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The Most Memorable 2020 Moments In L.A.
Secret Los Angeles • December 31, 2020
A few moments that weren't absolutely terrible in 2020…
We've gone from bartering our toilet paper and coveted canned goods, to watching the city go into full lockdown and truly recognizing the devastating effects of the pandemic. To say it's been a roller coaster of a year is an understatement and most of us would rather just forget it even happened. While we could all agree to never utter the word "twenty" twice in a row ever again, it's worth remembering the moments that made us laugh, smile and restored our hope for humanity. [Featured Image: Major Feels ]
Here are 21 things that happened, that are actually worth remembering.
1. L.A.'s Air Was Exceptionally Clear
Thanks to the major reduction of cars and traffic on the roads during the lockdown, the smog that famously chokes the city had finally vanished and air quality was showing nothing but green on the Environmental Protection Agency's Air Quality Index. It just goes to show that if we collectively take action, we can make positive changes in a short amount of time.
2. Beautiful Murals Inspired By The Pandemic Appeared Across The City
Artists responded to the pandemic with stunning murals that expressed and reflected the times. It gave us comfort knowing we shared the
3. The City Lit Up In Blue For Healthcare Workers
Over 150 sites all over the U.S. lit up blue in solidarity with the hospital workers and first responders fighting COVID-19. Among them were Staples Center, LA Convention Center and LAX Airport.
4. We Got A Taste Of European Dining With Some Creative Flair
As cities began to emerge from the lockdown and shuttered businesses had the opportunity to reopen for outdoor service, local restaurants go creative and transform spaces into magical al fresco scenes. We think this European-style dining culture should stay in sunny California for good
5. Plankton Blooms Made SoCal Waters Glow
There was a wave of bioluminescence along the SoCal coast, thanks to a plankton bloom. While too much plankton can have an effect on other underwater life, that wasn't the case with this year's natural spectacle. It's also an undeniably rare and magical thing to see the blue glow, which a few locals were lucky enough to see. Some even caught footage of dolphins creating luminous trails as they glided through it.
6-9. There Were A Number Of Historic Gatherings Across The City
The death of George Floyd triggered a worldwide movement that resulted in powerful protests despite the pandemic. Numerous peaceful marches took place all over the city and culminated in a gathering of 50,000 people along Hollywood Boulevard, the largest in L.A. Here are some moments of unity that reminded us all of the power of community.
Over 50,000 People Showed Up In Hollywood For L.A.'s Largest Protest Yet
Around 10,000 Peaceful Protestors Marched Through Hollywood And DTLA
Compton Cowboys Take A Peace Ride To Protest Police Brutality
Thousands Gathered At Santa Monica And Venice In Honor Of George Floyd And Breonna Taylor
10. And Hollywood Got A Powerful New Artwork In Honor Of It
Hollywood Boulevard, between Highland Avenue and Orange Drive, is now home to the permanent installation of the 'All Black Lives Matter' street mural honoring the historic march that took place on June 14. The street artwork is painted yellow to represent Black Lives Matter and LGBTQ and transgender pride flag colors. Read more about it here.
11. We Saw The Neowise Comet Shoot Over The Skies
Back in July, the NEOWISE comet beamed into view creating a dazzling display before vanishing for another 6,800 years. Take a look at some of the best pictures taken in the city here.
12. The Lakers Won The NBA Championship
After losing NBA legend Kobe Bryant earlier this year, we all needed this Lakers' win. The team managed to play through a pandemic and even do their part in putting a spotlight on important social and political issues. So when the team took home the trophy home, beating the Miami Heat 106-93, there was an overwhelming response across the city. Along with a giant mural featuring Bryant and a newly painted Lakers House, here's how the city responded.
13. Iconic Landmarks In L.A. Were Turned Into Voting Centers
L.A. had arguably one of the best years for voting. Not only did major sports teams get involved in encouraging people to register and vote, but major venues around the city were turned into voting centers. For the first time, the process became more of an experience than an arduous chore. Dodger Stadium took things to the next level—and not just because it took place on the Top Deck— by welcoming first-time voters with mariachi bands. We hope we never go back to voting in pokey garages.
14. We Got A Full 'Blue Moon' On Halloween
This literally only happens once in a blue moon! If you looked up on Halloween you would have seen a gorgeous full moon and to make the holiday all the more spooky.
15. The Dodgers Won The World Series
L.A.'s boys in blue brought home the trophy for the first time in 32 years and after a year of misery, it provided a temporary antidote. As expected the excitement took over and the skies were filled with illegal fireworks, unlawful street gatherings and honking became the celebratory roar for the night. Along with that, the Dodgers got an entire graffitied house dedicated to them and everything that could light in blue was.
16. Records Were Broken During The Election
Not only did California break its own record for highest voter turnout, but Joe Biden also broke the record for the highest number of votes ever received in a U.S. presidential election.
17. And L.A. Hosted A Spontaneous Block Party
Joe Biden's win set off a celebration around the nation and, of course, L.A. didn't hesitate to do the same. Watch this video for all the highlights.
18. There Was A Rare Double Rainbow
A stormy election week was followed by a rare double rainbow, which almost never happens in this sunny city. Here are some of the best pictures from around the city.
19-21. California Had A Couple Of Historic Moments
While Kamala Harris made history nationally, California saw a year of progressive moves in government. Here's a look at a few groundbreaking moments:
Alex Padilla To Replace Kamala Harris, Becoming CA's First Latino U.S. Senator
L.A. County Will Have An All-Female Board Of Supervisors For The First Time In 168 Years
California Confirms First Openly Gay Supreme Court Justice

redpajama_set_name: RedPajamaCommonCrawl


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Birkeland Church ( or ) is a parish church of the Church of Norway in Bergen Municipality in Vestland county, Norway. It is located in the Nesttun neighborhood of Fana in the city of Bergen. It is the church for the Birkeland parish which is part of the Fana prosti (deanery) in the Diocese of Bjørgvin. The white, stone church was built in a long church style in 1878 using designs by the architect Giovanni Jacob Harbitz Müller. The church seats about 300 people. The church has a unique tower with an octagonal copper-clad steeple.

History
The earliest existing historical records of the church date back to the year 1306, but it was built before that time. The first church in Birkeland was a wooden stave church that was likely built during the 1200s. That church stood about  southeast of the present church. (Today, there is a historical marker with a plaque where the previous church once stood). Shortly before the year 1642, the old church was torn down and replaced with a new timber-framed long church. An inspection report from 1686 describes the church as having a  nave and a  choir, and a  church porch with a tower on the west end of the nave.

The wooden church was sold to private owners Arne Olsen Øvre Totland and Lars Olsen Øvre Birkeland in 1724. In 1839, the church was bought back by the parish. Due to maintenance issues and population growth, in the 1870s, it was decided to replace the old church. A new church site was chosen about  away in Nesttun. A new, larger stone church was built at the new site in 1877–1878. The architect for the church was Giovanni Müller, while Christian Christiansen Gyldenpris, Ivar Rasmussen Fyllingen, Lars Olsen Hougsdal, and Askild Aase was responsible for construction work. The new church was consecrated on 21 November 1878. Soon afterwards, the old church was torn down. In 1915–1916, the nave was redesigned using the designs of Gerhard Fischer and his father Adolph Fischer. In 1926, the sacristies were enlarged and the tower was rebuilt, again using designs by Gerhard Fischer. In 1960–1961, the nave was rebuilt under the leadership of Øistein Nestaas, and also on that occasion the northern sacristy was expanded and converted into a chapel.

Media gallery

See also
List of churches in Bjørgvin

References

Churches in Bergen
Long churches in Norway
Stone churches in Norway
19th-century Church of Norway church buildings
Churches completed in 1878
13th-century establishments in Norway

redpajama_set_name: RedPajamaWikipedia


The following is an electronic Answer sheet form; please save this locally to your computer and enter your answers on this sheet. Once you have entered your answers use the submit button on the bottom to submit the answer form to the appropriate officers/instructors. Please make sure that you save your answer sheet on your computer or print it out, until it has been confirmed that your form has been received.
This manual provides the regulation and guidance to administer the awards programs for NSCC Divisions, Squadrons, Battalions, and NLCC Training Ships.


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In mobilizing divers to be a force for good, scuba diving can help to promote marine conservation. Here are three ways in which ISO standards support this effort. Diving Sustainably Scuba diving is the passion of millions of people around the globe, all with one thing in common – a…
Towards a Circular Economy
Catherine Chevauché is leading the charge on the circular economy. Here, she explains the scale of the challenge and how we can rise to it. The circular economy is considered a pillar of climate action. As opposed to the linear model of production and consumption which evolves along the stages…
What's Trending in Global Tourism
A new age of travel is upon us. From sustainability to resilience to inclusiveness, let's take a closer look at three trends for travel and how standards support the journey. Redefining "All-Inclusive" Can you imagine a place where families and friends can holiday together so that nobody gets left behind?…
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ISO is on the right path to achieving its climate goals, says Sheila Leggett. Sheila Leggett, one of Canada's climate policy experts, is leading the way on standards for sustainability. She reflects on how the sustainability conversation has shifted through her career, and the role ISO has to play in…
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The past few years have seen mixed progress for the UN's Sustainable Development Goals. The time has come to leverage International Standards for actionable success. The year 2022 will be decisive as to whether the world can meet its sustainable development target by 2030. A recently published United Nations (UN)…
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Together with the IEC, we're changing the way in which experts come together to create standards. OSD programme manager Julie Suter tells us about the latest developments in standards collaboration. Amongst standards developers there's a lot of talk about ISO's new Online Standards Development platform, or OSD, but what is…
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More businesses are harnessing the power of projects to drive social and economic benefits. Standards get practical about the future of work. In an ideal world, a project economy is where people are empowered to have the skills and capabilities needed to turn ideas into a reality. It's a phenomenon…
Small Businesses: Keeping Up With Today's Economy
To be strong, resilient and fit for the future, MSMEs are encouraged to uphold the highest standards. Standards are not only for the minority of businesses with thousands of employees. According to the World Bank, micro-, small- and medium-sized enterprises (MSMEs) make up over 90 % of all companies and account…
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ALTOPREV- lovastatin tablet, extended release
Covis Pharma US, Inc
These highlights do not include all the information needed to use ALTOPREV® safely and effectively. See full prescribing information for Altoprev®.
ALTOPREV® (lovastatin extended-release) Tablets for oral administration
Initial U.S. Approval: 2002
RECENT MAJOR CHANGES
Warnings and Precautions, Immune-Mediated Necrotizing Myopathy (IMNM) (5.2) 07/2020
Altoprev® is an HMG-CoA reductase inhibitor (statin) indicated as an adjunctive therapy to diet to:
Reduce the risk of MI, revascularization procedures, and angina in patients without CHD, but with multiple risk factors. (1.1)
Slow the progression of coronary atherosclerosis in patients with CHD as part of a treatment strategy to lower Total-C and LDL-C. (1.1)
Reduce elevated Total-C, LDL-C, Apo B, and TG levels and increase HDL-C in adult patients with primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia. (1.2)
Altoprev®has not been studied in Fredrickson Types I, III, and V dyslipidemias. (1.3)
Dose range: 20 to 60 mg once daily. (2.1)
Recommended start dose: 20, 40 or 60 mg once daily. (2.1)
20, 40, and 60 mg tablets (3)
Concomitant administration of strong CYP3A inhibitors. (4, 5.1)
Concomitant administration of erythromycin. (4, 5.1)
Hypersensitivity to any component of this medication. (4)
Active liver disease, which may include unexplained persistent elevations in hepatic transaminase levels. (4, 5.3)
Pregnancy. (4, 8.1, 8.3)
Lactation. (4, 8.2)
Skeletal muscle effects (e.g., myopathy and rhabdomyolysis) Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Altoprev®. Predisposing factors include advanced age (≥ 65), female gender, uncontrolled hypothyroidism, and renal impairment. Advise patients to report promptly to their physician any unexplained and/or persistent muscle pain, tenderness, or weakness. Altoprev therapy should be discontinued immediately if myopathy is diagnosed or suspected. (5.1)
Immune-Mediated Necrotizing Myopathy (IMNM): There have been rare reports of IMNM, an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMG CoA reductase antibody; muscle biopsy showing necrotizing myopathy; and improvement with immunosuppressive agents. (5.2)
Liver enzyme abnormalities: Persistent elevations in hepatic transaminases can occur. Check liver enzyme tests before initiating therapy and as clinically indicated thereafter. (5.3)
The most commonly reported adverse reactions (incidence ≥ 5%) in patients treated with Altoprev® in placebo-controlled trials were: infection, headache and accidental injury. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Covis Pharma at 1-866-488-4423 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions Associated with Increased
Risk of Myopathy/Rhabdomyolysis (2.3, 5.1, 7, 12.3)
Interacting Agents
Prescribing Recommendations
Strong CYP3A inhibitors (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), Erythromycin
Contraindicated with lovastatin
Gemfibrozil, cyclosporine
Avoid with lovastatin
Danazol, diltiazem, dronedarone, verapamil
Do not exceed 20 mg lovastatin daily
Avoid grapefruit juice
Other Lipid-Lowering Medications: Use with other fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Caution should be used when prescribing with Altoprev®. (7)
Females of reproductive potential: Advise females of reproductive potential to use effective contraception during treatment with Altoprev. (8.3)
Elderly patients should be started at 20 mg/day. (2.2, 8.5)
Severe renal impairment patients: dosage increases above 20 mg/day should be carefully considered. (2.4)
See 17 for PATIENT COUNSELING INFORMATION.
Revised: 9/2020
FULL PRESCRIBING INFORMATION: CONTENTS*
1.1 Prevention of Coronary Heart Disease
1.2 Hyperlipidemia
1.3 Limitations of Use
2.1 Hyperlipidemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
2.2 Elderly Patients
2.3 Co-administration with Other Drugs
2.4 Dosage in Patients With Renal Impairment
5.1 Skeletal Muscle Effects
5.2 Immune-Mediated Necrotizing Myopathy
5.3 Liver Enzyme Abnormalities
5.4 Endocrine Effects
6.1 Clinical Trial Adverse Reactions
6.2 Postmarketing Experience
7.1 Strong CYP3A Inhibitors
7.2 Erythromycin
7.3 Interactions With Lipid-Lowering Drugs That Can Cause Myopathy When Given Alone
7.4 Niacin (nicotinic acid) (≥1 g/day)
7.5 Cyclosporine
7.6 Danazol, Diltiazem, Dronedarone or Verapamil
7.7 Amiodarone
7.8 Coumarin Anticoagulants
7.9 Colchicine
7.10 Ranolazine
8.2 Lactation
8.3 Females and Males of Reproductive Potential
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
12.3 Pharmacokinetics
14.1 Hypercholesterolemia
14.2 Heterozygous Familial Hypercholesterolemia
14.3 Prevention of Coronary Heart Disease
17.1 Muscle Pain
17.2 Liver Enzymes
17.3 Embryofetal Toxicity
17.4 Lactation
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION
Therapy with lipid-altering agents should be one component of multiple risk factor intervention in individuals who require modifications of their lipid profile. Drug therapy is recommended as an adjunct to a diet restricted in saturated fat and cholesterol only when the response to diet and other non-pharmacological measures has been inadequate.
In patients without symptomatic coronary heart disease (CHD), but at high risk, Altoprev® is indicated to reduce the risk of:
Unstable angina
Coronary revascularization procedures
Coronary Heart Disease
Altoprev® is indicated to slow the progression of coronary atherosclerosis in patients with coronary heart disease as part of a treatment strategy to lower Total-C and LDL-C to target levels.
Altoprev® is indicated as an adjunct to diet for the reduction of elevated Total-C, LDL-C, Apo B, and TG, and to increase HDL-C in patients with primary hypercholesterolemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa and IIb).
Altoprev® has not been studied in Fredrickson Types I, III, and V.
The recommended dosing range is 20-60 mg/day, in single doses taken in the evening at bedtime.
The usual recommended starting dose in elderly patients (age≥65 years) is 20 mg once a day given in the evening at bedtime. Higher doses should be used only after careful consideration of the potential risks and benefits [see Use in Specific Populations (8.5) and Warnings and Precautions (5.1)].
Patients Taking Danazol, Diltiazem, Dronedarone, or Verapamil
The dose of Altoprev should not exceed 20 mg/day [see Warnings and Precautions (5.1)].
Patients Taking Amiodarone
The dose of Altoprev should not exceed 40 mg/day. [see Warnings and Precautions (5.1) and Drug Interactions (7.6)].
In patients with severe renal impairment (creatinine clearance <30 mL/min), dosage increases above 20 mg/day should only be considered if the expected benefit exceeds the increased risk of myopathy/rhabdomyolysis. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Altoprev® (lovastatin extended-release) tablets are supplied as round, convex shaped tablets containing 20 mg, 40 mg and 60 mg of lovastatin.
The use of Altoprev® is contraindicated in the following conditions:
Concomitant administration of strong CYP3A inhibitors [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
Concomitant administration of erythromycin [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].
Hypersensitivity to any component of this product [see Adverse Reactions (6.1)].
Active liver disease, which may include unexplained persistent elevations of hepatic transaminase levels [see Warnings and Precautions (5.3)].
Pregnancy. [see Use in Specific Populations (8.1)].
Lactation. Because another drug in this class passes into breast milk, and because statins have the potential to cause serious adverse reactions in breastfed infants, women who require Altoprev® treatment should not breastfeed their infants. [see Use in Specific Populations (8.2)].
Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including Altoprev®. These risks can occur at any dose level, but increase in a dose-dependent manner. Predisposing factors for myopathy include advanced age (≥65 years), female gender, renal impairment, and inadequately treated hypothyroidism. In a clinical study (EXCEL) in which patients were carefully monitored and some interacting drugs were excluded, there was one case of myopathy among 4933 patients randomized to lovastatin 20-40 mg daily for 48 weeks, and 4 among 1649 patients randomized to 80 mg daily.
All patients starting therapy with Altoprev®, or whose dose of Altoprev® is being increased, should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing Altoprev. Altoprev therapy should be discontinued immediately if myopathy is diagnosed or suspected.
Altoprev® therapy should be discontinued if markedly elevated creatine kinase (CK) levels occur or myopathy is diagnosed or suspected. Altoprev® therapy should also be temporarily withheld in any patient experiencing an acute or serious condition predisposing to the development of renal failure secondary to rhabdomyolysis, e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled epilepsy.
• Drug Interactions that Can Cause Skeletal Muscle Effects
Strong CYP3A Inhibitors: The risk of myopathy and rhabdomyolysis is increased by high levels of statin activity in plasma. Lovastatin is metabolized by the cytochrome P450 isoform 3A4. Certain drugs which inhibit this metabolic pathway can raise the plasma levels of lovastatin and may increase the risk of myopathy. Co-administration of these drugs with Altoprev is contraindicated. If treatment with strong CYP3A inhibitors is unavoidable, therapy with Altoprev should be suspended during the course of treatment [see Contraindications (4); Clinical Pharmacology (12.3); Drug Interactions (7.1)].
Erythromycin: Co-administration of erythromycin with Altoprev is contraindicated. If treatment with erythromycin is unavoidable, therapy with Altoprev should be suspended during the course of treatment [see Contraindications (4); Drug Interactions (7.2)].
Gemfibrozil: Avoid the combined use of Altoprev with gemfibrozil.
Other lipid-lowering drugs (other fibrates, or lipid-lowering doses (≥ 1 g/day) of niacin: Use caution when prescribing other fibrates or lipid-lowering doses (≥ 1 g/day) of niacin with Altoprev, as these agents can cause myopathy when given alone and the risk is increased when they are coadministered with Altoprev. Carefully weigh the expected benefit of further alterations in lipid levels by the combined use of lovastatin with other fibrates or niacin against the potential risks of these combinations [see Drug Interactions (7.3)].
Cyclosporine: Avoid the combined use of Altoprev with cyclosporine [see Drug Interactions (7.4)].
Danazol, diltiazem, dronedarone or verapamil with higher doses of lovastatin: Do not exceed 20 mg of Altoprev daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone or verapamil. Weigh carefully the benefits of the use of Altoprev in patients receiving danazol, diltiazem, dronedarone or verapamil against the risks of these combinations [see Drug Interactions (7.6)].
Amiodarone: Do not exceed 40 mg of Altoprev daily in patients receiving concomitant therapy with amiodarone. Avoid the combined use of Altoprev at doses exceeding 40 mg daily with amiodarone unless the clinical benefit is likely to outweigh the increased risk of myopathy. The concomitant use of higher doses of a closely related member of the HMG-CoA reductase inhibitor class with amiodarone increased the risk of myopathy/rhabdomyolysis [see Drug Interactions (7.6)].
Colchicine: There have been cases of myopathy, including rhabdomyolysis, reported in patients receiving lovastatin coadministered with colchicine. Use caution when prescribing Altoprev with colchicine [see Drug Interactions (7.9)].
Ranolazine: Concomitant use of ranolazine and Altoprev may increase the risk of myopathy, including rhabdomyolysis. Consider dose adjustment of Altoprev if coadministering with ranolazine [see Drug Interactions (7.9)].
Prescribing recommendations for interacting agents are summarized in Table 1.
Table 1 Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis
Strong CYP3A inhibitors (e.g.,
ketoconazole, itraconazole, posaconazole,
voriconazole, clarithromycin, telithromycin,
HIV protease inhibitors, boceprevir, telaprevir,
and nefazodone), Erythromycin
Verapamil
There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; positive anti-HMGCoA reductase antibody; muscle biopsy showing necrotizing myopathy and improvement with immunosuppressive agents.
Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. Consider risk of IMNM carefully prior to initiation of a different statin. If therapy is initiated with a different statin, monitor for signs and symptoms of IMNM.
Increases in serum transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) have been reported with HMG-CoA reductase inhibitors, including Altoprev®.
Persistent increases (to more than 3 times the upper limit of normal) in serum transaminases occurred in 1.9% of adult patients who received lovastatin for at least one year in early clinical trials [see Adverse Reactions (6.1)]. When the drug was interrupted or discontinued in these patients, the transaminase levels usually fell slowly to pretreatment levels.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with Altoprev and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including lovastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with Altoprev, promptly interrupt therapy. If an alternate etiology is not found, do not restart Altoprev.
The drug should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease. Active liver disease or unexplained transaminase elevations are contraindications to the use of Altoprev®.
Altoprev®
In controlled clinical trials (467 patients treated with Altoprev® and 329 patients treated with lovastatin immediate-release) no meaningful differences in transaminase elevations between the two treatments were observed.
Lovastatin Immediate-Release
In the EXCEL study [see Clinical Studies (14)], the incidence of persistent increases in serum transaminases over 48 weeks was 0.1% for placebo, 0.1% at 20 mg/day, 0.9% at 40 mg/day, and 1.5% at 80 mg/day in patients on lovastatin. However, in post-marketing experience with lovastatin immediate-release, symptomatic liver disease has been reported rarely at all dosages [see Adverse Reactions (6.2)].
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including lovastatin.
HMG-CoA reductase inhibitors interfere with cholesterol synthesis and as such might theoretically blunt adrenal and/or gonadal steroid production. Results of clinical trials with drugs in this class have been inconsistent with regard to drug effects on basal and reserve steroid levels. However, clinical studies have shown that lovastatin does not reduce basal plasma cortisol concentration or impair adrenal reserve, and does not reduce basal plasma testosterone concentration. Another HMG-CoA reductase inhibitor has been shown to reduce the plasma testosterone response to HCG. The effects of HMG-CoA reductase inhibitors on male fertility have not been studied in adequate numbers of male patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Patients treated with lovastatin who develop clinical evidence of endocrine dysfunction should be evaluated appropriately. Caution should also be exercised if an HMG-CoA reductase inhibitor or other agent used to lower cholesterol levels is administered to patients also receiving other drugs (e.g., spironolactone, cimetidine) that may decrease the levels or activity of endogenous steroid hormones.
The following serious adverse reactions are discussed in greater detail in other sections of the label:
Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.3)]
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In controlled clinical trials with Altoprev®, (467 patients with mean exposure to study drug of approximately 11.6 weeks), 3.2% of patients were discontinued due to adverse reactions. This was similar to the discontinuation rate in the placebo (2/34, 5.9%) and lovastatin immediate-release (3.3%) treatment groups.
Pooled results from clinical trials with Altoprev® show that the most frequently reported adverse reactions in the Altoprev® group were infection, headache and accidental injury. Similar incidences of these adverse reactions were seen in the lovastatin and placebo groups. In controlled clinical trials, clinical adverse reactions reported in >5% of patients in any treatment group are shown in Table 2 below.
Table 2 Pooled Controlled Studies TESS by Body System and COSTART Term, Most Common (≥5% in Any Group)
Randomized Patients, n=
Mevacor®
COSTART Term
Body as a Whole
Arthralgia
Myalgia
Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)
In AFCAPS/TexCAPS [see Clinical Pharmacology (12)] involving 6,605 participants treated with 20-40 mg/day of lovastatin immediate-release (n=3,304) or placebo (n=3,301), the safety and tolerability profile of the group treated with lovastatin immediate-release was comparable to that of the group treated with placebo during a median of 5.1 years of follow-up.
In AFCAPS/TexCAPS, the number of participants with consecutive elevations of either alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times the upper limit of normal), over a median of 5.1 years of follow-up, was not significantly different between the lovastatin immediate-release and placebo groups [18 (0.6%) vs. 11 (0.3%)]. The starting dose of lovastatin immediate-release was 20 mg/day; 50% of the lovastatin immediate-release treated participants were titrated to 40 mg/day at Week 18. Of the 18 participants on lovastatin immediate-release with consecutive elevations of either ALT or AST, 11 (0.7%) elevations occurred in participants taking 20 mg/day, while 7 (0.4%) elevations occurred in participants titrated to 40 mg/day. Elevated transaminases resulted in discontinuation of 6 (0.2%) participants from therapy in the lovastatin immediate-release group (n=3,304) and 4 (0.1%) in the placebo group (n=3,301).
The following adverse reactions have been identified during post-approval use of Altoprev® and/or are class effects of HMG CoA reductase inhibitors (statins). 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.
Skeletal: muscle cramps, myalgia, myopathy, rhabdomyolysis, arthralgias.
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].
Neurological: dysfunction of certain cranial nerves (including alteration of taste, impairment of extra-ocular movement, facial paresis), tremor, dizziness, vertigo, paresthesia, peripheral neuropathy, peripheral nerve palsy, psychic disturbances, anxiety, insomnia, depression.
There have been rare postmarketing reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use. These cognitive issues have been reported for all statins. The reports are generally nonserious, and reversible upon statin discontinuation, with variable times to symptom onset (1 day to years) and symptom resolution (median of 3 weeks).
Hypersensitivity Reactions: An apparent hypersensitivity syndrome has been reported rarely which has included one or more of the following features: anaphylaxis, angioedema, lupus erythematous-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, purpura, thrombocytopenia, leukopenia, hemolytic anemia, positive ANA, ESR increase, eosinophilia, arthritis, arthralgia, urticaria, asthenia, photosensitivity, fever, chills, flushing, malaise, dyspnea, toxic epidermal necrolysis, erythema multiforme, including Stevens-Johnson syndrome.
Gastrointestinal: pancreatitis, hepatitis, including chronic active hepatitis, cholestatic jaundice, fatty change in liver; and rarely, cirrhosis, fulminant hepatic necrosis, and hepatoma; anorexia, vomiting, fatal and non-fatal hepatic failure.
Skin: alopecia, pruritus. A variety of skin changes (e.g., nodules, discoloration, dryness of skin/mucous membranes, changes to hair/nails) have been reported.
Reproductive: gynecomastia, loss of libido, erectile dysfunction.
Eye: progression of cataracts (lens opacities), ophthalmoplegia.
Laboratory Abnormalities: elevated transaminases, alkaline phosphatase, γ-glutamyl transpeptidase, and bilirubin; thyroid function abnormalities.
Respiratory: interstitial lung disease.
Drug interaction studies have not been performed with Altoprev®. The types, frequencies and magnitude of drug interactions that may be encountered when Altoprev® is administered with other drugs may differ from the drug interactions encountered with the lovastatin immediate-release formulation. In addition, as the drug exposure with Altoprev® 60 mg is greater than that with lovastatin immediate-release 80 mg (maximum recommended dose), the severity and magnitude of drug interactions that may be encountered with Altoprev® 60 mg are not known. It is therefore recommended that the following precautions and recommendations for the concomitant administration of lovastatin immediate-release with other drugs be interpreted with caution, and that the monitoring of the pharmacologic effects of Altoprev® and/or other concomitantly administered drugs be undertaken where appropriate.
Lovastatin is metabolized by CYP3A4 but has no CYP3A inhibitory activity; therefore it is not expected to affect the plasma concentrations of other drugs metabolized by CYP3A. Strong inhibitors of CYP3A (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, and nefazodone), increase the risk of myopathy by reducing the elimination of lovastatin. The use of lovastatin with strong CYP3A inhibitors is contraindicated [see Contraindications (4), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
Do not use Altoprev concomitantly with erythromycin [see Contraindications (4) and Warnings and Precautions (5.1)].
The risk of myopathy is also increased by the following lipid-lowering drugs that are not strong CYP3A inhibitors, but which can cause myopathy when given alone. [see Warnings and Precautions (5.1)].
Gemfibrozil – Avoid the concomitant use of Altoprev with gemfibrozil [see Warnings and Precautions (5.1)].
Other fibrates - Use caution when prescribing Altoprev with other fibrates. [see Warnings and Precautions (5.1)].
Use caution when prescribing Altoprev with lipid-modifying (≥1 g/day) doses of niacin. [see Warnings and Precautions (5.1)].
Avoid the concomitant use of Altoprev with cyclosporine [see Warnings and Precautions (5.1)].
Do not exceed 20 mg of Altoprev daily in patients receiving concomitant therapy with danazol, diltiazem, dronedarone, or verapamil. [see Dosage and Administration (2.3),Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
Do not exceed 40 mg of Altoprev daily in patients receiving concomitant therapy with amiodarone. [see Dosage and Administration (2.3),Warnings and Precautions (5.1)].
In a small clinical trial in which lovastatin was administered to warfarin treated patients, no effect on prothrombin time was detected. However, another HMG-CoA reductase inhibitor has been found to produce a less than two second increase in prothrombin time in healthy volunteers receiving low doses of warfarin. Also, bleeding and/or increased prothrombin time has been reported in a few patients taking coumarin anticoagulants concomitantly with lovastatin. In patients taking anticoagulants, prothrombin time should be determined before starting Altoprev and frequently enough during early therapy to ensure that no significant alteration of prothrombin time occurs. Once a stable prothrombin time has been documented, prothrombin times can be monitored at the intervals usually recommended for patients on coumarin anticoagulants. If the dose of Altoprev is changed, the same procedure should be repeated. Lovastatin therapy has not been associated with bleeding or with changes in prothrombin time in patients not taking anticoagulants.
Cases of myopathy, including rhabdomyolysis have been reported with lovastatin coadministered with colchicine. Exercise caution when prescribing Altoprev with colchicine.
The risk of myopathy, including rhabdomyolysis, may be increased by concomitant administration of ranolazine. Exercise caution when prescribing Altoprev with ranolazine. Dose adjustment of Altoprev may be necessary during coadministration with ranolazine.
Altoprev is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit to therapy with Altoprev during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, Altoprev may cause fetal harm when administered to pregnant women. Altoprev should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of lovastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies, no evidence of fetal malformations was seen in mice or rats at doses 5 and 25 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day lovastatin immediate-release, based on body surface area. No evidence of malformations was noted in rabbits with oral administration of lovastatin during organogenesis at doses up to 4 times the MRHD, based on body surface area. Skeletal malformations occurred at doses 50 times the MRHD in mice and rats, based on body surface area.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Human Data
Limited published data on lovastatin have not shown an increased risk of major congenital malformations or miscarriage. Rare reports of congenital anomalies have been received following intrauterine exposure to other statins. In a review of approximately 100 prospectively followed pregnancies in women exposed to simvastatin or lovastatin, the incidences of congenital anomalies, spontaneous abortions, and fetal deaths/stillbirths did not exceed what would be expected in the general population. The number of cases is adequate to exclude a ≥3 to 4-fold increase in congenital anomalies over the background incidence. In 89% of the prospectively followed pregnancies, drug treatment was initiated prior to pregnancy and was discontinued at some point in the first trimester when pregnancy was identified.
Animal Data
In pregnant rats given oral gavage doses of 100, 200, 400, 800 mg/kg/day lovastatin from gestation days 6 through 20, reduced fetal body weights were observed at all doses and skeletal malformations were observed at ≥400 mg/kg/day, corresponding to 50 times the 80 mg/day MRHD of lovastatin immediate-release, based on body surface area (mg/m2).
In pregnant mice given oral gavage doses of 8, 80, 800 mg/kg/day lovastatin from gestation days 6 through 15, reduced fetal body weights were observed at ≥80 mg/kg/day and skeletal malformations were observed at 800 mg/kg/day, corresponding to 5 and 50 times the 80 mg/day MRHD, based on body surface area (mg/m2).
In pregnant rabbits given an oral gavage dose of 15 mg/kg/day lovastatin from gestation days 6 through 18, no teratogenic effects were observed. Doses were 4 times the 80 mg/day MRHD, based on body surface area (mg/m2).
In pregnant rats given oral gavage doses of 2, 20, 200 mg/kg/day lovastatin by oral gavage from gestation day 15 through lactation day 21 (weaning), increased mortality of offspring was observed at ≥20 mg/kg/day and development delays were observed at 200 mg/kg/day, corresponding to 2.4 and 24 times, respectively, the 80 mg/day MRHD, based on body surface area (mg/m2).
Altoprev is contraindicated during breastfeeding [see Contraindications (4)]. There is no available information on the effects of the drug on the breastfed infant or the effects of the drug on milk production. However, a small amount of another drug in this class is present in human breast milk. Because of the potential for serious adverse reactions in breastfed infants, advise patients that breastfeeding is not recommended during treatment with Altoprev.
Altoprev may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with Altoprev.
Safety and effectiveness in pediatric patients have not been established. Because pediatric patients are not likely to benefit from cholesterol lowering for at least a decade and because experience with this drug is limited (no studies in subjects below the age of 20 years), treatment of pediatric patients with Altoprev® is not recommended at this time.
Of the 467 patients who received Altoprev® in controlled clinical studies, 18% were 65 years and older. Of the 297 patients who received Altoprev® in uncontrolled clinical studies, 22% were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Thus, lower starting doses of Altoprev® are recommended for elderly patients. [see Dosage and Administration (2.2)].
In pharmacokinetic studies with lovastatin immediate-release, the mean plasma level of HMG-CoA reductase inhibitory activity was shown to be approximately 45% higher in elderly patients between 70-78 years of age compared with patients between 18-30 years of age; however, clinical study experience in the elderly indicates that dosage adjustment based on this age-related pharmacokinetic difference is not needed. In the two large clinical studies conducted with lovastatin immediate-release (EXCEL and AFCAPS/TexCAPS), 21% (3094/14850) of patients were ≥65 years of age. Lipid-lowering efficacy with lovastatin was at least as great in elderly patients compared with younger patients, and there were no overall differences in safety over the 20 to 80 mg dosage range [see Clinical Pharmacology (12.3)].
In a study of patients with severe renal impairment (creatinine clearance 10–30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers. [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
After oral administration of lovastatin immediate-release to mice the median lethal dose observed was >15 g/m2.
Five healthy human volunteers have received up to 200 mg of lovastatin as a single dose without clinically significant adverse experiences. A few cases of accidental overdosage with lovastatin immediate-release have been reported; no patients had any specific symptoms, and all patients recovered without sequelae. The maximum dose taken was 5 g to 6 g.
Until further experience is obtained, no specific treatment of overdosage with Altoprev® can be recommended.
The dialyzability of lovastatin and its metabolites in man is not known at present.
Altoprev® lovastatin extended-release tablets contain a cholesterol-lowering agent isolated from a strain of Aspergillus terreus. After oral ingestion, lovastatin, which is an inactive lactone, is hydrolyzed to the corresponding β-hydroxyacid form. This is a principal metabolite and inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate limiting step in the biosynthesis of cholesterol.
Lovastatin is [1 S -[1α(R*),3α,7β,8β(2 S*,4 S*),8aβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl 2-methylbutanoate. The empirical formula of lovastatin is C24H36O5 and its molecular weight is 404.55. Its structural formula is:
Lovastatin is a white, nonhygroscopic crystalline powder that is insoluble in water and sparingly soluble in ethanol, methanol, and acetonitrile.
Altoprev® extended-release tablets are designed for once-a-day oral administration and deliver 20 mg, 40 mg, or 60 mg of lovastatin. In addition to the active ingredient lovastatin, each tablet contains the following inactive ingredients: acetyltributyl citrate; butylated hydroxy anisole; candellila wax; cellulose acetate; confectioner's sugar (contains corn starch); F D & C yellow # 6; glyceryl monostearate; hypromellose; hypromellose phthalate; lactose; methacrylic acid copolymer, type B; polyethylene glycols (PEG 400, PEG 8000); polyethylene oxides; polysorbate 80; propylene glycol; silicon dioxide; sodium chloride; sodium lauryl sulfate; synthetic black iron oxide; red iron oxide; talc; titanium dioxide and triacetin.
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.
Lovastatin, as well as some of its metabolites, are pharmacologically active in humans. The liver is the primary site of action and the principal site of cholesterol synthesis and LDL clearance.
The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) levels are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (Total-C) and LDL-C levels in the lower end of this range.
Lovastatin immediate-release tablets have been shown to reduce elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high-affinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin immediate-release may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. The independent effect of raising HDL or lowering TG on the risk of coronary and cardiovascular morbidity and mortality has not been determined. The effects of lovastatin immediate-release on lipoprotein (a) [Lp(a)], fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown.
Absorption: The appearance of lovastatin in plasma from an Altoprev® extended-release tablet is slower and more prolonged compared to the lovastatin immediate-release formulation.
A pharmacokinetic study carried out with Altoprev® involved measurement of the systemic concentrations of lovastatin (pro-drug), lovastatin acid (active-drug) and total and active inhibitors of HMG-CoA reductase. The pharmacokinetic parameters in 12 hypercholesterolemic subjects at steady state, after 28 days of treatment, comparing Altoprev® 40 mg to lovastatin immediate-release 40 mg, are summarized in Table 3.
Table 3 Altoprev® vs. Lovastatin Immediate-Release (IR) (Steady-State Pharmacokinetic Parameters at Day 28)
L = lovastatin, LA = lovastatin acid, TI = total inhibitors of HMG-CoA reductase, AI = active inhibitors of HMG-CoA reductase, Cmax = highest observed plasma concentration, Cmin = trough concentration at t = 24 hours after dosing, Tmax = time at which the Cmax occurred, AUC0-24hr = area under the plasma concentration-time curve from time 0 to 24 hr after dosing, calculated by the linear trapezoidal rule.
* Administered at bedtime.
** Administered with the evening meal.
Cmax (ng/mL)
Cmin (ng/mL)
Tmax (h)
AUC0-24hr
(ng• hr/mL)
40 mg*
Lovastatin IR
40 mg**
The mean plasma concentration-time profiles of lovastatin and lovastatin acid in patients after multiple doses of Altoprev® or lovastatin immediate-release at day 28 are shown in Figure 1.
Figure 1 Mean (SD) plasma concentration-time profiles of lovastatin and lovastatin acid in hypercholesterolemic patients (n=12) after 28 days of administration of Altoprev® or lovastatin immediate-release
The extended-release properties of Altoprev® are characterized by a prolonged absorptive phase, which results in a longer Tmax and lower Cmax for lovastatin (pro-drug) and its major metabolite, lovastatin acid, compared to lovastatin immediate-release.
The bioavailability of lovastatin (pro-drug) as measured by the AUC0-24hr was greater for Altoprev® compared to lovastatin immediate-release (as measured by a chemical assay), while the bioavailability of total and active inhibitors of HMG-CoA reductase were equivalent to lovastatin immediate-release (as measured by an enzymatic assay).
With once-a-day dosing, mean values of AUCs of active and total inhibitors at steady state were about 1.8-1.9 times those following a single dose. Accumulation ratio of lovastatin exposure was 1.5 after multiple daily doses of Altoprev® compared to that of a single dose measured using a chemical assay. Altoprev® appears to have dose linearity for doses from 10 mg up to 60 mg per day.
When Altoprev® was given after a meal, plasma concentrations of lovastatin and lovastatin acid were about 0.5 - 0.6 times those found when Altoprev® was administered in the fasting state, indicating that food decreases the bioavailability of Altoprev®. There was an association between the bioavailability of Altoprev® and dosing after mealtimes. Bioavailability was lowered under the following conditions, (from higher bioavailability to lower bioavailability) in the following order: under overnight fasting conditions, before bedtime, with dinner, and with a high fat breakfast. In a multicenter, randomized, parallel group study, patients were administered 40 mg of Altoprev® at three different times; before breakfast, after dinner and at bedtime. Although there was no statistical difference in the extent of lipid change between the three groups, there was a numerically greater reduction in LDL-C and TG and an increase in HDL-C when Altoprev® was administered at bedtime. Results of this study are displayed in Table 4.
Table 4 Altoprev® 40 mg (Least Squares Mean Percent Changes from Baseline to Endpoint at 4 Weeks of Treatment*)
N = 22 for the Before Breakfast group, N = 23 for the After Dinner group, and N = 23 for the Before Bedtime group.
* All changes from baseline are statistically significant.
LDL-C
HDL-C
TOTAL-C
Before Breakfast
Before Bedtime
At steady state in humans, the bioavailability of lovastatin, following the administration of Altoprev®, was 190% compared to lovastatin immediate-release.
Absorption of lovastatin, estimated relative to an intravenous reference dose in each of four animal species tested, averaged about 30% of an oral dose. Following an oral dose of 14C-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors.
Distribution: Both lovastatin and its β-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers.
In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues.
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable.
Metabolism: Metabolism studies with Altoprev® have not been conducted.
Lovastatin
Lovastatin is a lactone that is readily hydrolyzed in vivo to the corresponding β-hydroxyacid, a strong inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the β-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin.
The major active metabolites present in human plasma are the β-hydroxyacid of lovastatin, its 6'-hydroxy derivative, and two additional metabolites. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Strong inhibitors of CYP3A can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy [see Warnings and Precautions (5.1), Drug Interactions (7)].
Lovastatin is a substrate for CYP3A4 [see Drug Interactions (7)]. Grapefruit juice contains one or more components that inhibit CYP3A and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study1, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted in mean increases in the concentration of lovastatin and its beta-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15-fold and 5-fold respectively (as measured using a chemical assay – liquid chromatography/tandem mass spectrometry). In a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day. This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using a validated enzyme inhibition assay different from that used in the first study, both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34-fold and 1.36-fold, respectively, and of lovastatin and its β-hydroxyacid metabolite (measured using a chemical assay – liquid chromatography/tandem mass spectrometry) of 1.94-fold and 1.57-fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
Table 5 The Effect of Other Drugs on Lovastatin Exposure When Both Were Co-administered
* Results based on a chemical assay.
† Lovastatin acid refers to the β-hydroxyacid of lovastatin.
‡ Results could be representative of strong CYP3A inhibitors such as ketoconazole, posaconazole, clarithromycin, telithromycin, HIV protease inhibitors, and nefazodone.
§ The mean total AUC of lovastatin without itraconazole phase could not be determined due to assay's detection limit.
¶ The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.
# Double-strength: one can of frozen concentrate diluted with one can of water. Grapefruit juice was administered TID for 2 days, and 200 mL together with single dose lovastatin and 30 and 90 minutes following single dose lovastatin on Day 3.
Þ Single-strength: one can of frozen concentrate diluted with 3 cans of water. Grapefruit juice was administered with breakfast for 3 days, and lovastatin was administered in the evening on Day 3.
ß Cyclosporine-treated post kidney transplant patients with stable graft function, transplanted at least 9 months prior to study.
à NR = Analyte not reported.
è Lactone converted to acid by hydrolysis prior to analysis. Figure represents total unmetabolized acid and lactone.
Π Analyte not determined
Coadministered Drug or
Dosing of
Coadministered
Drug or Grapefruit
AUC Ratio*
(with / without
coadministered drug)
No Effect = 1.00
Cmax Ratio*
Lovastatin acid†
Contraindicated with lovastatin, [see Contraindications (4) and Warnings and Precautions (5.1)]
Itraconazole‡
200 mg QD for 4 days
40 mg on Day 4
> 25§
> 14.8§
Avoid with lovastatin, [see Warnings and Precautions (5.1)]
Not describedß
10 mg QD for 10 days on Day 10
3- to 5-fold
NRà
600 mg BID for
Grapefruit Juice¶
(high dose)
200 mL of double-strength TID for 2 days
(low dose)
8 oz (about 250 mL) of single-strengthÞ for 4 days
Avoid taking with > 20 mg lovastatin, [see Warnings and Precautions (5.1)]
120 mg BID for 14 days
20 mg on Day 14
3.57è
NDΠ
No dosing adjustments required for the following:
Propanolol
40 mg BID for 2.5 days
Digoxin: In patients with hypercholesterolemia, concomitant administration of lovastatin and digoxin resulted in no effect on digoxin plasma concentrations.
Oral Hypoglycemic Agents: In pharmacokinetic studies of lovastatin immediate-release in hypercholesterolemic non-insulin dependent diabetic patients, there was no drug interaction with glipizide or with chlorpropamide.
Excretion: In a single-dose study with Altoprev®, the amounts of lovastatin and lovastatin acid excreted in the urine were below the lower limit of quantitation of the assay (1.0 ng/mL), indicating that negligible excretion of Altoprev® occurs through the kidney.
Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action, with subsequent excretion of drug equivalents in the bile.
Geriatric: Lovastatin Immediate-Release
In a study with lovastatin immediate-release which included 16 elderly patients between 70-78 years of age who received lovastatin immediate-release 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18-30 years of age [see Use in Specific Populations (8.5)].
Pediatric: Pharmacokinetic data in the pediatric population are not available.
Gender: In a single dose pharmacokinetic study with Altoprev®, there were no statistically significant differences in pharmacokinetic parameters between men (n=12) and women (n=10), although exposure tended to be higher in men than women.
In clinical studies with Altoprev®, there was no clinically significant difference in LDL-C reduction between men and women.
Renal Impairment: In a study of patients with severe renal impairment (creatinine clearance 10-30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers.
Hemodialysis: The effect of hemodialysis on plasma levels of lovastatin and its metabolites have not been studied.
Hepatic Impairment: No pharmacokinetic studies with Altoprev® have been conducted in patients with hepatic impairment.
In a 21-month carcinogenic study in mice with lovastatin immediate-release, there was a statistically significant increase in the incidence of hepatocellular carcinomas and adenomas in both males and females at 500 mg/kg/day. This dose produced a total plasma drug exposure 3 to 4 times that of humans given the highest recommended dose of lovastatin (drug exposure was measured as total HMG-CoA reductase inhibitory activity in extracted plasma). Tumor increases were not seen at 20 and 100 mg/kg/day, doses that produced drug exposures of 0.3 to 2 times that of humans at the 80 mg/day lovastatin immediate-release dose. A statistically significant increase in pulmonary adenomas was seen in female mice at approximately 4 times the human drug exposure. [Although mice were given 300 times the human dose (HD) on a mg/kg body weight basis, plasma levels of total inhibitory activity were only 4 times higher in mice than in humans given 80 mg of lovastatin immediate-release].
There was an increase in incidence of papilloma in the non-glandular mucosa of the stomach of mice beginning at exposures of 1 to 2 times that of humans given lovastatin immediate-release. The glandular mucosa was not affected. The human stomach contains only glandular mucosa.
In a 24-month carcinogenicity study in rats, there was a positive dose response relationship for hepatocellular carcinogenicity in males at drug exposures between 2-7 times that of human exposure at 80 mg/day lovastatin immediate-release (doses in rats were 5, 30 and 180 mg/kg/day).
An increased incidence of thyroid neoplasms in rats appears to be a response that has been seen with other HMG-CoA reductase inhibitors.
A chemically similar drug in this class was administered to mice for 72 weeks at 25, 100, and 400 mg/kg body weight, which resulted in mean serum drug levels approximately 3, 15, and 33 times higher than the mean human serum drug concentration (as total inhibitory activity) after a 40 mg oral dose of lovastatin immediate-release. Liver carcinomas were significantly increased in high-dose females and mid- and high-dose males, with a maximum incidence of 90 percent in males. The incidence of adenomas of the liver was significantly increased in mid- and high-dose females. Drug treatment also significantly increased the incidence of lung adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a gland of the eye of rodents) were significantly higher in high dose mice than in controls.
No evidence of mutagenicity was observed with lovastatin immediate-release in a microbial mutagen test using mutant strains of Salmonella typhimurium with or without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic material was noted in an in vitro alkaline elution assay using rat or mouse hepatocytes, a V-79 mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
Drug-related testicular atrophy, decreased spermatogenesis, spermatocytic degeneration and giant cell formation were seen in dogs starting at 20 mg/kg/day with lovastatin immediate-release. Similar findings were seen with another drug in this class. No drug-related effects on fertility were found in studies with lovastatin in rats. However, in studies with a similar drug in this class, there was decreased fertility in male rats treated for 34 weeks at 25 mg/kg body weight, although this effect was not observed in a subsequent fertility study when this same dose was administered for 11 weeks (the entire cycle of spermatogenesis, including epididymal maturation). In rats treated with this same reductase inhibitor at 180 mg/kg/day, seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was observed. No microscopic changes were observed in the testes from rats of either study. The clinical significance of these findings is unclear.
Altoprev® has been shown to reduce Total-C, LDL-C, and TG and increase HDL-C in patients with hypercholesterolemia. Near maximal response was observed after four weeks of treatment and the response was maintained with continuation of therapy for up to 6 months.
In a 12-week, multicenter, placebo-controlled, double-blind, dose-response study in adult men and women 21 to 70 years of age with primary hypercholesterolemia, once daily administration of Altoprev® 10 to 60 mg in the evening was compared to placebo. Altoprev® produced dose related reductions in LDL-C and Total-C. Altoprev® produced mean reductions in TG across all doses that varied from approximately 10% to 25%. Altoprev® produced mean increases in HDL-C across all doses that varied from approximately 9% to 13%.
The lipid changes with Altoprev® treatment in this study, from baseline to endpoint, are displayed in Table 6.
Table 6 Altoprev® vs. Placebo (Mean Percent Change from Baseline After 12 Weeks)*
N = the number of patients with values at both baseline and endpoint.
* Except for the HDL-C elevation with Altoprev® 10 mg, all lipid changes with Altoprev® were statistically significant compared to placebo.
** For LDL-C, 33 patients had values at baseline and endpoint.
Altoprev® 10 mg
34**
The range of LDL-C responses is represented graphically in the following figure (Figure 2):
Figure 2 Altoprev® vs. Placebo LDL-C Percent Change from Baseline After 12 Weeks
The distribution of LDL-C responses is represented graphically by the boxplots in Figure 2. The bottom line of the box represents the 25th percentile and the top line, the 75th percentile. The horizontal line in the box represents the median and the gray area is the 95% confidence interval for the median. The range of responses is depicted by the tails and outliers.
Expanded Clinical Evaluation of Lovastatin (EXCEL) Study
Lovastatin immediate-release was compared to placebo in 8,245 patients with hypercholesterolemia [Total-C 240-300mg/dL (6.2 mmol/L-7.6 mmol/L), LDL-C >160 mg/dL (4.1 mmol/L)] in the randomized, double-blind, parallel, 48-week EXCEL study. All changes in the lipid measurements (see Table 7) observed in lovastatin immediate-release-treated patients were dose-related and significantly different from placebo (p≤0.001). These results were sustained throughout the study.
Table 7 Lovastatin Immediate-Release (IR) vs. Placebo (Percent Change from Baseline - Average Values Between Weeks 12 and 48)
** Patients enrolled
N**
(mean)
LDL-C/
TOTAL-C/
(median)
Lovastatin IR 20 mg q.p.m.
40 mg q.p.m.
20 mg b.i.d.
Altoprev® Long-Term Study
A total of 365 patients were enrolled in an extension study in which all patients were administered Altoprev® 40 mg or 60 mg once daily for up to 6 months of treatment. The lipid-altering effects of Altoprev® were comparable to what was observed in the dose-response study, and were maintained for up to 6 months of treatment.
In clinical studies with Altoprev®, there were no statistically significant differences in LDL-C reduction in an older population (≥65 years old), compared to a younger population (<65 years old). There were also no statistically significant differences in LDL-C reduction between male and female patients.
Lovastatin immediate-release has been shown to be effective in reducing Total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4-6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainly at night.
Lovastatin immediate-release was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin immediate-release on lipids and lipoproteins and the safety profile of lovastatin immediate-release were similar to that demonstrated in studies in nondiabetics. Lovastatin immediate-release had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin immediate-release decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up. Participants were middle-aged and elderly men (ages 45-73) and women (ages 55-73) without symptomatic cardiovascular disease with average to moderately elevated Total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated Total-C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C <35 mg/dL, hypertension, family history, smoking and diabetes).
AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: Total-C range of 180-264 mg/dL, LDL-C range of 130-190 mg/dL, HDL-C of ≤45 mg/dL for men and ≤47 mg/dL for women, and TG of ≤400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin immediate-release 20 mg - 40 mg daily (n= 3,304) or placebo (n= 3,301). Approximately 50% of the participants treated with lovastatin immediate-release were titrated to 40 mg daily when their LDL-C remained >110 mg/dL at the 20-mg starting dose.
Lovastatin immediate-release reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin immediate-release 3.5%, placebo 5.5%; p<0.001; Figure 3). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin immediate-release, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, lovastatin immediate-release reduced the risk of unstable angina by 32% (1.8% vs. 2.6%; p=0.023), of myocardial infarction by 40% (1.7% vs. 2.9%; p=0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2% vs. 4.8%; p=0.001). Trends in risk reduction associated with treatment with lovastatin immediate-release were consistent across men and women, smokers and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants with ≥2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary revascularization procedures (RR 37%). Because there were too few events among those participants with age as their only risk factor in this study, the effect of lovastatin immediate-release on outcomes could not be adequately assessed in this subgroup.
Figure 3 Acute Major Coronary Events (Primary Endpoint)
In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients. In this randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either lovastatin 20 mg - 80 mg daily or placebo. Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean change per-patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%).
In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to 11% of placebo patients.
The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double- blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10-40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p=0.001). The predictive value of changes in IMT for stroke has not yet been established. In the lovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).
There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin immediate-release. During these trials the appearance of new opacities was noted in both the lovastatin immediate-release and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacities noted at baseline, discontinued from therapy because of a decrease in visual acuity.
A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin immediate-release on the human lens demonstrated that there were no clinically or statistically significant differences between the lovastatin immediate-release and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.
1. Kantola, T, et al. Clin Pharmacol Ther 1998; 63(4):397-402.
Altoprev® lovastatin extended-release tablets are supplied as round, convex shaped tablets containing 20 mg, 40 mg and 60 mg of lovastatin.
NDC 70515-628-30: 20 mg extended-release orange-colored tablets imprinted with Andrx logo and 20 on one side, bottles of 30.
NDC 70515-629-30: 40 mg extended-release peach-colored tablets imprinted with Andrx logo and 40 on one side, bottles of 30.
NDC 70515-630-30: 60 mg extended-release light peach-colored tablets imprinted with Andrx logo and 60 on one side, bottles of 30.
Store at 20º-25°C (68º-77°F) - Excursions Permitted to 15°-30°C (59° -86°F) [See USP Controlled Room Temperature]. Avoid excessive heat and humidity.
Patients taking Altoprev should be advised that cholesterol is a chronic condition and they should adhere to their medication along with their National Cholesterol Education Program (NCEP)-recommended diet, a regular exercise program as appropriate, and periodic testing of a fasting lipid panel to determine goal attainment.
Patients should be advised about substances they should not take concomitantly with lovastatin [see Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking Altoprev.
All patients starting therapy with Altoprev should be advised of the risk of myopathy, including rhabdomyolysis, and told to report promptly any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever or if these muscle signs or symptoms persist after discontinuing Altoprev. The risk of this occurring is increased when taking certain types of medication or consuming grapefruit juice. Patients should discuss all medication, both prescription and over the counter, with their healthcare professional.
It is recommended that liver enzyme tests be performed before the initiation of Altoprev and if signs or symptoms of liver injury occur. All patients treated with Altoprev should be advised to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice.
Advise females of reproductive potential of the risk to a fetus, to use effective contraception during treatment, and to inform their healthcare provider of a known or suspected pregnancy [see Contraindications (4) and Use in Specific Populations (8.1, 8.3)].
Advise women not to breastfeed during treatment with Altoprev [see Contraindications (4) and Use in Specific Populations (8.2)].
Manufactured for:
Covis Pharma
Zug, 6300 Switzerland
© 2020, Covis Pharma All rights reserved.
PRINCIPAL DISPLAY PANEL - 20 mg BOTTLE
20 mg Bottle
NDC 70515-628-30 30 Tablets
(lovastatin)
extended-release tablets
Each tablet contains lovastatin 20 mg.
Read package insert for prescribing
Dispense in tight, light-resistant container
as defined in the USP.
Store at 20°-25°C (68°-77°F). Excursions
permitted to 15°-30°C (59°-86°F) [See
USP Controlled Room Temperature].
Avoid excessive heat and humidity.
Made in Hungary Rev. 3/16 100242
ALTOPREV
lovastatin tablet, extended release
LOVASTATIN (UNII: 9LHU78OQFD) (LOVASTATIN - UNII:9LHU78OQFD) LOVASTATIN 20 mg
ACETYLTRIBUTYL CITRATE (UNII: 0ZBX0N59RZ)
BUTYLATED HYDROXYANISOLE (UNII: REK4960K2U)
CANDELILLA WAX (UNII: WL0328HX19)
CELLULOSE ACETATE (UNII: 3J2P07GVB6)
SUCROSE (UNII: C151H8M554)
FD&C YELLOW NO. 6 (UNII: H77VEI93A8)
GLYCERYL MONOSTEARATE (UNII: 230OU9XXE4)
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
HYPROMELLOSE PHTHALATE (24% PHTHALATE, 55 CST) (UNII: 87Y6436BKR)
LACTOSE, UNSPECIFIED FORM (UNII: J2B2A4N98G)
METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) (UNII: 5KY68S2577)
POLYETHYLENE GLYCOL 400 (UNII: B697894SGQ)
POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B)
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
POLYSORBATE 80 (UNII: 6OZP39ZG8H)
SODIUM CHLORIDE (UNII: 451W47IQ8X)
SODIUM LAURYL SULFATE (UNII: 368GB5141J)
TALC (UNII: 7SEV7J4R1U)
TRIACETIN (UNII: XHX3C3X673)
Color ORANGE Score no score
Shape ROUND Size 7mm
Flavor Imprint Code 20
NDC:70515-628-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 05/01/2016
NDA NDA021316 05/01/2016
Color ORANGE (peach) Score no score
Color ORANGE (light peach) Score no score
Labeler - Covis Pharma US, Inc (118094829)
Actavis Laboratories FL, Inc. 020778751 MANUFACTURE(70515-628, 70515-629, 70515-630)
Actavis Laboratories FL, Inc. 014759176 ANALYSIS(70515-628, 70515-629, 70515-630) , LABEL(70515-628, 70515-629, 70515-630) , MANUFACTURE(70515-628, 70515-629, 70515-630) , PACK(70515-628, 70515-629, 70515-630)
Revised: 12/2021
Document Id: 6ae2aacf-9571-4194-ac9a-14e29cd9061a
Set id: 8c0db100-5df9-49c3-8af9-1bc03ae609b9
Effective Time: 20211203


text:
Researchers say the FBI's statistics on hate crimes across the country are flawed
By Sergio Olmos
SARAH MCCAMMON, HOST:
The FBI recently released their annual statistics on hate crimes across the country. But researchers say the data is flawed, and that could undermine efforts to tackle hate crimes. NPR's Sergio Olmos has been digging into these stats, and he joins us now. Hi, Sergio.
SERGIO OLMOS, BYLINE: Hey, Sarah.
MCCAMMON: So what does this latest FBI report say about hate crimes in America, first of all?
OLMOS: The FBI hate crime statistics reported that last year, there were 7,262 hate crimes across the country. That's a slight decrease from the year before, but researchers say that those numbers may paint an incomplete picture. Law enforcement agencies volunteer to participate. They're not required to send in their data to the FBI. There's 18,000 agencies across the country, and last year, only about two-thirds of those agencies sent in any data. And you might imagine that some of those agencies are small police departments or sheriffs in rural towns, you know, stubbornly refusing to send in their stats, except that that's not the case. The largest cities in America - New York, LA, Chicago - didn't contribute any data.
MCCAMMON: And is this the only way that the government tracks hate crimes?
OLMOS: There's other ways. That's the interesting part. I talked to Eaven Holder at the University of Florida, who published a study looking at 18 years of the FBI's hate crime statistics. He compared it to a different set of data collected by the Bureau of Justice Statistics, widely seen as a more reliable indicator of hate crime stats. So instead of a police officer taking a report, it's researchers asking people directly about their experience to crime. And people tend to open up more. Here's how Eaven Holder described it.
EAVEN HOLDER: So what that database tells us is that, you know, there's 200- to 300,000 hate crime incidents in a given year. And the UCR FBI data records less than 10,000.
OLMOS: And Holder says that even if you look at that data, last year, 80% of the 15,000 agencies that participated reported zero hate crime incidents.
MCCAMMON: Zero hate crimes - I mean, is that reliable? Is that even possible?
OLMOS: There's a mix of reasons why that happened. Some victims may not see themselves as a victim of a hate crime, and some police departments may record, for example, an assault without labeling it a hate crime. And that may be because it's a higher burden of proof to prove the motivation behind a crime. I talked to Jacob Kaplan, who's a professional specialist at the Princeton School of Public and International Affairs. Let's listen to how he described it.
JACOB KAPLAN: There needs to be evidence of bias that plays at least a small part in the crime. And then the police need to have actual evidence, not just, like, I think I was the victim of a hate crime. They need some kind of evidence to suggest that bias was a motivating factor.
OLMOS: So even among police departments that are making a sincere effort to track hate crimes in their district, it's still a challenge.
MCCAMMON: So, Sergio, what could this incomplete data you're describing mean in terms of trying to police hate crimes in the future?
OLMOS: So police and community relationships are already stressed. And researchers say that not taking identity-based crime seriously contributes to a vicious circle where victims of hate may be less likely to turn to the police to solve their problems. And police record less of those and so on, undermining the overall legitimacy of police as an institution, especially in marginalized communities. The Justice Department themselves acknowledge how difficult it is to draw any conclusions from this data set because of the inconsistent way cities are reporting hate crimes year by year. And even if all cities that participated reported their data, among law enforcement, there's just not a universal agreement on what constitutes a hate crime. For example, a mass shooting last year in Atlanta at spa and massage parlors that left eight people dead, including six people who were Asian, were not counted as a hate crime in these stats. So these flawed numbers could mask a very real problem at a time of rising domestic extremism.
MCCAMMON: NPR's Sergio Olmos, thanks so much.
OLMOS: Thank you. Transcript provided by NPR, Copyright NPR.
Sergio Olmos
Former President Bolsonaro is now living in Florida, far away from unrest in Brazil
Bolsonaro backers in Florida decry what they see as a stolen election in Brazil
Ten people have been killed in a shooting near LA after a Lunar New Year festival
The attack on Brazil's Congress was stoked by social media — and by Trump allies


The BRC standard establishes criteria drawn up by the British retail trade. The standard aims to promote uniform requirements and assessments of food products suppliers. This standard has also been copied in the Netherlands.
Welke voedselveiligheidschema's auditten en certificeren jullie binnen de zuivel?


text:
Q: How to push data in nested array in angular JS and then later sort the whole data together Below is my HTML page, i am trying to fetch data from controller and display on page, later an user submits the comment ad the comments gets added to existing data and to be sorted by either date, author or rating.
i am getting an undefined error on push while doing this. where am i going wrong

{{food.name}}
                     {{food.label}}
                     {{food.price | currency}}

{{food.description}}

Customer comments &nbsp &nbsp &nbsp   Sort by <input type="text" ng-model="sortBy">

{{commen.rating}} Stars

{{commen.comment}}

              {{commen.author}}  {{commen.date| date:'mediumDate'}}

{{putComment.rating}} Stars

{{putComment.comment}}

                       {{putComment.author}}, {{putComment.date| date:'mediumDate'}}

            <form class="form-horizontal" name="commentForm" ng-submit="submitComment()" novalidate>

                     Your Name

                        <input type="text" class="form-control" name="fullName" id="fullname" ng-model="putComment.author" required>
                        Your Name is required.

                     Number of Stars

                    <input type="radio" name="stars" value="1" ng-model="putComment.rating">1
                    <input type="radio" name="stars" value="2" ng-model="putComment.rating">2
                    <input type="radio" name="stars" value="3" ng-model="putComment.rating">3
                    <input type="radio" name="stars" value="4" ng-model="putComment.rating">4
                    <input type="radio" name="stars" value="5" ng-model="putComment.rating">5

                    Your Feedback

                        <textarea class="form-control" id="feedback" name="feedback" rows="12" ng-model="putComment.comment" required>
                        </textarea>
                        Comments are required.

                        <button type="submit" class="btn btn-primary" ng-disabled="commentForm.$invalid">Submit Comment</button>

            </form>

below is my controller code. Also i get undefined when i log on console this-console.log($scope.dish.comments) while i get data for this console.log($scope.dish)
    .controller('DishDetailController', ['$scope', function($scope) {

           $scope.sortBy="";

            var dish = [
                         {
                          name:'Uthapizza',
                          image: 'images/uthapizza.png',
                          category: 'mains',
                          label:'Hot',
                          price:'4.99',
                          description:'A unique combination of Indian Uthappam (pancake) and Italian pizza, topped with Cerignola olives, ripe vine cherry tomatoes, Vidalia onion, Guntur chillies and Buffalo Paneer.',
                           comments: [
                               {
                                   rating:5,
                                   comment:"Imagine all the eatables, living in conFusion!",
                                   author:"John Lemon",
                                   date:"2012-10-16T17:57:28.556094Z"
                               },
                               {
                                   rating:4,
                                   comment:"Sends anyone to heaven, I wish I could get my mother-in-law to eat it!",
                                   author:"Paul McVites",
                                   date:"2014-09-05T17:57:28.556094Z"
                               },
                               {
                                   rating:3,
                                   comment:"Eat it, just eat it!",
                                   author:"Michael Jaikishan",
                                   date:"2015-02-13T17:57:28.556094Z"
                               },
                               {
                                   rating:4,
                                   comment:"Ultimate, Reaching for the stars!",
                                   author:"Ringo Starry",
                                   date:"2013-12-02T17:57:28.556094Z"
                               },
                               {
                                   rating:2,
                                   comment:"It's your birthday, we're gonna party!",
                                   author:"25 Cent",
                                   date:"2011-12-02T17:57:28.556094Z"
                               }

                           ]
                      }
            ];

            $scope.dish=dish;
        }])

        .controller('DishCommentController', ['$scope', function($scope) {
         $scope.submitted=false;

         $scope.putComment = { rating:5, comment:"", author:"", date:"" };

        $scope.submitComment = function () {

        $scope.putComment.date= new Date().toISOString();

        console.log($scope.putComment);
        console.log($scope.dish.comments);

        $scope.dish.comments.push($scope.putComment);

          $scope.commentForm.$setPristine();

          $scope.submitted=true;

         $scope.putComment={rating:5, comment:"", author:"", date:""};

            }
         }]);

A: i got this working by changing the following code :
$scope.dish.comments.push($scope.putComment);

to below one
$scope.dish[0].comments.push($scope.putComment);

redpajama_set_name: RedPajamaStackExchange


Hopefully its a case of getting a group together and head down, its a lonely train journey that far.
Received an email this morning to say I passed assessment and been offered a position!
Over the moon Just a waiting game to get a starting date now!
YAY! I am so glad for you!
Seeing all these people pass just makes me feel more pressure for my assessment!
Im sure you will be fine. Its quite an enjoyable day actually. The day is over before you know it!
Its the 2 interviews I wasnt looking forward to. Just be yourself, concentrate on H+S and customer service and you will be fine.
Theres only so much you can prepare for really. Only a couple of questions each but they delve into your answers to find out more about you and also how you handled situations in previous jobs etc. All quite relaxed and dont feel as though they are trying to trip you up at all.
Nice one, where abouts are you waiting on?
Does anyone know about car parking for the Exeter Assessment on commercial road?
Congrats, mate! That is awesome news!
I'll second your comments that the day really is quite fun and very relaxed. I just need to wait and hear back now. Nice to be able to switch the brain off and relax for a few days haha.
�We just wanted to drop you an email to give you an update on your application for the Openreach Trainee Engineer role.
As you have been successful so far by passing both the online Strengths Test and the Video Interview, we are now in the process of matching candidates like yourself to where our vacancies are located. This will enable us to select the right people to attend our assessment centres.
The really great news is that this year we are planning to recruit in excess of 2500 new engineers, so this will naturally increase your chance of getting called up to an assessment centre.
Has anybody else had a similar email and then got an assement date? I�m really hoping I get an assessment day but not sure how much longer the process will take and whether not I will know if I have been sucessful/unsuccessful either way.
If anybody could share a little insight, i would be extremely grateful, thanks!
I think that sounds positive, so I would hold tight and see what happens. That echoes what management said about recruiting the whole year round � new intake literally every week � so don't worry just yet. Fingers crossed mate!


The Xydakis Apartments in Mykonos Town are stylishly furnished and fully equipped, offering comfortable, relaxing and carefree holidays on Mykonos (Myconos) Island. All these Mykonos Town apartments have their own ambience and design, catering to all preferences, so that you can chose the one that suits your style and character. They offer a spectacular panoramic view of Mykonos Town and port, the deep blue Aegean Sea and the neighboring islands, competing with other Mykonos Town hotels for the finest spot on the island.
In order to make your vacations on Mykonos Island as comfortable and enjoyable as possible, Mykonos Apartments Xydakis also provides car rental services. Choose from our wide range of small, medium and large cars and truly experience the spectacular island of Mykonos , in a safe and carefree manner.


A Year Ago, DT Promised Carrier Workers Help. We're Still Waiting.
From the Washington Post. We thought this would be very good and of interest to the general Union Working Cause. The author is the former President of the United Steelworkers Union.


text:
Q: How to replace hidden nodes by "virtual" edges? Take a simple network A=B=C, where node B has the attribute minor. When I just filter out that attribute, I'll get the graph A   C. However, I want a visualisation of the fact that A and C are indirectly connected, i.e. A---C. How can this be achieved? Are filters even the proper way?

A: I could be wrong but I don't think this is something you can achieve without processing your data first, looping through all the edges that involve B, creating an array of B's neighbours and then creating new edges linking them.
The exact way to do this depends on the format of your data and the programming language.
You could also add edges manually in Gephi, but that is of course only realistic for small graphs.
I don't think filters are the right tool for this because they simply exclude nodes (and edges) but don't create new ones. https://github.com/gephi/gephi/wiki/Filter