Get your patient on Lopinavir - Ritonavir - Lopinavir - Ritonavir solution (Lopinavir-Ritonavir)

Lopinavir and Ritonavir Dosage Form

Recommended Dosage

80 mg/20 mg per mL Oral Solution

800 mg/200 mg (10 mL) once daily

Lopinavir and Ritonavir Dosage Form

Recommended Dosage

80 mg/20 mg per mL Oral Solution

400 mg/100 mg (5 mL) twice daily

Lopinavir and Ritonavir Dosage Form

Recommended Dosage

80 mg/20 mg per mL Oral Solution

520 mg/130 mg (6.5 mL) twice daily

Based on Weight (mg/kg)

Patient Age

Based on Weight
(mg/kg)

Based on BSA
(mg/m ² )

Frequency

> 6 months to < 18 years

<15 kg

13/3.25

300/75

Given twice daily

≥15 kg to 45 kg

11/2.75

System Organ Class (SOC) and Adverse Reaction

n

%

BLOOD AND LYMPHATIC SYSTEM DISORDERS

anemia•

54

2.1

leukopenia and neutropenia•

44

1.7

lymphadenopathy•

35

1.3

CARDIAC DISORDERS

atherosclerosis such as myocardial infarction•

10

0.4

atrioventricular block•

3

0.1

tricuspid valve incompetence•

3

0.1

EAR AND LABYRINTH DISORDERS

vertigo•

7

0.3

tinnitus

6

0.2

ENDOCRINE DISORDERS

hypogonadism•

16

0.8 ¹

EYE DISORDERS

visual impairment•

8

0.3

GASTROINTESTINAL DISORDERS

diarrhea•

510

19.5

nausea

269

10.3

vomiting•

177

6.8

abdominal pain (upper and lower)•

160

6.1

gastroenteritis and colitis•

66

2.5

dyspepsia

53

2.0

pancreatitis•

45

1.7

Gastroesophageal Reflux Disease (GERD)•

40

1.5

hemorrhoids

39

1.5

flatulence

36

1.4

abdominal distension

34

1.3

constipation•

26

1.0

stomatitis and oral ulcers•

24

0.9

duodenitis and gastritis•

20

0.8

gastrointestinal hemorrhage including rectal hemorrhage•

13

0.5

dry mouth

9

0.3

gastrointestinal ulcer•

6

0.2

fecal incontinence

5

0.2

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS

fatigue including asthenia•

198

7.6

HEPATOBILIARY DISORDERS

hepatitis including AST, ALT, and GGT increases•

91

3.5

hepatomegaly

5

0.2

cholangitis

3

0.1

hepatic steatosis

3

0.1

IMMUNE SYSTEM DISORDERS

hypersensitivity including urticaria and angioedema•

70

2.7

immune reconstitution syndrome

3

0.1

INFECTIONS AND INFESTATIONS

upper respiratory tract infection•

363

13.9

lower respiratory tract infection•

202

7.7

skin infections including cellulitis, folliculitis, and furuncle•

86

3.3

METABOLISM AND NUTRITION DISORDERS

hypercholesterolemia•

192

7.4

hypertriglyceridemia•

161

6.2

weight decreased•

61

2.3

decreased appetite

52

2.0

blood glucose disorders including diabetes mellitus•

30

1.1

weight increased•

20

0.8

lactic acidosis•

11

0.4

increased appetite

5

0.2

MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS

musculoskeletal pain including arthralgia and back pain•

166

6.4

myalgia•

46

1.8

muscle disorders such as weakness and spasms•

34

1.3

rhabdomyolysis•

18

0.7

osteonecrosis

3

0.1

NERVOUS SYSTEM DISORDERS

headache including migraine•

165

6.3

insomnia•

99

3.8

neuropathy and peripheral neuropathy•

51

2.0

dizziness•

45

1.7

ageusia•

19

0.7

convulsion•

9

0.3

tremor•

9

0.3

cerebral vascular event•

6

0.2

PSYCHIATRIC DISORDERS

anxiety•

101

3.9

abnormal dreams•

19

0.7

libido decreased

19

0.7

RENAL AND URINARY DISORDERS

renal failure•

31

1.2

hematuria•

20

0.8

nephritis•

3

0.1

REPRODUCTIVE SYSTEM AND BREAST DISORDERS

erectile dysfunction•

34

1.7 ¹

menstrual disorders - amenorrhea, menorrhagia•

10

1.7 ²

SKIN AND SUBCUTANEOUS TISSUE DISORDERS

rash including maculopapular rash•

99

3.8

lipodystrophy acquired including facial wasting•

58

2.2

dermatitis/rash including eczema and seborrheic dermatitis•

50

1.9

night sweats•

42

1.6

pruritus•

29

1.1

alopecia

10

0.4

capillaritis and vasculitis•

3

0.1

VASCULAR DISORDERS

hypertension•

47

1.8

deep vein thrombosis•

17

0.7

^{1.000000000000000e+00} Percentage of male population (N=2,038)

^{2.000000000000000e+00} Percentage of female population (N=574)

Study 863
(48 Weeks)

Study 730
(48 Weeks)

Variable

Limit ¹

Lopinavir and Ritonavir
400/100 mg
Twice Daily + d4T + 3TC
(N=326)

Nelfinavir
750 mg Three Times Daily + d4T + 3TC
(N=327)

Lopinavir and Ritonavir
Twice Daily + d4T + 3TC
(N=100)

Lopinavir and Ritonavir
Once Daily + TDF + FTC
(N=333)

Lopinavir and Ritonavir
Twice Daily + TDF + FTC
(N=331)

Chemistry

High

Glucose

>250 mg/dL

2%

2%

0%

<1%

Uric Acid

>12 mg/dL

2%

2%

5%

<1%

1%

SGOT/AST ²

>180 U/L

2%

4%

10%

1%

2%

SGPT/ALT ²

>215 U/L

4%

4%

1%

1%

GGT

>300 U/L

N/A

N/A

N/A

N/A

Total
Cholesterol

>300 mg/dL

9%

5%

4%

3%

Triglycerides

>750 mg/dL

9%

1%

3%

6%

Amylase

>2 x ULN

3%

2%

N/A

N/A

Lipase

>2 x ULN

N/A

N/A

3%

5%

Chemistry

Low

Calculated Creatinine Clearance

<50 mL/min

N/A

N/A

2%

2%

Neutrophils

<0.75 x 10 ⁹ /L

1%

2%

² Criterion for Study 730 was >5x ULN (AST/ALT).

Study 888
(48 Weeks)

Study 957 ² and Study 765 ³
(84-144 Weeks)

Study 802
(48 Weeks)

Variable

Limit ¹

Lopinavir and
Ritonavir
400/100 mg Twice Daily + NVP + NRTIs
(N=148)

Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs
(N=140)

Lopinavir and
Ritonavir
Twice Daily + NNRTI + NRTIs
(N=127)

Lopinavir and
Ritonavir
800/200 mg Once Daily
+ NRTIs
(N=300)

Lopinavir and
Ritonavir
400/100 mg Twice Daily
+ NRTIs
(N=299)

Chemistry

High

Glucose

>250 mg/dL

1%

2%

5%

2%

2%

Total Bilirubin

>3.48 mg/dL

1%

3%

1%

1%

1%

SGOT/AST ⁴

>180 U/L

5%

11%

8%

3%

2%

SGPT/ALT ⁴

>215 U/L

6%

13%

10%

2%

2%

GGT

>300 U/L

N/A

N/A

29%

N/A

N/A

Total
Cholesterol

>300 mg/dL

20%

21%

39%

6%

7%

Triglycerides

>750 mg/dL

25%

21%

36%

5%

6%

Amylase

>2 x ULN

4%

8%

8%

4%

4%

Lipase

>2 x ULN

N/A

N/A

N/A

4%

1%

Creatine
Phosphokinase

>4 x ULN

N/A

N/A

N/A

4%

5%

Chemistry

Low

Calculated
Creatinine
Clearance

<50 mL/min

N/A

N/A

N/A

3%

3%

Inorganic
Phosphorus

<1.5 mg/dL

1%

0%

2%

1%

<1%

Hematology

Low

Neutrophils

<0.75 x 10 ⁹ /L

1%

2%

4%

3%

4%

Hemoglobin

<80 g/L

1%

1%

1%

1%

2%

² Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n=29) or 533/133 mg twice daily (n=28) for 84 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and efavirenz.

₃ Includes clinical laboratory data from patients receiving 400/100 mg twice daily (n=36) or 400/200 mg twice daily (n=34) for 144 weeks. Patients received lopinavir and ritonavir in combination with NRTIs and nevirapine.

⁴ Criterion for Study 802 was >5x ULN (AST/ALT).

Variable

Limit ¹

Lopinavir and Ritonavir
Twice Daily + RTIs
(N=100)

Chemistry

High

Sodium

>149 mEq/L

3%

Total Bilirubin

≥3.0 x ULN

3%

SGOT/AST

>180 U/L

8%

SGPT/ALT

>215 U/L

7%

Total Cholesterol

>300 mg/dL

3%

Amylase

>2.5 x ULN

7% ²

Chemistry

Low

Sodium

<130 mEq/L

3%

Hematology

Low

Platelet Count

<50 x 10 ⁹ /L

4%

Neutrophils

<0.40 x 10 ⁹ /L

2%

² Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase.

Concomitant Drug Class:

Drug Name

Effect on Concentration of Lopinavir or Concomitant Drug

Clinical Comments

HIV-1 Antiviral Agents

HIV-1 Protease Inhibitor:

fosamprenavir/ritonavir

↓amprenavir

↓lopinavir

An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor:

indinavir•

↑ indinavir

Decrease indinavir dose to 600 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with indinavir.

HIV-1 Protease Inhibitor:

nelfinavir•

↑ nelfinavir

↑ M8 metabolite of nelfinavir

↓ lopinavir

Lopinavir and ritonavir once daily in combination with nelfinavir is not recommended [see Dosage and Administration (2 )] .

HIV-1 Protease Inhibitor:

ritonavir•

↑ lopinavir

Appropriate doses of additional ritonavir in combination with lopinavir and ritonavir with respect to safety and efficacy have not been established.

HIV-1 Protease Inhibitor:

saquinavir

↑ saquinavir

The saquinavir dose is 1000 mg twice daily, when co-administered with lopinavir and ritonavir 400/100 mg twice daily. Lopinavir and ritonavir once daily has not been studied in combination with saquinavir.

HIV-1 Protease Inhibitor:

tipranavir•

↓ lopinavir

Co-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.

HIV CCR5 – Antagonist:

maraviroc•

↑ maraviroc

When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc.

Non-nucleoside Reverse Transcriptase Inhibitors:

efavirenz•,

nevirapine•

↓ lopinavir

Increase the dose of lopinavir and ritonavir tablets to 500/125 mg when lopinavir and ritonavir tablet is co-administered with efavirenz or nevirapine. Lopinavir and ritonavir once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration (2 )] .

Non-nucleoside Reverse Transcriptase Inhibitor:

delavirdine

↑ lopinavir

Appropriate doses of the combination with respect to safety and efficacy have not been established.

Nucleoside Reverse Transcriptase Inhibitor:

didanosine

For lopinavir and ritonavir oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after lopinavir and ritonavir oral solution (given with food).

Nucleoside Reverse Transcriptase Inhibitor:

tenofovir disoproxil fumarate•

↑ tenofovir

Patients receiving lopinavir and ritonavir and tenofovir should be monitored for adverse reactions associated with tenofovir.

Nucleoside Reverse Transcriptase Inhibitors:

abacavir

zidovudine

↓ abacavir

↓ zidovudine

The clinical significance of this potential interaction is unknown.

Other Agents

Alpha 1- Adrenoreceptor Antagonist:

Antianginal:

Antiarrhythmics:     dronedarone

amiodarone,

bepridil,

lidocaine (systemic),

Anticancer Agents:

abemaciclib,

apalutamide,

encorafenib,

ibrutinib,

ivosidenib,

dasatinib,

neratinib,

nilotinib,

venetoclax,

vinblastine,

vincristine

↑ anticancer agents

↓ lopinavir/ritonavir ^#

Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors [see Contraindications ( 4 )] .

Avoid co-administration of encorafenib or ivosidenib with lopinavir and ritonavir due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with lopinavir and ritonavir cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with lopinavir and ritonavir cannot be avoided, reduce ivosidenib dose to 250 mg once daily.

Avoid use of neratinib, venetoclax or ibrutinib with lopinavir and ritonavir.

For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when lopinavir and ritonavir is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.

A decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as lopinavir and ritonavir. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions.

Anticoagulants:

warfarin,

rivaroxaban

↑↓ warfarin

↑ rivaroxaban

Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during lopinavir and ritonavir and warfarin co-administration is recommended.

Avoid concomitant use of rivaroxaban and lopinavir and ritonavir. Co-administration of lopinavir and ritonavir and rivaroxaban may lead to risk of increased bleeding.

Anticonvulsants:

carbamazepine,

phenobarbital,

phenytoin

↓ lopinavir

↓ phenytoin

Lopinavir and ritonavir may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution.

Lopinavir and ritonavir once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended.

In addition, co-administration of phenytoin and lopinavir and ritonavir may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with lopinavir and ritonavir.

Anticonvulsants:

lamotrigine,

valproate

↓ lamotrigine

↓ or ↔ valproate

A dose increase of lamotrigine or valproate may be needed when co-administered with lopinavir and ritonavir and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments.

Antidepressant:

bupropion

↓ bupropion

↓ active metabolite,

hydroxybupropion

Patients receiving lopinavir and ritonavir and bupropion concurrently should be monitored for an adequate clinical response to bupropion.

Antidepressant:

trazodone

↑ trazodone

Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. A lower dose of trazodone should be considered.

Anti-infective:

clarithromycin

↑ clarithromycin

For patients with renal impairment, adjust clarithromycin dose as follows:

• For patients on lopinavir and ritonavir with CL _CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.

• For patients on lopinavir and ritonavir with CL _CR < 30 mL/min the dose of clarithromycin should be decreased by 75%.

No dose adjustment for patients with normal renal function is necessary.

Antifungals:

ketoconazole•,

itraconazole,

voriconazole

isavuconazonium sulfate•

↑ ketoconazole

↑ itraconazole

↓ voriconazole

↑ isavuconazonium

High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.

The co-administration of voriconazole and lopinavir and ritonavir should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.

Isavuconazonium and lopinavir and ritonavir should be co-administered with caution. Alternative antifungal therapies should be considered in these patients.

Anti-gout:

colchicine

↑ colchicine

Contraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications (4 )] .

For patients with normal renal or hepatic function:

Treatment of gout flares-co-administration of colchicine in patients on lopinavir and ritonavir :

0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.

Prophylaxis of gout flares-co-administration of colchicine in patients on lopinavir and ritonavir :

If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day.

If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.

Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on lopinavir and ritonavir :

Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

bedaquiline

↑ bedaquiline

Antimycobacterial:

rifabutin•

↑ rifabutin and rifabutin metabolite

Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.

Antiparasitic:

atovaquone

↓ atovaquone

Clinical significance is unknown; however, increase in atovaquone doses may be needed.

Antipsychotics:

lurasidone

↑ lurasidone

Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications (4 )] .

Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4 )] .

quetiapine

Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring.

Initiation of quetiapine in patients taking lopinavir and ritonavir:

Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine.

Contraceptive:

ethinyl estradiol•

felodipine,

nifedipine,

nicardipine

↑ dihydropyridine calcium channel blockers

Endothelin Receptor Antagonists:

bosentan

↑ bosentan

Co-administration of bosentan in patients on lopinavir and ritonavir:

In patients who have been receiving lopinavir and ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Co-administration of lopinavir and ritonavir in patients on bosentan:

Discontinue use of bosentan at least 36 hours prior to initiation of lopinavir and ritonavir.

After at least 10 days following the initiation of lopinavir and ritonavir, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.

Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine

Contraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4 )] .

↑ elagolix

Hepatitis C direct acting antiviral:       elbasvir/grazoprevir

↑

elbasvir/grazoprevir

Contraindicated due to increased risk of alanine transaminase (ALT) elevations [see Contraindications (4 )] .

Hepatitis C direct acting antivirals:

boceprevir•

glecaprevir/pibrentasvir

simeprevir

sofosbuvir/velpatasvir/ voxilaprevir

ombitasvir/paritaprevir/

ritonavir and dasabuvir•

↓ lopinavir

↓ boceprevir

↓ ritonavir

↑ glecaprevir

↑ pibrentasvir

↑ simeprevir

↑ sofosbuvir

↑ velpatasvir

↑ voxilaprevir

↑ ombitasvir

↑ paritaprevir

↑ ritonavir

↔ dasabuvir

It is not recommended to co-administer lopinavir and ritonavir and boceprevir, glecaprevir/pibrentasvir, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir.

Herbal Products:

Lipid-modifying agents

HMG-CoA Reductase Inhibitors:

lovastatin

simvastatin

atorvastatin

rosuvastatin

↑ lovastatin

↑ simvastatin

↑ atorvastatin

↑ rosuvastatin

Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications (4 )] .

Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day.

Lomitapide is a sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold.

Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications (4 )] .

Immunosuppressants: e.g.

cyclosporine,

tacrolimus,

↑

immunosuppressants

Kinase Inhibitors:

↑ fostamatinib

Long-acting beta-adrenoceptor Agonist:

salmeterol

↑ salmeterol

Concurrent administration of salmeterol and lopinavir and ritonavir is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.

Narcotic Analgesics:

methadone,•fentanyl

↓ methadone

↑ fentanyl

Dosage of methadone may need to be increased when co-administered with lopinavir and ritonavir.

Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with lopinavir and ritonavir.

PDE5 inhibitors:

avanafil,

sildenafil,

tadalafil,

vardenafil

↑ avanafil

↑ sildenafil

↑ tadalafil

↑ vardenafil

Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio ^® ) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications (4 )] .

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

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

Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH):

Sildenafil (Revatio ^® ) is contraindicated [see Contraindications (4 )] .

The following dose adjustments are recommended for use of tadalafil (Adcirca ^® ) with lopinavir and ritonavir:

Co-administration of ADCIRCA in patients on lopinavir and ritonavir :

In patients receiving lopinavir and ritonavir for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability.

Co-administration of lopinavir and ritonavir in patients on ADCIRCA:

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

Use of PDE5 inhibitors for erectile dysfunction:

It is recommended not to exceed the following doses:

• Sildenafil: 25 mg every 48 hours

• Tadalafil: 10 mg every 72 hours

• Vardenafil: 2.5 mg every 72 hours

Use with increased monitoring for adverse events.

↑ triazolam

Nasal/Ophthalmic

Corticosteroids: e.g.,

betamethasone

budesonide

ciclesonide         dexamethasone            fluticasone   methylprednisolone mometasone

prednisone

↓ lopinavir

Co-administration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression.

• see Clinical Pharmacology (12.3 ) for magnitude of interaction.

^# refers to interaction with apalutamide.

Absorption

T _max (hr) ^a

4.4 ± 0.8

Effect of meal

(relative to fasting)

Tablet

Oral Solution

↑ 19% ^b

↑ 130% ^b

Distribution

% Bound to human plasma proteins

> 98

V _d /F ^a (L)

16.9

Metabolism

Metabolism

CYP3A

Elimination

Major route of elimination

hepatic

t _1/2 (h) ^a

6.9 ± 2.2

% of dose excreted in urine

10.4 ± 2.3

% of dose excreted in feces

82.6 ± 2.5

^a. Lopinavir and ritonavir tablet

^b. Changes in AUC values

^a. 19 HIV-1 subjects, lopinavir and ritonavir 400/100 mg twice daily

C _max (μg/mL)

C _min (μg/mL)

AUC ₁₂ (μg•hr/m )

Age ≥ 14 Days to < 6 Weeks Cohort (N = 9):

5.17 ± 1.84 ^a

1.40 ± 0.48 ^a

43.39 ± 14.80 ^a

Age ≥ 6 Weeks to < 6 Months Cohort (N = 18):

9.39 ± 4.91 ^a

1.95 ± 1.80 ^a

74.50 ± 37.87 ^a

Age ≥ 6 Months to ≤ 12 years Cohort (N = 24):

8.2 ± 2.9 ^b

3.4 ± 2.1 ^b

72.6 ± 31.1 ^b

10.0 ± 3.3 ^c

3.6 ± 3.5 ^c

85.8 ± 36.9 ^c

^a. Lopinavir and ritonavir oral solution 300/75 mg/m ² twice daily without concomitant NNRTI therapy

^b. Lopinavir and ritonavir oral solution 230/57.5 mg/m ² twice daily without nevirapine (n=12)

^c. Lopinavir and ritonavir oral solution 300/75 mg/m ² twice daily with nevirapine (n=12)

Co-administered Drug

Dose of Co-administered Drug

(mg)

Dose of Lopinavir and

Ritonavir

(mg)

n

Ratio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00

C _max

AUC

C _min

Efavirenz ¹

600 at bedtime

400/100 capsule twice daily

11, 7 ³

0.97

(0.78, 1.22)

0.81

(0.64, 1.03)

0.61

(0.38, 0.97)

600 at bedtime

500/125 tablet

twice daily

19

1.12

(1.02, 1.23)

1.06

(0.96, 1.17)

0.90

(0.78, 1.04)

600 at bedtime

600/150 tablet

twice daily

23

1.36

(1.28, 1.44)

1.36

(1.28, 1.44)

1.32

(1.21, 1.44)

Etravirine

200 twice daily

400/100 mg twice day (tablets)

16

0.89

(0.82-0.96)

0.87

(0.83-0.92)

0.80

(0.73-0.88)

Fosamprenavir ²

700 twice daily plus ritonavir 100 twice daily

400/100 capsule twice daily

18

1.30

(0.85, 1.47)

1.37

(0.80, 1.55)

1.52

(0.72, 1.82)

Ketoconazole

200 single dose

400/100 capsule twice daily

12

0.89

(0.80, 0.99)

0.87

(0.75, 1.00)

0.75

(0.55, 1.00)

Nelfinavir

1000 twice daily

400/100 capsule twice daily

13

0.79

(0.70, 0.89)

0.73

(0.63, 0.85)

0.62

(0.49, 0.78)

Nevirapine

200 twice daily

steady-state

400/100 capsule twice daily

22, 19 ³

0.81

(0.62, 1.05)

0.73

(0.53, 0.98)

0.49

(0.28, 0.74)

7 mg/kg or 4 mg/kg once daily;

twice daily

1 wk ⁵

(> 1 yr) 300/75 mg/m ²

oral solution

twice daily

12, 15 ³

0.86

(0.64, 1.16)

0.78

(0.56, 1.09)

0.45

(0.25, 0.81)

Ombitasvir/

paritaprevir/

ritonavir+

dasabuvir ²

25/150/100 +

dasabuvir 400

400/100 tablet

twice daily

6

0.87

(0.76, 0.99)

0.94

(0.81, 1.10)

1.15

(0.93, 1.42)

Omeprazole

40 once daily, 5 d

400/100 tablet twice daily, 10 d

12

1.08

(0.99, 1.17)

1.07

(0.99, 1.15)

1.03

(0.90, 1.18)

40 once daily, 5 d

800/200 tablet once daily, 10 d

12

0.94

(0.88, 1.00)

0.92

(0.86, 0.99)

0.71

(0.57, 0.89)

Pravastatin

20 once daily, 4 d

400/100 capsule twice daily, 14 d

12

0.98

(0.89, 1.08)

0.95

(0.85, 1.05)

0.88

(0.77, 1.02)

Ranitidine

150 single dose

400/100 tablet twice daily, 10 d

12

0.99

(0.95, 1.03)

0.97

(0.93, 1.01)

0.90

(0.85, 0.95)

150 single dose

800/200 tablet once daily, 10 d

10

0.97

(0.95, 1.00)

0.95

(0.91, 0.99)

0.82

(0.74, 0.91)

Rifabutin

150 once daily

400/100 capsule twice daily

14

1.08

(0.97, 1.19)

1.17

(1.04, 1.31)

1.20

(0.96, 1.65)

Rifampin

600 once daily

400/100 capsule twice daily

22

0.45

(0.40, 0.51)

0.25

(0.21, 0.29)

0.01

(0.01, 0.02)

600 once daily

800/200 capsule twice daily

10

1.02

(0.85, 1.23)

0.84

(0.64, 1.10)

0.43

(0.19, 0.96)

600 once daily

400/400 capsule twice daily

9

0.93

(0.81, 1.07)

0.98

(0.81, 1.17)

1.03

(0.68, 1.56)

Rilpivirine

150 once daily

400/100 twice daily (capsules)

15

0.96

(0.88-1.05)

0.99

(0.89-1.10)

0.89

(0.73-1.08)

Ritonavir

100 twice daily

400/100 capsule twice daily

8, 21 ³

1.28

(0.94, 1.76)

1.46

(1.04, 2.06)

2.16

(1.29, 3.62)

Tipranavir/

ritonavir

500/200 twice daily

400/100 capsule twice daily

21

69 ³

0.53

(0.40, 0.69)

0.45

(0.32, 0.63)

0.30

(0.17, 0.51)

0.48 ⁴

(0.40, 0.58)

² Data extracted from the U.S. prescribing information of co-administered drugs.

³ Parallel group design

⁴ Drug levels obtained at 8-16 hours post dose

N/A = Not available.

Co-administered Drug

Dose of Co-administered Drug

(mg)

Dose of Lopinavir and

Ritonavir

(mg)

n

Ratio (in combination with Lopinavir and Ritonavir /alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00

C _max

AUC

C _min

Bedaquiline ¹

400 single dose

400/100 twice daily

N/A

N/A

1.22

(1.11, 1.34)

N/A

Efavirenz

600 at bedtime

400/100

capsule twice daily

11, 12 ³

0.91

(0.72, 1.15)

0.84

(0.62, 1.15)

0.84

(0.58, 1.20)

Elbasvir/

grazoprevir ¹

50 once daily

400/100

twice daily

10

2.87

(2.29, 3.58)

3.71

(3.05, 4.53)

4.58

(3.72, 5.64)

200 once daily

13

7.31

(5.65, 9.45)

12.86

(10.25, 16.13)

21.70

(12.99, 36.25)

Ethinyl

Estradiol

35 µg once daily

(Ortho Novum ^® )

400/100

capsule twice daily

12

0.59

(0.52, 0.66)

0.58

(0.54, 0.62)

0.42

(0.36, 0.49)

Etravirine

200 twice daily

400/100 tablet twice day

16

0.70

(0.64-0.78)

0.65

(0.59-0.71)

0.55

(0.49-0.62)

Fosamprenavir ¹

700 twice daily plus ritonavir 100 twice daily

400/100

capsule twice daily

18

0.42

(0.30, 0.58)

0.37

(0.28, 0.49)

0.35

(0.27, 0.46)

Indinavir

600 twice daily combo nonfasting vs. 800 three times daily alone fasting

400/100

capsule twice daily

13

0.71

(0.63, 0.81)

0.91

(0.75, 1.10)

3.47

(2.60, 4.64)

Ketoconazole

200 single dose

400/100

capsule twice daily

12

1.13

(0.91, 1.40)

3.04

(2.44, 3.79)

N/A

Maraviroc ¹

300 twice daily

400/100

twice daily

11

1.97

(1.66, 2.34)

3.95

(3.43, 4.56)

9.24

(7.98, 10.7)

Methadone

5 single dose

400/100

capsule twice daily

11

0.55

(0.48, 0.64)

0.47

(0.42, 0.53)

N/A

Nelfinavir

1000 twice daily combo vs. 1250 twice daily alone

400/100

capsule twice daily

13

0.93

(0.82, 1.05)

1.07

(0.95, 1.19)

1.86

(1.57, 2.22)

M8 metabolite

2.36

(1.91, 2.91)

3.46

(2.78, 4.31)

7.49

(5.85, 9.58)

Nevirapine

200 once daily twice daily

400/100

capsule twice daily

5,

6 ³

1.05

(0.72, 1.52)

1.08

(0.72, 1.64)

1.15

(0.71, 1.86)

Norethindrone

1 once daily

(Ortho Novum ^® )

400/100

capsule twice daily

12

0.84

(0.75, 0.94)

0.83

(0.73, 0.94)

0.68

(0.54, 0.85)

Ombitasvir/

paritaprevir/

ritonavir+

dasabuvir ¹

25/150/100 +

dasabuvir 400

400/100

tablet twice

daily

6

1.14

(1.01, 1.28)

1.17

(1.07, 1.28)

1.24

(1.14, 1.34)

2.04

(1.30, 3.20)

2.17

(1.63, 2.89)

2.36

(1.00, 5.55)

1.55

(1.16, 2.09)

2.05

(1.49, 2.81)

5.25

(3.33, 8.28)

0.99

(0.75, 1.31)

0.93

(0.75, 1.15)

0.68

(0.57, 0.80)

Pitavastatin ¹

4 once daily

400/100 tablet twice daily

23

0.96

(0.84-1.10)

0.80

(0.73-0.87)

N/A

Pravastatin

20 once daily

400/100 capsule twice daily

12

1.26

(0.87, 1.83)

1.33

(0.91, 1.94)

N/A

Rifabutin

150 once daily combo vs. 300 once daily alone

400/100 capsule twice daily

12

2.12

(1.89, 2.38)

3.03

(2.79, 3.30)

4.90

(3.18, 5.76)

25- O -desacetyl rifabutin

23.6

(13.7, 25.3)

47.5

(29.3, 51.8)

94.9

(74.0, 122)

Rifabutin + 25- O -desacetyl rifabutin

3.46

(3.07, 3.91)

5.73

(5.08, 6.46)

9.53

(7.56, 12.01)

Rilpivirine

150 once daily

400/100 capsules twice daily

15

1.29

(1.18-1.40)

1.52

(1.36-1.70)

1.74

(1.46-2.08)

Rosuvastatin ²

20 once daily

400/100 tablet twice daily

15

4.66

(3.4, 6.4)

2.08

(1.66, 2.6)

1.04

(0.9, 1.2)

Tenofovir

alafenamide ¹

10 once daily

800/200

tablet once daily

10

2.19

(1.72, 2.79)

1.47

(1.17, 1.85)

N/A

Tenofovir

disoproxil

fumarate ¹

300 once daily

400/100 capsule twice daily

24

No

Change

1.32

(1.26, 1.38)

1.51

(1.32, 1.66)

² Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8.

³ Parallel group design

N/A = Not available.

Susceptibility reduced by >4 fold

Susceptibility reduced to LPV

Indinavir (n=16)

5.7 fold

Nelfinavir (n=13)

<4 fold

Ritonavir (n=3)

8.32 fold

Saquinavir (n=4)

<4 fold

Number of protease inhibitor substitutions at baseline ¹

Study 888 (Single protease inhibitor-experienced ² , NNRTI-naïve) n=130

Study 765 (Single protease inhibitor-experienced ³ , NNRTI-naïve) n=56

Study 957 (Multiple protease inhibitor-experienced ⁴ , NNRTI-naïve) n=50

0-2

76/103 (74%)

34/45 (76%)

19/20 (95%)

3-5

13/26 (50%)

8/11 (73%)

18/26 (69%)

6 or more

0/1 (0%)

N/A

1/4 (25%)

² 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir.

³ 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir.

⁴ 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.

Lopinavir susceptibility ² at baseline

HIV-1 RNA <400 copies/mL (%)

HIV-1 RNA <50 copies/mL (%)

< 10 fold

25/27 (93%)

22/27 (81%)

> 10 and < 40 fold

11/15 (73%)

9/15 (60%)

≥ 40 fold

2/8 (25%)

2/8 (25%)

² Fold change in susceptibility from wild type.

Outcome

Lopinavir and Ritonavir +d4T+3TC
(N = 326)

Nelfinavir+d4T+3TC
(N = 327)

Responder ¹

75%

62%

Virologic failure ²

Rebound

Never suppressed through Week 48

9%

7%

2%

25%

15%

9%

Death

2%

1%

Discontinued due to adverse events

4%

4%

Discontinued for other reasons ³

10%

8%

² Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.

³ Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the lopinavir and ritonavir arm and 24% in the nelfinavir arm.

Baseline Viral Load
(HIV-1 RNA copies/mL)

Lopinavir and Ritonavir +d4T+3TC

Nelfinavir +d4T+3TC

<400 copies/mL ¹

<50 copies/mL ²

n

<400 copies/mL ¹

<50 copies/mL ²

n

< 30,000

74%

71%

82

79%

72%

87

≥ 30,000 to < 100,000

81%

73%

79

67%

54%

79

≥ 100,000 to < 250,000

75%

64%

83

60%

47%

72

≥ 250,000

72%

60%

82

44%

33%

89

² Patients achieved HIV-1 RNA < 50 copies/mL at Week 48.

Outcome

Lopinavir and Ritonavir Once Daily + TDF + FTC
(n = 333)

Lopinavir and Ritonavir Twice Daily + TDF + FTC
(n = 331)

Responder ¹

78%

77%

Virologic failure ²

Rebound

Never suppressed through Week 48

10%

5%

5%

8%

5%

3%

Death

1%

<1%

Discontinued due to adverse events

4%

3%

Discontinued for other reasons ³

8%

11%

² Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48.

³ Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.

Outcome

Lopinavir and Ritonavir + nevirapine + NRTIs
(n = 148)

Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs
(n = 140)

Responder ¹

57%

33%

Virologic failure ²

Rebound

Never suppressed through Week 48

24%

11%

13%

41%

19%

23%

Death

1%

2%

Discontinued due to adverse events

5%

11%

Discontinued for other reasons ³

14%

13%

² Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.

³ Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.

Outcome

Lopinavir and Ritonavir Once Daily + NRTIs
(n = 300)

Lopinavir and Ritonavir Twice Daily + NRTIs
(n = 299)

Virologic Success
(HIV-1 RNA <50 copies/mL)

57%

54%

Virologic failure ¹

22%

24%

No virologic data in Week 48 window

Discontinued study due to adverse event or death ²

5%

7%

Discontinued study for other reasons ³

13%

12%

Missing data during window but on study

3%

3%

² Includes patients who discontinued due to adverse events or death at any time from Day 1 through Week 48 if this resulted in no virologic data on treatment at Week 48.

³ Includes withdrawal of consent, loss to follow-up, non-compliance, protocol violation and other reasons.