Interactions : אינטראקציות

7       DRUG INTERACTIONS
See also Contraindications (4), Clinical Pharmacology (11.2).
If LEXIVA is used in combination with ritonavir, see full prescribing information for ritonavir for additional information on drug interactions.
7.1     Cytochrome P450 Inhibitors and Inducers
Amprenavir, the active metabolite of fosamprenavir, is an inhibitor of CYP3A4 metabolism and therefore should not be administered concurrently with medications with narrow therapeutic windows that are substrates of CYP3A4. Data also suggest that amprenavir induces CYP3A4.
Amprenavir is metabolized by CYP3A4. Coadministration of LEXIVA and drugs that induce CYP3A4, such as rifampin, may decrease amprenavir concentrations and reduce its therapeutic effect. Coadministration of LEXIVA and drugs that inhibit CYP3A4 may increase amprenavir concentrations and increase the incidence of adverse effects.
The potential for drug interactions with LEXIVA changes when LEXIVA is coadministered with the potent CYP3A4 inhibitor ritonavir. The magnitude of CYP3A4-mediated drug interactions (effect on amprenavir or effect on coadministered drug) may change when LEXIVA is coadministered with ritonavir. Because ritonavir is a CYP2D6 inhibitor, clinically significant interactions with drugs metabolized by CYP2D6 are possible when coadministered with LEXIVA plus ritonavir.
There are other agents that may result in serious and/or life-threatening drug interactions [see Contraindications (4)].
7.2     Drugs that Should Not Be Coadministered with LEXIVA
See Contraindications (4).
7.3     Established and Other Potentially Significant Drug Interactions Table 6 provides a listing of established or potentially clinically significant drug interactions.
Information in the table applies to LEXIVA with or without ritonavir, unless otherwise indicated.



Table 6. Established and Other Potentially Significant Drug Interactions Effect on
Concentration of
Concomitant Drug          Amprenavir or
Class: Drug Name        Concomitant Drug                  Clinical Comment HCV/HIV-Antiviral Agents
HCV protease inhibitor: LEXIVA                    Coadministration of LEXIVA or Boceprevir                Amprenavir             LEXIVA/ritonavir and boceprevir is not (predicted)             recommended.

 or Boceprevir
(predicted)

LEXIVA/ritonavir:
Amprenavir
(predicted)
Boceprevir
(predicted)
HCV protease inhibitor:    LEXIVA:                Coadministration of LEXIVA or Simeprevir                 Amprenavir            LEXIVA/ritonavir and simeprevir is not (predicted)            recommended.
 or Simeprevir
(predicted)
LEXIVA/ritonavir:
Amprenavir
(predicted)
Simeprevir
(predicted)
HCV protease inhibitor: LEXIVA:                   Appropriate doses of the combinations Paritaprevir (coformulated Amprenavir            with respect to safety and efficacy have with ritonavir and         (predicted)            not been established.
ombitasvir and              or Paritaprevir     LEXIVA 1,400 mg once daily may be coadministered with        (predicted)            considered when coadministered with dasabuvir)                                        paritaprevir/ritonavir/ombitasvir/ LEXIVA/ritonavir: dasabuvir.
 or Amprenavir
(predicted)            Coadministration of LEXIVA/ritonavir
Paritaprevir          and paritaprevir/ritonavir/ombitasvir/

(predicted)           dasabuvir is not recommended.
Non-nucleoside reverse     LEXIVA:               For contraindicated NNRTIs transcriptase inhibitor:   Amprenavir           (delavirdine), [see Contraindications (4)].
Efavirenza
Appropriate doses of the combinations
LEXIVA/ritonavir:     with respect to safety and efficacy have
Amprenavir           not been established.

An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz is administered with
LEXIVA/ritonavir once daily. No change in the ritonavir dose is required when efavirenz is administered with LEXIVA plus ritonavir twice daily.
Non-nucleoside reverse     LEXIVA:               For contraindicated NNRTIs transcriptase inhibitor:   Amprenavir           (delavirdine), [see Contraindications (4)].
Nevirapinea                Nevirapine
Coadministration of nevirapine and
LEXIVA/ritonavir:     LEXIVA without ritonavir is not
Amprenavir           recommended.
Nevirapine
No dosage adjustment required when nevirapine is administered with
LEXIVA/ritonavir twice daily.

The combination of nevirapine administered with LEXIVA/ritonavir once-daily regimen has not been studied.
HIV protease inhibitor:    LEXIVA:               Appropriate doses of the combinations Atazanavira                Interaction has not   with respect to safety and efficacy have been evaluated.       not been established.

LEXIVA/ritonavir:
Atazanavir
Amprenavir
HIV protease inhibitors:   LEXIVA:               Appropriate doses of the combinations Indinavira, nelfinavira    Amprenavir           with respect to safety and efficacy have not been established.
Effect on indinavir

and nelfinavir is not well established.

LEXIVA/ritonavir:
Interaction has not been evaluated.
HIV protease inhibitors:   Amprenavir             An increased rate of adverse events has Lopinavir/ritonavira       Lopinavir              been observed. Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV protease inhibitor:    LEXIVA:                 Appropriate doses of the combination Saquinavira                Amprenavir             with respect to safety and efficacy have not been established.
Effect on saquinavir is not well established.

LEXIVA/ritonavir:
Interaction has not been evaluated.
HIV integrase inhibitor:   LEXIVA:                 Appropriate doses of the combination Raltegravira               Amprenavir             with respect to safety and efficacy have Raltegravir            not been established.


LEXIVA/ritonavir:
Amprenavir
Raltegravir
HIV integrase inhibitor:   LEXIVA/ritonavir:       The recommended dose of dolutegravir is Dolutegravira              ↓Dolutegravir           50 mg twice daily when coadministered with LEXIVA/ritonavir.

Use an alternative combination where possible in patients with known or suspected integrase inhibitor resistance.



HIV CCR5 co-receptor        LEXIVA/ritonavir:    No dosage adjustment required for antagonist:                 Amprenavir          LEXIVA/ritonavir. The recommended Maraviroca                  Maraviroc           dose of maraviroc is 150 mg twice daily when coadministered with
LEXIVA/ritonavir. LEXIVA should be given with ritonavir when coadministered with maraviroc.
Other Agents
Antiarrhythmics:            Antiarrhythmics      For contraindicated antiarrhythmics Amiodarone, lidocaine                             (flecainide, propafenone), [see (systemic), and quinidine                         Contraindications (4)].

Use with caution. Increased exposure may be associated with life-threatening reactions such as cardiac arrhythmias.
Therapeutic concentration monitoring, if available, is recommended for antiarrhythmics.
Anticoagulant:                                    Concentrations of warfarin may be Warfarin                                          affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants:            LEXIVA:               Use with caution. LEXIVA may be less Carbamazepine,              Amprenavir           effective due to decreased amprenavir phenobarbital, phenytoin                          plasma concentrations in patients taking these agents concomitantly.

Phenytoina                  LEXIVA/ritonavir:     Plasma phenytoin concentrations should Amprenavir           be monitored and phenytoin dose should
Phenytoin            be increased as appropriate. No change in
LEXIVA/ritonavir dose is recommended.
Antidepressant:             Paroxetine           Any paroxetine dose adjustment should Paroxetine, trazodone                             be guided by clinical effect (tolerability and efficacy).

Adverse events of nausea, dizziness,
hypotension, and syncope have been observed following coadministration of
Trazodone            trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as

LEXIVA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antifungals:     Ketoconazole   Increase monitoring for adverse events.
Ketoconazolea,   Itraconazole itraconazole                     LEXIVA:
Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day.
LEXIVA/ritonavir:
High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.
Anti-gout:       Colchicine     Patients with renal or hepatic impairment Colchicine                       should not be given colchicine with
LEXIVA/ritonavir.

LEXIVA/ritonavir and coadministration of colchicine:
Treatment of gout flares:
0.6 mg (1 tablet) x 1 dose, followed by
0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 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).
LEXIVA and coadministration of colchicine:
Treatment of gout flares:
1.2 mg (2 tablets) x 1 dose. Dose to be repeated no earlier than 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 twice a day or
0.6 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 a day.

Treatment of FMF:
Maximum daily dose of 1.2 mg (may be given as 0.6 mg twice a day).
Antimycobacterial:   Rifabutin and          For contraindicated antimycobacterials Rifabutina            rifabutin metabolite   (rifampin), [see Contraindications (4)].

A complete blood count should be performed weekly and as clinically indicated to monitor for neutropenia.

LEXIVA:
A dosage reduction of rifabutin by at least half the recommended dose is required.
LEXIVA/ritonavir:
Dosage reduction of rifabutin by at least
75% of the usual dose of 300 mg/day is recommended (a maximum dose of
150 mg every other day or 3 times per week).
Antipsychotics:      LEXIVA/ritonavir:       For contraindicated antipsychotics Quetiapine           Quetiapine             (lurasidone, pimozide), [see Contraindications (4)].

Initiation of LEXIVA with ritonavir in patients taking quetiapine:
Consider alternative antiretroviral therapy to avoid increases in quetiapine drug 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
LEXIVA with ritonavir:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

Lurasidone                 Lurasidone        LEXIVA:
If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors.
LEXIVA/ritonavir:
Use of lurasidone is contraindicated.
Benzodiazepines:           Benzodiazepines   For contraindicated sedative/hypnotics Alprazolam, clorazepate,                      (midazolam, triazolam), [see diazepam, flurazepam                          Contraindications (4)].

Clinical significance is unknown. A decrease in benzodiazepine dose may be needed.
Calcium channel            Calcium channel   Use with caution. Clinical monitoring of blockers:                   blockers          patients is recommended.
Diltiazem, felodipine,
nifedipine, nicardipine,
nimodipine, verapamil,
amlodipine, nisoldipine,

isradipine
Corticosteroid:             Amprenavir            Use with caution. LEXIVA may be less Dexamethasone                                      effective due to decreased amprenavir plasma concentrations.
Endothelin-receptor         Bosentan              Coadministration of bosentan in patients antagonists:                                       on LEXIVA:
Bosentan
In patients who have been receiving
LEXIVA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Coadministration of LEXIVA in patients on bosentan:
Discontinue use of bosentan at least
36 hours prior to initiation of LEXIVA.
After at least 10 days following the initiation of LEXIVA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Histamine H2-receptor       LEXIVA:                Use with caution. LEXIVA may be less antagonists:                Amprenavir            effective due to decreased amprenavir Cimetidine, famotidine,
plasma concentrations.
nizatidine, ranitidinea
LEXIVA/ritonavir:
Interaction not evaluated
HMG-CoA reductase           Atorvastatin          For contraindicated HMG-CoA reductase inhibitors:                                        inhibitors (lovastatin, simvastatin), [see Atorvastatina                                      Contraindications (4)].

Titrate atorvastatin dose carefully and use the lowest necessary dose; do not exceed atorvastatin 20 mg/day.
Immunosuppressants:         Immunosuppressants Therapeutic concentration monitoring is Cyclosporine, tacrolimus,                       recommended for immunosuppressant sirolimus                                       agents.
Inhaled beta-agonist:       Salmeterol         Concurrent administration of salmeterol Salmeterol                                      with LEXIVA is not recommended. The combination may result in increased risk of cardiovascular adverse events

associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.
Inhaled/nasal steroid:   LEXIVA:              Use with caution. Consider alternatives to Fluticasone              Fluticasone         fluticasone, particularly for long-term use.

LEXIVA/ritonavir:    May result in significantly reduced serum
Fluticasone         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.
Coadministration of fluticasone and
LEXIVA/ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Narcotic analgesic:      Methadone           Data suggest that the interaction is not Methadone                                     clinically relevant; however, patients should be monitored for opiate withdrawal symptoms.
Oral contraceptives:                          Alternative methods of non-hormonal Ethinyl estradiol/                            contraception are recommended.
norethindronea
LEXIVA:              May lead to loss of virologic response.a
Amprenavir
Ethinyl estradiol

LEXIVA/ritonavir:    Increased risk of transaminase elevations.
Ethinyl estradiol   No data are available on the use of
LEXIVA/ritonavir with other hormonal therapies, such as hormone replacement therapy (HRT) for postmenopausal women.
PDE5 inhibitors:         Sildenafil          For contraindicated PDE5 inhibitors Sildenafil, tadalafil,   Tadalafil           [sildenafil (REVATIO)], [see vardenafil               Vardenafil          Contraindications (4)].

May result in an increase in PDE5

inhibitor-associated adverse events,
including hypotension, syncope, visual disturbances, and priapism.
Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):
• Use of sildenafil is contraindicated when used for the treatment of PAH
[see Contraindications (4)].
• The following dose adjustments are recommended for use of tadalafil with
LEXIVA:
Coadministration of tadalafil in patients on LEXIVA:
In patients receiving LEXIVA for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.
Coadministration of LEXIVA in patients on tadalafil:
Avoid use of tadalafil during the initiation of LEXIVA. Stop tadalafil at least 24 hours prior to starting
LEXIVA. After at least one week following the initiation of LEXIVA,
resume tadalafil at 20 mg once daily.
Increase to 40 mg once daily based upon individual tolerability.

Use of PDE5 inhibitors for erectile dysfunction:
LEXIVA:
Sildenafil: 25 mg every 48 hours.
Tadalafil: no more than 10 mg every
72 hours.
Vardenafil: no more than 2.5 mg every
24 hours.


LEXIVA/ritonavir:
Sildenafil: 25 mg every 48 hours.
Tadalafil: no more than 10 mg every
72 hours.
Vardenafil: no more than 2.5 mg every
72 hours.
Use with increased monitoring for adverse events.
Proton pump inhibitors:     LEXIVA:                  Proton pump inhibitors can be Esomeprazolea,              Amprenavir              administered at the same time as a dose of lansoprazole, omeprazole,   Esomeprazole            LEXIVA with no change in plasma pantoprazole, rabeprazole                            amprenavir concentrations.
LEXIVA/ritonavir:
Amprenavir
Esomeprazole
Tricyclic                  Tricyclics               Therapeutic concentration monitoring is antidepressants:                                     recommended for tricyclic Amitriptyline, imipramine                            antidepressants.
a
See Clinical Pharmacology (11.2) Tables 8, 9, 10, or 11 for magnitude of interaction.