Drug Interactions between acetaminophen / caffeine / dihydrocodeine and fidanacogene elaparvovec

GENERALLY AVOID: Chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, which has included rare cases of fatal hepatitis and frank hepatic failure requiring liver transplantation. The proposed mechanism is induction of hepatic microsomal enzymes during chronic alcohol use, which may result in accelerated metabolism of acetaminophen and increased production of potentially hepatotoxic metabolites.

MANAGEMENT: In general, chronic alcoholics should avoid regular or excessive use of acetaminophen. Alternative analgesic/antipyretic therapy may be appropriate in patients who consume three or more alcoholic drinks per day. However, if acetaminophen is used, these patients should be cautioned not to exceed the recommended dosage (maximum 4 g/day in adults and children 12 years of age or older).

GENERALLY AVOID: Coadministration with other hepatotoxic agents such as alcohol may increase the risk of liver injury and decrease the therapeutic efficacy of liver-directed adeno-associated virus (AAV) vector fidanacogene elaparvovec, designed to help replace missing and coagulation factor IX. Increased transaminase levels from AAV therapy have been attributed to immune-mediated injury of transduced hepatocytes, which may decrease their therapeutic efficacy. In addition, alcohol may impact liver enzyme elevation as well as reduce the activity of coagulation factor IX. In a prospective, open-label, single-arm, multinational clinical study of adult male patients with moderately severe to severe hemophilia B (n=45) receiving a single dose of fidanacogene elaparvovec (5 x 10[11] vector genomes [vg]/kg), increased transaminase levels greater than or equal to 1.5 times baseline were reported in 29 patients. Of these patients, 28 received treatment with corticosteroids due to increased transaminases and/or a decline in factor IX activity, with a mean initiation time to corticosteroid therapy reported at 45 days.

MANAGEMENT: According to the manufacturer, for the first year after administration of fidanacogene elaparvovec, alcohol consumption should be limited.

MONITOR: Smoking cessation may lead to elevated plasma concentrations and enhanced pharmacologic effects of drugs that are substrates of CYP450 1A2 (and possibly CYP450 1A1) and/or certain drugs with a narrow therapeutic index (e.g., flecainide, pentazocine). One proposed mechanism is related to the loss of CYP450 1A2 and 1A1 induction by polycyclic aromatic hydrocarbons in tobacco smoke; when smoking cessation agents are initiated and smoking stops, the metabolism of certain drugs may decrease leading to increased plasma concentrations. The mechanism by which smoking cessation affects narrow therapeutic index drugs that are not known substrates of CYP450 1A2 or 1A1 is unknown. The clinical significance of this interaction is unknown as clinical data are lacking.

MANAGEMENT: Until more information is available, caution is advisable if smoking cessation agents are used concomitantly with drugs that are substrates of CYP450 1A2 or 1A1 and/or those with a narrow therapeutic range. Patients receiving smoking cessation agents may require periodic dose adjustments and closer clinical and laboratory monitoring of medications that are substrates of CYP450 1A2 or 1A1.

The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.