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Drug Interactions between osilodrostat and Quadrinal

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

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Interactions between your drugs

Major

PHENobarbital osilodrostat

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline) and osilodrostat

MONITOR CLOSELY: Coadministration with potent inducers of CYP450 3A4 and/or 2B6 may decrease the plasma concentrations of osilodrostat, which is partially metabolized by these isoenzymes. According to the product labeling, multiple CYP450 isoenzymes (CYP450 3A4, 2B6, and 2D6) and UDP-glucuronosyltransferases contribute to osilodrostat metabolism, and no single pathway contributes greater than 25% to the total clearance. Some of the known potent CYP450 3A4 and 2B6 inducers also induce UDP-glucuronosyltransferases. Pharmacokinetic data for osilodrostat in combination with a potent inducer of one or more of these pathways have not been reported. Reduced therapeutic efficacy of osilodrostat may occur during coadministration. On the other hand, discontinuation of a potent CYP450 3A4 and/or 2B6 inducer during treatment with osilodrostat may result in increased osilodrostat plasma concentrations and increased risk of adverse effects such as hypocortisolism (which may lead to life-threatening adrenal insufficiency), QT prolongation (which may increase the risk of ventricular arrhythmias including torsade de pointes and sudden death), and elevated androgen and 11-deoxycorticosterone levels (the latter of which may activate mineralocorticoid receptors and cause hypokalemia, edema, and hypertension).

MANAGEMENT: An increase in the dosage of osilodrostat may be required during concomitant use of a potent CYP450 3A4 and/or 2B6 inducer. Dosage adjustments should be based on clinical response and tolerance. Patients should have regular monitoring of 24-hour urine free cortisol and serum or plasma cortisol during treatment, as well as regular evaluations of their signs and symptoms. A reduction in dosage of osilodrostat may be required if the potent CYP450 3A4 and/or 2B6 inducer is discontinued during treatment with osilodrostat.

References

  1. (2020) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases Inc
  2. (2022) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases Australia Pty Ltd, ISTURISA PI v1.1
  3. (2021) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases UK Ltd

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Moderate

theophylline PHENobarbital

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline) and Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline)

MONITOR: Barbiturates may decrease serum levels and therapeutic effects of the methylxanthines. The mechanism is barbiturate induction of CYP450 3A4 and 1A2 hepatic metabolism of methylxanthines.

MANAGEMENT: Close observation for clinical and laboratory evidence of decreased methylxanthine effect is indicated if these drugs must be used together. Patients should be advised to notify their physician if they experience a worsening of their respiratory symptoms.

References

  1. Upton RA (1991) "Pharmacokinetic interactions between theophylline and other medication (Part I)." Clin Pharmacokinet, 20, p. 66-80
  2. Bukowskyj M, Nakatsu K, Munt PW (1984) "Theophylline reassessed." Ann Intern Med, 101, p. 63-73
  3. Landay RA, Gonzalez MA, Taylor JC (1978) "Effect of phenobarbital on theophylline disposition." J Allergy Clin Immunol, 62, p. 27-9
  4. Dahlqvist R, Steiner E, Koike Y, von Bahr C, Lind M, Billing B (1989) "Induction of theophylline metabolism by pentobarbital." Ther Drug Monit, 11, p. 408-10
View all 4 references

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Moderate

theophylline osilodrostat

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline) and osilodrostat

MONITOR: Coadministration with osilodrostat may increase the plasma concentrations of drugs that are metabolized by CYP450 1A2, 2C19, 2D6, and/or 3A4. Osilodrostat has been shown to be a moderate inhibitor of CYP450 1A2, a mild to borderline moderate inhibitor of CYP450 2C19, and a weak inhibitor of CYP450 2D6 and 3A4. In a pharmacokinetic study with 20 healthy volunteers using a single 50 mg dose of osilodrostat and a probe drug cocktail, osilodrostat increased the exposures to caffeine (CYP450 1A2 substrate), omeprazole (CYP450 2C19 substrate), dextromethorphan (CYP450 2D6 substrate), and midazolam (CYP450 3A4/5 substrate) by 2.5-, 1.9-, 1.5- and 1.5-fold, respectively.

MANAGEMENT: Caution is advised when osilodrostat is used concurrently with drugs that are substrates of CYP450 1A2, 2C19, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever osilodrostat is added to or withdrawn from therapy.

References

  1. (2020) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases Inc
  2. (2022) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases Australia Pty Ltd, ISTURISA PI v1.1
  3. (2021) "Product Information. Isturisa (osilodrostat)." Recordati Rare Diseases UK Ltd

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Minor

theophylline ePHEDrine

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline) and Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline)

Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

References

  1. Weinberger M, Bronsky E, Bensch GW, Bock GN, Yecies JJ (1975) "Interaction of ephedrine and theophylline." Clin Pharmacol Ther, 17, p. 585-92
  2. Sims JA, doPico GA, Reed CE (1978) "Bronchodilating effect of oral theophylline-ephedrine combination." J Allergy Clin Immunol, 62, p. 15-21
  3. Tinkelman DG, Avner SE (1977) "Ephedrine therapy in asthmatic children. Clinical tolerance and absence of side effects." JAMA, 237, p. 553-7
  4. Weinberger MM, Brousky EA (1974) "Evaluation of oral bronchodilator therapy in asthmatic children: bronchodilators in asthmatic children." J Pediatr, 84, p. 421-7
  5. Badiei B, Faciane J, Sly M (1975) "Effect of throphylline, ephedrine and theri combination upon exercise-induced airway obstruction." Ann Allergy, 35, p. 32-6
View all 5 references

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Drug and food interactions

Major

PHENobarbital food

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline)

GENERALLY AVOID: Concurrent acute use of barbiturates and ethanol may result in additive CNS effects, including impaired coordination, sedation, and death. Tolerance of these agents may occur with chronic use. The mechanism is related to inhibition of microsomal enzymes acutely and induction of hepatic microsomal enzymes chronically.

MANAGEMENT: The combination of ethanol and barbiturates should be avoided.

References

  1. Gupta RC, Kofoed J (1966) "Toxological statistics for barbiturates, other sedatives, and tranquilizers in Ontario: a 10-year survey." Can Med Assoc J, 94, p. 863-5
  2. Misra PS, Lefevre A, Ishii H, Rubin E, Lieber CS (1971) "Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats." Am J Med, 51, p. 346-51
  3. Saario I, Linnoila M (1976) "Effect of subacute treatment with hypnotics, alone or in combination with alcohol, on psychomotor skills related to driving." Acta Pharmacol Toxicol (Copenh), 38, p. 382-92
  4. Stead AH, Moffat AC (1983) "Quantification of the interaction between barbiturates and alcohol and interpretation of fatal blood concentrations." Hum Toxicol, 2, p. 5-14
  5. Seixas FA (1979) "Drug/alcohol interactions: avert potential dangers." Geriatrics, 34, p. 89-102
View all 5 references

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Moderate

theophylline food

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline)

GENERALLY AVOID: Coadministration with caffeine may increase the serum concentrations of theophylline. The proposed mechanism involves competitive inhibition of theophylline metabolism via CYP450 1A2, as well as metabolic conversion of caffeine to theophylline in vivo and saturation of theophylline metabolism at higher serum concentrations. In six healthy male volunteers (all smokers), serum concentrations of theophylline (administered as aminophylline 400 mg single oral dose) were significantly higher following consumption of caffeine (2 to 7 cups of instant coffee over 24 hours, equivalent to approximately 120 to 630 mg of caffeine) than after caffeine deprivation for 48 hours. Caffeine consumption also increased the apparent elimination half-life of theophylline by an average of 32% and reduced its total body clearance by 23%. In another study, steady-state concentration and area under the concentration-time curve of theophylline (1200 mg intravenously over 24 hours) increased by 23% and 40%, respectively, in eight healthy volunteers following administration of caffeine (300 mg orally three times a day).

MANAGEMENT: Given the narrow therapeutic index of theophylline, patients should limit or avoid significant fluctuations in their intake of pharmacologic as well as dietary caffeine.

ADJUST DOSING INTERVAL: Administration of theophylline with continuous enteral nutrition may reduce the serum levels or the rate of absorption of theophylline. The mechanism has not been reported. In one case, theophylline levels decreased by 53% in a patient receiving continuous nasogastric tube feedings and occurred with both theophylline tablet and liquid formulations, but not with intravenous aminophylline.

MANAGEMENT: When administered to patients receiving continuous enteral nutrition , some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 1 hour after the dose of theophylline is given; rapid-release formulations are preferable, and theophylline levels should be monitored.

References

  1. Jonkman JH, Sollie FA, Sauter R, Steinijans VW (1991) "The influence of caffeine on the steady-state pharmacokinetics of theophylline." Clin Pharmacol Ther, 49, p. 248-55
  2. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K (1993) "Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects." Eur J Clin Pharmacol, 44, p. 295-8
  3. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT (2009) "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm, 66, p. 1438-67

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Moderate

theophylline food

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline)

GENERALLY AVOID: Coadministration with caffeine may increase the serum concentrations of theophylline. The proposed mechanism involves competitive inhibition of theophylline metabolism via CYP450 1A2, as well as metabolic conversion of caffeine to theophylline in vivo and saturation of theophylline metabolism at higher serum concentrations. In six healthy male volunteers (all smokers), serum concentrations of theophylline (administered as aminophylline 400 mg single oral dose) were significantly higher following consumption of caffeine (2 to 7 cups of instant coffee over 24 hours, equivalent to approximately 120 to 630 mg of caffeine) than after caffeine deprivation for 48 hours. Caffeine consumption also increased the apparent elimination half-life of theophylline by an average of 32% and reduced its total body clearance by 23%. In another study, steady-state concentration and area under the concentration-time curve of theophylline (1200 mg intravenously over 24 hours) increased by 23% and 40%, respectively, in eight healthy volunteers following administration of caffeine (300 mg orally three times a day).

MANAGEMENT: Given the narrow therapeutic index of theophylline, patients should limit or avoid significant fluctuations in their intake of pharmacologic as well as dietary caffeine.

References

  1. Jonkman JH, Sollie FA, Sauter R, Steinijans VW (1991) "The influence of caffeine on the steady-state pharmacokinetics of theophylline." Clin Pharmacol Ther, 49, p. 248-55
  2. Sato J, Nakata H, Owada E, Kikuta T, Umetsu M, Ito K (1993) "Influence of usual intake of dietary caffeine on single-dose kinetics of theophylline in healthy human subjects." Eur J Clin Pharmacol, 44, p. 295-8

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Moderate

ePHEDrine food

Applies to: Quadrinal (ephedrine / phenobarbital / potassium iodide / theophylline)

MONITOR: Coadministration of two or more sympathomimetic agents may increase the risk of adverse effects such as nervousness, irritability, and increased heart rate. Central nervous system (CNS) stimulants, particularly amphetamines, can potentiate the adrenergic response to vasopressors and other sympathomimetic agents. Additive increases in blood pressure and heart rate may occur due to enhanced peripheral sympathetic activity.

MANAGEMENT: Caution is advised if two or more sympathomimetic agents are coadministered. Pulse and blood pressure should be closely monitored.

References

  1. Rosenblatt JE, Lake CR, van Kammen DP, Ziegler MG, Bunney WE Jr (1979) "Interactions of amphetamine, pimozide, and lithium on plasma norepineophrine and dopamine-beta-hydroxylase in schizophrenic patients." Psychiatry Res, 1, p. 45-52
  2. Cavanaugh JH, Griffith JD, Oates JA (1970) "Effect of amphetamine on the pressor response to tyramine: formation of p-hydroxynorephedrine from amphetamine in man." Clin Pharmacol Ther, 11, p. 656
  3. (2001) "Product Information. Adderall (amphetamine-dextroamphetamine)." Shire Richwood Pharmaceutical Company Inc
  4. (2001) "Product Information. Tenuate (diethylpropion)." Aventis Pharmaceuticals
  5. (2001) "Product Information. Sanorex (mazindol)." Novartis Pharmaceuticals
  6. (2001) "Product Information. Focalin (dexmethylphenidate)." Mikart Inc
  7. (2002) "Product Information. Strattera (atomoxetine)." Lilly, Eli and Company
View all 7 references

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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.

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