Interactions : אינטראקציות

7 DRUG INTERACTIONS
7.1 Potential for KALETRA to Affect Other Drugs
Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co- administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life- threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 7.
Additionally, KALETRA induces glucuronidation.
Published data suggest that lopinavir is an inhibitor of OATP1B1.
These examples are a guide and not considered a comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information.


7.2 Potential for Other Drugs to Affect Lopinavir
Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA’s therapeutic effect. Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.


7.3 Established and Other Potentially Significant Drug Interactions
Table 7 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications (4), Warnings and Precautions (5.1), Clinical Pharmacology (11.3)] for magnitude of interaction.


Table 7. Established and Other Potentially Significant Drug Interactions Concomitant Drug Class:         Effect on                    Clinical Comments Drug Name                            Concentration of
Lopinavir or
Concomitant Drug
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor:            ↓ amprenavir             An increased rate of adverse fosamprenavir/ritonavir              ↓ lopinavir              reactions has been observed with co- administration of these medications.
Appropriate doses of the combinations with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:            ↑ indinavir              Decrease indinavir dose to 600 mg indinavir*                                                    twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor:            ↑ nelfinavir             KALETRA once daily in nelfinavir*                          ↑ M8 metabolite of       combination with nelfinavir is not nelfinavir               recommended [see Dosage and
↓ lopinavir              Administration (2)].
HIV-1 Protease Inhibitor:            ↑ lopinavir              Appropriate doses of additional 
ritonavir*                                                  ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
HIV-1 Protease Inhibitor:          ↑ saquinavir             The saquinavir dose is 1000 mg saquinavir                                                  twice daily, when co-administered with KALETRA 400/100 mg twice daily.
KALETRA once daily has not been studied in combination with saquinavir.
HIV-1 Protease Inhibitor:          ↓ lopinavir              Co-administration with tipranavir tipranavir*                                                 (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.
HIV CCR5 – Antagonist:             ↑ maraviroc              When co-administered, patients maraviroc*                                                  should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.
Non-nucleoside Reverse             ↓ lopinavir              Increase the dose of KALETRA Transcriptase Inhibitors:                                   tablets to 500/125 mg when efavirenz*,                                                 KALETRA tablet is co-administered nevirapine*                                                 with efavirenz or nevirapine.
KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see
Dosage and Administration (2)].
Non-nucleoside Reverse             ↑ lopinavir              Appropriate doses of the Transcriptase Inhibitor:                                    combination with respect to safety delavirdine                                                 and efficacy have not been established.
Nucleoside Reverse Transcriptase                            KALETRA tablets can be Inhibitor:                                                  administered simultaneously with didanosine                                                  didanosine without food.

Nucleoside Reverse Transcriptase ↑ tenofovir              Patients receiving KALETRA and Inhibitor:                                                tenofovir should be monitored for tenofovir disoproxil fumarate*                            adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase ↓ abacavir               The clinical significance of this Inhibitors:                      ↓ zidovudine             potential interaction is unknown.
abacavir zidovudine
Other Agents
Alpha 1- Adrenoreceptor          ↑ alfuzosin              Contraindicated due to potential Antagonist:                                               hypotension [see Contraindications alfuzosin                                                 (4)].
Antianginal:                     ↑ ranolazine             Contraindicated due to potential for ranolazine                                                serious and/or life-threatening reactions [see Contraindications (4)].
Antiarrhythmics:                 ↑ dronedarone            Contraindicated due to potential for dronedarone                                               cardiac arrhythmias [see Contraindications (4)].
Antiarrhythmics e.g .            ↑ antiarrhythmics        Caution is warranted and therapeutic amiodarone,                                               concentration monitoring (if bepridil,                                                 available) is recommended for lidocaine (systemic),                                     antiarrhythmics when co- quinidine                                                 administered with KALETRA.
Anticancer Agents:               ↑ anticancer agents      Apalutamide is contraindicated due abemaciclib                      ↓lopinavir/ritonavir# to potential for loss of virologic apalutamide                                               response and possible resistance to encorafenib                                               KALETRA or to the class of ibrutinib                                                 protease inhibitors [see ivosidenib                                                Contraindications (4)].
dasatinib,
neratinib,                                                Avoid co-administration of nilotinib,                                                encorafenib or ivosidenib with venetoclax,                                               KALETRA due to potential risk of 

serious adverse events such as QT vinblastine                   interval prolongation. If co- vincristine                   administration of encorafenib with
KALETRA cannot be avoided,
modify dose as recommended in encorafenib Prescribing Information.
If co-administration of ivosidenib with KALETRA cannot be avoided,
reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with KALETRA.

For vincristine and vinblastine,
consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when
KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.
A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co- administration with strong CYP3A inhibitors such as KALETRA. Please


refer to the nilotinib and dasatinib prescribing information for dosing instructions.
Anticoagulants:     ↑↓ warfarin             Concentrations of warfarin may be warfarin,           ↑ rivaroxaban           affected. Initial frequent monitoring rivaroxaban                                 of the INR during KALETRA and warfarin co-administration is recommended.
Avoid concomitant use of rivaroxaban and KALETRA. Co- administration of KALETRA and rivaroxaban may lead to increased risk of bleeding.
Anticonvulsants:    ↓ lopinavir             KALETRA may be less effective carbamazepine,      ↓ phenytoin             due to decreased lopinavir plasma phenobarbital,                              concentrations in patients taking phenytoin                                   these agents concomitantly and should be used with caution.
KALETRA once daily in combination with carbamazepine,
phenobarbital, or phenytoin is not recommended.
In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co- administering with KALETRA.
Anticonvulsants:    ↓ lamotrigine           A dose increase of lamotrigine or lamotrigine,        ↓ or ↔ valproate        valproate may be needed when co- valproate                                   administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated;
particularly during dosage adjustments.

Antidepressant:            ↓ bupropion             Patients receiving KALETRA and bupropion                  ↓ active metabolite,    bupropion concurrently should be hydroxybupropion        monitored for an adequate clinical response to bupropion.
Antidepressant:            ↑ trazodone             Adverse reactions of nausea, trazodone                                          dizziness, hypotension and syncope have been observed following co- administration of trazodone and ritonavir. A lower dose of trazodone should be considered.
Anti-infective:            ↑ clarithromycin        For patients with renal impairment, clarithromycin                                     adjust clarithromycin dose as follows:
• For patients on KALETRA with
CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.
• For patients on KALETRA with
CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:               ↑ ketoconazole          High doses of ketoconazole (>200 ketoconazole*,             ↑ itraconazole          mg/day) or itraconazole itraconazole,              ↓ voriconazole          (> 200 mg/day) are not voriconazole               ↑ isavuconazonium       recommended.
isavuconazonium sulfate*                           The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Isavuconazonium and KALETRA should be coadministered with caution. Alternative antifungal

therapies should be considered in these patients.
Anti-gout:          ↑ colchicine             Contraindicated due to potential for colchicine                                   serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see
Contraindications (4)].
For patients with normal renal or hepatic function:
Treatment of gout flares-co- administration of colchicine in patients on KALETRA:
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-co- administration of colchicine in patients on KALETRA:
If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.
If the original colchicine 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)-co-administration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).


Antimycobacterial:           ↓ lopinavir              Contraindicated due to potential loss rifampin                                              of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents
[see Contraindications (4)].
Antimycobacterial:           ↑ bedaquiline            Bedaquiline should only be used bedaquiline                                           with KALETRA if the benefit of co- administration outweighs the risk.
Antimycobacterial:           ↑ rifabutin and          Dosage reduction of rifabutin by at rifabutin*                   rifabutin metabolite     least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week).
Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antiparasitic:               ↓ atovaquone             Clinical significance is unknown; atovaquone                                            however, increase in atovaquone doses may be needed.
Antipsychotics: lurasidone                   ↑ lurasidone             Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications
(4)].
pimozide                     ↑ pimozide               Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias
[see Contraindications (4)].
Antipsychotics: quetiapine   ↑ quetiapine             Initiation of KALETRA in patients taking quetiapine:
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 KALETRA:
Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.
Contraceptive:                   ↓ ethinyl estradiol    Because contraceptive steroid ethinyl estradiol*                                      concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.
Dihydropyridine Calcium Channel ↑ dihydropyridine       Clinical monitoring of patients is Blockers:                        calcium channel        recommended and a dose reduction e.g. felodipine,                 blockers               of the dihydropyridine calcium nifedipine,                                             channel blocker may be considered.
nicardipine
Endothelin Receptor Antagonists: ↑ bosentan             Co-administration of bosentan in bosentan                                                patients on KALETRA: In patients who have been receiving
KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in


patients on bosentan:
Discontinue use of bosentan at least
36 hours prior to initiation of
KALETRA.
After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability
Ergot Derivatives:                   ↑ ergot derivatives     Contraindicated due to potential for dihydroergotamine, ergotamine,                               acute ergot toxicity characterized by methylergonovine                                             peripheral vasospasm and ischemia of the extremities and other tissues
[see Contraindications (4)].
GI Motility Agent:                   ↑ cisapride             Contraindicated due to potential for cisapride                                                    cardiac arrhythmias [see Contraindications (4)].
GnRH Receptor Antagonists:           ↑ elagolix              Concomitant use of elagolix 200 mg elagolix                             ↓ lopinavir/ritonavir twice daily and KALETRA for more than 1 month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and KALETRA to 6 months.
Hepatitis C direct acting antiviral: ↑ elbasvir/grazoprevir Contraindicated due to increased risk elbasvir/grazoprevir                                         of alanine transaminase (ALT) elevations [see Contraindications
(4)].
Hepatitis C direct acting antivirals: ↓lopinavir             It is not recommended to co- ↓boceprevir             administer boceprevir*                          ↓ ritonavir             KALETRA and boceprevir., ↑ glecaprevir
↑ pibrentasvir


glecaprevir/pibrentasvir                                     glecaprevir/pibrentasvir, ↑ simeprevir             simeprevir,
simeprevir
↑ sofosbuvir             sofosbuvir/velpatasvir/voxilaprevir,
↑ velpatasvir sofosbuvir/velpatasvir/voxilaprevir                          or ombitasvir/paritaprevir/ritonavir ↑ voxilaprevir and dasabuvir.

↑ ombitasvir
↑ paritaprevir ombitasvir/paritaprevir/ritonavir
↑ ritonavir and dasabuvir*
↔ dasabuvir
Herbal Products:                    ↓ lopinavir              Contraindicated due to potential for St. John's Wort (hypericum                                   loss of virologic response and perforatum)                                                  possible resistance to KALETRA or to the class of protease inhibitors
[see Contraindications (4)].
Lipid-modifying agents                                       Contraindicated due to potential for myopathy including rhabdomyolysis
HMG-CoA Reductase Inhibitors:
[see Contraindications (4)].
lovastatin                          ↑ lovastatin
Use atorvastatin with caution and at simvastatin                         ↑ simvastatin the lowest necessary dose. Titrate rosuvastatin dose carefully and use atorvastatin                        ↑ atorvastatin rosuvastatin                        ↑ rosuvastatin           the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.
Microsomal triglyceride                                      Lomitapide is a sensitive substrate transfer protein (MTTP) for CYP3A4 metabolism. CYP3A4
Inhibitor:
↑ lomitapide             inhibitors increase the exposure of lomitapide lomitapide, with strong inhibitors increasing exposure approximately
27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see
Contraindications (4)].
Immunosuppressants:                 ↑                        Therapeutic concentration 

e.g.                            immunosuppressants monitoring is recommended for cyclosporine,                                            immunosuppressant agents when co- tacrolimus,                                              administered with KALETRA.
sirolimus


Kinase Inhibitors:              ↑ fostamatinib           Monitor for toxicities of R406 such fostamatinib                    metabolite R406          as hepatotoxicity and neutropenia.
(also see anticancer                                     Fostamatinib dose reduction may be agents above)                                            required.
Long-acting beta-adrenoceptor   ↑ salmeterol             Concurrent administration of Agonist: salmeterol                                      salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including
QT prolongation, palpitations and sinus tachycardia.
Narcotic Analgesics:            ↓ methadone              Dosage of methadone may need to methadone*                      ↑ fentanyl               be increased when co-administered fentanyl                                                 with KALETRA.
Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA.
PDE5 inhibitors:                ↑ avanafil avanafil,                       ↑ sildenafil             Sildenafil when used for the sildenafil,                     ↑ tadalafil              treatment of pulmonary arterial tadalafil,                      ↑ vardenafil             hypertension is contraindicated due vardenafil                                               to the potential for sildenafil- associated adverse events, including visual abnormalities, hypotension,
prolonged erection, and syncope [see
Contraindications (4)].

Do not use KALETRA with avanafil because a safe and effective avanafil dosage regimen has not been established.

Particular caution should be used when prescribing sildenafil, tadalafil,
or vardenafil in patients receiving
KALETRA. Co-administration of
KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope,
visual changes and prolonged erection.


Use of PDE5 inhibitors for pulmonary arterial hypertension
(PAH):
Sildenafil is contraindicated [see
Contraindications (4)].
The following dose adjustments are recommended for use of tadalafil with KALETRA.
Co-administration of tadalafil in patients on KALETRA:
In patients receiving KALETRA for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability:

Co-administration of KALETRA in patients on tadalafil:

Avoid use of tadalafil during the initiation of KALETRA. Stop tadalafil at least 24 hours prior to starting KALETRA.
After at least one week following the initiation of KALETRA, resume tadalafil at 20 mg once daily.
Increase to 40 mg once daily based upon individual tolerability.


Use of PDE5 inhibitors for erectile dysfunction:
It is recommended not to exceed the following doses:
• Sildenafil: 25 mg every 48 hours
• Tadalafil: 10 mg every 72 hours
• Vardenafil: 2.5 mg every 72 hours
Use with increased monitoring for adverse events.
Sedative/Hypnotics:             ↑ triazolam             Contraindicated due to potential for triazolam,                      ↑ midazolam             prolonged or increased sedation or orally administered midazolam                           respiratory depression [see Contraindications (4)].
Sedative/Hypnotics:             ↑ midazolam             If KALETRA is co-administered parenterally administered                               with parenteral midazolam, close midazolam                                               clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.
Systemic/Inhaled/               ↓ lopinavir             Coadministration with oral Nasal/Ophthalmic                ↑ glucocorticoids       dexamethasone or other systemic Corticosteroids: e.g.,                                  corticosteroids that induce CYP3A betamethasone                                           may result in loss of therapeutic budesonide                                              effect and development of resistance ciclesonide                                             to lopinavir. Consider alternative 
dexamethasone                                             corticosteroids.
fluticasone methylprednisolone                                        Coadministration with mometasone                                                corticosteroids whose exposures are prednisone                                                significantly increased by strong triamcinolone                                             CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.


Alternative corticosteroids including beclomethasone and prednisolone
(whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.
* see Clinical Pharmacology
(11.3) for magnitude of interaction.
# refers to interaction with apalutamide.


7.4 Drugs with No Observed or Predicted Interactions with KALETRA
Drug interaction or clinical studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine, or rilpivirine.
Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.