Limbitrol

What is Limbitrol and how is it used?

• Limbitrol is a prescription medicine used to treat moderate to severe depression that can happen with moderate to severe anxiety.
• Limbitrol is a federal controlled substance (C-IV) because it contains chlordiazepoxide that can be abused or lead to dependence. Keep Limbitrol in a safe place to prevent misuse and abuse. Selling or giving away Limbitrol may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.
• It is not known if Limbitrol is safe and effective in children.

What are the possible side effects of Limbitrol?

Limbitrol may cause serious side effects, including:

• See “What is the most important information I should know about Limbitrol?”
• Limbitrol can make you sleepy or dizzy, and can slow your thinking and motor skills.
  • Do not drive, operate heavy machinery, or do other dangerous activities until you know how Limbitrol affects you.
  • Do not drink alcohol or take other drugs that may make you sleepy or dizzy while taking Limbitrol without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, Limbitrol may make your sleepiness or dizziness much worse.

The most common side effects of Limbitrol include:

• drowsiness
• constipation
• dizziness
• dry mouth
• blurred vision
• bloating

These are not all the possible side effects of Limbitrol.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

LIMBITROL combines for oral administration, chlordiazepoxide, an agent for the relief of anxiety and tension, and amitriptyline, an antidepressant. It is available in DS (double strength) white, film-coated tablets, each containing 10 mg chlordiazepoxide and 25 mg amitriptyline (as the hydrochloride salt); and in blue, film-coated tablets, each containing 5 mg chlordiazepoxide and 12.5 mg amitriptyline (as the hydrochloride salt). Each tablet also contains corn starch, hydroxypropyl cellulose, hyproxypropyl methylcellulose, lactose, magnesium stearate, polyethylene glycol, povidone and propylene glycol; LIMBITROL tablets contain the following colorant system-FD&C Blue No. 1, aluminum lake and titanium dioxide. LIMBITROL DS tablets contain titanium dioxide.

Chlordiazepoxide is a benzodiazepine with the formula 7-chloro-2-(methyl-amino)-5phenyl-3H-1,4-benzodiazepine 4-oxide. It is a slightly yellow crystalline material and is insoluble in water. The molecular weight is 299.76.

Amitriptyline is a dibenzocycloheptadiene derivative. The formula is 10,11-dihydroN,N-dimethyl-5H-dibenzo [a,d] cycloheptene-Δ⁵γ-propylamine hydrochloride. It is a white or practically white crystalline compound that is freely soluble in water. The molecular weight is 313.87.

INDICATIONS

LIMBITROL is indicated for the treatment of patients with moderate to severe depression associated with moderate to severe anxiety.

The therapeutic response to LIMBITROL occurs earlier and with fewer treatment failures than when either amitriptyline or chlordiazepoxide is used alone.

Symptoms likely to respond in the first week of treatment include: insomnia, feelings of guilt or worthlessness, agitation, psychic and somatic anxiety, suicidal ideation and anorexia.

DOSAGE AND ADMINISTRATION

Optimum dosage varies with the severity of the symptoms and the response of the individual patient. When a satisfactory response is obtained, dosage should be reduced to the smallest amount needed to maintain the remission. The larger portion of the total daily dose may be taken at bedtime. In some patients, a single dose at bedtime may be sufficient. In general, lower dosages are recommended for elderly patients.

LIMBITROL DS (double strength) Tablets are recommended in an initial dosage of 3 or 4 tablets daily in divided doses; this may be increased to 6 tablets daily as required. Some patients respond to smaller doses and can be maintained on 2 tablets daily.

LIMBITROL Tablets in an initial dosage of 3 or 4 tablets daily in divided doses may be satisfactory in patients who do not tolerate higher doses.

Screen For Bipolar Disorder Prior To Starting LIMBITROL

Prior to initiating treatment with LIMBITROL or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania (see WARNINGS: Activation of Mania or Hypomania).

Discontinuation Or Dosage Reduction Of LIMBITROL

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LIMBITROL or reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly (see WARNINGS: Dependence and Withdrawal Reactions and Drug Abuse And Dependence: Dependence).

HOW SUPPLIED

LIMBITROL DS (double strength) Tablets are available as white, filmcoated, biconvex tablets containing 10 mg chlordiazepoxide and 25 mg amitriptyline (as the hydrochloride salt) in bottles of 100 (NDC 23155-562-01). Each tablet is engraved “V 3806” on one side.

LIMBITROL Tablets are available as blue, film-coated, biconvex tablets containing 5 mg chlordiazepoxide and 12.5 mg amitriptyline (as the hydrochloride salt) in bottles of 100 (NDC 23155-563-01). Each tablet is engraved “V 3805” on one side.

Store at 20° to 25°C (68° to 77°F). [See USP controlled room temperature.] Store in a dry place.

Keep in a tightly closed, child-resistant container and out of the light.

Distributed by: Avet Pharmaceuticals Inc., East Brunswick, NJ 08816, 1.866.901.DRUG (3784). Revised: Feb 2021

SIDE EFFECTS

Adverse reactions to LIMBITROL are those associated with the use of either component alone. Most frequently reported were drowsiness, dry mouth, constipation, blurred vision, dizziness and bloating. Other side effects occurring less commonly included vivid dreams, impotence, tremor, confusion and nasal congestion. Many symptoms common to the depressive state, such as anorexia, fatigue, weakness, restlessness and lethargy, have been reported as side effects of treatment with both LIMBITROL and amitriptyline.

Granulocytopenia, jaundice and hepatic dysfunction of uncertain etiology have also been observed rarely with LIMBITROL. When treatment with LIMBITROL is prolonged, periodic blood counts and liver function tests are advisable.

Note: Included in the listing which follows are adverse reactions which have not been reported with LIMBITROL. However, they are included because they have been reported during therapy with one or both of the components or closely related drugs.

Cardiovascular

Hypotension, hypertension, tachycardia, palpitations, myocardial infarction, arrhythmias, heart block, stroke.

Psychiatric

Euphoria, apprehension, poor concentration, delusions, hallucinations, hypomania and increased or decreased libido.

Neurologic

Incoordination, ataxia, numbness, tingling and paresthesias of the extremities, extrapyramidal symptoms, syncope, changes in EEG patterns.

Anticholinergic

Disturbance of accommodation, paralytic ileus, urinary retention, dilatation of urinary tract.

Allergic

Skin rash, urticaria, photosensitization, edema of face and tongue, pruritus.

Hematologic

Bone marrow depression including agranulocytosis, eosinophilia, purpura, thrombocytopenia.

Gastrointestinal

Nausea, epigastric distress, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue.

Endocrine

Testicular swelling and gynecomastia in the male, breast enlargement, galactorrhea and minor menstrual irregularities in the female, elevation and lowering of blood sugar levels, and syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Other

Headache, weight gain or loss, increased perspiration, urinary frequency, mydriasis, jaundice, alopecia, parotid swelling.

DRUG INTERACTIONS

Drug-Drug Interactions

The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and monitor patients closely for respiratory depression and sedation.

Topiramate

Some patients may experience a large increase in amitriptyline concentration in the presence of topiramate and any adjustments in amitriptyline dose should be made according to the patient's clinical response and not on the basis of plasma levels.

Drug And Treatment Interactions

Because of its amitriptyline component, LIMBITROL may block the antihypertensive action of guanethidine or compounds with a similar mechanism of action.

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 cotherapy, 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.

The effects of concomitant administration of LIMBITROL and other psychotropic drugs have not been evaluated. Sedative effects may be additive.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants and benzodiazepines, thereby delaying elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine (Tagamet).

The drug should be discontinued several days before elective surgery.

Concurrent administration of ECT and LIMBITROL should be limited to those patients for whom it is essential.

Drug Abuse And Dependence

Controlled Substance

Limbitrol contains chlordiazepoxide, a Schedule IV controlled substance.

Abuse

LIMBITROL is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction.

Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders (see WARNINGS: Abuse, Misuse, and Addiction).

The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.

The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

Dependence

Physical Dependence

LIMBITROL may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use (see WARNINGS: Dependence and Withdrawal Reactions).

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LIMBITROL or reduce the dosage (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of Limbitrol and WARNINGS: Dependence and Withdrawal Reactions).

Acute Withdrawal Signs And Symptoms

Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality.

Protracted Withdrawal Syndrome

Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.

Tolerance

Tolerance to LIMBITROL may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of LIMBITROL may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

WARNINGS

Risks From Concomitant Use With Opioids

Concomitant use of benzodiazepines, including Limbitrol, and opioids may result in profound sedation, respiratory depression, coma, and death.

Because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate.

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. If a decision is made to prescribe Limbitrol concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. In patients already receiving an opioid analgesic, prescribe a lower initial dose of Limbitrol than indicated in the absence of an opioid and titrate based on clinical response. If an opioid is initiated in a patient already taking Limbitrol, prescribe a lower initial dose of the opioid and titrate based upon clinical response.

Advise both patients and caregivers about the risks of respiratory depression and sedation when Limbitrol is used with opioids. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined [see DRUG INTERACTIONS].

Abuse, Misuse, And Addiction

The use of benzodiazepines, including LIMBITROL, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death (see Drug Abuse And Dependence: Abuse).

Before prescribing LIMBITROL and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). Use of LIMBITROL, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of LIMBITROL along with monitoring for signs and symptoms of abuse, misuse, and addiction. Prescribe the lowest effective dosage; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.

Dependence And Withdrawal Reactions

To reduce the risk of withdrawal reactions, use a gradual taper to discontinue LIMBITROL or reduce the dosage (a patient-specific plan should be used to taper the dose) (see DOSAGE AND ADMINISTRATION: Discontinuation or Dosage Reduction of LIMBITROL).

Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use.

Acute Withdrawal Reactions

The continued use of benzodiazepines, including LIMBITROL, may lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of LIMBITROL after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) (see Drug Abuse And Dependence: Dependence).

Protracted Withdrawal Syndrome

In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months (see Drug Abuse And Dependence: Dependence).

Suicidal Thoughts And Behaviors In Adolescent And Young Adults

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1.

Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients

It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors.

Monitor all antidepressant-treated patients for any indication for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing Limbitrol, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

Activation Of Mania Or Hypomania

In patients with bipolar disorder, treating a depressive episode with Limbitrol or another antidepressant may precipitate a mixed/manic episode. Prior to initiating treatment with Limbitrol, screen patients for any personal or family history of bipolar disorder, mania, or hypomania.

Angle-Closure Glaucoma

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

General

Because of the atropine-like action of the amitriptyline component, great care should be used in treating patients with a history of urinary retention or angle-closure glaucoma. In patients with glaucoma, even average doses may precipitate an attack. Severe constipation may occur in patients taking tricyclic antidepressants in combination with anticholinergic-type drugs.

Patients with cardiovascular disorders should be watched closely. Tricyclic antidepressant drugs, particularly when given in high doses, have been reported to produce arrhythmias, sinus tachycardia and prolongation of conduction time. Myocardial infarction and stroke have been reported in patients receiving drugs of this class.

Because of the sedative effects of LIMBITROL, patients should be cautioned about combined effects with alcohol or other CNS depressants. The additive effects may produce a harmful level of sedation and CNS depression.

Patients receiving LIMBITROL should be cautioned against engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle.

Usage In Pregnancy

Safe use of LIMBITROL during pregnancy and lactation has not been established. Because of the chlordiazepoxide component, please note the following:

An increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of pregnancy has been suggested in several studies. Because use of these drugs is rarely a matter of urgency, their use during this period should almost always be avoided. The possibility that a woman of childbearing potential may be pregnant at the time of institution of therapy should be considered. Patients should be advised that if they become pregnant during therapy or intend to become pregnant they should communicate with their physicians about the desirability of discontinuing the drug.

PRECAUTIONS

General

Use with caution in patients with a history of seizures.

Close supervision is required when LIMBITROL is given to hyperthyroid patients or those on thyroid medication.

The usual precautions should be observed when treating patients with impaired renal or hepatic function.

Patients with suicidal ideation should not have easy access to large quantities of the drug. The possibility of suicide in depressed patients remains until significant remission occurs.

Essential Laboratory Tests

Patients on prolonged treatment should have periodic liver function tests and blood counts.

Pregnancy

See WARNINGS section.

Nursing Mothers

It is not known whether this drug is excreted in human milk. As a general rule, nursing should not be undertaken while a patient is on a drug, since many drugs are excreted in human milk.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS: Suicidal Thoughts and Behaviors in Adolescents and Young Adults).

Anyone considering the use of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

In elderly and debilitated patients it is recommended that dosage be limited to the smallest effective amount to preclude the development of ataxia, oversedation, confusion or anticholinergic effects.

Of the total number of subjects in clinical studies of LIMBITROL, 74 individuals were 65 years and older. An additional 34 subjects were between 60 and 69 years of age. No overall differences in safety and 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.

The active ingredients in LIMBITROL are 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. 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.

Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of LIMBITROL and observed closely.

Clinical studies of LIMBITROL did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently than 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.

Information For Patients

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Risks From Concomitant Use With Opioids

Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when LIMBITROL is used with opioids and not to use such drugs concomitantly unless supervised by a health care provider. Advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined (see WARNINGS: Risks from Concomitant Use with Opioids and DRUG INTERACTIONS).

Abuse, Misuse, And Addiction

Inform patients that the use of LIMBITROL, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug (see WARNINGS: Abuse, Misuse, and Addiction and Drug Abuse And Dependence).

Withdrawal Reactions

Inform patients that the continued use of LIMBITROL may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of LIMBITROL may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of LIMBITROL may require a slow taper (see WARNINGS-Dependence and Withdrawal Reactions and Drug Abuse And Dependence).

Suicidal Thoughts and Behaviors: Advise patients and caregivers to look for the emergence of suicidal thoughts and behaviors, especially early during treatment and when the dosage is adjusted up or down (see WARNINGS-Suicidal Thoughts and Behaviors in Adolescents and Young Adults).

OVERDOSE

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, convulsions and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia or any of the symptoms listed under ADVERSE REACTIONS.

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 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 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. Serum alkalinization, to a pH of 7.45 to 7.56, using intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted for patients with dysrhythmias and/or QRS widening. A pH > 7.60 or a pCO2 < 20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.

CNS

In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines, or if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in consultation with a poison control center.

Psychiatric Follow-up

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

Pediatric Management

The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Chlordiazepoxide Overdosage

Manifestations of benzodiazepine overdosage include somnolence, confusion, coma and diminished reflexes. Dialysis is of limited value. There have been occasional reports of excitation in patients following benzodiazepine overdosage; if this occurs, barbiturates should not be used. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see Drug Abuse And Dependence). Since LIMBITROL contains amitriptyline, it is important to note that use of the benzodiazepine antagonist flumazenil is contraindicated in patients who are showing signs of serious cyclic antidepressant overdose.

CONTRAINDICATIONS

LIMBITROL is contraindicated in patients with hypersensitivity to either benzodiazepines or tricyclic antidepressants. It should not be given concomitantly with a monoamine oxidase inhibitor. Hyperpyretic crises, severe convulsions and deaths have occurred in patients receiving a tricyclic antidepressant and a monoamine oxidase inhibitor simultaneously. When it is desired to replace a monoamine oxidase inhibitor with LIMBITROL, a minimum of 14 days should be allowed to elapse after the former is discontinued. LIMBITROL should then be initiated cautiously with gradual increase in dosage until optimum response is achieved. This drug is contraindicated during the acute recovery phase following myocardial infarction.

*Poisindex® Toxicologic Management. Topic: Antidepressants, Tricyclic.
Micromedex Inc. Vol. 85.

CLINICAL PHARMACOLOGY

Actions

Both components of LIMBITROL exert their action in the central nervous system. Extensive studies with chlordiazepoxide in many animal species suggest action in the limbic system. Recent evidence indicates that the limbic system is involved in emotional response. Taming action was observed in some species. The mechanism of action of amitriptyline in man is not known, but the drug appears to interfere with the reuptake of norepinephrine into adrenergic nerve endings. This action may prolong the sympathetic activity of biogenic amines.

PATIENT INFORMATION

Antidepressant Medicines, Depression and other Serious Mental Illness,  and Suicidal Thoughts or Actions

Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:

• All risks and benefits of treatment with antidepressant medicines
• All treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illness, and suicidal thoughts or actions?

1. Antidepressant medications may increase suicidal thoughts or actions in some children, teenagers, and young adults when the medicine is first started.

2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.

3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?

• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is first started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• acting aggressive, being angry, or violent
• attempts to commit suicide
• new or worse depression
• acting on dangerous impulses
• new or worse anxiety
• an extreme increase in activity and talking (mania)
• feeling very agitated or restless
• panic attacks
• other unusual changes inbehavior or mood
• trouble sleeping (insomnia)
• new or worse irritability

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risk of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
• Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child's healthcare provider for more information.