Dextromethorphan and quinidine

Desipramine: Exposure increases 8-fold. Reduce desipramine dose and adjust based on clinical response. ( 7.5 , 12.4 ) Paroxetine: Exposure increases 2-fold. Reduce paroxetine dose and adjust based on clinical response. ( 7.5 , 12.4 ) Digoxin: Increased digoxin substrate plasma concentration may occur. ( 7.6 )

7.1 MAOIs Do not use NUEDEXTA with monoamine oxidase inhibitors (MAOIs) or in patients who have taken MAOIs within the preceding 14 days [ see Contraindications ( 4.3 ) ] .

7.2 Drugs that Prolong QT and are Metabolized by CYP2D6 Do not use with drugs that both prolong QT interval and are metabolized by CYP2D6 (e.g., thioridazine or pimozide) [ see Contraindications ( 4.4 ) ] .

7.3 Drugs that Prolong QT and Concomitant CYP3A4 Inhibitors Recommend ECG in patients taking drugs with NUEDEXTA that prolong the QT interval and in patients taking concomitant moderate or strong CYP3A4 inhibitors [ see Warnings and Precautions ( 5.3 ) ] .

7.4 SSRIs and Tricyclic Antidepressants Use of NUEDEXTA with SSRIs or tricyclic antidepressants increases the risk of 'serotonin syndrome' [ see Warnings and Precautions ( 5.6 ) ] .

7.5 CYP2D6 Substrate The co-administration of NUEDEXTA with drugs that undergo extensive CYP2D6 metabolism may result in altered drug effects, due to accumulation of parent drug and/or failure of metabolite formation [ see Warnings and Precautions ( 5.4 ) ] . Therapy with medications that are primarily metabolized by CYP2D6 and that have a relatively narrow therapeutic index should be initiated at a low dose if a patient is receiving NUEDEXTA concurrently. If NUEDEXTA is added to the treatment regimen of a patient already receiving a drug primarily metabolized by CYP2D6, the need for a dose modification of the original medication should be considered.

The extent to which CYP2D6 interactions may pose clinical problems will depend on the pharmacokinetics of the substrate involved. In cases of prodrugs whose actions are mediated by the CYP2D6-produced metabolites (for example, codeine and hydrocodone, whose analgesic and antitussive effects appear to be mediated by morphine and hydromorphone, respectively), it may not be possible to achieve the desired clinical benefits in the presence of NUEDEXTA due to quinidine-mediated inhibition of CYP2D6. Consider use of alternative treatment with NUEDEXTA when clinically indicated.

Drug interactions with desipramine and paroxetine have been studied in controlled clinical trials with a higher dose combination of dextromethorphan/quinidine (dextromethorphan 30 mg/quinidine 30 mg) than NUEDEXTA; study results are described below. No other drug interactions with CYP2D6 substrates have been systematically investigated, although concomitant use of such drugs was allowed in clinical trials with NUEDEXTA and in clinical trials with higher dose formulations of dextromethorphan/quinidine. Desipramine (CYP2D6 substrate): The tricyclic antidepressant desipramine is metabolized primarily by CYP2D6.

A drug interaction study was conducted between a higher combination dose of dextromethorphan (dextromethorphan 30 mg/quinidine 30 mg) and desipramine 25 mg. The combination dose of dextromethorphan/quinidine increased steady state desipramine levels approximately 8-fold. If NUEDEXTA and desipramine are prescribed concomitantly, the initial dose of desipramine should be markedly reduced. The dose of desipramine can then be adjusted based on clinical response; however, a dose above 40 mg/day is not recommended.

Paroxetine (CYP2D6 inhibitor and substrate) : When the combination dose of dextromethorphan 30 mg/quinidine 30 mg was added to paroxetine at steady state, paroxetine exposure (AUC 0-24 ) increased by 1.7 fold and C max increased by 1.5 fold. Consideration should be given to initiating treatment with a lower dose of paroxetine if given with NUEDEXTA. The dose of paroxetine can then be adjusted based on clinical response; however, dosage above 35 mg/day is not recommended.

7.6 Digoxin Quinidine is an inhibitor of P-glycoprotein. Concomitant administration of quinidine with digoxin, a P-glycoprotein substrate, results in serum digoxin levels that may be as much as doubled. Plasma digoxin concentrations should be closely monitored in patients taking NUEDEXTA concomitantly, and the digoxin dose reduced, as necessary.

7.7 Alcohol As with any other CNS drug, caution should be used when NUEDEXTA is taken in combination with other centrally acting drugs and alcohol.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of NUEDEXTA in pregnant women. In oral studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including teratogenicity (rabbits) and embryo lethality, when given to pregnant animals (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

Data Animal Data When dextromethorphan/quinidine was administered orally (0/0, 5/100, 15/100, and 50/100 mg/kg/day) to pregnant rats during the period of organogenesis, embryo-fetal deaths were observed at the highest dose tested and reduced skeletal ossification was observed at all doses. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the recommended human dose (RHD) of 40/20 mg/day on a mg/m 2 basis. Oral administration to pregnant rabbits during organogenesis in two separate studies (0/0, 5/60, 15/60, and 30/60 mg/kg/day; 0/0, 5/100, 15/100, and 50/100 mg/kg/day) resulted in an increased incidence of fetal malformations at all but the lowest dose tested.

The no-effect dose (5/100 mg/kg/day) is approximately 2/100 times the RHD on a mg/m 2 basis. When dextromethorphan/quinidine was orally administered to female rats during pregnancy and lactation in two separate studies (0/0, 5/100, 15/100, and 30/100 mg/kg/day; 0/0, 5/100, 15/100, and 50/100 mg/kg/day), pup survival and pup weight were decreased at all doses, and developmental delay was observed in offspring at the mid and high doses. A no-effect dose for adverse developmental effects was not identified. The lowest dose tested (5/100 mg/kg/day) is approximately 1/50 times the RHD on a mg/m 2 basis.

When dextromethorphan/quinidine was orally administered (0/0, 5/50, 15/50, 25/50 mg/kg) to male and female rats on Postnatal Day 7, the highest dose resulted in neuronal death in brain (thalamus and medulla oblongata). Postnatal Day 7 in rat corresponds to the third trimester of the gestation through the first several months of life but may extend to approximately three years of age in humans.