Tofranil

Imipramine tablets and capsules are used to treat depression. Imipramine tablets are also used to prevent bedwetting in children. Imipramine is in a class of medications called tricyclic antidepressants. It treats depression by increasing the amounts of certain natural substances in the brain that are needed to maintain mental balance. There is not enough information to explain how imipramine prevents bedwetting.

Other medications and drugs that slow the brain's processes, such as alcohol, barbiturates, benzodiazepines, for example, lorazepam (Ativan), diazepam (Valium), temazepam (Restoril), oxazepam (Serax), clonazepam (Klonopin), zolpidem (Ambien), and narcotics, may add to the effect of imipramine on the brain.

Reserpine, given to patients taking TCAs, can cause agitation and anxiety. Imipramine and other TCAs should not be used with monoamine oxidase inhibiting drugs, for example, isocarboxazid (Marplan), phenelzine (Nardil), tranylcypromine (Parnate), and procarbazine (Matulane), since high fever, convulsions and even death can occur.

Concurrent use of cimetidine (Tagamet) can increase imipramine blood levels by reducing elimination of imipramine from the body and possibly lead to imipramine- related side effects. Other drugs which share this effect include propafenone (Rythmol), flecainide (Tonocard), quinidine (Quinidex, Quinaglute), methylphenidate (Ritalin), and fluoxetine (Prozac).

You should not take this medicine if you have recently had a heart attack, or if you are allergic to imipramine or similar antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, doxepin, nortriptyline, protriptyline, or trimipramine.

Do not use imipramine if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include furazolidone, isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

To make sure imipramine is safe for you, tell your doctor if you have:

• heart disease, a history of heart attack, stroke, or seizures;
• bipolar disorder (manic-depression);
• kidney or liver disease;
• overactive thyroid, adrenal gland tumor (pheochromocytoma);
• diabetes (imipramine may raise or lower blood sugar);
• glaucoma;
• problems with urination; or
• if you are being treated with methylene blue injection.

Some young people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using imipramine. Your family or other caregivers should also be alert to changes in your mood or symptoms.

FDA pregnancy category C. It is not known whether imipramine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

Imipramine can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to a child without medical advice.

Common side effects include:

• nausea
• drowsiness
• weakness or tiredness
• excitement or anxiety
• confusion
• nightmares
• dry mouth
• sun sensitivity
• weight loss or gain
• constipation
• difficulty urinating
• frequent urination
• blurred vision
• changes in sex drive or ability
• excessive sweating

This is not a complete list of Tofranil side effects. Ask your doctor or pharmacist for more information.

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

If you take too much Tofranil, call your healthcare provider or local Poison Control Center, or seek emergency medical attention right away.

• Store Tofranil tablets at 15°C-25°C (59°-77°F).
• Keep this and all medicines out of the reach of children.

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

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

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

In the U.S.

• Tofranil
• Tofranil-PM

Available Dosage Forms:

• Tablet
• Capsule

Therapeutic Class: Antidepressant

Pharmacologic Class: Antidepressant, Tricyclic

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine 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

Appropriate studies have not been performed on the relationship of age to the effects of imipramine capsules to treat depression in the pediatric population. Safety and efficacy have not been established.

Appropriate studies have not been performed on the relationship of age to the effects of imipramine tablets in children with enuresis (bedwetting) younger than 6 years of age. Safety and efficacy have not been established.

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of imipramine in the elderly. However, elderly patients are more likely to have age-related kidney, liver, or heart problems, which may require caution and an adjustment in the dose for patients receiving imipramine.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

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 this medicine, 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 this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

• Amifampridine
• Bepridil
• Bromopride
• Cisapride
• Dronedarone
• Furazolidone
• Grepafloxacin
• Iproniazid
• Isocarboxazid
• Levomethadyl
• Linezolid
• Mesoridazine
• Methylene Blue
• Metoclopramide
• Moclobemide
• Pargyline
• Phenelzine
• Pimozide
• Piperaquine
• Procarbazine
• Ranolazine
• Rasagiline
• Safinamide
• Saquinavir
• Selegiline
• Sparfloxacin
• Terfenadine
• Thioridazine
• Tranylcypromine
• Ziprasidone

Using this medicine 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.

• Acecainide
• Aceclofenac
• Acemetacin
• Albuterol
• Alfentanil
• Alfuzosin
• Almotriptan
• Amiodarone
• Amisulpride
• Amitriptyline
• Amoxapine
• Amphetamine
• Amtolmetin Guacil
• Anagrelide
• Apomorphine
• Aprindine
• Aripiprazole
• Aripiprazole Lauroxil
• Arsenic Trioxide
• Artemether
• Asenapine
• Aspirin
• Astemizole
• Atazanavir
• Azimilide
• Azithromycin
• Benzphetamine
• Bretylium
• Bromfenac
• Bufexamac
• Buprenorphine
• Bupropion
• Buserelin
• Celecoxib
• Chloral Hydrate
• Chloroquine
• Chlorpromazine
• Choline Salicylate
• Ciprofloxacin
• Clarithromycin
• Clomipramine
• Clonidine
• Clonixin
• Clozapine
• Codeine
• Crizotinib
• Cyclobenzaprine
• Dabrafenib
• Darifenacin
• Darunavir
• Dasatinib
• Degarelix
• Delamanid
• Desipramine
• Deslorelin
• Desmopressin
• Desvenlafaxine
• Deutetrabenazine
• Dexibuprofen
• Dexketoprofen
• Dextroamphetamine
• Dextromethorphan
• Diclofenac
• Diflunisal
• Dihydrocodeine
• Dipyrone
• Disopyramide
• Dofetilide
• Dolasetron
• Domperidone
• Donepezil
• Droperidol
• Droxicam
• Efavirenz
• Enflurane
• Epinephrine
• Erythromycin
• Escitalopram
• Etilefrine
• Etodolac
• Etofenamate
• Etoricoxib
• Felbinac
• Fenoprofen
• Fentanyl
• Fepradinol
• Feprazone
• Fingolimod
• Flecainide
• Floctafenine
• Fluconazole
• Flufenamic Acid
• Fluoxetine
• Flurbiprofen
• Foscarnet
• Frovatriptan
• Gatifloxacin
• Gemifloxacin
• Gonadorelin
• Goserelin
• Granisetron
• Halofantrine
• Haloperidol
• Halothane
• Histrelin
• Hydrocodone
• Hydromorphone
• Hydroxychloroquine
• Hydroxyzine
• Ibuprofen
• Ibutilide
• Iloperidone
• Indomethacin
• Iobenguane I 123
• Isoflurane
• Isradipine
• Ivabradine
• Ketoprofen
• Ketorolac
• Lapatinib
• Leuprolide
• Levalbuterol
• Levofloxacin
• Levomilnacipran
• Levorphanol
• Levothyroxine
• Lidoflazine
• Lisdexamfetamine
• Lorcainide
• Lorcaserin
• Lornoxicam
• Loxoprofen
• Lumefantrine
• Lumiracoxib
• Meclofenamate
• Mefenamic Acid
• Mefloquine
• Meloxicam
• Meperidine
• Methadone
• Methamphetamine
• Methoxamine
• Metronidazole
• Midodrine
• Mifepristone
• Mirtazapine
• Moricizine
• Morniflumate
• Morphine
• Morphine Sulfate Liposome
• Moxifloxacin
• Nabumetone
• Nafarelin
• Nalbuphine
• Naproxen
• Naratriptan
• Nefopam
• Nepafenac
• Niflumic Acid
• Nilotinib
• Nimesulide
• Nimesulide Beta Cyclodextrin
• Norepinephrine
• Norfloxacin
• Nortriptyline
• Octreotide
• Ofloxacin
• Ondansetron
• Oxaprozin
• Oxilofrine
• Oxycodone
• Oxymetazoline
• Oxymorphone
• Oxyphenbutazone
• Paliperidone
• Palonosetron
• Panobinostat
• Parecoxib
• Paroxetine
• Pasireotide
• Pazopanib
• Peginterferon Alfa-2b
• Pentamidine
• Pentazocine
• Phenylbutazone
• Phenylephrine
• Piketoprofen
• Pimavanserin
• Piroxicam
• Pitolisant
• Pixantrone
• Posaconazole
• Pranoprofen
• Procainamide
• Prochlorperazine
• Proglumetacin
• Promethazine
• Propafenone
• Propyphenazone
• Proquazone
• Protriptyline
• Quetiapine
• Quinidine
• Quinine
• Remifentanil
• Ribociclib
• Risperidone
• Rofecoxib
• Salicylic Acid
• Salsalate
• Sematilide
• Sertindole
• Sertraline
• Sevoflurane
• Sodium Phosphate
• Sodium Phosphate, Dibasic
• Sodium Phosphate, Monobasic
• Sodium Salicylate
• Solifenacin
• Sorafenib
• Sotalol
• Spiramycin
• Sufentanil
• Sulfamethoxazole
• Sulindac
• Sulpiride
• Sultopride
• Sumatriptan
• Sunitinib
• Tacrolimus
• Tapentadol
• Tedisamil
• Telavancin
• Telithromycin
• Tenoxicam
• Tetrabenazine
• Tiaprofenic Acid
• Tiotropium
• Tolfenamic Acid
• Tolmetin
• Toremifene
• Tramadol
• Trazodone
• Trifluoperazine
• Trimethoprim
• Triptorelin
• Tryptophan
• Valdecoxib
• Vandetanib
• Vardenafil
• Vasopressin
• Vemurafenib
• Venlafaxine
• Vilanterol
• Vilazodone
• Vinflunine
• Voriconazole
• Vortioxetine
• Zolmitriptan
• Zotepine
• Zuclopenthixol

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

• Acenocoumarol
• Alprazolam
• Arbutamine
• Atomoxetine
• Cannabis
• Carbamazepine
• Cimetidine
• Citalopram
• Dicumarol
• Fluvoxamine
• Fosphenytoin
• Mibefradil
• Phenindione
• Phenprocoumon
• Phenytoin
• Ritonavir
• S-Adenosylmethionine

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. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is usually not recommended, but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Tobacco

Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.

• Ethanol

Other Medical Problems

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

• Bipolar disorder (mood disorder with mania and depression), or risk of or
• Diabetes or
• Glaucoma (angle-closure type), or
• Heart or blood vessel disease or
• Hyperthyroidism (overactive thyroid) or
• Mania, history of or
• Schizophrenia (mental illness) or
• Seizures, history of or
• Urinary retention (trouble urinating), history of—Use with caution. May make these conditions worse.

• Heart attack, recent—Should not be used in patients with this condition.

• Kidney disease or
• Liver disease—Use with caution. The effects may be increased because of slower removal of the medicine from the body.

This section provides information on the proper use of a number of products that contain imipramine. It may not be specific to Tofranil. Please read with care.

Take this medicine only as directed by your doctor to benefit your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

This medicine comes with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

Dosing

The dose of this medicine 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 this medicine. 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 oral dosage form (capsules):
  • For depression:
    • Adults—At first, 75 milligrams (mg) once a day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 200 mg per day, unless you are in the hospital. Some hospitalized patients may need higher doses.
    • Teenagers and older adults—At first, 25 to 50 mg per day using the tablets. Your doctor may adjust your dose as needed and switch you to the capsule form. However, the dose is usually not more than 100 mg per day.
    • Children—Use and dose must be determined by your doctor.
• For oral dosage form (tablets):
  • For depression:
    • Adults—At first, 75 milligrams (mg) per day. Your doctor may adjust your dose as needed. However the dose is usually not more than 200 mg per day. Some hospitalized patients may need higher doses.
    • Teenagers and older adults—30 to 40 mg per day. Your doctor may adjust your dose as needed. However, the dose is usually not more than 100 mg per day.
    • Children—Use and dose must be determined by your doctor.
  • For enuresis (bedwetting):
    • Children 6 years of age and older—At first, 25 milligrams (mg) once a day, taken 1 hour before bedtime. Your doctor may adjust the dose as needed.
    • Children younger than 6 years of age—Use and dose must be determined by your 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

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

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• It is used to treat low mood (depression).
• It is used to help prevent bedwetting in children.
• It may be given to you for other reasons. Talk with the doctor.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists. This medicine may need to be stopped before certain types of surgery as your doctor has told you. If Tofranil is stopped, your doctor will tell you when to start taking this medicine again after your surgery or procedure.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Tofranil affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Tofranil, you will want to slowly stop it as ordered by your doctor.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Tell your doctor if you have signs of high or low blood sugar like breath that smells like fruit, dizziness, fast breathing, fast heartbeat, feeling confused, feeling sleepy, feeling weak, flushing, headache, more thirsty or hungry, passing urine more often, shaking, or sweating.
• Talk with your doctor before you drink alcohol or use other drugs and natural products that slow your actions.
• It may take several weeks to see the full effects.
• Some people may have a higher chance of eye problems with this medicine. Your doctor may want you to have an eye exam to see if you have a higher chance of these eye problems. Call your doctor right away if you have eye pain, change in eyesight, or swelling or redness in or around the eye.
• You may get sunburned more easily. Avoid sun, sunlamps, and tanning beds. Use sunscreen and wear clothing and eyewear that protects you from the sun.
• Be careful in hot weather or while being active. Drink lots of fluids to stop fluid loss.
• You may need to have an ECG checked before starting Tofranil (imipramine tablets) and while taking it. Talk with your doctor.
• A very bad and sometimes deadly health problem called serotonin syndrome may happen. The risk may be greater if you take this medicine with drugs for depression, migraines, or certain other drugs. Call your doctor right away if you have agitation; change in balance; confusion; hallucinations; fever; fast or abnormal heartbeat; flushing; muscle twitching or stiffness; seizures; shivering or shaking; sweating a lot; very bad diarrhea, upset stomach, or throwing up; or very bad headache.
• If you are 65 or older, use Tofranil with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.

Tofranil™ is supplied in tablet form for oral administration.

Tofranil, 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:

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.

Inactive Ingredients: Calcium phosphate, cellulose compounds, docusate sodium, iron oxides, magnesium stearate, polyethylene glycol, povidone, sodium starch glycolate, sucrose, talc, and titanium dioxide.

General

An ECG recording should be taken prior to the initiation of larger-than-usual doses of Tofranil 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 Tofranil.

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 Tofranil, 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, Tofranil 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 Tofranil 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.

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.

Patients should be advised that taking Tofranil can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

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, 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 for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

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% to 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 interaction may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration 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 coadministered 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 Tofranil 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 Tofranil cannot be excluded. Therefore, Tofranil 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 Tofranil 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 Tofranil 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 Tofranil in the original application did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Postmarketing 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, Adolescent and Geriatric Patients.)

(See alsoPRECAUTIONS, General.)

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 Tofranil 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 Tofranil 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.

Postmarketing Experience

The following adverse drug reaction has been reported during post-approval use of Tofranil. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.

Eye disorders: angle-closure glaucoma