AZOR - amlodipine besylate and olmesartan medoxomil tablet, film coated
Physicians Total Care, Inc.
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Azor safely and effectively. See full prescribing information for Azor.
Azor (amlodipine and olmesartan medoxomil) tablet, film coated for oral use
Initial U.S. Approval: 2007
RECENT MAJOR CHANGESIndications and Usage (1)
11/2011
INDICATIONS AND USAGE
DOSAGE AND ADMINISTRATION
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONSNone (4). WARNINGS AND PRECAUTIONS
ADVERSE REACTIONSMost common adverse reaction (incidence ≥3%) is edema (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION. Revised: 5/2011 |
Azor®
(amlodipine and olmesartan
medoxomil) tablets
When pregnancy is detected, discontinue Azor as soon as possible. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus [see Warning and Precautions (5.1)].
Azor is indicated for the treatment of hypertension, alone or with other antihypertensive agents , to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Azor.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.
Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Azor may also be used as initial therapy in patients who are likely to need multiple antihypertensive agents to achieve their blood pressure goals.
Patients with moderate or severe hypertension are at relatively high risk for cardiovascular events (such as strokes, heart attacks, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. The decision to use a combination as initial therapy should be individualized and should be shaped by considerations such as baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination compared to monotherapy. Individual blood pressure goals may vary based upon the patient’s risk.
Data from an 8-week, placebo-controlled, parallel-group factorial study [see Clinical Studies (14.1)] provide estimates of the probability of reaching a blood pressure goal with Azor compared to amlodipine or olmesartan medoxomil monotherapy. The figures below provide estimates of the likelihood of achieving the targeted systolic or diastolic blood pressure goals with Azor 10/40 mg compared with amlodipine or olmesartan medoxomil monotherapy, based upon baseline systolic or diastolic blood pressure. The curve of each treatment group was estimated by logistic regression modeling from all available data of that treatment group. The right tail of each curve is less reliable because of small numbers of subjects with high baseline blood pressures.
Figure 1: Probability of Achieving Systolic Blood Pressure (SBP) <140 mmHg at Week 8 With LOCF
Figure 2: Probability of Achieving Diastolic Blood Pressure (DBP) <90 mmHg at Week 8 With LOCF
Figure 3: Probability of Achieving Systolic Blood Pressure (SBP) <130 mmHg at Week 8 With LOCF
Figure 4: Probability of Achieving Diastolic Blood Pressure (DBP) <80 mmHg at Week 8 With LOCF
The figures above provide an approximation of the likelihood of reaching a targeted blood pressure goal (e.g., Week 8 SBP <140 mmHg or <130 mmHg or a DBP <90 mmHg or <80 mmHg) for the high-dose treatment groups evaluated in the study. Azor 5/20 mg, the lowest dose combination treatment group, increases the probability of reaching blood pressure goal compared with the highest dose monotherapies, amlodipine 10 mg and olmesartan medoxomil 40 mg.
For example, a patient with a baseline blood pressure of 160/100 mmHg has about a 48% likelihood of achieving a goal of <140 mmHg (systolic) and a 51% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with olmesartan medoxomil 40 mg, and about a 46% likelihood of achieving a goal of <140 mmHg (systolic) and a 60% likelihood of achieving a goal of <90 mmHg (diastolic) on monotherapy with amlodipine 10 mg. The likelihood of achieving these same goals increases to 63% (systolic) and 71% (diastolic) on Azor 5/20 mg, and to 68% (systolic) and 85% (diastolic) on Azor 10/40 mg.
General Considerations
The side effects of olmesartan medoxomil are generally rare and apparently independent of dose. Those of amlodipine are generally dose-dependent (mostly edema).
Maximum antihypertensive effects are attained within 2 weeks after a change in dose.
Azor may be taken with or without food.
Azor may be administered with other antihypertensive agents.
Dosage may be increased after 2 weeks. The maximum recommended dose of Azor is 10/40 mg.
Replacement Therapy
Azor may be substituted for its individually titrated components.
When substituting for individual components, the dose of one or both of the components can be increased if blood pressure control has not been satisfactory.
Add-on Therapy
Azor may be used to provide additional blood pressure lowering for patients not adequately controlled with amlodipine (or another dihydropyridine calcium channel blocker) alone or with olmesartan medoxomil (or another angiotensin receptor blocker) alone.
Initial Therapy
The usual starting dose of Azor is 5/20 mg once daily. The dosage can be increased after 1 to 2 weeks of therapy to a maximum dose of one 10/40 mg tablet once daily as needed to control blood pressure [See Clinical Studies (14.1)].
Initial therapy with Azor is not recommended in patients ≥75 years old or with hepatic impairment [See Warnings and Precautions (5.7) and Use in Specific Populations (8.5, 8.6)].
Azor tablets are formulated for oral administration in the following strength combinations:
5/20 |
5/40 |
10/20 |
10/40 |
|
Amlodipine equivalent (mg) |
5 | 5 | 10 | 10 |
Olmesartan medoxomil (mg) |
20 | 40 | 20 | 40 |
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Olmesartan medoxomil. Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. There have been several dozen cases reported in the world literature of patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, discontinue Azor as soon as possible.
During the second and third trimesters of pregnancy, these drugs have been associated with fetal injury that includes hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Azor as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, discontinue Azor unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m2 basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m2 basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricular, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.
Olmesartan medoxomil. Symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Initiate treatment with Azor under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Amlodipine. Since the vasodilation attributable to amlodipine in Azor is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution, as with any other peripheral vasodilator, when administering Azor, particularly in patients with severe aortic stenosis.
Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Amlodipine. In general, calcium channel blockers should be used with caution in patients with heart failure. Amlodipine (5-10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8-12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.
Azor. There are no studies of Azor in patients with renal impairment.
Olmesartan medoxomil. Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Azor because of the olmesartan medoxomil component [See Clinical Pharmacology (12.3)].
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with olmesartan medoxomil and Azor.
Amlodipine. Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with severely impaired hepatic function, exercise caution when administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients [See Use in Specific Populations (8.6)].
Azor. There was a greater decrease in hemoglobin and hematocrit in the combination product compared to either component. Other laboratory changes can usually be attributed to either monotherapy component.
Amlodipine. In post-marketing experience, hepatic enzyme elevations have been reported (6.2).
Olmesartan medoxomil. In post-marketing experience, increased blood creatinine levels and hyperkalemia have been reported.
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Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
AzorThe data described below reflect exposure to Azor in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Azor was studied in one placebo-controlled factorial trial (see Section 14.1). The population had a mean age of 54 years and included approximately 55% males. Seventy-one percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily.
The overall incidence of adverse reactions on therapy with Azor was similar to that seen with corresponding doses of the individual components of Azor, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for Azor and 6.8% for placebo).
EdemaEdema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil.
The placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil was added to the 10 mg amlodipine dose.
| Olmesartan Medoxomil | ||||
| Placebo | 20 mg | 40 mg | ||
| Amlodipine | Placebo | –%* | -2.4% | 6.2% |
| 5mg | 0.7% | 5.7% | 6.2% | |
| 10 mg | 24.5% | 13.3% | 11.2% |
*12.3% = actual placebo incidence
Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine.
Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with Azor at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.
The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period.
Initial Therapy
Analyzing the data described above specifically for initial therapy, it was observed that higher doses of Azor caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of Azor 5/20 mg. No increase in the incidence of syncope or near syncope was observed. The incidences of discontinuation because of any treatment emergent adverse events in the double blind phase are summarized in the table below.
| Olmesartan Medoxomil | |||||
| Placebo | 10 mg | 20 mg | 40 mg | ||
| Amlodipine | Placebo | 4.9% | 4.3% | 5.6% | 3.1% |
| 5mg | 3.7% | 0.0% | 1.2% | 3.7% | |
| 10 mg | 5.5% | 6.8% | 2.5% | 5.6% |
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows:
Adverse Event |
Placebo |
2.5 mg |
5.0 mg |
10.0 mg |
| Edema | 0.6 | 1.8 | 3.0 | 10.8 |
| Dizziness | 1.5 | 1.1 | 3.4 | 3.4 |
| Flushing | 0.0 | 0.7 | 1.4 | 2.6 |
| Palpitation | 0.6 | 0.7 | 1.4 | 4.5 |
For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table;
Adverse Event |
Placebo |
Amlodipine |
||
Male=% |
Female=% |
Male=% |
Female=% |
|
| Edema | 1.4 | 5.1 | 5.6 | 14.6 |
| Flushing | 0.3 | 0.9 | 1.5 | 4.5 |
| Palpitation | 0.9 | 0.9 | 1.4 | 3.3 |
| Somnolence | 0.8 | 0.3 | 1.3 | 1.6 |
Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.
The overall frequency of adverse events was not dose-related. Analysis of gender, age, and race groups demonstrated no differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse events in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse event that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%).
The following adverse reactions have been identified during post-approval use of the individual components of Azor. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Amlodipine. The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Olmesartan medoxomil. The following adverse reactions have been reported in post-marketing experience:
Body as a Whole: asthenia,
angioedema
Gastrointestinal:
vomiting
Musculoskeletal:
rhabdomyolysis
Urogenital System: acute
renal failure
Skin and Appendages:
alopecia, pruritus, urticaria
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The pharmacokinetics of amlodipine and olmesartan medoxomil are not altered when the drugs are co-administered.
No drug interaction studies have been conducted with Azor and other drugs, although studies have been conducted with the individual amlodipine and olmesartan medoxomil components of Azor, as described below, and no significant drug interactions have been observed.
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Effect of Other Agents on Amlodipine
Cimetidine: Co-administration of amlodipine
with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: Co-administration of 240 mL of grapefruit
juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had
no significant effect on the pharmacokinetics of amlodipine.
Maalox® (antacid): Co-administration
of the antacid Maalox® with a single dose of amlodipine
had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: A single 100 mg dose of sildenafil in subjects
with essential hypertension had no effect on the pharmacokinetic parameters of
amlodipine. When amlodipine and sildenafil were used in combination, each agent
independently exerted its own blood pressure lowering effect.
Effect of Amlodipine on Other Agents
Atorvastatin: Co-administration of multiple 10
mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant
change in the steady state pharmacokinetic parameters of
atorvastatin.
Digoxin: Co-administration of
amlodipine with digoxin did not change serum digoxin levels or digoxin renal
clearance in normal volunteers.
Ethanol (alcohol):
Single and multiple 10 mg doses of amlodipine had no significant effect
on the pharmacokinetics of ethanol.
Warfarin:
Co-administration of amlodipine with warfarin did not change the warfarin
prothrombin response time.
In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers.
The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH)3/Mg(OH)2].
Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.
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Olmesartan medoxomil. Pregnancy Categories C (first trimester) and D (second and third trimesters). [See Warnings and Precautions (5.1)].
Amlodipine. No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
It is not known whether the amlodipine or olmesartan medoxomil components of Azor are excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
The safety and effectiveness of Azor in pediatric patients have not been established.
Amlodipine. The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
Olmesartan medoxomil. Safety and effectiveness of olmesartan medoxomil in pediatric patients have not been established.
Of the total number of subjects in the double-blind clinical study of Azor, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.
Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in patients ≥75 years old.
Amlodipine. Reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required.
Olmesartan medoxomil. Of the total number of hypertensive patients receiving olmesartan medoxomil in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
There are no studies of Azor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients with hepatic impairment is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients.
There are no studies of Azor in patients with renal impairment.
Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Olmesartan medoxomil. Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min).
Of the total number of subjects in the double-blind clinical study of Azor, 25% (481/1940) were black patients. Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.
There is no information on overdosage with Azor in humans.
Amlodipine. Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Olmesartan medoxomil. Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown.
Azor is a combination of the calcium channel receptor blocker (CCB) amlodipine besylate and the angiotensin II receptor blocker (ARB) olmesartan medoxomil.
The amlodipine besylate component of Azor is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate, monobenzenesulphonate. Its empirical formula is C20H25CIN2O5•C6H6O3S.
Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
The olmesartan medoxomil component of Azor is chemically described as 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate. Its empirical formula is C29H30N6O6.
The structural formula for amlodipine besylate is:
The structural formula for olmesartan medoxomil is:
Azor contains amlodipine besylate, a white to off-white crystalline powder, and olmesartan medoxomil, a white to light yellowish-white powder or crystalline powder. The molecular weights of amlodipine besylate and olmesartan medoxomil are 567.1 and 558.59, respectively. Amlodipine besylate is slightly soluble in water and sparingly soluble in ethanol. Olmesartan medoxomil is practically insoluble in water and sparingly soluble in methanol.
Each tablet of Azor also contains the following inactive ingredients: silicified microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, and magnesium stearate. The color coatings contain polyvinyl alcohol, macrogol/polyethylene glycol 3350, titanium dioxide, talc, iron oxide yellow (5/40 mg, 10/20 mg, 10/40 mg tablets), iron oxide red (10/20 mg and 10/40 mg tablets), and iron oxide black (10/20 mg tablets).
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Azor. Azor is a combination of two antihypertensive drugs: a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker), amlodipine besylate, and an angiotensin II receptor blocker, olmesartan medoxomil. The amlodipine component of Azor inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle, and the olmesartan medoxomil component of Azor blocks the vasoconstrictor effects of angiotensin II.
Amlodipine. Experimental data suggests that amlodipine binds to both dihydropyridine and nonhydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
Olmesartan medoxomil. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.
An AT2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT1 receptor than for the AT2 receptor.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.
Amlodipine. Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Olmesartan medoxomil. Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.
Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.
The pharmacokinetics of amlodipine and olmesartan medoxomil from Azor are equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when administered separately. The bioavailability of both components is well below 100%, but neither component is affected by food. The effective half-lives of amlodipine (45±11 hours) and olmesartan (7±1 hours) result in a 2- to 3- fold accumulation for amlodipine and negligible accumulation for olmesartan with once-daily dosing.
Amlodipine. After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability is estimated as between 64% and 90%.
Olmesartan medoxomil. Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan medoxomil.
Distribution
Amlodipine. Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Olmesartan medoxomil. The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism and Excretion
Amlodipine. Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine.
Olmesartan medoxomil. Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Geriatric
The pharmacokinetic properties of Azor in the elderly are similar to those of the individual components.
Amlodipine. Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%, and a lower initial dose may be required.
Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil were studied in the elderly (>65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCѕѕ, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Pediatric
Amlodipine. Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
Olmesartan medoxomil. The pharmacokinetics of olmesartan medoxomil have not been investigated in patients <18 years of age.
Gender
Population pharmacokinetic analysis indicated that female patients had approximately 15% smaller clearances of olmesartan than male patients. Gender had no effect on the clearance of amlodipine.
Olmesartan medoxomil. Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and Cmax were 10% to 15% higher in women than in men.
Renal Insufficiency
Amlodipine. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Olmesartan medoxomil. In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). The pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied. No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min).
Hepatic Insufficiency
Amlodipine. Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
Olmesartan medoxomil. Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Heart Failure
Amlodipine. Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
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Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
Olmesartan medoxomil. Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan. Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
Enter section text here
An 8-week multicenter, randomized, double-blind, placebo controlled, parallel group factorial study in patients with mild to severe hypertension was conducted to determine if treatment with Azor was associated with clinically significant reduction in blood pressure compared to the respective monotherapies. The study randomized 1940 patients equally to one of the following 12 treatment arms: placebo, monotherapy treatment with amlodipine 5 mg or 10 mg, monotherapy treatment with olmesartan medoxomil 10 mg, 20 mg, or 40 mg, or combination therapy with amlodipine/olmesartan medoxomil at doses of 5/10 mg, 5/20 mg, 5/40 mg, 10/10 mg, 10/20 mg, and 10/40 mg. Patients discontinued their prior antihypertensive treatment. The mean baseline blood pressure of the study population was 164/102 mmHg. Of the total cohort, 970 patients were treated with the combination as initial therapy.
Treatment with Azor resulted in statistically significant greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components.
The following table presents the results for mean reduction in seated systolic and diastolic blood pressure following 8 weeks of treatment with Azor. Placebo-adjusted reductions from baseline in blood pressure were progressively greater with increases in dose of both amlodipine and olmesartan medoxomil components of Azor.
| Olmesartan medoxomil | ||||||
| (mmHg) | Placebo | 10 mg | 20 mg | 40 mg | ||
| Amlodipine | Placebo | Mean Change | -5/-3 | -12/-8 | -14/-9 | -16/-10 |
| Placebo-Adjusted Mean Change | -- | -8/-5 | -10/-6 | -13/-7 | ||
| 5 mg | Mean Change | -15/-9 | -24/-14 | -24/-14 | -25/-16 | |
| Placebo-Adjusted Mean Change | -12/-7 | -20/-11 | -20/-11 | -22/-13 | ||
| 10mg | Mean Change | -20/-13 | -25/-16 | -29/-17 | -30/-19 | |
| Placebo-Adjusted Mean Change | -16/-10 | -22/-13 | -25/-14 | -26/-16 |
The antihypertensive effect of Azor was similar in patients with and without prior antihypertensive medication use, in patients with and without diabetes, in patients >65 years of age and <65 years of age, and in women and men. Limited data exist in patients >75 years of age.
Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-Black patients. This effect in black patients has been seen with ACE inhibitors, angiotensin receptor blockers, and beta-blockers.
The blood pressure lowering effect was maintained throughout the 24-hour period with Azor once daily, with trough-to-peak ratios for systolic and diastolic response between 71% and 82%.
Upon completing the 8-week, double-blind, placebo-controlled study, 1684 patients entered a 44-week open-label extension and received combination therapy with amlodipine 5 mg plus olmesartan medoxomil 40 mg. During the open-label extension, patients whose blood pressure was not adequately controlled (i.e., did not achieve a blood pressure goal of <140/90 mmHg, or <130/80 mmHg for those patients with diabetes) on amlodipine/olmesartan medoxomil 5/40 mg were titrated to amlodipine/olmesartan medoxomil 10/40 mg. Patients whose blood pressure was still not adequately controlled were offered additional hydrochlorothiazide 12.5 mg and subsequently 25 mg as required to achieve adequate blood pressure goal.
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind, placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 on placebo. Once daily administration produced statistically significant placebo-corrected reductions in supine and standing blood pressures at 24 hours postdose, averaging about 12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mild to moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosing interval was observed, with little difference in peak and trough effect.
The antihypertensive effects of olmesartan medoxomil have been demonstrated in seven placebo-controlled studies at doses ranging from 2.5 mg to 80 mg for 6 to 12 weeks, each showing statistically significant reductions in peak and trough blood pressure. A total of 2693 patients (2145 olmesartan medoxomil; 548 placebo) with essential hypertension were studied. The blood pressure lowering effect was maintained throughout the 24-hour period with olmesartan medoxomil once daily, with trough-to-peak ratios for systolic and diastolic response between 60% and 80%.
Azor tablets contain amlodipine besylate at a dose equivalent to 5 or 10 mg amlodipine and olmesartan medoxomil in the strengths described below.
Azor tablets are differentiated by tablet color/size and are debossed with an individual product tablet code on one side. Azor tablets are supplied for oral administration in the following strength and package configurations:
|
Tablet Strength (amlodipine equivalent/ olmesartan |
Package Configuration |
NDC# |
Product Code |
Tablet Color |
5/20 mg |
Bottle of 30 |
54868-6036-0 | C73 | White |
| 10/40 mg | Bottle of 30 |
54868-6250-0 | C77 | Brownish Red |
Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].
Physicians should instruct female patients of childbearing age about the consequences of second and third trimester exposure to drugs that act on the renin-angiotensin system and they should be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be informed to report pregnancies to their physicians as soon as possible. [See Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ].
Manufactured for Daiichi Sankyo, Inc., Parsippany, New Jersey
07054
Manufactured by Daiichi Sankyo Europe GmbH, Germany
Copyright © Daiichi Sankyo, Inc. 2007. All rights reserved.
Relabeling of "Additional" barcode label by: Physicians Total Care, Inc., Tulsa, OK 74146
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AZOR
amlodipine besylate and olmesartan medoxomil tablet, film coated | ||||||||||||||||||||
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AZOR
amlodipine besylate and olmesartan medoxomil tablet, film coated | ||||||||||||||||||||||||||
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| Labeler - Physicians Total Care, Inc. (194123980) |
| Establishment | |||
| Name | Address | ID/FEI | Business Operations |
|---|---|---|---|
| Physicians Total Care, Inc. | 194123980 | relabel |


Enter Phase 0 Week 9 of Dev Bootcamp. Phase 1 is nearly here, and I'll spend some final momements reflecting on building this site as well as what to look forward to throughout the rest of DBC.
- Overall impressions of site building
- The path forward
Overall impressions of site building
Building a personal website has been pretty fun overall. The thing I liked most about building the site was designing it, specifically the brainstorming process and laying out the structure and content. The most challenging tasks were making the site responsive and manipulating CSS to make the site actually reflect the design. With so many different devices accessing websites at different screen sizes and orientations, it is quite the challenge to ensure the website's appearance looks consistent across all platforms. I found I had to compromise some of my initial design, since there was such a drastic difference for the landing page on mobile and tablet compared to a desktop. In terms of developing, I think having a complete list of good requirements is essential to the entire development process. However, depending on the project and other constraints, this might not be necessary when using developing in spirals.
The path forward
I plan to continue writing on this blog. Doing this will definitely help reinforce what I'm learning while also making knowledge available to any readers. I think I'll make a weekly post, but posts may be more frequent depending on how much information I'm digesting during any given day or week. The next nine weeks are going be fun and exhausting. Good luck to the Fiery Skippers of 2016!


assert
messages that are not of the java.lang.String
type.
Using a string provides more information to help diagnose the failure or the assertion reason.
Example:
void foo(List<Integer> myList) {
assert myList.isEmpty() : false;
}
Use the Only warn when the assert
message type is 'boolean' or 'java.lang.Boolean' option to only warn when the assert
message type is boolean
or java.lang.Boolean
.
A boolean
detail message is unlikely to provide additional information about an assertion failure
and could result from a mistakenly entered :
instead of &
.


My name is Hafidz
我叫何飞志
I am an Application Developer at KAF Investment Bank. As a professional developer, my interests focus on UI/UX design and development, and building applications using modern web technologies and JavaScript frameworks.
Nov 2018 - Current
KAF Investment Bank
Application Developer
Collaborated with senior developers in developing and maintaining KAF in-house applications.
Designed and developed wireframes, workflows and contributed to the front-end and back-end development.
Technologies: ASP.NET Web Forms, VB.NET, jQuery, Bootstrap, HTML and CSS.
May 2018 - Sep 2018
Breadcrumb Digital
Front End Developer Intern
Demonstrated development tasks using SharePoint SPFx framework, Restful API, ReactJS and TypeScript.
Performed and maintained existing applications for SharePoint and WordPress development.
Technologies: SharePoint, SPFx, Restful API, ReactJS, TypeScript, SASS, WordPress.
017 444 8226
LinkedIn: Click Link Here!
GitHub: Click Link Here!
Indeed: Click Link Here!
Publius Horatius Cocles once said:
To every man upon this earth,
Death cometh soon or late.
And how can man die better
Than facing fearful odds,
For the ashes of his fathers,
And the temples of his gods.
― Thomas Babington Macaulay, Lays of Ancient Rome


Mostly Cloudy
20
Tuesday
79
55
Wednesday
81
61
Thursday
72
57
Friday
70
57
Saturday
69
63
Sunday
74
61


Markov Decision Processes¶
Introduction¶
In RL, we have an agent that interacts with it’s environment. At each time step, the agent will get some representation of the environment’s. Then, the agent selects an action to take. The environment is then transitioned into a new state and the agent is given a reward as a consequence of the previous action.
Any RL task can be defined with the following components:
Agent
States
Actions
Rewards
Markov Chain¶
Markov’s property states that the future depends only on the present, not on the past. A Markov chain is a probabilistic model that represent this kind of approach. Moving from one state to another is called transition and its probability is called transition probability. We can represent a Markov chain as a state diagram:
Markov Decision Process (MDP)¶
When an stochastic process is called follows Markov’s property, it is called a Markov Process. MDP is an extension of the Markov chain. It provides a mathematical framework for modeling decision-making.
A MDP is completely defined with 4 elements:
A set of states(\(S\)) the agent can be in.
A set of actions (\(A\)) that can be performed by an agent to move from one state to another.
A set of transition probabilities (\(P^a_{ss'}\)), which define the probability of moving from state \(s\) to state \(s'\) by performing action \(a\).
A set of reward probabilities (\(R^a_{ss'}\)), which defines the probability of a reward acquired for moving from state \(s\) to state \(s'\) by performing action \(a\).
Rewards and returns¶
At each time step \(t=0,1,2,...\), the agent receives some representation of the environment’s state \(s_t \in S\). Based on this state, the agent selects an action \(a_t \in A\). The agent’s goal is to maximize the total amount of rewards instead of immediate rewards. The total reward can be formulated as: \(R=r_{t+1}+r_{t+1}+\dots+r_{T}\).
\(r_{t+i}\) is the reward received at time step \(t_{i-1}\) while performing an action \(a_{i-1}\) to move from state \(s_{i-1}\) to state \(s_{i}\).
Episodic VS Continuous Tasks¶
Episodic tasks are those that have a terminal state at time \(T\), which is followed by resetting the environment to its initial state. The next episode then begins independently from how the previous episode ended. TicTacToe is an episodic task, being each episode a round.
In a continuous task, there is not a terminal state. This kind of tasks will never end.
Discount Factor¶
In continuous tasks we do not have a final time step \(T\), so the total reward will sum to infinity. To maximize this return, a discount factor \(\gamma\) is introduced:
\(R=\sum_{k=0}^\infty\gamma^kr_{t+k+1}\)
This factor decides how much importance we give to the future rewards and immediate rewards. The value of the discount factor lies within 0 to 1. A discount factor of 0 means that immediate rewards are more important, while a factor of 1 would mean that furure rewards are more important. Typical values of the discount factor are between 0.2 and 0.8.
Policy Function¶
A policy function \(\pi\) maps the states to actions. It can be represented as \(\pi(s): S \rightarrow A\). Basically, a policy function says what action to perform in each state. The ultimate goal is finding the optimal policy that results in the correct action to perform in each state maximizing the reward.
State Value Function¶
A state value function (or simply value function) specifies how good it is for an agent to be in a particular state with a policy \(\pi\). The value functions is defined as \(V^\pi(s)=\mathbb{E}_\pi [R_t|s_t=s]\):
For episodic tasks: \(V^\pi(s)=\mathbb{E}_\pi [\sum_{k=1}^{T}r_{t+k}|s_t=s]\).
For continuous tasks: \(V^\pi(s)=\mathbb{E}_\pi [\sum_{k=0}^{\infty}\gamma^kr_{t+k+1}|s_t=s]\).
This is the expected return starting from state \(s\) according to policy \(\pi\).
Based on the value of each state, we can tell how good it is for our agent to be in each one.
State |
Value |
|---|---|
State 1 |
0.7 |
State 2 |
0.5 |
State-action Value function (Q function)¶
A state-action value function is also called the Q function. It specifies how good it is for an agent to perform a particular action in a state with a policy \(\pi\). The Q function is defined as \(Q^\pi(s,a)=\mathbb{E}_\pi [R_t|s_t=s]\):
For episodic tasks: \(Q^\pi(s,a)=\mathbb{E}_\pi [\sum_{k=1}^{T}r_{t+k}|s_t=s,a_t=a]\)
For continuous tasks: \(Q^\pi(s,a)=\mathbb{E}_\pi [\sum_{k=0}^{\infty}\gamma^kr_{t+k+1}|s_t=s,a_t=a]\)
This function specifies the expected return starting from state \(s\) performing action \(a\) according to policy \(\pi\).
State |
Action |
Value |
|---|---|---|
State 1 |
Action 1 |
0.7 |
State 1 |
Action 2 |
0.01 |
State 2 |
Action 1 |
0.5 |
State 2 |
Action 2 |
0.8 |
Note
The difference between the value function and the Q function is that the first one specifies the goodness of a state and the latter specifies the goodness of an action in a state.
Bellman equation¶
The Bellman equation helps us finding the optimal policies and value functions. The optimal value function is the one yielding maximum value compared to all other value functions. Similarly, the optimal policy is the one which results in an optimal value function.
Since the optimal value function is the one that has a higher value, it will be the maximum ot the Q functions: \(V^*(s)=max_aQ^*(s,a)\)
The Bellman equation for the value and Q functions is:
\(V^\pi(s)=\sum_{a}\pi(s,a)\sum_{s'}P^a_{ss'}[R^a_{ss'}+\gamma V^\pi(s')]\)
\(Q^\pi(s,a)=\sum_{s'}P^a_{ss'}[R^a_{ss'}+\gamma\sum_{a'}Q^\pi(s',a')]\)
Finally, the Bellman optimality equation is:
\(V^*(s)=max_a\sum_{s'}P^a_{ss'}[R^a_{ss'}+\gamma\sum_{a'}Q^\pi(s',a')]\)
To solve this equation, two algorithms are used:
Value iteration.
Policy iteration.
Value Iteration¶
The steps involved in the value iteration are as follows:
We initialize the value function randomly.
Then we compute the Q function for all state-action pairs of \(Q(s,a)\).
Then we update our value function with the max value from \(Q(s,a)\).
We repeat these steps until the change in the value function is very small.
Policy Iteration¶
We start with the random policy, then we find the value function of that policy; if the value function is not optimal, then we find the new improved policy. We repeat this process till we find the optimal policy. The steps involved in policy iteration are as follows:
First, we initialie some random policy.
Then, we find the value function for that random policy and evaluate to check if it is optimal (policy evaluation).
If it is not optimal, we find a new improved policy (policy improvement).
We repeat steps till we find an optimal policy.


In computer science, a stack is a particular kind of data type or collection in which the principal operations in the collection are the addition of an entity to the collection (also known as push) and the removal of an entity (also known as pop). The relation between the push and pop operations is such that the stack is a Last-In-First-Out (LIFO) data structure. In a LIFO data structure, the last element added to the structure must be the first one to be removed. Often a peek, or top operation is also implemented, returning the value of the top element without removing it.
We will emulate the stack process with Python. You are given a sequence of commands:
- "PUSH X" -- add X in the stack, where X is a digit.
- "POP" -- look and remove the top position. If the stack is empty, then it returns 0 (zero) and does nothing.
- "PEEK" -- look at the top position. If the stack is empty, then it returns 0 (zero).
The stack can only contain digits.
You should process all commands and sum all digits which were taken from the stack ("PEEK" or "POP"). Initial value of the sum is 0 (zero).
Let's look at an example, here’s the sequence of commands:
["PUSH 3", "POP", "POP", "PUSH 4", "PEEK", "PUSH 9", "PUSH 0", "PEEK", "POP", "PUSH 1", "PEEK"]
| Command | Stack | Sum |
|---|---|---|
| PUSH 3 | 3 | 0 |
| POP | 0+3 | |
| POP | 3+0 | |
| PUSH 4 | 4 | 3 |
| PEEK | 4 | 3+4 |
| PUSH 9 | 4,9 | 7 |
| PUSH 0 | 4,9,0 | 7 |
| PEEK | 4,9,0 | 7+0 |
| POP | 4,9 | 7+0 |
| PUSH 1 | 4,9,1 | 7 |
| PEEK | 4,9,1 | 7+1=8 |
Input: A sequence of commands as a list of strings.
Output: The sum of the taken digits as an integer.
Example:
digit_stack(["PUSH 3", "POP", "POP", "PUSH 4", "PEEK", "PUSH 9", "PUSH 0", "PEEK", "POP", "PUSH 1", "PEEK"]) == 8 digit_stack(["POP", "POP"]) == 0 digit_stack(["PUSH 9", "PUSH 9", "POP"]) == 9 digit_stack([]) == 0
How it is used: Stacks have numerous applications. We see stacks in everyday life, from the books in our library, to the blank sheets of paper in our printer tray. All of them follow the Last In First Out (LIFO) logic, that is when we add a book to a pile of books, we add it to the top of the pile, whereas when we remove a book from the pile, we generally remove it from the top of the pile.
Precondition:
0 ≤ len(commands) ≤ 20;
all(re.match("\APUSH \d\Z", c) or с == "POP" or c == "PEEK" for c in commands)


Welcome to TeamSpeakPHPBots' example Multiple Bot Types.
This example demonstrates how to deal with different bot types.
It also shows the user and bot management capabilities of the framework.
Please, login in order to begin the journey.
Bot Configuration
User Management
Bot Server


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We sell protest gear, poster equipment, and merch. All proceeds are donated to protester bail funds.
Here is a list of all verified organizations working towards the movement: anything helps.
This is a list of petitions ranging from arresting George Floyd's murders to defunding the police department.
June 4, 2020
That’s how long a police officer kept his knee on George Floyd’s neck. George Floyd struggled, pleading for his life: “I can’t breathe,” until he drew his final breaths. Today, at 3:45 p.m. ET / 12:45 p.m. PT, we will be silent for 8 minutes, 46 seconds — to remember George Floyd.
June 1, 2020
Our pain, our cries, and our need to be seen and heard resonate throughout this entire country. We demand acknowledgment and accountability for the dehumanization of Black life at the hands of the police. We call for radical, sustainable solutions that affirm the prosperity of Black lives.
May 25, 2020
Just before 1 a.m. on March 13, three officers forced their way into Breonna Taylor's Louisville, Kentucky apartment with a battering ram, shooting her at least eight times until she died on her hallway floor. Taylor was an ER technician and former EMT; her mom, Tamika Palmer, told the Louisville Courier Journal that she had plans of "becoming a nurse and buying a house and then starting a family.
Our protest gear kit comes with a tear gas mask, heat resistant gloves, a fask mask, a fanny-pack, a durible helmet, and knee & elbow pads.
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Learn More.The poster equipment kit comes with protest sign essentials- multicolor king sized markers, poster board, wooden sticks, and super glue.
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CS-Script settings
Information about CS-Script engine configuration. This section
describes how to control the script engine behavior through CS-Script
configuration file. It also includes the overview of the version
compatibility between CS-Script and CLR.
CS-Script application configuration
Information about script
application configuration. This section describes how to
access application (script application) specific configuration
data through <script>.config file.
CS-Script Runtume Environment
This section describes class CSSEnvironment, which provides information about the CS-Script runtime environment.


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Overview
This document describes how to use SSL in Twisted servers and clients. It assumes that you know what SSL is, what some of the major reasons to use it are, and how to generate your own SSL certificates, in particular self-signed certificates. It also assumes that you are comfortable with creating TCP servers and clients as described in the server howto and client howto. After reading this document you should be able to create servers and clients that can use SSL to encrypt their connections, switch from using an unencrypted channel to an encrypted one mid-connection, and require client authentication.
Using SSL in Twisted requires that you have
pyOpenSSL installed. A quick test to
verify that you do is to run from OpenSSL import SSL
at a
python prompt and not get an error.
Twisted provides SSL support as a transport - that is, as an alternative
to TCP. When using SSL, use of the TCP APIs you're already familiar
with, TCP4ClientEndpoint
and TCP4ServerEndpoint
-
or reactor.listenTCP
and reactor.connectTCP
-
is replaced by use of parallel SSL APIs. To create an SSL server, use
SSL4ServerEndpoint
or
listenSSL
.
To create an SSL client, use
SSL4ClientEndpoint
or
connectSSL
.
SSL connections require SSL contexts. As with protocols, these context
objects are created by factories - so that each connection can be given a
unique context, if necessary. The context factories typically also keep
state which is necessary to properly configure an SSL context object for
its desired use - for example, private key or certificate data. The
context factory is passed as a mandatory argument to any and all of the
SSL APIs mentioned in the previous
paragraph. twisted.internet.ssl.CertificateOptions
is one commonly useful context factory for both clients and
servers. twisted.internet.ssl.PrivateCertificate.options
is a convenient way to create a CertificateOptions
instance
configured to use a particular key and certificate.
Those are the big immediate differences between TCP and SSL connections, so let's look at an example. In it and all subsequent examples it is assumed that keys and certificates for the server, certificate authority, and client should they exist live in a keys/ subdirectory of the directory containing the example code, and that the certificates are self-signed.
SSL echo server and client without client authentication
Authentication and encryption are two separate parts of the SSL protocol. The server almost always needs a key and certificate to authenticate itself to the client but is usually configured to allow encrypted connections with unauthenticated clients who don't have certificates. This common case is demonstrated first by adding SSL support to the echo client and server in the core examples.
SSL echo server
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
if __name__ == '__main__': import echoserv_ssl raise SystemExit(echoserv_ssl.main()) import sys from twisted.internet import reactor from twisted.internet.protocol import Factory from twisted.internet import ssl, reactor from twisted.python import log import echoserv def main(): with open('server.pem') as keyAndCert: cert = ssl.PrivateCertificate.loadPEM(keyAndCert.read()) log.startLogging(sys.stdout) factory = Factory() factory.protocol = echoserv.Echo reactor.listenSSL(8000, factory, cert.options()) reactor.run()
SSL echo client
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
if __name__ == '__main__': import echoclient_ssl raise SystemExit(echoclient_ssl.main()) import sys from twisted.internet.protocol import ClientFactory from twisted.protocols.basic import LineReceiver from twisted.internet import ssl, reactor class EchoClient(LineReceiver): end="Bye-bye!" def connectionMade(self): self.sendLine("Hello, world!") self.sendLine("What a fine day it is.") self.sendLine(self.end) def connectionLost(self, reason): print 'connection lost (protocol)' def lineReceived(self, line): print "receive:", line if line==self.end: self.transport.loseConnection() class EchoClientFactory(ClientFactory): protocol = EchoClient def clientConnectionFailed(self, connector, reason): print 'connection failed:', reason.getErrorMessage() reactor.stop() def clientConnectionLost(self, connector, reason): print 'connection lost:', reason.getErrorMessage() reactor.stop() def main(): factory = EchoClientFactory() reactor.connectSSL('localhost', 8000, factory, ssl.CertificateOptions()) reactor.run()
Notice how all of the protocol code from the TCP version of the echo client and server examples is the same (imported or repeated) in these SSL versions - only the reactor method used to initiate a network action is different.
One part of the SSL connection contexts control is which version of the
SSL protocol will be used. This is often called the context's "method".
By default, CertificateOptions
creates contexts which will
select the TLSv1 protocol. CertificateOptions
also supports
the older SSLv3 protocol (which may be required interoperate with an
existing service or piece of software), just
pass OpenSSL.SSL.SSLv3_METHOD
to its
initializer: CertificateOptions(..., method=SSLv3_METHOD)
.
SSLv23_METHOD
is also supported (to enable either SSLv3 or
TLSv1 based on negotiation). SSLv2 is explicitly not supported.
Using startTLS
If you want to switch from unencrypted to encrypted traffic
mid-connection, you'll need to turn on SSL with startTLS
on both
ends of the connection at the same time via some agreed-upon signal like the
reception of a particular message. You can readily verify the switch to an
encrypted channel by examining the packet payloads with a tool like
Wireshark.
startTLS server
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26
from twisted.internet import reactor, ssl from twisted.internet.protocol import ServerFactory from twisted.protocols.basic import LineReceiver class TLSServer(LineReceiver): def lineReceived(self, line): print "received: " + line if line == "STARTTLS": print "-- Switching to TLS" self.sendLine('READY') self.transport.startTLS(self.factory.contextFactory) if __name__ == '__main__': with open("keys/server.key") as keyFile: with open("keys/server.crt") as certFile: cert = PrivateCertificate.loadPEM( keyFile.read() + certFile.read()) factory = ServerFactory() factory.protocol = TLSServer factory.contextFactory = cert.options() reactor.listenTCP(8000, factory) reactor.run()
startTLS client
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41
from twisted.internet import reactor, ssl from twisted.internet.protocol import ClientFactory from twisted.protocols.basic import LineReceiver class TLSClient(LineReceiver): pretext = [ "first line", "last thing before TLS starts", "STARTTLS"] posttext = [ "first thing after TLS started", "last thing ever"] def connectionMade(self): for l in self.pretext: self.sendLine(l) def lineReceived(self, line): print "received: " + line if line == "READY": self.transport.startTLS(ssl.CertificateOptions()) for l in self.posttext: self.sendLine(l) self.transport.loseConnection() class TLSClientFactory(ClientFactory): protocol = TLSClient def clientConnectionFailed(self, connector, reason): print "connection failed: ", reason.getErrorMessage() reactor.stop() def clientConnectionLost(self, connector, reason): print "connection lost: ", reason.getErrorMessage() reactor.stop() if __name__ == "__main__": factory = TLSClientFactory() reactor.connectTCP('localhost', 8000, factory) reactor.run()
startTLS
is a transport method that gets passed a context
factory. It is invoked at an agreed-upon time in the data reception method
of the client and server protocols. The server
uses PrivateCertificate.options
to create a context factory
which will use a particular certificate and private key (a common
requirement for SSL servers). The client creates an
uncustomized CertificateOptions
which is all that's necessary
for an SSL client to interact with an SSL server, although it is missing
some verification settings necessary to ensure correct authentication of the
server and confidentiality of data exchanged.
Client authentication
Server and client-side changes to require client authentication fall largely under the dominion of pyOpenSSL, but few examples seem to exist on the web so for completeness a sample server and client are provided here.
Client-authenticating server
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
from twisted.internet import ssl, reactor from twisted.internet.protocol import Factory, Protocol class Echo(Protocol): def dataReceived(self, data): self.transport.write(data) if __name__ == '__main__': factory = Factory() factory.protocol = Echo with open("keys/ca.pem") as certAuthCertFile: certAuthCert = ssl.Certificate.loadPEM(certAuthCertFile.read()) with open("keys/server.key") as keyFile: with open("keys/server.crt") as certFile: serverCert = ssl.PrivateCertificate.loadPEM( keyFile.read() + certFile.read()) contextFactory = serverCert.options(certAuthCert) reactor.listenSSL(8000, factory, contextFactory) reactor.run()
When one or more certificates are passed
to PrivateCertificate.options
, the resulting context factory
will use those certificates as trusted authorities and require that the
peer present a certificate with a valid chain terminating in one of those
authorities.
Client with certificates
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35
from twisted.internet import ssl, reactor from twisted.internet.protocol import ClientFactory, Protocol class EchoClient(Protocol): def connectionMade(self): print "hello, world" self.transport.write("hello, world!") def dataReceived(self, data): print "Server said:", data self.transport.loseConnection() class EchoClientFactory(ClientFactory): protocol = EchoClient def clientConnectionFailed(self, connector, reason): print "Connection failed - goodbye!" reactor.stop() def clientConnectionLost(self, connector, reason): print "Connection lost - goodbye!" reactor.stop() if __name__ == '__main__': with open("keys/server.key") as keyFile: with open("keys/server.crt") as certFile: clientCert = ssl.PrivateCertificate.loadPEM( keyFile.read() + certFile.read()) ctx = clientCert.options() factory = EchoClientFactory() reactor.connectSSL('localhost', 8000, factory, ctx) reactor.run()
Notice this client code does not pass any certificate authority
certificates to PrivateCertificate.options
. This means that
it will not validate the server's certificate, it will only present its
certificate to the server for validation.
Other facilities
twisted.protocols.amp
supports encrypted
connections and exposes a startTLS
method one can use or
subclass. twisted.web
has built-in SSL support in
its client
, http
, and xmlrpc
modules.
Conclusion
After reading through this tutorial, you should be able to:
- Use
listenSSL
andconnectSSL
to create servers and clients that use SSL - Use
startTLS
to switch a channel from being unencrypted to using SSL mid-connection - Add server and client support for client authentication


Files CCore/inc/CompactNodeAllocator.h CCore/src/CompactNodeAllocator.cpp
Compact node allocator is used to allocate and destroy list and tree nodes in compact lists and tree maps. It is similar to node allocators, but have different node deletion methods. This allocator is efficient both in the performance and the memory utilization.
template <NothrowDtorType Node>
class CompactNodeAllocator : NoCopy
{
....
ulen count;
public:
// constructors
static const ulen DefaultCount = 100 ;
explicit CompactNodeAllocator(ulen block_len_=DefaultCount);
~CompactNodeAllocator();
// std move
CompactNodeAllocator(CompactNodeAllocator<Node> &&obj) noexcept;
CompactNodeAllocator<Node> & operator = (CompactNodeAllocator<Node> &&obj) noexcept;
// props
ulen operator + () const { return count; }
bool operator ! () const { return !count; }
ulen getCount() const { return count; }
// methods
template <class ... SS>
Node * alloc(SS && ... ss) requires ( ConstructibleType<Node,SS...> ) ;
ulen erase();
Node * todel();
void del();
// swap/move objects
void objSwap(CompactNodeAllocator<Node> &obj);
explicit CompactNodeAllocator(ToMoveCtor<CompactNodeAllocator<Node> > obj);
};
Constructor takes a node block length as the argument, it is 100 by default. Memory for nodes is allocated in blocks of this capacity. Destructor calls abort, if not all nodes are destroyed.
CompactNodeAllocator is not copyable, but std movable. The original object is nullified during the move.
operator + and operator ! can be used to check, if there are allocated nodes.
getCount() returns the number of allocated nodes.
alloc() allocates a node. Arguments are forwarder to the node constructor.
erase() destroys all allocated nodes. The number of nodes is returned.
todel() points to the "special" node, which can be deleted. If there are no allocated nodes, null is returned. Unlike other node allocators, compact variant can delete only one special node from the set of allocated nodes.
del() deletes the special node, if any.
CompactNodeAllocator is swappable and movable.


Exploitation vectors
Upload unexpected file format to achieve RCE or webshells (swf, html, php, php3, aspx, ...)
Execute XSS via allowed type of file
XSS or DOS the target via injecting payload to metadata of allowed file type
Store malware on sites via file polyglots
PHP functions used to RCE
system Executes a command and returns its output
shell_exec Executes a command and displays the output immediately
passthru Executes a command and displays the raw output
backtick operator (``) Executes contents inside the backtick as a shell command
popen Executes a command and returns a pointer
exec Executes a command and returns the last line of the output
pcntl_exec Executes a command or a program
proc_open Similar to popen()
Bypassing upload protections
Basic bypass
.phP, .pHp, .Php, .PHP, .jpg.php,
Change MIME type in Content-Disposition in POST body
Apache .htaccess trick (SetHandler method)
Upload .htaccesswith content as follows
<FilesMatch "_php.gif">
SetHandler application/x-httpd-php
</FilesMatch>
Now it's possible to upload phpinfo_php.gif and let it be executed as phpfile
Apache .htaccess trick (AddType method)
Upload .htaccess with content as follows
AddType application/x-httpd-php.lol
Now it's possible to upload phpinfo_php.lol and let it be executed as phpfile
Bypassing image content verification
Add php code to binary jpg
Uploaded file must have .php suffix


True or False: If the keys in a Map are Strings, the values must also be Strings
False: keys and values can be of different types. However, all keys must be of one type and all values of the other.
- True: However, this rule does not extend to Maps where Integers are keys.
- False: Each key must be of a differnet type.
- False: If the keys in a Map are Strings, the values must be Integers.


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LeVar Burton Awards and Nominations
category Outstanding Children's Series for Reading Rainbow (1983) (TV) shared with Twila Liggett (executive producer); Larry Lancit, Cecily Truett (supervising .
http://www.aceshowbiz.com/celebrity/levar_burton/awards.html
Treatment for Herniated or Bulging Discs
Reading Rainbow - Wikipedia, the free encyclopedia
The series was created under the leadership of Cecily Truett Lancit and Larry Lancit, at Lancit Media Productions in New York. The concept of a reading series .
http://en.wikipedia.org/wiki/Reading_Rainbow
Reading Rainbow | Free Music, Tour Dates, Photos, Videos
Bio: Reading Rainbow is an acclaimed American children's television series aired . and from LANCIT MEDIA PRODUCTIONS, Larry Lancit, Cecily Truett and .
http://www.myspace.com/r3adingr4inbow
cecily truett lancit bio Herniated or Bulging Discs
LeVar Burton - Awards
Top Links. biographyby votesawardsNewsDeskmessage board . Shared with: Larry Lancit (supervising producer) . Cecily Truett (supervising producer) .
http://www.imdb.com/name/nm0000996/awards
Watch Reading Rainbow Free Online
Mike Tyson on Broadway, Ann Curry Leaving Today, Ryan Gosling Dancing, Reading Rainbow iPad - Biography.com. Reading Rainbow Video. Watch Reading .
http://www.ovguide.com/tv/reading_rainbow.htm
Score Media announces sale of Television Business to Rogers ...
Aug 25, 2012 . News; Videos; Video Details; Biography; Images; Related Links . The series was created under the leadership of Cecily Truett Lancit and .
http://article.wn.com/view/2012/08/25/Score_Media_announces_sale_of_Television_Business_to_Rogers_/
Official Impairment Listing for Spinal Disorders
Emmy Awards 1996 (List of Award Winners and Nominees)
Sep 7, 1996. Twila Liggett, Tony Buttino, LeVar Burton, Cecily Truett, Larry Lancit, Orly . Biography (1987), Josh Howard, Michael Cascio, Randy Martin, .
http://www.whosdatedwho.com/tpx_2870920/emmy-awards/1996
- replacement spring for garage door (narrowing of the spine)
Daytime Emmy Awards (1996)
Reading Rainbow: Mark Mannucci, Ed Wiseman, Larry Lancit (PBS) . Cecily Truett (supervising producer), Orly Wiseman (supervising producer), Larry Lancit .
http://www.imdb.com/event/ev0000206/1996Winthrop University - The Full Wiki
Mar 6, 2010 . Education (with emphasis in Art, Biology, Business/Marketing, English, . Cecily Truett Lancit, (1971), Emmy Award-winning educational .
http://www.thefullwiki.org/Winthrop_University
Reading Rainbow: Series Info
The series was created under the leadership of Cecily Truett Lancit and Larry Lancit, at Lancit Media Productions in New York. The concept of a reading series .
http://thetvdb.com/?tab=series&id=77547
CINE GOLDEN EAGLE FILM & VIDEO COMPETITION 1995 ...
Sonia Rosario, Larry Lancit, Cecily Truett,. Stephen Kulczycki . PRODUCTION: Lancit Media Productions, Ltd. . Desmond Morris' The Human Animal: Biology .
http://www.cine.org/archives/winner-archives/pdfs/1995-CINE-Winner-Directory.pdf
Medical-Vocational Allowance for Herniated Disc
Primetime Emmy Awards (1996)
Biography: (A&E, A&E Television Network) . LeVar Burton, Cecily Truett, Larry Lancit, Orly Wiseman, Robin Fogelman, Mark Mannucci, Stacey Raider, Ronnie .
http://www.imdb.com/event/ev0000223/1996
???????? ????????? george_ha @ EX.UA
The series was created under the leadership of Cecily Truett Lancit and Larry . The series and the book are cast as an adventure story, or the biography of .
http://www.ex.ua/user/george_ha
Emmy Awards 1996 (List of Award Winners and Nominees)
Sep 7, 1996. Twila Liggett, Tony Buttino, LeVar Burton, Cecily Truett, Larry Lancit, Orly . Biography (1987), Josh Howard, Michael Cascio, Randy Martin, .
http://www.whosdatedwho.com/tpx_2870920/emmy-awards/1996
Appealing a Denial of Benefits
Primetime Emmy Awards (1996)
Biography: (A&E, A&E Television Network) . LeVar Burton, Cecily Truett, Larry Lancit, Orly Wiseman, Robin Fogelman, Mark Mannucci, Stacey Raider, Ronnie .
http://www.imdb.com/event/ev0000223/1996
CINE GOLDEN EAGLE FILM & VIDEO COMPETITION 1995 ...
Sonia Rosario, Larry Lancit, Cecily Truett,. Stephen Kulczycki . PRODUCTION: Lancit Media Productions, Ltd. . Desmond Morris' The Human Animal: Biology .
http://www.cine.org/archives/winner-archives/pdfs/1995-CINE-Winner-Directory.pdf


Mostly cloudy with heavy rain in south-west and north-east
Most areas will be cloudy today with rain at times.
The rain will be heaviest in the southwest this morning then in the northeast later.
Temperatures will be close to the seasonal average but it will feel chilly in the rain, and with a brisk breeze in the northeast.
Maximum temperature 12 Celsius, 54F.


#}
{% include "apidataget/Nav.html" %}
{% if messages %}
{% for message in messages %}
{{ message }}
{% endfor %}
{% endif %}
{% block content %}
{% for article in top_headline %}
{% if article.urlToImage is not None and article.title is not None and article.description is not None and article.url is not None%}
{{ article.title }}
{% endif %}
{% endfor %}
{# #}
{# Business#}
Business
{% for article in business %}
{% if article.urlToImage is not None and article.title is not None and "jpeg" not in article.urlToImage%}
{{ article.title }}
{% endif %}
{% endfor %}
{# Sports #}
Sports
{% for article in sports %}
{% if article.urlToImage is not None and article.title is not None and "jpeg" not in article.urlToImage%}
{{ article.title }}
{% endif %}
{% endfor %}
Entertainment
{% for article in entertainment %}
{% if article.urlToImage is not None and article.title is not None and "jpeg" not in article.urlToImage%}
{{ article.title }}
{% endif %}
{% endfor %}
Health
{% for article in health %}
{% if article.urlToImage is not None and article.title is not None and "jpeg" not in article.urlToImage%}
{{ article.title }}
{% endif %}
{% endfor %}
Science
{% for article in science %}
{% if article.urlToImage is not None and article.title is not None and "jpeg" not in article.urlToImage%}
{{ article.title }}
{% endif %}
{% endfor %}
Technology
{% for article in technology %}
{% if article.urlToImage is not None and article.title is not None and "jpeg" not in article.urlToImage%}
{{ article.title }}
{% endif %}
{% endfor %}
{% endblock %}
{% include "apidataget/footer.html" %}


The Korchek Way
We Are Committed
Providing, supporting, and implementing information technology solutions that comply with regulatory requirements and optimize the business processes of our customers.
Years of Experience
After working with hundreds of healthcare provider organizations, Korchek understands that true clinical transformation and the optimization of clinical information systems implementation is only realized by using the right people, processes and technologies. Keeping your business needs in mind we assemble a team of consultants and technology experts to work in tandem with your team.


Module: Octokit::EnterpriseAdminClient::Orgs
| Relationships & Source Files | |
| Extension / Inclusion / Inheritance Descendants | |
|
Included In:
| |
| Defined in: | lib/octokit/enterprise_admin_client/orgs.rb |
Overview
Methods for the Enterprise Orgs API
Instance Method Summary
-
#create_organization(login, admin, options = {}) ⇒ nil
Create a new organization on the instance.
Instance Method Details
#create_organization(login, admin, options = {}) ⇒ nil
Create a new organization on the instance.
# File 'lib/octokit/enterprise_admin_client/orgs.rb', line 19
def create_organization(login, admin, = {}) [:login] = login [:admin] = admin post 'admin/organizations', end


In the absence of payday lenders, financial institutions like credit unions can fill the gap. Many credit unions, which are non-profits, offer payday alternative loans to their members. These loans function much like payday loans, but with interest rates that are much more reasonable. Removing bad actors like payday lenders creates more space for financial services like these to be successul in our communities.
in-context


CreateBrush ( [red#][,green#][,blue#] )
Parameters:
| red# (optional) - brush red value green# (optional) - brush green value blue# (optional) - brush blue value |
Description:
| Creates a brush and returns a brush handle. The optional green, red and blue values
allow you to set the colour of the brush. Values should be in the range
0-255. If omitted the values default to 255. When creating your own mesh, if you wish for certain surfaces to look differently from one another, then you will need to use brushes to paint individual surfaces. Using commands such as EntityColor, EntityAlpha will apply the effect to all surfaces at once, which may not be what you wish to achieve. See also: LoadBrush. |
| ; CreateBrush Example ; ------------------- Graphics3D 640,480 SetBuffer BackBuffer() camera=CreateCamera() light=CreateLight() RotateEntity light,90,0,0 cube=CreateCube() PositionEntity cube,0,0,5 ; Load texture tex=LoadTexture("../media/b3dlogo.jpg") ; Create brush brush=CreateBrush() ; Apply texture to brush BrushTexture brush,tex ; And some shininess BrushShininess brush,1 ; Paint mesh with brush PaintMesh cube,brush While Not KeyDown( 1 ) pitch#=0 yaw#=0 roll#=0 If KeyDown( 208 )=True Then pitch#=-1 If KeyDown( 200 )=True Then pitch#=1 If KeyDown( 203 )=True Then yaw#=-1 If KeyDown( 205 )=True Then yaw#=1 If KeyDown( 45 )=True Then roll#=-1 If KeyDown( 44 )=True Then roll#=1 TurnEntity cube,pitch#,yaw#,roll# RenderWorld Flip Wend End |


Tcl_SetRecursionLimit - set maximum allowable nesting depth in interpreter
#include <tcl.h>
int
Tcl_SetRecursionLimit(interp, depth)
- Tcl_Interp *interp (in)
-
Interpreter whose recursion limit is to be set.
Must be greater than zero.
- int depth (in)
-
New limit for nested calls to Tcl_Eval for interp.
At any given time Tcl enforces a limit on the number of recursive
calls that may be active for Tcl_Eval and related procedures
such as Tcl_GlobalEval.
Any call to Tcl_Eval that exceeds this depth is aborted with
an error.
By default the recursion limit is 1000.
Tcl_SetRecursionLimit may be used to change the maximum
allowable nesting depth for an interpreter.
The depth argument specifies a new limit for interp,
and Tcl_SetRecursionLimit returns the old limit.
To read out the old limit without modifying it, invoke
Tcl_SetRecursionLimit with depth equal to 0.
The Tcl_SetRecursionLimit only sets the size of the Tcl
call stack: it cannot by itself prevent stack overflows on the
C stack being used by the application. If your machine has a
limit on the size of the C stack, you may get stack overflows
before reaching the limit set by Tcl_SetRecursionLimit.
If this happens, see if there is a mechanism in your system for
increasing the maximum size of the C stack.
nesting depth, recursion
Copyright © 1995-1997 Roger E. Critchlow Jr.
Copyright © 1989-1993 The Regents of the University of California.
Copyright © 1994-1996 Sun Microsystems, Inc.


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A connect4 game implemented on the Ethereum blockchain
Board
Move
Move
Move
Move
Move
Move
Move
Info
Player 1
Player 2
Buy in
Current turn
Game state
Join game
Join


iNeed is an application that helps students measure which grade they need to pass a course.
It is useful to keep the student attentive to the notes, to avoid their disapproval.
Through a mobile application, the student can get the information quickly and agile, wherever he is.
iNeed was implemented using PHP technologies for the backend (API) and native Android for the creation of the mobile application.


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{% block title %}PyCon TW x PyHUG Co-hosting Online/Offline Meet-up Streaming{% endblock title %}
{% block meta_description %}PyCon Taiwan are co-hosting the mixed online/offline event together with PyHUG this time!{% endblock meta_description %}
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PyCon TW x taipei.py Co-hosting Online/Offline Meet-up Streaming
Here comes the third warm-up event. We are co-hosting the mixed online/offline event together with PyHUG this time!
Welcome to PyHUG! We are a group of Python programmers near the Hsinchu, Taiwan. We regularly hold seminar and coding meetings. You are very welcomed to join us!
| Time | Event |
|---|---|
| 19:00 - 19:25 | Welcome |
| 19:25 - 19:30 | Speaker introduction |
| 19:30 - 20:00 | 用 Loki 做個能究責的 NLU 模型 - 以金融場景應用為例 |
| 20:00 - 20:20 | Q & A |
| 20:20 - 21:00 | Free sharing |


Emergency surgery thrusts Vanna White into ‘Wheel of Fortune' host spotlight
by Kelli Dugan, Cox Media Group National Content DeskLOS ANGELES - With Pat Sajak sidelined by emergency surgery, “Wheel of Fortune” showrunners have tapped Vanna White to fill the longtime host’s shoes while he’s on the mend, People reported.
Sajak, 73, underwent emergency surgery to repair an intestinal blockage, forcing the cancellation of Thursday’s taping, the magazine reported.
According to KDVR, taping resumed Friday with White, 62, assuming hosting responsibilities.
Her first outing appeared to go smoothly, CNN reported, with a few special guests joining White in her hosting debut.
In its 37th season, “Wheel of Fortune” is the longest-running syndicated game show in the United States and taped its 7,000th episode in May 2018, People reported.