Limbitrol

Amitriptyline is a tricyclic antidepressant. Chlordiazepoxide is a benzodiazepine (ben-zoe-dye-AZE-eh-peen). These medicines affect chemicals in the brain that may be unbalanced in people with depression.

Amitriptyline and chlordiazepoxide is a combination medicine used to treat moderate to severe depression and anxiety.

Amitriptyline and chlordiazepoxide may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have recently had a heart attack.

Do not use this medicine if you have used an MAO inhibitor in the past 14 days, such as isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, or tranylcypromine.

Some young people have thoughts about suicide when first taking an antidepressant. Stay alert to changes in your mood or symptoms. Report any new or worsening symptoms to your doctor.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of amitriptyline and chlordiazepoxide can be fatal, especially if taken with alcohol.

Overdose symptoms may include irregular heartbeats, extreme drowsiness, overactive reflexes, stiff muscles, dilated pupils, vomiting, feeling hot or cold, feeling like you might pass out, or seizure (convulsions).

Chlordiazepoxide and amitriptyline combination is used to treat mental depression that occurs with anxiety or nervous tension.

This medicine is available only with your doctor's prescription.

Antidepressants increased the risk of suicidal thinking and behavior (suicidality) in short-term studies in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. Anyone considering the use of Chlordiazepoxide and Amitriptyline Hydrochloride Tablets or any other antidepressant in a child or adolescent must balance this risk with the clinical need. Patients who are started on therapy should be 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. Chlordiazepoxide and Amitriptyline Hydrochloride Tablets is not approved for use in pediatric patients. (See Warnings and Precautions: Pediatric Use.)

Pooled analyses of short-term (4 to 16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality) during the first few months of treatment in those receiving antidepressants. The average risk of such events in patients receiving antidepressants was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.

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.

Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuance of chlordiazepoxide. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (eg, dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Withdrawal symptoms (e.g., nausea, headache and malaise) have also been reported in association with abrupt amitriptyline discontinuation. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addictionprone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving chlordiazepoxide or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

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 ³ 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< 20mm 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 (eg, 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.

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

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 section). 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.

Limbitrol DS (double strength) Tablets are available as white, film-coated, biconvex tablets containing 10 mg chlordiazepoxide and 25 mg amitriptyline (as the hydrochloride salt) in bottles of 100 (NDC 0187-3806-10). 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 0187-3805-10). Each tablet is engraved “V 3805” on one side.

Store at 25°C (77°F); excursions permitted to 15°C – 30°C (59°F – 86°F). Store in a dry place.

General

• Fixed-ratio combination preparations generally should not be used as initial therapy.d e First administer each drug separately.d e If the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, a fixed-combination preparation may be used.d e If dosage adjustment is necessary, administer the drugs separately.d e Fixed-ratio combination preparations do not permit individual titration of dosages.m

• Allow at least 2 weeks to elapse between discontinuance of therapy with an MAO inhibitor and initiation of amitriptyline and vice versa.c Also allow at least 5 weeks to elapse when switching from fluoxetine.c

• Monitor for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.c i j k (See Worsening of Depression and Suicidality Risk under Cautions.)

• Sustained therapy may be required; monitor periodically for need for continued therapy.c

• Avoid abrupt discontinuance in patients receiving high dosages for prolonged periods.d To avoid withdrawal reactions, taper dosage gradually.d

Administration

Oral Administration

Administer in up to 4 divided doses or as a single daily dose at bedtime to avoid daytime sedation.c d

Dosage

Available as amitriptyline hydrochloride (alone and in fixed combination with perphenazine or chlordiazepoxide); dosage is expressed in terms of the salt.103 g n

Pediatric Patients

Adolescents ≥12 years of age: 10 mg 3 times daily plus 20 mg at bedtime.c

Adolescents: Initially, 10 mg (in fixed combination with 4 mg perphenazine) 3 or 4 times daily; adjust as required.n

Maximum daily dosages of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.n

Adults

Initially, 75 mg daily in divided doses or 50–100 mg once daily at bedtime.c Increase dosages in 25- or 50-mg increments until maximal therapeutic effect with minimal toxicity is achieved or up to a maximum dosage of 150 mg daily.c

Usual maintenance dosage: 50–100 mg daily, administered as a single daily dose, preferably at bedtime.c For some patients, 25–40 mg daily may be sufficient.d Continue therapy for at least 3 months to prevent relapse.c

Initially, 100 mg daily; dosage may be increased gradually to 200–300 mg daily as needed.c

Initially, amitriptyline hydrochloride 75 or 100 mg daily (in fixed combination with chlordiazepoxide 30 or 40 mg daily, respectively) in divided doses.g If needed, increase dosage to amitriptyline hydrochloride 150 mg daily (in fixed combination with chlordiazepoxide 60 mg daily) in divided doses.g

Alternatively, in patients who do not tolerate larger dosages, initial dosage of amitriptyline hydrochloride 37.5 or 50 mg daily (in fixed combination with chlordiazepoxide 15 or 20 mg daily, respectively) in divided doses.g

For some patients, amitriptyline hydrochloride 50 mg daily (in fixed combination with chlordiazepoxide 20 mg daily) in divided doses may be adequate.g

Initially, amitriptyline hydrochloride 25 mg (in fixed combination with perphenazine 2 or 4 mg) 3 or 4 times daily.n Alternatively, amitriptyline hydrochloride 50 mg (in fixed combination with perphenazine 4 mg) twice daily.n

Carefully adjust subsequent dosage according to patient’s tolerance and therapeutic response.n During maintenance therapy, keep dosage at the lowest effective level.n Amitriptyline hydrochloride maintenance dosages usually range from 50–100 mg daily and perphenazine maintenance dosages usually range from 4–16 mg daily.n

Maximum daily dosage of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.n

Initially, 2 tablets of amitriptyline hydrochloride 25 mg (in fixed combination with perphenazine 4 mg) 3 times daily.n If needed, a fourth dose may be given at bedtime.n

Carefully adjust subsequent dosage according to patient’s tolerance and therapeutic response.n During maintenance therapy, keep dosage at the lowest effective level.n Amitriptyline hydrochloride maintenance dosages usually range from 50–100 mg daily and perphenazine maintenance dosages usually range from 4–16 mg daily.n

Maximum daily dosage of perphenazine and amitriptyline hydrochloride not to exceed 16 and 200 mg, respectively.n

Prescribing Limits

Pediatric Patients

Adolescents: Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.n

Adults

Maximum 150 mg daily.c

Maximum 300 mg daily.c

Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.n

Maximum 16 and 200 mg daily of perphenazine and amitriptyline hydrochloride, respectively.n

Special Populations

Geriatric Patients

10 mg 3 times daily plus 20 mg at bedtime.c

When used in fixed combination with chlordiazepoxide, select initial dosages at the lower end of the usual ranges and gradually increase dosages if needed and tolerated.g

When used in fixed combination with perphenazine, an oral dosage of 10 mg of amitriptyline hydrochloride and 4 mg of perphenazine 3 or 4 times daily is recommended initially.n Subsequent dosage adjustments may be made as necessary.n

Metabolized in the liver by various CYP isoenzymes (e.g., CYP1A2, CYP2C, CYP2D6, CYP3A4).a

Drugs Affecting Hepatic Microsomal Enzymes

Inhibitors of CYP2D6: potential pharmacokinetic interaction (increased amitriptyline concentrations).a Adjust amitriptyline dosage whenever a CYP2D6 inhibitor is added or discontinued.a

Specific Drugs