Kaletra PI Version 33 7 July 2020 Page 1 of 59 AUSTRALIAN PRODUCT INFORMATION – KALETRA ® (LOPINAVIR / RITONAVIR) TABLETS AND ORAL SOLUTION 1 NAME OF THE MEDICINE Lopinavir / Ritonavir 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Kaletra is a co-formulation of lopinavir and ritonavir. Tablets Kaletra tablets are available for oral administration in a strength of 200 mg of lopinavir and 50 mg of ritonavir with the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal anhydrous silica, and sodium stearylfumarate and the following inactive ingredients in the film coating: hypromellose, titanium dioxide, macrogol 400, hyprolose, talc, colloidal anhydrous silica, macrogol 3350, iron oxide yellow CI 77492, and polysorbate 80. Kaletra tablets are also available in a strength of 100 mg of lopinavir and 25 mg of ritonavir with the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal anhydrous silica, and sodium stearylfumarate and the following inactive ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, macrogol 3350, iron oxide yellow CI 77492. Oral Solution Kaletra Oral Solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per millilitre with the following ingredients: PEG-40 hydrogenated castor oil, purified water, sodium chloride, sodium citrate, saccharin sodium, acesulfame potassium, citric acid, absolute ethanol, propylene glycol, menthol, povidone, glycerol, high fructose maize syrup, peppermint oil, water, Magnasweet Flavour (2x) (ARTG No. 4333), Vanilla natural & artificial flavour (Yarnilla) 33869 (ARTG No. 4338) and Artificial cotton candy flavour (ARTG No. 4381). Kaletra Oral Solution contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v).
59
Embed
AUSTRALIAN PRODUCT INFORMATION KALETRA (LOPINAVIR ... · Recommended number of 100/25 mg Tablets Twice-Daily Administered Dose 7 < 10 1 100/25 mg ≥ 10 < 25 2 200/50 mg ≥ 25
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Kaletra PI Version 33
7 July 2020
Page 1 of 59
AUSTRALIAN PRODUCT INFORMATION – KALETRA®
(LOPINAVIR / RITONAVIR) TABLETS AND ORAL SOLUTION
1 NAME OF THE MEDICINE
Lopinavir / Ritonavir
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Kaletra is a co-formulation of lopinavir and ritonavir.
Tablets
Kaletra tablets are available for oral administration in a strength of 200 mg of lopinavir and 50
mg of ritonavir with the following inactive ingredients: copovidone, sorbitan monolaurate,
colloidal anhydrous silica, and sodium stearylfumarate and the following inactive ingredients
in the film coating: hypromellose, titanium dioxide, macrogol 400, hyprolose, talc, colloidal
anhydrous silica, macrogol 3350, iron oxide yellow CI 77492, and polysorbate 80.
Kaletra tablets are also available in a strength of 100 mg of lopinavir and 25 mg of ritonavir
with the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal anhydrous
silica, and sodium stearylfumarate and the following inactive ingredients in the film coating:
polyvinyl alcohol, titanium dioxide, talc, macrogol 3350, iron oxide yellow CI 77492.
Oral Solution
Kaletra Oral Solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir
per millilitre with the following ingredients: PEG-40 hydrogenated castor oil, purified water,
ElagolixCo-administration of elagolix with lopinavir/ritonavir could increase elagolix exposure
through inhibition of OATP, CYP3A, and P-gp. Known serious adverse events for elagolix
include suicidal ideation and hepatic transaminase elevations. In addition, elagolix is a
weak/moderate inducer of CYP3A, which may decrease exposure of lopinavir/ritonavir. Refer
to the elagolix product information for dosing information with strong CYP-3A4 inhibitors
Kaletra PI Version 33
7 July 2020
Page 24 of 59
Clinically Significant Drug Interactions Are Not Expected
A drug interaction study has revealed no clinically significant interaction with Kaletra
administered once or twice daily, and omeprazole or ranitidine (see Table 6 below).
Clinical studies showed no clinically significant interaction between lopinavir/ritonavir and
raltegravir.
Based on known metabolic profiles, clinically significant drug interactions are not expected
between Kaletra and desipramine (CYP2D6 probe), fluvastatin, dapsone,
trimethoprim/sulfamethoxazole, azithromycin, or fluconazole in patients with normal renal and
hepatic function.
Drug Interaction Studies
Drug interaction studies were performed with Kaletra and other drugs likely to be co-
administered and some drugs commonly used as probes for pharmacokinetic interactions.
The effects of co-administration of Kaletra on the AUC, Cmax and Cmin are summarised in Table
6 (effect of other drugs on lopinavir) and Table 7 (effect of Kaletra on other drugs). The effects
of other drugs on ritonavir are not shown since they generally correlate with those observed
with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are
decreased) unless otherwise indicated in the table footnotes.
Table 6: Drug Interactions Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug (see 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE for Recommended Alterations in Dose or Regimen)
Co-administered
Drug
Dose of Co-administered
Drug (mg)
Dose of Kaletra (mg)
n
Ratio (with/without co-administered drug) of Lopinavir Pharmacokinetic
Parameters (90% CI); No Effect = 1.00
Cmax AUC Cmin
Amprenavir 750 BD; 10 days
400/100 capsule BD; 21 days
12
0.72 (0.65, 0.79)
0.62 (0.56, 0.70)
0.43 (0.34, 0.56)
Atorvastatin 20 Daily; 4 days
400/100 capsule BD; 14 days
12 0.90
(0.78, 1.06) 0.90
(0.79, 1.02) 0.92
(0.78, 1.10)
Efavirenz1 600 nocte; 9 days
400/100 capsule BD; 9 days
11, 7*
0.97 (0.78, 1.22)
0.81 (0.64, 1.03)
0.61 (0.38, 0.97)
600 nocte; 9 days
500/125 tablet BD 10 days
19 1.12
(1.02 – 1.23) 1.06
(0.96 – 1.17) 0.9
(0.78 – 1.04)
600 nocte; 9 days
600/150 tablet BD; 10 days
23 1.36
(1.28 - 1.44) 1.36
(1.28 - 1.44) 1.32
(1.21 - 1.44)
Kaletra PI Version 33
7 July 2020
Page 25 of 59
Table 6: Drug Interactions Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug (see 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE for Recommended Alterations in Dose or Regimen)
Co-administered
Drug
Dose of Co-administered
Drug (mg)
Dose of Kaletra (mg)
n
Ratio (with/without co-administered drug) of Lopinavir Pharmacokinetic
Parameters (90% CI); No Effect = 1.00
Cmax AUC Cmin
Ketoconazole 200 single dose 400/100 capsule BD; 16 days
12 0.89
(0.80, 0.99) 0.87
(0.75, 1.00) 0.75
(0.55, 1.00)
Nelfinavir
1000 BD, 10 days
400/100 capsule BD; 21 days
13 0.79
(0.70, 0.89) 0.73
(0.63, 0.85) 0.62
(0.49, 0.78)
Nevirapine 200 BD, steady-state (>1yr)2
400/100 capsule BD, steady-state (>1yr)
22, 19*
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 Daily, 2 weeks; BD 1 week3
300/75 mg/m2 oral solution BD; 3 weeks
12, 15*
0.86 (0.64, 1.16)
0.78 (0.56, 1.09)
0.45 (0.25, 0.81)
Omeprazole 40 Daily, 5 days
400/100 tablet BD; 10 days
11 1.08
(0.99, 1.17) 1.07
(0.99, 1.15) 1.03
(0.90, 1.18) 800/200 tablet
Daily; 10 days 12
0.94 (0.88, 1.00)
0.92 (0.86, 0.99)
0.71 (0.57, 0.89)
Pravastatin 20 Daily; 4 days
400/100 capsule BD; 14 days
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 BD; 10 days
12 0.98
(0.95, 1.02) 0.98
(0.94, 1.01) 0.93
(0.89, 0.98)
800/200 tablet Daily; 10 days
11 0.97
(0.95, 1.00) 0.95
(0.91, 0.99) 0.82
(0.74, 0.91)
Rifabutin 150 Daily; 10 days
400/100 capsule BD; 20 days
14 1.08
(0.97, 1.19) 1.17
(1.04, 1.31) 1.20
(0.96, 1.65)
Rifampicin 600 Daily, 10 days
400/100 capsule BD; 20 days
22
0.45 (0.40, 0.51)
0.25 (0.21, 0.29)
0.01 (0.01, 0.02)
600 Daily, 14 days
800/200 capsule BD; 9 days4
10 1.02 (0.85, 1.23)
0.84 (0.64, 1.10)
0.43 (0.19, 0.96)
600 Daily, 14 days
400/400 capsule BD; 9 days5
9 0.93 (0.81, 1.07)
0.98 (0.81, 1.17)
1.03 (0.68, 1.56)
Co-administration of standard dose Kaletra and rifampicin is not
recommended. (See 4.4 SPECIAL WARNINGS AND PRECAUTIONS
FOR USE)
Kaletra PI Version 33
7 July 2020
Page 26 of 59
Table 6: Drug Interactions Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug (see 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE for Recommended Alterations in Dose or Regimen)
Co-administered
Drug
Dose of Co-administered
Drug (mg)
Dose of Kaletra (mg)
n
Ratio (with/without co-administered drug) of Lopinavir Pharmacokinetic
Parameters (90% CI); No Effect = 1.00
Cmax AUC Cmin
Ritonavir2 100 BD; 3 to 4 weeks
400/100 capsule BD; 3 to 4 weeks
8, 21*
1.28 (0.94, 1.76)
1.46 (1.04, 2.06)
2.16 (1.29, 3.62)
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1 The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2 Study conducted in HIV-positive adult subjects. 3 Study conducted in HIV-positive paediatric subjects ranging in age from 6 months to 12 years. 4 Titrated to 800/200 BD as 533/133 BD x 1 day, 667/167 BD x 1 day, then 800/200 BD x 7 days, compared to
400/100 BD x 10 days alone. 5 Titrated to 400/400 BD as 400/200 BD x 1 day, 400/300 BD x 1 day, then 400/400 BD x 7 days, compared to
400/100 BD x 10 days alone. * Parallel group design; n for Kaletra + co-administered drug, n for Kaletra alone
Table 7: Drug Interactions Pharmacokinetic Parameters for Co-administered Drug in the Presence of Kaletra (see 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE for Recommended Alterations in Dose or Regimen)
Co-administered
Drug
Dose of Co-administered
Drug (mg)
Dose of Kaletra (mg)
n
Ratio (with/without Kaletra) of Co-administered Drug
Pharmacokinetic Parameters (90% CI);
No Effect = 1.00
Cmax AUC Cmin
Amprenavir1
750 BD, 10 days combo vs. 1200 BD, 14 days alone
400/100 capsule BD, 21 days
11 1.12 (0.91, 1.39)
1.72 (1.41, 2.09)
4.57 (3.51, 5.95)
Atorvastatin 20 Daily; 4 days
400/100 capsule BD; 14 days
12 4.67 (3.35, 6.51)
5.88 (4.69, 7.37)
2.28 (1.91, 2.71)
Desipramine2 100 single dose 400/100 capsule BD; 10 days
15 0.91 (0.84, 0.97)
1.05 (0.96, 1.16)
NA
Efavirenz 600 nocte; 9 days
400/100 capsule BD; 9 days
11, 12* 0.91 (0.72, 1.15)
0.84 (0.62, 1.15)
0.84 (0.58, 1.20)
Ethinyl Oestradiol
35 microgram Daily; 21 days (Brevinor-1®)
400/100 capsule BD; 14 days
12 0.59 (0.52, 0.66)
0.58 (0.54, 0.62)
0.42 (0.36, 0.49)
Indinavir1
600 BD, 10 days combo non-fasting vs. 800 TDS, 5 days alone fasting
400/100 capsule BD, 15 days
13 0.71 (0.63, 0.81)
0.91 (0.75, 1.10)
3.47 (2.60, 4.64)
Kaletra PI Version 33
7 July 2020
Page 27 of 59
Table 7: Drug Interactions Pharmacokinetic Parameters for Co-administered Drug in the Presence of Kaletra (see 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE for Recommended Alterations in Dose or Regimen)
Co-administered
Drug
Dose of Co-administered
Drug (mg)
Dose of Kaletra (mg)
n
Ratio (with/without Kaletra) of Co-administered Drug
Pharmacokinetic Parameters (90% CI);
No Effect = 1.00
Cmax AUC Cmin
Ketoconazole 200 single dose 400/100 capsule BD; 16 days
12 1.13 (0.91, 1.40)
3.04 (2.44, 3.79)
NA
Methadone 5 single dose 400/100 capsule BD; 10 days
11 0.55 (0.48, 0.64)
0.47 (0.42, 0.53)
NA
Nelfinavir1
1000 BD, 10 days combo vs.
400/100 capsule BD, 21 days
13 0.93 (0.82, 1.05)
1.07 (0.95, 1.19)
1.86 (1.57, 2.22)
M8 metabolite 1250 BD, 14
days alone 2.36
(1.91, 2.91) 3.46
(2.78, 4.31) 7.49
(5.85, 9.58)
Nevirapine 200 Daily, 14 days; BD, 6 days
400/100 capsule BD; 20 days
5, 6* 1.05 (0.72, 1.52)
1.08 (0.72, 1.64)
1.15 (0.71, 1.86)
Norethisterone 1 Daily, 21 days (Brevinor-1®)
400/100 capsule BD; 14 days
12 0.84 (0.75, 0.94)
0.83 (0.73, 0.94)
0.68 (0.54, 0.85)
Pravastatin 20 Daily; 4 days
400/100 capsule BD; 14 days
12 1.26 (0.87, 1.83)
1.33 (0.91, 1.94)
NA
Rifabutin
150 Daily 10 days combo vs. 300 Daily, 10 days; alone
400/100 capsule BD, 10 days
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
3.46 (3.07, 3.91)
5.73 (5.08, 6.46)
9.53 (7.56, 12.01)
Saquinavir1 800 BD, 10 days combo vs. 1200 TDS, 5 days alone,
400/100 capsule BD, 15 days 400/100 capsule BD, 20 days
14
6.34 (5.32, 7.55)
9.62 (8.05, 11.49)
16.74 (13.73, 20.42)
1200 BD, 5 days combo vs. 1200 TDS 5 days alone
10 6.44 (5.59, 7.41)
9.91 (8.28, 11.86)
16.54 (10.91, 25.08)
All interaction studies conducted in healthy, HIV-negative subjects unless otherwise indicated. 1 Ratio of parameters for amprenavir, indinavir, nelfinavir, and saquinavir are not normalised for dose. 2 Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism. 3 Effect on the dose-normalised sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite. * Parallel group design; n for Kaletra + co-administered drug, n for co-administered drug alone. NA = not available.
Kaletra PI Version 33
7 July 2020
Page 28 of 59
4.6 Fertility, pregnancy and lactation
Effects on fertility
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and
female rats at levels up to 100/50 mg/kg/day. Based on AUC measurements, the exposures
in rats at the high doses were approximately 0.6-fold for lopinavir and 0.8-fold for ritonavir of
the exposures in humans at the recommended therapeutic dose (400/100 mg BD).
Use in pregnancy
Pregnancy Category B3. No treatment-related malformations were observed when lopinavir
in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and
foetal development toxicities (early resorption, decreased foetal viability, decreased foetal
body weight, increased incidence of skeletal variations and skeletal ossification delays)
occurred in rats at a maternally toxic dosage (100/50 mg/kg/day). Based on AUC
measurements, the drug exposures in rats at 100/50 mg/kg/day were approximately 0.6-fold
for lopinavir and 1.6-fold for ritonavir for males and females that of the exposures in humans
at the recommended therapeutic dose (400/100 mg BD). In a peri- and post-natal study in rats,
a developmental toxicity (a decrease in survival of pups between birth and post-natal day 21)
occurred at 40/20 mg/kg/day and greater.
No embryonic and foetal developmental toxicity was observed in rabbits at a maternally toxic
dosage (80/40 mg/kg/day). Based on AUC measurements, the drug exposures in rabbits at
80/40 mg/kg/day were approximately 0.6- fold for lopinavir and 1.0-fold for ritonavir that of the
exposures in humans at the recommended therapeutic dose (400/100 mg BD). There are,
however, no adequate and well-controlled studies in pregnant women. Because animal
reproduction studies are not always predictive of human response, Kaletra should be used
during pregnancy only if the potential benefits justify the potential risks to the foetus.
Use in lactation
It is not known whether lopinavir is secreted in human milk. Because of the potential for HIV
transmission and the potential for serious adverse reactions in nursing infants, mothers should
be instructed not to breast-feed when they are receiving Kaletra. Studies in rats showed that
lopinavir is secreted in milk. In a peri- and post-natal study in rats, there was decreased
survival of pups between birth and post-natal day 21 when dams were dosed at 40/20
mg/kg/day lopinavir/ritonavir and greater. Plasma drug levels were not measured in this study.
Kaletra PI Version 33
7 July 2020
Page 29 of 59
4.7 Effects on ability to drive and use machines
The effects of this medicine on a person’s ability to drive and use machines were not assessed
as part of its registration.
4.8 Adverse effects (Undesirable effects)
Adults
Treatment-Emergent Adverse Events
Kaletra has been studied in over 2154 HIV-1 infected patients as combination therapy in
Phase I/II and Phase III clinical trials. The most common adverse event associated with
Kaletra therapy was diarrhoea, which was generally of mild to moderate severity. Rates of
discontinuation of randomised therapy due to adverse events, including death, were 5.8% in
Kaletra-treated and 4.9% in nelfinavir-treated patients in Study 863.
Treatment-Emergent clinical adverse events of moderate or severe intensity in greater than
or equal to 2% of patients treated with combination therapy including Kaletra for up to 48
weeks (Studies 863, 418 and 730) and for up to 360 weeks (Study 720) are presented in Table
8 (antiretroviral -naïve patients) and for up to 48 weeks (Study 888 and 802), 84 weeks (Study
957) and 144 weeks (Study 765) in Table 9 (antiretroviral experienced patients). For other
information regarding observed or potentially serious adverse events, please see 4.4
SPECIAL WARNINGS AND PRECAUTIONS FOR USE.
Kaletra PI Version 33
7 July 2020
Page 30 of 59
Table 8: Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate
or Severe Intensity Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients
Table 9: Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult antiretroviral-Experienced Patients
Study 888
(48 Weeks)
(%)
Study 9572and
Study 7653
(84-144 Weeks)
(%)
Study 802
(48 Weeks)
Kaletra
400/100 mg BD
+ NVP + NRTIs
(n=148)
Investigator-selected protease
inhibitor(s)
+ NVP + NRTIs
(n=140)
Kaletra
BD
+ NNRTI + NRTIs
(n= 127)
Kaletra 800/200 mg Once daily
+ NRTIs
(n=300)
Kaletra 400/100 mg Twice daily
+NRTIs
(n=299)
Gastrointestinal disorders
Abdominal pain 2.0% 2.1% 3.9% 2.0% 0.3%
Abdominal pain Upper N/A N/A N/A 0.7% 2.0%
Abnormal faeces 0.0% 0.0% 2.4% 0.0% 0.0%
Diarrhoea 7.4% 9.3% 22.8% 14.0% 11.0%
Dysphagia 2.0% 0.7% 0.0% 0.0% 0.0%
Flatulence 0.7% 2.1% 1.6% 1.0% 1.0%
Nausea 6.8% 16.4% 4.7% 2.7% 7.4%
Vomiting 4.1% 12.1% 1.6% 2.0% 2.7%
General disorders and administration site conditions
Asthenia 2.7% 6.4% 9.4% 0.3% 0.3%
Chills 2.0% 0.0% 0.0% 0.0% 0.0%
Pyrexia 2.0% 1.4% 1.6% 0.0% 0.3%
Pain 0.0% 0.0% 3.9% 0.0% 0.0%
Nervous system disorders
Headache 2.0% 2.9% 2.4% 0.3% 0.0%
Paraesthesia 0.0% 1.4% 2.4% 0.0% 0.0%
Vascular disorders
Hypertension 0.0% 0.0% 2.4% 0.0% 0.0%
Metabolism and nutrition disorders
Anorexia 0.7% 2.9% 0.0% 0.0% 0.7%
Investigations
Weight decreased 0.0% 1.4% 3.1% 0.3% 0.3%
Skin and subcutaneous disorders
Rash 2.0% 1.4% 2.4% 0.0% 0.0%
Psychiatric disorders
Insomnia 0.0% 2.1% 2.4% 0.0% 0.3%
Depression 0.7% 2.1% 3.1% 0.3% 0.0%
Kaletra PI Version 33
7 July 2020
Page 33 of 59
Table 9: Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult antiretroviral-Experienced Patients
1 Includes adverse events of possible or probable relationship to study drug.
2 Includes adverse event data from patients receiving 400/100 mg BD (n=29) or 533/133 mg BD (n=28) for 84 weeks. Patients received Kaletra in combination with NRTIs and efavirenz.
3 Includes adverse event data from patients receiving 400/100 mg BD (n=36) or 400/200 mg BD (n=34) for 144 weeks. Patients received Kaletra in combination with NRTIs and nevirapine.
Arthralgia, arthropathy, back pain, muscular weakness, osteoarthritis, osteonecrosis and pain
in extremity.
Renal and urinary disorders
Haematuria, nephritis, nephrolithiasis, renal disorder urine abnormality and urine odour
abnormality.
Reproductive system disorders
Breast enlargement, ejaculation disorder, erectile dysfunction, gynaecomastia and
menorrhagia.
General disorders and administration site conditions
Chest pain, cyst, drug interaction, oedema, oedema peripheral, face oedema, fatigue,
hypertrophy and malaise.
Investigations
Drug level increased, glucose tolerance decreased and weight increased.
Laboratory Abnormalities
The percentages of adult patients treated with combination therapy including Kaletra with
Grade 3 to 4 laboratory abnormalities are presented in Table 10 and 11.
Kaletra PI Version 33
7 July 2020
Page 36 of 59
Table 10: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-naïve Patients
Study 863 (48
Weeks) Study 418 (48 Weeks)
Study 720 (360
Weeks) Study 730 (48 Weeks)
Variable Limit1
KALETRA 400/100 mg BD + d4T +3TC (N = 326)
Nelfinavir 750 mg
TID + d4T + 3TC
(N = 327)
KALETRA 800/200 mg QD +
TDF + FTC (N = 115)
KALETRA 400/100 mg BD + TDF +
FTC (N = 75)
KALETRA BD + d4T
+ 3TC (N = 100)
KALETRA QD + TDF
+FTC (N=333)
KALETRA BD + TDF
+FTC (N=331)
Chemistry High
Glucose > 250 mg/dL
2% 2% 3% 1% 4%
0%
<1%
Uric Acid > 12
mg/dL 2% 2% 0% 3% 5%
<1%
1%
SGOT/ AST2
> 180 U/L
2% 4% 5% 3% 10% 1% 2%
SGPT/ ALT2
> 215 U/L
4% 4% 4% 3% 11% 1% 1%
GGT > 300 U/L
N/A N/A N/A N/A 10% N/A N/A
Total Cholesterol
> 300 mg/dL
9% 5% 3% 3% 27% 4% 3%
Triglycerides > 750 mg/dL
9% 1% 5% 4% 29% 3% 6%
Amylase > 2 x ULN
3% 2% 7% 5% 4% N/A N/A
Lipase > 2x ULN NA NA NA NA NA 3% 5%
Chemistry Low
Calculated Creatinine Clearance
< 50 mL/min
NA NA NA NA NA 2% 2%
Haematology Low
Neutrophils 0.75 x 109/L
1% 3% 5% 1% 5% 2% 1%
1 ULN = upper limit of the normal range; N/A = Not Applicable. 2 Criterion for Study 730 was >5x ULN.(AST/ALT)
Kaletra PI Version 33
7 July 2020
Page 37 of 59
Table 11: Grade 3 - 4 Laboratory Abnormalities Reported in ≥ 2% of Adult antiretroviral-Experienced Patients
Study 888 (48 Weeks)
(%)
Study 9572
and Study 7653
(84-144 Weeks)
(%)
Study 802 (48 weeks)
(%)
Variable Limit1
Kaletra 400/100 mg BD + NVP + NRTIs
(n=148)
Investigator-
selected protease
inhibitor(s)
+ NVP + NRTIs
(n=140)
Kaletra BD
+ NNRTI + NRTIs
(n=127)
Kaletra 800/200mg Once daily
+ NRTIs (n=300)
Kaletra 400/100mg
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 > 180 U/L 5 11 8 3 2
SGPT/ALT > 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 > 2x ULN N/A N/A N/A 4 1
Creatine Phosphokinase
> 4x ULN N/A N/A N/A 4 5
Chemistry Low
Calculated Creatinine Clearance
< 50mL/min N/A N/A N/A 3 3
Inorganic Phosphorus
< 1.5 mg/dL 1 0 2 1 < 1
Haematology Low
Neutrophils 0.75 x 109/L 1 2 4 3 4
Haemoglobin < 80g/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 BD (n=29) or 533/133 mg BD (n=28) for 84 weeks. Patients received Kaletra in combination with NRTIs and efavirenz. 3 Includes laboratory data from patients receiving 400/100 mg BD (n=36) or 400/200 mg BD (n=34) for 144 weeks. Patients received Kaletra in combination with NRTIs and nevirapine. 4 Criterion for Study 802 was > 5x ULN (AST/ALT)
Paediatrics
Treatment-Emergent Adverse Events
Kaletra has been studied in 100 paediatric patients 6 months to 12 years of age. The adverse
event profile seen during a clinical trial was similar to that for adult patients.
Kaletra PI Version 33
7 July 2020
Page 38 of 59
Dysgeusia, vomiting, and diarrhoea were the most commonly reported drug related adverse
events of any severity in paediatric patients treated with combination therapy including Kaletra
for up to 48 weeks in Study 940. A total of 8 children experienced moderate or severe adverse
events at least possibly related to Kaletra. Rash (reported in 3%) was the only drug-related
clinical adverse event of moderate to severe intensity observed in greater than or equal to 2%
of children enrolled.
Laboratory Abnormalities
The percentages of paediatric patients treated with combination therapy including Kaletra with
Grade 3 to 4 laboratory abnormalities are presented in Table 12.
Table 12: Grade 3 to 4 Laboratory Abnormalities Reported in ≥ 2% Paediatric Patients
Variable Limit+ Kaletra
BD + RTIs (n=100)
Chemistry High
Sodium >149 mEq/L 3.0%
Total bilirubin > 2.9 x ULN 3.0%
SGOT/AST > 180 U/L 8.0%
SGPT/ALT > 215 U/L 7.0%
Total Cholesterol >300 mg/dL or > 7.77 mmol/L 3.0%
Amylase > 2.5 x ULN 7.0%++
Chemistry Low
Sodium < 130 mEq/L 3.0%
Hematology Low
Platelet Count < 50 x 109/L 4.0%
Neutrophils < 0.40 x 109/L 2.0% + ULN = upper limit of the normal range. ++Subjects with Grade 3 to 4 amylase confirmed by elevations in pancreatic amylase.
Postmarketing Experience
Hepatobiliary disorders: Hepatitis has been reported in patients on Kaletra therapy.
Skin and subcutaneous tissue disorders: Toxic epidermal necrolysis, Stevens Johnson
Syndrome and erythema multiforme have been reported.
Cardiac disorders: Bradyarrhythmia has been reported.
Renal and urinary disorders: Nephrolithiasis
Kaletra PI Version 33
7 July 2020
Page 39 of 59
Reporting suspected adverse effects
Reporting suspected adverse reactions after registration of the medicinal product is important.
It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare
professionals are asked to report any suspected adverse reactions at
http://www.tga.gov.au/reporting-problems
4.9 Overdose
Human experience of acute overdosage with Kaletra is limited. Treatment of overdose with
Kaletra 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
Kaletra. Activated charcoal may reduce absorption of the medicine if given within one or two
hours after ingestion. In patients who are not fully conscious or have impaired gag reflex,
consideration should be given to administering activated charcoal via a nasogastric tube, once
the airway is protected.
Since Kaletra is highly protein bound, dialysis is unlikely to be beneficial in significant removal
of the drug. In cases of overdosage with Kaletra Oral Solution, consideration may be given to
dialysis for removal of propylene glycol.
Kaletra Oral Solution contains 42.4% (v/v) alcohol. Accidental ingestion of the product by a
young child could result in significant alcohol related toxicity.
For information on the management of overdose, contact the Poison Information Centre on
131126 (Australia).
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Mechanism of action
Lopinavir, an inhibitor of the HIV-1 and HIV-2 proteases, prevents cleavage of the gag-pol
polyprotein, resulting in the production of immature, non-infectious virus. As co-formulated in
Kaletra, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing
Antiviral Activity of Kaletra in Patients With Previous Protease Inhibitor Therapy
The clinical relevance of reduced in-vitro susceptibility to lopinavir has been examined by
assessing the virologic response to Kaletra therapy, with respect to baseline viral genotype
and phenotype, in 56 NNRTI-naive patients with HIV RNA greater than 1000 copies/mL
despite previous therapy with at least two protease inhibitors selected from nelfinavir, indinavir,
saquinavir, and ritonavir (Study M98-957). In this study, patients were initially randomised to
receive one of two doses of Kaletra in combination with efavirenz and nucleoside reverse
transcriptase inhibitors. The EC50 values of lopinavir against the 56 baseline viral isolates
ranged from 0.5- to 96-fold higher than the EC50 against wild-type HIV. Fifty-five percent
(31/56) of these baseline isolates displayed a greater than 4-fold reduced susceptibility to
lopinavir. These 31 isolates had a mean reduction in lopinavir susceptibility of 27.9-fold.
After 48 weeks of treatment with Kaletra, efavirenz and nucleoside reverse transcriptase
inhibitors, plasma HIV RNA less than or equal to 400 copies/mL was observed in 93% (25/27),
73% (11/15), and 25% (2/8) of patients with less than or equal to 10-fold, greater than 10 and
less than 40-fold, and greater than or equal to 40-fold reduced susceptibility to lopinavir at
baseline, respectively. Lopinavir susceptibility was determined by recombinant phenotypic
technology performed by Virologic; genotype also performed by Virologic. Plasma HIV RNA
less than or equal to 50 copies/mL was observed in 81% (22/27), 60% (9/15), and 25% (2/8)
in the above groups of patients, respectively.
There are insufficient data at this time to identify lopinavir-associated mutational patterns in
isolates from patients on Kaletra therapy. Further studies are needed to assess the association
between specific mutational patterns and virologic response rates.
Patients Without Prior Antiretroviral Therapy
Study M98-863: Kaletra capsules BD + stavudine + lamivudine compared to nelfinavir
TDS + stavudine + lamivudine.
Study M98-863 was a randomised, double-blind, multicentre trial comparing treatment with
Kaletra capsules (400/100 mg BD) plus stavudine and lamivudine versus nelfinavir (750 mg
TDS) plus stavudine and lamivudine in 653 antiretroviral treatment naive patients. Patients
had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male.
Mean baseline CD4 cell count was 259 cells/mm3 (range: 2 to 949 cells/mm3) and mean
baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 2.6 to 6.8 log10 copies/mL).
Kaletra PI Version 33
7 July 2020
Page 44 of 59
Treatment response and outcomes of randomised treatment are presented in Figure 1 and
Table 15, respectively.
Figure 1: Treatment Response Through 48 Weeks* (Study 863)
Weeks
* Proportion of patients at each time point who have achieved and maintained HIV RNA less than 400
copies/mL, are on their original study medication, and have not experienced a new CDC Class C event.
0
20
40
60
80
100
0 8 16 24 32 40 48
KA LET R A 400/ 100 mg B ID + d4T + 3T C (n=326)
N elf inavir 750 mg T ID +d4T + 3T C (n=327)
Pro
po
rtio
n R
espo
nd
ing
Kaletra PI Version 33
7 July 2020
Page 45 of 59
Table 15: Outcomes of Randomised Treatment Through Week 48 (Study 863)
Outcome Kaletra+d4T+3TC
(n=326)
Nelfinavir+d4T+3TC
(n=327)
Responder*1 75% 62%
Virologic failure2
Rebound Never suppressed through Week 48
9%
7%
2%
25%
15%
9%
Death 2% 1%
Discontinued due to adverse event 4% 4%
Discontinued for other reasons3 10% 8%
* Corresponds to rates at Week 48 in Figure 1. 1 Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48. 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 Kaletra arm and 24% in the nelfinavir arm.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of
patients in the Kaletra arm compared to the nelfinavir arm with HIV RNA less than 400
copies/mL (75% vs. 62%, respectively) and HIV RNA less than 50 copies/mL (67% vs. 52%,
respectively). Treatment response by baseline HIV RNA level subgroups is presented in Table
16.
Table 16: Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863)
Baseline Viral Load
(HIV-1 RNA copies/mL)
Kaletra +d4T+3TC Nelfinavir +d4T+3TC
<400
copies/mL1
<50 copies/mL2
n
<400 copies/mL1
<50 copies/mL2
n
<30,000 74% 71% 82 79% 72% 87
=30,000 to <100,00 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
1 Patients achieved and maintained confirmed HIV RNA <400 copies/mL through Week 48. 2 Patients achieved HIV RNA <50 copies/mL at Week 48.
Through 48 weeks of therapy, the mean increase from baseline in CD4 cell count was 207
cells/mm3 for the Kaletra arm and 195 cells/mm3 for the nelfinavir arm.
Figure 2 displays the Kaplan-Meier estimates of the time to treatment failure in Study 863. The
time of treatment failure was defined as the earliest time a patient experienced virologic failure
Kaletra PI Version 33
7 July 2020
Page 46 of 59
(two consecutive HIV RNA values demonstrating rebound above 400 copies/mL), a new CDC
Class C event, or premature discontinuation from the study.
Figure 2: Time to Treatment Failure (Study 863)
Study M05-730: Kaletra 800/200mg Once Daily + tenofovir DF + emtricitabine compared
to Kaletra 400/100mg BD + tenofovir DF + emtricitabine.
Study M05-730 was a randomised, open-label, multicentre trial comparing treatment with
Kaletra 800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra 400/100 mg
twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients.
Patients were randomised in a 1:1 ratio to receive either Kaletra 800/200 mg once daily (n =
333) or Kaletra 400/100 mg twice daily (n = 331). Further stratification within each group was
1:1 (tablet versus soft capsule). Patients were administered either the tablet or the soft capsule
formulation for 8 weeks, after which all patients were administered the tablet formulation once
daily or twice daily for the remainder of the study. Patients were administered emtricitabine
200 mg once daily and tenofovir DF 300 mg once daily. Mean age of patients enrolled was 39
years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell
count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA
was 5.0 log10 copies/mL (range: 1.7 to 7.0 log10 copies/mL).
Through 48 weeks of therapy, 78% in the Kaletra once-daily arm and 77% in the Kaletra twice-
daily arm achieved and maintained HIV-1 RNA < 50 copies/mL (95% confidence interval for
0
0.2
0.4
0.6
0.8
1
0 8 16 24 32 40 48
W eeks
Pro
po
rtio
n S
till
Re
sp
on
din
gK ALET R A 400/100 m g BID + d4T + 3TC
N elfinavir 750 m g T ID + d4T + 3TC
Kaletra PI Version 33
7 July 2020
Page 47 of 59
the difference: -5.9% to 6.8%). Mean CD4+ cell count increases at Week 48 were 186
cells/mm3 for the Kaletra once-daily arm and 198 cells/mm3 for the Kaletra twice-daily arm.
Study M97-720: Kaletra capsules BD + stavudine + lamivudine
Study M97-720 is a randomised, blinded, multicentre trial evaluating treatment with Kaletra
capsules at three dose levels (Group I: 200/100 mg BD and 400/100 mg BD; Group II: 400/100
mg BD and 400/200 mg BD) plus lamivudine (150 mg BD) and stavudine (40 mg BD) in 100
patients. All patients were converted to open label Kaletra at the 400/100 mg BD dose between
weeks 48 and 72 of the study. Patients had a mean age of 35 years (range: 21 to 59), 70%
were Caucasian, and 96% were male. Mean baseline CD4 cell count was 338 cells/mm3
(range: 3 to 918 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL
(range: 3.3 to 6.3 log10 copies/mL).
Through 360 weeks of treatment in study 720, the proportion of patients with HIV RNA less
than 400 (less than 50) copies/mL was 61% (59%) [n=100], and the corresponding mean
increase in CD4 cell count was 501 cells/mm3. Thirty-nine patients (39%) discontinued the
study, including 15 (15%) discontinuations due to adverse events and 1 (1%) death. 18
patients demonstrated loss of virologic response (two consecutive rebound HIV-1 RNA values
above 400 copies/mL, one rebound HIV-1 RNA value followed by discontinuation, or failure to
achieve HIV RNA <400 copies/mL). Genotypic analysis of viral isolates was conducted on
these patients and 10 additional patients with isolated HIV-1 RNA values > 400 copies/mL
after week 24. Results were available from 19 patients and confirmed no primary or active site
mutations in protease (amino acids at positions 8, 30, 32, 36, 47, 48, 50, 82, 84 and 90) or
protease inhibitor phenotypic resistance.
Patients with Prior Antiretroviral Therapy
Study M98-888: Kaletra capsules BD + nevirapine + NRTIs compared to investigator-
Study 888 is a randomised, open-label, multicentre trial comparing treatment with Kaletra
capsules (400/100 mg BD) plus nevirapine and nucleoside reverse transcriptase inhibitors
versus investigator-selected protease inhibitor(s) plus nevirapine and NRTIs in 288 single
protease inhibitor-experienced, NNRTI-naive patients. Patients had a mean age of 40 years
(range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD4 cell count
was 322 cells/mm3 (range: 10 to 1059 cells/mm3) and mean baseline plasma HIV-1 RNA was
4.1 log10 copies/mL (range: 2.6 to 6.0 log10 copies/mL).
Kaletra PI Version 33
7 July 2020
Page 48 of 59
Treatment response and outcomes of randomised treatment through Week 48 are presented
in Figure 3 and Table 17 respectively.
Figure 3: Virologic Response Through Week 48, Study 888*†
Study Week
* Roche AMPLICOR HIV-1 MONITOR Assay.
† Responders at each visit are patients who had achieved and maintained HIV-1 RNA <400 copies/mL without discontinuation by that visit.
Table 17: Outcomes of Randomised Treatment Through Week 48 (Study 888)
Outcome
Kaletra +
nevirapine + NRTIs
(n=148)
Investigator-Selected Protease Inhibitor(s) +
nevirapine + NRTIs
(n=140)
Responder*1 57% 33%
Virologic Failure2 24% 41%
Rebound 11% 19%
Never suppressed through Week 48 13% 23%
Death 1% 2%
Discontinued due to adverse events 5% 11%
Discontinued for other reasons3 14% 13%
* Corresponds to rates at Week 48 in Figure 4. 1 Patients achieved and maintained confirmed HIV RNA < 400 copies/mL through Week 48. 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.