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Strattera (Atomoxetine Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

  • Monoamine Oxidase Inhibitors. (4.2, 7.1)
  • CYP2D6 Inhibitors - Concomitant use may increase atomoxetine steady-state plasma concentrations in EMs. (7.2)
  • Antihypertensive Drugs and Pressor Agents - Possible effects on blood pressure. (7.3)
  • Albuterol (or other beta2 agonists) - Action of albuterol on cardiovascular system can be potentiated. (7.4)

With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Contraindications].

 

In extensive metabolizers (EMs), inhibitors of CYP2D6 (e.g., paroxetine, fluoxetine, and quinidine) increase atomoxetine steady-state plasma concentrations to exposures similar to those observed in poor metabolizers (PMs). In EM individuals treated with paroxetine or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and Css, max is about 3- to 4-fold greater than atomoxetine alone.

In vitro studies suggest that coadministration of cytochrome P450 inhibitors to PMs will not increase the plasma concentrations of atomoxetine.

 

Because of possible effects on blood pressure, STRATTERA should be used cautiously with antihypertensive drugs and pressor agents (e.g., dopamine, dobutamine) or other drugs that increase blood pressure.

 

STRATTERA should be administered with caution to patients being treated with systemically-administered (oral or intravenous) albuterol (or other beta2 agonists) because the action of albuterol on the cardiovascular system can be potentiated resulting in increases in heart rate and blood pressure. Albuterol (600 mcg iv over 2 hours) induced increases in heart rate and blood pressure. These effects were potentiated by atomoxetine (60 mg BID for 5 days) and were most marked after the initial coadministration of albuterol and atomoxetine. However, these effects on heart rate and blood pressure were not seen in another study after the coadministration with inhaled dose of albuterol (200-800 mcg) and atomoxetine (80 mg QD for 5 days) in 21 healthy Asian subjects who were excluded for poor metabolizer status.

 

Atomoxetine did not cause clinically important inhibition or induction of cytochrome P450 enzymes, including CYP1A2, CYP3A, CYP2D6, and CYP2C9.

 

CYP3A Substrate (e.g., Midazolam) — Coadministration of STRATTERA (60 mg BID for 12 days) with midazolam, a model compound for CYP3A4 metabolized drugs (single dose of 5 mg), resulted in 15% increase in AUC of midazolam. No dose adjustment is recommended for drugs metabolized by CYP3A.

 

CYP2D6 Substrate (e.g., Desipramine) — Coadministration of STRATTERA (40 or 60 mg BID for 13 days) with desipramine, a model compound for CYP2D6 metabolized drugs (single dose of 50 mg), did not alter the pharmacokinetics of desipramine. No dose adjustment is recommended for drugs metabolized by CYP2D6.

 

Consumption of ethanol with STRATTERA did not change the intoxicating effects of ethanol.

 

Coadministration of methylphenidate with STRATTERA did not increase cardiovascular effects beyond those seen with methylphenidate alone.

 

In vitro drug-displacement studies were conducted with atomoxetine and other highly-bound drugs at therapeutic concentrations. Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin. Similarly, these compounds did not affect the binding of atomoxetine to human albumin.

 

Drugs that elevate gastric pH (magnesium hydroxide/aluminum hydroxide, omeprazole) had no effect on STRATTERA bioavailability.

 

OVERDOSAGE

No fatal overdoses occurred in clinical trials. There is limited clinical trial experience with STRATTERA overdose. During postmarketing, there have been fatalities reported involving a mixed ingestion overdose of STRATTERA and at least one other drug. There have been no reports of death involving overdose of STRATTERA alone, including intentional overdoses at amounts up to 1400 mg. In some cases of overdose involving STRATTERA, seizures have been reported. The most commonly reported symptoms accompanying acute and chronic overdoses of STRATTERA were gastrointestinal symptoms, somnolence, dizziness, tremor, and abnormal behavior. Hyperactivity and agitation have also been reported. Signs and symptoms consistent with mild to moderate sympathetic nervous system activation (e.g., tachycardia, blood pressure increased, mydriasis, dry mouth) have also been observed. Most events were mild to moderate. Less commonly, there have been reports of QT prolongation and mental changes, including disorientation and hallucinations [see Clinical Pharmacology].

 

Consult with a Certified Poison Control Center for up to date guidance and advice. Because atomoxetine is highly protein-bound, dialysis is not likely to be useful in the treatment of overdose.

 

CONTRAINDICATIONS

  • Hypersensitivity to atomoxetine or other constituents of product. (4.1)
  • STRATTERA use within 2 weeks after discontinuing MAOI or other drugs that affect brain monoamine concentrations. (4.2, 7.1)
  • Narrow Angle Glaucoma. (4.3)
  • Pheochromocytoma or history of pheochromocytoma. (4.4)
  • Severe Cardiovascular Disorders that might deteriorate with clinically important increases in HR and BP. (4.5)

STRATTERA is contraindicated in patients known to be hypersensitive to atomoxetine or other constituents of the product [see Warnings and Precautions (5.8)].

 

STRATTERA should not be taken with an MAOI, or within 2 weeks after discontinuing an MAOI. Treatment with an MAOI should not be initiated within 2 weeks after discontinuing STRATTERA. With other drugs that affect brain monoamine concentrations, there have been reports of serious, sometimes fatal reactions (including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma) when taken in combination with an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. Such reactions may occur when these drugs are given concurrently or in close proximity [see Drug Interactions ].

 

In clinical trials, STRATTERA use was associated with an increased risk of mydriasis and therefore its use is not recommended in patients with narrow angle glaucoma.

 

Serious reactions, including elevated blood pressure and tachyarrhythmia, have been reported in patients with pheochromocytoma or a history of pheochromocytoma who received STRATTERA. Therefore, STRATTERA should not be taken by patients with pheochromocytoma or a history of pheochromocytoma.

 

STRATTERA should not be used in patients with severe cardiovascular disorders whose condition would be expected to deteriorate if they experience increases in blood pressure or heart rate that could be clinically important (for example, 15 to 20 mm Hg in blood pressure or 20 beats per minute in heart rate). [See Warnings and Precautions].

 

DRUG ABUSE AND DEPENDENCE

STRATTERA is not a controlled substance.

 

In a randomized, double-blind, placebo-controlled, abuse-potential study in adults comparing effects of STRATTERA and placebo, STRATTERA was not associated with a pattern of response that suggested stimulant or euphoriant properties.

 

Clinical study data in over 2000 children, adolescents, and adults with ADHD and over 1200 adults with depression showed only isolated incidents of drug diversion or inappropriate self-administration associated with STRATTERA. There was no evidence of symptom rebound or adverse reactions suggesting a drug-discontinuation or withdrawal syndrome.

 

Animal Experience — Drug discrimination studies in rats and monkeys showed inconsistent stimulus generalization between atomoxetine and cocaine.

 

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