Introduction to tofranil (imipramine)
Tofranil is the brand name for imipramine, a medication that belongs to the class of tricyclic antidepressants (TCAs). Imipramine was the first tricyclic antidepressant to be discovered and remains one of the most studied medications in psychiatry. Its discovery in the 1950s was serendipitous; researchers were initially studying imipramine as a potential antipsychotic medication but discovered its remarkable antidepressant properties instead. This breakthrough fundamentally changed the landscape of psychiatric treatment and paved the way for the development of numerous other antidepressant medications. Tofranil is approved by the U.S. Food and Drug Administration (FDA) for the treatment of major depressive disorder (MDD) in adults and, in some countries, for the treatment of childhood enuresis (bedwetting) in children aged 6 years and older. Despite being an older medication, Tofranil remains in use today, particularly for patients with treatment-resistant depression, certain types of chronic pain, and anxiety disorders. Although newer antidepressants with more favorable side effect profiles have largely replaced TCAs as first-line treatments, imipramine retains an important role in specific clinical situations where its unique pharmacological properties offer distinct advantages. For patients seeking to access Tofranil, Happy Family Store provides a reliable resource for obtaining this classic antidepressant medication.
The pharmacological profile of imipramine
Imipramine, the active ingredient in Tofranil, is a tertiary amine tricyclic antidepressant. It functions primarily as a reuptake inhibitor of the neurotransmitters norepinephrine and serotonin, though it has a more balanced effect on these two systems compared to some other TCAs. Imipramine is actually a prodrug; it is metabolized in the liver to its active metabolite, desipramine (Norpramin), which is itself a potent and selective norepinephrine reuptake inhibitor. This biotransformation means that the pharmacological effects of Tofranil result from the combined action of both imipramine and desipramine. The parent drug imipramine has relatively balanced effects on the serotonin and norepinephrine transporters, while its metabolite desipramine is more selective for the norepinephrine transporter. This dual action, involving both the parent drug and its active metabolite, provides a broad-spectrum effect on the noradrenergic and serotonergic systems that is characteristic of TCA therapy. By increasing the synaptic availability of both norepinephrine and serotonin, imipramine enhances neurotransmission in pathways that are important for mood regulation, attention, motivation, and stress response. The therapeutic effect typically requires several weeks to develop, consistent with the time needed for adaptive changes in receptor sensitivity and intracellular signaling pathways.
In addition to its effects on monoamine reuptake, imipramine also interacts with several other receptor systems. It is a potent antagonist at histamine H1 receptors, which accounts for its significant sedative effects. It also blocks muscarinic acetylcholine receptors (M1), leading to the characteristic anticholinergic side effects of TCAs, including dry mouth, blurred vision, constipation, and urinary retention. Imipramine also has moderate activity as an alpha-1 adrenergic receptor antagonist, which can contribute to orthostatic hypotension. The drug undergoes extensive hepatic metabolism through several cytochrome P450 enzymes, including CYP1A2, CYP2C19, CYP2D6, and CYP3A4. This multi-pathway metabolism means that imipramine’s blood levels can be affected by drugs that induce or inhibit any of these enzymes. The half-life of imipramine is approximately 11 to 25 hours, while its active metabolite desipramine has a longer half-life of 12 to 60 hours. Steady-state plasma concentrations are typically achieved within 1 to 2 weeks of initiating a fixed dose. Therapeutic drug monitoring can be helpful to guide dosing, as a therapeutic window of 150 to 300 ng/mL (for imipramine plus desipramine) has been established for the treatment of depression. Levels above this range are associated with increased toxicity without additional therapeutic benefit.
Indications and clinical applications
Tofranil (imipramine) is FDA-approved for the treatment of major depressive disorder (MDD) in adults. It is effective for all subtypes of depression, including melancholic depression, atypical depression, and depression with psychotic features (when used in combination with an antipsychotic medication). In contemporary practice, imipramine is typically reserved for patients who have not responded adequately to first-line treatments such as SSRIs or SNRIs. However, for some patients, particularly those with prominent melancholic features, psychomotor retardation, or significant weight loss, Tofranil may be considered earlier in the treatment algorithm due to its potent noradrenergic effects. The antidepressant efficacy of imipramine has been well established in numerous clinical trials over the past six decades, and it is considered a gold standard against which newer antidepressants are often compared. In addition to its use in unipolar depression, imipramine is sometimes used in the treatment of bipolar depression, though this requires careful management with mood stabilizers to minimize the risk of switching to mania.
Tofranil also has several important off-label uses. One of its most known non-psychiatric indications is for the treatment of nocturnal enuresis (bedwetting) in children. Imipramine has been shown to reduce the frequency of bedwetting episodes, likely through a combination of its anticholinergic effects (which reduce bladder detrusor muscle activity and increase bladder capacity) and its effects on sleep architecture. For this indication, the medication is typically used for short-term treatment at lower doses ranging from 25 mg to 75 mg per day. Tofranil is also used off-label for the treatment of panic disorder with or without agoraphobia. Clinical studies have demonstrated that imipramine is effective in reducing the frequency and severity of panic attacks, though the onset of its antipanic effect may be delayed for several weeks. Another important application is in the treatment of chronic pain, particularly neuropathic pain conditions such as diabetic neuropathy and postherpetic neuralgia. Imipramine’s analgesic effects are mediated through its enhancement of descending inhibitory pain pathways in the central nervous system. It has also been used for tension-type headaches and migraine prophylaxis. Other off-label uses include the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adults when stimulant medications are not effective or are contraindicated, the treatment of bulimia nervosa, and as a second-line treatment for certain anxiety disorders, including generalized anxiety disorder and social anxiety disorder.
Dosage and administration of tofranil
Tofranil is available in tablet form in strengths of 10 mg, 25 mg, and 50 mg, and in capsule form as a sustained-release formulation in strengths of 75 mg, 100 mg, 125 mg, and 150 mg. The dosage of imipramine must be carefully individualized based on the condition being treated, the patient’s age and medical status, and their response to therapy. For the treatment of depression in adults, therapy is typically initiated at a low dose of 25 mg to 50 mg per day, usually taken at bedtime to minimize daytime sedation. The dose is then gradually increased by 25 mg to 50 mg every few days or weekly, depending on tolerability, until a therapeutic response is achieved or the maximum recommended dose is reached. The usual effective dose for depression is 75 mg to 150 mg per day, though some patients may require up to 200 mg per day, and in rare cases, up to 300 mg per day for severe depression. Doses exceeding 100 mg per day are often divided into two or three doses to improve tolerability, with the largest dose given at bedtime. The sustained-release formulation can be taken once daily, which may improve adherence. For elderly patients, lower starting doses of 10 mg to 25 mg per day are recommended, with slower dose titration to minimize the risk of side effects.
For the treatment of nocturnal enuresis in children, the dosage is based on age and weight. A typical starting dose is 25 mg taken one hour before bedtime for children aged 6 to 12 years, with a maximum of 50 mg per day if needed. For children over 12 years, the starting dose is 50 mg, with a maximum of 75 mg per day. Treatment is usually limited to a few months at a time, with a gradual taper before discontinuation. For off-label use in chronic pain, lower doses are typically used, starting at 10 mg to 25 mg at bedtime and gradually increasing to 50 mg to 100 mg per day as needed. The analgesic effect may be noticeable within 1 to 2 weeks, which is faster than the antidepressant response. Therapeutic drug monitoring is recommended for patients taking imipramine for depression, especially if they are not responding adequately to treatment or if there is concern about toxicity. The combined plasma concentration of imipramine and desipramine should be maintained within the therapeutic window of 150 to 300 ng/mL. Levels above 300 ng/mL are associated with increased risk of cardiotoxicity, while levels below 150 ng/mL are often subtherapeutic. When discontinuing Tofranil, the dose should be gradually tapered over 2 to 4 weeks to minimize withdrawal symptoms and to allow for monitoring of depressive relapse. Abrupt discontinuation can lead to nausea, headache, dizziness, fatigue, and sleep disturbance.
Side effects of imipramine
The side effect profile of Tofranil (imipramine) is consistent with its tricyclic antidepressant class and results from its actions on multiple receptor systems. Anticholinergic side effects are common and include dry mouth, blurred vision, constipation, urinary hesitancy or retention, and cognitive impairment (such as memory difficulties or confusion, particularly in elderly patients). Dry mouth is the most frequently reported side effect and can be managed with increased fluid intake, sugar-free gum or candies, and attention to oral hygiene to prevent dental caries. Constipation should be addressed with adequate dietary fiber, hydration, and regular exercise. If persistent, stool softeners or laxatives may be necessary. Blurred vision is usually temporary but warrants caution when driving or performing tasks that require sharp vision. Sedation and drowsiness are also very common, especially at the beginning of treatment. This side effect is often managed by taking the entire daily dose at bedtime. Tolerance to the sedative effects usually develops over several weeks of treatment. Weight gain is another frequent side effect, driven by increased appetite and carbohydrate cravings. Regular monitoring of weight and proactive dietary management can help limit weight gain. Patients may experience a weight increase of 5 to 15 pounds or more during therapy.
Cardiovascular side effects are a significant concern with imipramine, particularly at higher doses. The most common cardiovascular effects are orthostatic hypotension (a drop in blood pressure upon standing leading to dizziness or fainting) and tachycardia (rapid heart rate). ECG changes, including QT interval prolongation, QRS widening, and ST-T wave abnormalities, can occur. Imipramine has quinidine-like effects on cardiac conduction and can slow intraventricular conduction. These effects are dose-dependent and more pronounced in patients with pre-existing cardiac disease. At toxic levels (plasma concentrations above 1000 ng/mL), imipramine can cause severe cardiac arrhythmias, including ventricular tachycardia and fibrillation. Other cardiovascular effects include hypertension in some patients and an increased risk of sudden cardiac death, particularly in patients with pre-existing heart disease. Sexual side effects are common and include decreased libido, erectile dysfunction, delayed ejaculation, and anorgasmia. These effects are caused by the serotonergic and anticholinergic actions of the medication and can be distressing for patients. Endocrine side effects may include gynecomastia (breast enlargement) in men, galactorrhea (milk production) in women, and changes in blood glucose levels. Less common but serious side effects include seizures (imipramine lowers the seizure threshold), hepatitis, agranulocytosis, and hypersensitivity reactions. Imipramine can also cause photosensitivity, making the skin more prone to sunburn. As with all antidepressants, there is a risk of activation of mania or hypomania in patients with bipolar disorder, and an increased risk of suicidal thinking and behavior in children, adolescents, and young adults.
Drug interactions and contraindications
Tofranil (imipramine) has a many clinically significant drug interactions that require careful management. The most critical interaction is with monoamine oxidase inhibitors (MAOIs), including the antibiotic linezolid and intravenous methylene blue. The combination of TCAs with MAOIs can cause a severe and potentially fatal reaction characterized by hyperpyrexia (extremely high fever), hypertension or hypotension, seizures, and cardiovascular collapse. A minimum of 14 days must separate the use of A MAOI and imipramine. Imipramine can also interact with other serotonergic medications, leading to serotonin syndrome. These include SSRIs, SNRIs, other TCAs, tramadol, fentanyl, buspirone, triptans, St. John’s wort, and tryptophan. Imipramine is metabolized by multiple CYP450 enzymes, and drugs that inhibit these enzymes can increase imipramine levels. CYP2D6 inhibitors such as fluoxetine, paroxetine, bupropion, quinidine, and certain antipsychotics (including haloperidol and risperidone) can increase imipramine and desipramine levels. CYP1A2 inhibitors such as fluvoxamine and cimetidine can also increase imipramine levels. Conversely, CYP450 inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin can decrease imipramine levels and reduce efficacy.
Imipramine can potentiate the effects of alcohol and other central nervous system depressants, including benzodiazepines, barbiturates, opioid analgesics, and antihistamines, leading to excessive sedation, respiratory depression, and impaired psychomotor function. Patients should avoid or strictly limit alcohol consumption while taking Tofranil. Anticholinergic medications, including certain antihistamines, antispasmodics (such as oxybutynin), antipsychotics, and antiparkinsonian drugs, can have additive anticholinergic effects when combined with imipramine, increasing the risk of severe constipation, urinary retention, and confusion. Imipramine can counteract the effects of certain antihypertensive medications, particularly guanethidine, clonidine, and alpha-methyldopa, due to its inhibition of norepinephrine reuptake. Conversely, additive hypotensive effects can occur when imipramine is combined with diuretics, vasodilators, or other antihypertensives that cause orthostatic hypotension. Thyroid medications can increase the risk of cardiac arrhythmias when combined with TCAs. Imipramine can also increase the anticoagulant effect of warfarin by inhibiting its metabolism. Tofranil is contraindicated in patients with recent myocardial infarction, as TCAs can cause cardiac arrhythmias and hemodynamic instability in the post-infarction setting. It is also contraindicated in patients with narrow-angle glaucoma, severe urinary retention, and known hypersensitivity to tricyclic antidepressants. Due to the risk of QT prolongation, imipramine should be used with caution in patients predisposed to arrhythmias or in combination with other QT-prolonging drugs.
Special warnings and precautions
Several important precautions should be observed when using Tofranil (imipramine). Cardiovascular monitoring is especially important, as imipramine can cause significant cardiac effects. A baseline ECG is recommended before starting treatment, particularly in patients over 50 years of age or those with a history of cardiovascular disease. ECG should be repeated periodically during therapy, especially when doses are increased. Patients should be monitored for the development of orthostatic hypotension, which can lead to falls and injuries, particularly in elderly patients. Blood pressure should be checked regularly, both lying and standing. Imipramine can lower the seizure threshold, and caution is required in patients with a history of seizures or epilepsy. The dose should be increased slowly in these patients, and anticonvulsant levels should be monitored if the patient is taking seizure medications. Patients with hepatic or renal impairment may have altered clearance of imipramine and may require lower doses. Liver function tests and renal function should be monitored periodically. In patients with thyroid disease, imipramine should be used with caution, as it may increase the risk of cardiac arrhythmias. Thyroid function should be optimized before starting imipramine therapy.
Electroconvulsive therapy (ECT) may increase the risk of seizures and cardiac arrhythmias in patients taking imipramine, and the medication is typically discontinued before ECT is administered. Patients with a history of bipolar disorder should be carefully screened before starting imipramine, as antidepressants can trigger manic or hypomanic episodes. If manic symptoms develop, imipramine should be discontinued and a mood stabilizer may be needed. The risk of suicidal thinking and behavior is increased in children, adolescents, and young adults taking antidepressants, including imipramine. Close monitoring is essential during the first several months of therapy and whenever doses are adjusted. Parents and caregivers should be alerted to watch for sudden changes in mood or behavior. Imipramine is classified as pregnancy category D, meaning there is evidence of human fetal risk. Use during pregnancy is generally not recommended unless the potential benefits clearly outweigh the risks. Use during the third trimester may cause withdrawal symptoms in the newborn, including jitteriness, irritability, and feeding difficulties. Imipramine is excreted in breast milk, and nursing mothers should discuss the risks and benefits with their healthcare provider. It is generally recommended to avoid breastfeeding while taking imipramine due to the potential for adverse effects in the infant, including sedation and respiratory depression. Due to the risk of overdose, which can be fatal, patients with a history of suicidal thoughts should be prescribed only limited quantities of Tofranil.
Overdose and toxicity of imipramine
Overdose of Tofranil (imipramine) is one of the most dangerous medication overdoses in clinical medicine and requires immediate, aggressive medical intervention. Tricyclic antidepressant overdose is a leading cause of death from prescription drug overdose, and imipramine is among the most toxic TCAs in this regard. The potentially fatal dose of imipramine in adults is approximately 1 to 2 grams (1000 to 2000 mg), though severe toxicity can occur at lower doses in children, elderly patients, or those with pre-existing cardiac conditions. Symptoms of imipramine overdose typically begin within 30 minutes to 2 hours after ingestion and can progress with alarming rapidity due to the drug’s rapid absorption and extensive distribution. The clinical presentation of TCA overdose has been characterized using a staging system. Stage 1 involves anticholinergic symptoms such as confusion, delirium, hallucinations, dilated pupils, dry skin, and urinary retention. Stage 2 is marked by central nervous system depression, with decreasing level of consciousness, respiratory depression, and the appearance of seizures. Stage 3 involves cardiovascular toxicity, including cardiac conduction abnormalities, arrhythmias, and hypotension. The most characteristic ECG finding in TCA overdose is QRS prolongation, which reflects sodium channel blocking effect of TCAs in the cardiac conduction system. A QRS duration greater than 100 milliseconds is associated with increased risk of seizures, while a QRS duration greater than 160 milliseconds is strongly predictive of ventricular arrhythmias. Other ECG findings include QT prolongation, right axis deviation of the terminal QRS vector, and the presence of A R wave in lead aVR. Ventricular arrhythmias, including ventricular tachycardia, torsades de pointes, and ventricular fibrillation, are the primary cause of death in TCA overdose. The management of imipramine overdose begins with aggressive supportive care. Endotracheal intubation and mechanical ventilation may be necessary for patients with decreased consciousness. Intravenous sodium bicarbonate is the foundation of treatment for TCA-induced cardiotoxicity. It works by increasing the serum sodium concentration, which helps overcome the sodium channel blockade, and by inducing alkalosis, which reduces the free concentration of the drug. Sodium bicarbonate should be administered as a 1 to 2 mEq/kg intravenous bolus for patients with QRS prolongation beyond 110 to 120 milliseconds, followed by an infusion if needed to maintain arterial pH between 7.50 and 7.55. Seizures should be treated with benzodiazepines. Hypotension may require intravenous fluids and vasopressors such as norepinephrine. Activated charcoal can be useful if administered within one to two hours of ingestion, but the risk of aspiration in patients with altered mental status must be carefully weighed. Hemodialysis is not effective for removing TCAs due to their extensive protein binding and large volume of distribution. Patients who have ingested a significant amount of imipramine should be monitored in an intensive care unit for at least 24 hours after the resolution of symptoms and ECG abnormalities. The extreme lethality of imipramine overdose mandates that this medication be prescribed with the utmost caution, particularly in patients with a history of suicidal ideation or attempts.
Clinical research and evidence-based applications
The clinical research base for imipramine is one of the most extensive of any psychotropic medication, reflecting its long history of use and its status as a reference standard in antidepressant research. Numerous placebo-controlled trials conducted since the 1950s have established imipramine as an effective treatment for major depressive disorder, with response rates typically ranging from 50% to 70% compared to 25% to 40% for placebo. The landmark NIMH Collaborative Depression Study and the Treatment of Depression Collaborative Research Program both included imipramine as a reference treatment, and these studies provided important data on the comparative efficacy of pharmacotherapy and psychotherapy for depression. In these studies, imipramine was found to be superior to placebo and at least as effective as cognitive-behavioral therapy and interpersonal therapy for the acute treatment of moderate to severe depression. In the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, which is one of the largest and most influential studies in the treatment of depression, imipramine was used as a reference medication in some treatment arms, and its efficacy was compared to other agents in patients who had not responded to initial treatment with A SSRI. For panic disorder, imipramine has been studied and is considered one of the most effective medications for this condition. The Cross-National Collaborative Panic Study, a large multicenter trial, demonstrated that imipramine was superior to placebo and comparable to alprazolam in reducing the frequency and severity of panic attacks, with the additional benefit of reducing baseline depression in patients with comorbid mood symptoms. For nocturnal enuresis, a meta-analysis of multiple controlled trials confirmed that imipramine is more effective than placebo in reducing bedwetting episodes in children, with success rates (defined as complete or near-complete cessation of bedwetting) ranging from 15% to 50% depending on the study design and outcome criteria. However, the high relapse rate upon discontinuation limits the long-term utility of imipramine for enuresis. For chronic pain, systematic reviews have supported the efficacy of imipramine for neuropathic pain conditions, particularly diabetic neuropathy and postherpetic neuralgia, though the number needed to treat for benefit is generally higher than for more commonly used agents such as amitriptyline, nortriptyline, and gabapentin. Despite the wealth of evidence supporting imipramine’s efficacy, its use in contemporary practice is limited by its side effect profile and safety concerns, particularly the risk of cardiotoxicity and the potential for fatal overdose. Nevertheless, imipramine remains an important treatment option for carefully selected patients and continues to be studied in clinical research for new indications and applications.
Strategies for optimizing treatment with tofranil
Optimizing treatment with Tofranil (imipramine) requires a comprehensive approach that encompasses appropriate patient selection, careful dose titration, therapeutic drug monitoring, and proactive management of side effects. Patient selection is perhaps the most critical factor in determining the success of imipramine therapy. The ideal candidate for imipramine is a patient with moderate to severe melancholic depression who has not responded to one or more trials of SSRIs or SNRIs and who does not have significant contraindications such as cardiovascular disease, narrow-angle glaucoma, or urinary retention. Patients with prominent symptoms of psychomotor retardation, anhedonia, and weight loss may be particularly good candidates due to imipramine’s potent noradrenergic effects. Before starting imipramine therapy, a thorough medical evaluation is essential, including a comprehensive cardiovascular assessment with ECG, measurement of blood pressure and heart rate, and evaluation for contraindications. A baseline ECG is particularly important to rule out conduction abnormalities that could be exacerbated by imipramine. Once treatment is initiated, dose titration should be gradual, with dose increases of 25 mg to 50 mg every 3 to 7 days as tolerated. The dose should be increased until a therapeutic response is achieved, side effects become limiting, or the maximum recommended dose is reached. Therapeutic drug monitoring plays an important role in optimizing imipramine therapy. The combined plasma concentration of imipramine plus desipramine should be measured after the patient has been on a stable dose for at least 5 to 7 days. The target therapeutic range is 150 to 300 ng/mL. If the patient has not responded after 4 to 6 weeks at a therapeutic dose and plasma level, the diagnosis should be reassessed, and alternative treatment strategies should be considered. If the patient has responded but continues to experience significant side effects, a reduction in dose (if plasma levels allow) may improve tolerability. For patients with partial response, augmentation with another agent such as lithium or thyroid hormone may be considered before switching to an entirely different treatment. The management of side effects is an ongoing process that requires active collaboration between the patient and healthcare provider. Regular follow-up visits, at least every 2 to 4 weeks during the acute phase of treatment, allow for assessment of response, monitoring of side effects, dose adjustment, and reinforcement of adherence. Patients should be encouraged to report any side effects they are experiencing rather than simply stopping the medication. With careful attention to these optimization strategies, imipramine can provide significant benefit to patients who have not found relief with other treatments, while minimizing the risks and discomfort associated with TCA therapy.
Frequently asked questions about tofranil
1. Is Tofranil still used today for depression?
Yes, Tofranil is still used today, though it is typically reserved for patients who have not responded to newer antidepressants such as SSRIs and SNRIs. It is considered a second- or third-line treatment for depression in most clinical guidelines. However, some psychiatrists still consider it a valuable option for treatment-resistant depression, melancholic depression, and certain other conditions.
2. Can Tofranil be used for bedwetting in children?
Yes, Tofranil is one of the few medications approved for the treatment of nocturnal enuresis (bedwetting) in children aged 6 years and older. It is effective in reducing the frequency of bedwetting episodes, though the effect is usually temporary, and bedwetting often returns when the medication is stopped. It is typically used as a short-term treatment.
3. How long does it take for Tofranil to work for depression?
The antidepressant effect of Tofranil usually begins to appear within 2 to 4 weeks of starting therapy at a therapeutic dose. The full effect may take 6 to 8 weeks or longer to develop. The sedative effects are typically noticed immediately, which can provide early relief for patients with significant insomnia.
4. What is the difference between Tofranil and other TCAs like amitriptyline?
Both Tofranil (imipramine) and amitriptyline are tricyclic antidepressants, but they have some pharmacological differences. Imipramine is a prodrug that is converted to desipramine, which is more selective for norepinephrine. Amitriptyline is converted to nortriptyline and has more pronounced sedative and anticholinergic effects. The choice between them depends on the patient’s symptoms and tolerance of side effects.
5. Can Tofranil be used for anxiety?
Yes, Tofranil is used off-label for several anxiety disorders, including panic disorder, generalized anxiety disorder, and social anxiety disorder. It has been particularly well studied in panic disorder, where it has been shown to reduce both the frequency of panic attacks and the associated anticipatory anxiety. However, SSRIs are generally preferred as first-line treatments for anxiety disorders due to their better tolerability.
6. Is weight gain a concern with Tofranil?
Weight gain is a relatively common side effect of Tofranil and other TCAs. It is thought to be related to histamine H1 receptor blockade and associated increases in appetite and carbohydrate cravings. The amount of weight gain varies among individuals, and some patients may gain a significant amount of weight during treatment. Regular monitoring of weight is recommended.
7. What should I do if I miss a dose of Tofranil?
If you miss a dose of Tofranil, take it as soon as you remember, unless it is almost time for your next scheduled dose. In that case, skip the missed dose and resume your regular dosing schedule. Do not take a double dose to make up for a missed one. If you are taking Tofranil once daily at bedtime and you miss a dose, you can take it the next morning if you are not too sedated, but skip it if it is late in the day and take it at the regular bedtime instead.