Imipramine

Dosage Form: tablet, film coated
Imipramine

HYDROCHLORIDE

TABLETS USP

Rx only

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 Imipramine 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. Imipramine hydrochloride is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use).

Imipramine Description

Imipramine 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:

C19H24N • HCl                                          M.W. 316.87

Imipramine hydrochloride tablets are available in 10 mg, 25 mg and 50 mg for oral administration.

Imipramine hydrochloride USP is a white to off-white, odorless, or practically odorless crystalline powder. It is freely soluble in water and in alcohol; soluble in acetone; and insoluble in ether and in benzene.

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.

Imipramine - Clinical Pharmacology

The 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 and Usage for Imipramine

Depression: 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.

Childhood Enuresis: 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.

Contraindications

The 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.

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 18-24) 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 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 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 Imipramine hydrochloride is not approved for use in treating bipolar depression.

Children: 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:

• patients with cardiovascular disease because of the possibility of conduction defects, arrhythmias, congestive heart failure, myocardial infarction, strokes and tachycardia. These patients require cardiac surveillance at all dosage levels of the drug;


• patients with increased intraocular pressure, history of urinary retention, or history of narrow-angle glaucoma because of the drug's anticholinergic properties;


• hyperthyroid patients or those on thyroid medication because of the possibility of cardiovascular toxicity;


• patients with a history of seizure disorder because this drug has been shown to lower the seizure threshold;


• patients receiving guanethidine, clonidine, or similar agents, since Imipramine may block the pharmacologic effects of these drugs;


• patients receiving methylphenidate hydrochloride. Since methylphenidate hydrochloride may inhibit the metabolism of Imipramine hydrochloride, downward dosage adjustment of Imipramine hydrochloride may be required when given concomitantly with methylphenidate hydrochloride.

Imipramine may enhance the CNS depressant effects of alcohol. Therefore, it should be borne in mind that the dangers inherent in a suicide attempt or accidental overdosage with the drug may be increased for the patient who uses excessive amounts of alcohol. (See PRECAUTIONS.)

Since Imipramine may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks, such as operating an automobile or machinery, the patient should be cautioned accordingly.

Precautions

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 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.

General: 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. See WARNINGS.) 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.

Concurrent administration of Imipramine with electroshock therapy may increase the hazards; such treatment should be limited to those patients for whom it is essential, since there is limited clinical experience.

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 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%–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 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 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. (See WARNINGS.)

Pregnancy

Animal reproduction studies have yielded inconclusive results. (See also ANIMAL 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 Mothers

Limited 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 Use

Safety and effectiveness in the pediatric population other than pediatric patients with nocturnal enuresis have not been established (see BOX WARNING and WARNINGS—Clinical 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.

The safety of the drug for long-term, chronic use as adjunctive therapy for nocturnal enuresis in pediatric patients 6 years of age or older has not been established; consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response.

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 Use

In 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 also DOSAGE AND ADMINISTRATION in Adolescent and geriatric patients)

(See also PRECAUTIONS General)

Adverse Reactions

Note: 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.

Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions; anxiety, restlessness, agitation; insomnia and nightmares; hypomania; exacerbation of psychosis.

Neurological: Numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy; extrapyramidal symptoms; seizures, alterations in EEG patterns; tinnitus.

Anticholinergic: Dry mouth, and, rarely, associated sublingual adenitis; blurred vision, disturbances of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.

Allergic: Skin rash, petechiae, urticaria, itching, photosensitization; edema (general or of face and tongue); drug fever; cross-sensitivity with desipramine.

Hematologic: Bone marrow depression including agranulocytosis; eosinophilia; purpura; thrombocytopenia.

Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue.

Endocrine: Gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; inappropriate antidiuretic hormone (ADH) secretion syndrome.

Other: Jaundice (simulating obstructive); altered liver function; weight gain or loss; perspiration; flushing; urinary frequency; drowsiness, dizziness, weakness and fatigue; headache; parotid swelling; alopecia; proneness to falling.

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.

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.

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.

Manifestations

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.

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 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.

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.

Imipramine Dosage and Administration

Depression

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 patients—Initially, 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.

Outpatients—Initially, 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—Initially, 30 to 40 mg/day; it is generally not necessary to exceed 100 mg/day.

Childhood Enuresis

Initially, an oral dose of 25 mg/day should be tried in children aged 6 and older. Medication should be given one hour before bedtime. If a satisfactory response does not occur within one week, increase the dose to 50 mg nightly in children under 12 years; children over 12 may receive up to 75 mg nightly. A daily dose greater than 75 mg does not enhance efficacy and tends to increase side effects. Evidence suggests that in early night bedwetters, the drug is more effective given earlier and in divided amounts, i.e., 25 mg in midafternoon, repeated at bedtime. Consideration should be given to instituting a drug-free period following an adequate therapeutic trial with a favorable response. Dosage should be tapered off gradually rather than abruptly discontinued; this may reduce the tendency to relapse. Children who relapse when the drug is discontinued do not always respond to a subsequent course of treatment.

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 is Imipramine Supplied

Imipramine hydrochloride tablets, USP are available as follows:

10 mg - round, yellow film coated tablets, debossed MP 4

Bottles of 100

NDC 54738-912-01

25 mg - round, brown film coated tablets, debossed MP 8

Bottles of 100

NDC 54738-913-01

50 mg - round, green film coated tablets, debossed MP 79

Bottles of 100

NDC 54738-914-01

Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature]

DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

ANIMAL PHARMACOLOGY & TOXICOLOGY

A. 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.

B. Reproduction/Teratogenic: 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.

Manufactured by:

MUTUAL PHARMACEUTICAL CO., INC.

Philadelphia, PA 19124 USA

Distributed by:

Richmond Pharmaceuticals, Inc.

Richmond, VA 23233

Rev 01, August 2010

Medication Guide

Antidepressant 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:

• all risks and benefits of treatment with antidepressant medicines


• all treatment choices for depression or other serious mental illness

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

1.

Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.

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.


• 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


• attempts to commit suicide


• new or worse depression


• new or worse anxiety


• feeling very agitated or restless


• panic attacks


• trouble sleeping (insomnia)


• new or worse irritability


• acting aggressive, being angry, or violent


• acting on dangerous impulses


• an extreme increase in activity and talking (mania)


• other unusual changes in behavior or mood

What else do I need to know about antidepressant medicines?

• Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.


• Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.


• Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.


• Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a 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.

This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.

Rev 01, August 2010

PRINCIPAL DISPLAY PANEL - 10 mg Bottle Label

NDC 54738-912-01

Imipramine HCl

TABLETS USP

10 mg

PHARMACIST:

PLEASE DISPENSE WITH MEDICATION GUIDE

100 TABLETS

Rx only

PRINCIPAL DISPLAY PANEL - 25 mg Bottle Label

NDC 54738-913-01

Imipramine HCl

TABLETS USP

25 mg

PHARMACIST:

PLEASE DISPENSE WITH MEDICATION GUIDE

100 TABLETS

Rx only

PRINCIPAL DISPLAY PANEL - 50 mg Bottle Label

NDC 54738-914-01

Imipramine HCl

TABLETS USP

50 mg

PHARMACIST:

PLEASE DISPENSE WITH MEDICATION GUIDE

100 TABLETS

Rx only

Imipramine HYDROCHLORIDE  Imipramine hydrochloride  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54738-912 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Imipramine Hydrochloride (Imipramine) Imipramine Hydrochloride 10 mg

Inactive Ingredients Ingredient Name Strength silicon dioxide   D&C red No. 30   aluminum oxide   D&C yellow No. 10   anhydrous dibasic calcium phosphate   FD&C blue No. 2   hypromelloses   magnesium stearate   cellulose, microcrystalline   polyethylene glycols   polysorbate 80   sodium starch glycolate type a potato   titanium dioxide

Product Characteristics Color YELLOW Score no score Shape ROUND Size 6mm Flavor Imprint Code MP;4 Contains

Packaging # NDC Package Description Multilevel Packaging 1 54738-912-01 100 TABLET In 1 BOTTLE, PLASTIC None

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
ANDA	ANDA081048	06/05/1990

Imipramine HYDROCHLORIDE  Imipramine hydrochloride  tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG NDC Product Code (Source) 54738-913 Route of Administration ORAL DEA Schedule

Tramacet 37.5 mg / 325 mg film-coated tablets

1. Name Of The Medicinal Product

TRAMACET 37.5 mg/325 mg, film coated-tablets

2. Qualitative And Quantitative Composition

One film-coated tablet contains 37.5 mg tramadol hydrochloride and 325 mg paracetamol

For a full list of excipients, see section 6.1.

3. Pharmaceutical Form

Film-coated tablet

Pale yellow film-coated tablet, marked with the manufacturer's logo

4. Clinical Particulars

4.1 Therapeutic Indications

TRAMACET tablets are indicated for the symptomatic treatment of moderate to severe pain.

The use of TRAMACET should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol (see also Section 5.1).

4.2 Posology And Method Of Administration

Posology

ADULTS AND ADOLESCENTS (12 years and older)

The use of TRAMACET should be restricted to patients whose moderate to severe pain is considered to require a combination of tramadol and paracetamol.

The dose should be individually adjusted according to intensity of pain and response of the patient.

An initial dose of two tablets of TRAMACET is recommended. Additional doses can be taken as needed, not exceeding 8 tablets (equivalent to 300 mg tramadol and 2600 mg paracetamol) per day.

The dosing interval should not be less than six hours.

TRAMACET should under no circumstances be administered for longer than is strictly necessary (see also section 4.4 - Special warnings and precautions for use). If repeated use or long term treatment with TRAMACET is required as a result of the nature and severity of the illness, then careful, regular monitoring should take place (with breaks in the treatment, where possible), to assess whether continuation of the treatment is necessary.

Children

The effective and safe use of TRAMACET has not been established in children below the age of 12 years. Treatment is therefore not recommended in this population.

Elderly patients

The usual dosages may be used although it should be noted that in volunteers aged over 75 years the elimination half life of tramadol was increased by 17% following oral administration. In patients over 75 years old, it is recommended that the minimum interval between doses should be not less than 6 hours, due to the presence of tramadol.

Renal insufficiency

Because of the presence of tramadol, the use of TRAMACET is not recommended in patients with severe renal insufficiency (creatinine clearance < 10 ml/min). In cases of moderate renal insufficiency (creatinine clearance between 10 and 30 ml/min), the dosing should be increased to 12-hourly intervals. As tramadol is removed only very slowly by haemodialysis or by haemofiltration, post dialysis administration to maintain analgesia is not usually required.

Hepatic insufficiency

In patients with severe hepatic impairment TRAMACET should not be used (see Section 4.3). In moderate cases prolongation of the dosage interval should be carefully considered (see Section 4.4).

Method of administration

Oral use

Tablets must be swallowed whole, with a sufficient quantity of liquid. They must not be broken or chewed.

4.3 Contraindications

- Hypersensitivity to tramadol, paracetamol or to any of the excipients (see 6.1. List of excipients) of the medicinal product,

- acute intoxication with alcohol, hypnotic drugs, centrally-acting analgesics, opioids or psychotropic drugs,

- TRAMACET should not be administered to patients who are receiving monoamine oxidase inhibitors or within two weeks of their withdrawal (see 4.5. Interactions with other medicinal products and other forms of interaction),

- severe hepatic impairment,

- epilepsy not controlled by treatment (see. 4.4. Special Warnings).

4.4 Special Warnings And Precautions For Use

Warnings:

- In adults and adolescents 12 years and older. The maximum dose of 8 tablets of TRAMACET should not be exceeded. In order to avoid inadvertent overdose, patients should be advised not to exceed the recommended dose and not to use any other paracetamol (including over the counter) or tramadol hydrochloride containing products concurrently without the advice of a physician.

- In severe renal insufficiency (creatinine clearance <10 ml/mm), TRAMACET is not recommended.

- In patients with severe hepatic impairment TRAMACET should not be used ( See Section 4.3). The hazards of paracetamol overdose are greater in patients with non-cirrhotic alcoholic liver disease. In moderate cases prolongation of dosage interval should be carefully considered.

- In severe respiratory insufficiency, TRAMACET is not recommended.

- Tramadol is not suitable as a substitute in opioid-dependent patients. Although it is an opioid agonist, tramadol cannot suppress morphine withdrawal symptoms.

- Convulsions have been reported in tramadol-treated patients susceptible to seizures or taking other medications that lower the seizure threshold, especially selective serotonin re-uptake inhibitors, tricyclic antidepressants, antipsychotics, centrally acting analgesics or local anaesthesia. Epileptic patients controlled by a treatment or patients susceptible to seizures should be treated with TRAMACET only if there are compelling circumstances. Convulsions have been reported in patients receiving tramadol at the recommended dose levels. The risk may be increased when doses of tramadol exceed the recommended upper dose limit

- Concomitant use of opioid agonists-antagonists (nalbuphine, buprenorphine, pentazocine) is not recommended (see 4.5 Interactions with other medicinal products and other forms of interaction).

Precautions for use

TRAMACET should be used with caution in opioid dependent patients, or in patients with cranial trauma, in patients prone to convulsive disorder, biliary tract disorders, in a state of shock, in an altered state of consciousness for unknown reasons, with problems affecting the respiratory center or the respiratory function, or with an increased intracranial pressure.

Paracetamol in overdosage may cause hepatic toxicity in some patients.

At therapeutic doses, tramadol has the potential to cause withdrawal symptoms. Rarely, cases of dependence and abuse have been reported (see section 4.8).

Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur (see section 4.8).

In one study, use of tramadol during general anaesthesia with enflurane and nitrous oxide was reported to enhance intra-operative recall. Until further information is available, use of tramadol during light planes of anaesthesia should be avoided.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

Concomitant use is contraindicated with:

• Non-selective MAO Inhibitors

Risk of serotoninergic syndrome: diarrhoea, tachycardia, sweating, trembling, confusion, even coma.

• Selective-A MAO Inhibitors

Extrapolation from non-selective MAO inhibitors

Risk of serotoninergic syndrome: diarrhoea, tachycardia, sweating, trembling, confusion, even coma.

• Selective-B MAO Inhibitors

Central excitation symptoms evocative of a serotoninergic syndrome: diarrhoea, tachycardia, sweating, trembling, confusion, even coma.

In case of recent treatment with MAO inhibitors, a delay of two weeks should occur before treatment with tramadol

Concomitant use is not recommended with:

• Alcohol

Alcohol increases the sedative effect of opioid analgesics.

The effect on alertness can make driving of vehicles and the use of machines dangerous.

Avoid intake of alcoholic drinks and of medicinal products containing alcohol.

• Carbamazepine and other enzyme inducers

Risk of reduced efficacy and shorter duration due to decreased plasma concentrations of tramadol.

• Opioid agonists-antagonists (buprenorphine, nalbuphine, pentazocine)

Decrease of the analgesic effect by competitive blocking effect at the receptors, with the risk of occurrence of withdrawal syndrome.

Concomitant use which needs to be taken into consideration:

• In isolated cases there have been reports of Serotonin Syndrome in a temporal connection with the therapeutic use of tramadol in combination with other serotoninergic medicines such as selective serotonin re-uptake inhibitors (SSRIs) and triptans. Signs of Serotonin Syndrome may be for example, confusion, agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and diarrhoea.

• Other opioid derivatives (including antitussive drugs and substitutive treatments), benzodiazepines and barbiturates

Increased risk of respiratory depression which can be fatal in cases of overdose.

• Other central nervous system depressants, such as other opioid derivatives (including antitussive drugs and substitutive treatments), barbiturates, benzodiazepines, other anxiolytics, hypnotics, sedative antidepressants, sedative antihistamines, neuroleptics, centrally-acting antihypertensive drugs, thalidomide and baclofen.

These drugs can cause increased central depression. The effect on alertness can make driving of vehicles and the use of machines dangerous.

• As medically appropriate, periodic evaluation of prothrombin time should be performed when TRAMACET and warfarin like compounds are administered concurrently due to reports of increased INR.

• Other drugs known to inhibit CYP3A4, such as ketoconazole and erythromycin, might inhibit the metabolism of tramadol (N-demethylation) probably also the metabolism of the active O-demethylated metabolite. The clinical importance of such an interaction has not been studied.

• Medicinal products reducing the seizure threshold, such as bupropion, serotonin reuptake inhibitor antidepressants, tricyclic antidepressants and neuroleptics. Concomitant use of tramadol with these drugs can increase the risk of convulsions. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.

• In a limited number of studies the pre- or postoperative application of the antiemetic 5-HT3 antagonist ondansetron increased the requirement of tramadol in patients with postoperative pain.

4.6 Pregnancy And Lactation

Pregnancy

Since TRAMACET is a fixed combination of active ingredients including tramadol, it should not be used during pregnancy.

• Data regarding paracetamol:

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosages.

• Data regarding tramadol:

Tramadol should not be used during pregnancy as there is inadequate evidence available to assess the safety of tramadol in pregnant women. Tramadol administered before or during birth does not affect uterine contractility. In neonates it may induce changes in the respiratory rate which are usually not clinically relevant. Long-term treatment during pregnancy may lead to withdrawal symptoms in the newborn after birth, as a consequence of habituation.

Lactation:

Since TRAMACET is a fixed combination of active ingredients including tramadol, it should not be ingested during breast feeding.

• Data regarding paracetamol:

Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding by women using single ingredient medicinal products containing only paracetamol.

• Data regarding tramadol:

Tramadol and its metabolites are found in small amounts in human breast milk. An infant could ingest about 0.1% of the dose given to the mother. Tramadol should not be ingested during breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Tramadol may cause drowsiness or dizziness, which may be enhanced by alcohol or other CNS depressants. If affected, the patient should not drive or operate machinery.

4.8 Undesirable Effects

The most commonly reported undesirable effects during the clinical trials performed with the paracetamol/tramadol combination were nausea, dizziness and somnolence, observed in more than 10 % of the patients.

Cardiovascular system disorders:

• Uncommon (

Central and peripheral nervous system disorders:

• Very common (

• Common (

• Uncommon (

• Rare (

Psychiatric disorders:

• Common (

• Uncommon (

• Rare (

Post marketing surveillance

very rare (< 1/10000): abuse.

Vision disorders:

• Rare (

Respiratory system disorders:

• Uncommon (

Gastro-intestinal disorders:

• Very common (

• Common (

• Uncommon (

Liver and biliary system disorders:

• Uncommon (

Skin and appendages disorders:

• Common (

• Uncommon (

Urinary system disorders:

• Uncommon (

Body as a whole:

• Uncommon (

Although not observed during clinical trials, the occurrence of the following undesirable effects known to be related to the administration of tramadol or paracetamol cannot be excluded:

Tramadol

• Postural hypotension, bradycardia, collapse (tramadol).

• Post-marketing surveillance of tramadol has revealed rare alterations of warfarin effect, including elevation of prothrombin times.

• Rare cases (

• Rare cases (

• Psychic side-effects may occur following administration of tramadol which vary individually in intensity and nature (depending on personality and duration of medication). These include changes in mood, (usually elation occasionally dysphoria), changes in activity (usually suppression occasionally increase) and changes in cognitive and sensorial capacity (e.g. decision behaviour perception disorders).

• Worsening of asthma has been reported though a causal relationship has not been established.

• Symptoms of withdrawal reactions, similar to those occurring during opiate withdrawal may occur as follows: agitation, anxiety, nervousness, insomnia, hyperkinesia, tremor and gastrointestinal symptoms. Other symptoms that have very rarely been seen if tramadol hydrochloride is discontinued abruptly include: panic attacks, severe anxiety, hallucinations, paraesthesia, tinnitus and unusual CNS symptoms.

Paracetamol

• Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.

• There have been several reports that suggest that paracetamol may produce hypoprothrombinemia when administered with warfarin-like compounds. In other studies, prothrombin time did not change.

4.9 Overdose

TRAMACET is a fixed combination of active ingredients. In case of overdose, the symptoms may include the signs and symptoms of toxicity of tramadol or paracetamol or of both these active ingredients.

Symptoms of overdose from tramadol:

In principle, on intoxication with tramadol, symptoms similar to those of other centrally acting analgesics (opioids) are to be expected. These include in particular, miosis, vomiting, cardiovascular collapse, consciousness disorders up to coma, convulsions and respiratory depression up to respiratory arrest.

Symptoms of overdose from paracetamol:

An overdose is of particular concern in young children. Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalophathy, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Liver damage is possible in adults who have taken 7.5-10 g or more of paracetamol. It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are ingested), become irreversibly bound to liver tissue.

Emergency treatment:

- Transfer immediately to a specialised unit.

- Maintain respiratory and circulatory functions

- Prior to starting treatment, a blood sample should be taken as soon as possible after overdose in order to measure the plasma concentration of paracetamol and tramadol and in order to perform hepatic tests.

- Perform hepatic tests at the start (of overdose) and repeat every 24 hours. An increase in hepatic enzymes (ASAT, ALAT) is usually observed, which normalizes after one or two weeks.

- Empty the stomach by causing the patient to vomit (when the patient is conscious) by irritation or gastric lavage.

- Supportive measures such as maintaining the patency of the airway and maintaining cardiovascular function should be instituted; naloxone should be used to reverse respiratory depression; fits can be controlled with diazepam.

- Tramadol is minimally eliminated from the serum by haemodialysis or haemofiltration. Therefore treatment of acute intoxication with TRAMACET with haemodialysis or haemofiltration alone is not suitable for detoxification.

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any adult or adolescent who had ingested around 7.5 g or more of paracetamol in the preceding 4 hours or any child who has ingested

Irrespective of the reported quantity of paracetamol ingested, the antidote for paracetamol, NAC, should be administered orally or intravenously, as quickly as possible, if possible, within 8 hours following the overdose.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Tramadol, combinations

ATC code: N02A X 52

ANALGESICS

Tramadol is an opioid analgesic that acts on the central nervous system. Tramadol is a pure non selective agonists of the μ, δ, and κ opioid receptors with a higher affinity for the µ receptors. Other mechanisms which contribute to its analgesic effect are inhibition of neuronal reuptake of noradrenaline and enhancement of serotonin release. Tramadol has an antitussive effect. Unlike morphine, a broad range of analgesic doses of tramadol has no respiratory depressant effect. Similarly, the gastro-intestinal motility is not modified. The cardiovascular effects are generally slight. The potency of tramadol is considered to be one-tenth to one-sixth that of morphine.

The precise mechanism of the analgesic properties of paracetamol is unknown and may involve central and peripheral effects.

TRAMACET is positioned as a step II analgesic in the WHO pain ladder and should be utilised accordingly by the physician.

5.2 Pharmacokinetic Properties

Tramadol is administered in racemic form and the [-] and [+] forms of tramadol and its metabolite M1, are detected in the blood. Although tramadol is rapidly absorbed after administration, its absorption is slower (and its half-life longer) than that of paracetamol.

After a single oral administration of a tramadol/paracetamol (37.5 mg/325 mg) tablet, peak plasma concentrations of 64.3/55.5 ng/ml [(+)-tramadol/(-)-tramadol] and 4.2 µg/ml (paracetamol) are reached after 1.8 h [(+)-tramadol/(-)-tramadol] and 0.9 h (paracetamol) respectively. The mean elimination half-lives t_1/2 are 5.1/4.7 h [(+)-tramadol/(-)-tramadol] and 2,5 h (paracetamol).

During pharmacokinetic studies in healthy volunteers after single and repeated oral administration of TRAMACET, no clinical significant change was observed in the kinetic parameters of each active ingredient compared to the parameters of the active ingredients used alone.

Absorption:

Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a single 100 mg dose is approximately 75 %. After repeated administration, the bioavailability is increased and reaches approximately 90 %.

After administration of TRAMACET , the oral absorption of paracetamol is rapid and nearly complete and takes place mainly in the small intestine. Peak plasma concentrations of paracetamol are reached in one hour and are not modified by concomitant administration of tramadol.

The oral administration of TRAMACET with food has no significant effect on the peak plasma concentration or extent of absorption of either tramadol or paracetamol so that TRAMACET can be taken independently of meal times.

Distribution:

Tramadol has a high tissue affinity (V_d,β=203 ± 40 l). It has a plasma protein binding of about 20%.

Paracetamol appears to be widely distributed throughout most body tissues except fat. Its apparent volume of distribution is about 0.9 l/kg. A relative small portion (~20%) of paracetamol is bound to plasma proteins.

Metabolism:

Tramadol is extensively metabolized after oral administration. About 30 % of the dose is excreted in urine as unchanged drug, whereas 60% of the dose is excreted as metabolites.

Tramadol is metabolised through O-demethylation (catalysed by the enzyme CYP2D6) to the metabolite M1, and through N-demethylation (catalysed by CYP3A) to the metabolite M2. M1 is further metabolised through N-demethylation and by conjugation with glucuronic acid. The plasma elimination half-life of M1 is 7 hours. The metabolite M1 has analgesic properties and is more potent than the parent drug. The plasma concentrations of M1 are several-fold lower than those of tramadol and the contribution to the clinical effect is unlikely to change on multiple dosing.

Paracetamol is principally metabolized in the liver through two major hepatic routes: glucuronidation and sulphation. The latter route can be rapidly saturated at doses above the therapeutic doses. A small fraction (less than 4%) is metabolized by cytochrome P 450 to an active intermediate (the N-acetyl benzoquinoneimine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and excreted in urine after conjugation to cysteine and mercapturic acid. However, during massive overdose, the quantity of this metabolite is increased.

Elimination:

Tramadol and its metabolites are eliminated mainly by the kidneys. The half-life of paracetamol is approximately 2 to 3 hours in adults. It is shorter in children and slightly longer in the newborn and in cirrhotic patients. Paracetamol is mainly eliminated by dose-dependent formation of glucuro- and sulpho-conjugate derivatives. Less than 9 % of paracetamol is excreted unchanged in urine. In renal insufficiency, the half-life of both compounds is prolonged.

5.3 Preclinical Safety Data

No preclinical study has been performed with the fixed combination (tramadol and paracetamol) to evaluate its carcinogenic or mutagenic effects or its effects on fertility.

No teratogenic effect that can be attributed to the medicine has been observed in the progeny of rats treated orally with the combination tramadol/paracetamol.

The combination tramadol/paracetamol has proven to be embryotoxic and foetotoxic in the rat at materno-toxic dose (50/434 mg/kg tramadol/paracetamol), i.e., 8.3 times the maximum therapeutic dose in man. No teratogenic effect has been observed at this dose. The toxicity to the embryo and the foetus results in a decreased foetal weight and an increase in supernumerary ribs. Lower doses, causing less severe materno-toxic effect (10/87 and 25/217 mg/kg tramadol/paracetamol) did not result in toxic effects in the embryo or the foetus.

Results of standard mutagenicity tests did not reveal a potential genotoxic risk for tramadol in man.

Results of carcinogenicity tests do not suggest a potential risk of tramadol for man.

Animal studies with tramadol revealed, at very high doses, effects on organ development, ossification and neonatal mortality, associated with maternotoxicity. Fertility reproductive performance and development of offspring were unaffected. Tramadol crosses the placenta. No effect on fertility has been observed after oral administration of tramadol up to doses of 50 mg/kg in the male rat and 75 mg/kg in the female rat.

Extensive investigations showed no evidence of a relevant genotoxic risk of paracetamol at therapeutic (i.e. non-toxic) doses.

Long-term studies in rats and mice yielded no evidence of relevant tumorigenic effects at non-hepatotoxic dosages of paracetamol.

Animal studies and extensive human experience to date yield no evidence of reproductive toxicity.

6. Pharmaceutical Particulars

6.1 List Of Excipients

Tablet core:

powdered cellulose

pregelatinised starch

sodium starch glycolate (Type A)

maize starch

magnesium stearate

Film-coating:

OPADRY yellow YS-1-6382 G (hypromellose, titanium dioxide (E171),

macrogol 400, yellow iron oxide (E172), polysorbate 80),

carnauba wax

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years in paper/PET/aluminium-PVC blister packs

6.4 Special Precautions For Storage

This medicinal product does not require any special storage conditions.

6.5 Nature And Contents Of Container

TRAMACET tablets are packed in paper/PET/aluminium-PVC blisters.

Box of 2 tablets, of 10, 20, 30, 40, 50, 60, 70, 80, 90 and 100 tablets

Not all packaging sizes may be marketed.

6.6 Special Precautions For Disposal And Other Handling

No special requirements.

7. Marketing Authorisation Holder

Grünenthal Ltd

Regus Lakeside House

1 Furzeground Way

Stockley Park East

Uxbridge

Middlesex UB11 1BD

United Kingdom

8. Marketing Authorisation Number(S)

PL 21727/0039

9. Date Of First Authorisation/Renewal Of The Authorisation

Date of first authorisation: 25 September 2003

Date of last renewal: 22/06/07

10. Date Of Revision Of The Text

April 2010

Insulin

Pronunciation: IN-su-lin
Generic Name: Insulin
Brand Name: Examples include Terumo and BD

Insulin is used for:

Drawing and injecting insulin (and other solutions as determined by your doctor) into a preselected site of the body.

Do NOT use Insulin if:

• you are allergic to any ingredient in Insulin

Contact your doctor or health care provider right away if any of these apply to you.

Before using Insulin:

Some medical conditions may interact with Insulin. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

• if you are pregnant, planning to become pregnant, or are breast-feeding


• if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement


• if you have allergies to medicines, foods, or other substances

Some MEDICINES MAY INTERACT with Insulin. However, no specific interactions with Insulin are known at this time.

Ask your health care provider if Insulin may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Insulin:

Use Insulin as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• To prepare your dose of insulin, pull the syringe plunger back to draw air into the syringe. The amount of air in the syringe should be equal to the number of units of insulin that you will be injecting. Insert the needle through the rubber cap of the insulin bottle and inject the air into the bottle. Invert the bottle and syringe. Pull back on the plunger to draw insulin into the syringe and measure the correct number of units of insulin. Check for any bubbles in the syringe. Eliminate any air bubbles found by tapping gently on the syringe.


• Insulin can be injected into the abdomen, buttocks, thighs, and arms. First clean the skin at the injection site with an alcohol pad or rubbing alcohol. Pinch a fold of skin at the injection site with your fingers. The pinch should include at least 3 inches of skin. Insert the needle at a 45 to 90 degree angle. Then, inject the insulin, withdraw the needle, and press lightly on the skin.


• Keep this product, as well as syringes and needles, out of the reach of children and pets. Do not reuse needles, syringes, or other materials. Ask your health care provider how to dispose of these materials after use. Follow all local rules for disposal.


• If you miss a dose of your medicine, follow the missed dose instructions that came with your medicine. Contact your doctor if you are unsure what to do if you miss a dose of insulin.

Ask your health care provider any questions you may have about how to use Insulin.

Important safety information:

• Do not reuse needles, syringes, or other materials.


• Use a different site for each injection; about 1 inch away from previous injection sites, but in the same general area. Use all available sites in the same general area before switching to a different area. Do not use the same injection site more often than once every month or two.


• If you have trouble seeing the small markings on the syringe, have someone help you. Also, let your doctor or pharmacist know about this problem. They can provide tools that are easier to read, special tools to help you fill the syringe, or prefilled syringes.

Possible side effects of Insulin:

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Redness, swelling, or itching at injection sites.

Seek medical attention right away if any of these SEVERE side effects occur:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue).

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

If OVERDOSE is suspected:

Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center or emergency room immediately.

Proper storage of Insulin:

Store the syringes at room temperature, between 59 and 86 degrees F (15 and 30 degrees C), in the original package. Store away from heat, moisture, and light. Keep Insulin and needles out of the reach of children and away from pets.

General information:

• If you have any questions about Insulin, please talk with your doctor, pharmacist, or other health care provider.


• Insulin is to be used only by the patient for whom it is prescribed. Do not share it with other people.


• If your symptoms do not improve or if they become worse, check with your doctor.


• Check with your pharmacist about how to dispose of unused medicine.

This information is a summary only. It does not contain all information about Insulin. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.

Issue Date: February 1, 2012

Database Edition 12.1.1.002

Copyright © 2012 Wolters Kluwer Health, Inc.

More Insulin resources

• Insulin Use in Pregnancy & Breastfeeding
• Insulin Drug Interactions
• Insulin Support Group
• 0 Reviews · Be the first to review/rate this drug

anti-inflammatory drugs, nonsteroidal Ophthalmic

Class Name: anti-inflammatory drugs, nonsteroidal (Ophthalmic route)

Commonly used brand name(s)

In the U.S.

• Acular


• Acular LS


• Acular PF


• Acuvail


• Bromday


• Nevanac


• Ocufen


• Voltaren


• Xibrom

In Canada

• Apo-Ketorolac


• Indocid


• Ratio-Ketorolac


• Vofenal


• Voltaren Ophtha

Available Dosage Forms:

• Solution


• Suspension

Uses For This Medicine

Ophthalmic anti-inflammatory medicines are used in the eye to lessen problems that can occur during or after some kinds of eye surgery. Sometimes, the pupil of the eye gets smaller during an operation. This makes it more difficult for the surgeon to reach some areas of the eye. Some of these medicines are used to help prevent this. Also, some of them are used after eye surgery, to relieve effects such as inflammation or edema (too much fluid in the eye).

These medicines may also be used for other conditions, as determined by your ophthalmologist (eye doctor).

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

Before Using This Medicine

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to medicines in this group or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

These medicines have been studied only in adults, and there is no specific information about their use in children.

Geriatric

These medicines have been tested and have not been shown to cause different side effects or problems in older people than they do in younger adults.

Pregnancy

Although studies on birth defects have not been done in pregnant women after use of these medicines in the eye, ophthalmic anti-inflammatory medicines have not been reported to cause birth defects or other problems. Studies have been done in animals receiving anti-inflammatory medicines by mouth in amounts that are much greater than the amounts used in the eye. These medicines did not cause birth defects in these studies. However, they decreased the weight or slowed the growth of the fetus and caused other, more serious, harmful effects on the fetus when they were given in amounts that were large enough to cause harmful effects in the mother. Also, when these medicines were given to animals late in pregnancy, they increased the length of pregnancy or prolonged labor.

Breast Feeding

It is not known whether any of these medicines pass into the breast milk after they are placed in the eye. Diclofenac, indomethacin, and suprofen pass into the breast milk when they are are taken by mouth. It is not known whether flurbiprofen passes into the breast milk when it is taken by mouth. However, these medicines have not been shown to cause problems in nursing babies.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking any of these medicines, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using medicines in this class with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Abciximab


• Argatroban


• Bivalirudin


• Cilostazol


• Ciprofloxacin


• Dabigatran Etexilate


• Dipyridamole


• Fondaparinux


• Heparin


• Lepirudin


• Protein C


• Rivaroxaban


• Sibutramine


• Ticlopidine


• Tirofiban


• Vilazodone

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of medicines in this class. Make sure you tell your doctor if you have any other medical problems, especially:

• Hemophilia or other bleeding problems—The possibility of bleeding may be increased.

• Viral eye infection (epithelial herpes simplex keratitis), or a history of having a viral eye infection—It is possible that a current infection could be made worse or an old infection could return.

• Use of soft contact lenses—Eye irritation, such as redness and burning of the eyes, may occur.

Proper Use of This Medicine

To use:

• First, wash your hands. Tilt the head back and, pressing your finger gently on the skin just beneath the lower eyelid, pull the lower eyelid away from the eye to make a space. Drop the medicine into this space. Let go of the eyelid and gently close the eyes. Do not blink. Keep the eyes closed and apply pressure to the inner corner of the eye with your finger for 1 or 2 minutes to allow the medicine to be absorbed by the eye.


• Immediately after using the eye drops, wash your hands to remove any medicine that may be on them.


• To keep the medicine as germ-free as possible, do not touch the applicator tip to any surface (including the eye). Also, always keep the container tightly closed.

Do not use this medicine more often or for a longer time than your doctor ordered. To do so may increase the chance of side effects.

Do not use any leftover medicine for future eye problems without first checking with your doctor. If certain kinds of infection are present, using this medicine may make the infection worse and possibly lead to eye damage.

Dosing

The dose medicines in this class will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of these medicines. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For diclofenac


• To treat photophobia (sensitivity to light) which may occur after incisional refractive surgery:
  
  • Adults—Your health care professional will probably give you the medicine before the operation, starting with 1 drop in the eye within one hour of surgery, then 1 drop fifteen minutes after surgery, then 1 drop four times a day beginning four to six hours after surgery and continuing for up to three days as needed.
  
  
  • Children—Use and dose must be determined by the doctor.
  
  


• To relieve inflammation in the eye following cataract surgery:
  
  • Adults—1 drop in the eye four times a day beginning twenty-four hours after cataract surgery and throughout the first two weeks following the operation.
  
  
  • Children—Use and dose must be determined by the doctor.
  
  

• For flurbiprofen


• For use before an eye operation:
  
  • Adults—Your health care professional will probably give you the medicine before your operation.
  
  
  • Children—Use and dose must be determined by the doctor.
  
  


• To relieve inflammation:
  
  • Adults and children—Use and dose must be determined by the doctor.
  
  

• For indomethacin


• For use before an eye operation:
  
  • Adults—Your health care professional will probably give you the medicine before your operation.
  
  
  • Children—Use and dose must be determined by the doctor.
  
  


• To relieve inflammation or edema in the eye:
  
  • Adults—1 drop in the eye four times a day.
  
  
  • Children—Use and dose must be determined by the doctor.
  
  

• For suprofen


• For use before an eye operation:
  
  • Adults—Your health care professional will probably give you the medicine before your operation.
  
  
  • Children—Use and dose must be determined by the doctor.
  
  

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Do not keep outdated medicine or medicine no longer needed.

Precautions While Using This Medicine

Wearing soft (hydrogel) contact lenses during treatment with diclofenac has caused severe irritation (redness and itching) in some people. Therefore, do not wear soft contact lenses during the time that you are being treated with diclofenac.

Side Effects of This Medicine

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

Less common or rare

• Bleeding in the eye or redness or swelling of the eye or the eyelid (not present before you started using this medicine or becoming worse while you are using this medicine)


• blurred vision or other change in vision


• fever or chills


• itching or tearing


• nausea or vomiting


• pain


• sensitivity to light


• shortness of breath


• sticky or matted eyelashes


• swelling of face


• throbbing pain


• tightness in chest


• troubled breathing


• wheezing

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

• Burning, stinging, or mild discomfort after application


• dry eyes

Less common or rare

• Bigger or smaller pupils (black part of eye)


• headache


• trouble in sleeping


• runny or stuffy nose


• unusual weakness

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

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

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