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Sony Cyber-shot HX90V and WX500 Compact Cameras With 30x Zoom Launched
If you find the RX100 series of cameras a little too expensive, Sony has a solution for you. The company on Monday launched the Cyber-shot HX90V which has the same compact form-factor as the Sony RX100 III, and yet manages to squeeze in a 30x optical zoom Vario-Sonnar T* lens into its compact body. Similarly, Sony also pulled the wraps off the Cyber-shot WX500, which also packs in the same lens into its body.
The biggest differences between the two cameras are the inclusion of an Electronic Viewfinder (EVF) in the HX90V, and their prices – the HX90V and WX500 are priced at $430 and $330, respectively. Moreover, both the cameras will be available from June.
Sony fits the Cyber-shot HX90V with a 30x optical zoom by using an adjustable fifth lens group and newly developed aspherical lenses, that actually makes the lens unit smaller and shorter. The EVF is smaller than the one on the RX1000 III and has a lower resolution of 638k dots. Additionally, Sony also adds a 180-degree tiltable 3-inch, 921k-dot LCD, which is great for capturing selfies as well.
The Cyber-shot HX90V and WX500 uses a 18.2-megapixel 1/2.3-inch Exmor R CMOS sensor, and has five-axis image stabilisation and a Bionz X processor. For connectivity, the Sony Cyber-shot HX90V and WX500 support Wi-Fi and NFC. The WX500 on the other hand doesn't have a grip on the front, and is also missing GPS. Both the cameras are compatible with select Sony PlayMemories Camera apps.
TechnologySony Cyber-shot HX90V and WX500
CrowdStrike Security Firm Claims Success in Deterring Chinese Hackers
HTC Desire 326G Dual SIM With 4.5-Inch Display, 8-Megapixel Camera Launched


A practicing Modern Traditional Witch for over 2 decades, her early days were defined by being a community leader and public spokesperson for Paganism. Laura was the Associate Editor of Crescent Magazine, A Pagan Publication of Art, Philosophy, and Belief from 1998-2004, founder of the Cauldron of Annwyn Pagan Society in New England, and the youngest attendee of the Pagan Leaders Summit in Bloomington, IN in 2001. After nearly a decade-long hiatus from being publicly active, Laura began to write and get involved again. She blogs at Patheos as A Modern Traditional Witchand at Witches & Pagans as Fine Art Witchery. She can be frequently found touring the country, doing workshops and performances at various events and festivals.
She lives in Seattle, Washington with her partner, musician Nathaniel Johnstone and three cats: Eleanor, Simon, and Sam. A fourth cat is imminent.


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Primary Care > Vaccines
Tell, Don't Ask When It Comes to Vaccinating Kids
— Pediatricians who told parents their child needed a vaccination rather than asked if they wanted one met less parental resistance, researchers found.
by Chris Kaiser November 4, 2013
Pediatricians who told parents their child needed a vaccination rather than asked if they wanted one met less parental resistance, researchers found.
Three-quarters of providers brought up the issue of vaccination by using a "presumptive" approach, which assumes parents will immunize their child, according to Douglas J. Opel, MD, MPH, of the University of Washington School of Medicine in Seattle, and colleagues.
Only 26% of parents were resistant to vaccine recommendations when providers used the presumptive approach. However, 83% resisted when providers used a "participatory" approach, which invites parental involvement, researchers noted in the study published online Nov. 4 in Pediatrics.
"I think we've known for sometime that ... we have to be careful in our language when we broach the subject of vaccines with parents, and especially now when more and more parents are resistant to vaccines," Robyn Strosaker, MD, a pediatrician at University Hospitals Rainbow Babies & Children's Hospital in Cleveland told MedPage Today. She was not involved in the study.
When the researchers controlled for parental hesitancy status, parent and child demographics, and visit characteristics, they found that the participatory approach was associated with a significantly increased odds of parental resistance to the physician recommendation, but the confidence interval was very wide (OR 17.5, 95% CI 1.2–253.5).
This is the first study to "address the existing gap in evidence for provider communication behaviors that are effective in increasing parental acceptance of childhood vaccines," researchers wrote. And as such, the results can "help guide the development of quality improvement interventions aimed at increasing vaccination rates among vaccine-resistant parents."
Opel and colleagues cited studies that demonstrated the value parents place in their pediatrician for trusted vaccine recommendations.
Parents initially resistant to vaccine recommendations have cited their pediatrician's reassurance and vaccine information as reasons for changing their minds. In the current study, when pediatricians persisted in recommending vaccinations (50% persisted when initially met with resistance), 47% of the resistant parents eventually accepted the recommendation for vaccination.
"There is a lot of information out there and it can be really confusing to parents who mean well, but not all sources are credible," Jay Homme, MD, a pediatrician at the Mayo Clinic in Rochester, Minn., who was not involved with the study, told MedPage Today.
"I feel like we have to build on a trust relationship. I've seen their children since they were infants. I've seen other children of theirs and really work on developing a trusting relationship," he said.
Opel and colleagues enrolled 16 pediatric providers from nine primary care practices in the Seattle area. They videotaped and analyzed 111 vaccine discussions during a child's check-up visit.
Parents also filled out a questionnaire that assessed their level of hesitancy toward vaccines -- 55 were vaccine-hesitant parents and 56 were vaccine-receptive parents.
The children ranged in age from 1 to 19 months and 77% of parents were older than 29. Most of the parents were married or living with a partner, most had better than a high school education, and most were white.
More than half (57%) the participants had one child, 62% of the eligible children were the first born, and it was the first immunization discussion for 26%.
A total of 38% of providers explicitly solicited questions or concerns about shots -- a percentage that did not differ between vaccine-hesitant (36%) and vaccine-receptive (39%) parents.
A little more than half (55%) of providers gave a rationale for shots, with no difference among the two groups of parents (55% each). Slightly more than half (55%) the providers discussed side effects, again with no difference between the resistant and receptive parents (51% versus 59%).
Several experts contacted by MedPage Today said because parents don't see the diseases that these vaccines help to prevent, they don't think they are real anymore.
"I've seen whooping cough and we've had whooping cough in Arkansas and certainly in other parts of the country. So I try to tell the parents why that particular disease is so dangerous and potentially dangerous for their child, and try to address their concerns in that way," Eddie Ochoa, MD, a pediatrician at Arkansas Children's Hospital in Little Rock, told MedPage Today.
The study was limited because of the potential for the Hawthorne effect, the heterogeneity of the parents, and because the categorization of vaccine-resistant parents was not based on immunization records and was merely a proxy of immunization behavior, researchers said.
The research was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
The authors reported no relevant financial relationships.
Source Reference: Opel DJ, et al "The Architecture of Provider-Parent Vaccine Discussions at Health Supervision Visits" DOI: 10.1542/peds.2013-2037.

redpajama_set_name: RedPajamaCommonCrawl


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OBAMACARE PUNCHLINE: "IF YOU LIKE YOUR INSURANCE YOU CAN KEEP IT" BIG LAUGH WITH CHARLIE ROSE GANG…….
health care Lying Bastards Lying Socialist Bastards Obama Obama's Socialist Pals
By KGSaccess_time4 years agochat_bubble_outlineLeave a comment
These people are contemptible…..
Written by KGS
Previous Post Previous Post FINNAIR STEWARD FOUND GUILTY OF SMUGGLING 30 CHINESE CITIZENS INTO SCHENGEN REGION……
Next Post Next Post WORLD MINUS ONE MORE ISLAMONAZI AS HEZBOLLAH LEADER BADREDDINE KILLED IN SYRIA……
Donate to Elizabeth's legal fund here…
Contact the TT @ tundratabloids@gmail.com
Melting pot societies are the only way to secure the individual…
Multiculturalism is a gross failure. Assimilation, where celebrating one's own heritage but as a full member of the dominant culture, wins.
There Is No Such Thing As White Cultural Heritage. The West's Legacy Is Open To All….
There's No Common Cultural Legacy For The Alt-Right
Still, is there something to it? Is there a common heritage that will cover El Greco and Hume and Dostoyevsky? Is there one that can include the Jacobites and the Jacobins? There is, but it is not racial, and white supremacists reject it because it rejects them. The unifying heritage of Europe is religious and philosophical. It is Jerusalem and Athens, in one famous formulation. Christian religion and Greek philosophy, filtered through Roman law and culture, are the foundation of European culture. The tensions, agreements, developments and settlements between these have shaped the Western world, and these roots of Western civilization are not congenial to white supremacy.
Christianity is universal in its message and Jewish in its origins. For centuries after its founding, Christianity's center was the Mediterranean world, including Asia Minor and North Africa. Christianity has never been defined by race, and locally-grown racist heresies are only sustainable among those ignorant of Christianity's teachings, origins and history.
Greek philosophy is likewise ill-suited to serve as a basis for white identity. It is either too universal (addressing the human condition in general) or too local—none of us live as citizens of an ancient Greek polis. Later philosophical developments in Europe, such as the philosophies of the Enlightenment, likewise tend to be too universal for white supremacists seeking a tribal identity. As for the scientific revolution that developed within Western culture (albeit with much borrowed from outside Europe), math doesn't care what color someone is.
"More here"
Daniel Greenfield explains Islam 101:
"Every devout Muslim is an "Islamist". Islam is not a personal religion. It is a religion of the public space. A "moderate" Muslim would have to reject Islam as a religion of the public space, as theocracy, and that secularism would be a rejection of Islam.
Nothing in Islam exists apart from anything else. While liberals view culture and religion as a buffet that they can pick and choose from, it is a single integrated system. If you accept one part, you must accept the whole. Once you accept any aspect of Islam, you must accept its legal system and once you accept that, you must accept its governance and once you accept that, you lose your rights.''
Trending Israeli News…
Holocaust event in Jerusalem drags Israel into European memory wars Determination to learn the lessons of the Holocaust has become mired in controversy even before it has started, By SAM SOKOL/JTA JANUARY 23, 2020 05:02
Rivlin, world leaders vow to stand united against racism, antisemitism The King of Spain Felipe VI took the podium on behalf of the guests reunited at Rivlin's residence, starting his speech by quoting 12th century Jewish thinker Moises Maimonined. By ROSSELLA TERCATIN, GREER FAY CASHMAN JANUARY 22, 2020 22:35
Israeli Holocaust survivor shows world her diary from Auschwitz "I will die shortly and I don't want the people to be forgotten who were murdered," Miller-Ehrenwald said. By BENJAMIN WEINTHAL JANUARY 22, 2020 22:02
Israel's Defense Begins Laying Sensors to Foil Terrorist Tunnels
GW/CC debunked by premier climatologist Prof.Richard Lindzen
//www.youtube.com/watch?v=X2q9BT2LIUA
Trending European News…
Climate change hoax, how to destroy it…
//www.youtube.com/watch?v=bpxAIYrtGLw
Cars set alight for second consecutive night in Gävle
(Same church that houses the anti-Israel EAPPI) French President Macron orders Israeli police out of French church Legally speaking, the church is a French-held territory outside of France and is under that country's protection. By JERUSALEM POST STAFF JANUARY 22, 2020 18:04
France: Security Services Arrest Seven Islamic Radicals Plotting Terror Attacks
Serbian president flies Star of David flag to mark Holocaust Remembrance Day Before his departure for World Holocaust Forum in Jerusalem, Aleksandar Vucic tweets photo of yellow flag outside his office, says: 'Never again'
The Svensmark "The Cloud Mystery", what really drives Global Warming…
//www.youtube.com/watch?v=yZ7IEUBUe4s
Trending Middle East News…
Successor to slain Iran general faces same fate if he kills Americans By REUTERS
Lebanon's Halloween Government Protesters are right—the extent to which the country's new cabinet brings it closer to Iran is spooky.
Iranian commander gunned down in front of his own home Abdolhossein Mojaddami was gunned down by two gunmen on a motorcycle. By JERUSALEM POST STAFF JANUARY 22, 2020 16:17
Saudi Arabia Helps Violent Fugitives Flee U.S. Justice System, FBI Says
SECULARISM AND RELIGION: THE ONSLAUGHT AGAINST THE WEST'S MORAL CODES
War is being waged against Western culture from within which is in essence a war against Christianity and its moral origins in the Hebrew Bible. By attacking these Biblical foundations in the name of reason and human rights, the culture warriors of secularism are sawing off the branch on which they sit. The only way to defend Western civilisation is to reaffirm and restore its Biblical foundations. My argument is a development of ideas I first explored in my 2012 book The World Turned Upside Down: The Global Battle over God, Truth and Power.
We are living in an era which extols reason, science and human rights. These are said to be essential for progress, a civilised society and the betterment of humanity. Religion is said to be their antithesis, the source instead of superstitious mumbo-jumbo, oppression and backward-thinking.
Some of this hostility is being driven by the perceived threat from Islamic terrorism and the Islamisation of Western culture. However, this animus against religion has far deeper roots and can be traced back to what is considered the birthplace of Western reason, the 18th-century Enlightenment.
Actually, it goes back specifically to the French Enlightenment. In England and Scotland, the Enlightenment developed reason and political liberty within the framework of Biblical belief. In France, by contrast, anti-clericalism morphed into fundamental hostility to Christianity and to religion itself.
"Ecrasez l'infame," said Voltaire (crush infamy) — the infamy to which he referred being not just the Church but Christianity, which he wanted to replace with the religion of reason, virtue and liberty, "drawn from the bosom of nature".
Perfecting society
But this Enlightenment did not remove religion so much as pervert it. It took millenarian fantasies, the idea that the perfection of the world was at hand, and it secularised them. Instead of God producing heaven on earth, it would be mankind which would bring that about. Reason would create the perfect society and "progress" was the process by which utopia would be attained.
More here"
Middle East expert Mordechai Kedar: The Muslim Mind
//www.youtube.com/watch?v=7sL_8BvqHo0
What mainstream Islam really teaches, what they believe…
//www.youtube.com/watch?v=j4OCTslNeT8
ADL, Protecting American Muslims, Fooling American Jews…
//www.youtube.com/watch?v=jVqqPx-Cq8k
AG Barr speaks at the Federalist Society's National Lawyers Convention
//www.youtube.com/watch?v=8NdbANrjFWE
Lord Baron Pearson on Brexit…
//www.youtube.com/watch?v=dh-xT6951kc
Mohammed's Koran: Why Muslims Kill For Islam by Peter McLoughlin (Author), Tommy Robinson (Author)
Jenin: Massacring Truth (This documentary was made long before the term #FakeNews got started…
//vimeo.com/32218686?loop=0
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Women Can Fit in Fitness!
A significant focus of patient education at my practice is ensuring that patients understand the strong links between their overall health and oral health. Of course, this is not an age-specific or gender-specific issue, but today I'd like to take a moment to consider women in particular. Staying fit can go a long way to avoiding obesity, diabetes, osteoporosis, and other health issues that can contribute to or complicate oral health.
We're all inundated with reports about the dangers of obesity, and women are particularly vulnerable to social pressures about their weight. According to one study, over one-third of adult weight-loss-pill users were not obese and another third of those surveyed used non-prescription diet products. This is cause for concern because diet pills can create the discomfort of decreased salivary flow, or dry mouth, especially in mature patients, increasing the risk for cavities, gum disease, and oral candidiasis.
A balanced diet and working out make more sense, but statistics on women's fitness patterns are disheartening. According to experts, more than 60% of North American women do not get enough exercise and according to research from the University of North Carolina at Chapel Hill fewer than 1 in 4 pregnant women do.
Lack of time is cited as the biggest barrier so maybe the heart of the matter is fighting the trend by creating a routine that you can live with. Here are some simple ways I've read about that work your workout into your workday without too much effort: Jump rope in your office for five minutes. Take the stairs instead of the elevator. Ride your bicycle for short distances instead of driving your car. If you do drive, park your car at least a quarter mile from your destination and walk. Or, walk over to a colleague's desk to talk about work, rather than sending an email.
Even better yet – 30 minutes of gardening, pushing a stroller 1.5 miles in thirty minutes, and raking leaves for thirty minutes. If you like to watch TV, forgo a half-hour show and get outside for a walk. Or if it's a show you love, watch while you're exercising.
I understand completely that it's hard to fit in time to get fit when your schedule is already packed between the morning alarm and crawling back into bed at night. Especially after a day that keeps you on the run mentally ... but not physically.
Still, I hope you can see that you don't always have to join a gym. There is room to be creative and include a little physical workout without making any big changes to your schedule. And, of course, keeping time in your schedule to maintain your oral health will contribute to keeping you healthy.


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Museums of mortality — spooky, sublime
January 15, 2018 April 4, 2018 ~ Chris
Last year I paid visits to those twin emporiums of ick and awe, the Mütter Museum in Philadelphia and the smaller but almost equally macabre Kunstkamera Museum in St. Petersburg, Russia. Festooned with bullet-riddled skulls, deformed fetuses crammed into jars, gnarled, twisted skeletons, diseased human organs, rusty surgical tools and random gangrened digits, these palaces of the perverse satisfied the ghoulishly curious. They were extravagantly ack-inducing, deliciously quiver-making. Paradise.
He's checking his texts.
As noted earlier, I'm deliberating my next journey, and, because I went large last year, I'm thinking small this year. Which means I might go to Chicago, a 2.5-hour flight away. And which means, more importantly, the International Museum of Surgical Science, a less squishy warehouse of medical wonders than the two above, but still a marvelous assemblage of stuff that spurs contemplation about our mortal flesh and all that can go wrong with it via disease, accident and sheer shitty luck.
Highlights include a vintage iron lung machine (can I climb inside?), an exhibit about pain and anesthesia through the ages and one about the history of wound healing ("From the use of herbal ointments and therapeutic clays among prehistoric hunter-gatherers to Galen's treatment of injured gladiators in Ancient Rome, the care of wounds is among the earliest applications of medicine"), and the museum structure itself, an elegant, historic lakeside mansion. And who could pass up the exhibit "A History of Blood Transfusion: 350 Years of Apparatus Advancement"?
Mural of early Caesarean section. Gleefully gruesome.
Reviewers note that the four-story manse is compact and, naturally, its array of freakish displays is no match for Philly's world-class Mutter. Small is all right; I enjoy a good bite-size museum, especially one of such narrow scope. Sort of like the Russian Vodka Museum or Tokyo's Meguro Parasitological Museum.
Iron lung machine. May I?
For more grim exhilarations, I pivoted my research to Chicago cemeteries — I'm always up for a calming stroll through deathly opulence — but decided to skip the offerings. Several notable cemeteries pock the area, boasting the resting holes of everyone from Al Capone to Jesse Owens, Emmett Till to John Belushi, Gene Siskel to John Hughes. I sought out film critic Roger Ebert's grave, but he was cremated and his ashes are kept by a private party, most likely his lovely widow Chaz.
We should all be so lucky. Cremation is the way to go, although I don't want my cremains kept by anyone but the wind and the water -— whoosh. Thoughts like these will surely visit me at the Surgical Science Museum, a place rife with death and decrepitude. But they won't get me down. They're wondrous in their way and, far from depressing, something of a mind-reeling, soul-stirring tonic for the living.
Posted in death, Freaks, museums, Offbeat, Travel	ChicagoInternational Museum of Surgical Sciencejarred babiesKunstkamera MuseumMutter Museum
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2 thoughts on "Museums of mortality — spooky, sublime"
Like I said before, I definitely think you should go! I want to hear all about it, so I know if it's worth my making the (much longer) journey! I imagine they probably won't let people climb in the iron lung, but I'm not sure if I would want to anyway – those things freak me out, and I'd be worried I'd somehow get trapped inside!
Actually, iron lungs are some of my worst nightmares. I cannot imagine how horrible it would be. I saw a documentary about a writer who had to live in one. He had to do all his writing with a pencil in his teeth!!


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NDC Code(s): 71335-1010-1, 71335-1010-2, 71335-1010-3, 71335-1010-4, view more
71335-1010-5, 71335-1010-6, 71335-1011-1, 71335-1011-2, 71335-1011-3, 71335-1011-4
Packager: Bryant Ranch Prepack
Source NDC Code(s): 63304-828, 63304-829
ATORVASTATIN CALCIUM tablets for oral use
Dosage and Administration, Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or
Certain Protease Inhibitors (2.6) 11/2019
Warnings and Precautions, Skeletal Muscle (5.1) 11/2019
Atorvastatin calcium tablets are HMG-CoA reductase inhibitor indicated as an adjunct therapy to diet to: (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).
Limitations of Use: (1)
Atorvastatin calcium tablets have not been studied in Fredrickson Types I and V dyslipidemias (1.3). (1)
Patients requiring large LDL-C reduction (> 45%) may start at 40 mg once daily (2.1).
Tablets: 10, 20, 40, and 80 mg of atorvastatin (3). (3)
The most commonly reported adverse reactions (incidence ≥ 2%) in patients treated with atorvastatin calcium in placebo-controlled trials regardless of causality were: nasopharyngitis, arthralgia, diarrhea, pain in extremity, and urinary tract infection (6.1). (6)
To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. (6)
Drug Interactions Associated with Increased (7)
Risk of Myopathy/Rhabdomyolysis (2.6, 5.1, 7, 12.3) (7)
Interacting Agents (7)
Prescribing Recommendations (7)
Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir, letermovir when co-administered with cyclosporine (7)
Avoid atorvastatin (7)
Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir (7)
Do not exceed 20 mg atorvastatin daily (7)
Nelfinavir (7)
Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine (7)
Use with caution and lowest dose necessary (7)
Other Lipid-Lowering Medications: Use with 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 atorvastatin calcium (7).
Digoxin: Patients should be monitored appropriately (7.10).
Hepatic impairment: Plasma concentrations markedly increased in patients with chronic alcoholic liver disease (8.6, 12.3).
2.2 Heterozygous Familial Hypercholesterolemia in Pediatric Patients (10 Years to 17 Years of Age)
2.6 Dosage in Patients Taking Cyclosporine, Clarithromycin, Itraconazole, Letermovir, or Certain Protease Inhibitors
7.10 Digoxin
14.1 Prevention of Cardiovascular Disease
17.1 Muscle Pain
17.3 Embryofetal Toxicity
In adult patients without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as age, smoking, hypertension, low HDL-C, or a family history of early coronary heart disease, atorvastatin calcium tablets are indicated to:
In adult patients with type 2 diabetes, and without clinically evident coronary heart disease, but with multiple risk factors for coronary heart disease such as retinopathy, albuminuria, smoking, or hypertension, atorvastatin calcium tablets are indicated to:
In adult patients with clinically evident coronary heart disease, atorvastatin calcium tablets are indicated to:
Atorvastatin calcium tablets are indicated:
As an adjunct to diet to reduce elevated total-C, LDL-C, apo B, and TG levels and to increase HDL-C in adult patients with primary hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Types IIa and IIb);
As an adjunct to diet for the treatment of adult patients with elevated serum TG levels (Fredrickson Type IV);•For the treatment of adult patients with primary dysbetalipoproteinemia (Fredrickson Type III) who do not respond adequately to diet;
LDL-C remains ≥ 190 mg/dL or
LDL-C remains ≥ 160 mg/dL and:
Atorvastatin calcium tablets have not been studied in conditions where the major lipoprotein abnormality is elevation of chylomicrons (Fredrickson Types I and V).
The recommended starting dose of atorvastatin calcium tablets is 10 mg/day; the usual dose range is 10 to 20 mg orally once daily [see Clinical Studies (14.6)]. Doses should be individualized according to the recommended goal of therapy [see Indications and Usage (1.2) and Clinical Pharmacology (12)]. Adjustments should be made at intervals of 4 weeks or more.
Atorvastatin calcium tablets may be used with bile acid resins. The combination of HMG-CoA reductase inhibitors (statins) and fibrates should generally be used with caution [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Renal disease does not affect the plasma concentrations nor LDL-C reduction of atorvastatin calcium tablets; thus, dosage adjustment in patients with renal dysfunction is not necessary [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
In patients taking cyclosporine or the HIV protease inhibitor tipranavir plus ritonavir or the hepatitis C virus (HCV) protease inhibitor glecaprevir plus pibrentasvir, or letermovir when co-administered with cyclosporine, therapy with atorvastatin calcium tablets should be avoided. In patients with HIV taking lopinavir plus ritonavir, use the lowest dose necessary of atorvastatin calcium tablets. In patients taking clarithromycin, itraconazole, elbasvir plus grazoprevir, or in patients with HIV taking a combination of saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir or letermovir therapy with atorvastatin calcium tablets should be limited to 20 mg, and appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used. In patients taking the HIV protease inhibitor nelfinavir therapy with atorvastatin calcium tablets should be limited to 40 mg. When co-prescribing atorvastatin with other protease inhibitors, appropriate clinical assessment is recommended to ensure that the lowest dose necessary of atorvastatin calcium tablets is used [see Warnings and Precautions (5.1) and Drug Interactions (7)].
Atorvastatin calcium tablets, USP are white, elliptical, film-coated tablets containing atorvastatin calcium trihydrate, USP equivalent to 10, 20, 40, and 80 mg atorvastatin.
Table 1: Atorvastatin calcium Tablet Strengths and Identifying Features
white, elliptical, film-coated tablets, debossed with 'RX 12' on one side and plain on the other side.
white, elliptical, film-coated tablets, debossed with 'RX 828' on one side and plain on the other side
white, elliptical, film-coated tablets, debossed with 'RX 829' on one side and plain on the other side.
Pregnancy[see Use in Specific Populations (8.1)].
Lactation[see Use in Specific Populations (8.2)].
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with atorvastatin calcium and with other drugs in this class. A history of renal impairment may be a risk factor for the development of rhabdomyolysis. Such patients merit closer monitoring for skeletal muscle effects.
Atorvastatin, like other statins, occasionally causes myopathy, defined as muscle aches or muscle weakness in conjunction with increases in creatine phosphokinase (CPK) values > 10 times ULN. The concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine and strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., clarithromycin, itraconazole, and HIV and HCV protease inhibitors) increases the risk of myopathy/rhabdomyolysis.
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; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevation of CPK. Patients should be advised to report promptly unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever or if muscle signs and symptoms persist after discontinuing atorvastatin calcium. Atorvastatin calcium therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed or suspected.
The risk of myopathy during treatment with drugs in this class is increased with concurrent administration of the drugs listed in Table 2. Physicians considering combined therapy of atorvastatin with any of these drugs should carefully weigh the potential benefits and risks and should carefully monitor patients for any signs or symptoms of muscle pain, tenderness, or weakness, particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Lower starting and maintenance doses of atorvastatin should be considered when taken concomitantly with the aforementioned drugs [see Drug Interactions (7)]. Periodic creatine phosphokinase (CPK) determinations may be considered in such situations, but there is no assurance that such monitoring will prevent the occurrence of severe myopathy.
Prescribing recommendations for interacting agents are summarized in Table 2 [see Dosage and Administration (2.6), Drug Interactions (7), and Clinical Pharmacology (12.3)].
Clarithromycin, itraconazole, saquinavir plus ritonavir*, darunavir plus ritonavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir
Atorvastatin calcium therapy should be temporarily withheld or discontinued in any patient with an acute, serious condition suggestive of a myopathy or having a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., severe acute infection, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders, and uncontrolled seizures).
Statins, like some other lipid-lowering therapies, have been associated with biochemical abnormalities of liver function. Persistent elevations (> 3 times the upper limit of normal [ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received atorvastatin calcium in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively.
One patient in clinical trials developed jaundice. Increases in liver function tests (LFT) in other patients were not associated with jaundice or other clinical signs or symptoms. Upon dose reduction, drug interruption, or discontinuation, transaminase levels returned to or near pretreatment levels without sequelae. Eighteen of 30 patients with persistent LFT elevations continued treatment with a reduced dose of atorvastatin calcium.
It is recommended that liver enzyme tests be obtained prior to initiating therapy with atorvastatin calcium and repeated as clinically indicated. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including atorvastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with atorvastatin calcium, promptly interrupt therapy. If an alternate etiology is not found, do not restart atorvastatin calcium.
Atorvastatin calcium should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of liver disease. Active liver disease or unexplained persistent transaminase elevations are contraindications to the use of atorvastatin calcium [see Contraindications (4)].
Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including atorvastatin calcium.
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or gonadal steroid production. Clinical studies have shown that atorvastatin calcium does not reduce basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on male fertility have not been studied in adequate numbers of patients. The effects, if any, on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be exercised if a statin is administered concomitantly with drugs that may decrease the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, and cimetidine.
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain hemorrhage and optic nerve vacuolation were seen in another female dog that was sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human plasma area-under-the-curve (AUC, 0 to 24 hours) based on the maximum human dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions have been observed in mice after chronic treatment for up to 2 years at doses up to 400 mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times (mouse) and 8 to 16 times (rat) the human AUC (0 to 24) based on the maximum recommended human dose of 80 mg/day.
CNS vascular lesions, characterized by perivascular hemorrhages, edema, and mononuclear cell infiltration of perivascular spaces, have been observed in dogs treated with other members of this class. A chemically similar drug in this class produced optic nerve degeneration (Wallerian degeneration of retinogeniculate fibers) in clinically normal dogs in a dose-dependent fashion at a dose that produced plasma drug levels about 30 times higher than the mean drug level in humans taking the highest recommended dose.
In a post-hoc analysis of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study where atorvastatin calcium 80 mg vs. placebo was administered in 4,731 subjects without CHD who had a stroke or TIA within the preceding 6 months, a higher incidence of hemorrhagic stroke was seen in the atorvastatin calcium 80 mg group compared to placebo (55, 2.3% atorvastatin vs. 33, 1.4% placebo; HR: 1.68, 95% CI: 1.09, 2.59; p = 0.0168). The incidence of fatal hemorrhagic stroke was similar across treatment groups (17 vs. 18 for the atorvastatin and placebo groups, respectively). The incidence of nonfatal hemorrhagic stroke was significantly higher in the atorvastatin group (38, 1.6%) as compared to the placebo group (16, 0.7%). Some baseline characteristics, including hemorrhagic and lacunar stroke on study entry, were associated with a higher incidence of hemorrhagic stroke in the atorvastatin group [see Adverse Reactions (6.1)].
Rhabdomyolysis and myopathy [see Warnings and Precautions (5.1)]
Liver enzyme abnormalities [see Warnings and Precautions (5.2)]
In the atorvastatin calcium placebo-controlled clinical trial database of 16,066 patients (8755 atorvastatin calcium vs. 7311 placebo; age range 10 to 93 years, 39% women, 91% Caucasians, 3% Blacks, 2% Asians, 4% other) with a median treatment duration of 53 weeks, 9.7% of patients on atorvastatin calcium and 9.5% of the patients on placebo discontinued due to adverse reactions regardless of causality. The five most common adverse reactions in patients treated with atorvastatin calcium that led to treatment discontinuation and occurred at a rate greater than placebo were: myalgia (0.7%), diarrhea (0.5%), nausea (0.4%), alanine aminotransferase increase (0.4%), and hepatic enzyme increase (0.4%).
The most commonly reported adverse reactions (incidence ≥ 2% and greater than placebo) regardless of causality, in patients treated with atorvastatin calcium in placebo controlled trials (n = 8755) were: nasopharyngitis (8.3%), arthralgia (6.9%), diarrhea (6.8%), pain in extremity (6%), and urinary tract infection (5.7%).
Table 3 summarizes the frequency of clinical adverse reactions, regardless of causality, reported in ≥ 2% and at a rate greater than placebo in patients treated with atorvastatin calcium (n = 8755), from seventeen placebo-controlled trials.
Table 3. Clinical adverse reactions occurring in ≥ 2% in patients treated with any dose of atorvastatin calcium and at an incidence greater than placebo regardless of causality (% of patients).
*Adverse Reaction ≥ 2% in any dose greater than placebo
Pain in extremity
In ASCOT [see Clinical Studies (14.1)] involving 10,305 participants (age range 40 to 80 years, 19% women; 94.6% Caucasians, 2.6% Africans, 1.5% South Asians, 1.3% mixed/other) treated with atorvastatin calcium 10 mg daily (n = 5,168) or placebo (n = 5,137), the safety and tolerability profile of the group treated with atorvastatin calcium was comparable to that of the group treated with placebo during a median of 3.3 years of follow-up.
In CARDS [see Clinical Studies (14.1)] involving 2,838 subjects (age range 39 to 77 years, 32% women; 94.3% Caucasians, 2.4% South Asians, 2.3% Afro-Caribbean, 1% other) with type 2 diabetes treated with atorvastatin calcium 10 mg daily (n = 1,428) or placebo (n = 1,410), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 3.9 years. No cases of rhabdomyolysis were reported.
In TNT [see Clinical Studies (14.1)] involving 10,001 subjects (age range 29 to 78 years, 19% women; 94.1% Caucasians, 2.9% Blacks, 1% Asians, 2% other) with clinically evident CHD treated with atorvastatin calcium 10 mg daily (n = 5006) or atorvastatin calcium 80 mg daily (n = 4995), there were more serious adverse reactions and discontinuations due to adverse reactions in the high-dose atorvastatin group (92, 1.8%; 497, 9.9%, respectively) as compared to the low-dose group (69, 1.4%; 404, 8.1%, respectively) during a median follow-up of 4.9 years. Persistent transaminase elevations (≥ 3 times ULN twice within 4 to 10 days) occurred in 62 (1.3%) individuals with atorvastatin 80 mg and in nine (0.2%) individuals with atorvastatin 10 mg. Elevations of CK (≥ 10 times ULN) were low overall, but were higher in the high-dose atorvastatin treatment group (13, 0.3%) compared to the low-dose atorvastatin group (6, 0.1%).
In IDEAL [see Clinical Studies (14.1)] involving 8,888 subjects (age range 26 to 80 years, 19% women; 99.3% Caucasians, 0.4% Asians, 0.3% Blacks, 0.04% other) treated with atorvastatin calcium 80 mg/day (n = 4439) or simvastatin 20 to 40 mg daily (n = 4449), there was no difference in the overall frequency of adverse reactions or serious adverse reactions between the treatment groups during a median follow-up of 4.8 years.
In SPARCL involving 4731 subjects (age range 21 to 92 years, 40% women; 93.3% Caucasians, 3% Blacks, 0.6% Asians, 3.1% other) without clinically evident CHD but with a stroke or transient ischemic attack (TIA) within the previous 6 months treated with atorvastatin calcium 80 mg (n = 2365) or placebo (n = 2366) for a median follow-up of 4.9 years, there was a higher incidence of persistent hepatic transaminase elevations (≥ 3 times ULN twice within 4 to 10 days) in the atorvastatin group (0.9%) compared to placebo (0.1%). Elevations of CK (> 10 times ULN) were rare, but were higher in the atorvastatin group (0.1%) compared to placebo (0%). Diabetes was reported as an adverse reaction in 144 subjects (6.1%) in the atorvastatin group and 89 subjects (3.8%) in the placebo group [see Warnings and Precautions (5.5)].
In a post-hoc analysis, atorvastatin calcium 80 mg reduced the incidence of ischemic stroke (218/2365, 9.2% vs. 274/2366, 11.6%) and increased the incidence of hemorrhagic stroke (55/2365, 2.3% vs. 33/2366, 1.4%) compared to placebo. The incidence of fatal hemorrhagic stroke was similar between groups (17 atorvastatin calcium vs. 18 placebo). The incidence of non-fatal hemorrhagic strokes was significantly greater in the atorvastatin group (38 non-fatal hemorrhagic strokes) as compared to the placebo group (16 non-fatal hemorrhagic strokes). Subjects who entered the study with a hemorrhagic stroke appeared to be at increased risk for hemorrhagic stroke [7 (16%) atorvastatin calcium vs. 2 (4%) placebo].
There were no significant differences between the treatment groups for all-cause mortality: 216 (9.1%) in the atorvastatin calcium 80 mg/day group vs. 211 (8.9%) in the placebo group. The proportions of subjects who experienced cardiovascular death were numerically smaller in the atorvastatin calcium 80 mg group (3.3%) than in the placebo group (4.1%). The proportions of subjects who experienced non-cardiovascular death were numerically larger in the atorvastatin calcium 80 mg group (5%) than in the placebo group (4%).
In a 26-weekcontrolled study in boys and postmenarchal girls with HeFH (ages 10 years to17 years)(n = 140, 31% female; 92% Caucasians, 1.6% Blacks, 1.6% Asians, 4.8% other), the safety and tolerability profile of atorvastatin calcium 10 to 20mg daily, as an adjunct to diet to reduce total cholesterol, LDL-C, and apo B levels, was generally similar to that of placebo [see Use in Special Populations (8.4) and Clinical Studies(14.6)].
There have been rare reports of immune-mediated necrotizing myopathy associated with statin use [see Warnings and Precautions (5.1)].
The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3)].
Atorvastatin calcium is metabolized by cytochrome P450 3A4. Concomitant administration of atorvastatin calcium with strong inhibitors of CYP 3A4 can lead to increases in plasma concentrations of atorvastatin. The extent of interaction and potentiation of effects depend on the variability of effect on CYP 3A4.
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)]. Therefore, in patients taking clarithromycin, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)].
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium with several combinations of protease inhibitors [see Clinical Pharmacology (12.3)]. In patients taking tipranavir plus ritonavir or glecaprevir plus pibrentasvir, concomitant use of atorvastatin calcium should be avoided. In patients taking lopinavir plus ritonavir, or simeprevir, use the lowest necessary atorvastatin dose. In patients taking saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, or elbasvir plus grazoprevir, the dose of atorvastatin calcium should not exceed 20 mg. In patients taking nelfinavir the dose of atorvastatin calcium should not exceed 40 mg and close clinical monitoring is recommended [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)].
Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 40 mg and itraconazole 200 mg [see Clinical Pharmacology (12.3)]. Therefore, in patients taking itraconazole, caution should be used when the atorvastatin calcium dose exceeds 20 mg [see Dosage and Administration (2.6) and Warnings and Precautions (5.1)].
Contains one or more components that inhibit CYP 3A4 and can increase plasma concentrations of atorvastatin, especially with excessive grapefruit juice consumption (> 1.2 liters per day).
Atorvastatin is a substrate of the hepatic transporters. Atorvastatin-metabolites are substrates of the OATP1B1 transporter. Inhibitors of the OATP1B1 (e.g., cyclosporine) can increase the bioavailability of atorvastatin. Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin calcium 10 mg and cyclosporine 5.2 mg/kg/day compared to that of atorvastatin calcium alone [see Clinical Pharmacology (12.3)].
The co-administration of atorvastatin calcium with cyclosporine should be avoided [see Warnings and Precautions (5.1)].
7.4 Letermovir
Concomitant administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in an increase in exposure to atorvastatin (ratio of AUC: 3.29) [see Clinical Pharmacology (12.3)]. Letermovir inhibits efflux transporters P-gp, BCRP, MRP2, OAT2 and hepatic transporter OATP1B1/1B3, thus it increases exposure to atorvastatin. Do not exceed 20 mg atorvastatin calcium daily [see Dosage and Administration (2.6)].
The magnitude of CYP3A-and OATP1B1/1B3-mediated drug interactions on co-administered drugs may be different when letermovir is co-administered with cyclosporine. Use of atorvastatin calcium is not recommended in patients taking letermovir co-administered with cyclosporine.
Coadministration of glecaprevir and pibrentasvir with atorvastatin increase plasma concentrations of atorvastatin by 8.3-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, coadministration of atorvastatin calcium in patients receiving concomitant medications with products containing glecaprevir and pibrentasvir is not recommended.
Coadministration of elbasvir and grazoprevir with atorvastatin increase plasma concentrations of atorvastatin by 1.9-fold due in part to BCRP, OATP1B1/1B3, and CYP3A inhibition; therefore, the dose of atorvastatin calcium should not exceed 20 mg daily in patients receiving concomitant medications with products containing elbasvir and grazoprevir [see Dosage and Administration (2.6), Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].
Due to an increased risk of myopathy/rhabdomyolysis when HMG-CoA reductase inhibitors are co-administered with gemfibrozil, concomitant administration of atorvastatin calcium with gemfibrozil should be avoided [see Warnings and Precautions (5.1)].
Because it is known that the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with concurrent administration of other fibrates, atorvastatin calcium should be administered with caution when used concomitantly with other fibrates [see Warnings and Precautions (5.1)].
The risk of skeletal muscle effects may be enhanced when atorvastatin calcium is used in combination with niacin; a reduction in atorvastatin calcium dosage should be considered in this setting [see Warnings and Precautions (5.1)].
Concomitant administration of atorvastatin calcium with inducers of cytochrome P450 3A4 (e.g., efavirenz, rifampin) can lead to variable reductions in plasma concentrations of atorvastatin. Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin calcium with rifampin is recommended, as delayed administration of atorvastatin calcium after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
When multiple doses of atorvastatin calcium and digoxin were co-administered, steady state plasma digoxin concentrations increased [see Clinical Pharmacology (12.3)]. Patients taking digoxin should be monitored appropriately.
Co-administration of atorvastatin calcium and an oral contraceptive increased AUC values for norethindrone and ethinyl estradiol [see Clinical Pharmacology (12.3)]. These increases should be considered when selecting an oral contraceptive for a woman taking atorvastatin calcium.
Atorvastatin calcium had no clinically significant effect on prothrombin time when administered to patients receiving chronic warfarin treatment.
Atorvastatin calcium is contraindicated for use in pregnant women since safety in pregnant women has not been established and there is no apparent benefit of lipid lowering drugs during pregnancy. Because HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly the synthesis of other biologically active substances derived from cholesterol, atorvastatin calcium tablets may cause fetal harm when administered to a pregnant woman. Atorvastatin calcium tablets should be discontinued as soon as pregnancy is recognized [see Contraindications (4)]. Limited published data on the use of atorvastatin are insufficient to determine a drug-associated risk of major congenital malformations or miscarriage. In animal reproduction studies in rats and rabbits there was no evidence of embryo-fetal toxicity or congenital malformations at doses up to 30 and 20 times, respectively, the human exposure at the maximum recommended human dose (MRHD) of 80 mg, based on body surface area (mg/m2). In rats administered atorvastatin during gestation and lactation, decreased postnatal growth and development was observed at doses ≥ 6 times the MRHD (see Data).
Limited published data on atorvastatin calcium from observational studies, meta-analyses and case reports 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 HMG-CoA reductase inhibitors. 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.
Atorvastatin crosses the rat placenta and reaches a level in fetal liver equivalent to that of maternal plasma. Atorvastatin was administered to pregnant rats and rabbits during organogenesis at oral doses up to 300 mg/kg/day and 100 mg/kg/day, respectively. Atorvastatin was not teratogenic in rats at doses up to 300 mg/kg/day or in rabbits at doses up to 100 mg/kg/day. These doses resulted in multiples of about 30 times (rat) or 20 times (rabbit) the human exposure at the MRHD based on surface area (mg/m2). In rats, the maternally toxic dose of 300 mg/kg resulted in increased post-implantation loss and decreased fetal body weight. At the maternally toxic doses of 50 and 100 mg/kg/day in rabbits, there was increased post-implantation loss, and at 100 mg/kg/day fetal body weights were decreased.
Atorvastatin calcium use 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. It is not known whether atorvastatin is present in human milk, but it has been shown that another drug in this class passes into human milk and atorvastatin is present in rat milk. Because of the potential for serious adverse reactions in a breastfed infant, advise women that breastfeeding is not recommended during treatment with atorvastatin calcium.
Atorvastatin calcium may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with atorvastatin calcium [see Use in Specific Populations (8.1)].
LDL-C ≥ 160 mg/dL and
Use of atorvastatin calcium for this indication is supported by evidence from [see Dosage and Administration (2.2), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.6)]:
A three year open-label uncontrolled trial that included 163 pediatric patients 10 to 15 years of age with HeFH who were titrated to achieve a target LDL-C < 130 mg/dL. The safety and efficacy of atorvastatin calcium in lowering LDL-C appeared generally consistent with that observed for adult patients, despite limitations of the uncontrolled study design
Advise postmenarchal girls of contraception recommendations, if appropriate for the patient [see Use in Specific Populations (8.1), (8.3)].
The long-term efficacy of atorvastatin calcium therapy initiated in childhood to reduce morbidity and mortality in adulthood has not been established.
Additional pediatric use information is approved for Pfizer's LIPITOR (atorvastatin calcium) tablets. However, due to Pfizer's marketing exclusivity rights, this drug product is not labeled with that pediatric information.
Clinical efficacy of atorvastatin calcium with dosages up to 80 mg/day for 1 year was evaluated in an uncontrolled study of patients with HoFH including 8 pediatric patients [see Clinical Studies (14.5)].
Of the 39,828 patients who received atorvastatin calcium in clinical studies, 15,813 (40%) were ≥ 65 years old and 2,800 (7%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older adults cannot be ruled out. Since advanced age (≥ 65 years) is a predisposing factor for myopathy, atorvastatin calcium should be prescribed with caution in the elderly.
Atorvastatin calcium is contraindicated in patients with active liver disease which may include unexplained persistent elevations in hepatic transaminase levels [see Contraindications (4) and Clinical Pharmacology (12.3)].
There is no specific treatment for atorvastatin calcium overdosage. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required. Due to extensive drug binding to plasma proteins, hemodialysis is not expected to significantly enhance atorvastatin calcium clearance.
Atorvastatin calcium trihydrate, USP is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol biosynthesis.
Atorvastatin calcium trihydrate, USP is [R-(R*,R*)]-2-(4-fluorophenyl)-ß, δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, calcium salt (2:1) trihydrate. The molecular formula of atorvastatin calcium trihydrate, USP is (C33H34FN2O5)2Ca•3H2O and its molecular weight is 1209.41. Its structural formula is:
Atorvastatin calcium trihydrate, USP is a white to off-white crystalline powder. Atorvastatin calcium trihydrate, USP is freely soluble in methanol, slightly soluble in alcohol, insoluble in water, acetonitrile and aqueous solution of pH 4 and below and very slightly soluble in pH 7.4 phosphate buffer.
Atorvastatin calcium tablets, USP for oral administration contain atorvastatin calcium trihydrate, USP equivalent to 10, 20, 40, or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate; croscarmellose sodium; hydroxypropyl cellulose; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polysorbate 80; simethicone emulsion; talc, and titanium dioxide.
Meets USP dissolution test 1.
Atorvastatin calcium is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol. In animal models, atorvastatin calcium lowers plasma cholesterol and lipoprotein levels by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and by increasing the number of hepatic LDL receptors on the cell surface to enhance uptake and catabolism of LDL; atorvastatin calcium also reduces LDL production and the number of LDL particles.
Atorvastatin calcium, 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. Drug dosage, rather than systemic drug concentration, correlates better with LDL-C reduction. Individualization of drug dosage should be based on therapeutic response see Dosage and Administration (2)].
Absorption: Atorvastatin calcium is rapidly absorbed after oral administration; maximum plasma concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to atorvastatin calcium dose. The absolute bioavailability of atorvastatin (parent drug) is approximately 14% and the systemic availability of HMG-CoA reductase inhibitory activity is approximately 30%. The low systemic availability is attributed to presystemic clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food decreases the rate and extent of drug absorption by approximately 25% and 9%, respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether atorvastatin calcium is given with or without food. Plasma atorvastatin calcium concentrations are lower (approximately 30% for Cmax and AUC) following evening drug administration compared with morning. However, LDL-C reduction is the same regardless of the time of day of drug administration [see Dosage and Administration (2)].
Distribution: Mean volume of distribution of atorvastatin calcium is approximately 381 liters. Atorvastatin calcium is ≥ 98% bound to plasma proteins. A blood/plasma ratio of approximately 0.25 indicates poor drug penetration into red blood cells. Based on observations in rats, atorvastatin calcium is likely to be secreted in human milk [see Contraindications (4) and Use in Specific Populations (8.2)].
Metabolism: Atorvastatin calcium is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin calcium. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin calcium metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin calcium in humans following co-administration with erythromycin, a known inhibitor of this isozyme [see Drug Interactions (7.1)]. In animals, the ortho-hydroxy metabolite undergoes further glucuronidation.
Excretion: Atorvastatin calcium and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism; however, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin calcium in humans is approximately 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin calcium is recovered in urine following oral administration.
Geriatric: Plasma concentrations of atorvastatin calcium are higher (approximately 40% for Cmax and 30% for AUC) in healthy elderly subjects (age ≥ 65 years) than in young adults. Clinical data suggest a greater degree of LDL-lowering at any dose of drug in the elderly patient population compared to younger adults [see Use in Specific Populations (8.5)].
Pediatric: Apparent oral clearance of atorvastatin in pediatric subjects appeared similar to that of adults when scaled allometrically by body weight as the body weight was the only significant covariate in atorvastatin population PK model with data including pediatric HeFH patients (ages 10 years to 17 years of age, n = 29) in an open-label, 8 week study.
Gender: Plasma concentrations of atorvastatin calcium in women differ from those in men (approximately 20% higher for Cmax and 10% lower for AUC); however, there is no clinically significant difference in LDL-C reduction with atorvastatin calcium between men and women.
Renal Impairment: Renal disease has no influence on the plasma concentrations or LDL-C reduction of atorvastatin calcium; thus, dose adjustment in patients with renal dysfunction is not necessary [see Dosage and Administration (2.5) and Warnings and Precautions (5.1)].
Hemodialysis: While studies have not been conducted in patients with end-stage renal disease, hemodialysis is not expected to significantly enhance clearance of atorvastatin calcium since the drug is extensively bound to plasma proteins.
Hepatic Impairment: In patients with chronic alcoholic liver disease, plasma concentrations of atorvastatin calcium are markedly increased. Cmax and AUC are each 4-fold greater in patients with Childs-Pugh A disease. Cmax and AUC are approximately 16-fold and 11-fold increased, respectively, in patients with Childs-Pugh B disease [see Contraindications (4)].
Dose (mg)
Ratio of AUC&
Ratio of Cmax&
#, ‡ Saquinavir 400 mg BIDb/ ritonavir
400 mg BIDb, 15 days
#Letermovir 480 mg QDa, 10 days
Erythromycin 500 mg QIDe, 7 days
Maalox TC® 30 mL QIDe, 17 days
#Rifampin 600 mg QDa, 7 days (co‑administered) †
#Gemfibrozil 600 mg BIDb, 7 days
#Fenofibrate 160 mg QDa, 7 days
& Represents ratio of treatments (co-administered drug plus atorvastatin vs. atorvastatin alone).
* Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL to 1.2 liters per day).
** Ratio based on a single sample taken 8 to 16 h post dose.
† Due to the dual interaction mechanism of rifampin, simultaneous co-administration of atorvastatin with rifampin is recommended, as delayed administration of atorvastatin after administration of rifampin has been associated with a significant reduction in atorvastatin plasma concentrations.
‡ The dose of saquinavir plus ritonavir in this study is not the clinically used dose. The increase in atorvastatin exposure when used clinically is likely to be higher than what was observed in this study. Therefore, caution should be applied and the lowest dose necessary should be used.
- norethindrone 1 mg
- ethinylestradiol 35 mcg
# See Section 7 for clinical significance.
In a 2-year carcinogenicity study in rats at dose levels of 10, 30, and 100 mg/kg/day, 2 rare tumors were found in muscle in high-dose females: in one, there was a rhabdomyosarcoma and, in another, there was a fibrosarcoma. This dose represents a plasma AUC (0 to 24) value of approximately 16 times the mean human plasma drug exposure after an 80 mg oral dose.
In vitro, atorvastatin was not mutagenic or clastogenic in the following tests with and without metabolic activation: the Ames test with Salmonella typhimurium and Escherichia coli, the HGPRT forward mutation assay in Chinese hamster lung cells, and the chromosomal aberration assay in Chinese hamster lung cells. Atorvastatin was negative in the in vivo mouse micronucleus test.
In female rats, atorvastatin at doses up to 225 mg/kg (56 times the human exposure) did not cause adverse effects on fertility. Studies in male rats performed at doses up to 175 mg/kg (15 times the human exposure) produced no changes in fertility. There was aplasia and aspermia in the epididymis of 2 of 10 rats treated with 100 mg/kg/day of atorvastatin for 3 months (16 times the human AUC at the 80 mg dose); testis weights were significantly lower at 30 and 100 mg/kg and epididymal weight was lower at 100 mg/kg. Male rats given 100 mg/kg/day for 11 weeks prior to mating had decreased sperm motility, spermatid head concentration, and increased abnormal sperm. Atorvastatin caused no adverse effects on semen parameters, or reproductive organ histopathology in dogs given doses of 10, 40, or 120 mg/kg for two years.
In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), the effect of atorvastatin calcium on fatal and non-fatal coronary heart disease was assessed in 10,305 hypertensive patients 40 to 80 years of age (mean of 63 years), without a previous myocardial infarction and with TC levels ≤ 251 mg/dL (6.5 mmol/L). Additionally, all patients had at least 3 of the following cardiovascular risk factors: male gender (81.1%), age > 55 years (84.5%), smoking (33.2%), diabetes (24.3%), history of CHD in a first-degree relative (26%), TC:HDL > 6 (14.3%), peripheral vascular disease (5.1%), left ventricular hypertrophy (14.4%), prior cerebrovascular event (9.8%), specific ECG abnormality (14.3%), proteinuria/albuminuria (62.4%). In this double-blind, placebo-controlled study, patients were treated with anti-hypertensive therapy (Goal BP < 140/90 mm Hg for non-diabetic patients; < 130/80 mm Hg for diabetic patients) and allocated to either atorvastatin calcium 10 mg daily (n = 5168) or placebo (n = 5137), using a covariate adaptive method which took into account the distribution of nine baseline characteristics of patients already enrolled and minimized the imbalance of those characteristics across the groups. Patients were followed for a median duration of 3.3 years.
Atorvastatin calcium significantly reduced the rate of coronary events [either fatal coronary heart disease (46 events in the placebo group vs. 40 events in the atorvastatin calcium group) or non-fatal MI (108 events in the placebo group vs. 60 events in the atorvastatin calcium group)] with a relative risk reduction of 36% [(based on incidences of 1.9% for atorvastatin calcium vs. 3% for placebo), p = 0.0005 (see Figure 1)]. The risk reduction was consistent regardless of age, smoking status, obesity, or presence of renal dysfunction. The effect of atorvastatin calcium was seen regardless of baseline LDL levels. Due to the small number of events, results for women were inconclusive.
Atorvastatin calcium also significantly decreased the relative risk for revascularization procedures by 42% (incidences of 1.4% for atorvastatin calcium and 2.5% for placebo). Although the reduction of fatal and non-fatal strokes did not reach a pre-defined significance level (p = 0.01), a favorable trend was observed with a 26% relative risk reduction (incidences of 1.7% for atorvastatin calcium and 2.3% for placebo). There was no significant difference between the treatment groups for death due to cardiovascular causes (p = 0.51) or noncardiovascular causes (p = 0.17).
In the Collaborative Atorvastatin Diabetes Study (CARDS), the effect of atorvastatin calcium on cardiovascular disease (CVD) endpoints was assessed in 2838 subjects (94% white, 68% male), ages 40 to 75 with type 2 diabetes based on WHO criteria, without prior history of cardiovascular disease and with LDL ≤ 160 mg/dL and TG ≤ 600 mg/dL. In addition to diabetes, subjects had 1 or more of the following risk factors: current smoking (23%), hypertension (80%), retinopathy (30%), or microalbuminuria (9%) or macroalbuminuria (3%). No subjects on hemodialysis were enrolled in the study. In this multicenter, placebo-controlled, double-blind clinical trial, subjects were randomly allocated to either atorvastatin calcium 10 mg daily (1429) or placebo (1411) in a 1:1 ratio and were followed for a median duration of 3.9 years. The primary endpoint was the occurrence of any of the major cardiovascular events: myocardial infarction, acute CHD death, unstable angina, coronary revascularization, or stroke. The primary analysis was the time to first occurrence of the primary endpoint.
Atorvastatin calcium significantly reduced the rate of major cardiovascular events (primary endpoint events) (83 events in the atorvastatin calcium group vs. 127 events in the placebo group) with a relative risk reduction of 37%, HR 0.63, 95% CI (0.48, 0.83) (p = 0.001) (see Figure 2). An effect of atorvastatin calcium was seen regardless of age, sex, or baseline lipid levels.
Atorvastatin calcium significantly reduced the risk of stroke by 48% (21 events in the atorvastatin calcium group vs. 39 events in the placebo group), HR 0.52, 95% CI (0.31, 0.89) (p = 0.016) and reduced the risk of MI by 42% (38 events in the atorvastatin calcium group vs. 64 events in the placebo group), HR 0.58, 95.1% CI (0.39, 0.86) (p = 0.007). There was no significant difference between the treatment groups for angina, revascularization procedures, and acute CHD death.
There were 61 deaths in the atorvastatin calcium group vs. 82 deaths in the placebo group (HR 0.73, p = 0.059).
In the Treating to New Targets Study (TNT), the effect of atorvastatin calcium 80 mg/day vs. atorvastatin calcium 10 mg/day on the reduction in cardiovascular events was assessed in 10,001 subjects (94% white, 81% male, 38% ≥ 65 years) with clinically evident coronary heart disease who had achieved a target LDL-C level < 130 mg/dL after completing an 8-week, open-label, run-in period with atorvastatin calcium 10 mg/day. Subjects were randomly assigned to either 10 mg/day or 80 mg/day of atorvastatin calcium and followed for a median duration of 4.9 years. The primary endpoint was the time-to-first occurrence of any of the following major cardiovascular events (MCVE): death due to CHD, non-fatal myocardial infarction, resuscitated cardiac arrest, and fatal and non-fatal stroke. The mean LDL-C, TC, TG, non-HDL, and HDL cholesterol levels at 12 weeks were 73, 145, 128, 98, and 47 mg/dL during treatment with 80 mg of atorvastatin calcium and 99, 177, 152, 129, and 48 mg/dL during treatment with 10 mg of atorvastatin calcium.
Treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of MCVE (434 events in the 80 mg/day group vs. 548 events in the 10 mg/day group) with a relative risk reduction of 22%, HR 0.78, 95% CI (0.69, 0.89), p = 0.0002 (see Figure 3 and Table 6). The overall risk reduction was consistent regardless of age (< 65, ≥ 65) or gender.
HR = hazard ratio; CHD = coronary heart disease; CI = confidence interval; MI = myocardial infarction; CHF = congestive heart failure; CV = cardiovascular; PVD = peripheral vascular disease; CABG = coronary artery bypass graft
Confidence intervals for the Secondary Endpoints were not adjusted for multiple comparisons
Atorvastatin 10 mg (N = 5006)
0.78 (0.69, 0.89)
SECONDARY ENDPOINTS*
1.35 (0.91, 2)
Of the events that comprised the primary efficacy endpoint, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of non-fatal, non-procedure related MI and fatal and non-fatal stroke, but not CHD death or resuscitated cardiac arrest (Table 6). Of the predefined secondary endpoints, treatment with atorvastatin calcium 80 mg/day significantly reduced the rate of coronary revascularization, angina, and hospitalization for heart failure, but not peripheral vascular disease. The reduction in the rate of CHF with hospitalization was only observed in the 8% of patients with a prior history of CHF.
In the Incremental Decrease in Endpoints Through Aggressive Lipid Lowering Study (IDEAL), treatment with atorvastatin calcium 80 mg/day was compared to treatment with simvastatin 20 to 40 mg/day in 8,888 subjects up to 80 years of age with a history of CHD to assess whether reduction in CV risk could be achieved. Patients were mainly male (81%), white (99%) with an average age of 61.7 years, and an average LDL-C of 121.5 mg/dL at randomization; 76% were on statin therapy. In this prospective, randomized, open-label, blinded endpoint (PROBE) trial with no run-in period, subjects were followed for a median duration of 4.8 years. The mean LDL-C, TC, TG, HDL, and non-HDL cholesterol levels at Week 12 were 78, 145, 115, 45, and 100 mg/dL during treatment with 80 mg of atorvastatin calcium and 105, 179, 142, 47, and 132 mg/dL during treatment with 20 to 40 mg of simvastatin.
There was no significant difference between the treatment groups for the primary endpoint, the rate of first major coronary event (fatal CHD, non-fatal MI, and resuscitated cardiac arrest): 411 (9.3%) in the atorvastatin calcium 80 mg/day group vs. 463 (10.4%) in the simvastatin 20 to 40 mg/day group, HR 0.89, 95% CI ( 0.78, 1.01), p = 0.07.
In two multicenter, placebo-controlled, dose-response studies in patients with hyperlipidemia, atorvastatin calcium given as a single dose over 6 weeks, significantly reduced total-C, LDL-C, apo B, and TG. (Pooled results are provided in Table 7.)
a Results are pooled from 2 dose-response studies.
In patients with Fredrickson Types IIa and IIb hyperlipoproteinemia pooled from 24 controlled trials, the median (25th and 75th percentile) percent changes from baseline in HDL-C for atorvastatin calcium 10, 20, 40, and 80 mg were 6.4 (-1.4, 14), 8.7 (0, 17), 7.8 (0, 16), and 5.1 (-2.7, 15), respectively. Additionally, analysis of the pooled data demonstrated consistent and significant decreases in total-C, LDL-C, TG, total-C/HDL-C, and LDL-C/HDL-C.
1 A negative value for the 95% CI for the difference between treatments favors atorvastatin calcium for all except HDL-C, for which a positive value favors atorvastatin calcium. If the range does not include 0, this indicates a statistically significant difference.
a Significantly different from lovastatin, ANCOVA, p ≤ 0.05
b Significantly different from pravastatin, ANCOVA, p ≤ 0.05
c Significantly different from simvastatin, ANCOVA, p ≤ 0.05
Atorvastatin Calcium 10 mg
-10, -6.5
-1.7, 2
-8, -1.1
The impact on clinical outcomes of the differences in lipid-altering effects between treatments shown in Table 8 is not known. Table 8 does not contain data comparing the effects of atorvastatin calcium 10 mg and higher doses of lovastatin, pravastatin, and simvastatin. The drugs compared in the studies summarized in the table are not necessarily interchangeable.
The response to atorvastatin calcium in 64 patients with isolated hypertriglyceridemia (Fredrickson Type IV) treated across several clinical trials is shown in the table below (Table 9). For the atorvastatin calcium-treated patients, median (min, max) baseline TG level was 565 (267 to 1502).
-41 (-76.2, 49.4)
-40.5 (-60.6,-13.8)
11(-3.2, 25.2)
-1 (-31.9, 53.2)
-2.8 (-17.6, 30)
-33 (-52.1, -13.3)
442 (225, 1320)
-37 (-85, 17)
-58 (-90, -31)
-39 (-92, -8)
215 (111, 613)
-32 (-76, 9)
In a double-blind, placebo-controlled study followed by an open-label phase, 187 boys and post-menarchal girls 10 years to 17 years of age (mean age 14.1 years) with heterozygous familial hypercholesterolemia (HeFH) or severe hypercholesterolemia, were randomized to atorvastatin calcium (n = 140) or placebo (n = 47) for 26 weeks and then all received atorvastatin calcium for 26 weeks. Inclusion in the study required 1) a baseline LDL-C level ≥ 190 mg/dL or 2) a baseline LDL-C level ≥ 160 mg/dL and positive family history of FH or documented premature cardiovascular disease in a first or second-degree relative. The mean baseline LDL-C value was 218.6 mg/dL (range: 138.5 to 385 mg/dL) in the atorvastatin calcium group compared to 230 mg/dL (range: 160 to 324.5 mg/dL) in the placebo group. The dosage of atorvastatin calcium (once daily) was 10 mg for the first 4 weeks and uptitrated to 20 mg if the LDL-C level was > 130 mg/dL. The number of atorvastatin calcium-treated patients who required uptitration to 20 mg after Week 4 during the double-blind phase was 78 (55.7%).
The mean achieved LDL-C value was 130.7 mg/dL (range: 70 to 242 mg/dL) in the atorvastatin calcium group compared to 228.5 mg/dL (range: 152 to 385 mg/dL) in the placebo group during the 26-week double-blind phase.
The long-term efficacy of atorvastatin calcium therapy in childhood to reduce morbidity and mortality in adulthood has not been established.
Product: 71335-1010
NDC: 71335-1010-1 30 TABLET, FILM COATED in a BOTTLE
NDC: 71335-1010-4 9 TABLET, FILM COATED in a BOTTLE
NDC: 71335-1011-2 100 TABLET, FILM COATED in a BOTTLE
Patients taking atorvastatin calcium tablets 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 atorvastatin [see Warnings and Precautions (5.1)]. Patients should also be advised to inform other healthcare professionals prescribing a new medication that they are taking atorvastatin calcium tablets.
All patients starting therapy with atorvastatin calcium tablets should be advised of the risk of myopathy 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 atorvastatin calcium tablets. The risk of this occurring is increased when taking certain types of medication or consuming larger quantities (> 1 liter) of grapefruit juice. They 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 atorvastatin calcium tablets and if signs or symptoms of liver injury occur. All patients treated with atorvastatin calcium tablets 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 atorvastatin calcium tablets [see Contraindications (4) and Use in Specific Populations (8.2)].
Sun Pharmaceutical Industries Limited,
Mohali, INDIA
Sun Pharmaceutical Industries, Inc.
Cranbury, NJ 08512
December 2019	FDA-10
Patient Medication Information
Atorvastatin (a TORE va sta tin) Calcium Tablets
If you have any questions about atorvastatin calcium tablets, ask your doctor or pharmacist.
What are Atorvastatin Calcium Tablets?
Atorvastatin calcium tablets are a prescription medicine that lowers cholesterol in your blood. It lowers the LDL-C ("bad" cholesterol) and triglycerides in your blood. It can raise your HDL-C ("good" cholesterol) as well. Atorvastatin calcium tablets are for adults and children over 10 whose cholesterol does not come down enough with exercise and a low-fat diet alone.
Atorvastatin calcium tablets start to work in about 2 weeks.
Who Should Not Take Atorvastatin Calcium Tablets?
are allergic to atorvastatin calcium tablets or any of its ingredients. The active ingredient is atorvastatin calcium, USP. See the end of this leaflet for a complete list of ingredients in atorvastatin calcium tablets.
Before You Start Atorvastatin Calcium Tablets
anti-virals
Atorvastatin calcium tablets can cause serious side effects. These side effects have happened only to a small number of people. Your doctor can monitor you for them. These side effects usually go away if your dose is lowered or atorvastatin calcium tablets are stopped. These serious side effects include:
yellowing of your skin or the whites of your eyes
muscle problems that do not go away even after your doctor has advised you to stop taking atorvastatin calcium tablets. Your doctor may do further tests to diagnose the cause of your muscle problems.
passing brown or dark-colored urine.
In clinical studies, patients reported the following common side effects while taking atorvastatin calcium: diarrhea, upset stomach, muscle and joint pain, and alterations in some laboratory blood tests.
The following additional side effects have been reported with atorvastatin calcium tablets: tiredness, tendon problems, memory loss, and confusion.
How do I store Atorvastatin Calcium Tablets
Store atorvastatin calcium tablets at room temperature, 68 - 77° F (20 - 25° C).
Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use atorvastatin calcium tablets for a condition for which it was not prescribed. Do not give atorvastatin calcium tablets to other people, even if they have the same problem you have. It may harm them.
Active Ingredient: atorvastatin calcium trihydrate, USP
Inactive Ingredients: calcium carbonate; croscarmellose sodium; hydroxypropyl cellulose; hypromellose; lactose monohydrate; magnesium stearate; microcrystalline cellulose; polyethylene glycol; polysorbate 80; simethicone emulsion; talc, and titanium dioxide.
Atorvastatin Calcium 20mg Tablet
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-1010(NDC:63304-828)
HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)
DIMETHICONE (UNII: 92RU3N3Y1O)
Shape OVAL (elliptical) Size 12mm
Flavor Imprint Code RX828
NDC:71335-1010-6 20 in 1 BOTTLE; Type 0: Not a Combination Product 08/28/2013
NDC:71335-1010-4 9 in 1 BOTTLE; Type 0: Not a Combination Product 08/28/2013
HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P)
NDC:71335-1011-2 100 in 1 BOTTLE; Type 0: Not a Combination Product 09/19/2018
Labeler - Bryant Ranch Prepack (171714327)
Bryant Ranch Prepack 171714327 REPACK(71335-1010, 71335-1011) , RELABEL(71335-1010, 71335-1011)
https://dailymed.nlm.nih.gov/dailymed/labelrss.cfm?setid=bbb1a527-3b4d-4fd4-9e38-b231ad5d6d8f
10 71335-1011-4


text:
Ipopt Documentation
Mathematical Background
How to use Ipopt
More Information and Contributions
History of Ipopt
History of this document
This document is a guide to using Ipopt. It includes instructions on how to obtain and compile Ipopt, a description of the interface, user options, etc., as well as a tutorial on how to solve a nonlinear optimization problem with Ipopt. The documentation consists of the following pages:
Installing Ipopt
Interfacing your NLP to Ipopt
Ipopt Options
Ipopt Output
The Ipopt project website is https://github.com/coin-or/Ipopt.
Ipopt (Interior Point Optimizer, pronounced "Eye-Pea-Opt") is an open source software package for large-scale nonlinear optimization. It can be used to solve general nonlinear programming problems of the form
\begin{align} \min_{x\in\mathbb{R}^n} && f(x) \nonumber \\ \text{s.t.} \; && g^L \leq g(x) \leq g^U \tag{NLP} \\ && x^L \leq x \leq x^U, \nonumber \end{align}
where \(x \in \mathbb{R}^n\) are the optimization variables (possibly with lower and upper bounds, \(x^L\in(\mathbb{R}\cup\{-\infty\})^n\) and \(x^U\in(\mathbb{R}\cup\{+\infty\})^n\)) with \(x^L \leq x^U\), \(f:\mathbb{R}^n \to \mathbb{R}\) is the objective function, and \(g:\mathbb{R}^n \to \mathbb{R}^m\) are the general nonlinear constraints. The functions \(f(x)\) and \(g(x)\) can be linear or nonlinear and convex or non-convex (but should be twice continuously differentiable). The constraint functions, \(g(x)\), have lower and upper bounds, \(g^L\in(\mathbb{R}\cup\{-\infty\})^m\) and \(g^U\in(\mathbb{R}\cup\{+\infty\})^m\) with \(g^L \leq g^U\). Note that equality constraints of the form \(g_i(x)=\bar g_i\) can be specified by setting \(g^L_{i}=g^U_{i}=\bar g_i\).
Ipopt implements an interior point line search filter method that aims to find a local solution of (NLP). The mathematical details of the algorithm can be found in several publications [7], [13], [12], [11], [10].
The Ipopt package is available from COIN-OR under the EPL (Eclipse Public License) open-source license and includes the source code for Ipopt. This means, it is available free of charge, also for commercial purposes. However, if you give away software including Ipopt code (in source code or binary form) and you made changes to the Ipopt source code, you are required to make those changes public and to clearly indicate which modifications you made. After all, the goal of open source software is the continuous development and improvement of software. For details, please refer to the Eclipse Public License.
Also, if you are using Ipopt to obtain results for a publication, we politely ask you to point out in your paper that you used Ipopt, and to cite the publication [12]. Writing high-quality numerical software takes a lot of time and effort, and does usually not translate into a large number of publications, therefore we believe this request is only fair :). We also have space in the Ipopt usage stories and papers discussion where we list publications, projects, etc., in which Ipopt has been used. We would be very happy to hear about your experiences.
In order to build Ipopt, some third party components are required:
BLAS (Basic Linear Algebra Subroutines) and LAPACK (Linear Algebra PACKage). Many vendors of compilers and operating systems provide precompiled and optimized libraries for these dense linear algebra subroutines. You can also get the source code for a simple reference implementation from http://www.netlib.org. However, it is strongly recommended to use some optimized BLAS and LAPACK implementations, for large problems this can make a runtime difference of an order of magnitude!
Examples for efficient BLAS implementations are:
Generic:
OpenBLAS, BSD license
BLIS (BLAS-like Library Instantiation Software Framework), BSD license
ATLAS (Automatically Tuned Linear Algebra Software), BSD license
From hardware vendors:
Accelerate Framework by Apple
BLIS fork (BLAS-like Library Instantiation Software Framework) by AMD
ESSL (Engineering Scientific Subroutine Library) by IBM
MKL (Math Kernel Library) by Intel
Sun Performance Library by Sun
Note: BLAS libraries distributed with Linux were often not optimized in the past. Nowadays, OpenBLAS is often found in Linux distributions, but you should check.
A sparse symmetric indefinite linear solver. Ipopt needs to obtain the solution of sparse, symmetric, indefinite linear systems, and for this it relies on third-party code.
Currently, the following linear solvers can be used:
MA27 from the HSL Mathematical Software Library
HSL_MA77 from the HSL Mathematical Software Library
MUMPS (MUltifrontal Massively Parallel sparse direct Solver)
PARDISO (Parallel Sparse Direct Solver) from Pardiso Project or Intel MKL. Note that current versions from Pardiso Project typically offer much better performance than the one from Intel MKL.
SPRAL (Sparse Parallel Robust Algorithms Library)
WSMP (Watson Sparse Matrix Package)
You must include at least one of the linear solvers above in order to run Ipopt, and if you want to be able to switch easily between different alternatives, you can compile Ipopt with interfaces to all of them. The linear solvers from HSL and Pardiso Project can also be loaded from a shared library at runtime, see Providing a HSL library at runtime and Pardiso from Pardiso Project. For the latter, this is also the only option.
The solution of the linear systems is a central ingredient in Ipopt and the optimizer's performance and robustness depends on your choice. The best choice depends on your application, and it makes sense to try different options, but solvers from HSL or Pardiso Project are often a good choice. Most of the solvers also rely on efficient BLAS code (see above), so you should use a good BLAS library tailored to your system. Please keep this in mind, particularly when you are comparing Ipopt with other optimization codes. See also [9] for a comparison of Ipopt with various linear solvers.
If you are compiling MA57, HSL_MA77, HSL_MA86, HSL_MA97, MUMPS, or SPRAL within the Ipopt build system, you should also include the METIS linear system ordering package.
Interfaces to other linear solvers might be added in the future; if you are interested in contributing such an interface please contact us! Note that Ipopt requires that the linear solver is able to provide the inertia (number of positive and negative eigenvalues) of the symmetric matrix that is factorized.
Furthermore, Ipopt can also use the HSL package MC19 for scaling of the linear systems before they are passed to the linear solver. This may be particularly useful if Ipopt is used with MA27 or MA57. However, it is not required to have MC19; if this routine is missing, scaling is not performed.
ASL (AMPL Solver Library). The source code is available at http://www.netlib.org, and COIN-OR's ThirdParty-ASL project can be used to build a library that is recognized by Ipopt's build system. NOTE: This is only required if you want to use Ipopt from AMPL and want to compile the Ipopt AMPL solver executable.
For more information on third-party components and how to obtain them, see Download, build, and install dependencies.
Since the Ipopt code is written in C++, you will need a C++ compiler to build the Ipopt library. We tried very hard to write the code as platform and compiler independent as possible.
In addition, the configuration script also searches for a Fortran compiler. If all third party dependencies are available as self-contained libraries and no Ipopt/Fortran interface needs to be build, a Fortran compile is not necessary.
When using GNU compilers, we recommend you use the same version numbers for gcc, g++, and gfortran. Further, mixing clang (for C/C++) and gfortran has been problematic and should be avoided.
If desired, the Ipopt distribution generates an executable for the modeling environment AMPL. As well, you can link your problem statement with Ipopt using interfaces for C++, C, Java, or Fortran. Ipopt can be used with most Linux/Unix environments, and on Windows using Msys2/MinGW. In Interfacing your NLP to Ipopt this document demonstrates how to solve problems using Ipopt. This includes installation and compilation of Ipopt for use with AMPL as well as linking with your own code. An installation of the AMPL link to Ipopt is also available on NEOS.
Additionally, the Ipopt distribution includes an interface for the R project for statistical computing, see The R Interface ipoptr.
There is also software that facilitates use of Ipopt maintained by other people, among them are:
ADOL-C (automatic differentiation)
ADOL-C facilitates the evaluation of first and higher derivatives of vector functions that are defined by computer programs written in C or C++. It comes with examples that show how to use it in connection with Ipopt.
AIMMS (modeling environment)
The AIMMSlinks project on COIN-OR, maintained by Marcel Hunting, provides an interface for Ipopt within the AIMMS modeling tool.
APMonitor
MATLAB, Python, and Web Interface to Ipopt for Android, Linux, macOS, and Windows.
CasADi
CasADi is a symbolic framework for automatic differentiation and numeric optimization and comes with Ipopt.
CppAD (automatic differentiation)
Given a C++ algorithm that computes function values, CppAD generates an algorithm that computes corresponding derivative values (of arbitrary order using either forward or reverse mode). It comes with an example that shows how to use it in connection with Ipopt.
It is also possible to use Ipopt via CppADs Python interface. An example is available here.
csipopt
Interfacing Ipopt from .NET languages such as C#, F# and Visual Basic.NET.
cyipopt
A Python wrapper around Ipopt with a SciPy-style interface.
GAMS (modeling environment)
The GAMSlinks project on COIN-OR includes a GAMS interface for Ipopt.
An installation of GAMS with Ipopt is also available on NEOS.
ifopt
Modern, light-weight (~1k loc), Eigen-based C++ interface to Ipopt and Snopt.
IPyOpt
Interfacing Ipopt from Python.
JuliaOpt
Julia is a high-level, high-performance dynamic programming language for technical computing. JuliaOpt, is an umbrella group for Julia-based optimization-related projects. It includes the algebraic modeling language JuMP and an interface to Ipopt.
MADOPT (Modelling and Automatic Differentiation for Optimisation)
Light-weight C++ and Python modelling interfaces implementing expression building using operator overloading and automatic differentiation.
mexIPOPT
Matlab (mex) interface to you use Ipopt from Matlab.
OPTimization Interface (OPTI) Toolbox
OPTI is a free Matlab toolbox for constructing and solving linear, nonlinear, continuous and discrete optimization problem and comes with Ipopt, including binaries.
The Optimization Services (OS) project provides a set of standards for representing optimization instances, results, solver options, and communication between clients and solvers, including Ipopt, in a distributed environment using Web Services.
Scilab (free Matlab-like environment):
A Scilab interface is available at https://atoms.scilab.org/toolboxes/sci_ipopt.
An issue tracking and discussion system can be found at the Ipopt homepage,
https://github.com/coin-or/Ipopt.
Ipopt is an open source project, and we encourage people to contribute code (such as interfaces to appropriate linear solvers, modeling environments, or even algorithmic features). If you are interested in contributing code, please have a look at the COIN-OR contributions webpage and contact the Ipopt project leader.
There also has been a mailing list for Ipopt. Its archive (2002-2020) is available from the webpage
https://list.coin-or.org/pipermail/ipopt/.
An easy way to search the archive with Google is to specify site:http://list.coin-or.org/pipermail/ipopt in addition to your keywords in the search string.
A short tutorial on getting started with Ipopt is also available [14].
The original Ipopt(Fortran version) was a product of the dissertation research of Andreas Wächter [13], under the supervision of Lorenz T. Biegler at the Chemical Engineering Department at Carnegie Mellon University. The code was made open source and distributed by the COIN-OR initiative, which is now a non-profit corporation. Ipopt has been actively developed under COIN-OR since 2002.
To continue natural extension of the code and allow easy addition of new features, IBM Research decided to invest in an open source re-write of Ipopt in C++. With the help of Carl Laird, who came to the Mathematical Sciences Department at IBM Research as a summer intern in 2004 and 2005 during his PhD studies, the code was re-implemented from scratch.
The new C++ version of the Ipopt optimization code (Ipopt 3.0.0 and beyond) was maintained at IBM Research and remains part of the COIN-OR initiative. The development on the Fortran version has ceased, but the source code can still be downloaded from https://github.com/coin-or/Ipopt/tree/stable/2.3.
The initial version of this document was created by Yoshiaki Kawajir (then Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh PA) as a course project for 47852 Open Source Software for Optimization, taught by Prof. François Margot at Tepper School of Business, Carnegie Mellon University. After this, Carl Laird (then Department of Chemical Engineering, Carnegie Mellon University, Pittsburgh PA) has added significant portions, including the very nice tutorials. The current version is maintained by Stefan Vigerske (GAMS Software GmbH) and Andreas Wächter (Department of Industrial Engineering and Management Sciences, Northwestern University).
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