Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
5.1 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 12 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)].


5.2 Toxicity in Preterm Neonates
KALETRA oral solution contains the excipients ethanol, approximately 42 % (v/v) and propylene glycol, approximately 15 % (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. 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 ethanol 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 (2.4) and Overdosage (9)].


5.3 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.


5.4 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)].


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 (11.3)].


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 (11.3)].


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, autoimmune hepatitis, 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 (11.4) ].


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             0.81 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 *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              Study 720            Study 730
(48 Weeks)               (360 Weeks)           (48 Weeks)
Variable           Limit1            KALETRA Nelfinavir              KALETRA        KALETRA KALETRA 400/100 mg       750 mg      Twice Daily + d4T Once Daily       Twice Twice Daily      Three            + 3TC          + TDF          Daily + + d4T +3TC Times Daily           (N = 100)        +FTC      TDF +FTC
(N = 326)      + d4T +                          (N=333)        (N=331) 3TC
(N = 327)
Chemistry          High
Glucose            > 250 mg/dL           2%             2%               4%             0%            <1% Uric Acid          > 12 mg/dL            2%             2%               5%             <1%            1% SGOT/              > 180 U/L             2%             4%              10%             1%             2% 2
AST
SGPT/              >215 U/L              4%             4%              11%             1%             1% ALT2
GGT                >300 U/L             N/A            N/A              10%             N/A           N/A Total              >300 mg/dL            9%             5%              27%             4%             3% Cholesterol
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         <50 mL/min           N/A             N/A              N/A             2%             2% Creatinine
Clearance
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 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor- Experienced Patients
Study 888       Study 9572 and              Study 802
(48 Weeks)              Study 7653                (48 Weeks)
(84-144 Weeks)
Variable       Limit1     KALETRA Investigator- KALETRA                   KALETRA             KALETRA 400/100 mg     Selected        Twice Daily +    800/200 mg     400/100 mg Twice Twice        Protease          NNRTI +        Once Daily       Daily +NRTIs Daily +      Inhibitor(s)          NRTIs        +NRTIs              (N=299) NVP +        + NVP +            (N = 127)      (N=300)
NRTIs         NRTIs
(N = 148)      (N = 140)
Chemistry      High
Glucose        >250          1%               2%               5%              2%                 2% mg/dL
Total Bilirubin >3.48        1%               3%               1%              1%                 1% mg/dL
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          >300          20%           21%                 39%             6%                 7% Cholesterol    mg/dL
Triglycerides >750           25%           21%                 36%             5%                 6% mg/dL
Amylase        >2 x ULN      4%               8%               8%              4%                 4% Lipase         >2 x ULN      N/A           N/A                 N/A             4%                 1% 

Creatine        >4 x ULN       N/A           N/A               N/A             4%                  5% Phosphokinase
Chemistry       Low
Calculated      <50            N/A           N/A               N/A             3%                  3% Creatinine      mL/min
Clearance
Inorganic       <1.5            1%           0%                2%              1%                  <1% Phosphorus      mg/dL
Hematology Low
Neutrophils     <0.75 x         1%           2%                4%              3%                  4% 109/L
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 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 11.

Table 11. 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.


6.2 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].

Renal and Urinary Disorders
Nephrolithiasis

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form
https://sideeffects.health.gov.il

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