

In one breast-milk sample, the concentration of fluoxetine plus norfluoxetine was 70.4 ng/mL.

The concentration in the mother’s plasma was 295.0 ng/mL.

No adverse effects on the infant were reported.

In another case, an infant nursed by a mother on fluoxetine developed crying, sleep disturbance, vomiting, and watery stools.

The infant’s plasma drug levels were 340 ng/mL of fluoxetine and 208 ng/mL of norfluoxetine on the second day of feeding.

BOXED WARNING

WARNING: 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 fluoxetine capsules 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.

Fluoxetine is approved for use in pediatric patients with MDD and Obsessive Compulsive Disorder (OCD) [see WARNINGS AND PRECAUTIONS ( 5.1 ) and USE IN SPECIFIC POPULATIONS ( 8.4 )].

When using fluoxetine and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax.

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS See full prescribing information for complete boxed warning.

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants for Major Depressive Disorder (MDD) and other psychiatric disorders ( 5.1 ).

When using fluoxetine and olanzapine in combination, also refer to Boxed Warning section of the package insert for Symbyax .

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

Clinical Worsening and Suicide Risk: Monitor for clinical worsening and suicidal thinking and behavior ( 5.1 ) Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: Have been reported with fluoxetine.

Discontinue fluoxetine and initiate supportive treatment ( 5.2 ) Allergic Reactions and Rash: Discontinue upon appearance of rash or allergic phenomena ( 5.3 ) Activation of Mania/Hypomania: Screen for Bipolar Disorder and monitor for mania/hypomania ( 5.4 ) Seizures: Use cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold ( 5.5 ) Altered Appetite and Weight: Significant weight loss has occurred ( 5.6 ) Abnormal Bleeding: May increase the risk of bleeding.

Use with NSAIDs, aspirin, warfarin, or drugs that affect coagulation may potentiate the risk of gastrointestinal or other bleeding ( 5.7 ) Hyponatremia: Has been reported with fluoxetine in association with syndrome of inappropriate antidiuretic hormone (SIADH) ( 5.8 ) Anxiety and Insomnia: May occur ( 5.9 ) Potential for Cognitive and Motor Impairment: Has potential to impair judgment, thinking, and motor skills.

Use caution when operating machinery ( 5.11 ) Long Half-Life: Changes in dose will not be fully reflected in plasma for several weeks ( 5.12 ) Fluoxetine and Olanzapine in Combination: When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax ( 5.14 ) 5.1 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 to 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 versus 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 2.

Table 2.

Suicidality per 1000 Patients Treated Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 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.

If the decision has been made to discontinue treatment, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can be associated with certain symptoms [see WARNINGS AND PRECAUTIONS ( 5.13 ) ].

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

It should be noted that fluoxetine is approved in the pediatric population only for Major Depressive Disorder and Obsessive Compulsive Disorder.

Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 18 years of age have not been established.

5.2 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions The development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including fluoxetine treatment, but particularly with concomitant use of serotonergic drugs (including triptans) with drugs which impair metabolism of serotonin (including MAOIs), or with antipsychotics or other dopamine antagonists.

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms.

The concomitant use of fluoxetine with MAOIs intended to treat depression is contraindicated [see CONTRAINDICATIONS ( 4 ) and DRUG INTERACTIONS ( 7.1 ) ].

If concomitant treatment of fluoxetine with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see DRUG INTERACTIONS ( 7.4 ) ].

The concomitant use of fluoxetine with serotonin precursors (such as tryptophan) is not recommended [see DRUG INTERACTIONS ( 7.3 ) ].

Treatment with fluoxetine and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above reactions occur, and supportive symptomatic treatment should be initiated.

5.3 Allergic Reactions and Rash In US fluoxetine clinical trials as of May 8, 1995, 7% of 10,782 patients developed various types of rashes and/or urticaria.

Among the cases of rash and/or urticaria reported in premarketing clinical trials, almost a third were withdrawn from treatment because of the rash and/or systemic signs or symptoms associated with the rash.

Clinical findings reported in association with rash include fever, leukocytosis, arthralgias, edema, carpal tunnel syndrome, respiratory distress, lymphadenopathy, proteinuria, and mild transaminase elevation.

Most patients improved promptly with discontinuation of fluoxetine and/or adjunctive treatment with antihistamines or steroids, and all patients experiencing these reactions were reported to recover completely.

In premarketing clinical trials, 2 patients are known to have developed a serious cutaneous systemic illness.

In neither patient was there an unequivocal diagnosis, but one was considered to have a leukocytoclastic vasculitis, and the other, a severe desquamating syndrome that was considered variously to be a vasculitis or erythema multiforme.

Other patients have had systemic syndromes suggestive of serum sickness.

Since the introduction of fluoxetine, systemic reactions, possibly related to vasculitis and including lupus-like syndrome, have developed in patients with rash.

Although these reactions are rare, they may be serious, involving the lung, kidney, or liver.

Death has been reported to occur in association with these systemic reactions.

Anaphylactoid reactions, including bronchospasm, angioedema, laryngospasm, and urticaria alone and in combination, have been reported.

Pulmonary reactions, including inflammatory processes of varying histopathology and/or fibrosis, have been reported rarely.

These reactions have occurred with dyspnea as the only preceding symptom.

Whether these systemic reactions and rash have a common underlying cause or are due to different etiologies or pathogenic processes is not known.

Furthermore, a specific underlying immunologic basis for these reactions has not been identified.

Upon the appearance of rash or of other possibly allergic phenomena for which an alternative etiology cannot be identified, fluoxetine should be discontinued.

5.4 Screening Patients for Bipolar Disorder and Monitoring for Mania/Hypomania 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 for clinical worsening and suicide risk 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 fluoxetine and olanzapine in combination is approved for the acute treatment of depressive episodes associated with Bipolar I Disorder [ see Warnings and Precautions section of the package insert for Symbyax ].

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

In US placebo-controlled clinical trials for Major Depressive Disorder, mania/hypomania was reported in 0.1% of patients treated with fluoxetine and 0.1% of patients treated with placebo.

Activation of mania/hypomania has also been reported in a small proportion of patients with Major Affective Disorder treated with other marketed drugs effective in the treatment of Major Depressive Disorder [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ].

In US placebo-controlled clinical trials for OCD, mania/hypomania was reported in 0.8% of patients treated with fluoxetine and no patients treated with placebo.

No patients reported mania/hypomania in US placebo-controlled clinical trials for bulimia.

In all US fluoxetine clinical trials as of May 8, 1995, 0.7% of 10,782 patients reported mania/hypomania [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ].

5.5 Seizures In US placebo-controlled clinical trials for Major Depressive Disorder, convulsions (or reactions described as possibly having been seizures) were reported in 0.1% of patients treated with fluoxetine and 0.2% of patients treated with placebo.

No patients reported convulsions in US placebo-controlled clinical trials for either OCD or bulimia.

In all US fluoxetine clinical trials as of May 8, 1995, 0.2% of 10,782 patients reported convulsions.

The percentage appears to be similar to that associated with other marketed drugs effective in the treatment of Major Depressive Disorder.

Fluoxetine should be introduced with care in patients with a history of seizures.

5.6 Altered Appetite and Weight Significant weight loss, especially in underweight depressed or bulimic patients, may be an undesirable result of treatment with fluoxetine.

In US placebo-controlled clinical trials for Major Depressive Disorder, 11% of patients treated with fluoxetine and 2% of patients treated with placebo reported anorexia (decreased appetite).

Weight loss was reported in 1.4% of patients treated with fluoxetine and in 0.5% of patients treated with placebo.

However, only rarely have patients discontinued treatment with fluoxetine because of anorexia or weight loss [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ].

In US placebo-controlled clinical trials for OCD, 17% of patients treated with fluoxetine and 10% of patients treated with placebo reported anorexia (decreased appetite).

One patient discontinued treatment with fluoxetine because of anorexia [see USE IN SPECIFIC POPULATIONS ( 8.4 ) ].

In US placebo-controlled clinical trials for Bulimia Nervosa, 8% of patients treated with fluoxetine 60 mg and 4% of patients treated with placebo reported anorexia (decreased appetite).

Patients treated with fluoxetine 60 mg on average lost 0.45 kg compared with a gain of 0.16 kg by patients treated with placebo in the 16-week double-blind trial.

Weight change should be monitored during therapy.

5.7 Abnormal Bleeding SNRIs and SSRIs, including fluoxetine, may increase the risk of bleeding reactions.

Concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, warfarin, and other anti-coagulants may add to this risk.

Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding.

Bleeding reactions related to SNRIs and SSRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages.

Patients should be cautioned about the risk of bleeding associated with the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation [see DRUG INTERACTIONS ( 7.6 ) ].

5.8 Hyponatremia Hyponatremia has been reported during treatment with SNRIs and SSRIs, including fluoxetine.

In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cases with serum sodium lower than 110 mmol/L have been reported and appeared to be reversible when fluoxetine was discontinued.

Elderly patients may be at greater risk of developing hyponatremia with SNRIs and SSRIs.

Also, patients taking diuretics or who are otherwise volume depleted may be at greater risk [see USE IN SPECIFIC POPULATIONS ( 8.5 ) ].

Discontinuation of fluoxetine should be considered in patients with symptomatic hyponatremia and appropriate medical intervention should be instituted.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death.

5.9 Anxiety and Insomnia In US placebo-controlled clinical trials for Major Depressive Disorder, 12% to 16% of patients treated with fluoxetine and 7% to 9% of patients treated with placebo reported anxiety, nervousness, or insomnia.

In US placebo-controlled clinical trials for OCD, insomnia was reported in 28% of patients treated with fluoxetine and in 22% of patients treated with placebo.

Anxiety was reported in 14% of patients treated with fluoxetine and in 7% of patients treated with placebo.

In US placebo-controlled clinical trials for Bulimia Nervosa, insomnia was reported in 33% of patients treated with fluoxetine 60 mg, and 13% of patients treated with placebo.

Anxiety and nervousness were reported, respectively, in 15% and 11% of patients treated with fluoxetine 60 mg and in 9% and 5% of patients treated with placebo.

Among the most common adverse reactions associated with discontinuation (incidence at least twice that for placebo and at least 1% for fluoxetine in clinical trials collecting only a primary reaction associated with discontinuation) in US placebo-controlled fluoxetine clinical trials were anxiety (2% in OCD), insomnia (1% in combined indications and 2% in bulimia), and nervousness (1% in Major Depressive Disorder) [see Table 5 ].

5.10 Use in Patients with Concomitant Illness Clinical experience with fluoxetine in patients with concomitant systemic illness is limited.

Caution is advisable in using fluoxetine in patients with diseases or conditions that could affect metabolism or hemodynamic responses.

Cardiovascular – Fluoxetine has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease.

Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarket testing.

However, the electrocardiograms of 312 patients who received fluoxetine in double-blind trials were retrospectively evaluated; no conduction abnormalities that resulted in heart block were observed.

The mean heart rate was reduced by approximately 3 beats/min.

Glycemic Control – In patients with diabetes, fluoxetine may alter glycemic control.

Hypoglycemia has occurred during therapy with fluoxetine, and hyperglycemia has developed following discontinuation of the drug.

As is true with many other types of medication when taken concurrently by patients with diabetes, insulin and/or oral hypoglycemic, dosage may need to be adjusted when therapy with fluoxetine is instituted or discontinued.

5.11 Potential for Cognitive and Motor Impairment As with any CNS-active drug, fluoxetine has the potential to impair judgment, thinking, or motor skills.

Patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that the drug treatment does not affect them adversely.

5.12 Long Elimination Half-Life Because of the long elimination half-lives of the parent drug and its major active metabolite, changes in dose will not be fully reflected in plasma for several weeks, affecting both strategies for titration to final dose and withdrawal from treatment.

This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine [see CLINICAL PHARMACOLOGY ( 12.3 ) ].

5.13 Discontinuation of Treatment During marketing of fluoxetine, SNRIs, and SSRIs, there have been spontaneous reports of adverse reactions occurring upon discontinuation of these drugs, particularly when abrupt, including the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, and hypomania.

While these reactions are generally self-limiting, there have been reports of serious discontinuation symptoms.

Patients should be monitored for these symptoms when discontinuing treatment with fluoxetine.

A gradual reduction in the dose rather than abrupt cessation is recommended whenever possible.

If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered.

Subsequently, the physician may continue decreasing the dose but at a more gradual rate.

Plasma fluoxetine and norfluoxetine concentration decrease gradually at the conclusion of therapy which may minimize the risk of discontinuation symptoms with this drug.

5.14 Fluoxetine and Olanzapine in Combination When using fluoxetine and olanzapine in combination, also refer to the Warnings and Precautions section of the package insert for Symbyax.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION See the FDA-approved Medication Guide.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking fluoxetine as monotherapy or in combination with olanzapine.

When using fluoxetine and olanzapine in combination, also refer to the Patient Counseling Information section of the package insert for Symbyax.

17.1 General Information Healthcare providers should instruct their patients to read the Medication Guide before starting therapy with fluoxetine and to reread it each time the prescription is renewed.

Healthcare providers should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with fluoxetine and should counsel them in its appropriate use.

Healthcare providers 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.

Patients should be advised of the following issues and asked to alert their healthcare provider if these occur while taking fluoxetine.

When using fluoxetine and olanzapine in combination, also refer to the Medication Guide for Symbyax.

17.2 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-to-day 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 [see Box Warning and WARNINGS AND PRECAUTIONS ( 5.1 ) ].

17.3 Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions Patients should be cautioned about the risk of serotonin syndrome or NMS-like reactions with the concomitant use of fluoxetine and triptans, tramadol, or other serotonergic agents [see WARNINGS AND PRECAUTIONS ( 5.2 ) and DRUG INTERACTIONS ( 7.3 ) ].

Patients should be advised of the signs and symptoms associated with serotonin syndrome or NMS-like reactions that may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Serotonin syndrome, in its most severe form can resemble neuroleptic malignant syndrome, in which the symptoms may include hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes.

Patients should be cautioned to seek medical care immediately if they experience these symptoms.

17.4 Allergic Reactions and Rash Patients should be advised to notify their physician if they develop a rash or hives [see WARNINGS AND PRECAUTIONS ( 5.3 ) ].

Patients should also be advised of the signs and symptoms associated with a severe allergic reaction, including swelling of the face, eyes, or mouth, or have trouble breathing.

Patients should be cautioned to seek medical care immediately if they experience these symptoms.

17.5 Abnormal Bleeding Patients should be cautioned about the concomitant use of fluoxetine and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation since combined use of psychotropic drugs that interfere with serotonin reuptake and these agents have been associated with an increased risk of bleeding [see WARNINGS AND PRECAUTIONS ( 5.7 ) and DRUG INTERACTIONS ( 7.6 ) ].

Patients should be advised to call their doctor if they experience any increased or unusual bruising or bleeding while taking fluoxetine.

17.6 Hyponatremia Patients should be advised that hyponatremia has been reported as a result of treatment with SNRIs and SSRIs, including fluoxetine.

Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls.

More severe and/or acute cases have been associated with hallucination, syncope, seizure, coma, respiratory arrest, and death [see WARNINGS AND PRECAUTIONS ( 5.8 ) ].

17.7 Potential for Cognitive and Motor Impairment Fluoxetine may impair judgment, thinking, or motor skills.

Patients should be advised to avoid driving a car or operating hazardous machinery until they are reasonably certain that their performance is not affected [see WARNINGS AND PRECAUTIONS ( 5.11 ) ].

17.8 Use of Concomitant Medications Patients should be advised to inform their physician if they are taking, or plan to take, any prescription medication, including Symbyax®, Sarafem®, or over-the-counter drugs, including herbal supplements or alcohol.

Patients should also be advised to inform their physicians if they plan to discontinue any medications they are taking while on fluoxetine.

17.9 Discontinuation of Treatment Patients should be advised to take fluoxetine exactly as prescribed, and to continue taking fluoxetine as prescribed even after their symptoms improve.

Patients should be advised that they should not alter their dosing regimen, or stop taking fluoxetine without consulting their physician [see WARNINGS AND PRECAUTIONS ( 5.13 ) ].

Patients should be advised to consult with their healthcare provider if their symptoms do not improve with fluoxetine.

17.10 Use in Specific Populations Pregnancy – Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

Fluoxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see USE IN SPECIFIC POPULATIONS ( 8.1 ) ].

Nursing Mothers – Patients should be advised to notify their physician if they intend to breast-feed an infant during therapy.

Because fluoxetine is excreted in human milk, nursing while taking fluoxetine is not recommended [see USE IN SPECIFIC POPULATIONS ( 8.3 ) ].

Pediatric Use – Fluoxetine is approved for use in pediatric patients with MDD and OCD [see Box Warning and WARNINGS AND PRECAUTIONS ( 5.1 ) ].

Limited evidence is available concerning the longer-term effects of fluoxetine on the development and maturation of children and adolescent patients.

Height and weight should be monitored periodically in pediatric patients receiving fluoxetine.

Safety and effectiveness of fluoxetine and olanzapine in combination in patients less than 18 years of age have not been established.

[see WARNINGS AND PRECAUTIONS ( 5.6 ) and USE IN SPECIFIC POPULATIONS ( 8.4 ) ].

DOSAGE AND ADMINISTRATION

2 Indication Adult Pediatric MDD ( 2.1 ) 20 mg/day in am (initial dose) 10 to 20 mg/day (initial dose) OCD ( 2.2 ) 20 mg/day in am (initial dose) 10 mg/day (initial dose) Bulimia Nervosa ( 2.3 ) 60 mg/day in am – Panic Disorder ( 2.4 ) 10 mg/day (initial dose) – Depressive Episodes Associated with Bipolar I Disorder ( 2.5 ) Oral in combination with olanzapine: 5 mg of oral olanzapine and 20 mg of fluoxetine once daily (initial dose) – Consider tapering the dose of fluoxetine for pregnant women during the third trimester ( 2.7 ) A lower or less frequent dosage should be used in patients with hepatic impairment, the elderly, and for patients with concurrent disease or on multiple concomitant medications ( 2.7 ) Fluoxetine and olanzapine in combination : Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability ( 2.5 ) Fluoxetine monotherapy is not indicated for the treatment of Depressive Episodes associated with Bipolar I Disorder ( 2.5 ) Safety of the coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated ( 2.5 ) 2.1 Major Depressive Disorder Initial Treatment Adult – In controlled trials used to support the efficacy of fluoxetine, patients were administered morning doses ranging from 20 to 80 mg/day.

Studies comparing fluoxetine 20, 40, and 60 mg/day to placebo indicate that 20 mg/day is sufficient to obtain a satisfactory response in Major Depressive Disorder in most cases.

Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.

A dose increase may be considered after several weeks if insufficient clinical improvement is observed.

Doses above 20 mg/day may be administered on a once-a-day (morning) or BID schedule (i.e., morning and noon) and should not exceed a maximum dose of 80 mg/day.

Pediatric (children and adolescents) – In the short-term (8 to 9 week) controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Major Depressive Disorder, patients were administered fluoxetine doses of 10 to 20 mg/day [see CLINICAL STUDIES ( 14.1 ) ].

Treatment should be initiated with a dose of 10 or 20 mg/day.

After 1 week at 10 mg/day, the dose should be increased to 20 mg/day.

However, due to higher plasma levels in lower weight children, the starting and target dose in this group may be 10 mg/day.

A dose increase to 20 mg/day may be considered after several weeks if insufficient clinical improvement is observed.

All patients – As with other drugs effective in the treatment of Major Depressive Disorder, the full effect may be delayed until 4 weeks of treatment or longer.

Maintenance/Continuation/Extended Treatment – It is generally agreed that acute episodes of Major Depressive Disorder require several months or longer of sustained pharmacologic therapy.

Whether the dose needed to induce remission is identical to the dose needed to maintain and/or sustain euthymia is unknown.

Daily Dosing – Systematic evaluation of fluoxetine in adult patients has shown that its efficacy in Major Depressive Disorder is maintained for periods of up to 38 weeks following 12 weeks of open-label acute treatment (50 weeks total) at a dose of 20 mg/day [see CLINICAL STUDIES ( 14.1 ) ].

Switching Patients to a Tricyclic Antidepressant (TCA) – Dosage of a TCA may need to be reduced, and plasma TCA concentrations may need to be monitored temporarily when fluoxetine is coadministered or has been recently discontinued [see DRUG INTERACTIONS ( 7.9 ) ].

Switching Patients to or from a Monoamine Oxidase Inhibitor (MAOI) – At least 14 days should elapse between discontinuation of an MAOI and initiation of therapy with fluoxetine.

In addition, at least 5 weeks, perhaps longer, should be allowed after stopping fluoxetine before starting an MAOI [see CONTRAINDICATIONS ( 4 ) and DRUG INTERACTIONS ( 7.1 ) ].

2.2 Obsessive Compulsive Disorder Initial Treatment Adult – In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fixed daily doses of 20, 40, or 60 mg of fluoxetine or placebo [see CLINICAL STUDIES ( 14.2 ) ].

In one of these studies, no dose-response relationship for effectiveness was demonstrated.

Consequently, a dose of 20 mg/day, administered in the morning, is recommended as the initial dose.

Since there was a suggestion of a possible dose-response relationship for effectiveness in the second study, a dose increase may be considered after several weeks if insufficient clinical improvement is observed.

The full therapeutic effect may be delayed until 5 weeks of treatment or longer.

Doses above 20 mg/day may be administered on a once daily (i.e., morning) or BID schedule (i.e., morning and noon).

A dose range of 20 to 60 mg/day is recommended; however, doses of up to 80 mg/day have been well tolerated in open studies of OCD.

The maximum fluoxetine dose should not exceed 80 mg/day.

Pediatric (children and adolescents) – In the controlled clinical trial of fluoxetine supporting its effectiveness in the treatment of OCD, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see CLINICAL STUDIES ( 14.2 ) ].

In adolescents and higher weight children, treatment should be initiated with a dose of 10 mg/day.

After 2 weeks, the dose should be increased to 20 mg/day.

Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed.

A dose range of 20 to 60 mg/day is recommended.

In lower weight children, treatment should be initiated with a dose of 10 mg/day.

Additional dose increases may be considered after several more weeks if insufficient clinical improvement is observed.

A dose range of 20 to 30 mg/day is recommended.

Experience with daily doses greater than 20 mg is very minimal, and there is no experience with doses greater than 60 mg.

Maintenance/Continuation Treatment) – While there are no systematic studies that answer the question of how long to continue fluoxetine, OCD is a chronic condition and it is reasonable to consider continuation for a responding patient.

Although the efficacy of fluoxetine after 13 weeks has not been documented in controlled trials, adult patients have been continued in therapy under double-blind conditions for up to an additional 6 months without loss of benefit.

However, dosage adjustments should be made to maintain the patient on the lowest effective dosage, and patients should be periodically reassessed to determine the need for treatment.

2.3 Bulimia Nervosa Initial Treatment) – In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Bulimia Nervosa, patients were administered fixed daily fluoxetine doses of 20 or 60 mg, or placebo [see CLINICAL STUDIES ( 14.3 ) ].

Only the 60 mg dose was statistically significantly superior to placebo in reducing the frequency of binge-eating and vomiting.

Consequently, the recommended dose is 60 mg/day, administered in the morning.

For some patients it may be advisable to titrate up to this target dose over several days.

Fluoxetine doses above 60 mg/day have not been systematically studied in patients with bulimia.

Maintenance/Continuation Treatment) – Systematic evaluation of continuing fluoxetine 60 mg/day for periods of up to 52 weeks in patients with bulimia who have responded while taking fluoxetine 60 mg/day during an 8-week acute treatment phase has demonstrated a benefit of such maintenance treatment [see CLINICAL STUDIES ( 14.3 ) ].

Nevertheless, patients should be periodically reassessed to determine the need for maintenance treatment.

2.4 Panic Disorder Initial Treatment) – In the controlled clinical trials of fluoxetine supporting its effectiveness in the treatment of Panic Disorder, patients were administered fluoxetine doses in the range of 10 to 60 mg/day [see CLINICAL STUDIES ( 14.4 ) ].

Treatment should be initiated with a dose of 10 mg/day.

After one week, the dose should be increased to 20 mg/day.

The most frequently administered dose in the 2 flexible-dose clinical trials was 20 mg/day.

A dose increase may be considered after several weeks if no clinical improvement is observed.

Fluoxetine doses above 60 mg/day have not been systematically evaluated in patients with Panic Disorder.

Maintenance/Continuation Treatment) – While there are no systematic studies that answer the question of how long to continue fluoxetine, panic disorder is a chronic condition and it is reasonable to consider continuation for a responding patient.

Nevertheless, patients should be periodically reassessed to determine the need for continued treatment.

2.5 Fluoxetine and Olanzapine in Combination: Depressive Episodes Associated with Bipolar I Disorder When using fluoxetine and olanzapine in combination, also refer to the Clinical Studies section of the package insert for Symbyax .

Fluoxetine should be administered in combination with oral olanzapine once daily in the evening, without regard to meals, generally beginning with 5 mg of oral olanzapine and 20 mg of fluoxetine.

Dosage adjustments, if indicated, can be made according to efficacy and tolerability within dose ranges of fluoxetine 20 to 50 mg and oral olanzapine 5 to 12.5 mg.

Antidepressant efficacy was demonstrated with olanzapine and fluoxetine in combination with a dose range of olanzapine 6 to 12 mg and fluoxetine 25 to 50 mg.

Safety and efficacy of fluoxetine in combination with olanzapine was determined in clinical trials supporting approval of Symbyax (fixed-dose combination of olanzapine and fluoxetine).

Symbyax is dosed between 3 mg/25 mg (olanzapine/fluoxetine) per day and 12 mg/50 mg (olanzapine/fluoxetine) per day.

The following table demonstrates the appropriate individual component doses of fluoxetine and olanzapine versus Symbyax.

Dosage adjustments, if indicated, should be made with the individual components according to efficacy and tolerability.

Table 1: Approximate Dose Correspondence Between Symbyax Symbyax (olanzapine/fluoxetine HCl) is a fixed-dose combination of fluoxetine and olanzapine.

and the Combination of Fluoxetine and Olanzapine For Symbyax (mg/day) Use in Combination Olanzapine (mg/day) fluoxetine (mg/day) 3 mg olanzapine/25 mg fluoxetine 2.5 20 6 mg olanzapine/25 mg fluoxetine 5 20 12 mg olanzapine/25 mg fluoxetine 10+2.5 20 6 mg olanzapine/50 mg fluoxetine 5 40+10 12 mg olanzapine/50 mg fluoxetine 10+2.5 40+10 While there is no body of evidence to answer the question of how long a patient treated with fluoxetine and olanzapine in combination should remain on it, it is generally accepted that Bipolar I Disorder, including the depressive episodes associated with Bipolar I Disorder, is a chronic illness requiring chronic treatment.

The physician should periodically re-examine the need for continued pharmacotherapy.

Safety of coadministration of doses above 18 mg olanzapine with 75 mg fluoxetine has not been evaluated in clinical studies.

Fluoxetine monotherapy is not indicated for the treatment of depressive episodes associated with Bipolar I Disorder.

2.7 Dosing in Specific Populations Treatment of pregnant Women During the Third Trimester) – When treating pregnant women with fluoxetine during the third trimester, the physician should carefully consider the potential risks and potential benefits of treatment.

Neonates exposed to SNRIs or SSRIs late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.

The physician may consider tapering fluoxetine in the third trimester [see USE IN SPECIFIC POPULATIONS ( 8.1 ) ].

Geriatrics) – A lower or less frequent dosage should be considered for the elderly [see USE IN SPECIFIC POPULATIONS ( 8.5 ) ] Hepatic Impairment) – As with many other medications, a lower or less frequent dosage should be used in patients with hepatic impairment [see CLINICAL PHARMACOLOGY ( 12.4 ) and USE IN SPECIFIC POPULATIONS ( 8.6 ) ].

Concomitant Illness) – Patients with concurrent disease or on multiple concomitant medications may require dosage adjustments [see CLINICAL PHARMACOLOGY ( 12.4 ) and WARNINGS AND PRECAUTIONS ( 5.1 ) ].

Fluoxetine and Olanzapine in Combination) — The starting dose of oral olanzapine 2.5 to 5 mg with fluoxetine 20 mg should be used for patients with a predisposition to hypotensive reactions, patients with hepatic impairment, or patients who exhibit a combination of factors that may slow the metabolism of olanzapine or fluoxetine in combination (female gender, geriatric age, nonsmoking status), or those patients who may be pharmacodynamically sensitive to olanzapine.

Dosing modifications may be necessary in patients who exhibit a combination of factors that may slow metabolism.

When indicated, dose escalation should be performed with caution in these patients.

Fluoxetine and olanzapine in combination have not been systematically studied in patients over 65 years of age or in patients less than 18 years of age [see Warnings and Precautions ( 5.14 ) and Drug Interactions ( 7.9 )] .

2.8 Discontinuation of Treatment Symptoms associated with discontinuation of fluoxetine, SNRIs, and SSRIs, have been reported [see WARNINGS AND PRECAUTIONS ( 5.13 ) ].

Loratadine 10 MG Disintegrating Oral Tablet

WARNINGS

Do not use if you have ever had an allergic reaction to this product or any of its ingredients.

Ask a doctor before use if you have liver or kidney disease.

Your doctor should determine if you need a different dose.

When using this product do not take more than directed.

Taking more than directed may cause drowsiness.

Stop use and ask a doctor if an allergic reaction to this product occurs.

Seek medical help right away.

If pregnant or breast-feeding, ask a health professional before use.

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

INDICATIONS AND USAGE

USES temporarily relieves these symptoms due to hay fever or other upper respiratory allergies: runny nose itchy, watery eyes sneezing itching of the nose or throat

INACTIVE INGREDIENTS

aspartame, croscarmellose sodium, fruit flavors, magnesium stearate, mannitol, sodium stearyl fumarate

PURPOSE

Antihistamine

KEEP OUT OF REACH OF CHILDREN

Keep out of reach of children.

In case of overdose, get medical help or contact a Poison Control Center right away (1-800-222-1222).

ASK DOCTOR

Ask a doctor before use if you have liver or kidney disease.

Your doctor should determine if you need a different dose.

DOSAGE AND ADMINISTRATION

DIRECTIONS place 1 tablet on tongue; tablet disintegrates, with or without water adults and children 6 years and over 1 tablet daily; not more than 1 tablet in 24 hours children under 6 years of age ask a doctor consumers with liver or kidney disease ask a doctor

PREGNANCY AND BREAST FEEDING

If pregnant or breast-feeding, ask a health professional before use.

DO NOT USE

Do not use if you have ever had an allergic reaction to this product or any of its ingredients.

STOP USE

Stop use and ask a doctor if an allergic reaction to this product occurs.

Seek medical help right away.

ACTIVE INGREDIENTS

ACTIVE INGREDIENT (IN EACH TABLET) Loratadine, USP 10 mg

nortriptyline (as nortriptyline hydrochloride) 50 MG Oral Capsule

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 to 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 to 24 5 additional cases Decreases Compared to Placebo 25 to 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 nortriptyline hydrochloride should be written for the smallest quantity of capsules 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 nortriptyline hydrochloride is not approved for use in treating bipolar depression.

Patients with cardiovascular disease should be given nortriptyline hydrochloride only under close supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the conduction time.

Myocardial infarction, arrhythmia, and strokes have occurred.

The antihypertensive action of guanethidine and similar agents may be blocked.

Because of its anticholinergic activity, nortriptyline hydrochloride should be used with great caution in patients who have glaucoma or a history of urinary retention.

Patients with a history of seizures should be followed closely when nortriptyline hydrochloride is administered, inasmuch as this drug is known to lower the convulsive threshold.

Great care is required if nortriptyline hydrochloride is given to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.

Nortriptyline hydrochloride may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, the patient should be warned accordingly.

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

The concomitant administration of quinidine and nortriptyline may result in a significantly longer plasma half-life, higher AUC and lower clearance of nortriptyline.

Serotonin Syndrome The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including nortriptyline hydrochloride, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St.

John’s Wort) and with drugs that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular changes (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of nortriptyline hydrochloride with MAOIs intended to treat psychiatric disorders is contraindicated.

Nortriptyline hydrochloride should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue.

All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg.

No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses.

There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking nortriptyline hydrochloride.

Nortriptyline hydrochloride should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION ) .

If concomitant use of nortriptyline hydrochloride with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St.

John’s Wort is clinically warranted, patients should be made aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with nortriptyline hydrochloride and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

Use in Pregnancy Safe use of nortriptyline hydrochloride 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.

DRUG INTERACTIONS

Drug Interactions 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 nortriptyline hydrochloride 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).

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% to 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., 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 coadministration 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 coadministered with another drug known to be an inhibitor of P450 2D6.

Monoamine Oxidase Inhibitors (MAOIs) (See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .) Serotonergic Drugs (See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .)

OVERDOSAGE

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, 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 listed under ADVERSE REACTIONS .

There have been reports of patients recovering from nortriptyline overdoses of up to 525 mg.

Management 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 necessary.

If signs of toxicity occur at any time during this period, extended monitoring is required.

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 pC0 2 <20 mmHg 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.

DESCRIPTION

Nortriptyline hydrochloride, USP is 1-propanamine, 3-(10,11-dihydro-5 H -dibenzo [ a,d ]cyclohepten-5-ylidene)- N -methyl-, hydrochloride.

The structural formula is as follows: Nortriptyline Hydrochloride Capsules USP (equivalent to 10 mg, 25 mg, 50 mg and 75 mg Nortriptyline), for oral administration, contain the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, pregelatinized starch and sodium lauryl sulfate.

The 10 mg, 25 mg, 50 mg and 75 mg capsule shells contain: gelatin, methylparaben, propylparaben, sodium lauryl sulfate and titanium dioxide.

They may also contain: benzyl alcohol, butylparaben, edetate calcium disodium, silicon dioxide or sodium propionate.

The 10 mg, 25 mg and 75 mg capsule shells also contain D&C Yellow No.

10 and FD&C Blue No.

1.

The structural formula for Nortriptyline

HOW SUPPLIED

Nortriptyline Hydrochloride Capsules USP (equivalent to 25 mg nortriptyline) are #1, opaque deep green and opaque white capsules imprinted NORTRIPTYLINE and DAN 25 mg supplied in; Bottle of 30 – 68788-9969-3 Bottle of 60 – 68788-9969-6 Bottle of 90 – 68788-9969-9 Bottle of 100 – 68788-9969-1 Nortriptyline Hydrochloride Capsules USP (equivalent to 50 mg nortriptyline) are #1, opaque white capsules imprinted NORTRIPTYLINE and DAN 50 mg supplied in; Bottle of 30 – 68788-9324-3 Bottle of 60 – 68788-9324-6 Bottle of 90 – 68788-9324-9 Bottle of 100 – 68788-9324-1 Dispense in a tight container, as defined in the USP, with a child-resistant closure.

Store at 20°–25°C (68°–77°F).

[See USP controlled room temperature.] Manufactured by: Watson Pharma Private Limited Verna, Salcette Goa 403 722 INDIA Distributed by: Watson Pharma, Inc.

Parsippany, NJ 07054 USA Revised: March 2013 173679-1

GERIATRIC USE

Geriatric Use Clinical studies of nortriptyline hydrochloride 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 ).

INDICATIONS AND USAGE

Nortriptyline hydrochloride, USP is indicated for the relief of symptoms of depression.

Endogenous depressions are more likely to be alleviated than are other depressive states.

PEDIATRIC USE

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 nortriptyline hydrochloride in a child or adolescent must balance the potential risks with the clinical need.

BOXED WARNING

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 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.

(See WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS: Information for Patients ; and PRECAUTIONS, Pediatric Use ).

INFORMATION FOR PATIENTS

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 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 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 nortriptyline hydrochloride.

DOSAGE AND ADMINISTRATION

Nortriptyline hydrochloride is not recommended for children.

Nortriptyline hydrochloride is administered orally.

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.

Usual Adult Dose – 25 mg three or four times daily; dosage should begin at a low level and be increased as required.

As an alternate regimen, the total daily dosage may be given once a day.

When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL.

Doses above 150 mg/day are not recommended.

Elderly and Adolescent Patients – 30 to 50 mg/day, in divided doses, or the total daily dosage may be given once a day.

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with nortriptyline hydrochloride.

Conversely, at least 14 days should be allowed after stopping nortriptyline hydrochloride before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ).

Use of Nortriptyline Hydrochloride With Other MAOIs, Such as Linezolid or Methylene Blue Do not start nortriptyline hydrochloride in a patient who is being treated with linezolid or intravenous methylene blue because there is increased risk of serotonin syndrome.

In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ).

In some cases, a patient already receiving nortriptyline hydrochloride therapy may require urgent treatment with linezolid or intravenous methylene blue.

If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, nortriptyline hydrochloride should be stopped promptly, and linezolid or intravenous methylene blue can be administered.

The patient should be monitored for symptoms of serotonin syndrome for two weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first.

Therapy with nortriptyline hydrochloride may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with nortriptyline hydrochloride is unclear.

The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ).