Skip to Content
Vaccines aren’t just for kids. Is your teen protected?

Lopinavir and Ritonavir

Pronunciation

(loe PIN a veer & ri TOE na vir)

Index Terms

  • Lopinavir/Ritonavir
  • Ritonavir and Lopinavir

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, oral:

Kaletra: Lopinavir 80 mg and ritonavir 20 mg per 1 mL (160 mL) [contains ethanol 42.4%, menthol, propylene glycol; cotton candy flavor]]

Tablet:

Kaletra:

Lopinavir 100 mg and ritonavir 25 mg

Lopinavir 200 mg and ritonavir 50 mg

Brand Names: U.S.

  • Kaletra

Pharmacologic Category

  • Antiretroviral, Protease Inhibitor (Anti-HIV)

Pharmacology

A coformulation of lopinavir and ritonavir. The lopinavir component binds to the site of HIV-1 protease activity and inhibits the cleavage of viral Gag-Pol polyprotein precursors into individual functional proteins required for infectious HIV. This results in the formation of immature, noninfectious viral particles. The ritonavir component inhibits the CYP3A metabolism of lopinavir, allowing increased plasma levels of lopinavir.

Metabolism

Lopinavir: Hepatic via CYP3A4; 13 metabolites identified; may induce its own metabolism

Excretion

Lopinavir: Feces (83%, 20% as unchanged drug); urine (10%; <3% as unchanged drug)

Clearance: (Apparent oral): 6 to 7 L/hour

Time to Peak

Lopinavir: ~4 hours

Half-Life Elimination

Lopinavir: 5 to 6 hours

Protein Binding

Lopinavir: 98% to 99%; binds to both alpha-1 acid glycoprotein and albumin; higher affinity for alpha-1 acid glycoprotein; decreased with mild-to-moderate hepatic dysfunction

Use: Labeled Indications

Treatment of HIV-1 infection: Treatment of HIV-1 infection in combination with other antiretroviral agents

Contraindications

Hypersensitivity (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to lopinavir, ritonavir, or any component of the formulation; coadministration with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions; coadministration with the potent CYP3A inducers (where significantly decreased lopinavir levels may be associated with a potential for loss of virologic response and resistance and cross-resistance to develop): Alfuzosin, cisapride, ergot derivatives (eg, dihydroergotamine, ergotamine, methylergonovine), lovastatin, oral midazolam, pimozide, rifampin, sildenafil (when used to treat pulmonary arterial hypertension), simvastatin, St John's wort, and triazolam.

Canadian labeling: Additional contraindications (not in US labeling): Coadministration with fusidic acid, midazolam, salmeterol, vardenafil, astemizole (not available in Canada), terfenadine (not available in Canada)

Dosing: Adult

HIV infection (as a component of combination therapy): Oral:

Twice-daily dosing:

Therapy-naive or therapy-experienced: Lopinavir 400 mg/ritonavir 100 mg twice daily.

Therapy-naive or therapy-experienced patients receiving efavirenz, fosamprenavir, nelfinavir, nevirapine: See dosage adjustment for combination therapy.

Once-daily dosing: Therapy-naive or experienced patients with <3 lopinavir resistance-associated substitutions: Lopinavir 800 mg/ritonavir 200 mg once daily. Once-daily dosing is not recommended in those receiving efavirenz, fosamprenavir, nevirapine, nelfinavir, carbamazepine, phenobarbital, or phenytoin.

Pregnant women (with no lopinavir-resistance-associated amino acid substitutions): Lopinavir 400 mg/ritonavir 100 mg twice daily. Once-daily dosing is not recommended. Tablets are recommended; avoid use of the oral solution. Alternately, the HHS perinatal guidelines recommend an increased dose of lopinavir 600 mg/ritonavir 150 mg twice daily, or lopinavir 500 mg/ritonavir 125 mg twice daily, during the second and third trimesters of pregnancy, especially in PI-experienced pregnant women and women with a baseline viral load >50 copies/mL. If standard doses are used, close monitoring is recommended (HHS [perinatal] 2016).

Dosage adjustment for combination therapy with efavirenz, nelfinavir, or nevirapine (US labeling) or efavirenz, fosamprenavir, nelfinavir, or nevirapine (Canadian labeling): Oral:

Twice-daily dosing: Therapy-naive and therapy-experienced patients:

Solution: Lopinavir 533 mg/ritonavir 133 mg (6.5 mL) twice daily

Tablet: Lopinavir 500 mg/ritonavir 125 mg twice daily

Once-daily dosing: Once-daily dosing not recommended.

Dosage adjustment for combination therapy with carbamazepine, phenobarbital, phenytoin: Once-daily dosing not recommended

Dosing: Geriatric

Initial studies did not include enough elderly patients to determine effects based on age. Use with caution due to possible decreased hepatic, renal, and cardiac function.

Dosing: Pediatric

HIV infection (component of combination therapy): Oral: Dosage based on weight or body surface area (BSA), presented based on lopinavir component (maximum dose: Lopinavir 400 mg/ritonavir 100 mg). Note: Once daily dosing is not recommended in Infants, Children, or Adolescents <18 years of age. Use in infants <6 months of age is not approved in the Canadian labeling.

14 days to 6 months: 16 mg/kg or 300 mg/m2 twice daily; Note: Should not be administered to neonates age <14 days (defined as postmenstrual age of 42 weeks [first day of mother’s last menstrual period to birth plus postnatal age]) and a postnatal age of at least 14 days

6 months to 18 years: Note: FDA-approved dose and Health Canada-approved dose are approximately equivalent to lopinavir 230 mg/m2 per dose.

Oral solution:

<15 kg: 12 mg/kg twice daily

15 to 40 kg: 10 mg/kg twice daily

>40 kg: Lopinavir 400 mg/ritonavir 100 mg twice daily

Tablets:

<15 kg: Tablets are not recommended.

15 to 25 kg: Lopinavir 200 mg/ritonavir 50 mg twice daily

>25 kg to 35 kg: Lopinavir 300 mg/ritonavir 75 mg twice daily

>35 kg: Lopinavir 400 mg/ritonavir 100 mg twice daily

Dosage adjustment for combination therapy with efavirenz, nelfinavir, or nevirapine (US labeling) or efavirenz, fosamprenavir, nelfinavir, or nevirapine (Canadian labeling): Oral:

Twice-daily dosing:

Infants 14 days to 6 months: Combination therapy with these agents is not recommended due to lack of data.

Infants, Children, and Adolescents 6 months to 18 years: Solution or tablet (based on mg of lopinavir component): FDA-approved dose and Health Canada-approved dose are approximately equivalent to lopinavir 300 mg/m2 per dose:

Oral solution:

<15 kg: 13 mg/kg twice daily

15 to 45 kg: 11 mg/kg twice daily

>45 kg: Refer to adult dosing.

Tablets:

<15 kg: Tablets are not recommended.

15 kg to 20 kg: Lopinavir 200 mg/ritonavir 50 mg twice daily

>20 kg to 30 kg: Lopinavir 300 mg/ritonavir 75 mg twice daily

>30 kg to 45 kg: Lopinavir 400 mg/ritonavir 100 mg twice daily

>45 kg: Refer to adult dosing.

Once-daily dosing: Not recommended in children.

Dosing: Renal Impairment

Has not been studied in patients with renal impairment; however, a decrease in clearance is not expected.

Hemodialysis: Avoid once-daily dosing in hemodialysis patients (HHS [adult] 2015)

Dosing: Hepatic Impairment

Use caution in hepatic impairment (metabolized primarily by the liver).

Mild-to-moderate impairment: Mild-to-moderate impairment: There are no dosage adjustments provided in the manufacturer’s labeling; however, lopinavir is primarily metabolized by the liver and its AUC may be increased ~30%; use with caution.

Severe impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Administration

Solution: Must be administered with food; if using didanosine, take didanosine 1 hour before or 2 hours after lopinavir/ritonavir. Administer using calibrated dosing syringe.

Tablet: May be taken with or without food. Swallow whole, do not break, crush, or chew. May be taken with didanosine when taken without food. Tablets are not recommended in patients <15 kg.

Dietary Considerations

Solution must be taken with food. Tablet may be taken with or without food

Storage

Oral solution: Store at 2°C to 8°C (36°F to 46°F). Avoid exposure to excessive heat. If stored at room temperature (25°C or 77°F), use within 2 months.

Tablet: Store at USP controlled room temperature of 20°C to 25°C (68°F to 77°F). Exposure to high humidity outside of the original container for >2 weeks is not recommended.

Drug Interactions

Abacavir: Protease Inhibitors may decrease the serum concentration of Abacavir. Monitor therapy

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. Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Alfuzosin: Protease Inhibitors may increase the serum concentration of Alfuzosin. Avoid combination

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. Consider therapy modification

Alitretinoin (Systemic): CYP2C8 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP2C8 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP2C8 inhibitor. Consider therapy modification

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. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

ALPRAZolam: Protease Inhibitors may increase the serum concentration of ALPRAZolam. Management: Seek alternatives to alprazolam in patients treated with HIV protease inhibitors. Concurrent use of alprazolam with indinavir is contraindicated. All patients receiving such a combination should be monitored closely for excessive response to alprazolam. Consider therapy modification

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. Avoid combination

Amiodarone: 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. Avoid combination

AmLODIPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of AmLODIPine. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antihepaciviral Combination Products: Lopinavir may increase the serum concentration of Antihepaciviral Combination Products. Specifically, the serum concentrations of the paritaprevir component may increase significantly. Avoid combination

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. Consider therapy modification

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

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. Consider therapy modification

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. Consider therapy modification

Astemizole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: Protease Inhibitors may increase the serum concentration of AtorvaSTATin. Management: See full monograph for recommended dose limits. Avoid atorvastatin with tipranavir/ritonavir. Consider therapy modification

Atovaquone: Ritonavir may decrease the serum concentration of Atovaquone. Avoid combination

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

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. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

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). Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Boceprevir: May decrease the serum concentration of Protease Inhibitors. Protease Inhibitors may decrease the serum concentration of Boceprevir. Management: Some combinations are not recommended. See full drug interaction monograph for details. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

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. Monitor therapy

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. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination

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. Consider therapy modification

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. Monitor therapy

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. Monitor therapy

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. Consider therapy modification

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. Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy

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. Consider therapy modification

Canagliflozin: Ritonavir may decrease the serum concentration of Canagliflozin. Management: Consider increasing canagliflozin dose to 300 mg/day in patients with estimated GFR >60 mL/min/1.73 m2 who tolerate canagliflozin 100 mg/day and require greater glycemic control. Consider alternatives in patients with estimated GFR 45-60 mL/min/1.73 m2. Consider therapy modification

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

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. Consider therapy modification

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. Consider therapy modification

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. Avoid combination

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. Consider therapy modification

Cisapride: Protease Inhibitors may increase the serum concentration of Cisapride. This may result in QTc prolongation and malignant cardiac arrhythmias. Avoid combination

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. Avoid combination

Clobetasone: Ritonavir may increase the serum concentration of Clobetasone. Avoid combination

Clorazepate: Ritonavir may increase the serum concentration of Clorazepate. Monitor therapy

Cobicistat: May enhance the therapeutic effect of Ritonavir. Specifically, cobicistat and ritonavir have overlapping effects on the CYP3A4-mediated metabolism of other drugs. Avoid combination

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

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. Consider therapy modification

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. Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Contraceptives (Estrogens): Protease Inhibitors may decrease the serum concentration of Contraceptives (Estrogens). 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. Consider therapy modification

Contraceptives (Progestins): Lopinavir may decrease the serum concentration of Contraceptives (Progestins). Lopinavir may increase the serum concentration of Contraceptives (Progestins). 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. Consider therapy modification

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). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

Cyclophosphamide: Protease Inhibitors may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, the incidences of neutropenia, infection, and mucositis may be increased. Monitor therapy

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. Consider therapy modification

CYP2B6 Substrates: CYP2B6 Inducers (Moderate) may decrease the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2C19 Substrates: CYP2C19 Inducers (Strong) may increase the metabolism of CYP2C19 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Strong) may decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); AmLODIPine; Buprenorphine; Gefitinib; HYDROcodone; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification

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. Consider therapy modification

Dabrafenib: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

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. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Darunavir: Lopinavir may decrease the serum concentration of Darunavir. Darunavir may increase the serum concentration of lopinavir Avoid combination

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

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. Consider therapy modification

Delavirdine: Protease Inhibitors may decrease the serum concentration of Delavirdine. Delavirdine may increase the serum concentration of Protease Inhibitors. Consider therapy modification

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. Consider therapy modification

Digoxin: Protease Inhibitors may increase the serum concentration of Digoxin. Increased serum concentrations of digoxin may increase risk of AV nodal blockade. Monitor therapy

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 disulfiram-alcohol reaction if combined. Avoid combination

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 disulfiram-alcohol reaction if combined. Avoid combination

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

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. Consider therapy modification

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. Consider therapy modification

Dronabinol: Ritonavir may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

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 inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

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. Consider therapy modification

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

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. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

Enfuvirtide: Protease Inhibitors may increase the serum concentration of Enfuvirtide. Enfuvirtide may increase the serum concentration of Protease Inhibitors. Monitor therapy

Enzalutamide: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Enzalutamide. Management: Avoid concurrent use of strong CYP2C8 inhibitors and enzalutamide if possible. If the combination must be used, reduce enzalutamide to 80 mg once daily. Avoid combination

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Ergot Derivatives: Protease Inhibitors may increase the serum concentration of Ergot Derivatives. Exceptions: Nicergoline. Avoid combination

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). Consider therapy modification

Estazolam: Ritonavir may increase the serum concentration of Estazolam. Monitor therapy

Estriol (Systemic): Ritonavir may decrease the serum concentration of Estriol (Systemic). Monitor therapy

Estriol (Topical): Ritonavir may decrease the serum concentration of Estriol (Topical). Monitor therapy

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). Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

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. Consider therapy modification

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. Consider therapy modification

Flecainide: Ritonavir may increase the serum concentration of Flecainide. Avoid combination

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): Ritonavir may increase the serum concentration of Fluticasone (Nasal). Avoid combination

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. Consider therapy modification

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) Avoid combination

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. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Fosphenytoin. Consider therapy modification

Fusidic Acid (Systemic): Ritonavir may increase the serum concentration of Fusidic Acid (Systemic). Fusidic Acid (Systemic) may increase the serum concentration of Ritonavir. Avoid combination

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. Consider therapy modification

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

Grazoprevir: Lopinavir may increase the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Idelalisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib. Monitor therapy

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Indapamide: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Consider therapy modification

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. Avoid combination

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. Avoid combination

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. Consider therapy modification

Itraconazole: Ritonavir may increase the serum concentration of Itraconazole. Management: Limit the adult maximum itraconazole dose to 200 mg/day in patients receiving ritonavir. Consider therapy modification

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

LamoTRIgine: Ritonavir may decrease the serum concentration of LamoTRIgine. Consider therapy modification

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. Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

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. Consider therapy modification

Linagliptin: Ritonavir may increase the serum concentration of Linagliptin. Monitor therapy

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lovastatin: Protease Inhibitors may increase the serum concentration of Lovastatin. Avoid combination

Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

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. Consider therapy modification

Meperidine: Protease Inhibitors may enhance the adverse/toxic effect of Meperidine. Protease Inhibitors may decrease the serum concentration of Meperidine. Concentrations of the toxic Normeperidine metabolite may be increased. Consider therapy modification

Methadone: May enhance the QTc-prolonging effect of Lopinavir. Lopinavir may decrease the serum concentration of Methadone. More specifically, the combination of Lopinavir and Ritonavir may decrease Methadone serum concentrations. Avoid combination

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. Consider therapy modification

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. Avoid combination

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. Monitor therapy

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. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

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. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

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. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

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 such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may increase significantly. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

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. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

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.). Monitor therapy

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.). Monitor therapy

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. Consider therapy modification

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. Consider therapy modification

Phenytoin: May decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin. Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Protease Inhibitors may increase the serum concentration of Pimozide. Avoid combination

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pioglitazone: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Pioglitazone. Management: Limit pioglitazone adult maximum dose to 15 mg/day when used in combination with any strong CYP2C8 inhibitor. Consider therapy modification

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. Consider therapy modification

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Monitor therapy

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. Consider therapy modification

PredniSONE: Ritonavir may increase the serum concentration of PredniSONE. Monitor therapy

Proguanil: Ritonavir may decrease the serum concentration of Proguanil. Monitor therapy

Propafenone: Ritonavir may increase the serum concentration of Propafenone. Avoid combination

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. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

QuiNIDine: Ritonavir may increase the serum concentration of QuiNIDine. Avoid combination

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. Avoid combination

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. Avoid combination

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. Avoid combination

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

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. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

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. Monitor therapy

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. Consider therapy modification

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. Consider therapy modification

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. Avoid combination

RifAMPin: May decrease the serum concentration of Ritonavir. Avoid combination

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rilpivirine: Lopinavir may increase the serum concentration of Rilpivirine. Monitor therapy

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. Consider therapy modification

Rivaroxaban: Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Rivaroxaban. Avoid combination

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. Consider therapy modification

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

Saquinavir: May enhance the QTc-prolonging effect of Lopinavir. Avoid combination

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simeprevir: Protease Inhibitors may increase the serum concentration of Simeprevir. Simeprevir may increase the serum concentration of Protease Inhibitors. Avoid combination

Simvastatin: Protease Inhibitors may increase the serum concentration of Simvastatin. Avoid combination

Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

St John's Wort: May increase the metabolism of Protease Inhibitors. Avoid combination

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

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. Consider therapy modification

Tacrolimus (Topical): Protease Inhibitors may decrease the metabolism of Tacrolimus (Topical). Monitor therapy

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. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Telaprevir: Lopinavir may decrease the serum concentration of Telaprevir. Avoid combination

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. Consider therapy modification

Tenofovir Disoproxil Fumarate: Lopinavir may enhance the nephrotoxic effect of Tenofovir Disoproxil Fumarate. Lopinavir may increase the serum concentration of Tenofovir Disoproxil Fumarate. Monitor therapy

Terfenadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Theophylline Derivatives: Protease Inhibitors may decrease the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy

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. Avoid combination

Tipranavir: May decrease the serum concentration of Protease Inhibitors. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

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. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: Ritonavir may decrease serum concentrations of the active metabolite(s) of TraMADol. Ritonavir may increase the serum concentration of TraMADol. Monitor therapy

TraZODone: Lopinavir may enhance the QTc-prolonging effect of TraZODone. Lopinavir may increase the serum concentration of TraZODone. Management: Avoid this combination when possible due to the potential for enhanced QT prolongation. If used, consider decreasing the trazodone dose and monitor closely for toxicity. Avoid combination

Treprostinil: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Treprostinil. Management: Reduce the initial treprostinil extended release tablet dose to 0.125 mg twice daily, titrating by 0.125 mg twice daily every 3 to 4 days. No preemptive dose adjustment is recommended for other treprostinil products. Consider therapy modification

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). Monitor therapy

Triazolam: Protease Inhibitors may increase the serum concentration of Triazolam. Avoid combination

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination

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. Avoid combination

Valproate Products: Protease Inhibitors may decrease the serum concentration of Valproate Products. Monitor therapy

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. Consider therapy modification

Velpatasvir: CYP2B6 Inducers (Moderate) may decrease the serum concentration of Velpatasvir. Avoid combination

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

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. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination

Vinflunine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

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. Avoid combination

Voriconazole: Lopinavir may decrease the serum concentration of Voriconazole. Avoid combination

Warfarin: Lopinavir may decrease the serum concentration of Warfarin. Monitor therapy

Warfarin: Ritonavir may decrease the serum concentration of Warfarin. Monitor therapy

Zidovudine: Protease Inhibitors may decrease the serum concentration of Zidovudine. Monitor therapy

Zolpidem: Ritonavir may increase the serum concentration of Zolpidem. Monitor therapy

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. Consider therapy modification

Adverse Reactions

Data presented for short- and long-term combination antiretroviral therapy in both protease inhibitor experienced and naïve patients.

>10%:

Dermatologic: Skin rash (children 12%; adults ≤5%)

Endocrine & metabolic: Hypercholesterolemia (3% to 39%), increased serum triglycerides (3% to 36%), increased gamma-glutamyl transferase (10% to 29%)

Gastrointestinal: Diarrhea (7% to 28%; greater with once-daily dosing), dysgeusia (children 22%; adults <2%), vomiting (children 21%; adults 2% to 7%), nausea (5% to 16%), abdominal pain (1% to 11%)

Hepatic: Increased serum ALT (grade 3/4: 1% to 11%)

Respiratory: Upper respiratory tract infection (14%)

>2% to 10%:

Cardiovascular: Vasodilation (≤3%)

Central nervous system: Fatigue (8%, including weakness), headache (2% to 6%), anxiety (4%), insomnia (≤4%)

Dermatologic: Skin infection (3%, including cellulitis, folliculitis, furuncle)

Endocrine & metabolic: Hypertriglyceridemia (6%), hyperglycemia (≤5%), hyperuricemia (≤5%), alteration in sodium (children 3%), weight loss (≤3%)

Gastrointestinal: Increased serum amylase (3% to 8%), dyspepsia (≤6%), increased serum lipase (3% to 5%), flatulence (1% to 4%), gastroenteritis (3%)

Hematologic & oncologic: Thrombocytopenia (grade 3/4: 4% children), neutropenia (grade 3/4: 1% to 5%)

Hepatic: Increased serum AST (grade 3/4: 2% to 10%), hepatitis (4%, including increased AST, ALT, and gamma-glutamyl transferase), increased serum bilirubin (children 3%; adults 1%)

Hypersensitivity: Hypersensitivity (3%, including urticaria and angioedema)

Neuromuscular & skeletal: Weakness (≤9%), musculoskeletal pain (6%)

Respiratory: Lower respiratory tract infection (8%)

≤2% (Limited to important or life-threatening): Acne vulgaris, alopecia, amenorrhea, amnesia, anemia, anorexia, asthma, atherosclerotic disease, atrial fibrillation, atrioventricular block (second and third degree), atrophic striae, bacterial infection, benign neoplasm, bradycardia, brain disease, breast hypertrophy, bronchitis, cerebral infarction, cerebrovascular accident, cholangitis, cholecystitis, confusion, Cushing's syndrome, cyst, decreased creatinine clearance, decreased glucose tolerance, deep vein thrombosis, dehydration, depression, dermal ulcer, diabetes mellitus, duodenitis, dyskinesia, eczema, edema, enteritis, enterocolitis, erythema multiforme, exfoliative dermatitis, extrapyramidal reaction, facial paralysis, fecal incontinence, first degree atrioventricular block, gastritis, gastroesophageal reflux disease, gastrointestinal hemorrhage, gastrointestinal ulcer, gynecomastia, hematuria, hemorrhagic colitis, hemorrhoids, hepatic insufficiency, hepatomegaly, hyperacusis, hyperhidrosis, hypermenorrhea, hypersensitivity reaction, hypertension, hypertonia, hypogonadism (males), hypophosphatemia, hypothyroidism, immune reconstitution syndrome, impotence, jaundice, lactic acidosis, leukopenia, lipoma, liver steatosis, liver tenderness, lymphadenopathy, maculopapular rash, migraine, myocardial infarction, neoplasm, nephritis, neuropathy, obesity, oral mucosa ulcer, orthostatic hypotension, osteonecrosis, otitis media, pancreatitis, periodontitis, peripheral edema, peripheral neuropathy, prolonged Q-T interval on ECG, propylene glycol toxicity (preterm neonates [includes cardiomyopathy, lactic acidosis, acute renal failure, respiratory complications]), pulmonary edema, rectal hemorrhage, redistribution of body fat (including facial wasting), renal failure, rhabdomyolysis, seborrhea, seizure, sialadenitis, skin discoloration, splenomegaly, Stevens-Johnson syndrome, stomatitis, thrombophlebitis, torsades de pointes, tricuspid regurgitation, vasculitis, viral infection, vitamin deficiency, weight gain

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: May alter cardiac conduction and prolong the QTc and/or PR interval; second and third degree AV block and torsade de pointes have been observed. Use with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease or cardiomyopathies. Avoid use in combination with QTc- or PR-interval prolonging drugs or in patients with hypokalemia or congenital long QT syndrome.

• Cardiovascular concerns: Possible higher risk of myocardial infarction associated with the cumulative use of lopinavir/ritonavir; consider avoiding lopinavir/ritonavir-based regimens in patients with high cardiac risk (Bavinger 2013; HHS [adult] 2015).

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

• Increased cholesterol: Increases in total cholesterol and triglycerides have been reported; screening should be done prior to therapy and periodically throughout treatment.

Disease-related concerns:

• Diabetes: Changes in glucose tolerance, hyperglycemia, exacerbation of diabetes, DKA, and new-onset diabetes mellitus have been reported in patients receiving protease inhibitors.

• Hemophilia A or B: Use with caution in patients with hemophilia A or B; increased bleeding during protease inhibitor therapy has been reported.

• Hepatic impairment: May cause hepatitis and/or exacerbate pre-existing hepatic dysfunction; use with caution in patients with underlying hepatic disease, such as hepatitis B or C, cirrhosis, or unspecified hepatic impairment. Consider more frequent liver function test monitoring during therapy initiation in patients with pre-existing hepatic dysfunction.

• Pancreatitis: Use with caution in patients with increased triglycerides; pancreatitis has been observed. Patients with history of pancreatitis or advanced HIV-1 disease may be at increased risk. Monitor for clinical symptoms (nausea, vomiting, abdominal pain) and serum lipase and amylase.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatric: Safety, efficacy, and pharmacokinetic profiles of lopinavir and ritonavir have not been established for neonates <14 days of age. Neonates <14 days of age, particularly preterm neonates, are at risk for developing propylene glycol toxicity with use of the lopinavir/ritonavir oral solution. Oral solution contains ethanol and propylene glycol; ethanol competitively inhibits propylene glycol metabolism. Postmarketing reports in preterm neonates following use of the oral solution include cardiotoxicity (complete AV block, bradycardia, cardiomyopathy), lactic acidosis, CNS depression, respiratory complications, acute renal failure, and death. The oral solution should not be used in the immediate postnatal period, including full-term neonates age <14 days or preterm neonates until 14 days after their due date, unless the infant is closely monitored and benefits clearly outweigh risk. Once-daily dosing (oral solution or tablets) is not an approved regimen for children <18 years of age.

Dosage form specific issues:

• Oral solution: The oral solution is highly concentrated and contains large amounts of ethanol (42.4%) and propylene glycol (15.3%). Monitor patients with renal impairment or with decreased ability to metabolize propylene glycol (eg, patients of Asian origin) for propylene glycol toxicity (eg, seizures tachycardia, lactic acidosis, hyperosmolarity, stupor, hemolysis). Health care providers should pay special attention to accurate calculation, measurement, and administration of dose. Overdose (or cumulative ethanol or propylene glycol content in medications) in a child may lead to lethal ethanol or propylene glycol toxicity. Oral solution also contains fructose; consider fructose content in patients with fructose intolerance.

Other warnings/precautions:

• Appropriate use: Once-daily dosing is not recommended in patients with ≥3 of the following lopinavir-resistance-associated amino acid substitutions in protease (L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V); those receiving efavirenz, fosamprenavir, nevirapine, or nelfinavir, carbamazepine, phenobarbital, phenytoin, or in children <18 years of age.

Monitoring Parameters

Prior to therapy, consider genotypic or phenotypic testing for lopinavir resistance-associated substitutions.

Triglycerides and cholesterol (prior to initiation then periodically thereafter), LFTs, electrolytes, basic HIV monitoring, viral load and CD4 count, glucose

Pregnancy Considerations

Lopinavir/ritonavir has a low level of transfer across the human placenta. Based on information collected by the Antiretroviral Pregnancy Registry, an increased risk of teratogenic effects has not been observed in humans. A small increased risk of preterm birth has been associated with maternal use of protease inhibitor-based combination antiretroviral (ARV) therapy during pregnancy; however, the benefits of use generally outweigh this risk and protease inhibitors (PIs) should not be withheld if otherwise recommended. Hyperglycemia, new onset of diabetes mellitus, or diabetic ketoacidosis have been reported with PIs; it is not clear if pregnancy increases this risk.

Although there is an abundance of data related to the use of lopinavir/ritonavir during pregnancy, the HHS Perinatal HIV Guidelines consider lopinavir/ritonavir to be an alternative protease inhibitor for use in antiretroviral-naive pregnant women due to the need for twice daily dosing and increased incidence of nausea. Lopinavir/ritonavir is not recommended for use in pregnant women with lopinavir-resistance-associated amino acid substitutions. In addition, once-daily dosing is not recommended during pregnancy and use of the oral solution should be avoided (due to alcohol and propylene glycol content). Pharmacokinetic studies suggest that standard dosing during pregnancy may provide decreased plasma concentrations; dose adjustments are required in pregnant women.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV-infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience back pain, joint pain, muscle pain, headache, abdominal pain, diarrhea, or loss of strength and energy. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), angina, tachycardia, arrhythmia, dizziness, passing out, severe nausea, severe vomiting, bruising, bleeding, change in fat, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Hide