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imipramine hydrochloride tablet, film coated
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Suicidality and Antidepressant Drugs
Warnings: Clinical Worsening and Suicide Risk,Precautions: Information for Patients, andPrecautions: Pediatric Use).
DESCRIPTIONImipramine hydrochloride USP, the original tricyclic antidepressant, is a member of the dibenzazepine group of compounds. It is designated 5-[3-(dimethylamino) propyl] -10,11-dihydro-5H-dibenz [b,f]-azepine monohydrochloride. Its structural formula is:
Imipramine hydrochloride tablets are available in 10 mg, 25 mg and 50 mg for oral administration.
Imipramine HCl tablets, 10 mg contain the following inactive ingredients: colloidal silicon dioxide, D & C red No. 30 aluminum lake, D & C yellow No. 10 aluminum lake, dibasic calcium phosphate, FD & C blue No. 2 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Imipramine HCl tablets, 25 mg contain the following inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate, FD & C blue No. 2 aluminum lake, FD & C red No. 40 aluminum lake, FD & C yellow No. 6 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
Imipramine HCl tablets, 50 mg contain the following inactive ingredients: colloidal silicon dioxide, D & C yellow No. 10 aluminum lake, dibasic calcium phosphate, FD & C blue No. 1 aluminum lake, FD & C yellow No. 6 aluminum lake, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium starch glycolate, and titanium dioxide.
CLINICAL PHARMACOLOGYThe mechanism of action of imipramine is not definitely known. However, it does not act primarily by stimulation of the central nervous system. The clinical effect is hypothesized as being due to potentiation of adrenergic synapses by blocking uptake of norepinephrine at nerve endings. The mode of action of the drug in controlling childhood enuresis is thought to be apart from its antidepressant effect.
INDICATIONS & USAGEDepression
For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident.
May be useful as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older, after possible organic causes have been excluded by appropriate tests. In patients having daytime symptoms of frequency and urgency, examination should include voiding cystourethrography and cystoscopy, as necessary. The effectiveness of treatment may decrease with continued drug administration.
CONTRAINDICATIONSThe concomitant use of monoamine oxidase inhibiting compounds is contraindicated. Hyperpyretic crises or severe convulsive seizures may occur in patients receiving such combinations. The potentiation of adverse effects can be serious, or even fatal. When it is desired to substitute imipramine hydrochloride in patients receiving a monoamine oxidase inhibitor, as long an interval should elapse as the clinical situation will allow, with a minimum of 14 days. Initial dosage should be low and increases should be gradual and cautiously prescribed.
The drug is contraindicated during the acute recovery period after a myocardial infarction. Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind.
WARNINGSClinical 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
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.
AgeDrug-Placebo Difference in Number of Cases of Suicidality perRange1000 Patients TreatedIncreases Compared to Placebo<1814 additional cases18245 additional casesDecreases Compared to Placebo25641 fewer case6 fewer casesNo 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 imipramine hydrochloride 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 dose of 2.5 mg/kg/day of imipramine hydrochloride should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
Extreme caution should be used when this drug is given to:
PRECAUTIONSInformation for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with imipramine 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 imipramine 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 imipramine 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, or 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 of suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in medication.
An ECG recording should be taken prior to the initiation of larger-than-usual doses of imipramine and at appropriate intervals thereafter until steady state is achieved. (Patients with any evidence of cardiovascular disease require cardiac surveillance at all dosage levels of the drug. SeeWARNINGS.) Elderly patients and patients with cardiac disease or a prior history of cardiac disease are at special risk of developing the cardiac abnormalities associated with the use of imipramine.
It should be kept in mind that the possibility of suicide in seriously depressed patients is inherent in the illness and may persist until significant remission occurs. Such patients should be carefully supervised during the early phase of treatment with imipramine, and may require hospitalization. Prescriptions should be written for the smallest amount feasible. Hypomanic or manic episodes may occur, particularly in patients with cyclic disorders. Such reactions may necessitate discontinuation of the drug. If needed, imipramine may be resumed in lower dosage when these episodes are relieved.
Administration of a tranquilizer may be useful in controlling such episodes.
An activation of the psychosis may occasionally be observed in schizophrenic patients and may require reduction of dosage and the addition of a phenothiazine.
Patients taking imipramine hydrochloride should avoid excessive exposure to sunlight since there have been reports of photosensitization.
Both elevation and lowering of blood sugar levels have been reported with imipramine hydrochloride use.
Imipramine hydrochloride should be used with caution in patients with significantly impaired renal or hepatic function.
Patients who develop a fever and a sore throat during therapy with imipramine hydrochloride should have leukocyte and differential blood counts performed. Imipramine hydrochloride should be discontinued if there is evidence of pathological neutrophil depression.
Prior to elective surgery, imipramine hydrochloride should be discontinued for as long as the clinical situation will allow.
DRUG INTERACTIONSDrugs 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%
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.
The plasma concentration of imipramine may increase when the drug is given concomitantly with hepatic enzyme inhibitors (e.g., cimetidine, fluoxetine) and decrease by concomitant administration with hepatic enzyme inducers (e.g., barbiturates, phenytoin), and adjustment of the dosage of imipramine may therefore be necessary.
In occasional susceptible patients or in those receiving anticholinergic drugs (including antiparkinsonism agents) in addition, the atropine-like effects may become more pronounced (e.g., paralytic ileus). Close supervision and careful adjustment of dosage is required when imipramine hydrochloride is administered concomitantly with anticholinergic drugs.
Avoid the use of preparations, such as decongestants and local anesthetics, that contain any sympathomimetic amine (e.g., epinephrine, norepinephrine), since it has been reported that tricyclic antidepressants can potentiate the effects of catecholamines.
Caution should be exercised when imipramine hydrochloride is used with agents that lower blood pressure. Imipramine hydrochloride may potentiate the effects of CNS depressant drugs.
Patients should be warned that imipramine hydrochloride may enhance the CNS depressant effects of alcohol. (SeeWARNINGS.)
PREGNANCYAnimal reproduction studies have yielded inconclusive results. (See alsoANIMAL PHARMACOLOGY & TOXICOLOGY.)
There have been no well-controlled studies conducted with pregnant women to determine the effect of imipramine on the fetus. However, there have been clinical reports of congenital malformations associated with the use of the drug. Although a causal relationship between these effects and the drug could not be established, the possibility of fetal risk from the maternal ingestion of imipramine cannot be excluded. Therefore, imipramine should be used in women who are or might become pregnant only if the clinical condition clearly justifies potential risk to the fetus.
NURSING MOTHERSLimited data suggest that imipramine is likely to be excreted in human breast milk. As a general rule, a woman taking a drug should not nurse since the possibility exists that the drug may be excreted in breast milk and be harmful to the child.
PEDIATRIC USESafety and effectiveness in the pediatric population other than pediatric patients with nocturnal enuresis have not been established (seeBOX WARNINGandWARNINGSClinical Worsening and Suicide Risk). Anyone considering the use of imipramine hydrochloride in a child or adolescent must balance the potential risks with the clinical need.
The safety and effectiveness of the drug as temporary adjunctive therapy for nocturnal enuresis in pediatric patients less than 6 years of age has not been established.
A dose of 2.5 mg/kg/day should not be exceeded in childhood. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
GERIATRIC USEIn the literature, there were four well-controlled, randomized, double-blind, parallel group comparison clinical studies done with imipramine in the elderly population. There was a total number of 651 subjects included in these studies. These studies did not provide a comparison to younger subjects. There were no additional adverse experiences identified in the elderly.
Clinical studies of imipramine in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Post-marketing clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for the elderly should be cautious, usually starting at the low end of the dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
(See alsoDOSAGE AND ADMINISTRATIONin Adolescent and geriatric patients)
(See alsoPRECAUTIONS General)
ADVERSE REACTIONSNote: Although the listing which follows includes a few adverse reactions which have not been reported with this specific drug, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when imipramine is administered.
Cardiovascular: Orthostatic hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, ECG changes, precipitation of congestive heart failure, stroke.
Withdrawal Symptoms: Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache and malaise.
Note: In enuretic children treated with imipramine the most common adverse reactions have been nervousness, sleep disorders, tiredness, and mild gastrointestinal disturbances. These usually disappear during continued drug administration or when dosage is decreased. Other reactions which have been reported include constipation, convulsions, anxiety, emotional instability, syncope, and collapse. All of the adverse effects reported with adult use should be considered.
OVERDOSAGEDeaths 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.
Children have been reported to be more sensitive than adults to an acute overdosage of imipramine hydrochloride. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal.
These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. 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, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements.
Cardiac abnormalities may include tachycardia and signs of congestive failure. Respiratory depression, cyanosis, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present.
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.
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.
A maximal limb-lead QRS duration ofseconds 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 Pco2 < 20mmHg 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.
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.
Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.
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.
DOSAGE & ADMINISTRATIONDepression
Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients as compared to hospitalized patients who will be under close supervision. Dosage should be initiated at a low level and increased 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.
Usual Adult Dose
Hospitalized patientsInitially, 100 mg/day in divided doses gradually increased to 200 mg/day as required. If no response after two weeks, increase to 250 to 300 mg/day.
OutpatientsInitially, 75 mg/day increased to 150 mg/day. Dosages over 200 mg/day are not recommended. Maintenance, 50 to 150 mg/day.
Adolescent and geriatric patients
A dose of 2.5 mg/kg/day should not be exceeded. ECG changes of unknown significance have been reported in pediatric patients with doses twice this amount.
The safety and effectiveness of imipramine hydrochloride as temporary adjunctive therapy for nocturnal enuresis in children less than 6 years of age has not been established.
HOW SUPPLIEDImipramine hydrochloride tablets, USP are available as follows:
10 mg - round, yellow film coated tablets, debossed MP 4
Bottles of 30NDC 53489-330-07Bottles of 100NDC 53489-330-0125 mg - round, brown film coated tablets, debossed MP 8
Bottles of 30NDC 53489-331-07Bottles of 100NDC 53489-331-0150 mg - round, green film coated tablets, debossed MP 79
Bottles of 30NDC 53489-332-07Bottles of 100NDC 53489-332-01
STORAGE AND HANDLINGStore at 20to 25(68to 77
[See USP Controlled Room Temperature]
DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
ANIMAL PHARMACOLOGY & OR TOXICOLOGYA. Acute
Oral LD50 ranges are as follows:
Rat 355 to 682 mg/kg
Dog 100 to 215 mg/kg
Depending on the dosage in both species, toxic signs proceeded progressively from depression, irregular respiration and ataxia to convulsions and death.
The overall evaluation may be summed up in the following manner:
Oral: Independent studies in three species (rat, mouse and rabbit) revealed that when imipramine hydrochloride is administered orally in doses up to approximately 2 1/2 times the maximum human dose in the first 2 species and up to 25 times the maximum human dose in the third species, the drug is essentially free from teratogenic potential. In the three species studied, only one instance of fetal abnormality occurred (in the rabbit) and in that study there was likewise an abnormality in the control group. However, evidence does exist from the rat studies that some systemic and embryotoxic potential is demonstrable. This is manifested by reduced litter size, a slight increase in the stillborn rate and a reduction in the mean birth weight.
MUTUAL PHARMACEUTICAL CO., INC.
Philadelphia, PA 19124 USA
Rev 01, April 2009
SPL MEDGUIDEAntidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
Read the Medication Guide that comes with you or your family member's antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family member's, healthcare provider about:
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 started or when the dose is changed.
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTIONDRUG: Imipramine Hydrochloride
GENERIC: Imipramine Hydrochloride
DOSAGE: TABLET, FILM COATED
SCORE: No score
SIZE: 7 mm
Revised: 04/2011 REMEDYREPACK INC.
Reproduced with permission of U.S. National Library of Medicine
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