PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Tricyclic and other cyclic Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    Maprotiline is generally not recommended for use in children or adolescents under the age of 18 years old. Maprotiline is not FDA-approved for the treatment of depression in pediatric patients. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of therapy or at the time of dose increases or decreases; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary psychiatric disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with maprotiline. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Maprotiline should be used with caution in children and adolescents with a known family history of heart disease, or in children who are taking other medications concomitantly that might cause drug interactions. QTc interval prolongation, tachycardia, and other side effects have been reported in children who have taken cyclic antidepressants; there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving cyclic antidepressants due to the potential of these agents to produce adverse cardiac effects.

    DEA CLASS

    Rx

    DESCRIPTION

    Tetracyclic antidepressant of dibenzo-bicyclo-octadiene derivation; efficacy is similar to the TCAs for depression; occasionally administered for other indications.

    COMMON BRAND NAMES

    Ludiomil

    HOW SUPPLIED

    Ludiomil/Maprotiline Hydrochloride Oral Tab: 25mg, 50mg, 75mg

    DOSAGE & INDICATIONS

    For the treatment of depression.
    Oral dosage
    Adults 60 years or younger

    Initially, 75 mg/day PO (25 mg PO 3 times daily or as 75 mg PO at bedtime) for outpatients with mild to moderate depression. Some patients may need an initial dosage of 25 mg PO daily at bedtime. For severely depressed hospitalized patients, may use 100 to 150 mg/day PO initially. Maintain the initial dose for 2 weeks. Then may increase gradually in 25 mg increments as needed and tolerated. Usual Max (outpatients): 150 mg/day PO. Max (hospitalized patients): 225 mg/day PO. A single daily dose is an alternative to divided daily doses. For the maintenance dosage, use lowest effective dosage. May reduce to 75 to 150 mg/day PO, with subsequent adjustment based on therapeutic response.

    Geriatric Adults older than 60 years

    Initially, 25 mg PO at bedtime may be better tolerated by the elderly. Increase dose by 25 mg/day at weekly intervals (or every 3 days for inpatients), depending on response and tolerance. Dosages of 50 to 75 mg/day PO are usually satisfactory as maintenance therapy for elderly patients who do not tolerate higher doses; administer as a single daily dose at bedtime or may divide in 3 doses. Usual Max (outpatients): 150 mg/day PO. Max (hospitalized): 225 mg/day PO.

    MAXIMUM DOSAGE

    Adults

    225 mg/day PO.

    Geriatric

    225 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; but dosage adjustment may be needed. Maprotiline is metabolized in the liver to active metabolite and inactive metabolites. Enterohepatic circulation of both active drug and metabolites occurs.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration

    Maprotiline is administered orally.
    To reduce daytime sedation and improve sleep, may administer entire daily dose at bedtime. In the minority of patients that experience stimulation and insomnia with bedtime dosing, the dose should be given in the morning or administered in divided doses over the course of the day.

    STORAGE

    Ludiomil:
    - Protect from light
    - Store at room temperature (between 59 to 86 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Tricyclic antidepressant hypersensitivity

    Maprotiline is contraindicated in patients with a hypersensitivity to maprotiline or any inactive ingredients in the formulation. Maprotiline, a tetracyclic antidepressant, is structurally related to the tricyclic antidepressants. The potential for cross-reactivity between tricyclic antidepressants and maprotiline has not been established. However, alternative therapy should be considered in patients with tricyclic antidepressant hypersensitivity, particularly if the reaction was severe or life-threatening. Tricyclic antidepressants can also display cross-sensitivity with carbamazepine; however, the effect of administering a tetracyclic antidepressant like maprotiline to patients with a carbamazepine hypersensitivity is unknown.

    Bipolar disorder, mania

    All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, maprotiline should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or suicidality. It should be noted that maprotiline is not approved for treating bipolar depression.

    Children, suicidal ideation

    Maprotiline is generally not recommended for use in children or adolescents under the age of 18 years old. Maprotiline is not FDA-approved for the treatment of depression in pediatric patients. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. A causal role for antidepressants in inducing suicidality has been established in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4,400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Pooled analysis of short-term clinical trials during early phase treatment with SSRIs and other antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavior. The clinical need for an antidepressant in children or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of therapy or at the time of dose increases or decreases; such observation would generally include at least weekly face-to-face contact with patients during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between visits. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy (i.e., beyond several months). The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary psychiatric disorder. All patients with a history of suicidal ideation or behaviors and those with a prominence of suicidal ideation prior to treatment are considered at an increased risk for suicidal ideation or attempts, and should be closely monitored during treatment with maprotiline. In patients who exhibit changes in symptoms, worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. All antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Maprotiline should be used with caution in children and adolescents with a known family history of heart disease, or in children who are taking other medications concomitantly that might cause drug interactions. QTc interval prolongation, tachycardia, and other side effects have been reported in children who have taken cyclic antidepressants; there are rare reports of deaths due to cardiovascular side effects. Routine cardiovascular monitoring has been suggested for children receiving cyclic antidepressants due to the potential of these agents to produce adverse cardiac effects.

    MAOI therapy

    Maprotiline is contraindicated for concomitant use with monoamine oxidase inhibitor therapy (MAOI therapy). A minimum of 14 days should be allowed to elapse after discontinuation of MAOI before treatment with maprotiline is initiated. Effects should be monitored with gradual increase in dosage until optimum response is achieved.

    Electroconvulsive therapy (ECT), seizure disorder, seizures

    Maprotiline is contraindicated in patients with a known or suspected seizure disorder because this drug can lower the seizure threshold. Seizures have been associated with the use of maprotiline. Most of the seizures have occurred in patients without a known history of seizures. However, in some cases, other confounding factors were present, including concomitant use of medications known to lower the seizure threshold, rapid escalation of the dosage of maprotiline, and dosage that exceeded the recommended therapeutic range. The incidence of direct reports is less than 1/10 of 1%. The risk of seizures may be increased when maprotiline is used with phenothiazines, when the dosage of benzodiazepines is rapidly tapered in patients receiving maprotiline, or when the recommended dosage of maprotiline is exceeded. The risk of seizures in patients treated with maprotiline may be reduced by initiating therapy at a low dosage, maintaining the initial dosage for 2 weeks before raising it gradually in small increments due to the long half-life of maprotiline (average 51 hours), and using the lowest effective dose during maintenance therapy. Concurrent administration of maprotiline with electroconvulsive therapy (ECT) should be avoided because of the lack of experience in this area.

    Acute myocardial infarction, AV block, bradycardia, bundle-branch block, cardiac arrhythmias, cardiac disease, coronary artery disease, females, hypertension, hypocalcemia, hypokalemia, hypomagnesemia, long QT syndrome, malnutrition, myocardial infarction, QT prolongation, thyroid disease

    Maprotiline is contraindicated in patients who are in the acute recovery phase following acute myocardial infarction. Maprotiline is structurally related to the tricyclic antidepressants and should be used with caution in patients with any cardiac disease. The risk of cardiovascular adverse events with maprotiline is higher after acute overdose. Changes in the electrocardiogram (ECG), particularly in QRS axis or width are clinically significant indicators of toxicity. Patients with cardiac disease may need regular clinical exams and some may need ECG monitoring. In general, do not administer maprotiline to patients with QT prolongation or familial histories of long QT syndrome. Use with extreme caution in patients with cardiac conduction abnormalities (e.g., cardiac arrhythmias, AV block, bundle-branch block, tachycardia) or a previous history of myocardial infarction. Use maprotiline with caution in patients with other conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, hypertension, coronary artery disease, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, elderly patients, patients with diabetes, thyroid disease, malnutrition, alcoholism, or hepatic dysfunction may also be at increased risk for QT prolongation.

    Prostatic hypertrophy, urinary retention

    Because of its anticholinergic properties, maprotiline should be administered with caution in patients with history of urinary retention or risks for urinary retention, such as patients with prostatic hypertrophy.

    Closed-angle glaucoma, contact lenses, increased intraocular pressure

    Caution is recommended when prescribing maprotiline to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated. Maprotiline may also cause dryness of the eyes that may be of significance for the elderly or for wearers of contact lenses.

    Agranulocytosis, neutropenia

    On rare occasions, agranulocytosis, neutropenia or other blood count abnormalities have been reported with cyclic antidepressants. Maprotiline should be discontinued if there is evidence of neutropenia. Leukocyte and differential counts should be performed in patients who develop fever and sore throat during therapy.

    Hypothyroidism

    Caution should be exercised when administering maprotiline to patients with hypothyroidism or those hypothyroid patients on thyroid medication because of the possibility of enhanced potential for cardiovascular toxicity of maprotiline. Hypothyroidism that is untreated will prevent adequate response to antidepressant therapy, and hypothyroidism is often ruled out as a potential cause of depression prior to initiating antidepressant treatment.

    Hepatic disease, poor metabolizers

    Maprotiline should be used with caution in patients with hepatic disease. Maprotiline is metabolized in the liver to active metabolite and inactive metabolites. Enterohepatic circulation of both active drug and metabolites occurs. Metabolism of maprotiline may be altered in patients with hepatic impairment. Patients who are poor metabolizers of CYP2D6 may also have increased drug concentrations of maprotiline, and cautious dose adjustments may be necessary in these patients.

    Driving or operating machinery, ethanol ingestion

    Maprotiline can induce significant sedation, particularly during the initiation of treatment. Patients should use caution when driving or operating machinery until they are aware of the effects of the medication. As with other antidepressants, patients are recommended to avoid ethanol ingestion during maprotiline therapy.

    Surgery

    Prior to elective surgery, maprotiline should be discontinued for as long as clinically feasible, since little is known about the interaction between maprotiline and general anesthetics.

    Radiographic contrast administration

    Cyclic antidepressants (such as maprotiline) lower the seizure threshold. Because of a potential increased risk of seizures, cyclic antidepressants should not be used during intrathecal radiographic contrast administration. Therapy should be discontinued 48 hours before and not restarted for at least 24 hours after myelography.

    Sunlight (UV) exposure

    Patients may be more prone to sunburn during therapy with maprotiline. Suitable precautions should be taken prior to sunlight (UV) exposure, such as wearing long-sleeved clothing and a hat, and using sunscreens.

    Abrupt discontinuation

    Following prolonged therapy, abrupt discontinuation of maprotiline or other cyclic antidepressants should generally be avoided because it could precipitate symptoms of cholinergic rebound such as nausea, vomiting, or diarrhea.

    Anticholinergic medications, geriatric

    Maprotiline dose selection should be cautious in the geriatric patient, starting at the low end of the dosage range and with slow dosage titration and observation. In general, lower dosages are recommended for elderly patients over 60 years of age. The anticholinergic effects of maprotiline may be additive to those of other anticholinergic medications in any patient, but the older adult may be particularly susceptible to these effects. Geriatric patients are particularly sensitive to the peripheral and central anticholinergic side effects of cyclic antidepressants. According to the Beers Criteria, maprotiline is considered a potentially inappropriate medication (PIM) for use in geriatric patients with a chronic seizure condition or epilepsy and should generally be avoided in these populations because maprotiline lowers the seizure threshold. The Beers expert panel states that maprotiline may be acceptable in geriatric patients with a well-controlled seizure condition in whom alternative agents have not been effective. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of 2 or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    Neonates, pregnancy

    Maprotiline is a tetracyclic antidepressant. Animal studies with maprtotiline have failed to demonstrate teratogenicity, carcinogenicity, mutagenicity, or impairment of fertility. Because there are no adequate and well controlled studies in pregnant women, maprotiline should only be used in pregnancy if the benefits to the mother clearly outweigh the possible risks to the fetus. There are reports of complications in neonates after in utero exposure to cyclic antidepressants including hypoglycemia, respiratory diagnoses, developmental delays, and jaundice. In addition, neonatal withdrawal symptoms have been reported following in utero exposure to someantidepressants. More studies are needed. A prospective trial evaluating the effects of in utero exposure to cyclic antidepressants in infants 15 to 71 months of age compared to similar non-exposed controls found that exposure to antidepressants did not adversely affect IQ, language, behavior, or temperament. The effects of maprotiline during labor and obstetric delivery are unknown.

    Breast-feeding

    Maprotiline is excreted into human breast milk and caution is recommended when administering the drug during breast-feeding. At steady state, the concentrations in the milk correspond closely to the concentrations in maternal whole blood. Maprotiline has rarely caused galactorrhea in non-lactating women, and thus, interference with proper lactation is possible. Consider alternatives to maprotiline if possible. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 1.0-1.0
    ileus / Delayed / 0-1.0
    stroke / Early / Incidence not known
    torsade de pointes / Rapid / Incidence not known
    AV block / Early / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    ventricular tachycardia / Early / Incidence not known
    heart failure / Delayed / Incidence not known
    suicidal ideation / Delayed / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known

    Moderate

    urinary retention / Early / 1.0-10.0
    constipation / Delayed / 6.0-6.0
    blurred vision / Early / 4.0-4.0
    ataxia / Delayed / 0-1.0
    akathisia / Delayed / 0-1.0
    peripheral neuropathy / Delayed / 0-1.0
    dysarthria / Delayed / 0-1.0
    memory impairment / Delayed / 0-1.0
    confusion / Early / 0-1.0
    mania / Early / 0-1.0
    hallucinations / Early / 0-1.0
    psychosis / Early / 0-1.0
    stomatitis / Delayed / 0-1.0
    dysphagia / Delayed / 0-1.0
    galactorrhea / Delayed / 0-1.0
    impotence (erectile dysfunction) / Delayed / 0-1.0
    elevated hepatic enzymes / Delayed / 0-1.0
    QT prolongation / Rapid / Incidence not known
    hypotension / Rapid / Incidence not known
    hypertension / Early / Incidence not known
    PR prolongation / Rapid / Incidence not known
    orthostatic hypotension / Delayed / Incidence not known
    palpitations / Early / Incidence not known
    sinus tachycardia / Rapid / Incidence not known
    EEG changes / Delayed / Incidence not known
    depression / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    testicular swelling / Early / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    xerostomia / Early / 22.0-22.0
    drowsiness / Early / 16.0-16.0
    dizziness / Early / 8.0-8.0
    headache / Early / 4.0-4.0
    fatigue / Early / 4.0-4.0
    weakness / Early / 4.0-4.0
    tremor / Early / 3.0-3.0
    anxiety / Delayed / 3.0-3.0
    insomnia / Early / 2.0-2.0
    agitation / Early / 2.0-2.0
    nausea / Early / 2.0-2.0
    paresthesias / Delayed / 0-1.0
    tinnitus / Delayed / 0-1.0
    nightmares / Early / 0-1.0
    restlessness / Early / 0-1.0
    weight gain / Delayed / 0-1.0
    vomiting / Early / 0-1.0
    tongue discoloration / Delayed / 0-1.0
    dysgeusia / Early / 0-1.0
    abdominal pain / Early / 0-1.0
    diarrhea / Early / 0-1.0
    weight loss / Delayed / 0-1.0
    breast enlargement / Delayed / 0-1.0
    gynecomastia / Delayed / 0-1.0
    libido increase / Delayed / 0-1.0
    libido decrease / Delayed / 0-1.0
    increased urinary frequency / Early / 0-1.0
    nasal congestion / Early / 0-1.0
    syncope / Early / Incidence not known
    mydriasis / Early / Incidence not known
    hypersalivation / Early / Incidence not known
    photosensitivity / Delayed / Incidence not known
    fever / Early / Incidence not known
    hyperhidrosis / Delayed / Incidence not known
    pruritus / Rapid / Incidence not known
    alopecia / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    flushing / Rapid / Incidence not known
    petechiae / Delayed / Incidence not known
    purpura / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abarelix: (Major) Since abarelix can cause QT prolongation, abarelix should be used cautiously, if at all, with other drugs that are associated with QT prolongation including maprotiline.
    Acetaminophen; Butalbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Acetaminophen; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Acetaminophen; Dichloralphenazone; Isometheptene: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic and CNS effects may be seen when maprotiline is used concomitantly with dichloralphenazone.
    Acetaminophen; Diphenhydramine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker.
    Acetaminophen; Guaifenesin; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as maprotiline, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking maprotiline, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower maprotiline dose. Monitor patients for sedation and respiratory depression.
    Acetaminophen; Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with maprotiline may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Acetaminophen; Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as maprotiline, can potentiate respiratory depression and/or sedation. Use with caution.
    Acetaminophen; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Acetaminophen; Tramadol: (Moderate) Concomitant use of tramadol increases the seizure risk in patients taking tricyclic antidepressants and other tricyclic compounds. Tramadol use may increase the seizure risk in patients taking drugs that reduce the seizure threshold. Maprotiline is pharmacologic similar to the tricyclic antidepressants, may decrease the seizure threshold, and causes CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant. In vitro drug interaction studies in human liver microsomes suggest that concomitant administration of tricyclic antidepressants could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. It is not clear if maprotiline, a related cyclic antidepressant, would cause these types of interactions.
    Acrivastine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Albuterol: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Albuterol; Ipratropium: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Alfentanil: (Moderate) Concomitant use of alfentanil with other medications with CNS depressant activity, like maprotiline can potentiate the effects of alfentanil on respiration, CNS alertness, and blood pressure. A dose reduction of one or both drugs may be warranted.
    Alfuzosin: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), alfuzosin and maprotiline should be used together cautiously. Based on electrophysiology studies performed by the manufacturer, alfuzosin may prolong the QT interval in a dose-dependent manner. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Almotriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Alosetron: (Moderate) Alosetron, if combined with drugs that possess anticholinergic properties like maprotiline, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus.
    Alprazolam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Amantadine: (Moderate) Amantadine may exhibit anticholinergic activity. Medications with significant anticholinergic activity, such as maprotiline, may potentiate the anticholinergic effects of amantadine. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, neurologic function, and temperature regulation.
    Ambenonium Chloride: (Moderate) The therapeutic benefits of ambenonium may be diminished when co-administered with the antimuscarinics. Drugs known to exhibit anticholinergic properties that could potentially interfere with the cholinesterase inhibitor activity include maprotiline.
    Amiodarone: (Major) If possible, avoid coadministration of amiodarone and drugs known to prolong the QT interval. Amiodarone, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Although the frequency of TdP is less with amiodarone than with other Class III agents, amiodarone is still associated with a risk of TdP. Due to the extremely long half-life of amiodarone, a drug interaction is possible for days to weeks after discontinuation of amiodarone. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Additionally, amiodarone may also inhibit the CYP2D6 metabolism of maprotiline. The need to coadminister maprotiline with amiodarone should be done with a careful assessment of risk versus benefit; consider alternative therapy to maprotiline.
    Amitriptyline: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Amitriptyline; Chlordiazepoxide: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Amobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Amoxapine: (Severe) The use of amoxapine with chemically-related cyclic antidepressants like maprotiline or tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Amoxicillin; Clarithromycin; Lansoprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with maprotiline. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as clarithromycin.
    Amoxicillin; Clarithromycin; Omeprazole: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with maprotiline. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as clarithromycin.
    Amphetamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Amphetamine; Dextroamphetamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Amprenavir: (Major) Caution is advised with the concomitant use of amprenavir and maprotiline due to the potential for serious adverse reactions. Amprenavir inhibits CYP3A4; maprotiline is a substrate of CYP3A4. Concomitant use may result in increased maprotiline concentrations.
    Anagrelide: (Major) Torsades de pointes (TdP) and ventricular tachycardia have been reported during post-marketing use of anagrelide. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with anagrelide include maprotiline.
    Anxiolytics; Sedatives; and Hypnotics: (Moderate) CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Apomorphine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering maprotiline with apomorphine. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data indicate that QT prolongation is also possible with apomorphine administration. The change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines; however, large increases (> 60 msecs from pre-dose) have occurred in two patients receiving 6 mg doses. Doses <= 6 mg SC are associated with minimal increases in QTc; doses > 6 mg SC do not provide additional clinical benefit and are not recommended. In addition, apomorphine causes considerable somnolence, and concomitant administration of apomorphine and CNS agents like the tricyclic antidepressants could result in additive CNS effects.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if maprotiline and aprepitant, fosaprepitant are used concurrently and monitor for an increase in maprotiline-related adverse effects for several days after administration of a multi-day aprepitant regimen. Maprotiline is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of maprotiline. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
    Arformoterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Aripiprazole: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Aripiprazole should be used cautiously with maprotiline.
    Arsenic Trioxide: (Major) If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with arsenic trioxide include maprotiline. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Artemether; Lumefantrine: (Major) Artemether; lumefantrine is an inhibitor of and maprotiline is partially metabolized by the CYP2D6 isoenzyme; therefore, coadministration may lead to increased maprotiline concentrations. Furthermore, although there are no studies examining the effects of artemether; lumefantrine in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. Concomitant use of artemether; lumefantrine with drugs that may prolong the QT interval, such as maprotiline, should be avoided. Consider ECG monitoring if maprotiline must be used with or after artemether; lumefantrine treatment.
    Articaine; Epinephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Asenapine: (Major) Asenapine has been associated with QT prolongation. According to the manufacturer, asenapine should hould be avoided in combination with other agents also known to have this effect (e.g., maprotiline). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Aspirin, ASA; Carisoprodol: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as maprotiline, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking maprotiline, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower maprotiline dose. Monitor patients for sedation and respiratory depression.
    Atazanavir: (Moderate) Atazanavir competitively inhibits the enzymes CYP3A4, CYP1A2 and CYP2C9. Concentrations of drugs that are substrates of these enzymes (e.g., tricyclic antidepressants) may be increased with concomitant atazanavir use. According to the manufacturer of atazanavir, coadministration of atazanavir in a patient on a tricyclic antidepressant (TCA) may result in increased serum concentrations of the TCA, and the two drugs should be coadministered with caution due to a potential for serious adverse events. Monitor the patient for anticholinergic effects (e.g., sedation, confusion, constipation) associated with TCA use. The manufacturer recommends TCA concentration monitoring if atazanavir is used concomitantly with a TCA. Maprotiline is related to the tricyclic antidepressants, and until more data is available, similar caution is advised when using maprotiline with atazanavir.
    Atazanavir; Cobicistat: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate. (Moderate) Atazanavir competitively inhibits the enzymes CYP3A4, CYP1A2 and CYP2C9. Concentrations of drugs that are substrates of these enzymes (e.g., tricyclic antidepressants) may be increased with concomitant atazanavir use. According to the manufacturer of atazanavir, coadministration of atazanavir in a patient on a tricyclic antidepressant (TCA) may result in increased serum concentrations of the TCA, and the two drugs should be coadministered with caution due to a potential for serious adverse events. Monitor the patient for anticholinergic effects (e.g., sedation, confusion, constipation) associated with TCA use. The manufacturer recommends TCA concentration monitoring if atazanavir is used concomitantly with a TCA. Maprotiline is related to the tricyclic antidepressants, and until more data is available, similar caution is advised when using maprotiline with atazanavir.
    Atomoxetine: (Major) QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Atomoxetine is considered a drug with a possible risk of torsade de pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with atomoxetine include maprotiline.
    Atropine: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer, treatment initiation with maprotiline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than maprotiline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving maprotiline and requiring urgent treatment with IV methylene blue, maprotiline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Maprotiline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Atropine; Difenoxin: (Moderate) Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as maprotiline, may produce additive effects with diphenoxylate/difenoxin if used concomitantly. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Atropine; Diphenoxylate: (Moderate) Diphenoxylate/difenoxin decreases GI motility. Other drugs that also decrease GI motility, such as maprotiline, may produce additive effects with diphenoxylate/difenoxin if used concomitantly. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Atropine; Edrophonium: (Major) Maprotiline may antagonize some of the effects of edrophonium. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Azelastine: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including maptrotiline.
    Azelastine; Fluticasone: (Moderate) An enhanced CNS depressant effect may occur when azelastine is combined with other CNS depressants including maptrotiline.
    Azithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), cautious use of maprotiline with azithromycin is advised. Azithromycin has been associated with post-marketing reports of QT prolongation and TdP. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Baclofen: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Barbiturates: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Bedaquiline: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering bedaquiline with maprotiline. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Benzodiazepines: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) According to the manufacturer, treatment initiation with maprotiline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than maprotiline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving maprotiline and requiring urgent treatment with IV methylene blue, maprotiline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Maprotiline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Benzphetamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Benztropine: (Moderate) Additive anticholinergic effects may be seen when benztropine is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Bepridil: (Severe) Bepridil administration is associated with a well-established risk of QT prolongation and torsades de pointes and is contraindicated for use with drugs that prolong the QT interval, such as maprotiline, due to the risk of TdP.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include maprotiline.
    Bismuth Subsalicylate: (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of maprotiline may produce additive effects.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include maprotiline. (Moderate) Antidiarrheals decrease GI motility. Agents that inhibit intestinal motility or prolong intestinal transit time have been reported to induce toxic megacolon. The concomitant administration of maprotiline may produce additive effects.
    Brexpiprazole: (Moderate) Due to the CNS effects of brexpiprazole, caution is advisable when brexpiprazole is given in combination with other centrally-acting medications including heterocyclic antidepressants.
    Brompheniramine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Brompheniramine; Carbetapentane; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Brompheniramine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Budesonide; Formoterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Buprenorphine: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include maprotiline. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine with other CNS depressants can lead to additive CNS depressive effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants can include maprotiline. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. A dose reduction of one or both drugs may be warranted. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.
    Bupropion: (Major) Concurrent administration of maprotiline with bupropion should be undertaken only with extreme caution due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus may reduce the clearance of maprotiline leading to a potential for increased Cmax, AUC and half-life. Maprotiline appears to be metabolized via CYP2D6. Low initial dosing and gradual dose increases of both drugs should be employed. If bupropion is added to a regimen of a patient already receiving maprotiline, the need to reduce the maprotiline dosage should be considered.
    Bupropion; Naltrexone: (Major) Concurrent administration of maprotiline with bupropion should be undertaken only with extreme caution due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus may reduce the clearance of maprotiline leading to a potential for increased Cmax, AUC and half-life. Maprotiline appears to be metabolized via CYP2D6. Low initial dosing and gradual dose increases of both drugs should be employed. If bupropion is added to a regimen of a patient already receiving maprotiline, the need to reduce the maprotiline dosage should be considered.
    Buspirone: (Moderate) CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Butabarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Butorphanol: (Moderate) Pain medications such as buprenorphine; butorphanol; nalbuphine; pentazocine; should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Capsaicin; Metaxalone: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Carbamazepine: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Carbetapentane; Chlorpheniramine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Guaifenesin; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Phenylephrine; Pyrilamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbetapentane; Pyrilamine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane is combined with other CNS depressants including amoxapine, maprotiline, mirtazapine or trazodone.
    Carbidopa; Levodopa: (Moderate) Maprotiline exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Carbidopa; Levodopa; Entacapone: (Moderate) Maprotiline exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Carbinoxamine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Carbinoxamine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Carbinoxamine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution is advisable when cariprazine is given in combination with other centrally-acting medications including heterocyclic antidepressants.
    Carisoprodol: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Ceritinib: (Major) Periodically monitor electrolytes and ECGs in patients receiving concomitant treatment with ceritinib and maprotiline; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. Ceritinib causes concentration-dependent prolongation of the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Cetirizine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlophedianol; Guaifenesin; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Chlorcyclizine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlordiazepoxide: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Chlordiazepoxide; Clidinium: (Moderate) Additive anticholinergic and CNS effects may be seen when maprotiline is used concomitantly with clidinium. (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Chloroquine: (Major) Coadminister chloroquine with other drugs known to prolong the QT interval, such as maprotiline, with caution. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); fatalities have been reported. The risk of QT prolongation is increased with higher chloroquine doses. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Chlorpheniramine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpheniramine; Codeine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Chlorpheniramine; Dextromethorphan: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Chlorpheniramine; Hydrocodone: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Chlorpheniramine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpheniramine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Chlorpromazine: (Major) Phenothiazines have been reported to prolong the QT interval. Because maprotiline is associated with a possible risk for QT prolongation and torsade de pointes (TdP), concurrent use with chlorpromazine should be approached with caution. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. In addition, additive anticholinergic effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity such as maprotiline. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or CNS effects such as drowsiness may also occur.
    Chlorthalidone; Clonidine: (Major) Concurrent use of clonidine with maprotiline should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by cyclic antidepressants, such as maprotiline. If coadministration of maprotiline with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed.
    Cholinergic agonists: (Major) Maprotiline may antagonize some of the effects of parasympathomimetics. However, bethanechol has occasionally been used therapeutically to offset some of the adverse antimuscarinic effects of cyclic antidepressants. Due to their anticholinergic actions, some cyclic antidepressants like maprotiline may potentially antagonize the therapeutic actions of the cholinesterase-inhibitors used for the treatment of dementia.
    Cimetidine: (Moderate) Cimetidine can inhibit the systemic clearance of drugs that undergo oxidative metabolism, such as maprotiline, resulting in increased plasma levels of the antidepressant. Patients should be monitored for maprotiline-related side effects and toxicity if cimetidine is added; when possible, choose an alternative H2-blocker for treatment.
    Cinacalcet: (Moderate) Cinacalcet, a strong in vitro inhibitor of the CYP2D6 cytochrome P450 enzyme, may theoretically increase serum concentrations of other drugs metabolized by this enzyme, such as maprotiline.
    Ciprofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering maprotiline with ciprofloxacin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as ciprofloxacin.
    Cisapride: (Severe) Cisapride exhibits many important drug interactions that affect its safety and efficacy profile; the manufacturer only offers cisapride therapy through an investigational limited access program due to the need to appropriately screen for eligible patients. Cisapride has been implicated as a cause of QT prolongation, particularly in patients with known risk factors or when cisapride has been combined with drugs that increase cisapride serum concentrations or exhibit additive effects on cardiac repolarization. Maprotiline is related to the tricyclic antidepressants and has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Due to the potential for serious cardiac side effects, maprotiline is contraindicated for use along with cisapride. In addition to adverse cardiac effects, the antimuscarinic effects of maprotiline may hinder the therapeutic actions of cisapride on GI motility.
    Citalopram: (Major) Because citalopram and maprotiline are associated with a possible risk for QT prolongation and torsade de pointes (TdP), these combinations should be used cautiously and with close monitoring. Monitoring of the ECG is recommended in patients receiving citalopram with other drugs that may prolong the QT interval such as maprotiline. CYP2D6, the primary isoenzyme responsible for the metabolism of maprotiline, is inhibited to some extent by citalopram. Patients receiving maprotiline should be monitored closely for toxicity if an SSRI is added.
    Clarithromycin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering clarithromycin with maprotiline. Administration of clarithromycin has resulted in prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as clarithromycin.
    Clemastine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Clobazam: (Moderate) These drugs may be used together with caution. You may feel drowsy or more tired when taking these drugs together. Do not drive or operate machinery until you know how these drugs affect you. Notify your health care provider if you notice that your medication is not working as well for you, or if you experience confusion, dizziness, falls, unsteadiness, or other troublesome side effects. A dosage reduction of CYP2D6 substrates, such as maprotiline, may be necessary during co-administration of clobazam. Limited in vivo data suggest that clobazam is an inhibitor of CYP2D6. If these agents are used in combination, it is advisable to monitor the patient for maprotiline-related adverse reactions.
    Clomipramine: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Clonazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Clonidine: (Major) Concurrent use of clonidine with maprotiline should be avoided when possible, due to multiple possible interactions. Clonidine's antihypertensive effect can be reduced by cyclic antidepressants, such as maprotiline. If coadministration of maprotiline with clonidine cannot be avoided, the patient should be closely monitored for increased blood pressure and clonidine dosages adjusted as needed.
    Clorazepate: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Clozapine: (Major) Caution is recommended during concurrent treatment of clozapine with heterocyclic antidepressants including amoxapine or maprotiline. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Amoxapine and maprotiline have a possible risk of QT prolongation and TdP. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation. Additive anticholinergic effects may be seen when clozapine is used concomitantly with other drugs known to possess antimuscarinic activity like amoxapine or maprotiline. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or sedation is also possible when clozapine is combined with these drugs. In addition, clozapine is metabolized by CYP1A2 and CYP2D6 isoenzymes; maprotiline is also metabolized via CYP2D6 and could compete for the same metabolic pathway.
    Cobicistat: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Codeine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Codeine; Phenylephrine; Promethazine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Codeine; Promethazine: (Moderate) Concomitant use of codeine with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of codeine and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of codeine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of codeine and/or the CNS depressant is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    COMT inhibitors: (Moderate) COMT inhibitors, such as entacapone and tolcapone, should be given cautiously with other agents that cause CNS depression, such as heterocyclic antidepressants, due to the possibility of additive sedation.
    Crizotinib: (Major) Monitor ECGs for QT prolongation and monitor electrolytes in patients receiving crizotinib concomitantly with maprotiline. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. Crizotinib has been associated with concentration-dependent QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Cyclizine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Cyclobenzaprine: (Major) Cyclobenzaprine is associated with a possible risk of QT prolongation and torsades de pointes (TdP), particularly in the event of acute overdose, and should be used cautiously with other drugs with a possible risk of QT prolongation and TdP such as maprotiline. In addition, cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as maprotiline, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus. concurrent use of cyclobenzaprine should generally be avoided in patients taking maprotiline due to the additive risk of similar pharmacology and side-effect profiles. Patients should be monitored for excessive adverse effects from either agent.
    Cyproheptadine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Dantrolene: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Darifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like darifenacin are used concomitantly with maprotiline.
    Darunavir: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Darunavir is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Darunavir; Cobicistat: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate. (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with darunavir. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Darunavir is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of maprotiline. Since the magnitude of the interaction with the maprotiline is difficult to predict but may be significant, monitor patients receiving ritonavir and maprotiline concurrently closely. In addition, coadministration increases the risk for QT prolongation and torsade de pointes. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
    Dasatinib: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dasatinib and maprotiline should be used together cautiously. In vitro studies have shown that dasatinib has the potential to prolong cardiac ventricular repolarization (prolong QT interval). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Daunorubicin: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Maprotiline should be used cautiously with anthracyclines such as daunorubicin or doxorubicin due to the potential risks for anthracycline cardiac toxicity. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
    Degarelix: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include degarelix.
    Delavirdine: (Moderate) Delavirdine inhibits CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme including maprotiline. A dosage adjustment of maprotiline may be needed when given concurrently with delavirdine.
    Desflurane: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Desipramine: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Desloratadine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Deutetrabenazine: (Major) For patients taking a deutetrabenazine dosage more than 24 mg/day with maprotiline, assess the QTc interval before and after increasing the dosage of either medication. Clinically relevant QTc prolongation may occur with deutetrabenazine. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and neuroleptic malignant-like syndrome has been reported with maprotiline. Additionally, concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as maprotiline, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexchlorpheniramine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Dexmethylphenidate: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dextroamphetamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker.
    Dextromethorphan; Guaifenesin; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dextromethorphan; Promethazine: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Dextromethorphan; Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include maprotiline.
    Diazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when dicyclomine is used concomitantly with other drugs that possess anticholinergic properties, such as maprotiline. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Diethylpropion: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dimenhydrinate: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Diphenhydramine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Diphenhydramine; Ibuprofen: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker.
    Diphenhydramine; Naproxen: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker.
    Diphenhydramine; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as diphenhydramine, a sedating H1-blocker.
    Disopyramide: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Disopyramide is associated with a possible risk for QT prolongation and TdP and should be used cautiously with maprotiline. In addition to effects on the EKG, disopyramide also has significant anticholinergic effects that are additive to those of maprotiline.
    Disulfiram: (Moderate) The combination of cyclic antidepressants with disulfiram can produce transient delirium. Pharmacokinetic interactions have been noted between disulfiram and tricyclic antidepressants, but the clinical significance is uncertain. Disulfiram is known to inhibit some of the hepatic cytochrome P450 isoenzymes involved in cyclic antidepressant metabolism.
    Dobutamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Dofetilide: (Severe) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Because of the potential for TdP, use of dofetilide with maprotiline is contraindicated. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and TdP.
    Dolasetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), dolasetron and maprotiline should be used together cautiously. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs; however, the potential for additive effects warrants cautious use.
    Dolutegravir; Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with maprotiline. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Donepezil: (Major) Concurrent use of maprotiline and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and maprotiline has a possible risk for QT prolongation and TdP. In addition, maprotiline may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Donepezil; Memantine: (Major) Concurrent use of maprotiline and donepezil should be avoided if possible. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy, and maprotiline has a possible risk for QT prolongation and TdP. In addition, maprotiline may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of donepezil. Donepezil inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine.
    Dopamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Doxepin: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Doxorubicin: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Maprotiline should be used cautiously with anthracyclines such as daunorubicin, doxorubicin, epirubicin, and idarubicin due to the potential risks for anthracycline cardiac toxicity. Acute cardiotoxicity can occur during administration of daunorubicin or doxorubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported during anthracycline therapy.
    Doxylamine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Doxylamine; Pyridoxine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Dronabinol, THC: (Moderate) Use caution if the use of maprotioline is necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
    Dronedarone: (Severe) Concomitant use of dronedarone and maprotiline is contraindicated. Dronedarone is an inhibitor of CYP2D6. Maprotiline is a substrate for CYP2D6. Coadministration of dronedarone and maprotiline may result in elevated plasma concentrations of maprotiline. In addition, maprotiline has been established to have a possible risk of QT prolongation and Torsade de Pointes (TdP). Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation.
    Droperidol: (Major) Droperidol should be administered with extreme caution to patients receiving other agents that may prolong the QT interval. Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes (TdP). Any drug known to have potential to prolong the QT interval should not be coadministered with droperidol. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with droperidol include maprotiline.
    Duloxetine: (Major) Documentation is not available on the concurrent use of duloxetine with many CNS agents. Caution should be observed when administering duloxetine with other CNS-active drugs in the absence of clinical data regarding combined use. Examples of these drugs include the maprotiline. In addition, duloxetine is a moderate inhibitor of CYP2D6, and maprotiline appears to be metabolized by this isozyme. It is possible that duloxetine could increase the risk of cyclic-antidepressant-induced side effects or toxicity.
    Edrophonium: (Major) Maprotiline may antagonize some of the effects of edrophonium.
    Efavirenz: (Major) Coadministration of efavirenz and maprotiline may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, efavirenz may induce the CYP3A4 metabolism of maprotiline, potentially reducing the efficacy of maprotiline by decreasing its systemic exposure.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Coadministration of efavirenz and maprotiline may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with use of efavirenz. Although data are limited, the manufacturer of efavirenz recommends an alternative antiretroviral be considered for patients receiving medications with a known risk for TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, efavirenz may induce the CYP3A4 metabolism of maprotiline, potentially reducing the efficacy of maprotiline by decreasing its systemic exposure.
    Elbasvir; Grazoprevir: (Moderate) Administering maprotiline with elbasvir; grazoprevir may result in elevated maprotiline plasma concentrations. Maprotiline is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
    Eletriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Eliglustat: (Major) Coadminister maprotiline and eliglustat cautiously and with close monitoring; there may be an increased risk of QT prolongation and/or antidepressant-associated adverse effects. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). In addition, coadministration may result in increased concentrations of the antidepressant. If eliglustat and maprotiline are used together, consider reducing the dosage of maprotiline and titrating to clinical effect. Eliglustat is a CYP2D6 inhibitor, and maprotiline is a CYP2D6 substrate.
    Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with maprotiline. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with maprotiline. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Enflurane: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Ephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Epinephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Epirubicin: (Major) Acute cardiotoxicity can occur during the administration of epirubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with epirubicin include maprotiline.
    Eribulin: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include eribulin. ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.
    Erythromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with maprotiline. Erythromycin is associated with prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some cyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin's effectiveness.
    Erythromycin; Sulfisoxazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering erythromycin with maprotiline. Erythromycin is associated with prolongation of the QT interval and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, erythromycin is sometimes used to stimulate GI motility, for example, in patients with diabetic gastroparesis. In patients requiring erythromycin to enhance GI motility, some cyclic antidepressants with substantial antimuscarinic properties may counteract erythromycin's effectiveness.
    Escitalopram: (Major) Because escitalopram and maprotiline are associated with a possible risk for QT prolongation and torsade de pointes (TdP), these combinations should be used cautiously and with close monitoring. In addition, escitalopram is a modest inhibitor of CYP2D6, one of the isoenzymes responsible for the metabolism of maprotiline. Patients receiving maprotiline and escitalopram should be closely monitored for toxicity, including QT prolongation and maprotiline-related adverse effects such as drowsiness, dry mouth, dizziness, anxiety, and seizures. Patients should be adivsed against driving or performing potentially hazardous tasks until the effects of the combination are known.
    Estazolam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Ethanol: (Major) Ethanol should be combined cautiously with maprotiline because it could cause additive depressant effects and possible respiratory depression or hypotension.
    Ethosuximide: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Etomidate: (Moderate) General anesthetics may produce additive CNS depression when used in patients taking maprotiline.
    Everolimus: (Moderate) Monitor for an increase in maprotiline-related adverse reactions if coadministration with everolimus is necessary; consider reducing the dose of maprotiline if clinically appropriate. Maprotiline is a CYP2D6 substrate and everolimus is a CYP2D6 inhibitor; concomitant use may increase plasma concentrations of maprotiline.
    Ezogabine: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include ezogabine. Additionally, maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Felbamate: (Major) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients carefully.
    Fentanyl: (Moderate) Concomitant use of fentanyl with other central nervous system (CNS) depressants, such as maprotiline, can potentiate the effects of the opiate and may lead to additive CNS or respiratory depression, profound sedation, or coma. Prior to concurrent use of fentanyl in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If these agents are used together, a reduced dosage of the fentanyl and/or maprotiline is recommended. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Fesoterodine: (Moderate) Coadministration of fesoterodine and other drugs with moderate to significant anticholinergic effects such as maprotiline may increase the frequency and/or severity of anticholinergic effects such as blurred vision, constipation, xerostomia, and urinary retention. Additive effects may be seen on GI smooth muscle, bladder function, the CNS, the eye, and temperature regulation.
    Fexofenadine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Fingolimod: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include fingolimod. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. After the first fingolimod dose, overnight monitoring with continuous ECG in a medical facility is advised for patients taking QT prolonging drugs with a known risk of torsades de pointes (TdP). Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia.
    Flavoxate: (Moderate) Additive anticholinergic and CNS effects may be seen when maprotiline is used concomitantly with flavoxate.
    Flecainide: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include flecainide, Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval.
    Fluconazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering fluconazole with maprotiline. Fluconazole has been associated with QT prolongation and rare cases of TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Fluoxetine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including maprotiline. In addition, clinicians should be alert for pharmacokinetic or pharmacodynamic interactions between cyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants. The SSRIs are known to inhibit CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the cyclic antidepressants. CYP2D6 is impaired most by fluoxetine and is the isozyme most responsible for metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. Patients receiving maprotiline should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7-9 days).
    Fluoxetine; Olanzapine: (Major) Because QT prolongation and torsade de pointes (TdP) have been reported in patients treated with fluoxetine, the manufacturer recommends caution when using fluoxetine with other drugs that prolong the QT interval, including maprotiline. In addition, clinicians should be alert for pharmacokinetic or pharmacodynamic interactions between cyclic antidepressants and the selective serotonin reuptake inhibitors (SSRIs) class of antidepressants. The SSRIs are known to inhibit CYP2D6 and/or CYP3A4, the isozymes responsible for metabolism of many of the cyclic antidepressants. CYP2D6 is impaired most by fluoxetine and is the isozyme most responsible for metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. Patients receiving maprotiline should be monitored closely for toxicity if a SSRI-type drug is added. Clinicians should be particularly cautious in patients with fluoxetine due to the extremely long elimination half-life of its metabolite, norfluoxetine (7-9 days). (Major) Coadministration may result in additive effects on the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, additive anticholinergic effects may be seen with coadministration. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Fluphenazine: (Moderate) Fluphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with fluphenazine include maprotiline. CNS effects, orthostatic hypotension, antimuscarinic effects) may occur during coadministration because maprotiline and phenothiazines are metabolized via similar pathways (CYP2D6), have structural similarities, and produce similar pharmacologic effects, like antimuscarinic activity. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Flurazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Fluticasone; Salmeterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Umeclidinium; Vilanterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluticasone; Vilanterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Fluvoxamine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and maprotiline. In addition, these medications may be duplicate treatment for some conditions. Cases of QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with elevated serum concentrations from high dose therapy. Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in commonly prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT prolonging drugs. Therefore, coadministration with fluvoxamine should be avoided if possible. In addition, fluvoxamine is a CYP2D6 inhibitor and maprotiline is a substrate for CYP2D6. In several cases, symptoms of toxicity, including seizures, have been reported when selective serotonin reuptake inhibitors (SSRIs) and cyclic antidepressants were used together. Patients receiving maprotiline should be monitored closely for toxicity if fluvoxamine is added.
    Formoterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Formoterol; Mometasone: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as maprotiline. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
    Frovatriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Gabapentin: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Galantamine: (Moderate) Due to their anticholinergic actions, some cyclic antidepressants, including mapotiline, may antagonize the therapeutic actions of the cholinesterase-inhibitors such as galantamine, which are used for the treatment of dementia. Consider alternatives if concurrent therapy is needed. If alternative therapy is not possible, monitor for deceased efficacy of galantamine.
    Gefitinib: (Moderate) Gefitinib may inhibit cytochrome P450 2D6 at clinical doses. Caution is recommended when administering gefitinib with other CYP2D6 substrates, such as maprotiline, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
    Gemifloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering maprotiline with gemifloxacin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Gemifloxacin may prolong the QT interval in some patients, with the maximal change in the QTc interval occurring approximately 5 to 10 hours following oral administration. The likelihood of QTc prolongation may increase with increasing dose of gemifloxacin; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher.
    Gemtuzumab Ozogamicin: (Major) Use gemtuzumab ozogamicin and maprotiline together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline.
    Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline. (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Goserelin: (Moderate) Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Maprotiline is associated with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with goserelin.
    Granisetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), granisetron and maprotiline should be used together cautiously. Granisetron has been associated with QT prolongation. According to the manufacturer, use of granisetron with drugs known to prolong the QT interval or are arrhythmogenic, may result in clinical consequences. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Guaifenesin; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Guaifenesin; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Guanabenz: (Major) Maprotiline, as a cyclic antidepressant, can block the action of guanabenz, preventing or significantly reducing the expected antihypertensive effects. Avoid use of maprotiline concurrently with these antihypertensive drug categories when possible.
    Guanfacine: (Major) Cyclic antidepressants like maprotiline can inhibit the hypotensive effects of guanfacine, causing an increase in blood pressure if given concomitantly. Increased dosages of guanfacine may be required in patients who are receiving maprotiline concurrently. In addition, concurrent maprotiline use may enhance the potential for rebound hypertension following guanfacine discontinuation. If guanfacine is withdrawn in the presence of maprotiline or other cyclic antidepressants, guanfacine should be tapered gradually and the patient should be monitored for potential hypertension.
    Guselkumab: (Moderate) Clinically relevant drug interactions may occur when guselkumab is administered with sensitive substrates of CYP2D6, such as maprotiline. Monitor maprotiline concentrations if guselkumab is initiated or discontinued; the maprotiline dose may need to be adjusted. During chronic inflammation, increased levels of certain cytokines can alter the formation of CYP450 enzymes. Thus, the formation of CYP2D6 could be normalized during guselkumab administration.
    Halofantrine: (Severe) Halofantrine is considered to have a well-established risk for QT prolongation and torsades de pointes and should be avoided in patients receiving drugs which may induce QT prolongation including maprotiline.
    Halogenated Anesthetics: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Haloperidol: (Major) Haloperidol can potentiate the actions of other CNS depressants such as cyclic antidepressants. Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects. Limited data suggest that haloperidol may inhibit the metabolism of some tricyclic antidepressants, however, the clinical significance of this interaction and the effect on maprotiline is uncertain. Haloperidol is an inhibitor of hepatic CYP2D6, and coadministration with maprotiline (CYP2D6 substrate) may lead to elevated maprotiline serum concentrations, potentiating toxicity. Haloperidol has also been associated with a possible risk for QT prolongation and/or torsades de pointes, particularly when excessive doses are used or in overdose. Haloperidol should be used cautiously with other agents that may have this effect (e.g., maprotiline).
    Halothane: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Homatropine; Hydrocodone: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other drugs known to possess relatively significant antimuscarinic properties including maprotiline and should be used together cautiously. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydantoins: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold. Ethotoin, phenytoin or fosphenytoin may increase antidepressant metabolism. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Hydrochlorothiazide, HCTZ; Methyldopa: (Moderate) Maprotiline, as a cyclic antidepressant, can block the action of methyldopa, preventing or significantly reducing the expected antihypertensive effects. Avoid use of maprotiline concurrently with this antihypertensive drug when possible.
    Hydrocodone: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydrocodone; Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydrocodone; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Concomitant use of hydrocodone with other CNS depressants may lead to hypotension, profound sedation, coma, respiratory depression and death. Prior to concurrent use of hydrocodone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Hydrocodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate hydrocodone at 20 to 30% of the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider a using a lower dose of the CNS depressant. Monitor patients for sedation and respiratory depression. Drugs that may cause additive CNS effects include maprotiline.
    Hydromorphone: (Moderate) Concomitant use of hydromorphone with other central nervous system (CNS) depressants can potentiate the effects of hydromorphone and may lead to additive CNS or respiratory depression, profound sedation, or coma. Examples of drugs associated with CNS depression include maprotiline. Prior to concurrent use of hydromorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If hydromorphone is used concurrently with a CNS depressant, a reduced dosage of hydromorphone and/or the CNS depressant is recommended; start with one-third to one-half of the estimated hydromorphone starting dose when using hydromorphone extended-release tablets. Carefully monitor the patient for hypotension, CNS depression, and respiratory depression. Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.
    Hydroxychloroquine: (Major) Avoid coadministration of hydroxychloroquine and maprotiline. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes (TdP) have been reported with the use of hydroxychloroquine. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Hydroxyzine: (Major) Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include maprotiline. In addition, the anticholinergic effects of hydroxyzine are moderate and may be enhanced when combined with medications with anticholinergic effects, such as maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) According to the manufacturer, treatment initiation with maprotiline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than maprotiline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving maprotiline and requiring urgent treatment with IV methylene blue, maprotiline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Maprotiline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as maprotiline, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking maprotiline, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower maprotiline dose. Monitor patients for sedation and respiratory depression.
    Ibuprofen; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Ibutilide: (Major) Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP should be used cautiously with ibutilide. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Idarubicin: (Major) Acute cardiotoxicity can occur during the administration of idarubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously and with close monitoring with idarubicin include maprotiline.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with maprotiline, a CYP3A substrate, as maprotiline toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Iloperidone: (Major) Iloperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since iloperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as maprotiline.
    Imatinib: (Major) Imatinib, STI-571 is a potent inhibitor of CYP2D6 and may increase concentrations of other drugs metabolized by this enzyme. Caution is recommended when administering imatinib with other CYP2D6 substrates, such as maprotiline, that have a narrow therapeutic range or where large increases in serum concentrations may be associated with severe adverse reactions.
    Imipramine: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Indacaterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline. (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with maprotiline due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with maprotiline may result in increased serum concentrations of maprotiline. Maprotiline is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
    Isocarboxazid: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Isoflurane: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Isoproterenol: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as maprotiline. Both maprotiline and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole (a potent CYP3A4 inhibitor) with maprotiline (a CYP3A4 substrate) may result in elevated maprotiline plasma concentrations and an increased risk for adverse events, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
    Kava Kava, Piper methysticum: (Major) Maprotiline and other antidepressants may interact with herbal and dietary supplements, including kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Additive CNS effects are possible. These herbal products are probably best avoided in combination with prescription antidepressants unless closely monitored by a health care professional.
    Ketamine: (Moderate) General anesthetics may produce additive CNS depression when used in patients taking maprotiline.
    Ketoconazole: (Major) Caution is advised when administering ketoconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as maprotiline. Both maprotiline and ketoconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of ketoconazole (a potent CYP3A4 inhibitor) with maprotiline (a CYP3A4 substrate) may result in elevated maprotiline plasma concentrations and an increased risk for adverse events, including QT prolongation.
    Labetalol: (Moderate) An increased incidence of labetalol-induced tremor has been reported in patients being treated concurrently with tricyclic antidepressants. Similar interactions would be expected with the related cyclic antidepressant maprotiline.
    Lacosamide: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Lamotrigine: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Lapatinib: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include lapatinib.
    Lenvatinib: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include lenvatinib. QT prolongation was reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
    Leuprolide: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Leuprolide; Norethindrone: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
    Levalbuterol: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Levetiracetam: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Levodopa: (Moderate) Maprotiline exhibits antimuscarinic activity and can decrease gastric motility, decreasing the bioavailability of levodopa. In addition, severe hypertension occurred in a limited number of patients who received levodopa in combination with a tricyclic antidepressant.
    Levofloxacin: (Major) Concurrent use of maprotiline and levofloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Levofloxacin has been associated with prolongation of the QT interval and infrequent cases of arrhythmia. Additionally, rare cases of TdP have been spontaneously reported during postmarketing surveillance in patients receiving levofloxacin. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Levomethadyl: (Severe) Levomethadyl is associated with an established risk of QT prolongation and/or torsades de pointes and is contraindicated in combination with other agents that may prolong the QT interval, such as maprotiline.
    Levorphanol: (Moderate) Concomitant use of levorphanol with other CNS depressants such as maprotiline can potentiate the effects of levorphanol on respiration, blood pressure, and alertness. Severe hypotension, respiratory depression, profound sedation, or coma may occur. Prior to concurrent use of levorphanol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. When concomitant treatment with levorphanol with another CNS depressant is necessary, reduce the dose of 1 or both drugs. The initial dose of levorphanol should be reduced by approximately 50% or more when levorphanol is used with another drug that may depress respiration.
    Linezolid: (Severe) Treatment initiation with heterocyclic antidepressants (e.g., trazodone, amoxapine, maprotiline, mirtazapine) is contraindicated in patients currently receiving linezolid due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than these antidepressants (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving these antidepressants and requiring urgent treatment with linezolid, the antidepressant should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. The antidepressant may be re-initiated 24 hours after the last dose of linezolid
    Lisdexamfetamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Lithium: (Major) Maprotiline and lithium are associated with QT prolongation. Coadministration may increase the risk of QT prolongation; therefore, maprotiline and lithium should be coadministered with caution and close monitoring. Lithium has been used as an augmentation for antidepressant therapy in cases of refractory unipolar depression. Although cyclic antidepressants and lithium can be used together therapeutically, clinicians should be alert for possible interactions. Antidepressants may 'switch' a bipolar depressive patient to hypomania or mania, although data indicate this is a rare occurrence. Some data indicate that when lithium and tricyclic antidepressants are used together, the risk of neurotoxicity may be increased, despite the presence of therapeutic lithium concentrations. Serotonin syndrome and neuroleptic malignant syndrome (NMS) events have also been reported. The data are limited, and suggest that toxicity from this combination is more likely in the elderly. Events do not appear to be predictable, and the mechanism of the interactions is elusive. While tricyclic antidepressants and heterocyclic antidepressants are not precluded in patients receiving lithium, they nevertheless should be used very cautiously. Careful dosage titration is recommended. Clinicians should be alert for the presence of tremor (a common presenting symptom) or other CNS effects during concurrent use.
    Lomefloxacin: (Moderate) Lomefloxacin has been associated with QT prolongation and infrequent cases of arrhythmia. Other medications which may prolong the QT interval, such as maprotiline, should be used cautiously when given concurrently with lomefloxacin.
    Long-acting beta-agonists: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Loperamide: (Major) Loperamide should be used cautiously and with close monitoring with maprotiline. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. In addition, both drug may decrease gastrointestinal (GI) motility; concurrent use could produce additive GI effects and induce toxic megacolon. If these drugs are given together, monitor for prolongation of the QT interval and for signs of impaired intestinal motility.
    Loperamide; Simethicone: (Major) Loperamide should be used cautiously and with close monitoring with maprotiline. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. In addition, both drug may decrease gastrointestinal (GI) motility; concurrent use could produce additive GI effects and induce toxic megacolon. If these drugs are given together, monitor for prolongation of the QT interval and for signs of impaired intestinal motility.
    Lopinavir; Ritonavir: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering lopinavir; ritonavir with maprotiline. Lopinavir; ritonavir is associated with QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. (Major) Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of maprotiline. Since the magnitude of the interaction with the maprotiline is difficult to predict but may be significant, monitor patients receiving ritonavir and maprotiline concurrently closely. In addition, coadministration increases the risk for QT prolongation and torsade de pointes. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
    Loratadine; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Lorazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Loxapine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other drugs known to possess relatively significant antimuscarinic properties including loxapine.
    Magnesium Salts: (Minor) Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as heterocyclic antidepressants. Caution should be exercised when using these agents concurrently.
    Meclizine: (Moderate) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects, such as meclizine.
    Mefloquine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering maprotiline with mefloquine. There is evidence that the use of halofantrine after mefloquine causes significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation; however due to the lack of clinical data, mefloquine should be used with caution in patients receiving drugs that prolong the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Mepenzolate: (Moderate) Additive anticholinergic and CNS effects may be seen when maprotiline is used concomitantly with mepenzolate.
    Meperidine: (Moderate) Hypotension, respiratory and/or CNS depression can be additive if meperidine is used concomitantly with maprotiline. A dose reduction of one or both drugs may be warranted to avoid additive effects.
    Meperidine; Promethazine: (Moderate) Hypotension, respiratory and/or CNS depression can be additive if meperidine is used concomitantly with maprotiline. A dose reduction of one or both drugs may be warranted to avoid additive effects. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Mephobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Mepivacaine; Levonordefrin: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Mesoridazine: (Severe) Mesoridazine is associated with a well-established risk of QT prolongation and torsades de pointes and is generally considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval, cause orthostatic hypotension and/or torsade de pointes, like maprotiline.
    Metaproterenol: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Metaxalone: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Methadone: (Major) The need to coadminister methadone with drugs known to prolong the QT interval, such as maprotiline, should be done with extreme caution and a careful assessment of treatment risks versus benefits. Methadone is considered to be associated with an increased risk for QT prolongation and torsades de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). In addition, concomitant use of methadone with another CNS depressant, such as maprotiline, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of methadone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Methadone should be used with caution and in reduced dosages if used concurrently with a CNS depressant; in opioid-naive adults, use an initial methadone dose of 2.5 mg every 12 hours. Consider a lower dose of the CNS depressant.
    Methamphetamine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) According to the manufacturer, treatment initiation with maprotiline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than maprotiline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving maprotiline and requiring urgent treatment with IV methylene blue, maprotiline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Maprotiline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Methohexital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when methscopolamine is used concomitantly with other drugs with moderate to significant antimuscarinic effects including maprotiline.
    Methsuximide: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Methyldopa: (Moderate) Maprotiline, as a cyclic antidepressant, can block the action of methyldopa, preventing or significantly reducing the expected antihypertensive effects. Avoid use of maprotiline concurrently with this antihypertensive drug when possible.
    Methylene Blue: (Severe) According to the manufacturer, treatment initiation with maprotiline is contraindicated in patients currently receiving intravenous (IV) methylene blue due to an increased risk of serotonin syndrome. If urgent psychiatric treatment is required, interventions other than maprotiline (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving maprotiline and requiring urgent treatment with IV methylene blue, maprotiline should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits outweigh the risks. The patient should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Maprotiline may be re-initiated 24 hours after the last dose of methylene blue. Results from an in vitro study indicate that methylene blue is a potent, reversible inhibitor of the monoamine oxidase type A enzyme (MAO-A). MAO-A is responsible for the metabolism of serotonin. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent, in patients receiving serotonergic agents. It is not known if patients receiving other serotonergic psychiatric agents with IV methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between IV methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Signs and symptoms of serotonin syndrome include fever, diaphoresis, shivering, myoclonus, tremor, tachycardia, diarrhea, nausea, headache, incoordination, mental status changes (e.g., agitation, confusion), hyperreflexia, seizures, and coma.
    Methylphenidate: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Metronidazole: (Major) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with metronidazole include maprotiline.
    Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as maprotiline, should be used with caution. Additive drowsiness and/or dizziness is possible.
    Midazolam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Midodrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Midostaurin: (Major) The concomitant use of midostaurin and maprotiline may lead to additive QT interval prolongation. If these drugs are used together, consider electrocardiogram monitoring. In clinical trials, QT prolongation has been reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Mifepristone, RU-486: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), mifepristone and maprotiline should be used together cautiously. Mifepristone has been associated with dose-dependent prolongation of the QT interval. There is no experience with high exposure or concomitant use with other QT prolonging drugs. To minimize the risk of QT prolongation, the lowest effective dose should always be used. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as heterocyclic antidepressants (i.e., amoxapine, maprotiline, mirtazapine, and trazodone). Caution should be exercised when using these agents concurrently.
    Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as maprotiline may be increased when co-administered with mirabegron. Therefore, appropriate monitoring and dose adjustment may be necessary.
    Mirtazapine: (Major) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and maprotiline. In addition, these medications may be duplicate treatment for some conditions. Coadminister with caution. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily in the setting of mirtazapine overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in commonly prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Mitotane: (Moderate) Use caution if mitotane and maprotiline are used concomitantly, and monitor for decreased efficacy of maprotiline and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and maprotiline is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of maprotiline.
    Molindone: (Moderate) Antipsychotics are associated with anticholinergic effects; therefore, additive effects may be seen during concurrent use of molindone and other drugs having anticholinergic activity such as maprotiline. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
    Monoamine oxidase inhibitors: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Morphine: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include maprotiline. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of morphine with other CNS depressants can potentiate the effects of morphine on respiration, blood pressure, and alertness; examples of other CNS depressants include maprotiline. Prior to concurrent use of morphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with morphine, a reduced dosage of morphine and/or the CNS depressant is recommended; for extended-release products, start with the lowest possible dose of morphine (i.e., 15 mg PO every 12 hours, extended-release tablets; 30 mg or less PO every 24 hours; extended-release capsules). Monitor patients for sedation and respiratory depression.
    Moxifloxacin: (Major) Concurrent use of maprotiline and moxifloxacin should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Moxifloxacin has been associated with prolongation of the QT interval. Additionally, post-marketing surveillance has identified very rare cases of ventricular arrhythmias including TdP, usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Nabilone: (Moderate) Nabilone or other CNS depressants should be combined cautiously with heterocyclic antidepressants because they could cause additive depressant effects and possible respiratory depression or hypotension.
    Nalbuphine: (Moderate) Nalbuphine should be combined cautiously with maprotiline because it could cause additive depressant effects and possible respiratory depression or hypotension.
    Naproxen; Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Naproxen; Sumatriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Naratriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Neostigmine: (Major) Maprotiline may antagonize some of the effects of neostigmine.
    Nilotinib: (Major) Avoid the concomitant use of nilotinib with other agents that prolong the QT interval. Maprotiline is associated with a possible risk for QT prolongation and torsade de pointes. Additionally, nilotinib is a CYP2D6 inhibitor and maprotiline is a substrate of CYP2D6; administering these drugs together may result in increased maprotiline levels. If the use of maprotiline is necessary, hold nilotinib therapy. Use caution and monitor patients for toxicity (e.g., QT interval prolongation) if these drugs are used together.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering the use of intrathecal radiopaque contrast agents. Maprotiline should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Norepinephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Norfloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering maprotiline with norfloxacin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Quinolones have also been associated with QT prolongation and TdP. For norfloxacin specifically, extremely rare cases of TdP were reported during post-marketing surveillance. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.
    Nortriptyline: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Octreotide: (Major) QT prolongation has been reported rarely with the use of octreotide and until further data are available, use octreotide with caution in patients receiving drugs which have potential to prolong the QT interval.
    Ofloxacin: (Major) Due to an increased risk for QT prolongation and torsade de pointes (TdP), caution is advised when administering maprotiline with ofloxacin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Some quinolones, including ofloxacin, have also been associated with QT prolongation. Additionally, post-marketing surveillance for ofloxacin has identified very rare cases of TdP.
    Olanzapine: (Major) Coadministration may result in additive effects on the QT interval. Limited data, including some case reports, suggest that olanzapine may be associated with a significant prolongation of the QTc interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, additive anticholinergic effects may be seen with coadministration. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Olodaterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Ombitasvir; Paritaprevir; Ritonavir: (Major) Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of maprotiline. Since the magnitude of the interaction with the maprotiline is difficult to predict but may be significant, monitor patients receiving ritonavir and maprotiline concurrently closely. In addition, coadministration increases the risk for QT prolongation and torsade de pointes. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
    Ondansetron: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), ondansetron and maprotiline should be used together cautiously. Ondansetron has been associated with QT prolongation and post-marketing reports of torsade de pointes (TdP). Among 42 patients receiving a 4 mg bolus dose of intravenous ondansetron for the treatment of postoperative nausea and vomiting, the mean maximal QTc interval prolongation was 20 +/- 13 msec at the third minute after antiemetic administration (p < 0.0001). If ondansetron and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Orphenadrine: (Moderate) Skeletal muscle relaxants should be combined cautiously with cyclic antidepressants like maprotiline because they could cause additive CNS depressant effects. Depending on the specific agent (e.g., cyclobenzaprine, and orphenadrine), additive anticholinergic effects may also be seen. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Patients should be monitored for excessive adverse effects from either agent.
    Osimertinib: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of maprotiline with osimertinib is necessary; an interruption of osimertinib therapy and dose reduction may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Oxaliplatin: (Major) Monitor electrolytes and ECGs for QT prolongation if coadministration of maprotiline with oxaliplatin is necessary; correct electrolyte abnormalities prior to administration of oxaliplatin. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. QT prolongation and ventricular arrhythmias including fatal TdP have also been reported with oxaliplatin use in postmarketing experience. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Oxazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Oxcarbazepine: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when oxybutynin is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that anticholinergic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Oxycodone: (Moderate) Concomitant use of oxycodone with other CNS depressants, such as maprotiline, can lead to additive respiratory depression, hypotension, profound sedation, or coma. Prior to concurrent use of oxycodone in patients taking maprotiline, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. Oxycodone should be used in reduced dosages if used concurrently with a CNS depressant; initiate oxycodone at one-third to one-half the usual dosage in patients that are concurrently receiving another CNS depressant. Also consider using a lower maprotiline dose. Monitor patients for sedation and respiratory depression.
    Oxymorphone: (Moderate) Concomitant use of oxymorphone with other CNS depressants may produce additive CNS depressant effects. Hypotension, profound sedation, coma, respiratory depression, or death may occur; examples of other CNS depressants include maprotiline. Prior to concurrent use of oxymorphone in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If a CNS depressant is used concurrently with oxymorphone, a reduced dosage of oxymorphone (1/3 to 1/2 of the usual dose) and/or the CNS depressant is recommended. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, it is recommended to use an initial dosage of 5 mg PO every 12 hours. Monitor for sedation or respiratory depression.
    Paliperidone: (Major) Paliperidone has been associated with QT prolongation; however, torsade de pointes (TdP) has not been reported. According to the manufacturer, since paliperidone may prolong the QT interval, it should be avoided in combination with other agents also known to have this effect, such as maprotiline. However, if coadministration is considered necessary by the practitioner, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. Additionally, there is a potential for additive pharmacodynamic interactions, which might augment side effects like sedation.
    Panobinostat: (Major) QT prolongation has been reported with panobinostat therapy in patients with multiple myeloma in a clinical trial; use of panobinostat with other agents that prolong the QT interval is not recommended. Obtain an electrocardiogram at baseline and periodically during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Drugs with a possible risk for QT prolongation and torsade de pointes that should be used cautiously and with close monitoring with panobinostat include maprotiline.
    Paroxetine: (Major) Paroxetine is a potent inhibitor of CYP2D6, the primary isoenzyme responsible for the metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, have been reported when SSRIs and cyclic antidepressants have been used together. In addition, because maprotiline is a CYP2D6 substrate and has a possible risk of QT prolongation and torsade de pointes, concurrent use of a potent CYP2D6 inhibitor such as paroxetine may increase the risk of such events. Patients receiving maprotiline should be monitored closely for toxicity if paroxetine is added.
    Pasireotide: (Major) Cautious use of pasireotide and maprotiline is needed, as coadministration may have additive effects on the prolongation of the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Pazopanib: (Major) Coadministration of pazopanib and other drugs that prolong the QT interval is not advised; pazopanib has been reported to prolong the QT interval. If pazopanib and the other drug must be continued, closely monitor the patient for QT interval prolongation. Drugs with a possible risk for QT prolongation and TdP that should be avoided with pazopanib include maprotiline.
    Peginterferon Alfa-2b: (Moderate) Monitor for adverse effects associated with increased exposure to maprotiline if peginterferon alfa-2b is coadministered. Peginterferon alfa-2b is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate.
    Pemoline: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Pentamidine: (Major) Pentamidine has been associated with QT prolongation. Drugs with a possible risk for QT prolongation and torsades de pointes (TdP) that should be used cautiously with pentamidine include maprotiline. Maprotiline may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP have been described with maprotiline, but rarely occur at normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Pentazocine: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with maprotiline may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentazocine; Naloxone: (Moderate) Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity. Coadministration of pentazocine with maprotiline may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation.
    Pentobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Perampanel: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as maprotiline. In addition, maprotiline, when used concomitantly with anticonvulsants may lower the seizure threshold, leading to pharmacodynamic interactions.
    Perphenazine: (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with perphenazine include maprotiline. In addition to additive cardiac effects, additive anticholinergic effects are also possible. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Perphenazine; Amitriptyline: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Perphenazine, a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, perphenazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with perphenazine include maprotiline. In addition to additive cardiac effects, additive anticholinergic effects are also possible. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Phendimetrazine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Phenelzine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Phenobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Phentermine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Phentermine; Topiramate: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Phenylephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Phenylephrine; Promethazine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches. (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Pimavanserin: (Major) Pimavanserin may cause QT prolongation and should generally be avoided in patients receiving other medications known to prolong the QT interval, such as maprotiline. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, but coadministration may increase the risk for QT prolongation.
    Pimozide: (Severe) Pimozide is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). Because of the potential for TdP, use of maprotiline with pimozide is contraindicated.
    Pirbuterol: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Posaconazole: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering posaconazole with maprotiline. Posaconazole has been associated with QT prolongation and in rare cases, TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Pramipexole: (Moderate) Pramipexole may cause additive drowsiness when combined with maprotiline.
    Prilocaine; Epinephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Primaquine: (Major) Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include maprotiline.
    Primidone: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Procainamide: (Major) Maprotiline should be used cautiously with procainamide. Procainamide is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Procarbazine: (Major) Concurrent use of drugs with MAO-inhibiting activity, such as procarbazine, with maprotiline can cause hyperpyrexia, hypertension, or seizures. The combination should be avoided whenever possible and is considered contraindicated.
    Prochlorperazine: (Moderate) Prochlorperazine, a phenothiazine, is associated with a possible risk for QT prolongation. Because maprotiline is associated with a possible risk for QT prolongation and torsade de pointes (TdP), concurrent use with prochlorperazine should be approached with caution. If coadministration is considered necessary, and the patient has known risk factors for cardiac disease or arrhythmia, then close monitoring is essential. In addition, additive anticholinergic effects may be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity such as maprotiline. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive hypotension or CNS effects such as drowsiness may also occur.
    Promethazine: (Moderate) Promethazine carries a risk of QT prolongation and should be used cautiously with drugs that may prolong the QT interval and have additive anticholinergic properties such as maprotiline. Additive drowsiness and sedation are also possible. Clinicians should note that additive anticholinergic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Propafenone: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering propafenone with maprotiline. The need to coadminister these drugs should be done with a careful assessment of risk versus benefit; consider alternative therapy. Propafenone is a Class IC antiarrhythmic which increases the QT interval largely due to prolongation of the QRS interval. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Additionally, propafenone may inhibit the CYP2D6 metabolism of maprotiline.
    Propantheline: (Moderate) Additive anticholinergic effects may be seen when propantheline is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline.
    Propofol: (Moderate) General anesthetics may produce additive CNS depression when used in patients taking maprotiline.
    Propoxyphene: (Moderate) Concomitant use of propoxyphene with other CNS depressants, such as maprotiline, can potentiate respiratory depression and/or sedation. Use with caution.
    Protriptyline: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Pseudoephedrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Pyridostigmine: (Major) Maprotiline may antagonize some of the effects of pyridostigmine.
    Quazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Quetiapine: (Major) Concurrent use of quetiapine and maprotiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Limited data, including some case reports, suggest that quetiapine may be associated with a significant prolongation of the QTc interval in rare instances. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Quinidine: (Severe) Quinidine administration is associated with QT prolongation and torsades de pointes (TdP). Quinidine inhibits CYP2D6 and has QT-prolonging actions; quinidine is contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6 as the effects on the QT interval may be increased during concurrent use of these agents. Drugs that prolong the QT and are substrates for CYP2D6 that are contraindicated with quinidine include maprotiline.
    Quinine: (Major) Concurrent use of quinine and maprotiline should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). Quinine has been associated with prolongation of the QT interval and rare cases of TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, concentrations of maprotiline may be increased with concomitant use of quinine. Maprotiline is a CYP2D6 substrate and quinine is a CYP2D6 inhibitor.
    Racepinephrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Ranolazine: (Major) Ranolazine and/or metabolites are moderate inhibitors of CYP2D6 isoenzymes. Based on drug interaction studies with metoprolol, a CYP2D6 substrate, ranolazine may theoretically increase plasma concentrations of CYP2D6 substrates, such as maprotiline, and could lead to toxicity for drugs that have a narrow therapeutic range. Lower doses of some CYP2D6 substrates than are usually prescribed may be needed during therapy with ranolazine; monitor therapeutic response during coadministration. In addition, maprotiline is associated with QT prolongation. Ranolazine should be used cautiously with drugs that prolong the QT interval. The need to coadminister maprotiline with ranolazine should be done with a careful assessment of risk versus benefit; consider alternative therapy to maprotiline.
    Rasagiline: (Major) It is recommended to avoid concurrent use of rasagiline and antidepressants, including tricyclic antidepressants or related compounds (e.g., amoxapine, maprotiline). Severe CNS toxicity with hyperpyrexia has been reported during concurrent use of antidepressants and selective or non-selective MAOIs. During post-marketing use of rasagiline, non-fatal cases of serotonin syndrome have been reported during concomitant antidepressant administration. At least 2 weeks should elapse between stopping rasagiline treatment and beginning therapy with any tricyclic antidepressants or related compounds. Conversely, when discontinuing a tricyclic or related compound, it is advisable to wait the length of 45 half lives of the individual agent being discontinued prior to initiation with rasagiline.
    Regadenoson: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include regadenoson/
    Remifentanil: (Moderate) Concomitant use of remifentanil with other CNS depressants, such as maprotiline, can potentiate the effects of remifentanil on respiration, sedation, and hypotension. A dose reduction of one or both drugs may be warranted.
    Reserpine: (Major) Reserpine may have decreased antihypertensive effects in the presence of cyclic antidepressants, and a stimulating effect has been noted in depressed patients taking reserpine along with a TCA. Avoid use of maprotiline concurrently with reserpine when possible.
    Ribociclib: (Major) Avoid coadministration of ribociclib with maprotiline due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of maprotiline may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and maprotiline is a CYP3A4 substrate.
    Ribociclib; Letrozole: (Major) Avoid coadministration of ribociclib with maprotiline due to an increased risk for QT prolongation and torsade de pointes (TdP). Systemic exposure of maprotiline may also be increased resulting in increase in treatment-related adverse reactions. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Concomitant use may increase the risk for QT prolongation. Ribociclib is also a moderate CYP3A4 inhibitor and maprotiline is a CYP3A4 substrate.
    Rilpivirine: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering rilpivirine with maprotiline. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Risperidone: (Major) Since risperidone may prolong the QT interval, it should be used cautiously with other agents also known to have this effect. Medications known to prolong the QT interval include certain heterocyclic antidepressants (e.g., maprotiline), particularly during overdose. In addition, increased maprotiline concentrations have been reported during the coadministration of risperidone, some patients have reported increased anticholinergic side effects in the absence of significant cardiac toxicity. Monitor patients receiving maprotiline concurrently with risperidone for side effects.
    Ritodrine: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Ritonavir: (Major) Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of maprotiline. Since the magnitude of the interaction with the maprotiline is difficult to predict but may be significant, monitor patients receiving ritonavir and maprotiline concurrently closely. In addition, coadministration increases the risk for QT prolongation and torsade de pointes. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
    Rivastigmine: (Moderate) Concurrent use of maprotiline and rivastigmine should be avoided if possible. Rivastigmine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Maprotiline may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of rivastigmine.
    Rizatriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Rolapitant: (Major) Use caution if maprotiline and rolapitant are used concurrently, and monitor for maprotiline-related adverse effects. Maprotiline is a CYP2D6 substrate and rolapitant is a moderate CYP2D6 inhibitor; the inhibitory effect of rolapitant lasts for at least 7 days, and may last longer after single dose administration. The Cmax and AUC of another CYP2D6 substrate, dextromethorphan, were increased by 120% and 160%, respectively, on day 1 with rolapitant, and by 180% and 230%, respectively, on day 8 after rolapitant administration.
    Romidepsin: (Major) Romidepsin has been reported to prolong the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. If romidepsin and maprotiline must be coadministered, appropriate cardiovascular monitoring precautions should be considered, such as the monitoring of electrolytes and ECGs at baseline and periodically during treatment.
    Ropinirole: (Moderate) Ropinirole may cause additive drowsiness when combined with maprotiline.
    S-adenosyl-L-methionine, SAM-e: (Minor) Pharmacologic studies suggest that S-adenosyl-L-methionine, SAM-e may have additive pharmacodynamic effects with traditional antidepressant therapies such maprotiline, but the pharmacology is poorly understood. This dietary supplement is probably best avoided in combination with prescription antidepressants unless closely monitored by a health care professional.
    Safinamide: (Severe) Safinamide is contraindicated for use with heterocyclic antidepressants, such as maprotiline, due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of maprotiline.
    Salmeterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Saquinavir: (Major) Concurrent use of maprotiline and saquinavir should be avoided due to an increased risk for QT prolongation and torsade de pointes (TdP). If no acceptable alternative therapy is available, perform a baseline ECG prior to initiation of concomitant therapy and carefully follow monitoring recommendations. Saquinavir boosted with ritonavir increases the QT interval in a dose-dependent fashion, which may increase the risk for serious arrhythmias such as TdP. Maprotiline is related to the tricyclic antidepressants and has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations).
    Scopolamine: (Moderate) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Secobarbital: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Selegiline: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Serotonin-Receptor Agonists: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Sertraline: (Major) There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) during treatment with sertraline; therefore, caution is advisable when using sertraline in patients with risk factors for QT prolongation, including concurrent use of other drugs that prolong the QTc interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sertraline include maprotiline. CYP2D6 is impaired by sertraline to some extent and this is the isozyme most responsible for metabolism of maprotiline. In several cases, symptoms of toxicity, including seizures, were reported when drugs from these 2 categories were used together. Patients receiving maprotiline should be monitored closely for toxicity if a SSRI-type drug is added.
    Sevoflurane: (Major) Halogenated anesthetics can prolong the QT interval. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously and with close monitoring with halogenated anesthetics include maprotiline.
    Short-acting beta-agonists: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Solifenacin: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include solifenacin. Additive anticholinergic effects may also be seen.
    Sorafenib: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering sorafenib with maprotiline. If these drugs must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Sorafenib has been associated with QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Sotalol: (Major) Sotalol administration is associated with QT prolongation and torsades de pointes (TdP). Proarrhythmic events should be anticipated after initiation of therapy and after each upward dosage adjustment. Drugs with a possible risk for QT prolongation and TdP should be used cautiously with sotalol. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Sparfloxacin: (Severe) Sparfloxacin is associated with an established risk for QT prolongation and torsades de pointes and is contraindicated in patients receiving other drugs that can cause QT prolongation including maprotiline.
    St. John's Wort, Hypericum perforatum: (Major) St. John's wort, Hypericum perforatum appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Maprotiline appears metabolized extensively by hepatic CYP450 isoenzymes. A pharmacokinetic interaction has been reported between St. John's wort and amitriptyline; coadministration resulted in decreased amitriptyline and metabolite plasma concentrations. Due to limited data, clinicians should be alert for decreased effects of other antidepressants used in conjunction with St. John's wort. In addition, it is not known if additive pharmacodynamic effects (e.g., serotonin syndrome or other side effects) could occur as a result of coadministration of St. John's wort with maprotiline. Therefore, coadministration is not recommended.
    Sufentanil: (Moderate) Concomitant use of sufentanil with other CNS depressants, such as maprotiline, can potentiate sufentanil-induced CNS and cardiovascular effects and the duration of these effects. Dose reduction of sufentanil and/or maprotiline is recommended.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) QT prolongation resulting in ventricular tachycardia and torsade de pointes (TdP) have been reported during post-marketing use of sulfamethoxazole; trimethoprim. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with sulfamethoxazole; trimethoprim include maprotiline.
    Sumatriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Sunitinib: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), sunitinib and maprotiline should be used together cautiously. Sunitinib can prolong the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Sympathomimetics: (Major) Sympathomimetics may interact with maprotiline, resulting in severe cardiovascular effects including arrhythmias, severe hypertension, hyperpyrexia, and/or severe headaches.
    Tacrine: (Moderate) Concurrent use of maprotiline and tacrine should be avoided if possible. Tacrine inhibits acetylcholinesterase, the enzyme responsible for the degradation of acetylcholine, and improves the availability of acetylcholine. Maprotiline may exhibit significant anticholinergic activity, thereby interfering with the therapeutic effect of tacrine or other cholinesterase inhibitors for dementia.
    Tacrolimus: (Major) Due to a possible risk for QT prolongation and torsade de pointes (TdP), tacrolimus and maprotiline should be used together cautiously. Tacrolimus causes QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Tamoxifen: (Major) Caution is advised with the concomitant use of tamoxifen with maprotiline due to an increased risk of QT prolongation and torsade de pointes (TdP). Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs, such as tamoxifen.
    Tapentadol: (Moderate) Although not specifically studied, concomitant use of tapentadol and maprotiline may result in additive toxicity. Both agents have CNS depressant activity, block norepinephrine reuptake, and may decrease the seizure threshold. Additive CNS depressant effects including severe hypotension, profound sedation, coma, or respiratory depression are possible. Prior to concurrent use of tapentadol in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Consider the patient's use of alcohol or illicit drugs. If maprotiline is used concurrently with tapentadol, a reduced dosage of tapentadol and/or maprotiline is recommended. If the extended-release tapentadol tablets are used concurrently with a CNS depressant, it is recommended to use an initial tapentadol dose of 50 mg PO every 12 hours. Monitor patients for sedation and respiratory depression.
    Telavancin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telavancin with maprotiline. Telavancin has been associated with QT prolongation. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Telithromycin: (Major) Due to the potential for QT prolongation and torsade de pointes (TdP), caution is advised when administering telithromycin with maprotiline. Telithromycin is associated with QT prolongation and TdP. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation.
    Telotristat Ethyl: (Moderate) Use caution if coadministration of telotristat ethyl and maprotiline is necessary, as the systemic exposure of maprotiline may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of maprotiline; consider increasing the dose of maprotiline if necessary. Maprotiline is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
    Temazepam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Terbinafine: (Moderate) In vitro studies have shown systemic terbinafine to inhibit hepatic isoenzyme CYP2D6, and thus may inhibit the clearance of drugs metabolized by this isoenzyme, such as maprotiline.
    Terbutaline: (Minor) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tetrabenazine: (Major) Tetrabenazine causes a small increase in the corrected QT interval (QTc). The manufacturer recommends avoiding concurrent use of tetrabenazine with other drugs known to prolong QTc such as maprotiline, particularly when given in excessive doses or overdosage. Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. In addition, concurrent use should generally be avoided since the risk of adverse effects such as drowsiness, sedation, dizziness, or orthostatic hypotension may be increased.
    Thiethylperazine: (Moderate) Use caution in the concurrent administration of maprotiline and phenothiazines. Both maprotiline and phenothiazines are metabolized via CYP2D6, and additive side effects may occur due to structural similarities and similarity of pharmacologic effects, like anticholinergic activity and sedation. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Thiopental: (Moderate) Heterocyclic antidepressants can increase CNS and/or respiratory depression, dizziness, and may also lower the seizure threshold, leading to pharmacodynamic interactions with barbiturate sedatives and anticonvulsants. Psychomotor impairment may be increased.
    Thioridazine: (Severe) Thioridazine is associated with a well-established risk of QT prolongation and torsades de pointes (TdP). Thioridazine is considered contraindicated for use along with agents that, when combined with a phenothiazine, may prolong the QT interval and increase the risk of TdP, and/or cause orthostatic hypotension. Maprotiline is rarely associated with QT prolongation. Additionally, additive toxicities (e.g., cardiac effects, CNS effects, orthostatic hypotension, and antimuscarinic effects) may occur because maprotiline and thioridazine are both metabolized via similar pathways (CYP2D6), have structural similarities, and produce similar pharmacologic effects (antimuscarinic activity). Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Thyroid hormones: (Minor) Thyroid hormones may increase receptor sensitivity and enhance the effects of maprotiline.
    Tiagabine: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Tiotropium; Olodaterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Tizanidine: (Major) Maprotiline should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Tolterodine: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include tolterodine. Also, additive anticholinergic effects may be seen when maprotiline is used concomitantly with other drugs with moderate to significant anticholinergic effects including tolterodine.
    Topiramate: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Toremifene: (Major) Toremifene has been shown to prolong the QTc interval in a dose- and concentration-related manner. Drugs with a possible risk for QT prolongation and torsade de pointes (TdP) that should be used cautiously with toremifene include maprotiline. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Tramadol: (Moderate) Concomitant use of tramadol increases the seizure risk in patients taking tricyclic antidepressants and other tricyclic compounds. Tramadol use may increase the seizure risk in patients taking drugs that reduce the seizure threshold. Maprotiline is pharmacologic similar to the tricyclic antidepressants, may decrease the seizure threshold, and causes CNS depression. Tramadol use increases the risk of CNS depression and respiratory depression when used with other agents that are CNS depressants. Extreme caution is needed in using tramadol at the same time as other CNS depressants. A reduced dose of tramadol is recommended when used with another CNS depressant. In vitro drug interaction studies in human liver microsomes suggest that concomitant administration of tricyclic antidepressants could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. It is not clear if maprotiline, a related cyclic antidepressant, would cause these types of interactions.
    Tranylcypromine: (Severe) Due to the risk of serotonin syndrome, monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with heterocyclic antidepressants (e.g., trazodone, mirtazapine, amoxapine, maptrotiline) or within 14 days of discontinuing treatment with a heterocyclic antidepressant. Conversely, heterocyclic antidepressants should not be initiated within 14 days of stopping an MAOI. The manufacturer of rasagiline does not contraindicate the combination but recommends avoiding use of antidepressants with rasagiline or within 14 days of discontinuing rasagiline. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
    Trazodone: (Major) Avoid coadministration of trazodone and maprotiline. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Therefore, the manufacturer recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs.
    Triazolam: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
    Tricyclic antidepressants: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Trifluoperazine: (Moderate) Trifluoperazine, a phenothiazine, is associated with a possible risk of QT prolongation. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation. Because maprotiline is associated with a possible risk for QT prolongation, concurrent use with trifluoperazine should be approached with caution. Depending on the specific agent, additive anticholinergic effects may also be seen when phenothiazines are used concomitantly with other drugs with antimuscarinic activity, such as maprotiline. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
    Trihexyphenidyl: (Moderate) Anticholinergic effects may be seen when drugs with antimuscarinic properties like trihexyphenidyl are used concomitantly with other antimuscarinics.
    Trimipramine: (Severe) The use of maprotiline with tricyclic antidepressants (TCAs) is not generally recommended, due to the duplicative nature of therapy and the risk for side effects. Additive cardiac effects (e.g., prolonged QT interval), CNS effects, or antimuscarinic effects may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Triprolidine: (Major) Additive anticholinergic effects may be seen when maprotiline is used concomitantly with other commonly used drugs with moderate to significant anticholinergic effects including sedating h1-blockers.
    Triptorelin: (Major) Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include maprotiline.
    Trospium: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium are used concomitantly with other drugs with moderate to significant anticholinergic effects including maprotiline.
    Umeclidinium; Vilanterol: (Moderate) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation that should be used cautiously with maprotiline include the beta-agonists. Beta-agonists may be associated with adverse cardiovascular effects including QT prolongation, usually at higher doses and/or when associated with hypokalemia.
    Valproic Acid, Divalproex Sodium: (Major) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Vandetanib: (Major) The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP). Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib. Maprotiline has also been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. If coadministration is necessary, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec; then, vandetanib may be resumed at a reduced dose.
    Vardenafil: (Major) Therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produces an increase in QTc interval (e.g., 4 to 6 msec calculated by individual QT correction). When vardenafil (10 mg) was given with gatifloxacin (400 mg), an additive effect on the QT interval was observed. The effect of vardenafil on the QT interval should be considered when prescribing the drug. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with vardenafil include maprotiline.
    Vemurafenib: (Major) Vemurafenib has been associated with QT prolongation. If vemurafenib and another drug, such as maprotiline, that is associated with a possible risk for QT prolongation and torsade de pointes (TdP) must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation. Also, maprotiline is a CYP2D6 substrate, while vemurafenib is a CYP2D6 inhibitor; therefore, increased concentrations of maprotiline may occur.
    Venlafaxine: (Major) Coadministration may increase the risk for QT prolongation and torsade de pointes. Also monitor for an increase in CNS effects and drug toxicity, such as serotonin syndrome. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with maprotiline include venlafaxine. In addition, additive CNS and other effects are possible; one case of serotonin syndrome has been reported when maprotiline was used in combination with venlafaxine and a selective norepinephrine antidepressant.
    Vigabatrin: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.
    Voriconazole: (Major) Caution is advised when administering voriconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as maprotiline. Voriconazole has been associated with QT prolongation and rare cases of torsades de pointes (TdP), cardiac arrest, and sudden death. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and TdP tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. In addition, coadministration of voriconazole (a CYP3A4 inhibitor) with maprotiline (a CYP3A4 substrate) may result in elevated maprotiline plasma concentrations and could increase the risk for adverse events, including QT prolongation. If these drugs are given together, closely monitor for prolongation of the QT interval. Rigorous attempts to correct any electrolyte abnormalities (i.e., potassium, magnesium, calcium) should be made before initiating concurrent therapy.
    Vorinostat: (Major) Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Vorinostat therapy is associated with a risk of QT prolongation and should be used cautiously with maprotiline.
    Ziconotide: (Moderate) Due to potentially additive effects, dosage adjustments may be necessary if ziconotide is used with a drug that has CNS depressant effects such as maprotiline. Coadministration of CNS depressants may increase drowsiness, dizziness, and confusion that are associated with ziconotide.
    Ziprasidone: (Severe) According to the manufacturer, ziprasidone is contraindicated with any drugs that list QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs. Ziprasidone has been associated with a possible risk for QT prolongation and/or torsades de pointes (TdP). Clinical trial data indicate that ziprasidone causes QT prolongation. In one study, ziprasidone increased the QT interval 10 msec more than placebo at the maximum recommended dosage. Comparative data with other antipsychotics have shown that the mean QTc interval prolongation occurring with ziprasidone exceeds that of haloperidol, quetiapine, olanzapine, and risperidone, but is less than that which occurs with thioridazine. Given the potential for QT prolongation, ziprasidone is contraindicated for use with drugs that are known to cause QT prolongation with potential for torsades de pointes including maprotiline.
    Zolmitriptan: (Moderate) Maprotiline should be used cautiously with drugs that also augment serotonin, like the serotonin-receptor agonists ("triptans") used for the treatment of migraine. Additive effects may occur, and the risk of serotonin syndrome may be increased. Maprotiline, a tetracyclic antidepressant, shares some pharmacologic properties with tricyclic antidepressants (TCAs). However, as maprotiline primarily blocks norepinephrine uptake vs. serotonin uptake, the drug rarely causes serotonin side effects or serotonin syndrome when used alone. However, combination therapy with agents with serotonergic actions might increase the risk for serotonergic side effects.
    Zonisamide: (Moderate) Maprotiline, when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when maprotiline is used concurrently. Because of the lowering of seizure threshold, an alternative antidepressant may be a more optimal choice for patients taking drugs for epilepsy.

    PREGNANCY AND LACTATION

    Pregnancy

    Maprotiline is excreted into human breast milk and caution is recommended when administering the drug during breast-feeding. At steady state, the concentrations in the milk correspond closely to the concentrations in maternal whole blood. Maprotiline has rarely caused galactorrhea in non-lactating women, and thus, interference with proper lactation is possible. Consider alternatives to maprotiline if possible. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action: Maprotiline selectively inhibits the reuptake of norepinephrine at the neuronal membrane. Maprotiline shares many of the actions of the tricyclic antidepressants although, unlike tricyclic antidepressants, maprotiline does not affect the reuptake of serotonin. Recent evidence suggests that the upset of monoamine output seen in depressed patients may be regulated by antidepressants following long-term treatment due to their action on beta-adrenergic receptors. This action on beta-receptors may be a better explanation than the reuptake theory of their antidepressant effects.Maprotiline does not inhibit monoamine oxidase or interfere with dopamine reuptake. Maprotiline appears to produce sedation in depressed patients. The seizure threshold can be lowered, and anticholinergic activity is present. Cardiac dysrhythmias can result from the direct quinidine-like effect on cardiac function in combination with anticholinergic activity and the potentiation of norepinephrine. The effect of maprotiline on the endocrine system has not been evaluated but may be similar to that of the tricyclic antidepressants.

    PHARMACOKINETICS

    Maprotiline is administered orally. Maprotiline distributes widely throughout the body. A steady-state plasma concentration is achieved in about 7 days. The drug is about 88% protein-bound. Maprotiline is metabolized slowly in the liver to produce the active metabolite desmethylmaprotiline, which is known to be distributed into breast milk. Desmethylmaprotiline formation in vivo is expected to be mediated primarily by CYP2D6, with some contribution by CYP1A2. The half-life of elimination averages 51 hours. There may be enterohepatic circulation of both unchanged drug and metabolites. Primary excretion is in the urine; about 60% of a dose is excreted as metabolites within 3 weeks. About 30% is excreted via the feces.
     
    Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP1A2
    The formation of the active metabolite of maprotiline appears to be mediated via CYP2D6 and CYP1A2, with primary contribution by CYP2D6. It is possible that inhibitors of this enzyme could increase maprotiline concentrations.

    Oral Route

    Following oral administration, maprotiline is absorbed slowly, but completely, from the GI tract. The mean time to peak concentration (Tmax) is 12 hours. Mean plasma concentrations prior to a morning dose at steady state (maprotiline dose of 50 mg PO 3 times per day) are 181 to 295 ng/mL.