Kaletra (Lopinavir and ritonavir)

Kaletra is a co-formulation of Lopinavir and ritonavir. It inhibits viral replication in patients infected with HIV-1.

Kaletra uses:

HIV-1 infection:
- It is used in the treatment of HIV-1 infection in adults and children older than 14 days in combination with other antiretroviral agents.
Kaletra use in COVID-19 (Coronavirus) infection:
- Kaletra (Lopinavir and Ritonavir) has been found to be effective in the treatment of COVID-19 infection, although the reports have not been confirmed.
- Kaletra in combination with Interferon Beta has been proven to be effective in mice model infected with MERS-CoV [Ref].

Kaletra Dose in Adults:

Kaletra Dose in the treatment of HIV-1 infection as a component of combination therapy):

Patients who are receiving concomitant antiretroviral therapy without efavirenz, nelfinavir, or nevirapine:
- Twice-daily dosing:
  - Lopinavir 400 mg/ritonavir 100 mg two times a day.
- Once-daily dosing:
  - Lopinavir 800 mg/ritonavir 200 mg once a day in patients who are treatment-naive or experienced patients with less than 3 lopinavir resistance-associated substitutions.
  - Once a day dosing is not recommended in patients who are receiving efavirenz, fosamprenavir, nevirapine, nelfinavir, carbamazepine, phenobarbital, or phenytoin.
Pregnant women without lopinavir-resistance-associated amino acid substitutions:
- Lopinavir 400 mg/ritonavir 100 mg two times a day.
- Once a day dosing should be avoided.
- Pregnant patients should avoid oral solution as it contains alcohol. Tablets are recommended in pregnant patients.
- Alternately, the HHS perinatal guidelines recommend an increased dose of lopinavir 600 mg/ritonavir 150 mg two times a day, or lopinavir 500 mg/ritonavir 125 mg two times a day, during the second and third trimesters of pregnancy, especially in women with a baseline viral load of greater than 50 copies/mL and in PI-experienced pregnant women.

Kaletra dosage adjustment for combination therapy with efavirenz, nelfinavir, or nevirapine:

Twice-daily dosing:
- Therapy-naive and therapy-experienced patients:
  - Solution: Lopinavir 520 mg/ritonavir 130 mg (6.5 mL) twice daily
  - Tablet: Lopinavir 500 mg/ritonavir 125 mg twice daily
Once-daily dosing:
- Once-daily dosing not recommended.

Kaletra dosage adjustment for combination therapy with carbamazepine, phenobarbital, and phenytoin:

Once-daily dosing is not recommended

Kaletra Dose in Children:

Kaletra Dose in the treatment of HIV-1 infection in combination with other antiretroviral agents:

Note: Use oral solutions instead of tablets in patients less than 15 kgs or less than 0.6 m². Avoid once-daily dosing in pediatric patients.

Infants ≥42 weeks postmenstrual age:
- Patients receiving concomitant antiretroviral therapy without efavirenz, nelfinavir, or nevirapine:
  - Lopinavir 16 mg/kg/dose or 300 mg/m² /dose two times a day.
- Patients receiving concomitant antiretroviral therapy with efavirenz, nelfinavir, or nevirapine:
  - Kaletra is not recommended in infants who are receiving these agents.
Children and Adolescents:
- Patients receiving concomitant antiretroviral therapy without efavirenz, nelfinavir, or nevirapine:
  - BSA-directed dosing in Antiretroviral naïve:
    - Lopinavir 230 mg/m² /dose.
    - The maximum dose is 400 mg/dose twice daily.
  - Alternate fixed dosing for patients weighing 15 kgs or more who are able to swallow tablets:
    - - BSA ≥0.6 to <0.9 m²:
        
        Lopinavir 200 mg twice daily
      - BSA ≥0.9 to <1.4 m²:
        
        Lopinavir 300 mg twice daily
      - BSA ≥1.4 m²:
        
        Lopinavir 400 mg twice daily
  - Weight-directed dosing:
    - Children and Adolescents:
      - <15 kg:
        
        Lopinavir 12 mg/kg/dose twice daily
      - 15 to 40 kg:
        
        Lopinavir 10 mg/kg/dose twice daily
      - >40 kg:
        
        Lopinavir 400 mg twice daily
  - Alternate fixed dosing for patients weighing 15 kgs or more and able to swallow tablets:
    - ≥15 to 25 kg:
      - Lopinavir 200 mg twice daily
    - >25 to 35 kg:
      - Lopinavir 300 mg twice daily
    - >35 kg:
      - Lopinavir 400 mg twice daily
- Antiretroviral-experienced or suspected decreased sensitivity to lopinavir:
  - BSA-directed dosing in children and Adolescents:
    - Lopinavir 300 mg/m²/dose.
    - The maximum dose is 400 mg/dose twice daily
  - Weight-directed dosing in children and Adolescents:
    - <15 kg:
      - Lopinavir 13 mg/kg/dose twice daily
    - 15 to 45 kg:
      - Lopinavir 11 mg/kg/dose twice daily
    - >45 kg:
      - Lopinavir 400 mg twice daily
  - Weight band dosing for patients weighing 15 kgs or more and able to swallow tablets:
    - 15 to 20 kg:
      - 200 mg twice daily
    - >20 to 30 kg:
      - 300 mg twice daily
    - >30 kg:
      - 400 mg twice daily
  - Patients receiving concomitant antiretroviral therapy with efavirenz, nelfinavir, or nevirapine (or treatment-experienced patients not receiving these agents who have suspected decreased susceptibility to lopinavir):
    - BSA-directed dosing in Children and Adolescents:
      - Lopinavir 300 mg/m²/dose twice daily.
      - The maximum dose of the oral solution is 520 mg/dose and the Tablet is 500 mg/dose.
    - Alternate fixed dosing for patients who are able to swallow tablets:
      - BSA ≥0.6 to <0.8 m²:
        
        Lopinavir 200 mg twice daily
      - BSA ≥0.8 to < 1.2 m²:
        
        Lopinavir 300 mg twice daily
      - BSA ≥1.2 to < 1.7 m²:
        
        Lopinavir 400 mg twice daily
      - BSA ≥1.7 m²:
        
        Lopinavir 500 mg twice daily
    - Weight-directed dosing in Children and Adolescents:
      - <15 kg:
        
        Lopinavir 13 mg/kg/dose twice daily
      - ≥15 to 45 kg:
        
        Lopinavir 11 mg/kg/dose twice daily
      - >45 kg:
        
        Oral solution: Lopinavir 520 mg (6.5 mL) twice daily
        
        Tablets: Lopinavir 500 mg twice daily
    - Fixed dosing for patients weighing ≥15 kg who are able to swallow tablets:
      - ≥15 to 20 kg:
        
        Lopinavir 200 mg twice daily
      - >20 to 30 kg:
        
        Lopinavir 300 mg twice daily
      - >30 to 45 kg:
        
        Lopinavir 400 mg twice daily
      - >45 kg:
        
        Lopinavir 500 mg twice daily.

Kaletra Dose in the HIV-1 nonoccupational postexposure prophylaxis:

Note: Kaletra should be initiated in combination therapy within 72 hours and continued for a minimum of 28 days.

Infants at least 42 weeks postmenstrual age:
- 300 mg/m² /dose or 16 mg/kg/dose oral solution two times a day.
Children:
- Weight-directed dosing (Oral solution):
  - less than 15 kgs:
    - Lopinavir 12 mg/kg/dose twice daily
  - 15 to 40 kg:
    - Lopinavir 10 mg/kg/dose twice daily
  - >40 kg:
    - Lopinavir 400 mg twice daily
- Fixed dosing:
  - Patients weighing 15 kgs or more and able to swallow tablets:
    - ≥15 to 25 kg:
      - Lopinavir 200 mg twice daily
    - >25 to 35 kg:
      - Lopinavir 300 mg twice daily
    - >35 kg:
      - Lopinavir 400 mg twice daily
  - Adolescents:
    - It is not recommended.
    - Other antiretroviral medications should be used.

Pregnancy Risk Factor: B

Lopinavir has minimal excretion into breastmilk, however, fetal exposure with ritonavir may be increased.
Human studies have not shown adverse fetal outcomes.
Studies on a small scale have shown an increase in stillbirths, low birth weight, and infants of gestational age at risk.
It is important to continue maternal ART during pregnancy, as the potential benefits outweigh any adverse effects.
For long-term side effects, especially mitochondrial dysfunction, infants exposed to maternal ART need to be monitored.
Patients who are pregnant are at high risk for developing hyperglycemia and new-onset diabetes mellitus. It is essential to monitor blood glucose regularly.
When acute HIV infection is suspected during pregnancy, a ritonavir-boosted protease inhibitor regimen is recommended.
Pregnancy should be avoided because it contains alcohol.
Patients who are pregnant may require more frequent monitoring. After delivery, ART should continue. The regimen can be modified.
In the second and third trimesters of pregnancy, the Kaletra dose may need to be adjusted.
It is not recommended to take once daily during pregnancy.

Kaletra dose in renal impairment:

The manufacturer has not recommended any adjustment in the dose in patients with kidney disease.
However, a reduction in drug clearance is not expected.
In patients on hemodialysis, avoid once-daily dosing.

Kaletra Dose in patients with liver disease:

Mild to moderate impairment:
- The manufacturer has not recommended any adjustment in the dose in patients with liver disease.
- However, lopinavir is primarily metabolized in the liver and the serum levels may increase in patients with hepatic impairment.
- It should be used with caution.
Severe impairment:
- The manufacturer has not recommended any adjustment in the dose in patients with severe hepatic impairment. It should be used with caution.

Common Side Effects of Kaletra (Lopinavir and ritonavir) Include:

Dermatologic:
- Skin Rash
Endocrine & Metabolic:
- Hypercholesterolemia
- Increased Serum Triglycerides
- Increased Gamma-Glutamyl Transferase
Gastrointestinal:
- Diarrhea
- Dysgeusia
- Vomiting
- Nausea
- Abdominal Pain
Hepatic:
- Increased Serum ALT
Respiratory:
- Upper Respiratory Tract Infection

Less Common Side Effects Of Kaletra (Lopinavir And Ritonavir) Include:

Cardiovascular:
- Vasodilation
Central Nervous System:
- Fatigue
- Headache
- Anxiety
- Insomnia
Dermatologic:
- Skin Infection
Endocrine & Metabolic:
- Hypertriglyceridemia
- Hyperglycemia
- Hyperuricemia
- Alteration In Sodium
- Weight Loss
Gastrointestinal:
- Increased Serum Amylase
- Dyspepsia
- Increased Serum Lipase
- Flatulence
- Gastroenteritis
Hematologic & Oncologic:
- Thrombocytopenia
- Neutropenia
Hepatic:
- Increased Serum AST
- Hepatitis
- Increased Serum Bilirubin
Hypersensitivity:
- Hypersensitivity
Neuromuscular & Skeletal:
- Weakness
- Musculoskeletal Pain
Respiratory:
- Lower Respiratory Tract Infection

Contraindication to Kaletra (Lopinavir and ritonavir):

Severe allergic reactions to lopinavir, ritonavir, or any component of the formulation.
Allergic reactions may include toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, and angioedema.
Coadministration with CYP3A inducers that may significantly reduce the plasma levels of the drug resulting in poor virologic response and/or resistance to the drug. CYP3A inducers include:
- alfuzosin,
- amiodarone,
- cisapride,
- colchicine,
- dronedarone,
- ergot derivatives such as dihydroergotamine, ergotamine, and methylergonovine,
- flecainide,
- lomitapide,
- lovastatin,
- lurasidone,
- oral midazolam,
- pimozide,
- propafenone,
- quinidine,
- ranolazine,
- sildenafil,
- simvastatin,
- St John's wort,
- triazolam,
- voriconazole
Concomitant use with drugs that are highly dependent on CYP3A for clearance. Elevated plasma levels of these drugs may result in life-threatening reactions.
Concurrent use with the following drugs:
- astemizole,
- bepridil,
- fusidic acid,
- rivaroxaban,
- salmeterol,
- terfenadine,
- vardenafil,
- venetoclax or
- voriconazole
The oral solution should not be used in pregnant patients, those with renal or hepatic failure, and with concomitant disulfiram or metronidazole.

Warnings and Precautions

Modified cardiac conduction
- Combination therapy with Lopinavir/ritonavir may cause QTc and PR interval extension.
- Patients can develop heart blockage and torsade des pointes.
- Patients suffering from conduction defects, structural heart disease, cardiomyopathy or ischemic heart disease should not use it.
- Patients with hyperkalemia or those taking concomitant drugs that could prolong the PR and QTc interval should not use this drug.
Cardiovascular issues
- It has been shown that the risk of acute myocardial injury (AMI) increases with cumulative use of lopinavir/ritonavir.
- Lopinavir/ritonavir-based regimens should be avoided in patients with high cardiac risk factors.
Fat redistribution
- Lipodystrophy and redistribution fats can be caused by protease inhibitors.
- Patients might notice central obesity, facial wasting and peripheral wasting.
Hepatotoxicity:
- Protease inhibitors can cause jaundice or hepatitis or may worsen the underlying liver disease.
- Patients with liver disease, patients with elevated liver enzymes, hepatitis B or C infection, and those suffering from cirrhosis should not use it.
- It is important to monitor the liver enzymes regularly.
Immune reconstitution syndrome:
- Patients suffering from immunodeficiency, such as HIV infection, may experience an exaggerated inflammatory response or latent autoimmune disorders when they begin treatment.
- This is known as the immune reconstitution syndrome.
- This is common in patients with tuberculosis and autoimmune disorders like Graves' disease, Polymysitis, Guillain Barre syndrome, and Graves'.
- These patients might need to be given glucocorticoids for a brief period or withheld temporarily.
Increasing cholesterol
- Dyslipidemia should be checked at baseline and every other month.
Diabetes:
- It has been reported that patients taking protease inhibitors can develop hyperglycemia.
- This could be an exacerbation or new-onset diabetes mellitus, as well as diabetic ketoacidosis.
- Diabetes, diabetic control and diabetic ketoacidosis should all be checked.
- Patients with persistent hyperglycemia may need to stop taking the protease inhibitors.
Hemophilia A and B:
- Patients with hemophilia A and B may be more at risk from bleeding if they take protease inhibitors.
- These patients should use it with caution.
Hepatic impairment
- Lopinavir serum concentrations may increase. Patients with liver disease should not take it.
Pancreatitis
- Hypertriglyceridemia patients are at greater risk for developing pancreatitis.
- Every patient should be closely monitored for signs and symptoms of pancreatitis.
- Some patients may experience nausea, vomiting, or abdominal pain.
- If the patient experiences any of the above symptoms, serum amylase or lipase should always be checked.
- It may be necessary to receive appropriate treatment or to discontinue use of the drug permanently.

Lopinavir and ritonavir: Drug Interaction

Risk Factor C (Monitor therapy)
Abacavir	Protease Inhibitors may decrease the serum concentration of Abacavir.
Acenocoumarol	Ritonavir may decrease the serum concentration of Acenocoumarol.
Albendazole	Ritonavir may decrease the serum concentration of Albendazole.
Alosetron	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron.
AmLODIPine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine.
Antidiabetic Agents	Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
Artesunate	Ritonavir may decrease serum concentrations of the active metabolite(s) of Artesunate.
Atovaquone	Ritonavir may decrease the serum concentration of Atovaquone.
Benperidol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol.
Benzhydrocodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benzhydrocodone. Specifically, the concentration of hydrocodone may be increased.
Betamethasone (Ophthalmic	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic).
Bictegravir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bictegravir.
Bortezomib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib.
Brentuximab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Brentuximab Vedotin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Brinzolamide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide.
Budesonide (Nasal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal).
Budesonide (Oral Inhalation)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation).
Buprenorphine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Buprenorphine.
BuPROPion	Ritonavir may decrease the serum concentration of BuPROPion. Mixed effects on concentrations of the active hydroxybupropion metabolite have been reported. Management: Monitor for decreased bupropion effects. Significant bupropion dose adjustments may be necessary to maintain adequate response. Avoid the use of naltrexone/bupropion for weight management in patients receiving ritonavir.
BuPROPion	Lopinavir may decrease the serum concentration of BuPROPion. Concentrations of the active metabolite, hydroxybupropion, may also be decreased. Management: Monitor bupropion response closely. Significant bupropion dose adjustments may be necessary to maintain adequate response. Avoid the use of naltrexone/bupropion for weight management in patients receiving lopinavir.
Calcifediol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol.
Cannabidiol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol.
Cannabis	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.
Cat's Claw	May increase the serum concentration of Ritonavir.
Celiprolol	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol.
Cinacalcet	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet.
Clopidogrel	Ritonavir may diminish the antiplatelet effect of Clopidogrel. Ritonavir may decrease serum concentrations of the active metabolite(s) of Clopidogrel.
Clorazepate	Ritonavir may increase the serum concentration of Clorazepate.
CloZAPine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
CloZAPine	CYP1A2 Inducers (Weak) may decrease the serum concentration of CloZAPine.
Codeine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine.
Corticosteroids (Orally Inhaled)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic).
Corticosteroids (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE.
Cyclophosphamide	Protease Inhibitors may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased.
CYP2B6 Substrates (High risk with Inducers)	CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Darolutamide	Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Darolutamide.
DexAMETHasone (Ophthalmic	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DexAMETHasone (Ophthalmic).
Dofetilide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dofetilide.
Doxercalciferol	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol.
Dronabinol	Ritonavir may increase the serum concentration of Dronabinol.
Dutasteride	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride.
Enfortumab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Enfuvirtide	Protease Inhibitors may increase the serum concentration of Enfuvirtide. Enfuvirtide may increase the serum concentration of Protease Inhibitors.
Estriol (Systemic)	Ritonavir may decrease the serum concentration of Estriol (Systemic).
Estriol (Topical)	Ritonavir may decrease the serum concentration of Estriol (Topical).
Estrogen Derivatives	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives.
Evogliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin.
Fostamatinib	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fostamatinib.
Galantamine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Galantamine.
Gefitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib.
HYDROcodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone.
Idelalisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib.
Ifosfamide	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.
Imatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib.
Imidafenacin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin.
Lacosamide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide.
Levamlodipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levamlodipine.
Levobupivacaine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
Levomethadone	Lopinavir may decrease the serum concentration of Levomethadone.
Levomethadone	Ritonavir may decrease the serum concentration of Levomethadone.
LinaGLIPtin	Ritonavir may increase the serum concentration of LinaGLIPtin.
Lumefantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
Mebendazole	Ritonavir may decrease the serum concentration of Mebendazole.
Meperidine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine.
Methadone	Lopinavir may enhance the QTc-prolonging effect of Methadone. Lopinavir may decrease the serum concentration of Methadone. More specifically, the combination of Lopinavir and Ritonavir may decrease Methadone serum concentrations.
Methadone	Ritonavir may decrease the serum concentration of Methadone.
MetroNIDAZOLE (Topical)	May enhance the adverse/toxic effect of Lopinavir. Specifically, the use of topical metronidazole with lopinavir/ritonavir solution (which contains 42% alcohol) may result in a disulfiram-like reaction.
Mirtazapine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirtazapine.
Naldemedine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine.
Naldemedine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine.
Nalfurafine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine.
Nintedanib	Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib.
OLANZapine	Ritonavir may decrease the serum concentration of OLANZapine.
Orlistat	May decrease the serum concentration of Antiretroviral Agents.
Ospemifene	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene.
Oxybutynin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin.
Parecoxib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib.
Paricalcitol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol.
P-glycoprotein/ABCB1 Inhibitors	May increase the serum concentration of Pglycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of pglycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.).
P-glycoprotein/ABCB1 Substrates	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide.
Pimecrolimus	CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus.
Polatuzumab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased.
Posaconazole	May increase the serum concentration of Ritonavir.
Pranlukast	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast.
Praziquantel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel.
PredniSONE	Ritonavir may increase the serum concentration of PredniSONE.
Proguanil	Ritonavir may decrease the serum concentration of Proguanil.
Prucalopride	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride.
QT-prolonging Agents (Highest Risk)	QT-prolonging Agents (Indeterminate Risk - Avoid) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Ramelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon.
Repaglinide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure.
Retapamulin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations.
RifAXIMin	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin.
Rilpivirine	Lopinavir may increase the serum concentration of Rilpivirine.
RomiDEPsin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Sibutramine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Sibutramine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sibutramine.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
SORAfenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib.
Tacrolimus (Topical)	Protease Inhibitors may decrease the metabolism of Tacrolimus (Topical).
Talazoparib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs.
Talazoparib	BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib.
Tasimelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon.
Tegaserod	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod.
Telithromycin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Telithromycin.
Tenofovir Disoproxil Fumarate	Lopinavir may enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate.
Tetrahydrocannabinol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol.
Tetrahydrocannabinol and Cannabidiol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol.
Theophylline Derivatives	Ritonavir may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline.
Thyroid Products	Ritonavir may diminish the therapeutic effect of Thyroid Products.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
TraMADol	Ritonavir may decrease serum concentrations of the active metabolite(s) of TraMADol. Ritonavir may increase the serum concentration of TraMADol.
Triamcinolone (Systemic)	Ritonavir may enhance the adverse/toxic effect of Triamcinolone (Systemic). Specifically, risks of developing iatrogenic Cushing syndrome and secondary adrenal insufficiency may be increased. Ritonavir may increase the serum concentration of Triamcinolone (Systemic).
Tricyclic Antidepressants	Protease Inhibitors may increase the serum concentration of Tricyclic Antidepressants.
Upadacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib.
Valproate Products	Protease Inhibitors may decrease the serum concentration of Valproate Products.
Vilanterol	May increase the serum concentration of CYP3A4 Inhibitors (Strong).
Vindesine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine.
Vinorelbine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine.
Warfarin	Lopinavir may decrease the serum concentration of Warfarin.
Warfarin	Ritonavir may decrease the serum concentration of Warfarin.
Zidovudine	Protease Inhibitors may decrease the serum concentration of Zidovudine.
Zolpidem	Ritonavir may increase the serum concentration of Zolpidem.
Risk Factor D (Consider therapy modification)
Abemaciclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily.
Afatinib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib.
Alitretinoin (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor.
Almotriptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function.
Alpelisib	BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions.
ALPRAZolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam. Management: Consider using an alternative agent that is less likely to interact. If combined, monitor for increased therapeutic/toxic effects of alprazolam if combined with a strong CYP3A4 inhibitor.
Apixaban	Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Apixaban. Management: US labeling recommends a 50% apixaban dose reduction in patients who would otherwise receive 5 or 10 mg twice daily, and avoiding in patients who would otherwise receive 2.5 mg twice daily. Canadian labeling lists any combined use as contraindicated.
ARIPiprazole	May enhance the adverse/toxic effect of Ritonavir. The risk of metabolic disturbances (e.g. hyperglycemia, weight gain, hyperlipidemia) may be increased. Ritonavir may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph. Aripiprazole dose adjustment may not be required when used as adjunctive therapy for major depressive disorder.
ARIPiprazole Lauroxil	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments.
AtorvaSTATin	Protease Inhibitors may increase the serum concentration of AtorvaSTATin. Management: See full monograph for recommended dose limits. Avoid atorvastatin with tipranavir/ritonavir.
Bedaquiline	Lopinavir may increase the serum concentration of Bedaquiline. Management: Consider alternatives to this combination. Concomitant use should only occur if the benefit of coadministration outweighs the risk. If combined, monitor for increased bedaquiline effects/toxicities (eg, QTc interval prolongation).
Betrixaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor.
Bilastine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors.
Bosentan	Ritonavir may increase the serum concentration of Bosentan. Management: Use bosentan 62.5 mg daily or every other day in adult patients who have been on ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting ritonavir; wait until at least 10 days on ritonavir before restarting.
Bosentan	Lopinavir may increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of Lopinavir. Management: Use bosentan 62.5 mg/day or every other day in adult patients taking lopinavir/ritonavir for at least 10 days. Temporarily stop bosentan (for at least 36 hrs) before starting lopinavir/ritonavir; wait at least 10 days before restarting bosentan.
Brexpiprazole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer.
Brigatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg).
Budesonide (Topical)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased.
BusPIRone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of BusPIRone. Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities if combined with strong CYP3A4 inhibitors.
Cabazitaxel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose.
Cabozantinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details.
Calcium Channel Blockers (Nondihydropyridine	Protease Inhibitors may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Increased serum concentrations of the calcium channel blocker may increase risk of AV nodal blockade. Management: Avoid concurrent use when possible. If used, monitor for CCB toxicity. The manufacturer of atazanavir recommends a 50% dose reduction for diltiazem be considered. Saquinavir, tipranavir, and darunavir/cobicistat use with bepridil is contraindicated.
Canagliflozin	Ritonavir may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 200 mg/day in patients tolerating 100 mg/day. A further increase to 300 mg/day can be considered in patients with an estimated glomerular filtration rate (GFR) of 60 mL/min/1.73 m2 or greater.
CarBAMazepine	May decrease the serum concentration of Lopinavir. Management: Increased doses of lopinavir may be necessary when using these agents in combination. Do not use a once daily lopinavir/ritonavir regimen together with carbamazepine. Increase monitoring of therapeutic response in all patients using this combination.
Cariprazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details.
Ceritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Exceptions discussed in separate monographs.
Cilostazol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4.
Cladribine	BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration.
Cladribine	Inhibitors of Equilibrative Nucleoside (ENT1) and Concentrative Nucleoside (CNT3) Transport Proteins may increase the serum concentration of Cladribine. Management: Avoid concomitant use of ENT1 or CNT3 inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider an ENT1 or CNT3 inhibitor dose reduction and separation in the timing of administration.
Colchicine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details.
Colchicine	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details.
Copanlisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities.
Crizotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors whenever possible. If combined use cannot be avoided, decrease the crizotinib dose to 250 mg daily. Exceptions are discussed in separate monographs.
CycloSPORINE (Systemic)	Ritonavir may increase the serum concentration of CycloSPORINE (Systemic). Management: Consider empiric cyclosporine dose reductions and monitor cyclosporine serum concentrations closely if ritonavir is initiated.
CYP3A4 Inducers (Strong)	May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling.
CYP3A4 Substrates (High risk with Inhibitors)	CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors). Exceptions: Alitretinoin (Systemic); AmLODIPine; Benzhydrocodone; Buprenorphine; Gefitinib; HYDROcodone; Mirtazapine; Praziquantel; Telithromycin; Vinorelbine.
Dabigatran Etexilate	P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling.
Daclatasvir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat.
Dasatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: This combination should be avoided if possible. If combined, dasatinib dose reductions are recommended. See full monograph for details. Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Deferasirox	Ritonavir may decrease the serum concentration of Deferasirox. Management: Avoid combination when possible; if the combination must be used, consider a 50% increase in initial deferasirox dose, with monitoring of serum ferritin concentrations and clinical responses to guide further dosing.
Deflazacort	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deflazacort. Management: Administer one third of the recommended deflazacort dose when used together with a strong or moderate CYP3A4 inhibitor.
Delamanid	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Delamanid. Management: Increase ECG monitoring frequency if delamanid is combined with strong CYP3A4 inhibitors due to the risk for QTc interval prolongation. Continue frequent ECG assessments throughout full delamanid treatment period. Exceptions discussed separately.
Delavirdine	Protease Inhibitors may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Protease Inhibitors.
Didanosine	Lopinavir may decrease the serum concentration of Didanosine. This interaction refers only to lopinavir/ritonavir oral solution, which must be taken with food, and is principally the result of a food-didanosine interaction. Management: Didanosine should be administered 1 hour prior to or 2 hours after administration of lopinavir/ritonavir oral solution (which must be taken with food). Didanosine and lopinavir/ritonavir tablets can be administered together.
Digoxin	Ritonavir may increase the serum concentration of Digoxin.
DOCEtaxel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities.
DOXOrubicin (Conventional)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
DOXOrubicin (Conventional)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided.
Drospirenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Management: Drospirenone use is contraindicated specifically when the strong CYP3A4 inhibitors atazanavir and cobicistat are administered concurrently. Caution should be used when drospirenone is coadministered with other strong CYP3A4 inhibitors.
Duvelisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor.
Edoxaban	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation.
Efavirenz	May decrease the serum concentration of Lopinavir. Management: Avoid once daily use of lopinavir/ritonavir with efavirenz. Avoid use of this combination in patients less than 6 months of age. See lopinavir/ritonavir prescribing information for specific recommended dose increases in particular patient populations.
Eliglustat	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details.
Eluxadoline	Lopinavir may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with lopinavir and monitor patients for increased eluxadoline effects/toxicities.
Eluxadoline	Ritonavir may increase the serum concentration of Eluxadoline. Management: Decrease the eluxadoline dose to 75 mg twice daily if combined with ritonavir and monitor patients for increased eluxadoline effects/toxicities.
Elvitegravir	Lopinavir may increase the serum concentration of Elvitegravir. Specifically, lopinavir/ritonavir may increase the concentration of elvitegravir. Management: When elvitegravir is combined with lopinavir/ritonavir, the dose of elvitegravir should be reduced to 85 mg once daily and the dose of lopinavir/ritonavir should be 400 mg/100 mg twice daily.
Encorafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and strong CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose. See monograph for details.
Entrectinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 100 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. No alternative dosing provided for others.
Enzalutamide	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring.
Erdafitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly.
Erlotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements).
Estrogen Derivatives (Contraceptive)	Protease Inhibitors may decrease the serum concentration of Estrogen Derivatives (Contraceptive). Management: Use oral contraceptives containing at least 35mcg ethinyl estradiol with atazanavir/ritonavir, or no more than 30mcg in patients receiving atazanavir alone. Use of an alternative, non-hormonal contraceptive is recommended with other protease inhibitors.
Eszopiclone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression).
Etizolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely.
Etravirine	Ritonavir may decrease the serum concentration of Etravirine. Management: Avoid concomitant use of etravirine with antiviral doses of ritonavir; use with ritonavir-boosted fosamprenavir or with ritonavir-boosted tipranavir is also not recommended.
Fedratinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated.
FentaNYL	CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary.
Fesoterodine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors.
Fluticasone (Oral Inhalation)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely.
Fosphenytoin	May decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Fosphenytoin. Management: The manufacturer of lopinavir/ritonavir recommends avoiding once-daily administration if used together with phenytoin.
Fosphenytoin	May decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Fosphenytoin.
Garlic	May decrease the serum concentration of Protease Inhibitors. Management: Concurrent use of garlic supplements with protease inhibitors is not recommended. If this combination is used, monitor closely for altered serum concentrations/effects of protease inhibitors, and particularly for signs/symptoms of therapeutic failure.
Gilteritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of a strong CYP3A4 inhibitor with gilteritinib. If the combination cannot be avoided, monitor more closely for evidence of gilteritinib toxicities.
Glasdegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib.
GuanFACINE	CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination.
Iloperidone	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor.
Istradefylline	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Istradefylline. Management: Limit the maximum istradefylline dose to 20 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased istradefylline effects/toxicities.
Itraconazole	Lopinavir may increase the serum concentration of Itraconazole. Management: Limit the adult maximum itraconazole dose to 200 mg/day in patients receiving lopinavir/ritonavir.
Itraconazole	Ritonavir may increase the serum concentration of Itraconazole. Management: Limit the adult maximum itraconazole dose to 200 mg/day in patients receiving ritonavir.
Ivacaftor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for productspecific recommendations.
Ivosidenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivosidenib. Management: Avoid use of a strong CYP3A4 inhibitor with ivosidenib whenever possible. When combined use is required, reduce the ivosidenib dose to 250 mg once daily. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs.
Ixabepilone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone.
Ketoconazole (Systemic)	May increase the serum concentration of Lopinavir. Lopinavir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving lopinavir/ritonavir.
Ketoconazole (Systemic)	Ritonavir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving ritonavir.
LamoTRIgine	Ritonavir may decrease the serum concentration of LamoTRIgine.
Larotrectinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor half-life.
Levomilnacipran	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors.
Lorlatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Manidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required.
Maraviroc	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min.
MethylPREDNISolone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects.
Midostaurin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Exceptions are discussed in separate monographs.
MiFEPRIStone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 900 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication.
Mirodenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination.
Mitotane	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane.
Nefazodone	Protease Inhibitors may increase the serum concentration of Nefazodone. Management: Consider alternatives to, or reduced doses of, nefazodone in patients treated with HIV protease inhibitors. Monitor patients receiving these combinations closely for toxic effects of nefazodone.
Nelfinavir	May decrease the serum concentration of Lopinavir. Lopinavir may increase the serum concentration of Nelfinavir. Concentrations of the nelfinavir M8 metabolite may also be increased. Management: Avoid once daily use of lopinavir/ritonavir with nelfinavir. Avoid use of this combination in patients less than 6 months of age. See lopinavir/ritonavir prescribing information for recommended dose increases in other patients.
Nevirapine	May decrease the serum concentration of Lopinavir. Management: Avoid once daily use of lopinavir/ritonavir with nevirapine. Avoid use of this combination in patients less than 6 months of age. See lopinavir/ritonavir prescribing information for recommended dose increases in other patients.
Nilotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Management: Avoid if possible. If combination needed, decrease nilotinib to 300 mg once/day for patients with resistant or intolerant Ph+ CML or to 200 mg once/day for patients with newly diagnosed Ph+ CML in chronic phase. Exceptions discussed in separate monograph.
Olaparib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib, if possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 100 mg twice daily.
OxyCODONE	CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased.
Panobinostat	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor.
Pexidartinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pexidartinib. Management: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day.
PHENobarbital	May decrease the serum concentration of Lopinavir. Management: Increased doses of lopinavir may be necessary when using these agents in combination. Do not use a once daily lopinavir/ritonavir regimen together with phenobarbital. Increase monitoring of therapeutic response in all patients using this combination.
Phenytoin	May decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Phenytoin. Management: The manufacturer of lopinavir/ritonavir recommends avoiding once-daily administration if used together with phenytoin.
Phenytoin	May decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin.
Pimavanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors.
Piperaquine	CYP3A4 Inhibitors (Strong) may enhance the QTc-prolonging effect of Piperaquine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Piperaquine. Management: Avoid concomitant use of piperaquine and strong CYP3A4 inhibitors when possible. If the combination cannot be avoided, frequent ECG monitoring is recommended due to the risk for QTc prolongation. Exceptions are discussed separately.
PONATinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor.
PrednisoLONE (Systemic)	Ritonavir may increase the serum concentration of PrednisoLONE (Systemic). Management: Consider prednisolone dose reductions in patients receiving ritonavir and monitor for increased adverse effects with concomitant use.
Progestins (Contraceptive)	Lopinavir may decrease the serum concentration of Progestins (Contraceptive). Lopinavir may increase the serum concentration of Progestins (Contraceptive). Management: Consider using an alternative or additional means of contraception. Injected depot medroxyprogesterone acetate and etonogestrel implants may be used without a need for additional contraception.
Protease Inhibitors	May increase the serum concentration of other Protease Inhibitors. Management: Atazanavir--indinavir combination contraindicated. Tipranavir/ritonavir or atazanavir/ritonavir not recommended with other protease inhibitors (PI). Darunavir/cobicistat not recommended with PI that require boosting.Other combos may require dose changes.
QUEtiapine	Ritonavir may increase the serum concentration of QUEtiapine. Management: The ritonavir Canadian labeling states this combination should not be used. U.S. labeling recommends using an alternative when possible; if the combination must be used, quetiapine dose reductions are needed.
Reboxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine.
Ribociclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ribociclib. Management: Avoid use of ribociclib with strong CYP3A4 inhibitors when possible; if combined use cannot be avoided, reduce ribociclib dose to 400 mg once daily. Exceptions are discussed in separate monographs.
Rifabutin	Lopinavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Rifabutin may increase the serum concentration of Lopinavir. Lopinavir may increase the serum concentration of Rifabutin. Management: Reduce rifabutin doses. Lopinavir/ritonavir US labeling recommends a decrease of at least 75%, to 150 mg every other day or 3 times per week for adults, while clinical guidelines recommend 150 mg/day or 300 mg 3 times per week.
Rifabutin	Ritonavir may increase serum concentrations of the active metabolite(s) of Rifabutin. Ritonavir may increase the serum concentration of Rifabutin. Management: Ritonavir US prescribing information recommends reducing rifabutin doses by at least 75%. Refer to drug interaction monographs addressing concomitantly administered protease inhibitors for dosing recommendations specific to ritonavir-boosted regimens.
Riociguat	Protease Inhibitors may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day (for adults). Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension.
Rosuvastatin	Protease Inhibitors may increase the serum concentration of Rosuvastatin. Management: Start at the lowest rosuvastatin dose and monitor for toxicity. See full drug interaction monograph for details.
Ruxolitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details.
SAXagliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors.
Sildenafil	Protease Inhibitors may increase the serum concentration of Sildenafil. Management: Erectile dysfunction: sildenafil max = 25 mg/48 hrs with ritonavir, atazanavir, or darunavir; starting dose = 25 mg with other protease inhibitors (adult doses). Contraindicated if sildenafil being used for pulmonary arterial hypertension.
Sildenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours.
Sirolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sirolimus. Management: Consider avoiding concurrent use of sirolimus with strong CYP3A4 inhibitors in order to minimize the risk for sirolimus toxicity. Concomitant use of sirolimus and voriconazole or posaconazole is contraindicated.
Solifenacin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin. Management: Limit solifenacin doses to 5 mg daily when combined with strong CYP3A4 inhibitors.
SUFentanil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil. Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression).
SUNItinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose decreases are recommended, and vary by indication. See full monograph for details.
Tacrolimus (Systemic)	Ritonavir may increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose reductions may be needed with concurrent ritonavir. Monitor tacrolimus concentrations closely to determine dose; doses of tacrolimus 0.5 mg to 1 mg every week may be adequate.
Tadalafil	Ritonavir may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving ritonavir may vary based on indication and/or international labeling. Consult appropriate product labeling.
Temsirolimus	Protease Inhibitors may enhance the adverse/toxic effect of Temsirolimus. Levels of sirolimus, the active metabolite, may be increased, likely due to inhibition of CYP-mediated metabolism.
Temsirolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors whenever possible. If combined, decrease temsirolimus dose to 12.5 mg per week and monitor patients for increased temsirolimus effects and toxicities.
Tezacaftor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor alone should be administered.
Thiotepa	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inhibitors. If concomitant use is unavoidable, monitor for adverse effects and decreased efficacy.
Tofacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details.
Tolterodine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor.
Toremifene	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Management: Use of toremifene with strong CYP3A4 inhibitors should be avoided if possible. If coadministration is necessary, monitor for increased toremifene toxicities, including QTc interval prolongation. Exceptions are discussed in separate monograph.
TraZODone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors.
Valbenazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors.
Vardenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. See full drug interaction monograph for details.
Velpatasvir	Ritonavir may decrease the serum concentration of Velpatasvir. Ritonavir may increase the serum concentration of Velpatasvir.
Vemurafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. Consider use of an alternative that is not a strong inhibitor of CYP3A4 as clinically appropriate.
Venetoclax	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy.
Venetoclax	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors.
Vilazodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg daily in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor.
VinBLAStine	Lopinavir may increase the serum concentration of VinBLAStine. Management: Monitor closely for signs and symptoms of vinblastine toxicity; consider temporary interruption of lopinavir/ritonavir antiviral therapy if patients develop significant toxicity with concurrent use.
VinBLAStine	Ritonavir may increase the serum concentration of VinBLAStine. Management: Monitor closely for signs and symptoms of vinblastine toxicity; consider temporary interruption of ritonavir antiviral therapy if patients develop significant toxicity with concurrent use.
VinCRIStine	Lopinavir may increase the serum concentration of VinCRIStine. Management: Monitor closely for signs and symptoms of vincristine toxicity; consider temporary interruption of lopinavir/ritonavir antiviral therapy if patients develop significant toxicity with concurrent use.
VinCRIStine	Ritonavir may increase the serum concentration of VinCRIStine. Management: Monitor closely for signs and symptoms of vincristine toxicity; consider temporary interruption of ritonavir antiviral therapy if patients develop significant toxicity with concurrent use.
Voxelotor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inhibitors. If concomitant use is unavoidable, reduce the voxelotor dose to 1,000 mg once daily.
Zanubrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg once daily during coadministration with a strong CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details.
Zopiclone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined.
Zuclopenthixol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity.
Risk Factor X (Avoid combination)
Acalabrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Acalabrutinib.
Ado-Trastuzumab Emtansine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component.
Alfuzosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin.
Alfuzosin	Protease Inhibitors may increase the serum concentration of Alfuzosin.
Amiodarone	Lopinavir may enhance the QTc-prolonging effect of Amiodarone. Lopinavir may increase the serum concentration of Amiodarone. More specifically, Lopinavir/Ritonavir may increase the serum concentration of Amiodarone. Management: If this combination cannot be avoided, monitor for increased amiodarone serum concentrations and effects as well as for evidence of QT interval prolongation.
Amiodaron	Ritonavir may increase the serum concentration of Amiodarone. Management: Ritonavir US prescribing information lists this combination as contraindicated. Amiodarone use should be avoided with lopinavir/ritonavir, but if the combination must be used, monitor closely for increased amiodarone serum concentrations and effects.
Antihepaciviral Combination Products	Lopinavir may increase the serum concentration of Antihepaciviral Combination Products. Specifically, the serum concentrations of the paritaprevir component may increase significantly.
Apalutamide	May decrease the serum concentration of Lopinavir.
Aprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant.
Astemizole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Asunaprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir.
Asunaprevir	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Asunaprevir.
Avanafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
Avapritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avapritinib.
Axitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended.
Barnidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine.
Blonanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin.
Bosutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib.
Bromocriptine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine.
Budesonide (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic).
Cisapride	Protease Inhibitors may increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Clarithromycin	May enhance the QTc-prolonging effect of Lopinavir. Lopinavir may diminish the therapeutic effect of Clarithromycin. Specifically, lopinavir may decrease the formation of the active 14-hydroxy-clarithromycin metabolite, which may negatively impact clarithromycin effectiveness. Lopinavir may increase the serum concentration of Clarithromycin. Clarithromycin may increase the serum concentration of Lopinavir.
Clobetasone	Ritonavir may increase the serum concentration of Clobetasone.
Cobicistat	May enhance the therapeutic effect of Ritonavir. Specifically, cobicistat and ritonavir have overlapping effects on the CYP3A4-mediated metabolism of other drugs.
Cobimetinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib.
Conivaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan.
Dabrafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib.
Dapoxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine.
Darunavir	Lopinavir may decrease the serum concentration of Darunavir. Darunavir may increase the serum concentration of lopinavir
Disulfiram	Lopinavir may enhance the adverse/toxic effect of Disulfiram. Specifically, the combination of lopinavir/ritonavir solution, which contains 42% alcohol, may result in a disulfiramalcohol reaction if combined.
Disulfiram	Ritonavir may enhance the adverse/toxic effect of Disulfiram. Specifically, the combination of ritonavir oral solution, which contains 43% alcohol, may result in a disulfiramalcohol reaction if combined.
Domperidone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Dronedarone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Elagolix	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase the serum concentration of Elagolix.
Eletriptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan.
Eplerenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone.
Ergot Derivatives	Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Cabergoline; Nicergoline; Pergolide.
Everolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus.
Flecainide	Ritonavir may increase the serum concentration of Flecainide.
Flibanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin.
Fluticasone (Nasal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal).
Fosamprenavir	May decrease the serum concentration of Lopinavir. Specifically, amprenavir (the active metabolite of fosamprenavir) may decrease the serum concentration of lopinavir. Lopinavir may decrease the serum concentration of Fosamprenavir. Specifically, lopinavir/ritonavir may decrease the serum concentration of amprenavir (the active metabolite of fosamprenavir)
Fosaprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosaprepitant.
Fusidic Acid (Systemic)	Ritonavir may increase the serum concentration of Fusidic Acid (Systemic). Fusidic Acid (Systemic) may increase the serum concentration of Ritonavir.
Glecaprevir and Pibrentasvir	Lopinavir may increase the serum concentration of Glecaprevir and Pibrentasvir.
Glecaprevir and Pibrentasvir	Ritonavir may increase the serum concentration of Glecaprevir and Pibrentasvir.
Grazoprevir	Lopinavir may increase the serum concentration of Grazoprevir.
Halofantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Ibrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued.
Irinotecan Products	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products.
Isavuconazonium Sulfate	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4.
Ivabradine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine.
Lapatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor.
Lasmiditan	May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
Lefamulin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4.
Lemborexant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lemborexant.
Lercanidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine.
Lomitapide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide.
Lovastatin	Protease Inhibitors may increase the serum concentration of Lovastatin.
Lovastatin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin.
Lumateperone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumateperone.
Lurasidone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone.
Macitentan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan.
Meptazinol	Ritonavir may increase the serum concentration of Meptazinol.
MetroNIDAZOLE (Systemic)	Ritonavir may enhance the adverse/toxic effect of MetroNIDAZOLE (Systemic). Specifically, the combination of ritonavir oral solution or ritonavir soft gelatin capsule, both of which contain alcohol, and metronidazole may result in a disulfiram-like reaction.
Midazolam	Protease Inhibitors may increase the serum concentration of Midazolam. Management: Oral midazolam contraindicated with all protease inhibitors. IV midazolam contraindicated with fosamprenavir and nelfinavir; other protease inhibitors recommend caution, close monitoring, and consideration of lower IV midazolam doses with concurrent use.
Naloxegol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol.
Neratinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib.
NiMODipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine.
Nisoldipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine.
Palbociclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib.
PAZOPanib	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib.
PAZOPanib	BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib.
Pimozide	Protease Inhibitors may increase the serum concentration of Pimozide.
Pimozide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide.
Propafenone	Ritonavir may increase the serum concentration of Propafenone.
QuiNIDine	Ritonavir may increase the serum concentration of QuiNIDine.
QuiNIDine	Lopinavir may enhance the QTc-prolonging effect of QuiNIDine. Lopinavir may increase the serum concentration of QuiNIDine. Specifically, lopinavir/ritonavir may increase the serum concentration of quinidine.
QuiNINE	Ritonavir may decrease the serum concentration of QuiNINE. This effect has been seen with lopinavir/ritonavir. The individual contributions of lopinavir and ritonavir to this effect are unclear. QuiNINE may increase the serum concentration of Ritonavir. Ritonavir may increase the serum concentration of QuiNINE.
QuiNINE	Lopinavir may decrease the serum concentration of QuiNINE. This effect has been seen with lopinavir/ritonavir. The individual contributions of lopinavir and ritonavir to this effect are unclear.
Radotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib.
Ranolazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine.
Red Yeast Rice	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased.
Regorafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib.
Revefenacin	OATP1B1/1B3 (SLCO1B1/1B3) Inhibitors may increase serum concentrations of the active metabolite(s) of Revefenacin.
RifAMPin	May enhance the adverse/toxic effect of Lopinavir. Specifically, the risk of hepatocellular toxicity may be increased. RifAMPin may decrease the serum concentration of Lopinavir.
RifAMPin	May decrease the serum concentration of Ritonavir.
Rivaroxaban	Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Rivaroxaban.
Rupatadine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine.
Salmeterol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol.
Silodosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin.
Simeprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir.
Simeprevir	Protease Inhibitors may increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors.
Simvastatin	Protease Inhibitors may increase the serum concentration of Simvastatin.
Simvastatin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin.
Sonidegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib.
St John's Wort	May increase the metabolism of Protease Inhibitors.
Suvorexant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant.
Tamsulosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin.
Terfenadine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Ticagrelor	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor.
Tipranavir	May decrease the serum concentration of Protease Inhibitors.
Tolvaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan.
Topotecan	BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan.
Topotecan	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan.
Trabectedin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin.
Triazolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triazolam.
Ubrogepant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ubrogepant.
Udenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil.
Ulipristal	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity.
VinCRIStine (Liposomal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal).
VinCRIStine (Liposomal)	P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal).
Vinflunine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine.
Vorapaxar	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar.
Voriconazole	Ritonavir may decrease the serum concentration of Voriconazole. Management: Concurrent voriconazole and high-dose ritonavir (adult doses of 400 mg every 12 hrs or greater) is contraindicated. Voriconazole with lower-dose ritonavir should be avoided unless benefits outweigh risk of inadequate voriconazole concentrations.
Voriconazole	Lopinavir may decrease the serum concentration of Voriconazole.
Voxilaprevir	Lopinavir may increase the serum concentration of Voxilaprevir.

Monitor:

Prior to initiating treatment, consider genotypic or phenotypic testing for lopinavir resistance-associated substitutions.
Monitor serum triglycerides and cholesterol at baseline and then periodically thereafter,
Liver function tests,
Serum electrolytes,
basic HIV monitoring,
viral load and CD4 count,
Plasma glucose

How to administer Kaletra (Lopinavir and ritonavir)?

Kaletra Solution:

It must be administered with meals.
If Kaletra is to be used with concomitant didanosine, it should be taken 2 hours before or one hour after didanosine.
A calibrated dosing cup or syringe should be used.
The solution contains ethanol and propylene glycol and the drug should not be administered in polyurethane feeding tubes (silicone and polyvinyl chloride feeding tubes may be used).

Kaletra Tablet:

The tablet may be taken with or without food.
It should not be crushed, chewed, broken, and swallow whole.
It may be taken with didanosine when taken without food.

Mechanism of action of Lopinavir and ritonavir (Kaletra):

Kaletra is a combination of lopinavir (ritonavir) and ropinavir.
By binding to the HIV-1 protease activation site, the lopinavir component blocks the cleavage and synthesis of viral GagPol polyprotein precursors into the individual HIV proteins.
These non-infectious, immature viral particles are created.
The ritonavir components increase plasma levels of lopinavir through inhibition of the enzyme CYP3A.
Lopinavir can be taken in doses of 98% to 99 percent.

protein-bound(mainly to alpha-1-acid glycoprotein and albumin that has a higher affinity for alpha-1-acid glycoprotein).

Lopinavir can be taken orally.

Metabolized By the liver via CYP3A4 has ahalf-life eliminationIt takes between 5-6 hours.

It takes approximately 4 hours to reach peak plasma concentration. Lopinavir excreted primarily from the feces (83%), and urine (10%) See the pharmacology of Ritonavir.

Lopinavir and ritonavir brand names (International):

Kaletra
Aluvia
Kaletra
Kaluvia
Lopimune

Lopinavir and ritonavir brand names in Pakistan:

Lopinavir and ritonavir Capsules 133.3 mg
Kaletra	Abbott Laboratories (Pakistan) Limited.

Kaletra (Lopinavir and ritonavir)

Kaletra uses:

HIV-1 infection:

Kaletra use in COVID-19 (Coronavirus) infection:

Kaletra Dose in Adults:

Kaletra Dose in the treatment of HIV-1 infection as a component of combination therapy):

Patients who are receiving concomitant antiretroviral therapy without efavirenz, nelfinavir, or nevirapine:

Pregnant women without lopinavir-resistance-associated amino acid substitutions:

Kaletra dosage adjustment for combination therapy with efavirenz, nelfinavir, or nevirapine:

Twice-daily dosing:

Once-daily dosing:

Kaletra dosage adjustment for combination therapy with carbamazepine, phenobarbital, and phenytoin:

Kaletra Dose in Children:

Kaletra Dose in the treatment of HIV-1 infection in combination with other antiretroviral agents:

Infants ≥42 weeks postmenstrual age:

Children and Adolescents:

Weight-directed dosing:

Alternate fixed dosing for patients weighing 15 kgs or more and able to swallow tablets:

Antiretroviral-experienced or suspected decreased sensitivity to lopinavir:

Weight band dosing for patients weighing 15 kgs or more and able to swallow tablets:

Patients receiving concomitant antiretroviral therapy with efavirenz, nelfinavir, or nevirapine (or treatment-experienced patients not receiving these agents who have suspected decreased susceptibility to lopinavir):

Kaletra Dose in the HIV-1 nonoccupational postexposure prophylaxis:

Infants at least 42 weeks postmenstrual age:

Children:

Pregnancy Risk Factor: B

Kaletra dose in renal impairment:

Kaletra Dose in patients with liver disease:

Mild to moderate impairment:

Severe impairment:

Common Side Effects of Kaletra (Lopinavir and ritonavir) Include:

Dermatologic:

Endocrine & Metabolic:

Gastrointestinal:

Hepatic:

Respiratory:

Less Common Side Effects Of Kaletra (Lopinavir And Ritonavir) Include:

Cardiovascular:

Central Nervous System:

Dermatologic:

Endocrine & Metabolic:

Gastrointestinal:

Hematologic & Oncologic:

Hepatic:

Hypersensitivity:

Neuromuscular & Skeletal:

Respiratory:

Contraindication to Kaletra (Lopinavir and ritonavir):

Warnings and Precautions

Modified cardiac conduction

Cardiovascular issues

Fat redistribution

Hepatotoxicity:

Immune reconstitution syndrome:

Increasing cholesterol

Diabetes:

Hemophilia A and B:

Hepatic impairment

Pancreatitis