Interactions : אינטראקציות

7           DRUG INTERACTIONS

7.1         Potential for REYATAZ to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.
Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3)].
The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.
7.2         Potential for Other Drugs to Affect REYATAZ

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ’s therapeutic effect.
Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with REYATAZ [see Dosage and Administration].
7.3         Established and Other Potentially Significant Drug Interactions 
Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.
Table 16:                       Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:            Atazanavir or
Specific Drugs                   Concomitant Drug                                   Clinical Comment HIV Antiviral Agents
Nucleoside Reverse                   atazanavir      Coadministration of REYATAZ with didanosine buffered tablets resulted in a Transcriptase Inhibitors             didanosine      marked decrease in atazanavir exposure. It is recommended that REYATAZ be (NRTIs):                                              given (with food) 2 h before or 1 h after didanosine buffered formulations.
didanosine buffered                                   Simultaneous administration of didanosine EC and REYATAZ with food formulations                                          results in a decrease in didanosine exposure. Thus, REYATAZ and enteric-coated (EC) capsules                          didanosine EC should be administered at different times.
Nucleotide Reverse                   atazanavir      Tenofovir DF may decrease the AUC and Cmin of atazanavir. When Transcriptase Inhibitors:            tenofovir       coadministered with tenofovir DF in adults, it is recommended that REYATAZ tenofovir disoproxil fumarate                         300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single (DF)                                                  daily dose with food). REYATAZ increases tenofovir concentrations. The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir -associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant women taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.3).
Non-nucleoside Reverse               atazanavir      Efavirenz decreases atazanavir exposure.
Transcriptase Inhibitors                              In treatment-naive adult patients: (NNRTIs): efavirenz
If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime.
In treatment-experienced adult patients:
Coadministration of REYATAZ with efavirenz in treatment-experienced patients is not recommended due to decreased atazanavir exposure.
Protease Inhibitors:                 saquinavir      Appropriate dosing recommendations for this combination, with or without saquinavir (soft gelatin                              ritonavir, with respect to efficacy and safety have not been established. In a capsules)                                             clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily) plus nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2)].
Ritonavir                            atazanavir      If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.
Others                              other protease   Although not studied, the coadministration of REYATAZ/ritonavir and an inhibitor      additional protease inhibitor would be expected to increase exposure to the other protease inhibitor. Such coadministration is not recommended.
HCV Antiviral Agents
Protease Inhibitors:                 atazanavir      Concomitant administration of boceprevir and atazanavir/ritonavir resulted in boceprevir                                            reduced steady-state exposures to atazanavir and ritonavir. Coadministration of  ritonavir
REYATAZ/ritonavir and boceprevir is not recommended.
sofosbuvir, velpatasvir,            voxilaprevir     Coadministration with REYATAZ is not recommended.
voxilaprevir
Other Agents
Table 16:                         Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:              Atazanavir or
Specific Drugs                     Concomitant Drug                                      Clinical Comment Antacids and buffered                   atazanavir        Reduced plasma concentrations of atazanavir are expected if antacids, including medications                                                buffered medications, are administered with REYATAZ. REYATAZ should be administered 2 hours before or 1 hour after these medications.
Antiarrhythmics: amiodarone,           amiodarone,        Coadministration with REYATAZ has the potential to produce serious and/or bepridil, lidocaine (systemic),      bepridil, lidocaine   life-threatening adverse events and has not been studied. Caution is warranted quinidine                          (systemic), quinidine   and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
Anticoagulants: warfarin                 warfarin         Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored.
Antidepressants: tricyclic              tricyclic         Coadministration with REYATAZ has the potential to produce serious and/or antidepressants                      antidepressants       life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ.
Trazodone                               trazodone         Concomitant use of trazodone and REYATAZ with or without ritonavir may increase plasma concentrations of trazodone. Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered.
Antiepileptics:                        atazanavir         Plasma concentrations of atazanavir may be decreased when carbamazepine is carbamazepine                        carbamazepine        administered with REYATAZ without ritonavir. Coadministration of carbamazepine and REYATAZ without ritonavir is not recommended.
Ritonavir may increase plasma levels of carbamazepine. If patients beginning treatment with REYATAZ/ritonavir have been titrated to a stable dose of carbamazepine, a dose reduction for carbamazepine may be necessary.
phenytoin, phenobarbital               atazanavir         Plasma concentrations of atazanavir may be decreased when phenytoin or  phenytoin         phenobarbital is administered with REYATAZ without ritonavir.
 phenobarbital       Coadministration of phenytoin or phenobarbital and REYATAZ without ritonavir is not recommended. Ritonavir may decrease plasma levels of phenytoin and phenobarbital. When REYATAZ with ritonavir is coadministered with either phenytoin or phenobarbital, a dose adjustment of phenytoin or phenobarbital may be required.
Lamotrigine                            lamotrigine        Coadministration of lamotrigine and REYATAZ with ritonavir may decrease lamotrigine plasma concentrations. Dose adjustment of lamotrigine may be required when coadministered with REYATAZ and ritonavir. Coadministration of lamotrigine and REYATAZ without ritonavir is not expected to decrease lamotrigine plasma concentrations. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir.
Antifungals:                       REYATAZ/ritonavir:      Coadministration of ketoconazole has only been studied with REYATAZ ketoconazole, itraconazole            ketoconazole        without ritonavir (negligible increase in atazanavir AUC and Cmax). Due to the  itraconazole        effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously with REYATAZ/ritonavir.
Table 16:                       Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:            Atazanavir or
Specific Drugs                   Concomitant Drug                                       Clinical Comment Voriconazole                     REYATAZ/ritonavir       The use of voriconazole in patients receiving REYATAZ/ritonavir is not in subjects with a    recommended unless an assessment of the benefit/risk to the patient justifies the functional CYP2C19      use of voriconazole. Patients should be carefully monitored for voriconazole- allele:         associated adverse reactions and loss of either voriconazole or atazanavir  voriconazole       efficacy during the coadministration of voriconazole and REYATAZ/ritonavir.
Coadministration of voriconazole with REYATAZ (without ritonavir) may  atazanavir        affect atazanavir concentrations; however, no data are available.

REYATAZ/ritonavir in subjects without a functional CYP2C19 allele:
 voriconazole
 atazanavir

Antigout: colchicine                  colchicine        The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended.
Recommended adult dosage of colchicine when administered with
REYATAZ:
Treatment of gout flares:
0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days.
Prophylaxis of gout flares:
If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF):
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterials: rifabutin          rifabutin        A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted.
Table 16:                        Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:             Atazanavir or
Specific Drugs                    Concomitant Drug                                      Clinical Comment Antipsychotics: quetiapine and         quetiapine       Initiation of REYATAZ with ritonavir in patients taking quetiapine: lurasidone                                               Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.
Initiation of quetiapine in patients taking REYATAZ with ritonavir:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.


REYATAZ            REYATAZ without ritonavir
 lurasidone       If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.

REYATAZ/ritonavir      REYATAZ/ritonavir
 lurasidone       Use of lurasidone is contraindicated.

Benzodiazepines:                       midazolam        Concomitant use of parenteral midazolam with REYATAZ may increase parenterally administered                                plasma concentrations of midazolam. Coadministration should be done in a midazolamb                                               setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.
Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Coadministration of oral midazolam with REYATAZ is CONTRAINDICATED.
Calcium channel blockers:             diltiazem and     Caution is warranted. A dose reduction of diltiazem by 50% should be diltiazem                          desacetyl-diltiazem   considered. ECG monitoring is recommended. Coadministration of REYATAZ/ritonavir with diltiazem has not been studied.
felodipine, nifedipine,             calcium channel     Caution is warranted. Dose titration of the calcium channel blocker should be nicardipine, and verapamil              blocker          considered. ECG monitoring is recommended.

Endothelin receptor                    atazanavir       Plasma concentrations of atazanavir may be decreased when bosentan is antagonists:                                             administered with REYATAZ without ritonavir. Coadministration of bosentan  bosentan
Bosentan                                                 and REYATAZ without ritonavir is not recommended.
Coadministration of bosentan in adult patients on REYATAZ/ritonavir:
For patients who have been receiving REYATAZ/ritonavir for at least
10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability.
Coadministration of REYATAZ/ritonavir in adult patients on bosentan:
Discontinue bosentan at least 36 hours before starting REYATAZ/ritonavir.
At least 10 days after starting REYATAZ/ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability.
HMG-CoA reductase                     atorvastatin      Titrate atorvastatin dose carefully and use the lowest necessary dose.
inhibitors: atorvastatin,                                Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy,  rosuvastatin rosuvastatin                                             including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs.
Table 16:                       Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:            Atazanavir or
Specific Drugs                   Concomitant Drug                                      Clinical Comment 
H2-Receptor antagonists               atazanavir       Plasma concentrations of atazanavir were substantially decreased when REYATAZ 400 mg once daily was administered simultaneously with famotidine 40 mg twice daily in adults, which may result in loss of therapeutic effect and development of resistance.
In treatment-naive adult patients:
REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H2-receptor antagonist (H2RA). An H2RA dose comparable to famotidine
20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients.
OR
For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant women is not recommended.
In treatment-experienced adult patients:
Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA.
•   REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA.
•   REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA.
•   REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant women during the second and third trimester. REYATAZ is not recommended for pregnant women during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA.


Hormonal contraceptives:           ethinyl estradiol   Use with caution if coadministration of REYATAZ or REYATAZ/ritonavir ethinyl estradiol and                                   with oral contraceptives is considered. If an oral contraceptive is administered norgestimate or norethindrone       norgestimate   c with REYATAZ plus ritonavir, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol.
Potential safety risks include substantial increases in progesterone exposure.
 ethinyl estradiol   The long-term effects of increases in concentration of the progestational agent  norethindroned      are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne.
Coadministration of REYATAZ or REYATAZ/ritonavir with other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended.
Immunosuppressants:              immunosuppressants    Therapeutic concentration monitoring is recommended for these cyclosporine, sirolimus,                                immunosuppressants when coadministered with REYATAZ.
tacrolimus
Table 16:                 Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:      Atazanavir or
Specific Drugs             Concomitant Drug                                    Clinical Comment Inhaled beta agonist:          salmeterol      Coadministration of salmeterol with REYATAZ is not recommended.
Salmeterol                                      Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid:         REYATAZ          Concomitant use of fluticasone propionate and REYATAZ (without ritonavir) fluticasone                    fluticasone     may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long- term use.

REYATAZ/ritonavir    Concomitant use of fluticasone propionate and REYATAZ/ritonavir may  fluticasone      increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1)].
Macrolide antibiotics:       clarithromycin    Increased concentrations of clarithromycin may cause QTc prolongations; clarithromycin                   14-OH         therefore, a dose reduction of clarithromycin by 50% should be considered clarithromycin     when it is coadministered with REYATAZ. In addition, concentrations of the  atazanavir      active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ/ritonavir with clarithromycin has not been studied.
Opioids: Buprenorphine       buprenorphine     Coadministration of buprenorphine and REYATAZ with or without ritonavir  norbuprenorphine   increases the plasma concentration of buprenorphine and norbuprenorphine.
Coadministration of REYATAZ plus ritonavir with buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. Coadministration of buprenorphine and REYATAZ with ritonavir is not expected to decrease atazanavir plasma concentrations. Coadministration of buprenorphine and REYATAZ without ritonavir may decrease atazanavir plasma concentrations. The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended.
Table 16:                      Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on
Drug Interaction Studiesa or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Effect on
Concentration of
Concomitant Drug Class:           Atazanavir or
Specific Drugs                  Concomitant Drug                                   Clinical Comment PDE5 inhibitors: sildenafil,        sildenafil      Coadministration with REYATAZ has not been studied but may result in an tadalafil, vardenafil                tadalafil      increase in PDE5 inhibitor-associated adverse reactions, including hypotension,  vardenafil      syncope, visual disturbances, and priapism.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
Use of sildenafil* for the treatment of pulmonary hypertension (PAH) is contraindicated with REYATAZ [see Contraindications (4)].
The following dose adjustments are recommended for the use of tadalafil* with REYATAZ:
Coadministration of tadalafil* in patients on REYATAZ (with or without ritonavir):
•   For patients receiving REYATAZ (with or without ritonavir) for at least one week, start tadalafil* at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Coadministration of REYATAZ (with or without ritonavir) in patients on tadalafil*:
•   Avoid the use of tadalafil* when starting REYATAZ (with or without ritonavir). Stop tadalafil* at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting
REYATAZ (with or without ritonavir), resume tadalafil* at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability.
Use of PDE5 inhibitors for erectile dysfunction:
Use (sildenafil*) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
Use (tadalafil*) with caution at reduced doses of 10 mg every    72 hours with increased monitoring for adverse events.
REYATAZ/ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions.
REYATAZ: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions.

Proton-pump inhibitors:             atazanavir      Plasma concentrations of atazanavir were substantially decreased when omeprazole                                           REYATAZ 400 mg or REYATAZ 300 mg/ritonavir 100 mg once daily was administered with omeprazole 40 mg once daily in adults, which may result in loss of therapeutic effect and development of resistance.
In treatment-naive adult patients:
The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose.
In treatment-experienced adult patients:
The use of PPIs in treatment-experienced patients receiving REYATAZ is not recommended.
a
For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3).
b
See Contraindications (4), Table 6 for orally administered midazolam.
c
In combination with atazanavir 300 mg and ritonavir 100 mg once daily.
d
In combination with atazanavir 400 mg once daily.
7.4         Drugs with No Observed Interactions with REYATAZ

No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3)].