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Drug Interactions between lorlatinib and Lufyllin-EPG

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

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Interactions between your drugs

Major

PHENobarbital lorlatinib

Applies to: Lufyllin-EPG (dyphylline / ephedrine / guaifenesin / phenobarbital) and lorlatinib

CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of lorlatinib, which has been found to be metabolized primarily by CYP450 3A4 and UGT1A4 in vitro. In addition to the potential for diminished efficacy of lorlatinib, the risk of serious hepatotoxicity may be increased due to activation of the pregnane X receptor (PXR) by both lorlatinib and CYP450 3A4 inducers. When a single 100 mg oral dose of lorlatinib was administered to 12 healthy volunteers on day 8 of treatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 8 days), mean lorlatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 76% and 85%, respectively. The AUC of the two active metabolites also decreased--one by 92% and the other by 59%. Severe hepatotoxicity was reported in 10 of the 12 subjects, with Grade 4 alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations occurring in 50% of subjects, Grade 3 elevations in 33% of subjects, and Grade 2 elevations in 8% of subjects. ALT or AST elevations occurred within 3 days and returned to within normal limits within 7 to 34 days (median 15 days). The median time to recovery was 18 days in subjects with Grade 3 or 4 elevations and 7 days in subjects with Grade 2 elevations.

MANAGEMENT: Concomitant use of lorlatinib with potent CYP450 3A4 inducers is considered contraindicated. Lorlatinib should not be initiated until after discontinuation of potent CYP450 3A4 inducers for at least 3 plasma half-lives.

References

  1. "Product Information. Lorbrena (lorlatinib)." Pfizer U.S. Pharmaceuticals Group (2018):

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Minor

ePHEDrine dyphylline

Applies to: Lufyllin-EPG (dyphylline / ephedrine / guaifenesin / phenobarbital) and Lufyllin-EPG (dyphylline / ephedrine / guaifenesin / phenobarbital)

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

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Drug and food interactions

Major

lorlatinib food

Applies to: lorlatinib

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of lorlatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients treated with lorlatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. If coadministration is unavoidable, some authorities recommend reducing the initial dosage of lorlatinib from 100 mg orally once daily to 75 mg orally once daily. In patients who have had a dosage reduction to 75 mg orally once daily due to adverse reactions, the lorlatinib dosage should be further reduced to 50 mg orally once daily upon initiation of a potent CYP450 3A4 inhibitor. After 3 plasma half-lives following discontinuation of the potent CYP450 3A4 inhibitor, the lorlatinib dosage may be increased to that used prior to initiation of the inhibitor.

References

  1. Cerner Multum, Inc. "UK Summary of Product Characteristics." O 0
  2. "Product Information. Lorbrena (lorlatinib)." Pfizer U.S. Pharmaceuticals Group (2018):

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Major

PHENobarbital food

Applies to: Lufyllin-EPG (dyphylline / ephedrine / guaifenesin / phenobarbital)

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

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Moderate

ePHEDrine food

Applies to: Lufyllin-EPG (dyphylline / ephedrine / guaifenesin / phenobarbital)

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

Further information

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