Kaletra (Page 3 of 11)

5.5 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)] .

5.6 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)] .

5.7 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. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with KALETRA.

5.8 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.

5.9 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)] .

5.10 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.

5.11 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.

5.12 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)].

6 ADVERSE REACTIONS

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)]

6.1 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 8):

Table 8. 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)

System Organ Class (SOC) and Adverse Reaction		n	%
BLOOD AND LYMPHATIC SYSTEM DISORDERS
anemia*		54	2.1
leukopenia and neutropenia*		44	1.7
lymphadenopathy*		35	1.3
CARDIAC DISORDERS
atherosclerosis such as myocardial infarction*		10	0.4
atrioventricular block*		3	0.1
tricuspid valve incompetence*		3	0.1
EAR AND LABYRINTH DISORDERS
vertigo*		7	0.3
tinnitus		6	0.2
ENDOCRINE DISORDERS
hypogonadism*		16	0.8 1
EYE DISORDERS
visual impairment*		8	0.3
GASTROINTESTINAL DISORDERS
diarrhea*		510	19.5
nausea		269	10.3
vomiting*		177	6.8
abdominal pain (upper and lower)*		160	6.1
gastroenteritis and colitis*		66	2.5
dyspepsia		53	2.0
pancreatitis*		45	1.7
Gastroesophageal Reflux Disease (GERD)*		40	1.5
hemorrhoids		39	1.5
flatulence		36	1.4
abdominal distension		34	1.3
constipation*		26	1.0
stomatitis and oral ulcers*		24	0.9
duodenitis and gastritis*		20	0.8
gastrointestinal hemorrhage including rectal hemorrhage*		13	0.5
dry mouth		9	0.3
gastrointestinal ulcer*		6	0.2
fecal incontinence		5	0.2
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
fatigue including asthenia*		198	7.6
HEPATOBILIARY DISORDERS
hepatitis including AST, ALT, and GGT increases*		91	3.5
hepatomegaly		5	0.2
cholangitis		3	0.1
hepatic steatosis		3	0.1
IMMUNE SYSTEM DISORDERS
hypersensitivity including urticaria and angioedema*		70	2.7
immune reconstitution syndrome		3	0.1
INFECTIONS AND INFESTATIONS
upper respiratory tract infection*		363	13.9
lower respiratory tract infection*		202	7.7
skin infections including cellulitis, folliculitis, and furuncle*		86	3.3
METABOLISM AND NUTRITION DISORDERS
hypercholesterolemia*		192	7.4
hypertriglyceridemia*		161	6.2
weight decreased*		61	2.3
decreased appetite		52	2.0
blood glucose disorders including diabetes mellitus*		30	1.1
weight increased*		20	0.8
lactic acidosis*		11	0.4
increased appetite		5	0.2
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
musculoskeletal pain including arthralgia and back pain*		166	6.4
myalgia*		46	1.8
muscle disorders such as weakness and spasms*		34	1.3
rhabdomyolysis*		18	0.7
osteonecrosis		3	0.1
NERVOUS SYSTEM DISORDERS
headache including migraine*		165	6.3
insomnia*		99	3.8
neuropathy and peripheral neuropathy*		51	2.0
dizziness*		45	1.7
ageusia*		19	0.7
convulsion*		9	0.3
tremor*		9	0.3
cerebral vascular event*		6	0.2
PSYCHIATRIC DISORDERS
anxiety*		101	3.9
abnormal dreams*		19	0.7
libido decreased		19	0.7
RENAL AND URINARY DISORDERS
renal failure*		31	1.2
hematuria*		20	0.8
nephritis*		3	0.1
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
erectile dysfunction*		34	1.7 1
menstrual disorders — amenorrhea, menorrhagia*		10	1.7 2
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
rash including maculopapular rash*		99	3.8
lipodystrophy acquired including facial wasting*		58	2.2
dermatitis/rash including eczema and seborrheic dermatitis*		50	1.9
night sweats*		42	1.6
pruritus*		29	1.1
alopecia		10	0.4
capillaritis and vasculitis*		3	0.1
VASCULAR DISORDERS
hypertension*		47	1.8
deep vein thrombosis*		17	0.7
*Represents a medical concept including several similar MedDRA PTs 1. Percentage of male population (N=2,038) 2. Percentage of female population (N=574)

Laboratory Abnormalities in Adults

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 9 (treatment-naïve patients) and Table 10 (treatment-experienced patients).

Table 9. 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	Limit 1	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/ AST 2	> 180 U/L	2%	4%	10%	1%	2%
SGPT/ ALT 2	>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 10 9 /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 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients

		Study 888 (48 Weeks)		Study 957 2 and Study 765 3 (84-144 Weeks)	Study 802 (48 Weeks)
Variable	Limit 1	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/AST 4	>180 U/L	5%	11%	8%	3%	2%
SGPT/ALT 4	>215 U/L	6%	13%	10%	2%	2%
GGT	>300 U/L	N/A	N/A	29%	N/A	N/A
Total Cholesterol	>300 mg/dL	20%	21%	39%	6%	7%
Triglycerides	>750 mg/dL	25%	21%	36%	5%	6%
Amylase	>2 x ULN	4%	8%	8%	4%	4%
Lipase	>2 x ULN	N/A	N/A	N/A	4%	1%
Creatine Phosphokinase	>4 x ULN	N/A	N/A	N/A	4%	5%
Chemistry	Low
Calculated Creatinine Clearance	<50 mL/min	N/A	N/A	N/A	3%	3%
Inorganic Phosphorus	<1.5 mg/dL	1%	0%	2%	1%	<1%
Hematology	Low
Neutrophils	<0.75 x 10 9 /L	1%	2%	4%	3%	4%
Hemoglobin	<80 g/L	1%	1%	1%	1%	2%
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/m ² 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/m ² 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/m ² (without concomitant NNRTI) and 480/120 mg/m ² (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 11.

Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940

Variable	Limit 1	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 10 9 /L	4%
Neutrophils	< 0.40 x 10 9 /L	2%
1 ULN = upper limit of the normal range. 2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase.