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 12.
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 12 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 12. 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                                       reactions has been observed with co- ↓ lopinavir              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*                                                   combination with nelfinavir is not ↑ M8 metabolite of
recommended [see Dosage and
nelfinavir
Administration (2)].
↓ lopinavir

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.
For KALETRA oral solution, it is
recommended that didanosine be
administered on an empty stomach;
therefore, didanosine should be
given one hour before or two hours
after KALETRA oral solution (given
with 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:                                               potential interaction is unknown.
↓ zidovudine
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                                               to potential for loss of virologic ↓lopinavir/ritonavir#

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,                                  due to decreased lopinavir plasma phenobarbital,          ↓ phenytoin             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,                                    valproate may be needed when co- valproate               ↓ or ↔ valproate        administered with KALETRA and therapeutic concentration monitoring
for lamotrigine may be indicated;
particularly during dosage
adjustments.
Antidepressant:         ↓ bupropion             Patients receiving KALETRA and bupropion                                    bupropion concurrently should be ↓ active metabolite, monitored for an adequate clinical

hydroxybupropion        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*,                                  mg/day) or itraconazole itraconazole,           ↑ itraconazole          (> 200 mg/day) are not voriconazole                                    recommended.

isavuconazonium sulfate*   ↓ voriconazole           The coadministration of voriconazole and KALETRA should
↑ isavuconazonium        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*                                       least 75% of the usual dose of 300 rifabutin metabolite
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:                                                recommended and a dose reduction calcium channel
e.g. felodipine,                                         of the dihydropyridine calcium blockers
nifedipine,                                              channel blocker may be considered.
nicardipine


Disulfiram/metronidazole                                 KALETRA oral solution contains ethanol, which can produce
disulfiram-like reactions when co-
administered with disulfiram or other
drugs that produce this reaction (e.g.,
metronidazole).
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- administer
boceprevir*                         ↓boceprevir              KALETRA and boceprevir., 
↓ ritonavir

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



ombitasvir/paritaprevir/ritonavir   ↑ ombitasvir

and dasabuvir*                      ↑ paritaprevir
↑ ritonavir

↔ 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
simvastatin                     ↑ simvastatin            Use atorvastatin with caution and at the lowest necessary dose. Titrate
atorvastatin                    ↑ atorvastatin           rosuvastatin dose carefully and use rosuvastatin                    ↑ rosuvastatin
the lowest necessary dose; do not
exceed rosuvastatin 10 mg/day.
Microsomal triglyceride
Lomitapide is a sensitive substrate
transfer protein (MTTP)
Inhibitor:                                               for CYP3A4 metabolism. CYP3A4 ↑ 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.                                                     monitoring is recommended for immunosuppressants
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*                                       be increased when co-administered fentanyl                ↑ 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 when used for the sildenafil,             ↑ sildenafil             treatment of pulmonary arterial tadalafil,              ↑ tadalafil              hypertension is contraindicated due vardenafil                                       to the potential for sildenafil- ↑ vardenafil             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.