Dextromethorphan manufacturers

Beahm, J.S. Dextromethorphan Continuous Lozenge Manufacturing Process. US Patent 5,302,394, April 12, 1994. 

The alkaloid dextromethorphan is an antitussive drug manufactured by Lonza in enantiomerically pure form. While early synthesis involved the tedious resolution of an octahydroi-soquinoline intermediate with mandelic acid, a more recent process takes advantage of the catalytic reduction of a C-N double bond promoted by a chiral Ir/ferrocenylphosphine complex [70]. 

As parecoxib is rapidly metabolised to valdecoxib, the interactions are usually considered to be due to the effects of valdecoxib. The manufacturer of parecoxib cautions the concurrent use with carbamazepine, dexamethasone and rifampicin as their effects on parecoxib have not been studied. Valdecoxib increases the levels of dextromethorphan and omeprazole. Because of these interactions, caution is advised with drugs that are metabolised by the same isoenzymes, nameiy flecainide, metoprolol, propafenone, omeprazoie, diazepam, imipramine and phenytoin. No interaction appears to occur between parecoxib and midazolam. 

CYP2D6. The manufacturers say that treatment with 40 mg of valdecoxib twice daily for a week caused a threefold increase in the serum levels of dextromethorphan. This indicates that valdecoxib is an inhibitor of CYP2D6, and therefore the manufacturers suggest that caution should be observed with drugs that have a narrow therapeutic margin and are known to be predominantly metabolised by CYP2D6. They list flecainide, metoprolol and propafenone. The implication is that the serum levels of these... 

Because sibutramine inhibits serotonin uptake, and because the serious serotonin syndrome has been seen when serotonergic drugs were taken with SSRIs, the manufacturers say that sibutramine should not be taken with any serotonergic drugs. They name dextromethorphan, dihydroergot-amine, fentanyl, pentazocine, pethidine (meperidine), SSRIs, sumatriptan, and tryptophan. Possible cases have been reported for sibutramine and SSMs , (below).The US manufacturers also include lithium in their list. Note that this list is not exhaustive (see MAOIs under (d) above) and a case of the serotonin syndrome has been seen when venla-faxine was given with sibutramine. ... 

In a study in 14 healthy subjects, two 20-mg doses of dextromethorphan given 4 hours apart, before and during the use of linezolid 600 mg every 12 hours, had no effect on linezolid pharmacokinetics. The AUC and maximum level of the dextromethorphan metabolite, dextrorphan was decreased by 30%, but this was not considered sufficient to warrant any dosing alterations. There was no evidence of the serotonin syndrome, as measured by changes in body temperature, alertness and mental performance. However, the manufacturers describe one case where the concurrent use of linezolid and dextromethorphan resulted in the serotonin syndrome. Linezolid has mild reversible MAOI activity, and the serotonin syndrome has been described when dextromethorphan was taken by patients also taking antidepressant MAOIs, see MAOIs or RIMAs + Dextromethorphan , p.l 134. If the concurrent use of linezolid and dextromethorphan is considered necessary, it would seem prudent to monitor for symptoms of the serotonin syndrome , (p.9). 

The manufacturer of rasagiline su ests that its use with dextromethorphan should be avoided. Similarly, some consider that patients taking selegiline should try to avoid dextromethorphan. These warnings are based on the serious adverse reactions (the serotonin syndrome or similar) that have rarely occurred when dextromethorphan has been used with non-selective MAOIs or RIMAs , (p.ll34). The likelihood of any interaction with MAO-B... 

Memantine is chemically related to amantadine, and the manufacturer advises that concurrent use should be avoided or undertaken with caution because of the increased risk of adverse CNS-related drug reactions such as psychosis. Although there are no data, an increased risk is also predicted for ketamine and dextromethorphan, which are also NMDA antagonists. Avoidance of, or caution with, concurrent use is advised. 

Aripiprazole plasma levels are increased by inhibitors, and decreased by inducers, of CYP3A4. Quinidine increases aripiprazole levels. The manufacturers advise caution with drugs that can prolong the QT intervaL Food and famotidine do not have a clinically relevant effect on the pharmacokinetics of aripiprazole, and aripiprazole does not affect the pharmacokinetics of dextromethorphan, omeprazole, and warfarin. 

Aripiprazole 10 to 30 mg daily had no significant effects on the metabolism of dextromethorphan (CYP2D6 and CYP3A4 substrate), warfarin (CYP2C9 substrate) and omeprazole (CYP2C19 substrate). Aripiprazole is not expected to affect CYPl A2-mediated metabolism. The manufacturers therefore conclude that aripiprazole is unlikely to have clinically significant interactions with drugs that are substrates for these isoenzymes. ... 

The US manufacturer of tranylcypromine notes that the concurrent use of MAOIs and dextromethorphan has resulted in brief episodes of psychosis or bizarre behaviour. Similarly, the US manufacturer of phenelzine mentions one case of drowsiness and bizarre behaviour when dextromethorphan lozenges were used by a patient taking phenelzine. They also note that concurrent use of dextromethorphan may cause a reaction similar to... 

Moclobemide 300 mg twice daily for 9 days markedly reduced the O-demethylation of dextromethorphan (seven 20-mg doses given every 4 hours over 2 days), in 4 healthy subjects. The manufacturer notes that isolated cases of severe CNS adverse reactions have been seen with the combination. Concurrent use of dextromethorphan may have contributed to a fatality involving the illicit use of moclobemide and ecstasy , (p.1144). 

Despite the very limited information available, the severity of the reactions indicates that patients taking MAOIs should avoid taking dextromethorphan. The manufacturer of moclobemide also contraindicates the concurrent use of dextromethorphan. Patients should be warned that many cough preparations contain dextromethorphan. 

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