Drug Information Directory: July 2010

Wednesday, July 14, 2010

Amlexanox

U.S. BRAND NAMES — Aphthasol®

PHARMACOLOGIC CATEGORY
Anti-inflammatory, Locally Applied

DOSING: ADULTS — Aphthous ulcers: Topical: Administer ~1/4 inch (0.5 cm) directly on ulcers 4 times/day following oral hygiene, after meals, and at bedtime.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Paste, oral:
Aphthasol®: 5% (3 g) [contains benzyl alcohol]

DOSAGE FORMS: CONCISE
Paste, oral:
Aphthasol®: 5% (3 g)

GENERIC EQUIVALENT AVAILABLE — No

USE — Treatment of aphthous ulcers (ie, canker sores)

USE - UNLABELED / INVESTIGATIONAL — Allergic disorders

ADVERSE REACTIONS SIGNIFICANT
1% to 2%:
Dermatologic: Allergic contact dermatitis
Gastrointestinal: Oral irritation

<1% (Limited to important or life-threatening): Contact mucositis

CONTRAINDICATIONS — Hypersensitivity to amlexanox or any component of the formulation

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Mucositis: Discontinue therapy if contact mucositis develops. Rash: Discontinue therapy if rash develops.

Special populations: Pediatrics: Safety and efficacy have not been established in children.

DRUG INTERACTIONS — There are no known significant interactions.

PREGNANCY RISK FACTOR — B (show table)

PREGNANCY IMPLICATIONS — Due to lack of data, avoid use in pregnancy, if possible.

LACTATION — Excretion in breast milk unknown/use caution

PRICING — (data from drugstore.com)
Paste (Aphthasol)
5% (3): $29.99

INTERNATIONAL BRAND NAMES — Elics (JP); Solfa (JP)

MECHANISM OF ACTION — As a benzopyrano-bipyridine carboxylic acid derivative, amlexanox has anti-inflammatory and antiallergic properties; it inhibits chemical mediatory release of the slow-reacting substance of anaphylaxis (SRS-A) and may have antagonistic effects on interleukin-3

PHARMACODYNAMICS / KINETICS
Absorption: Some from swallowed paste

Metabolism: Hydroxylated and conjugated metabolites

Half-life elimination: 3.5 hours

Time to peak, serum: 2 hours

Excretion: Urine (17% as unchanged drug)

Sunday, July 4, 2010

Amitriptyline

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Amitriptyline may be confused with aminophylline, imipramine, nortriptyline
Elavil® may be confused with Aldoril®, Eldepryl®, enalapril, Equanil®, Mellaril®, Oruvail®, Plavix®

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088622.pdf, must be dispensed with this medication for each new outpatient prescription and refill.

PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)

DOSING: ADULTS
Depression: Oral: 50-150 mg/day single dose at bedtime or in divided doses; dose may be gradually increased up to 300 mg/day.

Chronic pain management (unlabeled use): Oral: Initial: 25 mg at bedtime; may increase as tolerated to 100 mg/day.

Migraine prophylaxis (unlabeled use): Oral: Initial: 10-25 mg at bedtime; usual dose: 150 mg; reported dosing ranges: 10-400 mg/day

Post-traumatic stress disorder (PTSD) (unlabeled use): Oral: 75-200 mg/day

DOSING: PEDIATRIC

(For additional information see "Amitriptyline: Pediatric drug information")
Chronic pain management (unlabeled use): Oral: Initial: 0.1 mg/kg at bedtime, may advance as tolerated over 2-3 weeks to 0.5-2 mg/kg at bedtime

Depressive disorders:
Children (unlabeled use): Oral: Initial doses of 1 mg/kg/day given in 3 divided doses with increases to 1.5 mg/kg/day have been reported in a small number of children (n=9) 9-12 years of age; clinically, doses up to 3 mg/kg/day (5 mg/kg/day if monitored closely) have been proposed
Adolescents: Initial: 25-50 mg/day; may administer in divided doses; increase gradually to 100 mg/day in divided doses.

Migraine prophylaxis (unlabeled use): Oral: Initial: 0.25 mg/kg/day, given at bedtime; increase dose by 0.25 mg/kg/day to maximum 1 mg/kg/day. Reported dosing ranges: 0.1-2 mg/kg/day; maximum suggested dose: 10 mg.

DOSING: ELDERLY — Depression: Oral: Initial: 10-25 mg at bedtime; dose should be increased in 10-25 mg increments every week if tolerated; dose range: 25-150 mg/day. See Renal/Hepatic Impairment.

DOSING: RENAL IMPAIRMENT — Nondialyzable

DOSING: HEPATIC IMPAIRMENT — Use with caution and monitor plasma levels and patient response.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

DOSAGE FORMS: CONCISE
Tablet: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Relief of symptoms of depression

USE - UNLABELED / INVESTIGATIONAL — Analgesic for certain chronic and neuropathic pain; prophylaxis against migraine headaches; treatment of depressive disorders in children; post-traumatic stress disorder (PTSD)

ADVERSE REACTIONS SIGNIFICANT — Anticholinergic effects may be pronounced; moderate to marked sedation can occur (tolerance to these effects usually occurs).

Frequency not defined.

Cardiovascular: Orthostatic hypotension, tachycardia, ECG changes (nonspecific), AV conduction changes, cardiomyopathy (rare), MI, stroke, heart block, arrhythmia, syncope, hypertension, palpitation

Central nervous system: Restlessness, dizziness, insomnia, sedation, fatigue, anxiety, cognitive function impaired, seizure, extrapyramidal symptoms, coma, hallucinations, confusion, disorientation, coordination impaired, ataxia, headache, nightmares, hyperpyrexia

Dermatologic: Allergic rash, urticaria, photosensitivity, alopecia

Endocrine & metabolic: Syndrome of inappropriate ADH secretion

Gastrointestinal: Weight gain, xerostomia, constipation, paralytic ileus, nausea, vomiting, anorexia, stomatitis, peculiar taste, diarrhea, black tongue

Genitourinary: Urinary retention

Hematologic: Bone marrow depression, purpura, eosinophilia

Neuromuscular & skeletal: Numbness, paresthesia, peripheral neuropathy, tremor, weakness

Ocular: Blurred vision, mydriasis, ocular pressure increased

Otic: Tinnitus

Miscellaneous: Diaphoresis, withdrawal reactions (nausea, headache, malaise)

Postmarketing and/or case reports: Neuroleptic malignant syndrome (rare), serotonin syndrome (rare)

CONTRAINDICATIONS — Hypersensitivity to amitriptyline or any component of the formulation (cross-sensitivity with other tricyclics may occur); use of MAO inhibitors within past 14 days; acute recovery phase following myocardial infarction; concurrent use of cisapride

WARNINGS / PRECAUTIONS
Boxed warnings: Suicidal thinking/behavior: .

Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥ 65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children <12 years of age. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. Amitriptyline is not FDA approved for the treatment of bipolar depression.

Concerns related to adverse effects: Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is high relative to other antidepressants. Hematologic effects: TCAs may rarely cause bone marrow suppression; monitor for any signs of infection and obtain CBC if symptoms (eg, fever, sore throat) evident. Orthostatic hypotension: May cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is very high relative to other antidepressants.

Disease-related concerns: Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants. Diabetes: Use with caution in patients with diabetes mellitus; may alter glucose regulation. Hepatic impairment: Use with caution in patients with hepatic impairment. Renal impairment: Use with caution in patients with renal impairment. Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation due to concerns of pro-arrhythmogenesis.

Concurrent drug therapy issues: Anticholinergic and/or neuroleptic agents: Hyperpyrexia has been observed with TCAs in combination with anticholinergics and/or neuroleptics, particularly during hot weather. Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: Elderly: Use with caution in the elderly.

Other warnings/precautions: Discontinuation of therapy: Recommended to discontinue prior to elective surgery requiring general anesthesia. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods. Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification

Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification

Altretamine: May enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy

BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. Risk X: Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy

NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification

Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy

Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Risk C: Monitor therapy

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS
Ethanol: Avoid ethanol (may increase CNS depression).

Food: Grapefruit juice may inhibit the metabolism of some TCAs and clinical toxicity may result.

Herb/Nutraceutical: St John's wort may decrease amitriptyline levels. Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Teratogenic effects have been observed in animal studies. Amitriptyline crosses the human placenta; CNS effects, limb deformities and developmental delay have been noted in case reports.

LACTATION — Enters breast milk/not recommended (AAP rates "of concern")

BREAST-FEEDING CONSIDERATIONS — Generally, it is not recommended to breast-feed if taking antidepressants because of the long half-life, active metabolites, and the potential for side effects in the infant.

PRICING — (data from drugstore.com)
Tablets (Amitriptyline HCl)
25 mg (90): $11.99
50 mg (90): $12.99
75 mg (100): $14.44
100 mg (30): $13.99
150 mg (90): $21.98

MONITORING PARAMETERS — Monitor blood pressure and pulse rate prior to and during initial therapy; evaluate mental status, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased); monitor weight; ECG in older adults and patients with cardiac disease

REFERENCE RANGE — Therapeutic: Amitriptyline and nortriptyline 100-250 ng/mL (SI: 360-900 nmol/L); nortriptyline 50-150 ng/mL (SI: 190-570 nmol/L); Toxic: >0.5 mcg/mL; plasma levels do not always correlate with clinical effectiveness

CANADIAN BRAND NAMES — Apo-Amitriptyline®; Levate®; Novo-Triptyn; PMS-Amitriptyline

INTERNATIONAL BRAND NAMES — Adepril (IT); Amilit (IT); Amineurin (DE); Amiplin (TW); Amiprin (JP); Amitrip (NZ); Amitriptylinum (PL); Amytril (BR); Anapsique (MX); Antalin (CN); Conmitrip (TH); Domical (GB); Elatrol (IL); Elatrolet (IL); Elavil (FR); Endep (AU, NZ); Lantron (JP); Laroxyl (BF, BJ, CI, ET, FR, GH, GM, GN, IT, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Miketorin (JP); Neurotol (PY); Noriline (ZA); Pinsaun (TW); Protanol (BR); Psiquium (CO); Qualitriptine (HK); Redomex (BE); Saroten (BF, BJ, CI, CY, DE, DK, EE, ET, GH, GM, GN, GR, IR, KE, LR, MA, ML, MR, MU, MW, NE, NG, PT, SC, SD, SE, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Saroten Retard (CH, MY, TW); Sarotena (IN); Sarotex (NL, NO, UY); Sarotex Retard (NO); Syneudon (DE); Teperin (HN, IQ, JO); Trepiline (ZA); Tridep (BG); Tripta (MY, TH); Triptanol (MX); Triptizol (IT); Trynol (TW); Tryptanol (AR, BR, JP, PE, TH); Tryptizol (AT, CH, EG, ES, GB, NL, PT, SE); Trytomer (IN); Uxen (AR)

MECHANISM OF ACTION — Increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane

PHARMACODYNAMICS / KINETICS
Onset of action: Migraine prophylaxis: 6 weeks, higher dosage may be required in heavy smokers because of increased metabolism; Depression: 4-6 weeks, reduce dosage to lowest effective level

Distribution: Crosses placenta; enters breast milk

Metabolism: Hepatic to nortriptyline (active), hydroxy and conjugated derivatives; may be impaired in the elderly

Half-life elimination: Adults: 9-27 hours (average: 15 hours)

Time to peak, serum: ~4 hours

Excretion: Urine (18% as unchanged drug); feces (small amounts)

PATIENT INFORMATION — Do not discontinue medication abruptly. Full effect may not occur for 3-6 weeks. Avoid alcohol. May cause urine to turn blue-green. May cause drowsiness. Dry mouth may be helped by sips of water, sugarless gum, or hard candy.

Amitriptyline and perphenazine

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088622.pdf, must be dispensed with this medication for each new outpatient prescription and refill.

PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Antipsychotic Agent, Typical, Phenothiazine

DOSING: ADULTS — Depression and anxiety: Oral: 1 tablet 2-4 times/day

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT — Avoid use in severe hepatic failure.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet:
2-10: Amitriptyline hydrochloride 10 mg and perphenazine 2 mg
2-25: Amitriptyline hydrochloride 25 mg and perphenazine 2 mg
4-10: Amitriptyline hydrochloride 10 mg and perphenazine 4 mg
4-25: Amitriptyline hydrochloride 25 mg and perphenazine 4 mg
4-50: Amitriptyline hydrochloride 50 mg and perphenazine 4 mg

DOSAGE FORMS: CONCISE
Tablet:
Generics:
2-10: Amitriptyline 10 mg and perphenazine 2 mg
2-25: Amitriptyline 25 mg and perphenazine 2 mg
4-10: Amitriptyline 10 mg and perphenazine 4 mg
4-25: Amitriptyline 25 mg and perphenazine 4 mg
4-50: Amitriptyline 50 mg and perphenazine 4 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Treatment of patients with moderate-to-severe anxiety and depression

USE - UNLABELED / INVESTIGATIONAL — Depression with psychotic features

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to amitriptyline, perphenazine, or any component of the formulation (cross-sensitivity with other phenothiazines may exist); angle-closure glaucoma; bone marrow depression; severe liver or cardiac disease; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Dementia: See "Disease-related concerns" below. Suicidal thinking/behavior: See "Major psychiatric warnings" below.

Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥ 65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amitriptyline is not FDA-approved for use in children <12 years of age; this combination is not FDA approved for use in children. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. This combination is not FDA approved for the treatment of bipolar depression.

Concerns related to adverse effects: Altered cardiac conduction: May alter cardiac conduction; life-threatening arrhythmias have occurred with therapeutic doses of antipsychotics. Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. Relative to other neuroleptics, perphenazine has a low potency of cholinergic blockade and relative to other antidepressants amitriptyline has a high potential for cholinergic blockade. Blood dyscrasias: Check blood counts periodically and discontinue at first signs of blood dyscrasias; use is contraindicated in patients with bone marrow suppression. Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; use with caution in patients at risk of pneumonia (ie, Alzheimer's disease). Extrapyramidal symptoms: May cause extrapyramidal symptoms, including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is moderate-high relative to other neuroleptics). Hyperprolactinemia: Perphenazine use is associated with increased prolactin levels; clinical significance of hyperprolactinemia in patients with breast cancer or other prolactin-dependent tumors is unknown. Neuroleptic malignant syndrome (NMS): Use of perphenazine may be associated with NMS; monitor for mental status changes, fever, muscle rigidity, and/or autonomic instability. Ocular effects: Perphenazine may cause pigmentary retinopathy, and lenticular and corneal deposits, particularly with prolonged therapy. Orthostatic hypotension: Both agents may cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Sedation: Both agents may cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is high relative to other antidepressants. SIADH and hyponatremia: Has been associated with the development of SIADH and hyponatremia. Temperature regulation: Impaired core body temperature regulation may occur with perphenazine use; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

Disease-related concerns: Cardiovascular disease: Use both agents with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk of conduction abnormalities with this agent is high relative to other antidepressants. Dementia: [U.S. Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Perphenazine is not approved for the treatment of dementia-related psychosis. Diabetes: Use amitriptyline with caution in patients with diabetes mellitus; may alter glucose regulation. Glaucoma: Use with caution in patients with narrow-angle glaucoma; condition may be exacerbated by cholinergic blockade. Hepatic impairment: Use both agents with caution in patients with hepatic impairment. Myasthenia gravis: Use with caution in patients with myasthenia gravis; condition may be exacerbated by cholinergic blockade. Parkinson's disease: Use perphenazine with caution in patients with Parkinson's disease; they may be more sensitive to adverse effects. Renal impairment: Use both agents with caution in patients with renal impairment. Seizure disorder: Use both agents with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation.

Concurrent drug therapy issues: Antiemetic effects: Perphenazine may mask toxicity of other drugs or conditions (eg, intestinal obstruction, Reye's syndrome, brain tumor) due to antiemetic effects. Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: Elderly: Use with caution in the elderly; increased risk for developing tardive dyskinesia from perphenazine. Poor metabloizers: Use with caution in patients with reduced functional alleles of CYP2D6. Poor metabolizers may have higher plasma concentrations at usual doses, increasing risk for adverse reactions.

Other warnings/precautions: Discontinuation of therapy: Recommended to discontinue several days prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods. Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.

METABOLISM / TRANSPORT EFFECTS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)

Perphenazine: Substrate of CYP1A2 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2D6 (weak)

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotics. Severe extrapyramidal symptoms have occurred in some patients. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification

Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification

Altretamine: May enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy

Amphetamines: Antipsychotics may diminish the stimulatory effect of Amphetamines. Risk C: Monitor therapy

Analgesics (Opioid): Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Analgesics (Opioid). Risk C: Monitor therapy

Antacids: May decrease the absorption of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Antimalarial Agents: May increase the serum concentration of Antipsychotic Agents (Phenothiazines). Risk C: Monitor therapy

Anti-Parkinson's Agents (Dopamine Agonist): Antipsychotics (Typical) may diminish the therapeutic effect of Anti-Parkinson's Agents (Dopamine Agonist). Risk D: Consider therapy modification

Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy

Beta-Blockers: Antipsychotic Agents (Phenothiazines) may enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Exceptions: Atenolol; Levobunolol; Metipranolol; Nadolol. Risk C: Monitor therapy

BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. Risk X: Avoid combination

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Lithium formulations: May enhance the neurotoxic effect of Antipsychotics. Lithium formulations may decrease the serum concentration of Antipsychotics. Specifically noted with chlorpromazine. Risk C: Monitor therapy

Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy

NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification

Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotics. Risk C: Monitor therapy

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy

Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Risk C: Monitor therapy

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Avoid ethanol (due to increased sedation).

PREGNANCY RISK FACTOR — D (show table)

LACTATION — Enters breast milk/contraindicated

PRICING — (data from drugstore.com)
Tablets (Perphenazine-Amitriptyline)
2-10 mg (60): $16.99
2-25 mg (30): $13.99
4-25 mg (60): $19.99
4-50 mg (60): $27.99

MONITORING PARAMETERS — Vital signs; lipid profile, fasting blood glucose/Hb A1c; BMI, weight; mental status, abnormal involuntary movement scale (AIMS), extrapyramidal symptoms (EPS), suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)

CANADIAN BRAND NAMES — Etrafon®

INTERNATIONAL BRAND NAMES — Mutabon A (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mutabon D (AE, AR, BH, CN, CY, EG, ID, IL, IQ, IR, JO, KW, LB, LY, OM, PY, QA, SA, SY, YE); Mutabon F (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mutabon M (AE, BH, CY, EG, ID, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Mutabon-A (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Mutabon-D (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Mutabon-F (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Mutabon-M (BB, BM, BS, BZ, GY, JM, NL, PR, SR, TT); Neuragon-A (TH); Neuragon-B (TH); Polybon (TH); Triptafen (GB); Triptafen M (GB)

MECHANISM OF ACTION
Amitriptyline increases the synaptic concentration of serotonin and/or norepinephrine in the central nervous system by inhibition of their reuptake by the presynaptic neuronal membrane.

Perphenazine is a piperazine phenothiazine antipsychotic which blocks postsynaptic mesolimbic dopaminergic receptors in the brain; exhibits alpha-adrenergic blocking effect and depresses the release of hypothalamic and hypophyseal hormones.

PHARMACODYNAMICS / KINETICS — See individual agents

Amitriptyline and perphenazine

Amitriptyline and chlordiazepoxide

MEDICATION GUIDE — An FDA-approved patient medication guide, which is available with the product information and at http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088622.pdf, must be dispensed with this medication for each new outpatient prescription and refill.

U.S. BRAND NAMES — Limbitrol®; Limbitrol® DS [DSC]

PHARMACOLOGIC CATEGORY
Antidepressant, Tricyclic (Tertiary Amine)
Benzodiazepine

DOSING: ADULTS — Depression and anxiety: Oral: Initial: 3-4 tablets in divided doses; this may be increased to 6 tablets/day as required. Some patients respond to smaller doses and can be maintained on 2 tablets.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline hydrochloride 12.5 mg and chlordiazepoxide 5 mg
Limbitrol® DS: 25/10: Amitriptyline hydrochloride 25 mg and chlordiazepoxide 10 mg [DSC]

DOSAGE FORMS: CONCISE
Tablet: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg; 25/10: Amitriptyline 25 mg and chlordiazepoxide 10 mg
Limbitrol®: 12.5/5: Amitriptyline 12.5 mg and chlordiazepoxide 5 mg

GENERIC EQUIVALENT AVAILABLE — Yes

USE — Treatment of moderate-to-severe anxiety and/or agitation and depression

ADVERSE REACTIONS SIGNIFICANT — See individual agents.

CONTRAINDICATIONS — Hypersensitivity to benzodiazepines, tricyclic antidepressants, or any component of the formulation; depression of CNS; MAO inhibitors; acute recovery phase following MI; angle-closure glaucoma; pregnancy

WARNINGS / PRECAUTIONS
Boxed warnings: Suicidal thinking/behavior: See "Major psychiatric warnings" below.

Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥ 65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Amitriptyline and chlordiazepoxide combination is FDA approved for depression associated with anxiety in children ≥ 12 years of age. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression or psychosis occur. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Patients presenting with depressive symptoms should be screened for bipolar disorder. This combination is not FDA approved for the treatment of bipolar depression.

Concerns related to adverse effects: Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia. Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by amitriptyline is very high relative to other antidepressants. Orthostatic hypotension: May cause orthostatic hypotension (risk is very high relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia). Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Sedation: Both agents may cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is very high relative to other antidepressants. SIADH and hyponatremia: Has been associated with the development of SIADH and hyponatremia.

Disease-related concerns: Cardiovascular disease: Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities); the risk conduction abnormalities with amitriptyline is high relative to other antidepressants. Depression: Use chlordiazepoxide with caution in patients with depression, particularly if suicidal risk may be present. Drug abuse: Use chlordiazepoxide with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use. Diabetes: Use amitriptyline with caution in patients with diabetes mellitus; may alter glucose regulation. Hepatic impairment: Use both agents with caution in patients with hepatic impairment. Impaired gag reflux: Use chlordiazepoxide with caution in patients with an impaired gag reflux. Porphyria: Use chlordiazepoxide with caution in patients with porphyria. Renal impairment: Use both agents with caution in patients with renal impairment. Respiratory disease: Use chlordiazepoxide with caution in patients with respiratory disease. Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold. Thyroid dysfunction: Use with caution in patients with hyperthyroidism or those receiving thyroid supplementation.

Concurrent drug therapy issues: CNS depressants/psychoactive medications: Use chlordiazepoxide with caution in patients receiving other CNS depressants or psychoactive medication. Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.

Special populations: Debilitated patients: Use chlordiazepoxide with caution in debilitated patients; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Elderly: Use both agents with caution in the elderly. Benzodiazepines have been associated with falls and traumatic injury; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Pediatrics: Use chlordiazepoxide with caution in children; active metabolites with extended half-lives may lead to delayed accumulation and adverse effects.

Dosage form specific issues: Chlordiazepoxide injection: Parenteral administration should be avoided in comatose patients or shock. Adequate resuscitative equipment/personnel should be available, and appropriate monitoring should be conducted at the time of injection and for several hours following administration. The parenteral formulation should be diluted for I.M. administration with the supplied diluent only. This diluent should not be used when preparing the drug for intravenous administration.

Other warnings/precautions: Appropriate use: Chlordiazepoxide does not have analgesic, antidepressant, or antipsychotic properties. Discontinuation of therapy: Amitriptyline therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods. Rebound or withdrawal symptoms may occur following abrupt discontinuation of chlordiazepoxide or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy. Electroconvulsive therapy: May increase the risks associated with electroconvulsive therapy; consider discontinuing, when possible, prior to ECT treatment.

RESTRICTIONS — C-IV

METABOLISM / TRANSPORT EFFECTS
Amitriptyline: Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (minor), 2C19 (minor), 2D6 (major), 3A4 (minor); Inhibits CYP1A2 (weak), 2C9 (weak), 2C19 (weak), 2D6 (weak), 2E1 (weak)

Chlordiazepoxide: Substrate of CYP3A4 (major)

DRUG INTERACTIONS
Acetylcholinesterase Inhibitors (Central): Anticholinergics may diminish the therapeutic effect of Acetylcholinesterase Inhibitors (Central). Acetylcholinesterase Inhibitors (Central) may diminish the therapeutic effect of Anticholinergics. If the anticholinergic action is a side effect of the agent, the result may be beneficial. Risk C: Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy

Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Tricyclic Antidepressants may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Exceptions: Dipivefrin. Risk D: Consider therapy modification

Alpha1-Agonists: Tricyclic Antidepressants may enhance the vasopressor effect of Alpha1-Agonists. Risk D: Consider therapy modification

Alpha2-Agonists: Tricyclic Antidepressants may diminish the antihypertensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification

Altretamine: May enhance the orthostatic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Amphetamines: Tricyclic Antidepressants may enhance the stimulatory effect of Amphetamines. Tricyclic Antidepressants may also potentiate the cardiovascular effects of Amphetamines. Risk C: Monitor therapy

Anticholinergics: May enhance the adverse/toxic effect of other Anticholinergics. Exceptions: Paliperidone. Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Aprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Aspirin: Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of Aspirin. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Beta2-Agonists: Tricyclic Antidepressants may enhance the adverse/toxic effect of Beta2-Agonists. Risk C: Monitor therapy

BuPROPion: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

CarBAMazepine: May increase the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Cinacalcet: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy

Cisapride: Amitriptyline may enhance the arrhythmogenic effect of Cisapride. Risk X: Avoid combination

Clozapine: Benzodiazepines may enhance the adverse/toxic effect of Clozapine. Risk D: Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Desmopressin: Tricyclic Antidepressants may enhance the adverse/toxic effect of Desmopressin. Risk C: Monitor therapy

Dexmethylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Disulfiram: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination

DULoxetine: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Fluconazole: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Fosaprepitant: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Specifically, the active metabolite aprepitant is likely responsible for this effect. Risk C: Monitor therapy

Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification

Grapefruit Juice: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Iobenguane I 123: Tricyclic Antidepressants may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Lithium: May enhance the neurotoxic effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Macrolide Antibiotics: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin. Risk D: Consider therapy modification

MAO Inhibitors: May enhance the serotonergic effect of Tricyclic Antidepressants. This may cause serotonin syndrome. Risk X: Avoid combination

MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy

Methylphenidate: May decrease the metabolism of Tricyclic Antidepressants. Risk C: Monitor therapy

Nefazodone: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

NSAID (COX-2 Inhibitor): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (COX-2 Inhibitor). Risk C: Monitor therapy

NSAID (Nonselective): Antidepressants (Tricyclic, Tertiary Amine) may enhance the antiplatelet effect of NSAID (Nonselective). Risk C: Monitor therapy

Oral Contraceptive (Estrogens): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Oral Contraceptive (Progestins): May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy

Phenytoin: Benzodiazepines may increase the serum concentration of Phenytoin. Short-term exposure to benzodiazepines may not present as much risk as chronic therapy. Risk C: Monitor therapy

Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination

Pramlintide: May enhance the anticholinergic effect of Anticholinergics. These effects are specific to the GI tract. Risk D: Consider therapy modification

Propoxyphene: May enhance the CNS depressant effect of Tricyclic Antidepressants. Risk C: Monitor therapy

Protease Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Management: Amprenavir, atazanavir, darunavir, indinavir, nelfinavir, ritonavir, and tipranavir are contraindicated with midazolam and triazolam according to each protease inhibitor's prescribing information. Risk D: Consider therapy modification

Protease Inhibitors: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Proton Pump Inhibitors: May increase the serum concentration of Benzodiazepines (metabolized by oxidation). Exceptions: Lansoprazole; Pantoprazole; Rabeprazole. Risk C: Monitor therapy

QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification

QuiNIDine: Tricyclic Antidepressants may enhance the QTc-prolonging effect of QuiNIDine. QuiNIDine may decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination

Rifamycin Derivatives: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May decrease the metabolism of Benzodiazepines (metabolized by oxidation). Exceptions: Citalopram; Escitalopram; PARoxetine; Sertraline. Risk C: Monitor therapy

Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification

Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid combination

St Johns Wort: May increase the metabolism of Tricyclic Antidepressants. The risk of serotonin syndrome may theoretically be increased. Risk D: Consider therapy modification

St Johns Wort: May increase the metabolism of Benzodiazepines (metabolized by oxidation). Risk C: Monitor therapy

Sulfonylureas: Cyclic Antidepressants may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy

Terbinafine: May decrease the metabolism of Tricyclic Antidepressants. Risk D: Consider therapy modification

Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification

Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination

TraMADol: Tricyclic Antidepressants may enhance the neuroexcitatory and/or seizure-potentiating effect of TraMADol. Risk C: Monitor therapy

Valproic Acid: May increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): Tricyclic Antidepressants may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Yohimbine: Tricyclic Antidepressants may increase the serum concentration of Yohimbine. Risk C: Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy

Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination

PREGNANCY RISK FACTOR — D (show table)

LACTATION — Excretion in breast milk unknown/contraindicated

PRICING — (data from drugstore.com)
Tablets (Chlordiazepoxide-Amitriptyline)
5-12.5 mg (60): $44.99
10-25 mg (60): $65.99

Tablets (Limbitrol DS)
10-25 mg (60): $99.99

MONITORING PARAMETERS — Suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased)

CANADIAN BRAND NAMES — Limbitrol®

INTERNATIONAL BRAND NAMES — Limbatril (DE); Limbatrilin (CN); Limbitrol (AE, AT, BE, BH, BR, CY, EG, FI, FR, GH, GR, ID, IL, IQ, IR, JO, KE, KW, LB, LY, NL, OM, QA, SA, SY, TW, TZ, UG, YE, ZM); Limbitryl (IT)

MECHANISM OF ACTION — See individual agents.

PHARMACODYNAMICS / KINETICS — See individual agents.

Aminophylline

MEDICATION SAFETY ISSUES
Sound-alike/look-alike issues:
Aminophylline may be confused with amitriptyline, ampicillin

PHARMACOLOGIC CATEGORY
Theophylline Derivative

DOSING: ADULTS
Treatment of acute bronchospasm: I.V.:
Loading dose (in patients not currently receiving aminophylline or theophylline): 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages: Based upon continuous infusions; bolus dosing may be determined by multiplying the hourly infusion rate by 24 hours and dividing by the desired number of doses/day
Smoker: 0.8 mg/kg/hour
Nonsmoker: 0.5 mg/kg/hour
Older patients and patients with cor pulmonale: 0.3 mg/kg/hour
Patients with congestive heart failure: 0.1-0.2 mg/kg/hour
Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period.

Reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing (unlabeled use): I.V.: 50-250 mg administered over 30-60 seconds, repeat as necessary
Note: Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required.

Bronchodilator: Oral: Initial: 380 mg/day (equivalent to theophylline 300 mg/day) in divided doses every 6-8 hours; may increase dose after 3 days; maximum dose: 928 mg/day (equivalent to theophylline 800 mg/day)

DOSING: PEDIATRIC

(For additional information see "Aminophylline: Pediatric drug information")
Treatment of acute bronchospasm: I.V.:
Loading dose: Patients not currently receiving aminophylline or theophylline: 6 mg/kg (based on aminophylline) administered I.V. over 20-30 minutes; administration rate should not exceed 25 mg/minute (aminophylline)
Approximate I.V. maintenance dosages: Based upon continuous infusions; bolus dosing (often used in children <6 months of age) may be determined by multiplying the hourly infusion rate by 24 hours and dividing by the desired number of doses/day
6 weeks to 6 months: 0.5 mg/kg/hour
6 months to 1 year: 0.6-0.7 mg/kg/hour
1-9 years: 1 mg/kg/hour
9-16 years: Refer to adult dosing.
Dosage should be adjusted according to serum level measurements during the first 12- to 24-hour period.

Bronchodilator: Oral: Children ≥ 45 kg: Refer to adult dosing.

DOSING: ELDERLY — Refer to adult dosing.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, solution, as dihydrate: 25 mg/mL (10 mL, 20 mL)

Injection, solution, as dihydrate [preservative free]: 25 mg/mL (10 mL, 20 mL)

Tablet, as dihydrate: 100 mg

DOSAGE FORMS: CONCISE
Injection, solution: 25 mg/mL (10 mL, 20 mL)

Injection, solution, [preservative free]: 25 mg/mL (10 mL, 20 mL)

Tablet: 100 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — Dilute with I.V. fluid to a concentration of 1 mg/mL and infuse over 20-30 minutes; maximum concentration: 25 mg/mL; maximum rate of infusion: 0.36 mg/kg/minute, and no greater than 25 mg/minute. I.M. administration is not recommended. Oral and I.V. should be administered around-the-clock rather than 4 times/day, 3 times/day, etc (eg, 12-6-12-6, not 9-1-5-9) to promote less variation in peak and trough serum levels.

For reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse events during nuclear cardiac stress testing, administer I.V. undiluted over 30-60 seconds, repeat as necessary. Since adenosine-induced side effects are short lived after discontinuation of the infusion, aminophylline administration is only very rarely required.

COMPATIBILITY — Stable in dextran 6% in D5W, dextran 6% in NS, D5LR, D5NS, D51/2NS, D51/4NS, D5W, D10W, D20W, LR, 1/2NS, NS; variable stability (consult detailed reference) in fat emulsion 10%.

Y-site administration: Compatible: Allopurinol, amifostine, amphotericin B cholesteryl sulfate complex, aztreonam, ceftazidime, cimetidine, cladribine, docetaxel, doxorubicin liposome, enalaprilat, esmolol, etoposide, famotidine, filgrastim, fluconazole, fludarabine, foscarnet, gatifloxacin, gemcitabine, granisetron, heparin with hydrocortisone sodium succinate, inamrinone, labetalol, levofloxacin, linezolid, melphalan, meropenem, morphine, paclitaxel, pancuronium, piperacillin/tazobactam, potassium chloride, propofol, ranitidine, remifentanil, sargramostim, tacrolimus, teniposide, thiotepa, tolazoline, vecuronium, vitamin B complex with C. Incompatible: Amiodarone, ciprofloxacin, clarithromycin, dobutamine, hydralazine, ondansetron, vinorelbine, warfarin. Variable (consult detailed reference): Cisatracurium, diltiazem.

Compatibility in syringe: Compatible: Heparin, metoclopramide, pentobarbital, thiopental. Incompatible: Doxapram.

Compatibility when admixed: Compatible: Amobarbital, bretylium, calcium gluconate, chloramphenicol, cimetidine, dexamethasone, diphenhydramine, dopamine, erythromycin lactobionate, esmolol, floxacillin, flumazenil, furosemide, heparin, hydrocortisone sodium succinate, lidocaine, mephentermine, meropenem, methyldopate, metronidazole with sodium bicarbonate, nitroglycerin, pentobarbital, phenobarbital, potassium chloride, ranitidine, sodium bicarbonate, terbutaline. Incompatible: Atracurium, bleomycin, cefepime, ceftazidime, ceftriaxone, chlorpromazine, ciprofloxacin, clindamycin, dobutamine, doxorubicin, epinephrine, hydralazine, hydrocortisone sodium succinate with cephalothin sodium, hydroxyzine, insulin (regular), isoproterenol, levorphanol, meperidine, morphine, norepinephrine, papaverine with trimecaine, penicillin G potassium, pentazocine, prochlorperazine edisylate, prochlorperazine mesylate, promazine, promethazine, vitamin B complex with C. Variable (consult detailed reference): Amikacin, ascorbic acid, corticotropin, dimenhydrinate, methylprednisolone sodium succinate, nafcillin, procaine, vancomycin, verapamil, zinc.

USE — Bronchodilator in reversible airway obstruction due to asthma or COPD; increase diaphragmatic contractility

USE - UNLABELED / INVESTIGATIONAL — Reversal of adenosine-, dipyridamole-, or regadenoson-induced adverse reactions (eg, angina, hypotension) during nuclear cardiac stress testing

ADVERSE REACTIONS SIGNIFICANT
Uncommon at serum theophylline concentrations ≤ 15 mcg / mL

1% to 10%:
Cardiovascular: Tachycardia
Central nervous system: Nervousness, restlessness
Gastrointestinal: Nausea, vomiting

<1% (Limited to important or life-threatening): Allergic reactions, gastric irritation, insomnia, irritability, skin rash, seizure, tremor

CONTRAINDICATIONS — Hypersensitivity to theophylline, ethylenediamine, or any component of the formulation

WARNINGS / PRECAUTIONS
Concerns related to adverse effects: Theophylline toxicity: If a patient develops signs and symptoms of theophylline toxicity (eg, persistent, repetitive vomiting), a serum level should be measured and subsequent doses held.

Disease-related concerns: Cardiovascular disease: Use with caution in patients with hypertension or cardiac arrhythmias (excluding bradyarrhythmias). Hyperthyroidism: Use with caution in patients with hyperthyroidism. Peptic ulcer disease: Use with caution in patient with peptic ulcer disease. Seizure disorder: Use with caution in patients with a history of seizure disorder.

Other warnings/precautions: Dosage adjustments: Due to potential saturation of theophylline clearance at serum levels within (or in some patients less than) the therapeutic range, dosage adjustment should be made in small increments (maximum: 25% reduction). Monitoring: Due to wide interpatient variability, theophylline serum level measurements must be used to optimize therapy and prevent serious toxicity.

METABOLISM / TRANSPORT EFFECTS — Substrate of CYP1A2 (major), 2E1 (minor), 3A4 (minor)

DRUG INTERACTIONS
Adenosine: Theophylline Derivatives may diminish the therapeutic effect of Adenosine. Risk D: Consider therapy modification

Allopurinol: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Aminoglutethimide: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Atomoxetine: May enhance the hypertensive effect of Sympathomimetics. Atomoxetine may enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

Barbiturates: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Benzodiazepines: Theophylline Derivatives may diminish the therapeutic effect of Benzodiazepines. Risk D: Consider therapy modification

Beta-Blockers (Beta1 Selective): May diminish the bronchodilatory effect of Theophylline Derivatives. This is true at higher beta-blockers doses where cardioselectivity is lost. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May diminish the bronchodilatory effect of Theophylline Derivatives. Risk D: Consider therapy modification

Cannabinoids: May enhance the tachycardic effect of Sympathomimetics. Risk C: Monitor therapy

CarBAMazepine: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Cimetidine: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification

CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy

CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification

Disulfiram: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Febuxostat: May increase the serum concentration of Theophylline Derivatives. Risk X: Avoid combination

Fluvoxamine: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification

Interferons: May decrease the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Iobenguane I 123: Sympathomimetics may diminish the therapeutic effect of Iobenguane I 123. Risk X: Avoid combination

Isoniazid: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification

Lithium: Theophylline Derivatives may increase the excretion of Lithium. Risk C: Monitor therapy

Macrolide Antibiotics: May decrease the metabolism of Theophylline Derivatives. Exceptions: Azithromycin; Dirithromycin [Off Market]; Spiramycin; Telithromycin. Risk D: Consider therapy modification

Mexiletine: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification

Moricizine: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Pentoxifylline: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Phenytoin: May increase the metabolism of Theophylline Derivatives. Theophylline Derivatives may decrease the serum concentration of Phenytoin. Risk C: Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Theophylline Derivatives. Exceptions: Amprenavir; Fosamprenavir. Risk C: Monitor therapy

QuiNINE: May increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy

Quinolone Antibiotics: May decrease the metabolism of Theophylline Derivatives. Ciprofloxacin and enoxacin are of greatest concern. Theophylline/quinolone therapy might augment the seizure-producing potential of each of the individual agents. Exceptions: Gatifloxacin; Gemifloxacin; Levofloxacin; Lomefloxacin; Moxifloxacin; Nalidixic Acid; Sparfloxacin; Trovafloxacin. Risk D: Consider therapy modification

Regadenoson: Aminophylline may diminish the vasodilatory effect of Regadenoson. Risk D: Consider therapy modification

Sympathomimetics: May enhance the adverse/toxic effect of other Sympathomimetics. Risk C: Monitor therapy

Tacrine: May decrease the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Thiabendazole: May decrease the metabolism of Theophylline Derivatives. Risk D: Consider therapy modification

Thyroid Products: May increase the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Ticlopidine: May decrease the metabolism of Theophylline Derivatives. Risk C: Monitor therapy

Zafirlukast: Theophylline Derivatives may decrease the serum concentration of Zafirlukast. Risk C: Monitor therapy

ETHANOL / NUTRITION / HERB INTERACTIONS — Food: Food does not appreciably affect absorption. Avoid extremes of dietary protein and carbohydrate intake. Changes in diet may affect the elimination of theophylline; charcoal-broiled foods may increase elimination, reducing half-life by 50%.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Theophylline crosses the placenta; adverse effects may be seen in the newborn. Theophylline metabolism may change during pregnancy; monitor serum levels.

LACTATION — Enters breast milk/compatible (AAP rates "compatible")

BREAST-FEEDING CONSIDERATIONS — Irritability may be observed in the nursing infant.

PRICING — (data from drugstore.com)
Tablets (Aminophylline)
100 mg (30): $12.99
200 mg (90): $19.00

CANADIAN BRAND NAMES — Phyllocontin®; Phyllocontin®-350

INTERNATIONAL BRAND NAMES — Aminocont (FI); Aminofilina (EC, GT, PL); Aminomal (CH, CZ, IT); Aminophyllin (HR, NO); Aminophylline Renaudin (FR); Aminophyllinum (PL); Aminophyllinum Prolongatum (PL); Aminophyllinum Retard (HU, PL); Aminoslow (LU); Anephyllin (JP); Asiphylline (TW); Asthcontin (KP); Cardiomin (CN); Cardirenal (AR); Cardophyllin (AU); Carine (AU); Clonofillin SR (HU); Diaphyllin (HU); Escophyllin (CH); Eufilina (ES); Eufilina Mite (PT); Eufilina Venosa (ES); Euphyllin (AT, BE, BG, CH, CZ, DE, LU, NL); Euphyllin Retard (BF, BJ, CI, ET, GH, GM, GN, KE, LR, MA, ML, MR, MU, MW, NE, NG, SC, SD, SL, SN, TN, TZ, UG, ZA, ZM, ZW); Godafilin (ES); Kyophyllin (JP); Minophyl (IN); Neophyllin (SG); Pediatric Asthcontin for Children SR (KP); Peterphyllin (ZA); Pharmafil (MX); Phyllocontin (AE, BB, BF, BH, BJ, BM, BS, BZ, CI, CY, EG, ET, GB, GH, GM, GN, GY, IE, IL, IQ, IR, JM, JO, KE, KW, LB, LR, LY, MA, ML, MR, MU, MW, NE, NG, OM, PK, QA, SA, SC, SD, SL, SN, SR, SY, TN, TT, TW, TZ, UG, YE, ZA, ZM, ZW); Phyllocontin Continus (AE, BH, CY, EG, IL, IQ, IR, JO, KW, LB, LY, OM, QA, SA, SY, YE); Phyllotemp (CH, DE, GR); Planphylline (FR); Retafilin (HR); Tefamin (IT); Teofylamin (DK); Teofyllamin Ipex (SE); Unifilin (BR)

MECHANISM OF ACTION — Causes bronchodilatation, diuresis, CNS and cardiac stimulation, and gastric acid secretion by blocking phosphodiesterase which increases tissue concentrations of cyclic adenine monophosphate (cAMP) which in turn promote catecholamine stimulation of lipolysis, glycogenolysis, and gluconeogenesis and induce release of epinephrine from adrenal medulla cells

PHARMACODYNAMICS / KINETICS
Theophylline:

Absorption: Oral: Dosage form dependent

Distribution: 0.45 L/kg based on ideal body weight

Protein binding: 40%, primarily to albumin

Metabolism: Children >1 year and Adults: Hepatic; involves CYP1A2, 2E1, and 3A4; forms active metabolites (caffeine and 3-methylxanthine)

Half-life elimination: Highly variable and dependent upon age, liver function, cardiac function, lung disease, and smoking history

Time to peak, serum:
Oral: Immediate release: 1-2 hours
I.V.: Within 30 minutes

Excretion: Children >3 months and Adults: Urine (10% as unchanged drug)

PATIENT INFORMATION — Do not drink or eat large quantities of caffeine-containing beverages or food (colas, coffee, chocolate).

Wednesday, July 14, 2010

Amlexanox

Sunday, July 4, 2010

Amitriptyline

Amitriptyline and perphenazine

Amitriptyline and perphenazine

Amitriptyline and chlordiazepoxide

Aminophylline

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