Kaletra Oral Solution

KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older).

The following points should be considered when initiating therapy with KALETRA:

• The use of other active agents with KALETRA is associated with a greater likelihood of treatment response [see Microbiology (12.4) and Clinical Studies (14)].
• Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA [see Microbiology (12.4)]. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA [see Microbiology (12.4)].

• KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.

• Co-administration of KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions.
• Co-administration of KALETRA is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance. These drugs are listed in Table 8.

Table 8. Drugs That are Contraindicated with KALETRA

Drug Class	Drugs Within Class That are Contraindicated with KALETRA	Clinical Comments
Alpha 1- Adrenoreceptor Antagonist	Alfuzosin	Potentially increased alfuzosin concentrations can result in hypotension.
Antimycobacterial	Rifampin	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents [see Drug Interactions (7)].
Ergot Derivatives	Dihydroergotamine, ergotamine, methylergonovine	Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent	Cisapride	Potential for cardiac arrhythmias.
Herbal Products	St. John's Wort (hypericum perforatum)	May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors.
HMG-CoA Reductase Inhibitors	Lovastatin, simvastatin	Potential for myopathy including rhabdomyolysis.
PDE5 Enzyme Inhibitor	Sildenafila (Revatio®) when used for the treatment of pulmonary arterial hypertension	A safe and effective dose has not been established when used with KALETRA. There is an increased potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Drug Interactions (7)].
Neuroleptic	Pimozide	Potential for cardiac arrhythmias.
Sedative/Hypnotics	Triazolam; orally administered midazolamb	Prolonged or increased sedation or respiratory depression.
a see Drug Interactions (7), Table 13 for co-administration of sildenafil in patients with erectile dysfunction. b see Drug Interactions (7), Table 13 for parenterally administered midazolam.

Risk of Serious Adverse Reactions Due to Drug Interactions

Initiation of KALETRA, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving KALETRA, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of KALETRA, 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 KALETRA.
• Loss of therapeutic effect of KALETRA and possible development of resistance.

See Table 13 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during KALETRA therapy; review concomitant medications during KALETRA therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

Toxicity in Preterm Neonates

Kaletra Oral Solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving Kaletra Oral Solution.

Kaletra Oral Solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of Kaletra Oral Solution in this patient population has not been established. However, if the benefit of using Kaletra Oral Solution 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 Kaletra Oral Solution 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. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see Dosage and Administration (2.3) and Overdosage (10)].

Pancreatitis

Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis [see Warnings and Precautions (5.9)]. 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 KALETRA 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 KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.

Hepatotoxicity

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 KALETRA.

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 KALETRA therapy has not been established.

Elevated transaminases 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 KALETRA in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with KALETRA therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA 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 KALETRA treatment [see Use in Specific Populations (8.6)].

QT Interval Prolongation

Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA 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 [see Clinical Pharmacology (12.3)].

PR Interval Prolongation

Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA 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 may be at increased risk for developing cardiac conduction abnormalities.

The impact on the PR interval of co-administration of KALETRA 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 KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Clinical Pharmacology (12.3)].

Diabetes Mellitus/Hyperglycemia

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 Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. 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 [PCP], 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 Elevations

Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions (6.1)]. Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors [see Contraindications (4) and Drug Interactions (7.3)].

Fat Redistribution

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 Hemophilia

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-resistance

Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors [see Microbiology (12.4)].

The following adverse reactions are discussed in greater detail in other sections of the labeling.

• QT Interval Prolongation, PR Interval Prolongation [see Warnings and Precautions (5.5, 5.6)]
• Drug Interactions [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]

Clinical Trials Experience

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.

Adverse Reactions in Adults

The safety of KALETRA has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.

In clinical studies the incidence of diarrhea in patients treated with either KALETRA 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 Kaletra capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily Kaletra and 1.8-3.7% of those taking twice daily Kaletra reported ongoing diarrhea.

Commonly reported adverse reactions to KALETRA included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, 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 9):

Table 9. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving KALETRA in Combined Phase II/IV Studies (N=2,612)

*Represents a medical concept including several similar MedDRA PTs 1. Percentage of male population (N=2,038) 2. Percentage of female population (N=574)
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
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	1.71
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

Laboratory Abnormalities in Adults

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 10 (treatment-naïve patients) and Table 11 (treatment-experienced patients).

Table 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients

		Study 863 (48 Weeks)		Study 720 (360 Weeks)	Study 730 (48 Weeks)
Variable	Limit1	KALETRA 400/100 mg Twice Daily + d4T +3TC (N = 326)	Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327)	KALETRA Twice Daily + d4T + 3TC (N = 100)	KALETRA Once Daily + TDF +FTC (N=333)	KALETRA 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 >5x ULN (AST/ALT).

Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients

		Study 888 (48 Weeks)		Study 9572 and Study 7653 (84-144 Weeks)	Study 802 (48 Weeks)
Variable	Limit1	KALETRA 400/100 mg Twice Daily + NVP + NRTIs (N = 148)	Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs (N = 140)	KALETRA Twice Daily + NNRTI + NRTIs (N = 127)	KALETRA 800/200 mg Once Daily +NRTIs (N=300)	KALETRA 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 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 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 KALETRA 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 KALETRA in combination with NRTIs and nevirapine. 4 Criterion for Study 802 was >5x ULN (AST/ALT).

Adverse Reactions in Pediatric Patients

Kaletra Oral Solution dosed up to 300/75 mg/m2 has been studied in 100 pediatric 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 diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric 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).

Kaletra Oral Solution dosed at 300/75 mg/m2 has been studied in 31 pediatric 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).

Kaletra 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 pediatric 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 in Pediatric Patients

The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 12.

Table 12. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940

Variable	Limit1	KALETRA 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 Experience

The following adverse reactions have been reported during postmarketing use of KALETRA. 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 KALETRA exposure.

Body as a Whole
Redistribution/accumulation of body fat has been reported [see Warnings and Precautions (5.10)].

Cardiovascular
Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [see Warnings and Precautions (5.5, 5.6)].

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

Mechanism of Action

Lopinavir is an antiviral drug [see Microbiology (12.4)]. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir. 

Pharmacokinetics

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 KALETRA 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 KALETRA is due to lopinavir.

Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after KALETRA 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 KALETRA 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 KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the Kaletra Oral Solution relative to the capsule formulation.

Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability.

Effects of Food on Oral Absorption

KALETRA Tablets

No clinically significant changes in Cmax and AUC were observed following administration of KALETRA tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9% but not Cmax. Therefore, KALETRA tablets may be taken with or without food.

Kaletra Oral Solution

Relative to fasting, administration of Kaletra Oral Solution with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 80 and 54%, respectively. Relative to fasting, administration of Kaletra 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 Kaletra Oral Solution should be taken with food.

Distribution

At steady state, lopinavir is approximately 98-99% 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 KALETRA twice daily, and is similar between healthy volunteers and HIV-1 positive patients.

Metabolism

In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 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 KALETRA 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.

Elimination

Following a 400/100 mg 14C-lopinavir/ritonavir 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).

Once Daily Dosing

The pharmacokinetics of once daily KALETRA have been evaluated in HIV-1 infected subjects naïve to antiretroviral treatment. KALETRA 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 KALETRA 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.

The pharmacokinetics of once daily KALETRA has also been evaluated in treatment experienced HIV-1 infected subjects. Lopinavir exposure (Cmax, AUC[0-24h], Ctrough) with once daily KALETRA administration in treatment experienced subjects is comparable to the once daily lopinavir exposure in treatment naïve subjects.

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 KALETRA, respectively. KALETRA 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 KALETRA doses at steady state.

PR interval prolongation was also noted in subjects receiving KALETRA 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 KALETRA, respectively [see Warnings and Precautions (5.5, 5.6)].

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.

Pediatric Patients

The pharmacokinetics of Kaletra Oral Solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 pediatric patients in Study 940, ranging in age from 6 months to 12 years [see Clinical Studies (14.4)]. 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).

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 Kaletra 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 (6 months to 8 years) or 4 mg/kg twice daily (> 8 years).

The pharmacokinetics of Kaletra 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 Kaletra Oral Solution was administered at approximately 300/75 mg/m2 twice daily without concomitant NNRTI therapy.

The pharmacokinetics of KALETRA soft gelatin capsule and oral solution (Group 1: 400/100 mg/m2 twice daily + 2 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. KALETRA 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.

Pregnancy

In an open-label pharmacokinetic study, 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg (two 200/50 mg tablets) twice daily as part of an antiretroviral regimen. Plasma concentrations of lopinavir were measured over 12-hour periods during the second trimester (20-24 weeks gestation), the third trimester (30 weeks gestation) and at 8 weeks post-partum. The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum, but this decrease is not considered clinically relevant in patients with no documented KALETRA-associated resistance substitutions receiving 400 mg/100 mg twice daily.

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.

Hepatic Impairment

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of KALETRA 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 KALETRA to subjects with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment [see Warnings and Precautions (5.4) and Use in Specific Populations (8.6)].

Drug Interactions

KALETRA is an inhibitor of the P450 isoform CYP3A in vitro. Co-administration of KALETRA and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects [see Contraindications (4) and Drug Interactions (7)].

KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.

KALETRA has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.

KALETRA is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

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 summarized in Table 14 (effect of other drugs on lopinavir) and Table 15 (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. For information regarding clinical recommendations, see Table 13 in Drug Interactions (7).

Table 14. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen

Co-administered Drug	Dose of Co-administered Drug (mg)	Dose of KALETRA (mg)	n	Ratio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Cmax	AUC	Cmin
Boceprevir	800 q8h, 6 d	400/100 tablet twice daily, 22 d	13	0.70 (0.65, 0.77)	0.6612 (0.60, 0.72)	0.57 (0.49, 0.65)
Efavirenz1,2	600 at bedtime, 9 d	400/100 capsule twice daily, 9 d	11, 7*	0.97 (0.78, 1.22)	0.81 (0.64, 1.03)	0.61 (0.38, 0.97)
	600 at bedtime, 9 d	500/125 tablet twice daily, 10 d	19	1.12 (1.02, 1.23)	1.06 (0.96, 1.17)	0.90 (0.78, 1.04)
	600 at bedtime, 9 d	600/150 tablet twice daily, 10 d	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)
Fosamprenavir3	700 twice daily plus ritonavir 100 twice daily, 14 d	400/100 capsule twice daily, 14 d	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, 16 d	12	0.89 (0.80, 0.99)	0.87 (0.75, 1.00)	0.75 (0.55, 1.00)
Nelfinavir	1000 twice daily, 10 d	400/100 capsule twice daily, 21 d	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 (> 1 yr)4#	400/100 capsule twice daily, steady-state	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 once daily, 2 wk; twice daily 1 wk5	(> 1 yr) 300/75 mg/m2 oral solution twice daily, 3 wk	12, 15*	0.86 (0.64, 1.16)	0.78 (0.56, 1.09)	0.45 (0.25, 0.81)
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)
Pitavastatin6	4 once daily, 5 d	400/100 tablet twice daily, 16 d	23	0.93 (0.88-0.98)	0.91 (0.86-0.97)	N/A
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)
Rifabutin	150 once daily, 10 d	400/100 capsule twice daily, 20 d	14	1.08 (0.97, 1.19)	1.17 (1.04, 1.31)	1.20 (0.96, 1.65)
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)
Rifampin	600 once daily, 10 d	400/100 capsule twice daily, 20 d	22	0.45 (0.40, 0.51)	0.25 (0.21, 0.29)	0.01 (0.01, 0.02)
	600 once daily, 14 d	800/200 capsule twice daily, 9 d7	10	1.02 (0.85, 1.23)	0.84 (0.64, 1.10)	0.43 (0.19, 0.96)
	600 once daily, 14 d	400/400 capsule twice daily, 9 d8	9	0.93 (0.81, 1.07)	0.98 (0.81, 1.17)	1.03 (0.68, 1.56)
Rilpivirine	150 once daily13	400/100 twice daily (capsules)	15	0.96 (0.88-1.05)	0.99 (0.89-1.10)	0.89 (0.73-1.08)
Ritonavir4	100 twice daily, 3-4 wk#	400/100 capsule twice daily, 3-4 wk	8, 21*	1.28 (0.94, 1.76)	1.46 (1.04, 2.06)	2.16 (1.29, 3.62)
Tenofovir9	300 once daily, 14 d	400/100 capsule twice daily, 14 d	24	NC†	NC†	NC†
Tipranavir/ ritonavir4	500/200 twice daily (28 doses)#	400/100 capsule twice daily (27 doses)	21 69	0.53 (0.40, 0.69)10	0.45 (0.32, 0.63)10	0.30 (0.17, 0.51)10 0.48 (0.40, 0.58)11
All interaction studies conducted in healthy, HIV-1 negative subjects unless otherwise indicated. 1  The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2  Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 3  Data extracted from the fosamprenavir package insert. 4  Study conducted in HIV-1 positive adult subjects. 5  Study conducted in HIV-1 positive pediatric subjects ranging in age from 6 months to 12 years. 6  Data extracted from the pitavastatin package insert and results presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (Morgan, et al, poster #MOPE170). 7  Titrated to 800/200 twice daily as 533/133 twice daily x 1 d, 667/167 twice daily x 1 d, then 800/200 twice daily x 7 d, compared to 400/100 twice daily x 10 days alone. 8  Titrated to 400/400 twice daily as 400/200 twice daily x 1 d, 400/300 twice daily x 1 d, then 400/400 twice daily x 7 d, compared to 400/100 twice daily x 10 days alone. 9  Data extracted from the tenofovir package insert. 10 Intensive PK analysis. 11 Drug levels obtained at 8-16 hrs post-dose. 12 AUC parameter is AUC(0-last) 13 This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the co-administered drug. *  Parallel group design; n for KALETRA + co-administered drug, n for KALETRA alone. N/A = Not available. †  NC = No change. #  For the nevirapine 200 mg twice daily study, ritonavir, and tipranavir/ritonavir studies, KALETRA was administered with or without food. For all other studies, KALETRA was administered with food.

Table 15. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or Regimen

Co-administered Drug	Dose of Co-administered Drug (mg)	Dose of KALETRA (mg)	n	Ratio (in combination with KALETRA/alone) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00
				Cmax	AUC	Cmin
Bedaquiline1	400 single dose	400/100 twice daily, 24 d	N/A	N/A	1.22 (1.11, 1.34)	N/A
Boceprevir	800 q8h, 6 d	400/100 tablet twice daily, 22 d	139	0.50 (0.45, 0.55)	0.55 (0.49, 0.61)	0.43 (0.36, 0.53)
Desipramine3	100 single dose	400/100  capsule twice daily, 10 d	15	0.91 (0.84, 0.97)	1.05 (0.96, 1.16)	N/A
Efavirenz	600 at bedtime, 9 d	400/100  capsule twice daily, 9 d	11, 12*	0.91 (0.72, 1.15)	0.84 (0.62, 1.15)	0.84 (0.58, 1.20)
Ethinyl Estradiol	35 µg once daily, 21 d (Ortho Novum®)	400/100  capsule twice daily, 14 d	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 twice day (tablets)	16	0.70 (0.64-0.78)	0.65 (0.59-0.71)	0.55 (0.49-0.62)
Fosamprenavir4	700 twice daily plus ritonavir 100 twice daily, 14 d	400/100  capsule twice daily, 14 d	18	0.42 (0.30, 0.58)	0.37 (0.28, 0.49)	0.35 (0.27, 0.46)
Indinavir2	600 twice daily, 10 d combo nonfasting vs. 800 three times daily, 5 d alone fasting	400/100  capsule twice daily, 15 d	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, 16 d	12	1.13 (0.91, 1.40)	3.04 (2.44, 3.79)	N/A
Methadone	5 single dose	400/100  capsule twice daily, 10 d	11	0.55 (0.48, 0.64)	0.47 (0.42, 0.53)	N/A
Nelfinavir2	1000 twice daily, 10 d combo vs. 1250 twice daily 14 d alone	400/100  capsule twice daily, 21 d	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, 14 d; twice daily, 6 d	400/100  capsule twice daily, 20 d	5, 6*	1.05 (0.72, 1.52)	1.08 (0.72, 1.64)	1.15 (0.71, 1.86)
Norethindrone	1 once daily, 21 d (Ortho Novum®)	400/100  capsule twice daily, 14 d	12	0.84 (0.75, 0.94)	0.83 (0.73, 0.94)	0.68 (0.54, 0.85)
Pitavastatin5	4 once daily, 5 d	400/100 tablet twice daily, 16 d	23	0.96 (0.84-1.10)	0.80 (0.73-0.87)	N/A
Pravastatin	20 once daily, 4 d	400/100 capsule twice daily, 14 d	12	1.26 (0.87, 1.83)	1.33 (0.91, 1.94)	N/A
Rifabutin	150 once daily, 10 d; combo vs. 300 once daily, 10 d; alone	400/100 capsule twice daily, 10 d	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 rifabutin6				3.46 (3.07, 3.91)	5.73 (5.08, 6.46)	9.53 (7.56, 12.01)
Rilpivirine	150 once daily10	400/100 twice daily (capsules)	15	1.29 (1.18-1.40)	1.52 (1.36-1.70)	1.74 (1.46-2.08)
Rosuvastatin7	20 once daily, 7 d	400/100 tablet twice daily, 7 d	15	4.66 (3.4, 6.4)	2.08 (1.66, 2.6)	1.04 (0.9, 1.2)
Tenofovir8	300 once daily, 14 d	400/100 capsule twice daily, 14 d	24	NC†	1.32 (1.26, 1.38)	1.51 (1.32, 1.66)
All interaction studies conducted in healthy, HIV-1 negative subjects unless otherwise indicated. 1 Data extracted from the bedaquiline package insert. 2  Ratio of parameters for indinavir, and nelfinavir, are not normalized for dose. 3  Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism. 4  Data extracted from the fosamprenavir package insert. 5  Data extracted from the pitavastatin package insert and results presented at the 2011 International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention (Morgan, et al, poster #MOPE170). 6  Effect on the dose-normalized sum of rifabutin parent and 25-O-desacetyl rifabutin active metabolite. 7   Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15;47(5):570-8. 8  Data extracted from the tenofovir package insert. 9  N=12 for Cmin (test arm) 10  This interaction study has been performed with a dose higher than the recommended dose for rilpivirine (25 mg once daily) assessing the maximal effect on the co-administered drug. * Parallel group design; n for KALETRA + co-administered drug, n for co-administered drug alone. N/A = Not available. †   NC = No change.

Microbiology

Mechanism of Action

Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.

Antiviral Activity

The antiviral activity of lopinavir against laboratory HIV strains and clinical HIV-1 isolates was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean 50% effective concentration (EC50) values of lopinavir against five different HIV-1 subtype B laboratory strains ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM) and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 subtype B clinical isolates (n = 6). In the presence of 50% human serum, the mean EC50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 µg/mL), representing a 7 to 11-fold attenuation. Combination antiviral drug activity studies with lopinavir in cell cultures demonstrated additive to antagonistic activity with nelfinavir and additive to synergistic activity with amprenavir, atazanavir, indinavir, saquinavir and tipranavir. The EC50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).

Resistance

HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.

The selection of resistance to KALETRA in antiretroviral treatment naïve patients has not yet been characterized. In a study of 653 antiretroviral treatment naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA > 400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to KALETRA was observed in 37 evaluable KALETRA-treated patients (0%). Evidence of genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M substitution in HIV-1 protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral treatment naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).

Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treatment naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (> 400 copies/mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhibitor (indinavir, nelfinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, ritonavir, and saquinavir). All four of these patients had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify patterns of lopinavir resistance-associated substitutions in isolates from patients on KALETRA therapy. The assessment of these patterns is under study.

Cross-resistance - Preclinical Studies

Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during KALETRA therapy.

The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed > 4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed < 4-fold reduced susceptibility to lopinavir. Isolates with > 4-fold reduced susceptibility to indinavir (n = 16) and ritonavir (n = 3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following paragraph.

Clinical Studies - Antiviral Activity of KALETRA in Patients with Previous Protease Inhibitor Therapies

The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.

Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 16 shows the 48-week virologic response (HIV-1 RNA <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765 [see Clinical Studies (14.2) and (14.3)] and study 957 (see below). Once daily administration of KALETRA for adult patients with three or more of the above substitutions is not recommended.

Table 16. Virologic Response (HIV-1 RNA <400 copies/mL) at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA1

Number of protease inhibitor substitutions at baseline1	Study 888 (Single protease inhibitor-experienced2, NNRTI-naïve) n=130	Study 765 (Single protease inhibitor-experienced3, NNRTI-naïve) n=56	Study 957 (Multiple protease inhibitor-experienced4, 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%)
1   Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 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.

Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC50 value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 17.

Table 17. HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility1

Lopinavir susceptibility2 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%)
1   Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2   Fold change in susceptibility from wild type.

Advise the patient to read the FDA-approved patient labeling (Medication Guide)

Patients or parents of patients should be informed that:

General Information

 They should pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of KALETRA.

 They should inform their healthcare provider if their children’s weight changes in order to make sure that the child’s KALETRA dose is the correct one.

 They should take the prescribed dose of KALETRA as directed and to set up a daily routine in order to do so.

 KALETRA tablets may be taken with or without food. Kaletra Oral Solution should be taken with food to enhance absorption.

 Sustained decreases in plasma HIV-1 RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using KALETRA. Patients should be advised to take KALETRA and other concomitant antiretroviral therapy every day as prescribed. KALETRA must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of KALETRA is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose. The amount of HIV-1 virus in their blood may increase if the medicine is stopped for even a short time. The virus may become resistant to KALETRA and become harder to treat.

 KALETRA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using KALETRA.

Patients should be advised to avoid doing things that can spread HIV-1 infection to others.

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safe sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
• Do not breastfeed. Mothers with HIV-1 should not breastfeed because HIV-1 can be passed to the baby in the breast milk.

Drug Interactions

 KALETRA may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's Wort.

 KALETRA tablets can be taken at the same time as didanosine without food. Patients taking didanosine should take didanosine one hour before or two hours after Kaletra Oral Solution.

 If they are receiving avanafil, sildenafil, tadalafil, or vardenafil for the treatment of erectile dysfunction, there may be an increased risk of associated adverse reactions including hypotension, visual changes, and sustained erection, and should promptly report any symptoms to their doctor. If they are currently using or planning to use avanafil or tadalafil (for the treatment of pulmonary arterial hypertension) they should ask their doctor about potential adverse reactions these medications may cause when taken with KALETRA. The doctor may choose not to keep them on avanafil, or may adjust the dose of tadalafil while initiating treatment with KALETRA.

 If they are receiving estrogen-based hormonal contraceptives, additional or alternate contraceptive measures should be used during therapy with KALETRA.

 If they are taking or before they begin using Serevent® (salmeterol) and KALETRA, they should talk to their doctor about problems these two medications may cause when taken together. The doctor may choose not to keep someone on Serevent® (salmeterol).

 If they are taking or before they begin taking Advair® (salmeterol in combination with fluticasone propionate) and KALETRA, they should talk to their doctor about problems these two medications may cause when taken together. The doctor may choose not to keep someone on Advair® (salmeterol in combination with fluticasone propionate).

Potential Adverse Effects

 Skin rashes ranging in severity from mild to toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme, urticaria, and angioedema have been reported in patients receiving KALETRA or its components lopinavir and/or ritonavir. Patients should be advised to contact their healthcare provider if they develop a rash while taking KALETRA. The healthcare provider will determine if treatment should be continued or an alternative antiretroviral regimen used.

 Patients should be advised that appropriate liver function testing will be conducted prior to initiating and during therapy with KALETRA. Pre-existing liver disease including Hepatitis B or C can worsen with use of KALETRA. This can be seen as worsening of transaminase elevations or hepatic decompensation. Patients should be advised that their liver function tests will need to be monitored closely especially during the first several months of KALETRA treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin.

 New onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during KALETRA use. Patients should be advised to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on KALETRA as they may require a change in their diabetes treatment or new treatment.

 KALETRA might produce changes in the electrocardiogram (e.g., PR and/or QT prolongation). Patients should consult their physician if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness.

 They should seek medical assistance immediately if they develop a sustained penile erection lasting more than 4 hours while taking KALETRA and a PDE 5 Inhibitor such as Viagra, Cialis or Levitra.

 Redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time.

 Patients should be informed that there may be a greater chance of developing diarrhea with the once daily regimen as compared with the twice daily regimen.

KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir

Manufactured by AbbVie LTD, Barceloneta, PR 00617

for AbbVie Inc., North Chicago, IL 60064 USA

KALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir and Kaletra Oral Solution

AbbVie Inc., North Chicago, IL 60064 USA

The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products.

© 2015 AbbVie Inc. All rights reserved.

MEDICATION GUIDE

KALETRA® (kuh-LEE-tra)

(lopinavir and ritonavir)

tablets

KALETRA® (kuh-LEE-tra)

(lopinavir and ritonavir)

oral solution

Read this Medication Guide before you start taking KALETRA and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. You and your doctor should talk about your treatment with KALETRA before you start taking it and at regular check-ups. You should stay under your doctor’s care when taking KALETRA.

What is the most important information I should know about KALETRA?

KALETRA may cause serious side effects, including:

• Interactions with other medicines. It is important to know the medicines that should not be taken with KALETRA. For more information, see "Who should not take KALETRA?”
• Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you:
  • already have a history of abnormal heart rhythm or other types of heart disease.
  • take other medicines that can affect your heart rhythm while you take KALETRA.

Tell your doctor right away if you have any of these symptoms while taking KALETRA:

• dizziness
• lightheadedness
• fainting
• sensation of abnormal heartbeats

See “What are the possible side effects of KALETRA?” for more information about serious side effects.

What is KALETRA?

KALETRA is a prescription HIV-1 medicine that is used with other HIV medicines to treat HIV-1 (Human Immunodeficiency Virus) infection in adults and children 14 days of age and older. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). KALETRA is a type of HIV medicine called a protease inhibitor. KALETRA contains two medicines: lopinavir and ritonavir.

When used with other HIV medicines, KALETRA may help to reduce the amount of HIV in your blood (called “viral load”). KALETRA may also help to increase the number of white blood cells called CD4 (T) cell which help fight off other infections. Reducing the amount of HIV and increasing the CD4 (T) cell count may improve your immune system. This may reduce your risk of death or infections that can happen when your immune system is weak (opportunistic infections).

It is not known if KALETRA is safe and effective in children under 14 days old.

KALETRA does not cure HIV infection or AIDS. People taking KALETRA may develop infections or other conditions associated with HIV infection, including opportunistic infections (for example, pneumonia and herpes virus infections).

Avoid doing things that can spread HIV-1 infection to others:

• Do not share needles or other injection equipment.
• Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
• Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.

Ask your doctor if you have any questions on how to prevent passing HIV to other people.

Who should not take KALETRA?

Do not take KALETRA if you take any of the following medicines:

• alfuzosin (Uroxatral®)
• cisapride (Propulsid®, Quicksolv®)
• ergot containing medicines including
  • ergotamine tartrate (Cafergot®, Migergot®, Ergomar®, Ergostat®, Medihaler®, Ergotamine, Wigraine®, Wigrettes®)
  • dihydroergotamine mesylate (D.H.E. 45®, Migranal®)
  • methylergonovine (Methergine®)
• lovastatin (Advicor®, Altoprev®, Mevacor®)
• midazolam oral syrup
• pimozide (Orap®)
• rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®)
• sildenafil (Revatio®), when used for the treatment of pulmonary arterial hypertension
• simvastatin (Zocor®, Vytorin®, Simcor®)
• St. John’s Wort (Hypericum perforatum)
• triazolam (Halcion®)

Serious problems can happen if you or your child take any of the medicines listed above with KALETRA.

• Do not take KALETRA if you are allergic to lopinavir, ritonavir or any of the ingredients in KALETRA. See the end of this Medication Guide for a complete list of ingredients in KALETRA.

What should I tell my doctor before taking KALETRA?

KALETRA may not be right for you. Tell your doctor about all your medical conditions, including if you:

• have any heart problems, including if you have a condition called Congenital Long QT Syndrome.
• have or had pancreas problems.
• have liver problems, including Hepatitis B or Hepatitis C.
• have diabetes.
• have hemophilia. People who take KALETRA may have increased bleeding.
• have low potassium in your blood.
• are pregnant or plan to become pregnant. Taking KALETRA during pregnancy has not been associated with an increased risk of birth defects. You and your doctor should decide if KALETRA is right for you.
  Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your doctor about how you can take part in this registry.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you take KALETRA.
  • You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.
  • Talk to your doctor about the best way to feed your baby.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Many medicines interact with KALETRA. Do not start taking a new medicine without telling your doctor or pharmacist. Your doctor can tell you if it is safe to take KALETRA with other medicines. Your doctor may need to change the dose of other medicines while you take KALETRA.

Especially tell your doctor if you take:

• medicine to treat HIV
• estrogen-based contraceptives (birth control pills and patches). KALETRA may reduce the effectiveness of estrogen-based contraceptives. During treatment with KALETRA, you should use a different type or an extra form of birth control. Talk to your doctor about what types of birth control you can use to prevent pregnancy while taking KALETRA.
• medicines to prevent organ transplant rejection
• medicines to treat cancer
• amiodarone (Cordarone®, Pacerone®)
• atorvastatin (Lipitor®)
• atovaquone (Marlarone®, Mepron®)
• avanafil (Stendra®), sildenafil (Viagra®), tadalafil (Cialis®), or vardenafil (Levitra®) for the treatment of erectile dysfunction (ED). If you get dizzy or faint (low blood pressure), have vision changes or have an erection that last longer than 4 hours, call your doctor or get medical help right away.
• bedaquiline (Sirturo®)
• bepridil (Bepadin®, Vascor®)
• boceprevir (Victrelis®)
• bosentan (Tracleer®)
• budesonide (Rhinocort®, Symbicort®, Pulmicort®, Entocort EC®)
• bupropion (Aplenzin®, Forfivo XL®, Wellbutrin®, Zyban®)
• carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®)
• clarithromycin (Biaxin®, Prevpac®)
• colchicine (Colcrys®)
• dexamethasone (Maxidex®, Ozurdex®)
• disulfiram
• felodipine
• fentanyl (Abstral®, Actiq®, Duragesic®, Fentora®, Lazanda®, Onsolis®, Subsys®)
• fluticasone (Cutivate®, Flonase®, Flovent®, Flovent Diskus®, Flovent HFA®, Veramyst®)
• itraconazole (Onmel®, Sporanox®)
• ketoconazole (Extina®, Ketozole®, Nizoral®, Xolegel®)
• lamotrigine (Lamictal®)
• lidocaine
• methadone hydrochloride (Dolphine hydrochloride, Methadose®)
• metronidazole
• nicardipine (Cardene®)
• nifedipine (Adalat CC®, Afeditab CR®, Procardia®)
• phenobarbital
• phenytoin (Dilantin®, Phenytek®)
• prednisone
• quinidine (Quinidex®)
• quetiapine (Seroquel®)
• rifabutin (Mycobutin®)
• rivaroxaban (Xarelto®)
• rosuvastatin (Crestor®)
• salmeterol (Serevent®) or salmeterol when taken in combination with fluticasone (Advair Diskus®, Advair HFA®)
• simeprevir (Olysio®)
• tadalafil (Adcirca®) for the treatment of pulmonary arterial hypertension
• trazodone (Oleptro®)
• valproate (Depakote®, Depakene®, Depacon®)
• voriconazole (Vfend®)
• warfarin (Coumadin®, Jantoven®)

KALETRA should not be administered once daily in combination with carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®), phenobarbital, or phenytoin (Dilantin®, Phenytek®)

Ask your doctor or pharmacist if you are not sure if your medicine is one that is listed above.

Know all the medicines that you take. Keep a list of them with you to show doctors and pharmacists when you get a new medicine.

If you are not sure if you are taking a medicine above, ask your doctor.

How should I take KALETRA?

• Take KALETRA every day exactly as prescribed by your doctor.
• It is very important to set up a dosing schedule and follow it every day.
• Do not change your treatment or stop treatment without first talking with your doctor.
• KALETRA tablets should not be taken 1 time each day if you are pregnant. You should not take Kaletra Oral Solution if you are pregnant.
• Swallow KALETRA tablets whole. Do not chew, break, or crush KALETRA tablets.
• KALETRA tablets can be taken with or without food.
• If you are taking both didanosine (Videx®) and KALETRA:
  • didanosine can be taken at the same time as KALETRA tablets, without food.
  • take didanosine either one hour before or two hours after taking Kaletra Oral Solution.
• Do not miss a dose of KALETRA. This could make the virus harder to treat. If you forget to take KALETRA, take the missed dose right away. If it is almost time for your next dose, do not take the missed dose. Instead, follow your regular dosing schedule by taking your next dose at its regular time. Do not take more than one dose of KALETRA at one time.
• If you take more than the prescribed dose of KALETRA, call your doctor or go to the nearest emergency room right away.
• Take Kaletra Oral Solution with food to help it work better.
• If your child is prescribed KALETRA, tell your doctor if your child’s weight changes.
• KALETRA should not be given one time each day in children. When giving KALETRA to your child, give KALETRA exactly as prescribed.
• Kaletra Oral Solution contains propylene glycol and a large amount of alcohol. Kaletra Oral Solution should not be given to babies younger than 14 days of age unless your doctor thinks it is right for your baby.
  • If a young child drinks more than the recommended dose, it could make them sick. Contact your local poison control center or emergency room right away.
  • Talk with your doctor if you take or plan to take metronidazole or disulfiram. You can have severe nausea and vomiting if you take these medicines with KALETRA.
• When your KALETRA supply starts to run low, get more from your doctor or pharmacy. It is important not to run out of KALETRA. The amount of HIV-1 virus in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to KALETRA and become harder to treat.

What are the possible side effects of KALETRA?

KALETRA can cause serious side effects, including:

• See “What is the most important information I should know about KALETRA?”
• Inflammation of the pancreas (pancreatitis). Some people who take KALETRA get inflammation of the pancreas which may be serious and cause death. You have a higher chance of getting pancreatitis if you have had it before. Tell your doctor if you have nausea, vomiting, or abdominal pain while taking KALETRA. These may be signs of pancreatitis.
• Liver problems. Liver problems, including death, can happen in people who take KALETRA. Your doctor should do blood tests before and during your treatment with KALETRA to check your liver function. Some people with liver disease such as Hepatitis B and Hepatitis C who take KALETRA may have worsening liver disease. Tell your doctor right away if you have any of these signs and symptoms of liver problems:
  • loss of appetite
  • yellow skin and whites of eyes (jaundice)
  • dark-colored urine
  • pale colored stools
  • itchy skin
  • stomach area (abdominal) pain.
• Diabetes and high blood sugar (hyperglycemia). Some people who take protease inhibitors including KALETRA get new or more serious diabetes, or high blood sugar. Tell your doctor if you notice an increase in thirst or urinate often while taking KALETRA.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Call your doctor right away if you start having new symptoms after starting your HIV medicine.
• Increases in certain fat (triglycerides and cholesterol) levels in your blood. Large increases of triglycerides and cholesterol can be seen in blood test results of some people who take KALETRA. Your doctor should do blood tests to check your cholesterol and triglyceride levels before you start taking KALETRA and during your treatment.
• Changes in body fat. Changes in body fat in some people who take antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck ("buffalo hump"), breast, and around the trunk. Loss of fat from the legs, arms and face may also happen. The cause and long-term health effects of these conditions are not known at this time.
• Increased bleeding for hemophiliacs. Some people with hemophilia have increased bleeding with protease inhibitors including KALETRA.
• Allergic reactions. Skin rashes, some of them severe, can occur in people who take KALETRA. Tell your doctor if you had a rash when you took another medicine for your HIV-1 infection or if you notice any skin rash when you take KALETRA.
• Babies taking Kaletra Oral Solution may have side effects. Kaletra Oral Solution contains alcohol and propylene glycol. Call your doctor right away if your baby appears too sleepy or their breathing has changed.

Common side effects of KALETRA include:

• diarrhea
• nausea
• increased fats in blood (triglycerides or cholesterol)
• vomiting

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all of the possible side effects of KALETRA. For more information, ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store KALETRA?

KALETRA tablets:

• Store KALETRA tablets at room temperature, between 59°F to 86°F (15°C to 30°C).
• Do not keep KALETRA tablets out of the container it comes in for longer than 2 weeks, especially in areas where there is a lot of humidity. Keep the container closed tightly.

Kaletra Oral Solution:

• Store Kaletra Oral Solution in a refrigerator, between 36°F to 46°F (2°C to 8°C). Kaletra Oral Solution that is kept refrigerated may be used until the expiration date printed on the label.
• Kaletra Oral Solution that is stored at room temperature (less than 77°F or 25°C) should be used within 2 months.
• Keep KALETRA away from high heat.

Throw away any medicine that is out of date or that you no longer need.

Keep KALETRA and all medicines out of the reach of children.

General information about KALETRA

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use KALETRA for a condition for which it was not prescribed. Do not give KALETRA to other people, even if they have the same condition you have. It may harm them.

This Medication Guide summarizes the most important information about KALETRA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about KALETRA that is written for health professionals.

For more information about KALETRA call 1-800-633-9110 or go to www.KALETRA.com.

What are the ingredients in KALETRA?

Active ingredients: lopinavir and ritonavir

Inactive ingredients:

KALETRA 200 mg lopinavir and 50 mg ritonavir tablets: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating contains: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide 172, and polysorbate 80.

KALETRA 100 mg lopinavir and 25 mg ritonavir tablets: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating contains: polyvinyl alcohol, titanium dioxide, talc, polytheylene glycol 3350, and yellow ferric oxide E172.

Kaletra Oral Solution: acesulfame potassium, alcohol, artificial cotton candy flavor, citric acid, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural and artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water.

Kaletra Oral Solution contains 42.4% alcohol (v/v). “See How should I take KALETRA?”.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir

Manufactured by AbbVie LTD, Barceloneta, PR 00617

for AbbVie Inc., North Chicago, IL 60064 USA

KALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir and Kaletra Oral Solution

AbbVie Inc., North Chicago, IL 60064 USA

Revised: November 2015

The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products.

© 2015 AbbVie Inc. All rights reserved.

03-B238

NDC 0074–0522–60

Kaletra® (Lopinavir/Ritonavir) Tablets

100 mg / 25 mg 60 Tablets

ALERT: Find out about medicines that should NOT be taken with Kaletra®

Attention Pharmacist: Do not cover ALERT box with pharmacy label.

Dispense the accompanying Medication Guide to each patient

Rx only abbvie

NDC 0074–6799–22

Kaletra® (Lopinavir/Ritonavir) Tablets

200 mg / 50 mg 120 Tablets

ALERT: Find out about medicines that should NOT be taken with Kaletra®

Attention Pharmacist: Do not cover ALERT box with pharmacy label.

Dispense the accompanying Medication Guide to each patient.

Rx only abbvie

NDC 0074–3956–46

Kaletra® Lopinavir/Ritonavir Oral Solution

80 mg /20 mg per mL

160 mL

ALERT: Find out about medicines that should NOT be taken with KALETRA

Attention Pharmacist: Do not cover ALERT box or expiration date with pharmacy label. Store and dispense in original container.

Dispense the enclosed Medication Guide to each patient.

Rx only abbvie

KALETRA  lopinavir and ritonavir tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0074-0522 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LOPINAVIR (LOPINAVIR) LOPINAVIR 100 mg RITONAVIR (RITONAVIR) RITONAVIR 25 mg

Inactive Ingredients Ingredient Name Strength SORBITAN MONOLAURATE   SODIUM STEARYL FUMARATE   TITANIUM DIOXIDE   TALC   POLYETHYLENE GLYCOL 3350   FERRIC OXIDE YELLOW   COPOVIDONE K25-31   POLYVINYL ALCOHOL   SILICON DIOXIDE

Product Characteristics Color YELLOW (Pale Yellow) Score no score Shape OVAL Size 19mm Flavor Imprint Code a;KC Contains

Packaging # Item Code Package Description 1 NDC:0074-0522-60 60 TABLET, FILM COATED in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021906 06/18/2010

KALETRA  lopinavir and ritonavir solution

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0074-3956 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LOPINAVIR (LOPINAVIR) LOPINAVIR 80 mg  in 1 mL RITONAVIR (RITONAVIR) RITONAVIR 20 mg  in 1 mL

Inactive Ingredients Ingredient Name Strength ALCOHOL   CITRIC ACID MONOHYDRATE   GLYCERIN   HIGH FRUCTOSE CORN SYRUP   PROPYLENE GLYCOL   SODIUM CHLORIDE   WATER   ACESULFAME POTASSIUM   PEPPERMINT OIL   AMMONIUM GLYCYRRHIZATE   POLYOXYL 40 HYDROGENATED CASTOR OIL   SACCHARIN SODIUM   POVIDONES   SODIUM CITRATE, UNSPECIFIED FORM   MENTHOL, UNSPECIFIED FORM   VANILLA

Packaging # Item Code Package Description 1 NDC:0074-3956-46 1 BOTTLE in 1 CARTON 1 160 mL in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021251 06/18/2010

KALETRA  lopinavir and ritonavir tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0074-6799 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength LOPINAVIR (LOPINAVIR) LOPINAVIR 200 mg RITONAVIR (RITONAVIR) RITONAVIR 50 mg

Inactive Ingredients Ingredient Name Strength COPOVIDONE K25-31   SORBITAN MONOLAURATE   SODIUM STEARYL FUMARATE   TITANIUM DIOXIDE   POLYETHYLENE GLYCOL 400   TALC   POLYETHYLENE GLYCOL 3350   FERRIC OXIDE YELLOW   POLYSORBATE 80   HYPROMELLOSES   HYDROXYPROPYL CELLULOSE (TYPE H)   SILICON DIOXIDE

Product Characteristics Color YELLOW Score no score Shape OVAL Size 19mm Flavor Imprint Code a;KA Contains

Packaging # Item Code Package Description 1 NDC:0074-6799-22 120 TABLET, FILM COATED in 1 BOTTLE 2 NDC:0074-6799-30 120 TABLET, FILM COATED in 1 BOTTLE

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021906 06/18/2010

Labeler - AbbVie Inc. (078458370)

Revised: 11/2015   AbbVie Inc.