Datasheet: Lopinavir and Ritonavir (40mg/10mg) Oral Pellets

Table of Content

Description

Lopinavir and Ritonavir Oral Pellets are a co-formulation of lopinavir and ritonavir (LPV/r). Lopinavir is an inhibitor of the HIV-1 protease. Ritonavir inhibits the cytochrome P450 (CYP)3A mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

The currently available paediatric formulations of LPV/r are the oral solution for young children and paediatric tablets for older children. The oral solution has an unpleasant taste, has a high alcohol concentration (42% v/v), and contains propylene glycol, which is especially undesirable in children aged <2 years. Moreover, LPV/r solution requires refrigeration, making it challenging for storage, transportation, and use in resource-limited settings. Dosing is based on body weight or surface area and requires accurate dose titration. The paediatric tablet is still relatively large and should not be crushed because this decreases bioavailability by 40% vs whole tablets.

The above factors suggest that an alternative formulation of LPV/r, not requiring cold chain transportation and storage is urgently needed. An additional attribute would be simplified dosing based on weight bands.

LPV/r Oral Pellets are a novel formulation, available for oral administration as 40/10 mg per capsule, which can be administered by sprinkling over food.

Indications and Dosage

Indications1

LPV/r Oral Pellets 40/10 mg are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in paediatric patients (aged 14 days and older).

The following points should be considered when initiating therapy with LPV/r:

  • The use of other active agents with LPV/r is associated with a greater likelihood of treatment response.
  • Genotypic or phenotypic testing and/or treatment history should guide the use of LPV/r. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to LPV/r.

Dosage1

Paediatric Patients

LPV/r Oral Pellets should not be administered once daily in paediatric patients <18 years of age.

LPV/r Oral Pellets should not be administered to neonates before a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a postnatal age of at least 14 days has been attained.

The following table lists the number of capsules containing LPV/r Oral Pellets 40/10 mg to be administered twice-daily, using a simplified weight band-based approach.

Weight Band

Number of capsules containing LPV/r Oral Pellets
40/10 mg* needed to prepare each dose

5 kg to less than 6 kg

2 capsules (80 mg) twice daily

6 kg to less than 10 kg

3 capsules (120 mg) twice daily

10 kg to less than 14 kg

4 capsules (160 mg) twice daily

14 kg to less than 20 kg

5 capsules (200 mg) twice daily

20 kg to less than 25 kg

6 capsules (240 mg) twice daily

* without concomitant efavirenz, nevirapine, amprenavir or nelfinavir

Administration1

The capsules containing LPV/r oral pellets SHOULD NOT be swallowed whole, and should be administered with food, as described below.

Method of Administration

  • Place a small amount of sweetened porridge (at room temperature) in a small bowl. The child should be able to easily consume this amount of porridge.
  • Count and remove the exact number of capsules required for the dose.
  • Hold both ends of the capsule between your fingertips, twist and pull apart so that all the pellets in the capsule are sprinkled over the sweetened porridge.

  • Repeat this step for the prescribed number of capsules per dose.
  • Ensure that all the porridge, with pellets, is swallowed by the child. The oral pellets SHOULD NOT be chewed or crushed.
  • This porridge/pellets mixture should be administered immediately and SHOULD NOT be stored for future use.
  • To ensure that no pellets are left behind in the mouth, give the child a drink of water.

Concomitant Therapy: Efavirenz, Nevirapine, or Nelfinavir

A dose increase of LPV/r to 300/75 mg/m2 is needed when co-administered with efavirenz, nevirapine or nelfinavir in children (both treatment-naïve and treatment-experienced) 6 months to 18 years of age, not to exceed the recommended adult dose (533/133 mg twice daily). If weight-based dosing is preferred, the recommended dosage for patients <15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients >15 kg to 45 kg is 11/2.75 mg/kg given twice daily.

However, precise dose titration may not be possible with LPV/r Oral Pellets. Thus, it is recommended that LPV/r oral solution be used in this situation.

Pharmacology

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-1 infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of LPV/r 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15-to 20-fold higher than those of ritonavir in HIV-1 infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice daily. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of LPV/r is due to lopinavir.1

Figure 1 displays the mean steady-state plasma concentrations of LPV/r after LPV/r 400/100 mg twice daily with food for 3 weeks from a pharmacokinetic study in HIV-1 infected adult subjects (N = 19).

Figure 1: Mean Steady-State Plasma Concentrations with 95% Confidence Intervals(CI) for HIV-1 Infected Adult Subjects (N = 19)

Absorption

In a pharmacokinetic study in HIV-1 positive subjects (N = 19), multiple dosing with 400/100 mg LPV/r twice daily with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.8 ± 3.7 μg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 μg/mL and minimum concentration within a dosing interval was 5.5 ± 2.7 μg/mL. Lopinavir AUC over a 12-hour dosing interval averaged 92.6 ± 36.7 μg.h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of LPV/r co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the LPV/r oral solution relative to the capsule formulation.1

Effects of Food on Oral Absorption

LPV/r Oral Solution, 80 mg/mL and 20 mg/mL

Relative to fasting, administration of LPV/r oral solution with a moderate fat meal (500 to 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 80 and 54%, respectively. Relative to fasting, administration of LPV/r oral solution with a high-fat meal (872 Kcal, 56% from fat) increased lopinavir AUC and Cmax by 130% and 56%, respectively. To enhance bioavailability and minimize pharmacokinetic variability LPV/r oral solution, 80 mg/mL and 20 mg/mL should be taken with food.1

Distribution

At steady state, lopinavir is approximately 98 to 99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg LPV/r twice daily, and is similar between healthy volunteers and HIV-1 positive patients.1

Metabolism

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic CYP450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg LPV/r dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.1

Elimination

Following a 400/100 mg 14C-LPV/r dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and feces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L/hr (mean ± SD, N = 19).1

Once-Daily Dosing

The pharmacokinetics of once-daily LPV/r have been evaluated in HIV-1 infected subjects naïve to antiretroviral treatment. LPV/r 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen. Multiple dosing of 800/200 mg LPV/r once daily for 4 weeks with food (N = 24) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 μg/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 μg/mL and minimum concentration within a dosing interval was 1.7 ± 1.6 μg/mL. Lopinavir AUC over a 24-hour dosing interval averaged 154.1 ± 61.4 μg.h/mL.1

The pharmacokinetics of once-daily LPV/r has been evaluated in treatment-experienced HIV-1 infected subjects. Lopinavir exposure (Cmax, AUC, Ctrough) with-once-daily LPV/r administration in treatment-experienced subjects is comparable to the once-daily lopinavir exposure in treatment-naïve subjects.1

Effects on Electrocardiogram

QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean time-matched (95% upper confidence-bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily LPV/r, respectively. LPV/r 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once-daily and twice-daily LPV/r doses at steady state.1

PR interval prolongation was also noted in subjects receiving LPV/r in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice- daily LPV/r, respectively.1

Special Populations

Gender, Race and Age

No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified. Lopinavir pharmacokinetics have not been studied in elderly patients.1

Paediatric Patients

The pharmacokinetics of LPV/r oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 paediatric patients in Study 940, ranging in age from 6 months to 12 years. The 230/57.5 mg/m2 twice-daily regimen without nevirapine and the 300/75 mg/m2 twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen (without nevirapine).1

The mean steady-state lopinavir AUC, Cmax, and Cmin were 72.6 ± 31.1 μg.h/mL, 8.2 ± 2.9 and 3.4 ± 2.1 μg/mL, respectively after LPV/r oral solution 230/57.5 mg/m2 twice daily without nevirapine (N = 12), and were 85.8 ± 36.9 μg.h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 μg/mL, respectively, after 300/75 mg/m2 twice daily with nevirapine
(N = 12). The nevirapine regimen was 7 mg/kg twice daily (aged 6 months to 8 years) or 4 mg/kg twice daily (aged >8 years).1

The pharmacokinetics of LPV/r oral solution at approximately 300/75 mg/m2 twice daily have also been evaluated in infants at approximately 6 weeks of age (N = 9) and between 6 weeks and 6 months of age (N = 18) in Study 1030. The mean steady-state lopinavir AUC12, Cmax, and C12 were 43.4 ± 14.8 μg.h/mL, 5.2 ± 1.8 μg/mL and 1.9 ± 1.1 μg/mL, respectively, in infants at approximately 6 weeks of age, and 74.5 ± 37.9 μg.h/mL, 9.4 ± 4.9 and 3.1 ± 1.8 μg/mL, respectively, in infants between 6 weeks and 6 months of age after LPV/r oral solution was administered at approximately 300/75 mg/m2 twice daily without concomitant non-nucleoside reverse transcriptase inhibitor (NNRTI) therapy.1

The pharmacokinetics of LPV/r soft gelatin capsule and oral solution (Group 1: 400/100 mg/m2 twice daily + 2 nucleoside reverse transcriptase inhibitors (NRTIs); Group 2: 480/120 mg/m2 twice daily + ≥1 NRTI + 1 NNRTI) have been evaluated in children and adolescents age ≥2 years to <18 years of age who had failed prior therapy (N = 26) in Study 1038. LPV/r doses of 400/100 and 480/120 mg/m2 resulted in high lopinavir exposure, as almost all subjects had lopinavir AUC12 above 100 μg.h/mL. Both groups of subjects also achieved relatively high average minimum lopinavir concentrations.1

LPV/r once-daily has not been evaluated in paediatric patients.

Renal Impairment

Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.1

Hepatic Impairment

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of LPV/r 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild-to-moderate hepatic impairment (N = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (N = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Caution should be exercised when administering LPV/r to subjects with hepatic impairment. LPV/r has not been studied in patients with severe hepatic impairment.1

Clinical Efficacy

Pharmacokinetics and Acceptability of LPV/r Oral Pellets

CHAPAS-2 (Children with HIV in Africa–Pharmacokinetics and Adherence of Simple Antiretroviral Regimens) study2

The CHAPAS-2 study assessed the pharmacokinetics and acceptability of a novel oral pellet formulation of LPV/r compared to the oral solution.

It was an open, randomized, Phase I, 2-period crossover comparative bioavailability trial conducted in 77 infants (aged 3 to <12 months) and children (aged 1 to <13 years weighing <25 kg) in Uganda, as follows:

Cohort A included infants aged 3 to <12 months (N = 19)

Cohort B included children aged 1 to <4 years (N = 26)

Cohort C included children aged 4 to <13 years (N = 32)

A 24-hour intensive pharmacokinetic sampling was performed 4 weeks after enrollment, after which children switched formulations and sampling was repeated at week 8. Acceptability data were also collected.

Pharmacokinetics

LPV/r exposure from the Oral Pellets was comparable with the oral solution, but lower than tablets, with no significant differences in subtherapeutic concentrations.

Figure 2: Geometric mean LPV plasma concentrations in infants/children after intake of LPV/r. A, Cohort A (Oral Pellets vs oral solution in infants aged 3 to <12 months). B, Cohort B (Oral Pellets vs oral solution in children aged 1 to <4 years). C, Cohort C (Oral Pellets vs tablet in children aged 4 to <13 years)2

Figure 3: LPV plasma concentrations 12 hours after intake of LPV/r vs age in cohorts A, B and C2

Acceptability

Caregivers found Oral Pellets more acceptable than the oral solution for their infants/children, particularly for transportation and storage reasons. However, for older children already able to swallow tablets, these were more acceptable than the Oral Pellets.

Figure 4: Percentage reporting various problems for the different formulations. A, Cohort A (Oral Pellets vs oral solution in infants aged 3 to <12 months). B, Cohort B (Oral Pellets vs oral solution in children aged 1 to <4 years). C, Cohort C (Oral Pellets vs tablet in children aged 4 to <13 years)2

 

Thus, the LPV/r Oral Pellets represent an alternative formulation to the oral solution for young children unable to swallow tablets.

Safety and Tolerability

The following adverse reactions are discussed in greater detail under the ‘Warnings and Precautions’ section.

  • QT Interval Prolongation, PR Interval Prolongation
  • Drug Interactions
  • Pancreatitis
  • Hepatotoxicity

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adult Clinical Trial Experience1

Treatment-Emergent Adverse Reactions

The safety of LPV/r has been investigated in about 2600 patients in Phase II-IV clinical trials, of which about 700 received a dose of 800/200 mg once daily. Along with NRTIs, in some studies, LPV/r was used in combination with efavirenz or nevirapine.

In clinical studies, the incidence of diarrhea in patients treated with either LPV/r capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once-daily LPV/r capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily LPV/r and 1.8-3.7% of those taking twice-daily LPV/r reported ongoing diarrhea.

Commonly reported adverse reactions to LPV/r included diarrhoea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhoea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 1)

Table 1: Treatment-Emergent Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving LPV/r in Combined Phase II/IV Studies (N = 2,612)

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

0.81

Eye Disorders

 

 

visual impairment*

8

0.3

Gastrointestinal Disorders

 

 

diarrhoea*

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

1.71

menstrual disorders – amenorrhea, menorrhagia*

10

1.72

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

*Represents a medical concept including several similar MedDRA PTs

1. Percentage of male population (N = 2,038)

2. Percentage of female population (N = 574)

Laboratory Abnormalities

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 2 (treatment-naïve patients) and Table 3 (treatment-experienced patients).

Table 2: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral- Naïve Patients

Variable

Limit1

Study 863
(48 Weeks)

Study 720
(360 Weeks)

Study 730
(48 Weeks)

LPV /r 400/100 mg
Twice Daily
+ d4T+3TC (N = 326)

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

LPV /r
Twice Daily
+ d4T + 3TC
(N = 100)

LPV /r
Once Daily
+ TDF + FTC
(N = 333)

LPV /r
Twice Daily
+ TDF + FTC
(N = 331)

Chemistry

High

 

 

 

 

 

Glucose

>250 mg/dL

2%

2%

4%

0%

<1%

Uric Acid

>12 mg/dL

2%

2%

5%

<1%

1%

SGOT/AST2

>180 U/L

2%

4%

10%

1%

2%

SGPT/ALT2

>215 U/L

4%

4%

11%

1%

1%

GGT

>300 U/L

N/A

N/A

10%

N/A

N/A

Total Cholesterol

>300 mg/dL

9%

5%

27%

4%

3%

Triglycerides

>750 mg/dL

9%

1%

29%

3%

6%

Amylase

>2 x ULN

3%

2%

4%

N/A

N/A

Lipase

>2 x ULN

N/A

N/A

N/A

3%

5%

Chemistry

Low

 

 

 

 

 

Calculated Creatinine Clearance

<50 mL/min

N/A

N/A

N/A

2%

2%

Hematology

Low

 

 

 

 

 

Neutrophils

<0.75 x 109/L

1%

3%

5%

2%

1%

1 ULN = upper limit of the normal range; N/A = Not Applicable.

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

Table 3: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of  Adult Protease Inhibitor-Experienced Patients

Variable

Limit1

Study 888
(48 Weeks)

Study 9572 and Study
7653
(84-144 Weeks)

Study 802
(48 Weeks)

LPV /r 400/100 mg Twice Daily
+ NVP + NRTIs
(N = 148)

Investigator-selected protease
Inhibitor (s) + NVP + NRTIs
(N = 140)

LPV /r
Twice Daily
+ NNRTI
+ NRTIs
(N = 127)

LPV /r 800/200 mg Once Daily
+ NRTIs
(N = 300)

LPV /r 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/AST4

>180 U/L

5%

11%

8%

3%

2%

SGPT/ALT4

>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 xULN

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

109/L

1%

2%

4%

3%

4%

Hemoglobin

<80 g/L

1%

1%

1%

1%

2%

1 ULN = upper limit of the normal range; N/A = Not Applicable.

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 LPV/r in combination with NRTls 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 LPV/r in combination with NRTls and nevirapine.

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

Paediatric Clinical Trial Experience1

LPV/r oral solution dosed up to 300/75 mg/m2 has been studied in 100 paediatric patients 6 months to 12 years of age. The adverse reaction profile seen during Study 940 was similar to that for adult patients.

Dysgeusia (22%), vomiting (21%), and diarrhoea (12%) were the most common adverse reactions of any severity reported in paediatric patients treated with combination therapy for up to 48 weeks in Study 940. A total of 8 patients experienced adverse reactions of moderate-to-severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in 2 or more subjects (N = 3).

LPV/r oral solution dosed at 300/75 mg/m2 has been studied in 31 paediatric patients 14 days to 6 months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate-to-severe intensity occurring in 2 or more subjects included decreased neutrophil count (N = 3), anemia (N = 2), high potassium (N = 2), and low sodium (N = 2).

LPV/r oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m2 (without concomitant NNRTI) and 480/120 mg/m2 (with concomitant NNRTI) have been studied in 26 paediatric patients 7 to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate-to-severe intensity occurring in 2 or more subjects included rash (N = 3), blood triglycerides abnormal (N = 3), and electrocardiogram QT prolonged (N = 2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities.

Laboratory Abnormalities

The percentages of paediatric patients treated with combination therapy including LPV/r with Grade 3-4 laboratory abnormalities are presented in
Table 4.

Table 4: Grade 3-4 Laboratory Abnormalities Reported in ≥2% Paediatric Patients in Study 940

Variable

Limit1

LPV /r
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 109/L

4%

Neutrophils

<0.40 x 109/L

2%

1 ULN = upper limit of the normal range.

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

Postmarketing Experience1

The following adverse reactions have been reported during postmarketing use of LPV/r. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to LPV/r exposure.

Body as a Whole:Redistribution/accumulation of body fat has been reported.

Cardiovascular: Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes.

Skin and Appendages:Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome and erythema multiforme.

Warnings and Precautions

Risk of Serious Adverse Reactions Due to Drug Interactions1

LPV/r are CYP3A inhibitors. Initiating treatment with LPV/r in patients receiving medications metabolized by CYP3A, or initiating medications metabolized by CYP3A in patients already receiving LPV/r, may increase plasma concentrations of medications metabolized by CYP3A.

Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of LPV/r, respectively. These interactions may lead to:

Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.

Clinically significant adverse reactions from greater exposures of LPV/r.

Loss of therapeutic effect of LPV/r and possible development of resistance.

Consider the potential for drug interactions prior to and during LPV/r therapy; review concomitant medications during LPV/r therapy, and monitor for the adverse reactions associated with the concomitant medications.

Toxicity in Preterm Neonates1

LPV/r should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of LPV/r in this patient population has not been established. However, if the benefit of using LPV/r to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to LPV/r including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis.

Pancreatitis1

Pancreatitis has been observed in patients receiving LPV/r therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to LPV/r has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis. Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during LPV/r therapy.

Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and LPV/r and/or other antiretroviral therapy should be suspended as clinically appropriate.

Hepatotoxicity1

Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of LPV/r.

There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with LPV/r therapy has not been established.

Elevated transminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of LPV/r in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive casual relationship with LPV/r therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with LPV/r and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of LPV/r treatment.

QT Interval Prolongation1

Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of LPV/r could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval.

PR Interval Prolongation1

LPV/r prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. LPV/r should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients maybe at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of LPV/r with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of LPV/r with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.

Diabetes Mellitus/Hyperglycemia1

New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

Immune Reconstitution Syndrome1

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including LPV/r. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia , or tuberculosis) which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Lipid Elevations1

Treatment with LPV/r has resulted in large increases in the concentration of total cholesterol and triglycerides. Triglyceride and cholesterol testing should be performed prior to initiating LPV/r therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with LPV/r and HMG-CoA reductase inhibitors.

Fat Redistribution1

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

Patients with Hemophilia1

Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

Resistance/Cross-resistance1

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in LPV/r-treated patients, it is unknown what effect therapy with LPV/r will have on the activity of subsequently administered protease inhibitors.

Overdosage1

Overdoses with LPV/r oral solution, 80 mg/mL and 20 mg/mL have been reported. One of these reports described fatal cardiogenic shock in a 2.1 kg infant who received a single dose of 6.5 mL of LPV/r oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior. The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure. Healthcare professionals should be aware that LPV/r oral solution, 80 mg/mL and 20 mg/mL is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of LPV/r, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose. This is especially important for infants and young children.

Human experience of acute overdosage with LPV/r is limited. Treatment of overdose with LPV/r should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with LPV/r. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with LPV/r oral solution.

Place in Therapy

With the higher risk of disease progression in young children, availability of appropriate child-friendly formulations is an imperative.3 LPV/r is considered by many as the first choice protease inhibitor for children.3 The World Health Organization (WHO) 2016 guidelines recommend the use of LPV/r along with abacavir/zidovudine plus lamivudine for children less than 3 years of age.4

Various paediatric studies have shown high virologic potency, an excellent toxicity profile and a high barrier to the development of viral resistance with LPV/r.5 Moreover, LPV/r based regimens have been found to be safe and effective in antiretroviral-naïve as well as antiretroviral-experienced HIV-infected children.6,7,8,9

However, the oral solution is associated with limitations such as need for a cold chain, high alcohol content and bitter taste, as also the need for exact dose titrations based on mg/kg or mg/m2. Whilst the paediatric tablets (LPV/r 100/25) circumvent these disadvantages, they can be administered only to children who can reliably swallow.

The availability of this novel formulation of LPV/r Oral Pellets expands the scope of use of this potent antiretroviral, by providing a convenient alternative to the oral solution in infants and young children unable to swallow the paediatric tablet. The formulation is heat-stable, and can be conveniently dosed using weight bands.

Table 5: Sequencing of ARV formulations for newborns starting treatment at around birth4

 

0-2 weeks →

2 weeks-3 months→

3-36 months

Preferred

AZT + 3TC+NVP

ABC or AZT + 3TC + LPV/r syrup

ABC or AZT + 3TC + LPV/r pellets*

Alternative

AZT + 3TC + NVP

ABC or AZT + 3TC + LPV/r pellets*

Special circumstances

AZT+3TC+NVP

ABC or AZT + 3TC + RAL

* LPV/r pellets are indicated for children aged ≥ 2 weeks and weighing ≥ 5kgs

References

1.Prescribing Information of Lopinavir and ritonavir Oral Pellets 40/10 mg – Cipla Ltd, May 2015

2.Musiime V et. al. The pharmacokinetics and acceptability of lopinavir/ritonavir Oral Pellets, tablets, and syrups in african HIV-infected children. J Acquir Immune Defic Syndr. 2014; 66(2): 148-54

3.Beatriz Larru Martinez et. al. Novel strategies in the use of lopinavir/ritonavir for the treatment of HIV infection in children. HIV/AIDS – Research and Palliative Care 2010; 2: 59–67

4.Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. WHO 2016, 2nd Edition.

5.Ramos J. Boosted protease inhibitors as a therapeutic option in the treatment of HIV-infected children. HIV Med 2009; 10(9): 536-47

6.Violari A et. al. Early Antiretroviral Therapy and Mortality among HIV-Infected Infants. N Engl J Med 2008; 359: 2233-44

7.Chadwick EG et. al. Long-term outcomes for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. AIDS 2011; 25(5): 643-9.

8.Rudin C et. al. Long-term safety and effectiveness of lopinavir/ritonavir in antiretroviral-experienced HIV-1-infected children. Arch Dis Child 2010; 95: 478–481

9.  Chadwick EG et. al. Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS 2008; 22(2): 249-55