imipramine

Absorption: Well absorbed from the GI tract.

Distribution: Widely distributed to tissues.

Protein Binding: 89–95%.

Metabolism/Excretion: Mostly metabolized by the liver (CYP2D6 isoenzyme) to desipramine; the CYP2D6 enzyme system exhibits genetic polymorphism; ∼7% of population may be poor metabolizers and may have significantly ↑ imipramine concentrations and an ↑ risk of adverse effects.

Half-Life: 8–16 hr.

Time/Action Profile ⬆ ⬇

(antidepressant effect)

ROUTE	ONSET	PEAK	DURATION
PO	hours	2–6 wk	weeks

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Angle-closure glaucoma;
Hypersensitivity to tartrazine or sulfites (in some preparations);
Recent MI, known history of QT interval prolongation, HF;
Concurrent use of MAO inhibitors or MAO-like drugs (linezolid or methylene blue);
Lactation: Lactation.

Use Cautiously in:

Pre-existing cardiovascular disease;
Seizures or history of seizure disorder;
Hypovolemia or dehydration (↑ risk of syndrome of inappropriate antidiuretic hormone secretion [SIADH]);
May ↑ risk of suicide attempt/ideation, especially during early treatment or dose adjustment; risk may be greater in children or adolescents
;
OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
Pedi: Children <6 yr (safety and effectiveness not established);
Geri: Appears on Beers list. ↑ risk of adverse reactions in older adults, including falls secondary to sedative and anticholinergic effects, orthostatic hypotension, and SIADH. Avoid use in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypotension, ARRHYTHMIAS, ECG changes

Derm: photosensitivity

EENT: blurred vision, dry eyes

Endo: gynecomastia, SIADH

F and E: hyponatremia

GI: constipation, dry mouth, nausea, paralytic ileus

GU: ↓libido, urinary retention

Hemat: blood dyscrasias

Metab: weight gain

Neuro: drowsiness, fatigue, agitation, confusion, hallucinations, insomnia, SUICIDAL THOUGHTS/BEHAVIORS

Interactions ⬆ ⬇

Drug-drug:

Concurrent use with MAO inhibitors may result in serious, potentially fatal reactions; MAO inhibitors should be stopped ≥14 days before imipramine therapy; imipramine should be stopped ≥14 days before MAO inhibitor therapy.
Concurrent use with MAO-inhibitor-like drugs, such as linezolid or methylene blue, may ↑ risk of serotonin syndrome; concurrent use contraindicated; do not start therapy in patients receiving linezolid or methylene blue; if linezolid or methylene blue need to be started in a patient receiving imipramine, immediately discontinue imipramine and monitor for signs/symptoms of serotonin syndrome for 2 wk or until 24 hr after last dose of linezolid or methylene blue, whichever comes first (may resume imipramine therapy 24 hr after last dose of linezolid or methylene blue).
Concurrent use with SSRIs may result in ↑ toxicity and should be avoided; fluoxetine should be stopped 5 wk before starting imipramine.
Hypertensive crisis may occur with clonidine.
CYP2D6 inhibitors, including cimetidine, quinidine, amiodarone, and ritonavir, may ↑ levels and risk of toxicity.
Concurrent use with levodopa may result in delayed/↓ absorption of levodopa or hypertension.
Rifampin and phenobarbital may ↓ levels and effectiveness.
↑risk of CNS depression with other CNS depressants, including alcohol, antihistamines, clonidine, opioids, and sedative/hypnotics.
Adrenergic and anticholinergic side effects may be ↑ with other agents having these properties.
Phenothiazines or hormonal contraceptives may levels and risk of toxicity.
Cigarette smoking(nicotine) may ↓ levels and effectiveness.
Drugs that affect serotonergic neurotransmitter systems, including SSRIs, SNRIs, fentanyl, buspirone, tramadol, and triptans, may ↑ risk of serotonin syndrome.

Drug-Natural Products:

St. John's wort may ↑ risk of serotonin syndrome.
Kava-kava, valerian, or chamomile may ↑ risk of CNS depression.
↑anticholinergic effects with jimson weed and scopolia.

Route/Dosage ⬆ ⬇

Major Depressive Disorder

PO (Adults ): 25–50 mg 3–4 times daily (not to exceed 300 mg/day); total daily dose may be given at bedtime.
PO Geriatric Patients ): 25 mg at bedtime initially, up to 100 mg/day in divided doses.
PO (Children >12 yr): 25–50 mg/day in divided doses (not to exceed 100 mg/day).
PO (Children 6–12 yr): 10–30 mg/day in 2 divided doses.

Enuresis

PO (Children ≥6 yr): 25 mg once daily 1 hr before bedtime; ↑ if necessary by 25 mg at weekly intervals to 50 mg in children <12 yr, up to 75 mg in children >12 yr.

Availability ⬆ ⬇

(Generic available)

Tablets: 10 mg; 25 mg; 50 mg; 75 mg
Capsules: 75 mg; 100 mg; 125 mg; 150 mg

Assessment ⬆ ⬇

Monitor BP and HR before and during initial therapy.
Monitor weight and BMI initially and periodically throughout therapy.
Assess for sexual dysfunction (↓ libido; erectile dysfunction).
Assess for suicidal tendencies, especially during early therapy. Restrict amount of drug available to patient. Risk may be ↑ in children, adolescents, and adults ≤24 yr. After starting therapy, children, adolescents, and young adults should be seen by health care provider face-to-face at least weekly for 4 wk, every 3 wk for next 4 wk, and on advice of health care provider thereafter.
Monitor baseline and periodic ECG in older adults or patients with heart disease and before ↑ dose with children treated for enuresis. May cause prolonged PR and QT intervals and may flatten T waves.
Depression: Assess mental status (orientation, mood, behavior) frequently. Confusion, agitation, and hallucinations may occur during initiation of therapy and may require dose ↓.
Enuresis: Assess frequency of bedwetting during therapy. Ask patient or caretaker to maintain diary.
Pain: Assess location, duration, and severity of pain periodically during therapy. Use pain scale to monitor effectiveness of therapy.

Lab Test Considerations:

Assess WBC and differential blood counts and renal and hepatic functions before and periodically during prolonged or high-dose therapy.
- Serum levels may be monitored in patients who fail to respond to usual therapeutic dose. Therapeutic plasma concentration range for depression is 150–300 ng/mL.
- May cause alterations in blood glucose levels and hyponatremia.

Toxicity and Overdose:

Symptoms of acute overdose include disturbed concentration, confusion, restlessness, agitation, seizures, drowsiness, mydriasis, arrhythmias, fever, hallucinations, vomiting, and dyspnea.
- Treatment of overdose includes gastric lavage, activated charcoal, and a stimulant cathartic. Maintain respiratory and cardiac function (monitor ECG for >5 days) and temperature. Treatment may also include antiarrhythmics and anticonvulsants.

Implementation ⬆ ⬇

Dose ↑ should be made at bedtime because of sedation. Dose titration is a slow process; may take weeks to months to see therapeutic effect. May be given as a single dose at bedtime to minimize sedation during the day.
- When discontinuing therapy, taper to avoid withdrawal effects. Gradually taper dose over 2–4 wk to prevent withdrawal effects.
PO: Administer with or immediately following a meal to minimize gastric irritation.
- For enuresis, administer dose 1 hr before bedtime; for early night bed-wetters, drug has been shown to be more effective if given earlier and in divided amounts (25 mg in midafternoon and repeated at bedtime).

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy. Instruct patient to take as directed. Take missed doses as soon as possible unless almost time for next dose; if regimen is a single dose at bedtime, do not take in the morning because of side effects. Advise patient that drug effects may not be noticed for ≥2 wk. Abrupt discontinuation may cause nausea, vomiting, diarrhea, headache, trouble sleeping with vivid dreams, and irritability.
Advise patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care provider before taking other medications.
May cause drowsiness and blurred vision. Caution patient to avoid driving and other activities requiring alertness until response to drug is known.
Instruct patient to notify health care provider if visual changes occur. Inform patient that periodic glaucoma testing may be needed during long-term therapy.
Caution patient to change positions slowly to minimize orthostatic hypotension.
Advise patient, family, and caregivers to look for suicidality, especially during early therapy or dose changes. Notify health care provider immediately if thoughts about suicide or dying, attempts to commit suicide, new or worse depression or anxiety, agitation or restlessness, panic attacks, insomnia, new or worse irritability, aggressiveness, acting on dangerous impulses, mania, or other changes in mood or behavior occur.
Advise patient, family, and caregivers to notify health care provider immediately if symptoms of serotonin syndrome occur.
Advise patient to avoid alcohol or other CNS depressant drugs during therapy and for ≥3–7 days after therapy has been discontinued.
Instruct patient to notify health care provider if urinary retention, dry mouth, or constipation persists. Sugarless candy or gum may diminish dry mouth and an increase in fluid intake or bulk may prevent constipation. If symptoms persist, dose ↓ or discontinuation may be necessary. Consult health care provider if dry mouth persists for >2 wk.
Caution patient to use sunscreen and protective clothing to prevent photosensitivity reactions.
Alert patient that urine may turn blue-green in color.
Inform patient of need to monitor dietary intake, as possible ↑ in appetite may lead to undesired weight gain. Inform patient that ↑ amounts of riboflavin in the diet may be required; consult health care provider.
Advise patient to notify health care provider of medication regimen before treatment or surgery.
Therapy for depression is usually prolonged. Emphasize the importance of follow-up exams to evaluate progress and improve coping skills.
Rep: Advise women of reproductive potential to notify health care provider if pregnancy is planned or suspected and to avoid breastfeeding.
Pedi: Inform caregivers that the side effects most likely to occur include nervousness, insomnia, unusual tiredness, and mild nausea and vomiting. Notify health care provider if these symptoms become pronounced.
- Advise patients to keep medication out of reach of children to prevent inadvertent overdose.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇