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Safety of olmesartan (Benicar)

Some patients and healthcare providers have expressed concerns about the safety of higher than typical doses of olmesartan (Benicar).

Ample research supports the fact that olmesartan is one of the safest and has the most gentle side effects profiles of almost any drug on the market – as opposed to Benicar HCT, which contains a thiazide and is harmful.

I feel there are simply no adverse reactions or negative side effects that I need to worry about while taking the Marshall Protocol medications. It is an extremely safe approach. Personally, I believe overtreating this condition is preferable than undertreating as the side effects of both antibiotics and Benicar are so minimal compared to the risk of [disease] recurrence.

Greg Blaney, M.D.

FDA safety guidelines

Although they do so for many other drugs, the U.S. Food and Drug Administration has set no unsafe upper limit for olmesartan. The FDA bases its safety data on “post-marketing experience” - how many dose-related adverse events have been linked to the drug – and for olmesartan, they are negligible. The FDA has consequently set no unsafe dosage level for Olmesartan.

According to the FDA's full prescribing information for Benicar:

  • “The overall frequency of adverse reactions was not dose-related.”
  • “Dosage must be individualized.”

Data supporting the safety of higher than typical dosing frequencies

A 2001 study published in the Journal of of Pharmacology found olmesartan to be safe and well tolerated at doses of up to 160 mg/day.1)

CS-866 [olmesartan] was safe and well tolerated at doses of up to 160 mg/day…. [Olmesartan] has no serious adverse effects.

Lee R. Schwocho, PhD and Harvey N. Masonson, MD 2)

Animal studies in mice, with olmesartan doses up to 480 times the human dose of 40 mg per day (relative to body weight), showed that olmesartan is not carcinogenic.

The label for olmesartan states that the drug is well-tolerated. Adverse events were similar to those experienced by the placebo group – a group of patients who were not given the drug at all. Adverse events were generally “mild, transient and not related to dose.” The frequency of adverse events also had no relationship to the dose of olmesartan.

Data implying the necessity of higher than typical dosing frequencies

Peleg and Nguyen observed that in the absence of an agonist such as 1,25-D, the VDR suffers from polyubiquitination and proteasome-mediated degradation in relatively short course – in the sub-4 hour region, and certainly in the sub-24hour region.3) This study offers some support for why sick patients need more frequent dosing than their healthy counterparts.

Recent published reports on the dynamics of VDR recruitment to promoters of target genes in cultured cells demonstrate that the time course for maximal recruitment of the 1,25D3–VDR complex to the promoter of the CYP24 gene in osteoblasts is 3 h, whereas the time course for maximal recruitment of the VDR to the promoter of this gene in IECs is only 30 min [Kim et al., 2005; Meyer et al., 2006].

S. Peleg and C. V. Nguyen 4)

Harmless side effects profile

In placebo-controlled trials, the only side effect that occurred in more than 1 percent of olmesartan-treated patients vs. placebo-treated patients was dizziness (3 percent vs. 1 percent). The label does state that olmesartan should not be used during pregnancy or breast-feeding, but since pregnant women are not allowed to do the Marshall Protocol, the warning is of little concern for those using the medicine to recover from Th1 diseaseAny of the chronic inflammatory diseases caused by bacterial pathogens..

According to the report:

In the dose-finding study, 792 patients were randomized to olmesartan (2.5-80 mg) or placebo once daily…. The results of the clinical studies in >3000 patients receiving olmesartan showed that the frequency and profile of adverse events with olmesartan were generally similar to those with placebo; the frequency of adverse events was not dose related. Olmesartan, with or without hydrochlorothiazide, was well tolerated over two years of treatment.

Hans R. Brunner, MD 5)

Results of FDA meeting

In April 2007, the staff of Autoimmunity Research FoundationNon-profit foundation dedicated to exploring a pathogenesis and therapy for chronic disease. had a high-level meeting at the FDA in Maryland. One of the topics on the agenda was how to put an end to concerns physicians express about the safety of olmesartan.

Those present included the head of CDER's Cardio-Renal Drug Products Division at the time olmesartan was approved, Dr. Robert Temple.

He [Dr. Temple] is expert on the drug’s behavior and is currently the medical director at the Food and Drug Administration division that evaluates drugs. He made it clear that the hypotensive effect of olmesartan is already in full effect at a low dose (less than 40 mg) and there is a graph in the package insert showing that beyond that 40mg the dose really doesn’t affect BP any more. Second, he pointed out that the FDA has set no toxic level for olmesartan, because its safety is not in question, and certainly not at the levels we are using.

Trevor Marshall, PhD

Additional research of olmesartan safety

Additional papers on the general safety of olmesartan state:

Frequency of adverse events is not dose related.6)

Peak plasma concentrations of olmesartan occur 1-3 hours after administration, after which concentrations decrease with an elimination half-life of 10-15 hours… Frequencies of adverse events during treatment with olmesartan medoxomil and placebo are similar, with no evidence of a dose response. There are no clinically significant effects on laboratory parameters, and the drug-interaction potential of olmesartan medoxomil is low.7)

High-dose ARB treatment in patients with chronic renal disease is not associated with any clinically significant long-term negative effects on serum creatinine or potassium and is thus an important therapeutic modality with which to achieve further reductions in urinary protein excretion.8)

The results of this pilot study suggest that supramaximal doses of ARBs are safe and well tolerated in patients with chronic kidney disease, while reducing both blood pressure and proteinuria.9)

Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models.10)

Misunderstanding side effects

Just as some patients mistakenly assume they're allergic to MP antibiotics, patients mistake certain symptoms brought about by olmesartan use for harmful side effects.

Hormonal adjustments

The most common reason that patients who begin the Marshall Protocol incorrectly assume that they are suffering from side effects of olmesartan is that they mistakenly attribute the hormonal adjustments that accompany the onset of a olmesartan blockade to side effects of the drug. These hormonal changes occur because in most patients with Th1 disease, the body has become accustomed to a higher than normal level of the hormone 1,25-DPrimary biologically active vitamin D hormone. Activates the vitamin D nuclear receptor. Produced by hydroxylation of 25-D. Also known as 1,25-dihydroxycholecalciferol, 1,25-hydroxyvitamin D and calcitirol., which rises as part of the immune system’s reaction to bacteria.

But the olmesartan blockade quickly and dramatically lowers 1,25-D - by as much as half in just two weeks. Since 1,25-D is a powerful hormone that affects nearly every cell in the body, and interacts with all the body’s major hormones, myriad other hormones are forced to adjust their levels according to the new lower level of 1,25-D. This often causes temporary neurological-type symptoms such as (but not limited to) fatigue, dizziness, headache, photosensitivityAbnormal sensitivity to sunlight and bright lights. Also referred to as "sun flare" or "light flare.", irritability, sleep disturbances, brain fogThe loss of intellectual functions such as reasoning; memory loss; and other neurological abilities that is severe enough to interfere with daily functioning., etc. As the body adjusts to this hormonal shift these symptoms dissipate, usually in a week or two.

Immunopathology

Patients should not confuse the rise in symptoms that occurs due to immunopathology with side effects of olmesartan. Immunopathology is absolutely necessary to make progress on the MP.

The ability to accept and tolerate a certain level of immunopathology is a requisite of continuing with the Marshall Protocol and is not always predictable. Usually symptoms wax and wane, but they can also be constant for varying periods of time. Immnopathology-generated symptoms often mimic a patient’s disease symptoms but they can also be surprisingly new, pointing to areas of previously undetected inflammation.

Meg Mangin

Protective effects of olmesartan

Olmesartan has a number of protective effects. For one, it's a potent anti-inflammatory. Since the anti-inflammatory actions of olmesartan actually protect organs, the medication will reduce damage to the body from immunopathology.

Olmesartan is designed to reduce the impact on the tissues of the inflammatory substances released by the immune system as part of the immunopathological reactionA temporary increase in disease symptoms experiences by Marshall Protocol patients that results from the release of cytokines and endotoxins as disease-causing bacteria are killed..

Other protective effects include:

Notes and comments

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August 2014… FDA Finds Olmesartan Does Not Cause Cardiovascular Events

http://www.fda.gov/drugs/drugsafety/ucm402323.htm http://www.lgmpharma.com/blog/fda-finds-olmesartan-does-not-cause-cardiovascular-events/

“There was no viable evidence found to cause the FDA to deem Olmesartan unsafe, and earlier concerns from study investigators claiming there was an increased risk for heart attack in patients taking Olmesartan was nullified”

“Patients ages six and older may safely be prescribed Olmesartan, which is in a class of medications deemed angiotensin II receptor antagonists. While tablet form of Olmesartan is most common a liquid form can be made for children who have trouble swallowing the tablet”

To be totally precise, the FDA judged that Olmesartan did not need approval for our study. They told us it was one of the safest drugs in the US formulary.

At a meeting in April 2007, the FDA said there were no barriers to any US physician prescribing the drug-off label in the idiopathic inflammatory diseases.

Trevor Marshall, PhD

New meta-analysis reassuring on ARBs and cancer, but questions remain

All these studies should be in the cancer article and link to each other:

Large registry study finds no excess cancer risk with ARB use By Joanna Lyford 27 April 2011 Circulation 2011; Advance online publication MedWire News: An analysis of more than 100,000 patients taking angiotensin receptor blockers (ARBs) has found no signal that these drugs are associated with an increased risk for cancer, with the exception of a small increase in male genital cancers.

Indeed, the data suggest that ARB use may actually be associated with a reduced overall risk for cancer death, write Björn Pasternak (Statens Serum Institut, Copenhagen, Denmark) and team in the journal Circulation.

The study was conducted after a recent meta-analysis of nine trials found that ARB users had a modestly increased risk for incident cancer, with a rate ratio (RR) of 1.08 versus placebo or comparator drugs. That analysis also identified a significantly increased risk for lung cancer associated with ARB use (RR=1.25).

To investigate further, Pasternak and team obtained data on new users of ARBs and ACE inhibitors from a nationwide registry-based cohort. All participants were aged 35 years or above and were started on treatment between 1998 and 2006.

Among 107,466 ARB users, 3954 cases of cancer were detected during 312,753 person-years of follow-up; meanwhile, among 209,692 ACE inhibitor users, 6214 cases of cancer were detected during 435,207 person-years of follow-up. The adjusted RR for the comparison was 0.99, indicating no significant difference.

Further analyses found no evidence that cancer risk increased with increasing duration of ARB exposure (RR increase per year=0.99) or that the risk differed among individual ARB agents.

The only significant findings were an increased risk for cancer of male genital organs (RR=1.15), observed in a subgroup analysis, and a reduced risk for overall cancer mortality (RR=0.77).

“Confidence intervals were narrow, allowing exclusion of a 4% increase in the risk of cancer,” the authors remark.

They conclude: “Although the angiotensin receptor system is involved in the process of carcinogenesis, experimental data point, if anything, toward beneficial effects of angiotensin signaling inhibition.

“Clinicians can continue to prescribe ARBs without concern about an excess risk of cancer.”

All these studies should be in the cardiovascular article and link to each other:

FDA Drug Safety Communication: Safety Review Update of Benicar (olmesartan)Medication taken regularly by patients on the Marshall Protocol for its ability to activate the Vitamin D Receptor. and cardiovascular events

FDA has issued preliminary guidance:

http://www.fda.gov/Drugs/DrugSafety/ucm251268.htm

..Trevor..

References

1) , 2)
Pharmacokinetics of CS-866, a new angiotensin II receptor blocker, in healthy subjects.
Schwocho LR, Masonson HN
J Clin Pharmacol41p515-27(2001 May)
5) , 6)
Clinical efficacy and tolerability of olmesartan.
Brunner HR
Clin Ther26 Suppl ApA28-32(2004)
8)
Long-term safety of high-dose angiotensin receptor blocker therapy in hypertensive patients with chronic kidney disease.
Weinberg AJ, Zappe DH, Ramadugu R, Weinberg MS
J Hypertens Suppl24pS95-9(2006 Mar)
11)
Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial.
Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G
JAMA289p65-9(2003 Jan 1)
13)
Augmentation of intrarenal angiotensin II levels in uninephrectomized aldosterone/salt-treated hypertensive rats; renoprotective effects of an ultrahigh dose of olmesartan.
Fan YY, Baba R, Nagai Y, Miyatake A, Hosomi N, Kimura S, Sun GP, Kohno M, Fujita M, Abe Y, Nishiyama A
Hypertens Res29p169-78(2006 Mar)
home/protocol/olmesartan/safety.txt · Last modified: 08.18.2014 by joyful
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