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Aponal

Aponal - General Information

A dibenzoxepin tricyclic compound. It displays a range of pharmacological actions including maintaining adrenergic innervation. Its mechanism of action is not fully understood, but it appears to block reuptake of monoaminergic neurotransmitters into presynaptic terminals. It also possesses anticholinergic activity and modulates antagonism of histamine H(1)- and H(2)-receptors.

 

Pharmacology of Aponal

Aponal, a tricyclic antidepressant of the dibenzoxepin type, is used to treat depression and anxiety and, topically, pruritus associated with eczema. Aponal has substantial anticholinergic and sedative effects.

 

Aponal for patients

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with SINEQUAN and should counsel them in its appropriate use. A patient Medication Guide About Using Antidepressants in Children and Teenagers is available for SINEQUAN. 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 SINEQUAN.

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 observe 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 medication.

 

Medication Guide

About Using Antidepressants in Children and Teenagers

What is the most important information I should know if my child is being prescribed an antidepressant?

Parents or guardians need to think about 4 important things when their child is prescribed an antidepressant:

  1. There is a risk of suicidal thoughts or actions
  2. How to try to prevent suicidal thoughts or actions in your child
  3. You should watch for certain signs if your child is taking an antidepressant
  4. There are benefits and risks when using antidepressants

1. There is a Risk of Suicidal Thoughts or Actions

Children and teenagers sometimes think about suicide, and many report trying to kill themselves.

Antidepressants increase suicidal thoughts and actions in some children and teenagers. But suicidal thoughts and actions can also be caused by depression, a serious medical condition that is commonly treated with antidepressants. Thinking about killing yourself or trying to kill yourself is called suicidality or being suicidal.

A large study combined the results of 24 different studies of children and teenagers with depression or other illnesses. In these studies, patients took either a placebo (sugar pill) or an antidepressant for 1 to 4 months. No one committed suicide in these studies, but some patients became suicidal. On sugar pills, 2 out of every 100 became suicidal. On the antidepressants, 4 out of every 100 patients became suicidal.

For some children and teenagers, the risks of suicidal actions may be especially high.These include patients with

  • Bipolar illness (sometimes called manic-depressive illness)
  • A family history of bipolar illness
  • A personal or family history of attempting suicide

If any of these are present, make sure you tell your health care provider before your child takes an antidepressant.

2. How to Try to Prevent Suicidal Thoughts and Actions

To try to prevent suicidal thoughts and actions in your child, pay close attention to changes in her or his moods or actions, especially if the changes occur suddenly. Other important people in your child's life can help by paying attention as well (e.g., your child, brothers and sisters, teachers, and other important people). The changes to look out for are listed in Section 3, on what to watch for.

Whenever an antidepressant is started or its dose is changed, pay close attention to your child.

After starting an antidepressant, your child should generally see his or her health care provider

  • Once a week for the first 4 weeks
  • Every 2 weeks for the next 4 weeks
  • After taking the antidepressant for 12 weeks
  • After 12 weeks, follow your health care provider's advice about how often to come back
  • More often if problems or questions arise

You should call your child's health care provider between visits if needed.

3. You Should Watch for Certain Signs If Your Child is Taking an Antidepressant

Contact your child's health care provider right away if your child exhibits any of the following signs for the first time, or if they seem worse, or worry you, your child, or your child's teacher:

  • Thoughts about suicide or dying
  • Attempts to commit suicide
  • New or worse depression
  • New or worse anxiety
  • Feeling very agitated or restless
  • Panic attacks
  • Difficulty sleeping (insomnia)
  • New or worse irritability
  • Acting aggressive, being angry, or violent
  • Acting on dangerous impulses
  • An extreme increase in activity and talking
  • Other unusual changes in behavior or mood

Never let your child stop taking an antidepressant without first talking to his or her health care provider. Stopping an antidepressant suddenly can cause other symptoms.

4. There are Benefits and Risks When Using Antidepressants

Antidepressants are used to treat depression and other illnesses. Depression and other illnesses can lead to suicide. In some children and teenagers, treatment with an antidepressant increases suicidal thinking or actions. It is important to discuss all the risks of treating depression and also the risks of not treating it. You and your child should discuss all treatment choices with your health care provider, not just the use of antidepressants.

Other side effects can occur with antidepressants.

Of all the antidepressants, only fluoxetine (Prozac) has been FDA approved to treat pediatric depression.

For obsessive compulsive disorder in children and teenagers, FDA has approved only fluoxetine (Prozac), sertraline (Zoloft), fluvoxamine, and clomipramine (Anafranil).

Your health care provider may suggest other antidepressants based on the past experience of your child or other family members.

Is this all I need to know if my child is being prescribed an antidepressant?

No. This is a warning about the risk for suicidality. Other side effects can occur with antidepressants. Be sure to ask your health care provider to explain all the side effects of the particular drug he or she is prescribing. Also ask about drugs to avoid when taking an antidepressant. Ask your health care provider or pharmacist where to find more information.

Prozac is a registered trademark of Eli Lilly and Company.

Zoloft is a registered trademark of Pfizer Pharmaceuticals.

Anafranil is a registered trademark of Mallinckrodt Inc.

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

 

Aponal 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., citalopram, escitalopram, 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.

Doxepin is primarily metabolized by CYP2D6 (with CYP1A2 & CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the plasma concentration of doxepin when administered concomitantly. The extent of interaction depends on the variability of effect on CYP2D6. The clinical significance of this interaction with doxepin has not been systematically evaluated.

MAO Inhibitors: Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Therefore, MAO inhibitors should be discontinued at least two weeks prior to the cautious initiation of therapy with SINEQUAN. The exact length of time may vary and is dependent upon the particular MAO inhibitor being used, the length of time it has been administered, and the dosage involved.

Cimetidine: Cimetidine has been reported to produce clinically significant fluctuations in steady-state serum concentrations of various tricyclic antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth, urinary retention and blurred vision) have been associated with elevations in the serum levels of tricyclic antidepressant when cimetidine therapy is initiated. Additionally, higher than expected tricyclic antidepressant levels have been observed when they are begun in patients already taking cimetidine. In patients who have been reported to be well controlled on tricyclic antidepressants receiving concurrent cimetidine therapy, discontinuation of cimetidine has been reported to decrease established steady-state serum tricyclic antidepressant levels and compromise their therapeutic effects.

Alcohol: It should be borne in mind that alcohol ingestion may increase the danger inherent in any intentional or unintentional SINEQUAN overdosage. This is especially important in patients who may use alcohol excessively.

Tolazamide: A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).

 

Aponal Contraindications

SINEQUAN is contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind.

SINEQUAN is contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.

 

Additional information about Aponal

Aponal Indication: For the treatment of psychoneurotic patients with depression and/or anxiety
Mechanism Of Action: The mechanism of action of doxepin is not completely understood. It is thought that Like amitriptyline, doxepin enhances the actions of norepinephrine and serotonin by blocking their reuptake at the neuronal membrane. Aponal may also act on histamine H1-receptors, resulting in sedative effects, and beta-adrenergic receptors.
Drug Interactions: Altretamine Risk of severe hypotension
Atazanavir Atazanavir increases the effect and toxicity of tricyclics
Carbamazepine The tricyclic increases the effect of carbamazepine
Cimetidine Cimetidine increases the effect of tricyclic agent
Cisapride Increased risk of cardiotoxicity and arrhythmias
Clonidine The tricyclic decreases the effect of clonidine
Dihydroquinidine barbiturate Quinidine increases the effect of tricyclic agent
Dobutamine The tricyclic increases the sympathomimetic effect
Donepezil Possible antagonism of action
Dopamine The tricyclic increases the sympathomimetic effect
Ephedra The tricyclic increases the sympathomimetic effect
Ephedrine The tricyclic increases the sympathomimetic effect
Fenoterol The tricyclic increases the sympathomimetic effect
Fluoxetine Fluoxetine increases the effect and toxicity of tricyclics
Fluvoxamine Fluvoxamine increases the effect and toxicity of tricyclics
Galantamine Possible antagonism of action
Grepafloxacin Increased risk of cardiotoxicity and arrhythmias
Guanethidine The tricyclics decreases the effect of guanethidine
Isocarboxazid Possibility of severe adverse effects
Isoproterenol The tricyclic increases the sympathomimetic effect
Mephentermine The tricyclic increases the sympathomimetic effect
Mesoridazine Increased risk of cardiotoxicity and arrhythmias
Metaraminol The tricyclic increases the sympathomimetic effect
Methoxamine The tricyclic increases the sympathomimetic effect
Moclobemide Possible severe adverse reaction with this combination
Norepinephrine The tricyclic increases the sympathomimetic effect
Orciprenaline The tricyclic increases the sympathomimetic effect
Phenelzine Possibility of severe adverse effects
Phenylephrine The tricyclic increases the sympathomimetic effect
Phenylpropanolamine The tricyclic increases the sympathomimetic effect
Pirbuterol The tricyclic increases the sympathomimetic effect
Procaterol The tricyclic increases the sympathomimetic effect
Pseudoephedrine The tricyclic increases the sympathomimetic effect
Quinidine Quinidine increases the effect of tricyclic agent
Quinidine barbiturate Quinidine increases the effect of tricyclic agent
Rasagiline Possibility of severe adverse effects
Rifabutin The rifamycin decreases the effect of tricyclics
Rifampin The rifamycin decreases the effect of tricyclics
Ritonavir Ritonavir increases the effect and toxicity of tricyclics
Rivastigmine Possible antagonism of action
Salbutamol The tricyclic increases the sympathomimetic effect
Sibutramine Increased risk of CNS adverse effects
Sparfloxacin Increased risk of cardiotoxicity and arrhythmias
Terbutaline The tricyclic increases the sympathomimetic effect
Terfenadine Increased risk of cardiotoxicity and arrhythmias
Thioridazine Increased risk of cardiotoxicity and arrhythmias
Tranylcypromine Possibility of severe adverse effects
Food Interactions: Avoid alcohol.
Take with food to reduce irritation.
Avoid excessive quantities of coffee or tea (Caffeine).
Avoid St.John's Wort.
Generic Name: Doxepin
Synonyms: Doxepin, Hydrochloride; Doxepin Hcl; Doxepina [Inn-Spanish]; Doxepine; Doxepinum [Inn-Latin]
Drug Category: Anti-anxiety Agents; Antipruritics; Antidepressants; Norepinephrine-Reuptake Inhibitors; Histamine Antagonists
Drug Type: Small Molecule; Approved
Other Brand Names containing Doxepin: Adapin; Aponal; Curatin; Quitaxon; Triadapin; Zonalon;
Absorption: well absorbed from the gut
Toxicity (Overdose): LD50=26 (mg/kg) (in mice, iv); LD50=16 (mg/kg) (in rats, iv); 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 antidepressant toxicity.
Protein Binding: highly protein-bound
Biotransformation: Hepatic
Half Life: 6 - 8 hours
Dosage Forms of Aponal: Cream Topical
Capsule Oral
Chemical IUPAC Name: (3E)-3-(6H-benzo[c][1]benzoxepin-11-ylidene)-N,N-dimethylpropan-1-amine
Chemical Formula: C19H21NO
Doxepin on Wikipedia: http://en.wikipedia.org/wiki/Doxepin
Organisms Affected: Humans and other mammals