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Drug Interactions between clomipramine and paroxetine

This report displays the potential drug interactions for the following 2 drugs:

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Interactions between your drugs

Major

clomiPRAMINE PARoxetine

Applies to: clomipramine and paroxetine

GENERALLY AVOID: Coadministration with paroxetine may significantly increase the plasma concentrations of some tricyclic antidepressants (TCAs). The proposed mechanism is paroxetine inhibition of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of many antidepressant and psychotropic drugs. Several-fold increases in plasma levels and decreases in metabolic clearance have been reported for desipramine and nortriptyline, while smaller changes have been reported for amitriptyline and imipramine, presumably because other CYP450 isoenzymes are also involved in their metabolism. Pharmacodynamically, the combination of paroxetine (or any other selective serotonin reuptake inhibitor) and a TCA may potentiate the risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5HT1A receptors.

MANAGEMENT: In general, the use of paroxetine (or other SSRIs) with TCAs should be avoided if possible, or otherwise approached with caution if potential benefit is deemed to outweigh the risk. Pharmacologic response and plasma TCA levels should be monitored more closely whenever paroxetine is added to or withdrawn from therapy in patients stabilized on their existing antidepressant regimen, and the TCA dosage adjusted as necessary. Patients should be monitored closely for signs and symptoms of TCA toxicity (e.g., sedation, dry mouth, blurred vision, constipation, urinary retention) and/or excessive serotonergic activity (e.g., CNS irritability, altered consciousness, confusion, myoclonus, ataxia, abdominal cramping, hyperpyrexia, shivering, pupillary dilation, diaphoresis, hypertension, and tachycardia).

References (19)
  1. Sternbach H (1991) "The serotonin syndrome." Am J Psychiatry, 148, p. 705-13
  2. Brosen K, Hansen JG, Nielsen KK, Sindrup SH, Gram LF (1993) "Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine." Eur J Clin Pharmacol, 44, p. 349-55
  3. Popli AP, Baldessarini RJ, Cole JO (1994) "Interactions of serotonin reuptake inhibitors with tricyclic antidepressants." Arch Gen Psychiatry, 51, p. 666-7
  4. Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE (1992) "The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes." Br J Clin Pharmacol, 34, p. 262-5
  5. Vonmoltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI (1995) "Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants." J Clin Psychopharmacol, 15, p. 125-31
  6. Taylor D (1995) "Selective serotonin reuptake inhibitors and tricyclic antidepressants in combination - interactions and therapeutic uses." Br J Psychiatry, 167, p. 575-80
  7. Riesenman C (1995) "Antidepressant drug interactions and the cytochrome p450 system: a critical appraisal." Pharmacotherapy, 15, s84-99
  8. Fischer P (1995) "Serotonin syndrome in the elderly after antidepressive monotherapy." J Clin Psychopharmacol, 15, p. 440-2
  9. Corkeron MA (1995) "Serotonin syndrome - a potentially fatal complication of antidepressant therapy." Med J Aust, 163, p. 481-2
  10. Albers LJ, Reist C, Helmeste D, Vu R, Tang SW (1996) "Paroxetine shifts imipramine metabolism." Psychiatry Res, 59, p. 189-96
  11. Ghahramani P, Ellis SW, Lennard MS, Ramsay LE, Tucker GT (1997) "Cytochromes p450 mediating the n-demethylation of amitriptyline." Br J Clin Pharmacol, 43, p. 137-44
  12. Mills KC (1997) "Serotonin syndrome: A clinical update." Crit Care Clin, 13, p. 763
  13. Mathew NT, Tietjen GE, Lucker C (1996) "Serotonin syndrome complicating migraine pharmacotherapy." Cephalalgia, 16, p. 323-7
  14. Leucht S, Hackl HJ, Steimer W, Angersbach D, Zimmer R (2000) "Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients." Psychopharmacology, 147, p. 378-83
  15. Ereshefsky L, Riesemman C, Lam YW (1995) "Antidepressant drug interactions and the cytochrome P450 system. The role of cytochrome P450 2D6." Clin Pharmacokinet, 29(Suppl 1), 10-8; discussion 18-9
  16. Venkatakrishnan K, Schmider J, Harmatz JS, et al. (2001) "Relative contribution of CYP3A to amitriptyline clearance in humans: in vitro and in vivo studies." J Clin Pharmacol, 41, p. 1043-54
  17. Laine K, Tybring G, Hartter S, et al. (2001) "Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test." Clin Pharmacol Ther, 70, p. 327-35
  18. Martin TG (1996) "Serotonin syndrome." Ann Emerg Med, 28, p. 520-6
  19. Yang TJ, Krausz KW, Sai Y, Gonzalez FJ, Gelbon HV (1999) "Eight inhibitory monoclonal antibodies define the role of individual P-450S in human liver microsomal diazepam, 7-ethoxycoumarin, and imipramine metabolism." Drug Metab Dispos, 27, p. 102-9

Drug and food interactions

Moderate

clomiPRAMINE food

Applies to: clomipramine

MONITOR: Limited data suggest that the administration of clomipramine with grapefruit juice or cranberry juice may significantly increase plasma drug concentrations of clomipramine. Clomipramine is initially demethylated by CYP450 1A2, 3A3 and 3A4 before undergoing further metabolism to 8-hydroxyclomipramine. The increase in clomipramine bioavailability may stem from inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The precise mechanism by which cranberry juice exerts its effects is unknown, but may involve inhibition of CYP450 isoenzymes. This interaction has occasionally been exploited in attempts to improve symptomatic control of obsessive compulsive disorder.

MANAGEMENT: Patients receiving clomipramine therapy who ingest cranberry juice, grapefruits, or grapefruit juice should be monitored for adverse effects and undue fluctuations in plasma drug levels.

References (4)
  1. Oesterheld J, Kallepalli BR (1997) "Grapefruit juice and clomipramine: shifting metabolitic ratios." J Clin Psychopharmacol, 17, p. 62-3
  2. Bailey DG, Dresser GR, Kreeft JH, Munoz C, Freeman DJ, Bend JR (2000) "Grapefruit-felodipine interaction: Effect of unprocessed fruit and probable active ingredients." Clin Pharmacol Ther, 68, p. 468-77
  3. Cerner Multum, Inc. "UK Summary of Product Characteristics."
  4. Cerner Multum, Inc. "Australian Product Information."
Moderate

PARoxetine food

Applies to: paroxetine

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

References (4)
  1. Warrington SJ, Ankier SI, Turner P (1986) "Evaluation of possible interactions between ethanol and trazodone or amitriptyline." Neuropsychobiology, 15, p. 31-7
  2. Gilman AG, eds., Nies AS, Rall TW, Taylor P (1990) "Goodman and Gilman's the Pharmacological Basis of Therapeutics." New York, NY: Pergamon Press Inc.
  3. (2012) "Product Information. Fycompa (perampanel)." Eisai Inc
  4. (2015) "Product Information. Rexulti (brexpiprazole)." Otsuka American Pharmaceuticals Inc
Moderate

clomiPRAMINE food

Applies to: clomipramine

GENERALLY AVOID: The combination of ethanol and a tricyclic antidepressant may result in additive impairment of motor skills, especially driving skills. Also, one study has suggested that clomipramine metabolism is significantly impaired for several weeks or more following discontinuation of chronic alcohol consumption.

MANAGEMENT: Patients should be warned of this interaction and advised to limit their ethanol intake while taking tricyclic antidepressants. Monitoring for TCA toxicity (CNS depression, excessive anticholinergic effects, hypotension, arrhythmias) is recommended during alcohol withdrawal.

References (3)
  1. Seppala T, Linnoila M, Elonen E, Mattila MJ, Makl M (1975) "Effect of tricyclic antidepressants and alcohol on psychomotor skills related to driving." Clin Pharmacol Ther, 17, p. 515-22
  2. Berlin I, Cournot A, Zimmer R, et al. (1990) "Evaluation and comparison of the interaction between alcohol and moclobemide or clomipramine in healthy subjects." Psychopharmacology (Berl), 100, p. 40-5
  3. Balant-Gorgia AE, Gay M, Gex-Fabry M, Balant LP (1992) "Persistent impairment of clomipramine demethylation in recently detoxified alcoholic patients." Ther Drug Monit, 14, p. 119-24

Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.

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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

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